AIIMS MAY 2008 Q & A With Explanations

Discussion in 'AIIMS Nov 2013' started by Meena., May 15, 2008.

  1. Frosty.

    Frosty. Guest

    post-transplant lymphoma is due to

    a)t-cell
    b)b cell

    The pathogenesis of posttransplant lymphoproliferative disease (PTLD) is intimately linked to EBV. EBV is a lymphotrophic DNA gamma herpes virus that replicates in squamous epithelial cells of the oropharynx, uterine cervix, and male genital tract. The virus infects and immortalizes human or primate B lymphocytes that bear EBV membrane C3d receptors.

    The free infectious virus can be recovered from saliva in essentially all healthy seropositive individuals. EBV is implicated in the pathogenesis of a spectrum of B-cell lymphoproliferative diseases in immunosuppressed organ transplant recipients, in immunodeficiency diseases (eg, common variable immunodeficiency, Wiskott-Aldrich syndrome, ataxia telangiectasia, severe combined immunodeficiency, acquired immunodeficiency syndrome), and in recipients of T-cell–depleted or mismatched bone marrow transplants.

    EBV causes 2 types of cellular infections: (1) a productive replicative infection in which mature infectious virus particles are assembled and released, resulting in cell death (the lytic cycle), and (2) a nonproductive infection in which the virus is incorporated into and replicates with the host DNA but remains in the latent state in transformed B cells and no mature virus is produced.

    Persistence of the EBV genome in the latent state in transformed B cells occurs following a primary EBV infection and results in a permanent carrier state, in which small numbers of latently infected B cells circulate in seropositive individuals. Elimination of these cells is carried out by human leukocyte antigen (HLA)-restricted, EBV-specific, cytotoxic T lymphocytes. Certain factors (eg, inhibition of anti-EBV T-cell immunity, such as that which occurs with posttransplant immunosuppression) allow latently infected cells to enter the lytic cycle. The suppression of EBV-specific CD8+ T cells also allows B-cell proliferation to go unchecked. In solid organ transplant recipients, the abnormal B cells are usually of recipient origin. In contrast, the abnormal B cells are usually of donor origin in recipients of bone marrow transplants.

    According to the above paradigm, all PTLDs should represent B-cell proliferations secondary to EBV infection; however, T-cell and natural killer (NK)–cell PTLDs have also been reported. Penn estimated that 87% of all PTLDs were of B-cell origin, 13% were of T-cell origin, and 0.5% were of null cell origin.15 PTLDs not associated with EBV have also been reported. A higher proportion of late-developing PTLDs (>2 y posttransplant) are more likely to be non–B-cell related or non-EBV related. Thus, gaps are still recognized in the understanding of the pathogenesis of PTLD.

    Although the EB virus can express up to 100 genes, in the posttransplant situation only 9-10 genes are expressed. The EB genome adopts an episomal configuration and expresses proteins such as BCRF1 and BARF1 that help avoid immune detection. The latent membrane proteins LMP1 and LMP2 are believed to act as oncogenes, allowing B cells to escape cell death and proliferate in uncontrolled fashion. In one study, some PTLDs demonstrated mutations in bcl-6, an intracellular protein of the bcl group of proteins that are involved in passive cell death pathways. Polymorphisms in 2 key anti-inflammatory cytokines, IL-10 and tumor growth factor (TGF)-beta, are associated with susceptibility to EBV-associated PTLD, suggesting that a shift in pro-/anti-inflammatory response is involved in the pathogenesis of PTLD.23

    Classification of posttransplant lymphoproliferative disease

    Two major different classification schemes for PTLD have been proposed to compare outcomes and determine prognosis: the World Health Organization (WHO) classification and the Harris classification.24 Of these 2, the WHO classification is now gaining wide acceptance. Both of these schemes are based on the following characteristics: clinical, histologic, immunologic cell typing, cytogenetic, immunoglobulin gene-rearrangement, and virologic. The different schemes identify either 3 or 4 distinct categories. The classification schemes have common features, including benign hyperplasia or mononucleosis as the mildest form, characterized by maintenance of the nodal architecture; malignant lymphoma, with all the features of malignancy, as the most severe form; and polymorphic or polyclonal proliferations (with nodal architecture destruction and local invasion) classified in the intermediate categories.

    Depending on the interplay of immunosuppressive effect and B-cell proliferation, patients may develop uncomplicated mononucleosis or polyclonal polymorphic B-cell hyperplasia, both of which depend on continued viral replication. These benign PTLDs can spontaneously resolve (if host immune response to the virus is adequate) and/or respond to antiviral therapy that interrupts the EBV replicative cycle. In some patients, these benign PTLDs may progress to an intermediate stage in which a small subpopulation of malignantly transformed cells is present in a predominantly polyclonal proliferation. This second step may involve a cytogenetic event or selection that confers malignant growth potential on an EBV-infected B cell, thus leading to the outgrowth of a malignant cell or single clone analogous to the pathogenesis of African Burkitt lymphoma.

    In some patients, the malignant cell clone may become the dominant proliferating cell type, leading to frank lymphoma. Tsao et al have provided a recent review of the pathological classifications and evolutions.25

    Much remains to be understood about the factors involved in determining the severity of PTLD in an individual patient.


    CLINICAL FEATURES
    Section 6 of 11 Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic

    * Authors and Editors
    * Introduction
    * Incidence
    * Risk Factors
    * Etiology and Pathogenesis
    * Clinical Features
    * Diagnosis
    * Treatment and Prophylaxis
    * Summary and Future Directions
    * Multimedia
    * References


    Clinical features of posttransplant lymphoproliferative disease (PTLD) can be multiple, varied, and complex. In many patients, the early symptoms are nonspecific, including fever, malaise, and weight loss. Maintaining a high index of suspicion for PTLD in all transplant recipients is strongly recommended.

    The most common presentation is of sudden-onset lymphoid mass swelling, either externally (eg, cervical lymph nodes) or internally (eg, abdominal or intracranial masses). Extranodal tumors are usually more common than nodal tumors. Occasionally, these masses may develop within the graft, such as the kidney or liver. The symptoms are then related to the secondary effects of the tumor, such as abdominal pain, respiratory difficulty, stridor, and seizures. CNS presentation is associated with a poorer prognosis.

    PTLD may present as a fever of unknown origin in the transplant recipient or may mimic graft rejection, particularly late rejection.

    The time to PTLD diagnosis posttransplant can widely vary, ranging from a few months to several years. The mean time in most series is 20-35 months, but this is skewed by the long-range interval. The median times are much shorter, approximately 4-5 months. NAPRTCS data and a report by Alfrey et al show a reduction in median time to PTLD in recent years.3, 1


    DIAGNOSIS
    Section 7 of 11 Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic

    * Authors and Editors
    * Introduction
    * Incidence
    * Risk Factors
    * Etiology and Pathogenesis
    * Clinical Features
    * Diagnosis
    * Treatment and Prophylaxis
    * Summary and Future Directions
    * Multimedia
    * References


    The diagnosis of PTLD may often be complicated. Initial studies are often focused on the manifesting symptoms, such as imaging localization of the mass and determination of its extent, invasiveness, and homogenicity. Ultrasonography, CT scanning, or MRI can be used, depending on the area of interest. Pickhardt et al have published an extensive series of reviews of imaging features of PTLD by body segment.26, 27, 28, 29, 30 CT scanning is preferred for abdominal and chest imaging. Either CT scanning or MRI can be performed for neuroimaging. Bone marrow biopsies are necessary to help define marrow involvement, which may rarely be the only affected tissue. These imaging and biopsy tests may also be repeated after treatment to assess the response.

    Concomitant serologic tests (ie, immunoglobulin [Ig] G and IgM) should be performed to determine recent EBV or CMV primary or secondary infection. The sera can also be analyzed for Epstein-Barr–viral capsid antigen (EB-VCA).

    Histopathologic diagnosis of biopsy tissue remains the criterion standard for making the diagnosis of PTLD. Using light microscopy, infiltrates of polymorphous or monomorphous mononuclear cells (small lymphocytes and plasma cells) are observed that disrupt the architecture of the invaded tissue, such as the lymph node. Depending on the degree of proliferation and dedifferentiation, lesions may be characterized as hyperplastic, lymphomatous, or intermediate. Abnormal cells may be positive for the B-cell markers CD19, CD20, CD21, or CD22, although not in every patient. Lymphocyte CD20 expression is of value on determining therapy choices. Determination of cell surface heavy and light chain Ig expression allows for classification as polyclonal or monoclonal. Detailed cytogenetic studies may be needed in patients with nuclear changes suggestive of frank malignancy.

    EBV can frequently be revealed within the abnormal cells using various methods. Epstein-Barr–encoded RNA can be detected by the Ebstein-Barr early region (EBER) immunostaining assay (see Media file 1). The EBV latent membrane protein (LMP) can also be identified through immunostaining. Some PTLDs demonstrate Reed-Sternberg–like cells that may cause confusion with Hodgkin disease; CD15 staining is typically positive in true Hodgkin disease and negative in the HD-like condition.

    PTLD may occur alongside acute rejection, and the diagnoses may be difficult to separate, especially with T-cell PTLD within the allograft. According to Nalesnik, the features that favor the diagnosis of PTLD in such cases include nodular infiltrates, serpiginous necrosis, plasmacytoid and immunoblastic cells, and absence of ancillary cells such as neutrophils.31

    In an effort to improve the likelihood of successful therapeutic interventions, many investigators have studied methods that may result in early identification of disease in patients at high risk for this disorder. Monoclonal proteins, particularly IgM-related proteins, have been reported to appear with greater frequency in serum and urine of patients with PTLD (71%) than in patients without PTLD (27%). Darenkov et al reported that CD19+ B cells could be detected in the peripheral blood of patients with PTLD but not in those without PTLD, provided no antiviral prophylaxis was used.32

    Of greater promise are the variations of quantitative or semiquantitative polymerase chain reaction (PCR) techniques to detect EBV viral DNA from the peripheral blood lymphocytes. These techniques measure DNA in blood that can be membrane bound or free. Multiple studies have demonstrated that increased EBV viral loads can be used to differentiate between latent infection and PTLD. Rooney et al showed that levels of EBV DNA between 20,000 and 200,000 copies per microgram of peripheral blood DNA were associated with subsequent PTLD (normal <2000 copies per microgram).33

    In a study by Rowe et al, an EBV genomic load greater than 500 copies per 100,000 lymphocytes was associated with PTLD development.34 Wadowsky et al (2003) have reported that whole blood or peripheral blood mononuclear amplification by competitive reverse transcriptase–PCR gives comparable results but not amplification from plasma. However, different techniques in different labs and different cut-off values between labs prevent standardization of results between those labs.

    In pediatric patients, viral load monitoring is associated with high sensitivity but poor specificity. Many pediatric patients exhibit higher viral loads than adults because of a primary EBV infection or a chronic high viral load state without ever developing PTLD.35 In anecdotal cases, pediatric PTLD lesions that were EBER or LMP stain positive were not associated with a high viral load in peripheral blood.36 In contrast, Tsai et al reported that in adult transplant recipients, EBV viral load monitoring was associated with a high specificity but low sensitivity, the opposite of what has been reported in children.37 This may be related to a relatively higher prevalence of non-EBV, T-cell type or late-onset PTLD in adult patients.

    Rooney et al reported that, in patients who had received bone marrow transplants, spontaneous outgrowth ex vivo of B cells transformed with EBV from the peripheral blood was associated with PTLD to a very high degree of sensitivity and specificity.33

    DNA levels may also provide evidence of successful therapy. A drop in viral load after intervention suggests a good response.38 However, this may not hold true after anti-CD20 antibody, where viral loads may remain high because of release of viral DNA from lysed B cells.

    Differential diagnosis

    A high index of suspicion for PTLD must be maintained in all transplant recipients. Dharnidharka et al reported several cases of catscratch disease that manifested with fever and lymphadenopathy and resembled PTLD.20 The diagnosis was suspected after inquiry for cat exposures and was confirmed by (1) serological detection of IgM antibodies to Bartonella henselae and (2) detection of Bartonella species in the lesions by Steiner stain. This condition is often self-limiting in immunocompetent patients and amenable to antimicrobial therapy (sulfamethoxazole-trimethoprim, gentamicin) in immunosuppressed patients. In developing countries, tuberculosis is endemic and also manifests with fever and lymphadenopathy.


    TREATMENT AND PROPHYLAXIS
    Section 8 of 11 Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic

    * Authors and Editors
    * Introduction
    * Incidence
    * Risk Factors
    * Etiology and Pathogenesis
    * Clinical Features
    * Diagnosis
    * Treatment and Prophylaxis
    * Summary and Future Directions
    * Multimedia
    * References


    Treatment

    No uniform consensus regarding optimal treatment options for posttransplant lymphoproliferative disease (PTLD) is available. This largely reflects the current multiple gaps in knowledge of this disorder. The American Society of Transplantation and American Society of Transplant Surgeons published an ad hoc joint committee consensus paper on management recommendations; however, they recognized that providing many evidence-based recommendations is impossible.39 Thus, this paper reflects guidelines only and allows for considerable flexibility. Most centers recommend a staged treatment regimen based on the degree of clonality and aggressiveness. Treatment recommendations may rapidly change with newer understanding of the disease pathogenesis.

    Reduction of immunosuppression is the first intervention recommended and should be performed in all patients. Most centers reduce the dose of calcineurin inhibitors, and many centers discontinue calcineurin inhibitors entirely if the disease is severe. Many centers also discontinue or reduce mycophenolate or azathioprine. Corticosteroids are usually continued without dosage modification. In mild cases, these steps may be the only interventions required. Graft rejection is an obvious risk but, surprisingly, is not observed in every patient. Immunomodulation by the underlying disease is speculated to prevent the normal alloimmune response in these patients.

    Anti-CD20 monoclonal antibody has recently been used, with promising results, to neutralize the CD20-expressing B cells. Several small uncontrolled series have documented good success rates (complete or partial remission) in the 60-70% range in polymorphic or polyclonal cases. In some situations, the PTLD lesions may not express CD20; thus, rituximab may not be useful in such cases. This agent has become the second-line therapy at many centers, overtaking the use of interferon-alfa. Some investigators have proposed its use as first-line therapy, but no data has compared rituximab to reduction of immunosuppression head on.

    Interferon-alfa is also reported to be efficacious in treatment of PTLD that is unresponsive to immunosuppressive dose reduction alone. Some protocols combine this agent with intravenous IG (IVIG) or CMV-specific Ig. Because of a higher prevalence of acute rejection episodes after interferon use, this agent is less commonly used.

    The role of antiviral drugs in treatment of PTLD is controversial. Acyclovir and ganciclovir are effective against replicating the virus but are reportedly not effective against latent EBV, which is the predominant form of EBV in PTLD. However, a few virions entering the lytic cycle are possible, and antiviral agents may eliminate these virions. Many centers thus add antiviral therapy to their regimens to eliminate any replicating virus that may be present.

    Standard cancer chemotherapy is reserved for patients with definitive features of malignancy. The usual regimen used has been the cyclophosphamide, doxorubicin (Adriamycin or doxorubicin hydrochloride), vincristine (Oncovin), and prednisone (CHOP) regimen used for non-Hodgkin lymphoma. Gross et al have used a modified CHOP protocol with lower doses of cyclophosphamide to prevent toxicity.40 Newer agents that have been tried in non-Hodgkin lymphoma but not tried yet in PTLD include radioconjugated anti-CD20 antibodies such as tositumomab (anti-CD20 tagged to I131) and ibritumomab (anti-CD20 tagged to Y90).

    Prognosis

    The prognosis of PTLD widely varies. Most mild cases regress, but graft rejection may occur (reported rates vary widely from 10-60%). The outlook for more severe cases is less favorable, particularly in frank malignancies or CNS PTLD. Although individual centers with high PTLD rates report good patient and graft survival rates, multicentered registry data suggest somewhat poorer graft survival outcomes. Non-EBV positive or late onset cases have a poorer prognosis.

    In a few cases in which graft loss occurs, retransplantation has been successfully performed. To date, 3 cases of repeat kidney transplant or liver transplant have been reported.41, 42, 43 PTLD recurrence in the repeat transplant has not been reported.

    Prophylaxis

    With the role of EBV and CMV infections in the development of PTLD now established, attention has recently turned toward prevention of these infections posttransplant in an effort to reduce prevalence of PTLD. Prevention can be primary or secondary.

    Primary prevention includes the following: (1) antiviral vaccine, (2) immunization minimization to prevent infection, (3) immunoprophylaxis via intravenous immunoglobulin preparations, and (4) chemoprophylaxis via antiviral drugs.

    Immunization

    No vaccine against EBV is currently available. A phase II trial of a gp350 glycoprotein based vaccine is currently underway in Great Britain.

    Chemoprophylaxis and immunoprophylaxis

    Ganciclovir and acyclovir are antiviral agents that have demonstrated efficacy against EBV and CMV. Davis et al reported in a retrospective analysis that the prevalence of PTLD appeared to be lower with the use of concomitant antiviral therapy (ie, initially IV ganciclovir, then oral acyclovir) in adult transplant recipients.44

    Darenkov et al conducted a prospective trial of prophylactic antiviral agent use during antilymphocyte antibody administration to adult transplant patients.32 Using acyclovir if both donor and recipient were CMV seronegative or ganciclovir if either were seropositive, prevalence of PTLD dropped to 0.5% in their study group, compared with 3.9% in historical controls. However, Green et al were unable to document any change in PTLD prevalence in a prospective trial utilizing acyclovir.45 In their study, initial intravenous ganciclovir followed by prolonged oral acyclovir was associated with a trend towards increased PTLD and significantly higher CMV incidence. Similarly, CMV-Ig did not have any impact on EBV infection rate or PTLD rate.46

    Funch et al performed a large retrospective case-control analysis that showed that ganciclovir was associated with a significant reduction in the odds ratio for PTLD (0.62; 95% CI, 0.38-1.0).47 Acyclovir was associated with a lower and nonsignificant reduction. The addition of IVIG to ganciclovir did not further reduce the PTLD rate.48

    The newer oral agents, valacyclovir and valganciclovir, have greater bioavailability but have not been tested for PTLD prevalence reduction, although many centers now routinely use valganciclovir for prophylaxis. A recently published study demonstrated that oral valganciclovir is not inferior to intravenous ganciclovir for the treatment of CMV disease.49

    Preemptive Interventions

    Using routine viral load monitoring and preemptive therapy, several studies have shown a reduction in PTLD prevalence based on historical controls, particularly in the pediatric liver transplant population.4, 32, 44 These results have led many centers to perform routine viral load monitoring, particularly for preemptive interventions. These interventions have included reduction in immunosuppression or initiation of antiviral therapy when a significant rise in EB viral load occurs. To date, no prospective clinical trials have been performed to confirm these results, but these types of studies are difficult to perform. The hypothesis that early detection leads to improved outcome remains also remains to be confirmed. Wagner et al have suggested that prompt invention rather than preemptive intervention may be a better strategy in combination with viral load monitoring.50

    Viral load monitoring provides evidence of EBV-infected B-cell proliferation but does not provide information about the host T-cell response. Studies of EBV-specific T-cell counts or cytotoxic T-cell assays may add further information to EBV viral loads.51
  2. Frosty.

    Frosty. Guest

    The pathogenesis of posttransplant lymphoproliferative disease (PTLD) is intimately linked to EBV. EBV is a lymphotrophic DNA gamma herpes virus that replicates in squamous epithelial cells of the oropharynx, uterine cervix, and male genital tract. The virus infects and immortalizes human or primate B lymphocytes that bear EBV membrane C3d receptors.

    The free infectious virus can be recovered from saliva in essentially all healthy seropositive individuals. EBV is implicated in the pathogenesis of a spectrum of B-cell lymphoproliferative diseases in immunosuppressed organ transplant recipients, in immunodeficiency diseases (eg, common variable immunodeficiency, Wiskott-Aldrich syndrome, ataxia telangiectasia, severe combined immunodeficiency, acquired immunodeficiency syndrome), and in recipients of T-cell–depleted or mismatched bone marrow transplants.

    EBV causes 2 types of cellular infections: (1) a productive replicative infection in which mature infectious virus particles are assembled and released, resulting in cell death (the lytic cycle), and (2) a nonproductive infection in which the virus is incorporated into and replicates with the host DNA but remains in the latent state in transformed B cells and no mature virus is produced.

    Persistence of the EBV genome in the latent state in transformed B cells occurs following a primary EBV infection and results in a permanent carrier state, in which small numbers of latently infected B cells circulate in seropositive individuals. Elimination of these cells is carried out by human leukocyte antigen (HLA)-restricted, EBV-specific, cytotoxic T lymphocytes. Certain factors (eg, inhibition of anti-EBV T-cell immunity, such as that which occurs with posttransplant immunosuppression) allow latently infected cells to enter the lytic cycle. The suppression of EBV-specific CD8+ T cells also allows B-cell proliferation to go unchecked. In solid organ transplant recipients, the abnormal B cells are usually of recipient origin. In contrast, the abnormal B cells are usually of donor origin in recipients of bone marrow transplants.

    According to the above paradigm, all PTLDs should represent B-cell proliferations secondary to EBV infection; however, T-cell and natural killer (NK)–cell PTLDs have also been reported. Penn estimated that 87% of all PTLDs were of B-cell origin, 13% were of T-cell origin, and 0.5% were of null cell origin.15 PTLDs not associated with EBV have also been reported. A higher proportion of late-developing PTLDs (>2 y posttransplant) are more likely to be non–B-cell related or non-EBV related. Thus, gaps are still recognized in the understanding of the pathogenesis of PTLD.

    Although the EB virus can express up to 100 genes, in the posttransplant situation only 9-10 genes are expressed. The EB genome adopts an episomal configuration and expresses proteins such as BCRF1 and BARF1 that help avoid immune detection. The latent membrane proteins LMP1 and LMP2 are believed to act as oncogenes, allowing B cells to escape cell death and proliferate in uncontrolled fashion. In one study, some PTLDs demonstrated mutations in bcl-6, an intracellular protein of the bcl group of proteins that are involved in passive cell death pathways. Polymorphisms in 2 key anti-inflammatory cytokines, IL-10 and tumor growth factor (TGF)-beta, are associated with susceptibility to EBV-associated PTLD, suggesting that a shift in pro-/anti-inflammatory response is involved in the pathogenesis of PTLD.23

    Classification of posttransplant lymphoproliferative disease

    Two major different classification schemes for PTLD have been proposed to compare outcomes and determine prognosis: the World Health Organization (WHO) classification and the Harris classification.24 Of these 2, the WHO classification is now gaining wide acceptance. Both of these schemes are based on the following characteristics: clinical, histologic, immunologic cell typing, cytogenetic, immunoglobulin gene-rearrangement, and virologic. The different schemes identify either 3 or 4 distinct categories. The classification schemes have common features, including benign hyperplasia or mononucleosis as the mildest form, characterized by maintenance of the nodal architecture; malignant lymphoma, with all the features of malignancy, as the most severe form; and polymorphic or polyclonal proliferations (with nodal architecture destruction and local invasion) classified in the intermediate categories.

    Depending on the interplay of immunosuppressive effect and B-cell proliferation, patients may develop uncomplicated mononucleosis or polyclonal polymorphic B-cell hyperplasia, both of which depend on continued viral replication. These benign PTLDs can spontaneously resolve (if host immune response to the virus is adequate) and/or respond to antiviral therapy that interrupts the EBV replicative cycle. In some patients, these benign PTLDs may progress to an intermediate stage in which a small subpopulation of malignantly transformed cells is present in a predominantly polyclonal proliferation. This second step may involve a cytogenetic event or selection that confers malignant growth potential on an EBV-infected B cell, thus leading to the outgrowth of a malignant cell or single clone analogous to the pathogenesis of African Burkitt lymphoma.

    In some patients, the malignant cell clone may become the dominant proliferating cell type, leading to frank lymphoma. Tsao et al have provided a recent review of the pathological classifications and evolutions.25

    Much remains to be understood about the factors involved in determining the severity of PTLD in an individual patient.


    CLINICAL FEATURES
    Section 6 of 11 Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic

    * Authors and Editors
    * Introduction
    * Incidence
    * Risk Factors
    * Etiology and Pathogenesis
    * Clinical Features
    * Diagnosis
    * Treatment and Prophylaxis
    * Summary and Future Directions
    * Multimedia
    * References


    Clinical features of posttransplant lymphoproliferative disease (PTLD) can be multiple, varied, and complex. In many patients, the early symptoms are nonspecific, including fever, malaise, and weight loss. Maintaining a high index of suspicion for PTLD in all transplant recipients is strongly recommended.

    The most common presentation is of sudden-onset lymphoid mass swelling, either externally (eg, cervical lymph nodes) or internally (eg, abdominal or intracranial masses). Extranodal tumors are usually more common than nodal tumors. Occasionally, these masses may develop within the graft, such as the kidney or liver. The symptoms are then related to the secondary effects of the tumor, such as abdominal pain, respiratory difficulty, stridor, and seizures. CNS presentation is associated with a poorer prognosis.

    PTLD may present as a fever of unknown origin in the transplant recipient or may mimic graft rejection, particularly late rejection.

    The time to PTLD diagnosis posttransplant can widely vary, ranging from a few months to several years. The mean time in most series is 20-35 months, but this is skewed by the long-range interval. The median times are much shorter, approximately 4-5 months. NAPRTCS data and a report by Alfrey et al show a reduction in median time to PTLD in recent years.3, 1


    DIAGNOSIS
    Section 7 of 11 Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic

    * Authors and Editors
    * Introduction
    * Incidence
    * Risk Factors
    * Etiology and Pathogenesis
    * Clinical Features
    * Diagnosis
    * Treatment and Prophylaxis
    * Summary and Future Directions
    * Multimedia
    * References


    The diagnosis of PTLD may often be complicated. Initial studies are often focused on the manifesting symptoms, such as imaging localization of the mass and determination of its extent, invasiveness, and homogenicity. Ultrasonography, CT scanning, or MRI can be used, depending on the area of interest. Pickhardt et al have published an extensive series of reviews of imaging features of PTLD by body segment.26, 27, 28, 29, 30 CT scanning is preferred for abdominal and chest imaging. Either CT scanning or MRI can be performed for neuroimaging. Bone marrow biopsies are necessary to help define marrow involvement, which may rarely be the only affected tissue. These imaging and biopsy tests may also be repeated after treatment to assess the response.

    Concomitant serologic tests (ie, immunoglobulin [Ig] G and IgM) should be performed to determine recent EBV or CMV primary or secondary infection. The sera can also be analyzed for Epstein-Barr–viral capsid antigen (EB-VCA).

    Histopathologic diagnosis of biopsy tissue remains the criterion standard for making the diagnosis of PTLD. Using light microscopy, infiltrates of polymorphous or monomorphous mononuclear cells (small lymphocytes and plasma cells) are observed that disrupt the architecture of the invaded tissue, such as the lymph node. Depending on the degree of proliferation and dedifferentiation, lesions may be characterized as hyperplastic, lymphomatous, or intermediate. Abnormal cells may be positive for the B-cell markers CD19, CD20, CD21, or CD22, although not in every patient. Lymphocyte CD20 expression is of value on determining therapy choices. Determination of cell surface heavy and light chain Ig expression allows for classification as polyclonal or monoclonal. Detailed cytogenetic studies may be needed in patients with nuclear changes suggestive of frank malignancy.

    EBV can frequently be revealed within the abnormal cells using various methods. Epstein-Barr–encoded RNA can be detected by the Ebstein-Barr early region (EBER) immunostaining assay (see Media file 1). The EBV latent membrane protein (LMP) can also be identified through immunostaining. Some PTLDs demonstrate Reed-Sternberg–like cells that may cause confusion with Hodgkin disease; CD15 staining is typically positive in true Hodgkin disease and negative in the HD-like condition.

    PTLD may occur alongside acute rejection, and the diagnoses may be difficult to separate, especially with T-cell PTLD within the allograft. According to Nalesnik, the features that favor the diagnosis of PTLD in such cases include nodular infiltrates, serpiginous necrosis, plasmacytoid and immunoblastic cells, and absence of ancillary cells such as neutrophils.31

    In an effort to improve the likelihood of successful therapeutic interventions, many investigators have studied methods that may result in early identification of disease in patients at high risk for this disorder. Monoclonal proteins, particularly IgM-related proteins, have been reported to appear with greater frequency in serum and urine of patients with PTLD (71%) than in patients without PTLD (27%). Darenkov et al reported that CD19+ B cells could be detected in the peripheral blood of patients with PTLD but not in those without PTLD, provided no antiviral prophylaxis was used.32

    Of greater promise are the variations of quantitative or semiquantitative polymerase chain reaction (PCR) techniques to detect EBV viral DNA from the peripheral blood lymphocytes. These techniques measure DNA in blood that can be membrane bound or free. Multiple studies have demonstrated that increased EBV viral loads can be used to differentiate between latent infection and PTLD. Rooney et al showed that levels of EBV DNA between 20,000 and 200,000 copies per microgram of peripheral blood DNA were associated with subsequent PTLD (normal <2000 copies per microgram).33

    In a study by Rowe et al, an EBV genomic load greater than 500 copies per 100,000 lymphocytes was associated with PTLD development.34 Wadowsky et al (2003) have reported that whole blood or peripheral blood mononuclear amplification by competitive reverse transcriptase–PCR gives comparable results but not amplification from plasma. However, different techniques in different labs and different cut-off values between labs prevent standardization of results between those labs.

    In pediatric patients, viral load monitoring is associated with high sensitivity but poor specificity. Many pediatric patients exhibit higher viral loads than adults because of a primary EBV infection or a chronic high viral load state without ever developing PTLD.35 In anecdotal cases, pediatric PTLD lesions that were EBER or LMP stain positive were not associated with a high viral load in peripheral blood.36 In contrast, Tsai et al reported that in adult transplant recipients, EBV viral load monitoring was associated with a high specificity but low sensitivity, the opposite of what has been reported in children.37 This may be related to a relatively higher prevalence of non-EBV, T-cell type or late-onset PTLD in adult patients.

    Rooney et al reported that, in patients who had received bone marrow transplants, spontaneous outgrowth ex vivo of B cells transformed with EBV from the peripheral blood was associated with PTLD to a very high degree of sensitivity and specificity.33

    DNA levels may also provide evidence of successful therapy. A drop in viral load after intervention suggests a good response.38 However, this may not hold true after anti-CD20 antibody, where viral loads may remain high because of release of viral DNA from lysed B cells.

    Differential diagnosis

    A high index of suspicion for PTLD must be maintained in all transplant recipients. Dharnidharka et al reported several cases of catscratch disease that manifested with fever and lymphadenopathy and resembled PTLD.20 The diagnosis was suspected after inquiry for cat exposures and was confirmed by (1) serological detection of IgM antibodies to Bartonella henselae and (2) detection of Bartonella species in the lesions by Steiner stain. This condition is often self-limiting in immunocompetent patients and amenable to antimicrobial therapy (sulfamethoxazole-trimethoprim, gentamicin) in immunosuppressed patients. In developing countries, tuberculosis is endemic and also manifests with fever and lymphadenopathy.


    TREATMENT AND PROPHYLAXIS
    Section 8 of 11 Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic

    * Authors and Editors
    * Introduction
    * Incidence
    * Risk Factors
    * Etiology and Pathogenesis
    * Clinical Features
    * Diagnosis
    * Treatment and Prophylaxis
    * Summary and Future Directions
    * Multimedia
    * References


    Treatment

    No uniform consensus regarding optimal treatment options for posttransplant lymphoproliferative disease (PTLD) is available. This largely reflects the current multiple gaps in knowledge of this disorder. The American Society of Transplantation and American Society of Transplant Surgeons published an ad hoc joint committee consensus paper on management recommendations; however, they recognized that providing many evidence-based recommendations is impossible.39 Thus, this paper reflects guidelines only and allows for considerable flexibility. Most centers recommend a staged treatment regimen based on the degree of clonality and aggressiveness. Treatment recommendations may rapidly change with newer understanding of the disease pathogenesis.

    Reduction of immunosuppression is the first intervention recommended and should be performed in all patients. Most centers reduce the dose of calcineurin inhibitors, and many centers discontinue calcineurin inhibitors entirely if the disease is severe. Many centers also discontinue or reduce mycophenolate or azathioprine. Corticosteroids are usually continued without dosage modification. In mild cases, these steps may be the only interventions required. Graft rejection is an obvious risk but, surprisingly, is not observed in every patient. Immunomodulation by the underlying disease is speculated to prevent the normal alloimmune response in these patients.

    Anti-CD20 monoclonal antibody has recently been used, with promising results, to neutralize the CD20-expressing B cells. Several small uncontrolled series have documented good success rates (complete or partial remission) in the 60-70% range in polymorphic or polyclonal cases. In some situations, the PTLD lesions may not express CD20; thus, rituximab may not be useful in such cases. This agent has become the second-line therapy at many centers, overtaking the use of interferon-alfa. Some investigators have proposed its use as first-line therapy, but no data has compared rituximab to reduction of immunosuppression head on.

    Interferon-alfa is also reported to be efficacious in treatment of PTLD that is unresponsive to immunosuppressive dose reduction alone. Some protocols combine this agent with intravenous IG (IVIG) or CMV-specific Ig. Because of a higher prevalence of acute rejection episodes after interferon use, this agent is less commonly used.

    The role of antiviral drugs in treatment of PTLD is controversial. Acyclovir and ganciclovir are effective against replicating the virus but are reportedly not effective against latent EBV, which is the predominant form of EBV in PTLD. However, a few virions entering the lytic cycle are possible, and antiviral agents may eliminate these virions. Many centers thus add antiviral therapy to their regimens to eliminate any replicating virus that may be present.

    Standard cancer chemotherapy is reserved for patients with definitive features of malignancy. The usual regimen used has been the cyclophosphamide, doxorubicin (Adriamycin or doxorubicin hydrochloride), vincristine (Oncovin), and prednisone (CHOP) regimen used for non-Hodgkin lymphoma. Gross et al have used a modified CHOP protocol with lower doses of cyclophosphamide to prevent toxicity.40 Newer agents that have been tried in non-Hodgkin lymphoma but not tried yet in PTLD include radioconjugated anti-CD20 antibodies such as tositumomab (anti-CD20 tagged to I131) and ibritumomab (anti-CD20 tagged to Y90).

    Prognosis

    The prognosis of PTLD widely varies. Most mild cases regress, but graft rejection may occur (reported rates vary widely from 10-60%). The outlook for more severe cases is less favorable, particularly in frank malignancies or CNS PTLD. Although individual centers with high PTLD rates report good patient and graft survival rates, multicentered registry data suggest somewhat poorer graft survival outcomes. Non-EBV positive or late onset cases have a poorer prognosis.

    In a few cases in which graft loss occurs, retransplantation has been successfully performed. To date, 3 cases of repeat kidney transplant or liver transplant have been reported.41, 42, 43 PTLD recurrence in the repeat transplant has not been reported.

    Prophylaxis

    With the role of EBV and CMV infections in the development of PTLD now established, attention has recently turned toward prevention of these infections posttransplant in an effort to reduce prevalence of PTLD. Prevention can be primary or secondary.

    Primary prevention includes the following: (1) antiviral vaccine, (2) immunization minimization to prevent infection, (3) immunoprophylaxis via intravenous immunoglobulin preparations, and (4) chemoprophylaxis via antiviral drugs.

    Immunization

    No vaccine against EBV is currently available. A phase II trial of a gp350 glycoprotein based vaccine is currently underway in Great Britain.

    Chemoprophylaxis and immunoprophylaxis

    Ganciclovir and acyclovir are antiviral agents that have demonstrated efficacy against EBV and CMV. Davis et al reported in a retrospective analysis that the prevalence of PTLD appeared to be lower with the use of concomitant antiviral therapy (ie, initially IV ganciclovir, then oral acyclovir) in adult transplant recipients.44

    Darenkov et al conducted a prospective trial of prophylactic antiviral agent use during antilymphocyte antibody administration to adult transplant patients.32 Using acyclovir if both donor and recipient were CMV seronegative or ganciclovir if either were seropositive, prevalence of PTLD dropped to 0.5% in their study group, compared with 3.9% in historical controls. However, Green et al were unable to document any change in PTLD prevalence in a prospective trial utilizing acyclovir.45 In their study, initial intravenous ganciclovir followed by prolonged oral acyclovir was associated with a trend towards increased PTLD and significantly higher CMV incidence. Similarly, CMV-Ig did not have any impact on EBV infection rate or PTLD rate.46

    Funch et al performed a large retrospective case-control analysis that showed that ganciclovir was associated with a significant reduction in the odds ratio for PTLD (0.62; 95% CI, 0.38-1.0).47 Acyclovir was associated with a lower and nonsignificant reduction. The addition of IVIG to ganciclovir did not further reduce the PTLD rate.48

    The newer oral agents, valacyclovir and valganciclovir, have greater bioavailability but have not been tested for PTLD prevalence reduction, although many centers now routinely use valganciclovir for prophylaxis. A recently published study demonstrated that oral valganciclovir is not inferior to intravenous ganciclovir for the treatment of CMV disease.49

    Preemptive Interventions

    Using routine viral load monitoring and preemptive therapy, several studies have shown a reduction in PTLD prevalence based on historical controls, particularly in the pediatric liver transplant population.4, 32, 44 These results have led many centers to perform routine viral load monitoring, particularly for preemptive interventions. These interventions have included reduction in immunosuppression or initiation of antiviral therapy when a significant rise in EB viral load occurs. To date, no prospective clinical trials have been performed to confirm these results, but these types of studies are difficult to perform. The hypothesis that early detection leads to improved outcome remains also remains to be confirmed. Wagner et al have suggested that prompt invention rather than preemptive intervention may be a better strategy in combination with viral load monitoring.50

    Viral load monitoring provides evidence of EBV-infected B-cell proliferation but does not provide information about the host T-cell response. Studies of EBV-specific T-cell counts or cytotoxic T-cell assays may add further information to EBV viral loads.51
  3. Frosty.

    Frosty. Guest

    Contraindications for undergoing an MRI scan include:
    Patients who have a heart pacemaker may not have an MRI scan

    Patients who have a metallic foreign body (metal sliver) in their eye, or who have an aneurysm clip in their brain, cannot have an MRI scan since the magnetic field may dislodge the metal.

    Patients with severe claustrophobia may not be able to tolerate an MRI scan, although more open scanners are now available, and medical sedation is available to make the test easier to tolerate.

    Patients who have had metallic devices placed in their back (such as pedicle screws or anterior interbody cages) can have an MRI scan, but the resolution of the scan is often severely hampered by the metal device and the spine is not well imaged
  4. Frosty.

    Frosty. Guest

    Contact dermatitis due to plants : Challenges and prospects

    --------------------------------------------------------------------------------

    ABSTRACT: Contact dermatitis due to plants is one of the major allergic dermatoses causing great concern for the dermatologists and practising physicians. Plants can cause dermatitis either by direct contact or due to dried plant components suspended in the air called air-borne contact dermatitis. People can get exposed to plants in a variety of ways depending on their occupation, hobbies, part-time activities etc. There are a number of plants which can cause contact dermatitis but Parthenium hysterophorus (Gaajar ghas) is at present the commonest cause of plant contact dermatitis in our country. It manifests as itchy, erythematous papulo-vesicular lesions at the site of contact. The distribution of the lesion is characteristic and suggests the diagnosis. The diagnosis can be confirmed by performing a patch test with suspected plants. The mild dermatitis can be treated with topical corticosteroids however moderate to severe dermatitis particularly air-borne contact dermatitis requires systemic corticosteroids and other immunosuppressive drugs.
  5. Frosty.

    Frosty. Guest

    Granulocytic Sarcoma

    Definitive diagnosis of a chloroma usually requires a biopsy of the lesion in question. Historically, even with a tissue biopsy, pathologic misdiagnosis was an important problem, particularly in patients without a clear pre-existing diagnosis of acute myeloid leukemia to guide the pathologist. In one published series on chloroma, the authors stated that 47% of the patients were initially misdiagnosed, most often as having a malignant lymphoma.

    However, with advances in diagnostic techniques, the diagnosis of chloromas can be made more reliable. Traweek et al. described the use of a commercially available panel of monoclonal antibodies, against myeloperoxidase, CD68, CD43, and CD20, to accurately diagnose chloroma via immunohistochemistry and differentiate it from lymphoma.[8] Nowadays, immunohistochemical staining using monoclonal antibodies against CD34 and CD117 would be the mainstay of diagnosis. The increasingly refined use of flow cytometry has also facilitated more accurate diagnosis of these lesions
  6. Frosty.

    Frosty. Guest

    Prevention of postoperative acute renal failure.

    :: Abstract

    Postoperative acute renal failure (PO-ARF) is a serious complication resulting in a prolonged stay and high mortality. Patients may be at risk for this problem because of an underlying medical illness, nature of surgery, nephrotoxin exposure, or combinations of these factors. An increase in the intra abdominal pressure above 20-mm Hg is associated with an increase in the incidence of PO-ARF. Based on many clinical studies in high-risk surgical patients and patients undergoing renal transplantation, the only proven management strategies for prevention of PO-ARF are adequate volume expansion and avoidance of hypovolaemia. Drugs known to be nephrotoxic should be avoided or used with caution. Three main pharmacological agents namely mannitol, frusemide and dopamine have been extensively tried in the prevention of PO-ARF. Mannitol has proven of value only in the presence of adequate volume expansion in attenuating renal dysfunction in transplant patients. Frusemide converts oliguric renal failure to non-oliguric renal failure. The bulk of the data, including that from prospective studies indicate dopamine is only a diuretic. Fenoldopam, a dopamine analogue, has shown early promise in reports. Calcium channel blockers have not been shown to improve the outcome in renal transplantation or help in the prevention of contrast-induced nephropathy. Atrial natriuretic peptide has not been proven to be of benefit in established renal failure and its role in prevention has not been assessed.

    Postoperative acute renal failure (PO-ARF) has been recognised as a complication of major vascular, cardiac and high-risk abdominal surgery. This review focuses on pathophysiology, predisposing risk factors, nephrotoxic drugs, role of increased abdominal pressure, fluid management, limitation of biochemical markers in identifying renal insufficiency and evidence based pharmacological support in the prevention of PO-ARF.

    This paper reviewed in humans the prevention of PO-ARF in randomised controlled trials and is based on a computerised MEDLINE literature search in English language journals from January 1970-October 2001. All review articles on PO-ARF and the biochemical investigations in identifying renal failure published in peer-reviewed journals from 1985–2001 were included in the literature search.


    The most common cause of PO-ARF is hypovolemia resulting in prerenal failure
  7. Frosty.

    Frosty. Guest

    Venous return is influenced by several factors.

    Muscle contraction. Rhythmical contraction of limb muscles as occurs during normal locomotory activity (walking, running, swimming) promotes venous return by the muscle pump mechanism.

    Decreased venous compliance. Sympathetic activation of veins decreases venous compliance, increases central venous pressure and promotes venous return indirectly by augmenting cardiac output through the Frank-Starling mechanism, which increases the total blood flow through the circulatory system.

    Respiratory activity. During respiratory inspiration, the venous return increases because of a decrease in right atrial pressure.

    Vena cava compression. An increase in the resistance of the vena cava, as occurs when the thoracic vena cava becomes compressed during a Valsalva maneuver or during late pregnancy, decreases return.

    Gravity. The effects of gravity on venous return seem paradoxical because when a person stands up hydrostatic forces cause the right atrial pressure to decrease and the venous pressure in the dependent limbs to increase. This increases the pressure gradient for venous return from the dependent limbs to the right atrium; however, venous return actually decreases. The reason for this is when a person initially stands, cardiac output and arterial pressure decrease (because right atrial pressure falls). The flow through the entire systemic circulation falls because arterial pressure falls more than right atrial pressure, therefore the pressure gradient driving flow throughout the entire circulatory system is decreased.
  8. Frosty.

    Frosty. Guest

    Autonomic Neuropathy

    Signs and symptoms
    Signs and symptoms of autonomic neuropathy vary widely, depending on which parts of your autonomic nervous system are affected. They may include:

    Dizziness and fainting upon standing (orthostatic hypotension), caused by a drop in blood pressure
    Urinary problems, including difficulty starting urination, overflow incontinence and inability to empty your bladder completely, which can lead to urinary tract infections
    Sexual difficulties, including erectile dysfunction or ejaculation problems in men, and vaginal dryness and difficulties with arousal and orgasm in women
    Difficulty digesting food (gastroparesis), which can cause a feeling of fullness after eating little, loss of appetite, diarrhea, constipation, abdominal bloating, nausea, vomiting and heartburn
    Sweating abnormalities, especially decreased sweating, so the body can't regulate its temperature; also excessive sweating, sometimes after eating
    Sluggish pupil reaction, making it difficult to adjust from light to dark and causing difficulties with driving at night
    Exercise intolerance, when your heart rate remains unchanged instead of increasing and decreasing in response to your activity level
    Lack of usual warning signs of low blood sugar (hypoglycemia), which include shakiness, increased heart rate, sweating and palpitations
  9. Angerguy.

    Angerguy. Guest

    DIAGNOSIS IN ONCOLOGY

    Two Unusual Lymphomas
    Case 1: Primary Malignant Lymphoma (Diffuse Large B-Cell Lymphoma) of the Spleen Mimicking Splenic Abscess


    Splenic lymphoma, or primary malignant lymphoma of the spleen (PMLS), is an unusual disease. The true incidence is difficult to estimate because of the variable definitions of the disease. It probably comprises less than 1% of non-Hodgkin’s lymphoma. Some authors consider PMLS to be an entity limited to the involvement of spleen and splenic hilum.1 Others consider PMLS to be an entity that develops in the spleen with the potential for spreading to adjacent organs or distant metastasis.2 The clinical features are characterized by nonspecific systemic symptoms. Most are of B-cell origin, with the most common histologic diagnosis being a low-grade or intermediate-grade lymphoma.3 Splenectomy is still the most effective therapy for all PMLSs.3-5 Although there are no controlled trials, some authors believe that multiagent chemotherapy and/or radiotherapy is useful.6 Cytopenias are common in PMLS, and their reversal early after splenectomy is associated with prolonged survival.7
    Single or multiple confluent nodules are seen quite often in diffuse large-cell lymphoma of the spleen.8 Our patient’s clinical presentation, which mimicked splenic abscess, is intriguing. Diffuse large-cell lymphoma of the spleen should be considered in the differential diagnosis of patients presenting with fever or other systemic symptoms associated with radiographic evidence of single or multiple focal lesions in the spleen
  10. Angerguy.

    Angerguy. Guest

    Leukodystrophy with Macrocaphaly

    Leukodystrophy with macrocephaly as the main features of infantile neurodegenerative disease are characteristics of Canavan's disease, L-2-hydroxyglutaric aciduria, type I glutaric aciduria, and Alexander's disease. Also occasionally described are occidental congenital muscular dystrophy, GM2-gangliosidosis, metachromatic leukodystrophy, Krabbe's disease, and mucopolysaccharidosis. Since 1995, over 60 patients with a new syndrome, vacuolating megalencephalic leukoencephalopathy, have been described. The syndrome is characterized by macrocephaly, a slowly progressive clinical course of ataxia, spastic paraparesis, and seizure disorder with relatively spared cognition. Unlike other leukodystrophies with macrocephaly (except Alexander's disease), no metabolic marker has been found. We describe a similar group of 12 patients from two different Jewish ethnic origins in whom consanguinity is prominent. These patients have neuroimaging features and magnetic resonance spectroscopy findings indicating that there is an initial increase in white-matter edema with subsequent cystic formation. Consistent with loss of tissue in these areas, brain metabolites are reduced. The familial incidence in this group of patients is suggestive of autosomal-recessive inheritance
  11. Angerguy.

    Angerguy. Guest

    ECG may reveal a right-heart strain pattern suggestive of pulmonary hypertension.

    Bronchoalveolar lavage fluid (BALF) studies have shown that after heavy exercise, under all conditions, athletes develop a permeability edema with high BALF RBC and protein concentrations in the absence of inflammation. Exercise at altitude (3810 m) caused significantly greater leakage of RBCs (92,000 [SD 3.1] cells/mL) into the alveolar space than that seen with normoxic exercise (54,000 [SD 1.2] cells/mL). At altitude, the 26-hour postexercise BALF had significantly higher RBC and protein concentrations, suggesting an ongoing capillary leak. These findings suggest that pulmonary capillary disruption occurs with intense exercise in healthy humans and that hypoxia augments the mechanical stresses on the pulmonary microcirculation.2


    Background

    High-altitude illness may result from short-term exposures to altitudes in excess of 2000 m (6560 ft). This illness comprises a spectrum of clinical entities that are probably the manifestations of the same disease process. High-altitude pulmonary edema (HAPE) and cerebral edema are the most ominous of these symptoms, while acute mountain sickness, retinal hemorrhages, and peripheral edema are the milder forms of the disease. The rate of ascent, the altitude attained, the amount of physical activity at high altitude, and individual susceptibility are contributing factors to the incidence and severity of high-altitude illness.
    Pathophysiology

    The pathophysiology is not well understood. HAPE is a noncardiogenic form of pulmonary edema resulting from a leak in the alveolar capillary membrane. The various mechanisms believed to be responsible are pulmonary arterial vasoconstriction resulting in circulatory shear forces and a consequent permeability leak and antidiuresis possibly mediated by increased antidiuretic hormones, which contribute to fluid retention. The inciting factor appears to be excessive hypoxia.

    A number of compensatory mechanisms improve oxygen delivery when its inspired concentration is reduced. The first adaptation to high altitude is an increase in minute ventilation. The ventilatory response to a relatively hypoxic stimulus can be divided into 4 phases: (1) initial increase on ascent, (2) subsequent course over hours and weeks, (3) deacclimatization on descent, and (4) long-term response of high-altitude natives.

    The barometric pressure decreases with distance above the Earth's surface in an approximately exponential manner. The pressure at 5500 m (18,000 ft) is only half the normal 760 mm Hg, so that the partial pressure of oxygen (PO2) of moist inspired gas is (380-47) X 0.2093 = 70 (47 mm Hg is the partial pressure of water vapor at body temperature [ie, 37ºC]). At the summit of Mount Everest (altitude 8848 m or 29,028 ft), the inspired PO2 is only 43. In spite of hypoxia associated with high altitude, approximately 15 million people live at elevations over 3050 m, and some permanent residents live higher than 4900 m in the Andes. A remarkable degree of acclimatization occurs when humans ascend to these altitudes. Climbers have lived for several days at altitudes that would cause unconsciousness within a few seconds in the absence of acclimatization.

    Spirometric studies have shown that with increasing altitude, both forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) are reduced by up to 25% (74.8% / 74.6% of baseline). In the same study, peak expiratory flow (PEF) initially increased up to 4451 m and returned to baseline values above 5000 m. After descent below 2000 m, all values normalized within one day. These findings were consistent with increasing pulmonary restriction at high altitudes (without a marked reduction of PEF). Portable spirometry may provide clinically relevant information (impending pulmonary edema) in high-altitude travelers.1

    Bronchoalveolar lavage fluid (BALF) studies have shown that after heavy exercise, under all conditions, athletes develop a permeability edema with high BALF RBC and protein concentrations in the absence of inflammation. Exercise at altitude (3810 m) caused significantly greater leakage of RBCs (92,000 [SD 3.1] cells/mL) into the alveolar space than that seen with normoxic exercise (54,000 [SD 1.2] cells/mL). At altitude, the 26-hour postexercise BALF had significantly higher RBC and protein concentrations, suggesting an ongoing capillary leak. These findings suggest that pulmonary capillary disruption occurs with intense exercise in healthy humans and that hypoxia augments the mechanical stresses on the pulmonary microcirculation.2

    Autopsy studies performed on patients who died of HAPE have shown a proteinaceous exudate with hyaline membranes. The studies have shown areas of pneumonitis with neutrophil accumulation, although none was noted to contain bacteria. Pulmonary veins were not dilated. Most reports mention capillary and arteriolar thrombi with deposits of fibrin, hemorrhage, and infarcts. The findings suggest a protein-rich edema with a possibility that clotting abnormalities may be partially responsible for this illness.

    Bronchoalveolar lavages performed on patients with HAPE have also shown the fluid to have a high protein content, higher than in patients with adult respiratory distress syndrome (ARDS). The fluid was also highly cellular. Unlike ARDS, which primarily has neutrophils in the lavage fluid, HAPE fluid contains a higher percentage of alveolar macrophages. Additionally, chemotactic (leukotriene B4) and vasoactive (thromboxane B2) mediators were present in the lavage.

    Frequency
    United States

    In one study on Colorado skiers, incidence of acute mountain sickness was as high as 15-40%. Incidence of HAPE is much lower, at about 0.1-1%.
    International

    In a study on Mount Everest trekkers, incidence of HAPE was about 1.6%. Incidence of mountain sickness appears to be unusually high in trekkers on Mount Rainier; however, the incidence of pulmonary edema is the same as in other places.
    Mortality/Morbidity

    HAPE may be fatal within a few hours if left untreated. Patients who recover from HAPE have rapid clearing of edema fluid and do not develop long-term complications.
    Sex

    Men and women are equally susceptible to acute mountain sickness, but women may be less likely to develop HAPE. In addition to individual differences in susceptibility, other factors, such as alcohol, respiratory depressants, and respiratory infections, may enhance vulnerability to altitude illness.
    Age

    The typical patient with HAPE is a young person who is otherwise physically fit. HAPE is rare in infants and small children.

    CLINICAL
    Section 3 of 10 Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic

    * Authors and Editors
    * Introduction
    * Clinical
    * Differentials
    * Workup
    * Treatment
    * Medication
    * Follow-up
    * Miscellaneous
    * References


    History

    * HAPE generally occurs 1-4 days after rapid ascent to altitudes in excess of 2500 m (8000 ft). Young people and previously acclimatized people reascending to a high altitude following a short stay at low altitude seem more predisposed to HAPE. Cold weather and physical exertion at high altitude are other predisposing factors.
    * The earliest indications are decreased exercise tolerance and slow recovery from exercise.
    * The person usually notices fatigue, weakness, and dyspnea on exertion.
    * The condition typically worsens at night, and tachycardia and tachypnea occur at rest. Periodic breathing during sleep is almost universal in sojourners at high altitude.
    * Cough, frothy sputum, cyanosis, rales, and dyspnea progressing to severe respiratory distress are symptoms of the disease.
    * A low-grade fever, respiratory alkalosis, and leukocytosis are other common features.
    * In severe cases, an altered mental status, hypotension, and death may result.

    Physical

    In addition to the symptoms discussed, HAPE is diagnosed by the presence of at least 2 of the following signs:

    * Tachycardia
    * Tachypnea
    * Crackles on auscultation
    * Central cyanosis
    * Disproportionately low oxygen saturation relative to altitude

    Causes

    * Rapid ascent
    * Physical exertion at high altitude
    * Exposure to cold


    DIFFERENTIALS
    Section 4 of 10 Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic

    * Authors and Editors
    * Introduction
    * Clinical
    * Differentials
    * Workup
    * Treatment
    * Medication
    * Follow-up
    * Miscellaneous
    * References


    Asthma
    Bronchitis
    Myocardial Infarction

    Other Problems to be Considered

    Anxiety
    Viral syndromes
    Thromboembolic disease

    WORKUP
    Section 5 of 10 Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic

    * Authors and Editors
    * Introduction
    * Clinical
    * Differentials
    * Workup
    * Treatment
    * Medication
    * Follow-up
    * Miscellaneous
    * References


    Lab Studies

    * Findings on laboratory studies are nonspecific.
    * Arterial blood gas measurement may show acute respiratory alkalosis. A mild leukocytosis also may be present.
    * Some studies have demonstrated increase in interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1ra), and cross-reacting protein (CRP) in response to high altitude. The systemic increase of these inflammatory markers may reflect considerable local inflammation.

    Imaging Studies

    * Chest radiograph reveals bilateral patchy infiltrates.
    * In one study,3 stress echocardiography was used to quantitate pulmonary artery systolic pressure responses to prolonged hypoxia and normoxic exercise. The data from the study indicate that individuals who are susceptible to HAPE have abnormal vascular responses not only to hypoxia but also to supine bicycle exercise under normoxic conditions. Thus, this modality may be a useful noninvasive screening method to identify subjects susceptible to HAPE.

    Other Tests

    * ECG may reveal a right-heart strain pattern suggestive of pulmonary hypertension.

    Procedures

    * Portable hyperbaric chambers (Gamow, CERTEC) are in wide use by trekkers. A physiologic (simulated) descent of about 2000 m may be achieved in a few minutes. Patients are typically treated in 1-hour increments. Patients should be closely observed for rebound symptoms after hyperbaric treatments.


    TREATMENT
    Section 6 of 10 Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic

    * Authors and Editors
    * Introduction
    * Clinical
    * Differentials
    * Workup
    * Treatment
    * Medication
    * Follow-up
    * Miscellaneous
    * References


    Medical Care

    The treatment of HAPE includes rest, administration of oxygen, and descent to a lower altitude. If diagnosed early, recovery is rapid with a descent of only 500-1000 m. A portable hyperbaric chamber or supplemental oxygen administration immediately increases oxygen saturation and reduces pulmonary artery pressure, heart rate, respiratory rate, and symptoms. In situations where descent is difficult, these treatments can be lifesaving.

    In one study,4 11 patients at 4240 m altitude in Pheriche, Nepal were treated for HAPE with bed rest, oxygen, nifedipine, and acetazolamide. Sildenafil and salmeterol were used in most, but not all patients. Seven of these had serious-to-severe HAPE (Hultgren grades 3 or 4). Oxygen saturation was improved at discharge (84% ±1.7%) compared with admission (59% ±11%), as was the ultrasound comet-tail score (11 ±4 at discharge vs 33 +/- 8.6 at admission), a measure of pulmonary edema for which admission and discharge values were obtained in 7 patients.

    A randomized, double-blinded, placebo-controlled study5 showed that adults with previous HAPE who received prophylactic tadalafil (10 mg) or dexamethasone (8 mg) had significantly less HAPE compared with those who received placebo twice daily. The medications were administered during ascent and at a stay at 4559 m altitude.

    Two participants who received tadalafil developed severe acute mountain sickness upon arrival at 4559 m and withdrew from the study; they did not have HAPE at that time. HAPE developed in 7 of 9 participants who received placebo and in 1 of the remaining 8 participants who received tadalafil, but it did not develop in any of the 10 participants who received dexamethasone (P = .007 for tadalafil vs placebo; P <.001 for dexamethasone vs placebo). Eight of 9 participants who received placebo, 7 of 10 who received tadalafil, and 3 of 10 who received dexamethasone had acute mountain sickness (P = 1.0 for tadalafil vs placebo; P = .020 for dexamethasone vs placebo).

    At high altitude, systolic pulmonary artery pressure increased less in participants who received dexamethasone (16 mm Hg [95% confidence interval, 9-23 mm Hg]) and tadalafil (13 mm Hg [95% confidence interval, 6-20 mm Hg]) than in those who received placebo (28 mm Hg [95% confidence interval, 20-36 mm Hg]) (P = .005 for tadalafil vs placebo; P = .012 for dexamethasone vs placebo).

    The conclusion was that both dexamethasone and tadalafil decrease systolic pulmonary artery pressure and may reduce the incidence of HAPE in adults with a history of HAPE. Dexamethasone prophylaxis may also reduce the incidence of acute mountain sickness in these adults.

    Finally, the use of an expiratory positive airway pressure mask improves oxygenation and may be useful as a temporizing measure.
    Diet

    * A diet rich in carbohydrates has shown to be helpful in prevention of the illness.
    * Alcohol and sedatives should be avoided.
  12. Angerguy.

    Angerguy. Guest

    Treatment of pain from osteoporotic vertebral collapse by percutaneous PMMA vertebroplasty

    Abstract:

    Background. Vertebral compression fractures are common complications in advanced osteoporosis. In general, this disease of the elderly patient is characterized by severe local back pain. Pathophysiologically, bony instability triggers local pain during body movement. Serious pain immobilizes the patients and forces them to bed rest. As a result, complications like thrombosis or pneumonia occur. Invasive treatment with surgical instrumentation for vertebral stabilization is not indicated in elderly patients especially with additional diseases.

    The purpose of this study was to test the hypothesis that percutaneous polymethylmethacrylate (PMMA) vertebroplasty significantly reduces pain due to vertebral collapse in osteoporotic patients and improves quality of life.

    Methods. A total of 38 patients with osteoporotic vertebral compression fractures of the thoracic and lumbar spine were treated by PMMA vertebroplasty. After admission, before discharge from the hospital, six weeks, half a year and one year later patients answered the Oswestry Low Back Pain Disability (OLBPD) Questionnaire for assessment of treatment related change in disability. In all patients percutaneous vertebroplasty was performed under local anesthesia.

    Findings. A total of 92% of patients reported a significant pain reduction immediately after treatment. Also one year after vertebroplasty pain remained significantly reduced. Vertebroplasty was highly beneficial for patients with pain related to local instability of the spine. Extravasation of PMMA beyond the vertebral margins was observed in 26% of the cases. No treatment related clinical or neurological complications were noticed.

    Interpretation. PMMA vertebroplasty is a useful and safe method of pain relief which rapidly regains quality of life for patients with osteoporotic vertebral compression.


    ans: PMMA is used in vertebroplasty
  13. Angerguy.

    Angerguy. Guest

    The blue-white screen is a molecular technique that allows for the detection of successful ligations in vector-based gene cloning. DNA of interest is ligated into a vector. The vector is then transformed into competent cell (bacteria). The competent cells are grown in the presence of X-gal. If the ligation was successful, the bacterial colony will be white; if not, the colony will be blue. This technique allows for the quick and easy detection of successful ligation, without the need to individually test each colony.

    ans: to find out the cloned fragment of gene in the vector/bacteria??
  14. Angerguy.

    Angerguy. Guest

    If Wernicke’s area is damaged in the non-dominant hemisphere, the syndrome resulting will be sensory dysprosody - the lack of ability to perceive the pitch, rhythm, and emotional tone of speech.

    Speech is preserved, but language content is incorrect. This may vary from the insertion of a few incorrect or nonexistent words to a profuse outpouring of jargon. Grammar, syntax, rate, intonation and stress are normal. Substitutions of one word for another (paraphasias, e.g. “telephone” for “television”) are common. Comprehension and repetition are poor

    ans: speech is irrelevant and rapid
  15. Angerguy.

    Angerguy. Guest

    Rituximab is used alone or with other medications to treat certain types of cancer (e.g., non-Hodgkin's lymphoma). It is a type of medication called a monoclonal antibody. It works by attaching to certain blood cells from your immune system (B cells) and killing them. It is also used with other monoclonal antibodies and radioactive drugs to treat certain cancers.

    Rituximab is also used with methotrexate to treat moderate-to-severe forms of rheumatoid arthritis. It is usually used for arthritis only after other medications have not worked. It can decrease joint pain and swelling.

    Rituximab is used in all except
    ans : PNH probably
  16. Angerguy.

    Angerguy. Guest

    Most common cause of neonatal seizures:

    ans: HIE

    Neonatal seizures are abnormal electrical discharges in the CNS of neonates usually manifesting as stereotyped muscular activity or autonomic changes. Diagnosis is confirmed by EEG; testing for causative conditions is indicated. Treatment depends on cause.

    Seizures occur in up to 1.4% of term infants and 20% of premature infants. Seizures may be a serious neonatal problem and require immediate evaluation. Most neonatal seizures are focal, probably because in neonates generalization of the electrical activity is impeded by lack of myelination and incomplete formation of dendrites and synapses in the brain. Some neonates undergoing EEG for assessment of symptoms of encephalopathy (eg, hypoactivity, decreased responsiveness) are found to have clinically silent seizures (epileptiform electrical activity during an EEG but without any visible seizure activity). Occasionally, clinically silent electrical activity is continuous and persists for > 20 min; at that point, it is defined as electrical status epilepticus.

    Etiology

    The abnormal CNS electrical discharge may be caused by a primary intracranial process (eg, meningitis, ischemic stroke, encephalitis, intracranial hemorrhage, tumor) or may be secondary to a systemic problem (eg, hypoxia-ischemia, hypoglycemia, hypocalcemia, hyponatremia). Seizures resulting from an intracranial process usually cannot be differentiated from seizures resulting from a systemic problem by their clinical features (eg, focal vs generalized).

    Hypoxia-ischemia, the most common cause of neonatal seizures, may occur before, during, or after delivery. Such seizures may be severe and difficult to treat, but they tend to abate after about 3 to 4 days.
  17. Angerguy.

    Angerguy. Guest

    Inhibin as a marker for granulosa-cell tumors

    Abstract

    Inhibin is a peptide hormone normally produced by ovarian granulosa cells. It reaches a peak of 772 +/- 38 U per liter in the follicular phase of the menstrual cycle and is undetectable in the serum of menopausal women. To determine whether measurements of serum inhibin levels would provide a biochemical marker of the presence or progression of ovarian granulosa-cell tumors and their metastases, we measured the serum immunoreactive inhibin concentrations in six women with such tumors. Three women had been treated by hysterectomy and bilateral salpingo-oophorectomy. In the two women with residual or recurrent disease, the serum inhibin levels were abnormally elevated 5 and 20 months before the clinical manifestations of recurrence became evident. The maximal concentrations approached 3000 U per liter. The serum inhibin level remained undetectable in one patient who was disease-free for 11 years. Serum inhibin concentrations were also elevated in three women with amenorrhea and infertility that resulted from small granulosa-cell tumors. After the removal of the tumors, the serum inhibin levels in these women became normal, and fertility returned. There was a significant negative correlation between the serum concentrations of inhibin and follicle-stimulating hormone, in a manner consistent with the autonomous production of inhibin by granulosa-cell tumors. We conclude that granulosa-cell tumors produce inhibin. Since serum inhibin levels reflect the size of the tumor, measurements of inhibin can be used as a marker for primary as well as recurrent disease.

    ans: Inhibin
  18. Angerguy.

    Angerguy. Guest

    CA 19.9



    CA 19.9 is a tumor-associated antigen, originally isolated from a human colon cancer cell line. It is present on gangliosides in tissues, but is carried by glycoproteins in serum. The oligosaccharide, bearing the CA 19.9 antigen, is related to sialylated Lewis A blood group antigen. Lewis A antigen must be present before CA 19.9 can be expressed. CA 19.9 is synthesized by normal cells in pancreatic and bile ducts, gastric and colonic mucosa, bronchial and salivary glands, endometrium, and prostate. Secretions from these organs are rich in CA 19.9, but very little antigen appears in the blood of healthy individuals.




    Even though CA 19.9 was originally isolated from a colon cancer cell line, its greatest clinical utility is detecting pancreatic cancer. CA 19.9 is not a very useful screening test for pancreatic cancer in asymptomatic patients. The maximum achievable sensitivity is 95%, since 5% of the U. S. population are Lewis a & b nonsecretors and do not synthesize CA 19.9. In practice, the sensitivity for early cancer is much less. Serum levels are elevated in less than 30% of patients with stage 1 cancers.

    Elevated CA 19.9 levels are not specific for pancreatic cancer, but are elevated in other benign and malignant disorders. Other GI malignancies are also associated with elevated CA 19.9 levels, but not usually to the same extent as pancreatic cancer. CA 19.9 is elevated in 67% of bile duct cancers, 41% of gastric cancers, 34% of colon cancers, 22% of esophageal cancers, 49% of hepatomas, and 14% of non-gastrointestinal tract cancers. Most benign disorders cause lower elevations of serum CA 19.9. However, two benign conditions, cirrhosis and acute cholangitis, can cause high CA 19.9 levels. In acute cholangitis, levels rapidly return to normal following decompression of the common duct.

    CA 19.9 is the most useful circulating tumor marker for evaluating patients who present with signs and symptoms of a chronic pancreatic disorder. In this population the prevalence of cancer is about 17%. Using an upper limit of normal of 40 U/mL, serum CA 19.9 assays have a sensitivity of 81%, specificity of 90%, and a positive predictive value of 72%. The specificity and positive predictive value for cancer increase with higher CA 19.9 values. The higher the CA 19.9 level, the greater the likelihood of cancer. Levels >300 have a positive predictive value of 92%.
  19. Meena.

    Meena. Guest

    The target disease areas for VISION 2020 are:
    1. Cataract
    2. Trachoma
    3. Onchocerciasis
    4. Childhood Blindness
    5. Refractive Error
    6. Low Vision
    7. Glaucoma
    8. Diabetic - Retinopathy
    9. Age Related Macular Degeneration
  20. Meena.

    Meena. Guest

    kassabach merritte syndrome-

    Background
    In 1940, Kasabach and Merritt described a male infant with a discolored, indurated lesion on his left thigh that rapidly grew and affected the entire left leg, scrotum, abdomen, and thorax. In addition, the infant also had consumptive thrombocytopenia. This association has become known as Kasabach-Merritt syndrome (KMS). The original case is now known to have been associated with kaposiform hemangioendothelioma and thrombocytopenia.

    Pathophysiology
    The vascular lesion triggers (1) intravascular coagulation with platelet trapping and activation and (2) consumption of coagulation factors.

    Thrombocytopenia is a consumptive process in the vascular tumor that is corrected when the tumor is controlled. The platelets consumed in the process, with the release of platelet-derived growth factor, which is a mitogen. Increased thrombin generation occurs, followed by the development of disseminated intravascular coagulopathy (DIC). Thrombin (also a mitogen) and other cytokines are released with DIC
    Histologic Findings
    Enjolras and colleagues characterized the histology of the vascular lesion associated with Kasabach-Merritt syndrome (KMS). The original case report described lobules of the fine capillaries separated by cellular intercapillary tissue consisting of spindle-shaped cells. Tufted angioma and kaposiform hemangioendothelioma of infancy and childhood are the vascular anomalies reported in KMS.

    The histologic picture of kaposiform hemangioendothelioma consists of lobules or sheets of tightly packed spindle cells or rounded endothelial cells and pericytes. The cellular areas have an infiltrative pattern in the dermis, subcutaneous fat, and muscles and generally contain few obvious vascular lumina.

    A tufted angioma is composed of small tufts or lobules of rounded capillaries with small lumina. The tufts are discrete and evenly distributed in a cannonball pattern and are characterized by peripheral, crescentic, slitlike vessels and an associated fibrosis.

    Both kaposiform hemangioendothelioma and tufted angioma contain aggregates of rounded, dilated capillaries lined by attenuated endothelial cells with small, dark nuclei and filled with RBCs. Microthrombi and hemosiderin deposits are often present. Lymphlike vessels are often part of the lesion. Findings of both kaposiform hemangioendothelioma and tufted angioma often appear in the same patient and are thought to be variations of one another.

    The histology of classic hemangioma of infancy, which is the most common benign vascular neoplasm in children, is distinct from these proliferations and is not associated with or precedes KMS
  21. Meena.

    Meena. Guest

    in osteopetrosis all are true except

    ans: delayed fracture healing


    Summary We report the occurrence and distribution of 17 fractures in four patients with malignant, autosomal recessive osteopetrosis. The frequency of the disease in the Caucasian population is in the order of 1 per 20,000, of which the vast majority suffer from a mild autosomal dominant form. The patients have been followed up for 17–22 years and have multiple handicaps. Their case histories indicate that the lower extremity is the most common site for pathological fractures. The traumata were all caused by common accidents, usually falls. Conservative treatment was successful, with normal healing time in the four cases presented
  22. Meena.

    Meena. Guest

    all are branches of cavernous segment of internal carotid artery except

    ans : ophthalmic artery

    The cavernous segment, or C4, of the internal carotid artery begins at the petrolingual ligament and extends to the proximal dural ring, which is formed by the medial and inferior periosteum of the anterior clinoid process. The cavernous segment is surrounded by the cavernous sinus.

    In this part of its course, the artery is situated between the layers of the dura mater forming the cavernous sinus, but covered by the lining membrane of the sinus. It at first ascends toward the posterior clinoid process, then passes forward by the side of the body of the sphenoid bone, and again curves upward on the medial side of the anterior clinoid process, and perforates the dura mater forming the roof of the sinus. This portion of the artery is surrounded by filaments of the sympathetic trunk, and on its lateral side is the abducent nerve, or cranial nerve VI.

    The named branches of the cavernous segment are:

    the meningohypophyseal artery
    the inferolateral trunk
    The cavernous segment also gives rise to small capsular arteries that supply the wall of the cavernous sinus.

    The ophthalmic segment, or C6, extends from the distal dural ring, which is continuous with the falciform ligament, and extends distally to the origin of the posterior communicating artery. The ophthalmic segment courses roughly horizontally, parallel to the optic nerve which runs superomedially to the carotid at this point.

    The named branches of the ophthalmic segment are:

    the ophthalmic artery
    the superior hypophyseal artery
  23. Meena.

    Meena. Guest

    Acoustic neuroma gold standard for diagnosis

    ans : MRI

    Magnetic resonance imaging (MRI) is the preferred diagnostic test for identifying acoustic neuromas.

    Other tests used to diagnose acoustic neuroma and to differentiate it from other causes of dizziness or vertigo include:

    Computed tomography (CT) scan of the head
    Audiology (a test for hearing)
    Caloric stimulation (a test for vertigo)
    Electronystagmography (a test of equilibrium and balance)
    Brain stem auditory evoked response (BAER, a test of hearing and brain stem function)
  24. Meena.

    Meena. Guest

    Lysobisphosphatidic acid (LBPA) can be regarded to represent a unique derivative of phosphatidylglycerol. This lipid is highly enriched in late endosomes where it can comprise up to 10–15 mol% of all lipids and in these membranes, LBPA appears to be segregated into microdomains. We studied the thermotropic behavior of pure dioleoyl-LBPA mono- and bilayers using Langmuir-lipid monolayers, electron microscopy, differential scanning calorimetry (DSC), and fluorescence spectroscopy. LBPA formed metastable, liquid-expanded monolayers at an air/buffer interface, and its compression isotherms lacked any indication for structural phase transitions. Neat LBPA formed multilamellar vesicles with no structural transitions or phase transitions between 10 and 80 °C at a pH range of 3.0–7.4. We then proceeded to study mixed LBPA/dipalmitoylphosphatidylcholine (DPPC) bilayers by DSC and fluorescence spectroscopy. Incorporating increasing amounts of LBPA (up to XLBPA (molar fraction) = 0.10) decreased the co-operativity of the main transition for DPPC, and a decrease in the main phase transition as well as pretransition temperature of DPPC was observed yet with no effect on the enthalpy of this transition. In keeping with the DSC data for DPPC, 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC)/LBPA mixed bilayers were more fluid, and no evidence for lateral phase segregation was observed. These results were confirmed using fluorescence microscopy of Langmuir-lipid films composed of POPC and LBPA up to XLBPA = 0.50 with no evidence for lateral phase separation. As late endosomes are eminently acidic, we examined the effect of lowering pH on lateral organization of mixed PC/LBPA bilayers by DSC and fluorescence spectroscopy. Even at pH 3.0, we find no evidence of LBPA-induced microdomain formation at LBPA contents found in cellular organelles.
  25. Meena.

    Meena. Guest

    Autoimmune diseases

    Rituximab has been shown to be an effective rheumatoid arthritis treatment in three randomised controlled trials and is now licensed for use in refractory rheumatoid disease.[2] (FDA-approved for use in combination with methotrexate (MTX) for reducing signs and symptoms in adult patients with moderately- to severely-active rheumatoid arthritis (RA) who have had an inadequate response to one or more anti-TNF-alpha therapies.) There is evidence for efficacy in a range of other autoimmune diseases, including idiopathic autoimmune hemolytic anemia, Pure red cell aplasia, idiopathic thrombocytopenic purpura (ITP)[3][4], Evans syndrome[5], vasculitis, multiple sclerosis,[6] [bleep] skin disorders (for example pemphigus, pemphigoid), type 1 diabetes mellitus, Sjogren's syndrome, Devic's Syndrome and systemic lupus erythematosus, although there are significant concerns about PML infection in SLE patients[1].


    -------------------------------------------
    Rituximab

    • Learn more about using Wikipedia for research •
    Jump to: navigation, search
    Rituximab?
    Therapeutic monoclonal antibody
    Source chimeric (mouse/human)
    Target CD20
    Identifiers
    CAS number 174722-31-7
    ATC code L01XC02
    PubChem ?
    DrugBank BTD00014
    Chemical data
    Formula C6416H9874N1688O1987S44
    Mol. mass 143859.7 g/mol
    Pharmacokinetic data
    Bioavailability 100% (IV)
    Metabolism ?
    Half life 30 to 400 hours (varies by dose and length of treatment)
    Excretion Uncertain: may undergo phagocytosis and catabolism in RES
    Therapeutic considerations
    Pregnancy cat.

    C(US) (no adequate human studies)
    Legal status

    ℞-only(US)
    Routes intravenous infusion only (never bolus or "push")

    Rituximab, sold under the trade names Rituxan and MabThera, is a chimeric monoclonal antibody used in the treatment of B cell non-Hodgkin's lymphoma, B cell leukemia, and some autoimmune disorders.
    Contents


    * 1 History
    * 2 Uses
    o 2.1 Neoplastic diseases
    o 2.2 Autoimmune diseases
    o 2.3 Anti-rejection treatment for organ transplants
    * 3 Mechanism
    * 4 Adverse events
    * 5 Other anti CD20 monoclonals
    * 6 References
    * 7 External links

    History

    Rituximab was developed by IDEC Pharmaceuticals and initially approved by the FDA in 1997 for lymphoma that was refractory to other chemotherapy regimens. The original approval followed the availability of the McLaughlin et al[1] study data. It now is standard therapy in the initial treatment of aggressive lymphomas (e.g. diffuse large B cell lymphoma) in combination with CHOP chemotherapy. It is currently co-marketed by Biogen Idec and Genentech in the U.S. market and Roche in the EU.

    Uses

    Rituximab depletes B cells, and therefore is used to treat diseases which are characterized by having too many B cells, overactive B cells or dysfunctional B cells.

    Neoplastic diseases

    Most patients taking rituximab have a neoplastic disease such as leukemia or lymphoma.

    Autoimmune diseases

    Rituximab has been shown to be an effective rheumatoid arthritis treatment in three randomised controlled trials and is now licensed for use in refractory rheumatoid disease.[2] (FDA-approved for use in combination with methotrexate (MTX) for reducing signs and symptoms in adult patients with moderately- to severely-active rheumatoid arthritis (RA) who have had an inadequate response to one or more anti-TNF-alpha therapies.) There is evidence for efficacy in a range of other autoimmune diseases, including idiopathic autoimmune hemolytic anemia, Pure red cell aplasia, idiopathic thrombocytopenic purpura (ITP)[3][4], Evans syndrome[5], vasculitis, multiple sclerosis,[6] [bleep] skin disorders (for example pemphigus, pemphigoid), type 1 diabetes mellitus, Sjogren's syndrome, Devic's Syndrome and systemic lupus erythematosus, although there are significant concerns about PML infection in SLE patients[1].

    Anti-rejection treatment for organ transplants

    Rituximab is now being used in the management of Renal Transplant recipients. This drug is especially useful in transplants involving incompatible blood groups. It is also used as induction therapy in highly sensitized patients going for renal transplantation.

    Mechanism

    The antibody binds to the cluster of differentiation 20 (CD20). CD20 is widely expressed on B-cells. It does not shed, modulate or internalise. Although the function of CD20 is relatively unknown it has been indicated that CD20 could play a role in Ca2+ influx across plasma membranes, maintaining intracellular Ca2+ concentration and allowing activation of B cells.

    The exact mode of action of rituximab is unclear, but the following effects have been found:[7]

    * The Fc portion mediates antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).
    * It has a general regulatory effect on the cell cycle.
    * It increases MHC II and adhesion molecules LFA-1 and LFA-3 (lymphocyte function-associated antigen).
    * It elicits shedding of CD23.
    * It downregulates the B-cell receptor.
    * It induces apoptosis of CD20+ cells.

    The combined effect results in the elimination of B cells (including the cancerous ones) from the body, allowing a new population of healthy B cells to develop from lymphoid stem cells.

    Binder et al further described the part of the CD20 molecule that rituximab binds to: amino acids 170-173 and 182-185, which are physically close to each other as a result of a disulfide bond between amino acids 167 and 183.[8]

    Adverse events

    Serious adverse events, which can cause death and disability, include:[9]

    * Severe infusion reactions
    * Cardiac Arrest
    * Tumor lysis syndrome, causing acute renal failure
    * Infections
    o Hepatitis B reactivation
    o Other viral infections
    o Progressive multifocal leukoencephalopathy (PML)
    * Immune toxicity, with depletion of B cells in 70% to 80% of patients with non-Hodgkins lymphoma
    * Pulmonary toxicity[10]

    Several patients with systemic lupus erythematosus have died after being treated with rituximab.[11] Rituximab triggered reactivation of latent JC virus (a common virus) in the brains of these patients. PML reactivation in an immunosuppressed person commonly results in death or severe brain damage.

    Other anti CD20 monoclonals

    The efficacy and success of Rituximab has led to a few other anti CD20 monoclonal antibodies being developed:

    * ocrelizumab, humanized (90%-905% human) B-cell agonist.
    * ofatumumab (HuMax-CD20) a fully-human B-cell agonist.[12]
    * Third-generation anti-CD20s have a glycoengineered Fc fragment (Fc)[13] with enhanced binding to Fc gamma receptors, which increase ADCC (antibody dependent cellular cytotoxicity).[14] Modifications in the variable regions (variable regions)[15] can enhance apoptosis.

    The value of a humanized molecule in oncology has not been demonstrated to this date. Another approach to B lymphocyte diseases is to confront their agonists and the receptors of these agonists. Belimumab is an example of such an approach.
  26. Meena.

    Meena. Guest

    MANAGEMENT OF PNH

    Medical Care

    Based on current understanding of the disease, ideal treatment is to replace the defective hematopoietic stem cell with a normal equivalent by stem cell transplantation; however, this is not realistic, because this requires a histocompatible donor and is associated with significant morbidity and mortality. This form of treatment is reserved for severe cases with aplastic anemia or those whose conditions transform to leukemia, both of which are life-threatening complications. The treatment is largely based on symptoms.

    Treatment for anemia, depending on the major cause and severity, can be approached with the following guidelines:

    * The anemia may have 3 components: intravascular hemolysis, inadequate erythropoiesis, and superimposed iron deficiency (massive iron loss through hemoglobinuria).
    *
    o In view of increased rate of erythropoiesis, give 5 mg/d of folic acid orally.
    o Assess iron stores using transferrin saturation index (TSI): Give oral ferrous sulfate if <20%. (Ferritin is acute-phase reactant and can be misleading.)
    o Determine steady state Hb levels after correction for iron deficiency.
    o Transfuse packed RBC (WBC depleted by filter) when appropriate. Washing red cells is no longer necessary, and irradiated blood products is recommended for future SCT.
    * Modulation of complement is controlled poorly by high doses of glucocorticoids. The usual adult dose of prednisone is 20-40 mg/d (0.3-0.6 mg/kg/d) given daily during hemolysis and changed to alternate days during remission. On this regimen, about 70% of adult patients experience improvement in hemoglobin levels, but long-term therapy is fraught with complications.
    * A new anticomplement agent, eculizumab, is a humanized monoclonal antibody against terminal protein C5; it has recently been shown to be highly effective in reducing intravascular hemolysis. Eleven transfusion-dependent PNH patients were given eculizumab at 900 mg IV over 30 minutes every 2 weeks. The mean LDH decreased along with transfusion requirements from 2.1 units per patient per month to 0.0 along with global improvement of quality of life. Long-term analysis show that these improvements can be maintained over 3 years now, and erythropoietin can overcome anemia due to marrow failure in patients on the drug. The current studies are closed for recruitment, and the data will be submitted for licensing. In March, 2007, the FDA approved eculizumab as an orphan drug for PNH.
    * Replacement of nutritional iron, because of increased loss of iron from the hemolysis and the 200 times increase in iron urinary excretion, is necessary to prevent development of iron deficiency. Iron replacement can stimulate reticulocytosis that can trigger hemolysis by releasing a new cohort of complement-sensitive cells. This can be prevented by adding prednisone during replacement therapy.
    * Stimulation of erythropoiesis using androgenic hormones has been successful in patients with moderate decrease in red cell production. This has been replaced mainly by using recombinant erythropoietin therapy.
    * Supportive care for severe anemia includes blood transfusion using leuko-depleted packed RBCs to prevent alloimmunization. Development of alloantibodies can be a problem with future transfusions because of activation of complement and delayed hemolysis of transfused blood.
    * Management of thrombotic complications follows standard principles, using heparin emergently, then maintenance using an oral anticoagulant, such as Coumadin. Sometimes, heparin can exacerbate the thrombotic problem, possibly by activating complement. This can be prevented using inhibitors of cyclooxygenase system, such as aspirin, ibuprofen, and sulfinpyrazone. Primary prophylaxis with warfarin has been advocated, but it remains controversial as to whether this approach is safe and effective in all patients PNH. It remains to be seen if eculizumab therapy, which is effective in decreasing hemolysis, can also decrease the risk for venous thrombosis.
    * Bone marrow hypoplasia is a serious cause of morbidity and mortality. It is treated most effectively with bone marrow transplantation; however, if there is no suitable donor available, antithymocyte globulin (ATG) has been used in the treatment of aplastic anemia with considerable success.

    Consultations

    In centers that do not have a bone marrow transplantation program, consultation and identification of possible donors should be undertaken early.

    * Stem cell transplantation (SCT) is a curative therapeutic option for PNH. However, the risks must be carefully weighed against factors related both to PNH and comorbid conditions. Furthermore, the heterogenous presentation of the disease, its unpredictable course, and its association with bone marrow failure conditions confound the decision process regarding transplantation.
    * A recent analysis by the International PNH Interest Group reviewed data from 67 patients from single centers and from 2 registry studies with special emphasis in eliminating duplication in patient reporting.
    *
    o Among the 67 patients, 7 were transplanted from a twin syngeneic donor. Four of the 7 syngeneic transplants had no conditioning therapy, and these 4 either failed to engraft or relapsed posttransplant indicating that a marrow ablative conditioning is necessary before syngeneic transplantation.
    o In 47 of 67 patients, an HLA-identical sibling was used as the donor, 1 from a haploidentical family member, and 12 from an unrelated donor (MUD).
    o In the only single-center study providing a Kaplan-Meier analysis, overall survival at 5 years was 58 +/- 13%. This is less favorable than the survival estimate of approximately 75% generated by combining the data from the other reports.
    o Investigation on whether reduced intensity conditioning can improve the outcome is currently underway.
  27. Meena.

    Meena. Guest

    Problems produced by androgen insensitivity

    Although many distinct mutations have been discovered, the clinical manifestations have been divided into six phenotypes, which roughly correspond to increasing amounts of androgen effect due to increasing tissue responsiveness. It should be emphasized that the disorders of androgen sensitivity represent a spectrum rather than 6 discrete diseases, and some affected persons will have features that fall between the phenotypes described.

    1. Complete AIS (CAIS): completely female body except no uterus, fallopian tubes or ovaries; testes in the abdomen; minimal androgenic (pubic or axillary) hair at puberty. OMIM 300068.

    2. Partial or incomplete AIS (PAIS): female body, with slightly virilized genitalia; testes in the abdomen; sparse to normal androgenic hair. Variant of OMIM 300068.

    3. Reifenstein syndrome: obviously ambiguous genitalia; small testes may be in abdomen or scrotum; sparse to normal androgenic hair; gynecomastia at puberty. OMIM 312300.

    4. Infertile male syndrome: normal male genitalia internally and externally; normal male body or possible female androgyny, normal virilization and androgenic hair; reduced sperm production; reduced fertility or infertility. OMIM 308370.

    5. Undervirilized fertile male syndrome: male internal and external genitalia with small penis; testes in scrotum; normal androgenic hair; sperm count and fertility normal or reduced. Variant of OMIM 312300.

    6. X-linked spinal and bulbar muscular atrophy: normal or nearly normal male body and fertility; exaggerated adolescent gynecomastia; adult onset degenerative muscle disease. OMIM 313200.

    OMIM (Online Mendelian Inheritance in Man) numbers are a genetic disease classification system available at the NCBI.
  28. Hemant.

    Hemant. Guest

    TRUE ABOUT ANDROGEN INSENSITIVITY SYNDROME

    a)complete female body

    b)testis -ovary ,gonad indistinguishable

    c)-------------

    d)-----------


    Androgen insensitivity syndrome
    From Wikipedia, the free encyclopedia
    • Ten things you may not know about Wikipedia •
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    This article needs additional citations for verification.
    Please help improve this article by adding reliable references. Unsourced material may be challenged and removed. (April 2008)
    Androgen insensitivity syndrome
    Classification and external resources
    Testosterone (structure pictured) and dihydrotestosterone to a lesser degree, are the primary androgens involved in AIS.
    ICD-10 E34.5
    ICD-9 259.5
    OMIM 312300 300068
    DiseasesDB 29662 12975
    eMedicine ped/2222
    MeSH D013734

    Androgen insensitivity syndrome (AIS, or "Androgen resistance syndrome") is a set of disorders of sexual differentiation that results from mutations of the gene encoding the androgen receptor.[1] It has also been called androgen resistance in the medical literature. The nature of the resulting problem varies according to the structure and sensitivity of the abnormal receptor. Most of the forms of AIS involve variable degrees of undervirilization and/or infertility in XY persons of either gender. A woman with complete androgen insensitivity syndrome (CAIS) has a female external appearance despite a 46XY karyotype and undescended testes, a condition termed testicular feminization in the past.

    Major changes in the understanding and management of the various forms of AIS have occurred since 1990. Laboratory research has greatly expanded our understanding of the molecular mechanisms of the clinical features, including a rare neuromuscular disorder. More importantly, patient advocacy groups for AIS and other intersex conditions have increased public awareness of these disorders, helped revise the understanding of gender identity, emphasized the value of accurate and sophisticated information for patients, and induced physicians to re-evaluate the effectiveness of the surgical corrections attempted in past decades. Surgery is increasingly seen as an elective option even for the more ambiguous conditions.
    Contents


    * 1 Incidence and genetics
    * 2 Normal function of androgens and the androgen receptor
    * 3 Defects in the androgen receptor
    o 3.1 Prenatal effects of testosterone in 46,XY fetus
    o 3.2 Early postnatal effects of testosterone in 46,XY infants
    o 3.3 Pubertal effects of testosterone in 46,XY children
    * 4 Problems produced by androgen insensitivity
    o 4.1 1. Complete AIS
    + 4.1.1 Natural history of CAIS
    + 4.1.2 Diagnostic circumstances of CAIS
    + 4.1.3 Aspects of medical treatment of CAIS
    + 4.1.4 Genetic counselling information
    + 4.1.5 A note on history and terminology
    o 4.2 2. Incomplete or partial AIS
    + 4.2.1 Another note on history and terminology
    o 4.3 3. Reifenstein syndrome
    + 4.3.1 Neonatal manifestations
    + 4.3.2 Diagnostic issues
    o 4.4 Aspects of management
    + 4.4.1 Yet another note on history and terminology
    o 4.5 4. Infertile male syndrome
    o 4.6 5. Undervirilized fertile male syndrome
    o 4.7 6. X-linked spinal and bulbar atrophy syndrome
    * 5 References
    * 6 External links

    Incidence and genetics

    The incidence of complete AIS is about in 1 in 20,000. The incidence of milder degrees of androgen resistance is not known and it has been suggested by various authorities that it might be both more common or less common than CAIS. Evidence suggests many cases of unexplained male infertility may be due to the mildest forms of androgen resistance.
    Schematic of AIS affecting an Androgen Receptor
    Schematic of AIS affecting an Androgen Receptor

    Because the Androgen Insensitivity Syndrome gives rise to ambiguity between the genetic and the phenotypic gender, we will use the convention 46,XY to designate a genotypic male, and 46,XX to designate a genotypic female. By this convention, a person with Androgen Insensitivity Syndrome is a 46,XY but a phenotypic female.

    The Androgen Insensitivity Syndrome has been linked to mutations in AR, the gene for the human Androgen Receptor, located at Xq11-12 (i.e. on the X chromosome). Thus, it is an X-linked recessive trait, causing minimal or no effects in 46,XX people.
    X-linked recessive inheritance.
    X-linked recessive inheritance.

    However, 46,XX women with a single mutated copy of the AR gene can be carriers of AIS, and their 46,XY children (male) will have a 50% chance of having the syndrome. As in some other X-linked recessive conditions, carrier mothers may display some minor traits of the condition: AIS carriers often have reduced axillary and pubic hair, and reduced normal adolescent acne.

    Except in the rare instance of a new mutation, a person affected with AIS has inherited his/her single X chromosome with the defective gene from his/her mother, who may have an affected sibling. Generally the condition caused by a familial mutation will affect family members similarly, though differing degrees of severity occasionally occur in different relatives with apparently the same mutation. Carrier testing is now available for relatives at risk when a diagnosis of AIS is made in a family member.

    Over 100 AR mutations causing various forms of AIS have been reported. In general, the milder types of AIS (4 and 5 in the list below) are caused by simple missense mutations with single codon/single amino acid difference, while CAIS and the nearly complete forms result from mutations that more severely affect the shape and structure of the protein. About one third of cases of AIS are new mutations rather than familial. A single case of CAIS attributed to an abnormality of the AF-1 coactivator (rather than AR itself) has been reported (OMIM 300274).

    Normal function of androgens and the androgen receptor

    Understanding the effects of androgen insensitivity begins with an understanding of the normal effects of testosterone in male and female development.[2] The principal mammalian androgens are testosterone and its more potent metabolite, dihydrotestosterone (DHT).

    The androgen receptor (AR) is a large protein of at least 910 amino acids. Each molecule consists of a portion which binds the androgen, a zinc finger portion that binds to DNA in steroid sensitive areas of nuclear chromatin, and an area that controls transcription.

    Testosterone diffuses from the circulation into the cytoplasm of a target cell. Some is metabolized to estradiol, some reduced to DHT, and some remains as testosterone (T). Both T and DHT can bind and activate the androgen receptor, though DHT does so with more potent and prolonged effect. As DHT (or T) binds to the receptor, a portion of the protein is cleaved. The AR-DHT combination dimerizes by combining with a second AR-DHT, both are phosphorylated, and the entire complex moves into the cell nucleus and binds to androgen response elements on the promoter region of androgen-sensitive target genes. The transcription effect is amplified or inhibited by coactivators or corepressors.

    Although testosterone can be produced directly and indirectly from ovaries and adrenals later in life, the primary source of testosterone in early fetal life is the testes, and it plays a major role in human sexual differentiation. Before birth, testosterone induces the primary sex characteristics of males. At puberty, testosterone is primarily responsible for the secondary sex characteristics of males.

    * See Testosterone article for fuller discussion of androgen sources and the role of testosterone in normal human development.
    * See Sexual differentiation for a brief but fuller overview of human sexual differentiation and biological sex differences.

    Defects in the androgen receptor

    The most common cause of AIS are point mutations in the androgen receptor gene resulting in a defective receptor protein which is unable to bind hormone or bind to DNA.[3]

    Prenatal effects of testosterone in 46,XY fetus

    In a normal fetus with a 46,XY karyotype, the presence of the SRY gene induces testes to form on the genital ridges in the fetal abdomen a few weeks after conception. By 6 weeks of gestation, genital anatomies of XY and XX fetuses are still indistinguishable, consisting of a tiny underdeveloped button of tissue able to become a phallus, and a urogenital midline opening flanked by folds of skin able to become either labia or a scrotum. By the 7th week, fetal testes begin to produce testosterone and release it into the blood.

    Directly and as DHT, testosterone acts on the skin and tissues of the genital area and by 12 weeks of gestation, has produced a recognizable male, with a growing penis with a urethral opening at the tip, and a perineum fused and thinned into a scrotum, ready for the testes. Evidence suggests that this "remodelling" of the genitalia can only occur during this period of fetal life; if not complete by about 13 weeks, no amount of testosterone later will move the urethral opening or close a vagina-like opening.

    For the remainder of gestation, the principal known effect of testosterone and DHT is continued growth of the penis and internal wolffian derivatives (part of prostate, epididymis, seminal vesicles, and vas deferens).

    Early postnatal effects of testosterone in 46,XY infants

    Testosterone levels are low at birth but rise within weeks, remaining at normal male pubertal levels for about 2 months before declining to the low, barely detectable childhood levels. The biological function of this rise is unknown. Animal research suggests a contribution to brain differentiation.

    Pubertal effects of testosterone in 46,XY children

    At puberty, many of the early physical changes in both sexes are androgenic (adult-type body odor, increased oiliness of skin and hair, acne, pubic hair, axillary hair, fine upper lip and sideburn hair).

    As puberty progresses, later secondary sex characteristics in males are nearly entirely due to androgens (continued growth of the penis, maturation of spermatogenic tissue and fertility, beard, deeper voice, masculine jaw and musculature, body hair, heavier bones). In males, the major pubertal changes attributable to estradiol are growth acceleration, epiphyseal closure, termination of growth, and (if it occurs) gynecomastia.

    Problems produced by androgen insensitivity

    Although many distinct mutations have been discovered, the clinical manifestations have been divided into six phenotypes, which roughly correspond to increasing amounts of androgen effect due to increasing tissue responsiveness. It should be emphasized that the disorders of androgen sensitivity represent a spectrum rather than 6 discrete diseases, and some affected persons will have features that fall between the phenotypes described.

    1. Complete AIS (CAIS): completely female body except no uterus, fallopian tubes or ovaries; testes in the abdomen; minimal androgenic (pubic or axillary) hair at puberty. OMIM 300068.

    2. Partial or incomplete AIS (PAIS): female body, with slightly virilized genitalia; testes in the abdomen; sparse to normal androgenic hair. Variant of OMIM 300068.

    3. Reifenstein syndrome: obviously ambiguous genitalia; small testes may be in abdomen or scrotum; sparse to normal androgenic hair; gynecomastia at puberty. OMIM 312300.

    4. Infertile male syndrome: normal male genitalia internally and externally; normal male body or possible female androgyny, normal virilization and androgenic hair; reduced sperm production; reduced fertility or infertility. OMIM 308370.

    5. Undervirilized fertile male syndrome: male internal and external genitalia with small penis; testes in scrotum; normal androgenic hair; sperm count and fertility normal or reduced. Variant of OMIM 312300.

    6. X-linked spinal and bulbar muscular atrophy: normal or nearly normal male body and fertility; exaggerated adolescent gynecomastia; adult onset degenerative muscle disease. OMIM 313200.

    OMIM (Online Mendelian Inheritance in Man) numbers are a genetic disease classification system available at the NCBI.

    1. Complete AIS

    People with CAIS are generally girls or women with internal testes, 46,XY karyotypes, and normal female bodies by external appearance except for some exceptions. The vagina is not as deep, and there are no ovaries or uterus— hence no menses or fertility. Gender identity is almost always female.

    Natural history of CAIS

    If a 46,XY fetus cannot respond to testosterone or DHT, only the non-androgenic aspects of male development begin to take place: formation of testes, production of testosterone and anti-müllerian hormone (AMH) by the testes, and suppression of müllerian ducts. The testes usually remain in the abdomen, or occasionally move into the inguinal canals but can go no further because there is no scrotum. AMH prevents the uterus and upper vagina from forming. The testes make male amounts of testosterone and DHT but no androgenic sexual differentiation occurs. Most of the prostate and other internal male genital ducts fail to form because of lack of testosterone action. A shallow vagina forms, surrounded by normally-formed labia. Phallic tissue remains small and becomes a clitoris. At birth, a child with CAIS appears to be a typical girl, with no reason to suspect an incongruous karyotype and testosterone level, or lack of uterus.

    Childhood growth is normal and the karyotypic incongruity remains unsuspected unless an inguinal lump is discovered to be a testis during surgical repair of an inguinal hernia, appendectomy, or other coincidental surgery.

    Puberty tends to begin slightly later than the average for girls. As the hypothalamus and pituitary signal the testes to produce testosterone, amounts more often associated with boys begin to appear in the blood. Some of the testosterone is converted into estradiol, which begins to induce normal breast development. Normal reshaping of the pelvis and redistribution of body fat occurs as in other girls. Little or no pubic hair or other androgenic hair appears, sometimes a source of worry or shame. Acne is rare.

    As menarche typically occurs about two years after breast development begins, no one usually worries about lack of menstrual periods until a girl reaches 14 or 15 years of age. At that point, an astute physician may suspect the diagnosis just from the breast/hair discrepancy. Diagnosis of complete AIS is confirmed by discovering an adult male testosterone level, 46,XY karotype, and a shallow vagina with no cervix or uterus.

    Hormone measurements in pubertal girls and women with CAIS and PAIS are similar, and are characterized by total testosterone levels in the upper male rather than female range, estradiol levels mildly elevated above the female range, mildly elevated LH levels, normal FSH levels, sex hormone binding globulin levels in the female range, and possibly mild elevation of AMH. DHT levels are in the normal male range in CAIS but reportedly in the lower male range in PAIS. Interpretation of hormone levels in infancy is more complex and cannot be as easily summarized for this article. Androgen receptor testing has become available commercially but is rarely needed for diagnosis of CAIS and PAIS.

    Adult women with CAIS tend to be taller than average, primarily because of their later timing of puberty. Breast development is said to be average to above average. Lack of responsiveness to androgen prevents some usual female adult hair development, including pubic, axillary, upper lip. In contrast, head hair remains fuller than average, without recession of scalp or thinning with age. Shallowness of the vagina varies and may or may not lead to mechanical difficulties during coitus. Although the testes develop fairly unexceptionally before puberty if not removed, the testes in adults with CAIS become increasingly distinctive, with unusual spermatogenic cells and no spermatogenesis.

    By clinical reports and information from support groups, women with CAIS are at least as likely as other women to have a female gender identity and to be attracted sexually to men.

    Diagnostic circumstances of CAIS

    Most cases of CAIS are diagnosed in the following circumstances.

    1. Prenatal amniocentesis discovers male karyotype not matched by ultrasound or obvious female appearance at birth.
    2. A lump in the inguinal canal is discovered to be a testis.
    3. Abdominal surgery done for repair of inguinal hernia, appendicitis or other reason discovers testes or lack of uterus and ovaries. Even in the absence of a visible inguinal lump, perhaps 1% of girls operated on for inguinal hernia are found to have AIS.
    4. Karyotype performed for unrelated purposes is found to be XY.
    5. The girl or family seeks evaluation for delayed menarche (primary amenorrhea).
    6. The woman seeks explanation for difficulty with sexual intercourse.
    7. The woman seeks explanation for infertility.

    Aspects of medical treatment of CAIS

    Accurate, sensitive explanation

    The need for explicit mention of such an obvious first step in the care of any disease reflects the difficulty felt by physicians in explaining testes to an adolescent girl, as well as the dissatisfactions with past medical care expressed by many women with CAIS.

    Counseling, referral to support network

    "Counseling" should be included in published recommendations for CAIS management. Many women with CAIS find value in making connections with others similarly affected. The internet now provides the simplest method of connecting with such support (AIS Support Group (AISSG)).

    Vaginal enlargement

    For women for whom vaginal shallowness is a problem, enlargement can be achieved by a prolonged course of self-dilation. Surgical construction of a vagina is sometimes performed for adults but carries its own potential problems.

    Gonadectomy decision

    Optimal timing of removal of the testes has been the management issue most often debated by physicians, though whether it is necessary has been questioned as well. The advantage of retaining the (usually intra-abdominal) testes until after puberty is that pubertal changes will happen "naturally," without hormone replacement. This happens because the testosterone produced by the testes gets converted to oestrogen in the body tissues (a process known as aromatisation).

    The primary argument for removal is that testes remaining in the abdomen throughout life may develop benign or malignant tumors and confer little benefit. The testicular cancer risk in CAIS appears to be higher than that which occurs with men whose testes have remained in the abdomen, and rare cases of testicular cancer occurring in adolescents with CAIS have been reported. Unfortunately the uncommonness of CAIS and the small numbers of women who have not had testes removed make cancer risk difficult to quantify. The best evidence suggests that women with CAIS and PAIS retaining their testes after puberty have a 25% chance of developing benign (harmless) tumors and a 4-9% chance of malignancy. It should be noted, however, that the risk of breast cancer in women as a whole is around 1 in 8 and yet clinicians do not remove the breasts of young girls/women on the off chance that they might develop cancer.

    There is also the issue of whether medical advances might enable tissue from testes in situ to be used with a donor egg to produce a child via IVF that is genetically related to the XY woman. This chance is lost for ever if the testes have been removed, unless they are preserved in some way. Apart from this, a significant number of CAIS women say that they never felt the same after gonadectomy as a young adult, that they lose their libido etc. Another benefit provided by testes in CAIS is the estradiol produced from testosterone. Although this can be provided pharmaceutically post-gonadectomy, many CAIS women have trouble adjusting to artificial HRT and regret losing their natural source of oestrogen.

    Estrogen replacement

    Once testes have been removed, estrogen needs to be taken in order to support pubertal development, bone development, and completion of growth. Among estrogen preparations available, transdermal patches are gaining in popularity. Since there is no uterus, progesterone is not considered necessary.

    Osteoporosis

    CAIS women appear to have a higher than average risk of thinning of the bones (osteoporosis) but possibly not with an associated tendency to increased fracture. The low bone density does not always relate to poor compliance with an HRT regimen or to the timing of gonadectomy. It has been speculated that the lack of androgen action might be a contributing factor since women with the partial form (PAIS) seem to fare better in this respect. More research is needed in this area.

    Genetic counselling information

    When a woman is diagnosed with CAIS or PAIS, referral to a genetic counselor may be warranted to explain the implications of the X-linked recessive inheritance.

    * The mother of the woman with AIS is likely to be an unaffected carrier of the gene on one of her X chromosomes.
    * A mother who carries the defect will, on average, pass it to 50% of her children, whether XX or XY. Those who are XX will be similarly unaffected carriers who can pass it to succeeding generations. Those who are XY will have the condition but, being infertile, cannot pass it.
    * If the family is large, other members can be found who have or carry AIS. Many women with AIS will be able to identify affected maternal relatives such as aunts or great aunts.
    * Carrier detection by gene testing is now possible.

    A small percentage of new cases of AIS are due to new, spontaneous mutations, and the above information about the family is not applicable. See the section above for more genetic details.

    A note on history and terminology

    Case reports compatible with CAIS date back to the 19th century, when hermaphroditism was the technical term for intersex conditions. In 1950, Lawson Wilkins hypothesized that this condition might be explained by resistance to testosterone but hormones could not be easily measured, and even chromosomes were just beginning to be understood. In 1953 J.C. Morris suggested the term testicular feminization, and by 1963 most of the essential pathophysiology of complete AIS was suspected. However, as the relationship with the partial forms became worked out in the 1980s, physicians began to prefer the less confusing and more comprehensive term androgen insensitivity. In the 1990s, patient advocacy groups also supported abandoning the term "testicular feminization," and it is now considered inaccurate, stigmatising and archaic.

    In an outcome study from one of the institutions (Johns Hopkins Hospital) with the greatest experience with this condition. Of 20 adult women seen in the clinic over the last 40 years with CAIS, 14 agreed to participate in a questionnaire and examination to assess long-term outcome. Most of the women agreed with delay of vaginal surgery until adolescence or later, and many felt inadequately informed about the details of their condition.[4]

    2. Incomplete or partial AIS

    As with CAIS, girls and women with PAIS also have a 46,XY karyotype, testes, and a female body lacking a uterus, ovaries and full vagina. However, the mutations associated with PAIS do not entirely eliminate all responsiveness to androgens, and mild testosterone effects occur.

    The most obvious testosterone effect seen in PAIS is pubic and axillary hair, which are usually normal. The clitoris may be enlarged, and the labia partially fused, though these features are usually not pronounced enough to cause noticeable ambiguity of the genitalia at birth, or may be subtle enough to be ascribed to normal anatomic variation. Internally, traces of undeveloped wolffian structures (epididymis, vas deferens, seminal vesicles, ejaculatory ducts) may be present.

    Circumstances of diagosis tend to be similar to those listed for CAIS, with the additional possibility that the mild differences of genital structure may elicit evaluation.

    Management issues for PAIS are virtually the same as for CAIS. Most women with PAIS do not seek genital reconstructive surgery for anatomic differences.

    Partial Androgen Insensitivity Syndrome manifests in a range of phenotypes ranging from almost normal male phenotype to typical female phneotype with certain differences from each other (Rajender et al., 2007). A thorough clinical experience is required to discriminate between the overlapping phenotypes in PAIS. Usually PAIS is assigned to one of the six phenotyps on PAIS scale:[5]

    PAIS-Grade 1: Represented by almost normal male genitals but infertility. PAIS-Grade 2: Represented by almost normal male genitals with mild undermasculinization and isolated hypospadias. PAIS-Grade 3: Predominantly male genitals,severely undermasculinized (undescended testis and/or bifid scrotum). PAIS-Grade 4: Ambiguous genitals, severely undermasculinized (Phallic structure that is intermediate between a penis and clitoris). PAIS-Grade 5: Female genitals including separate urinary and vaginal openings, and mild clitoromegaly. PAIS-Grade 6: Female Genitals with pubic/underarm hair.

    Another note on history and terminology

    In a biological sense, all other conditions (2,3,4,5,6) resulting from any degree of reduced but not absent androgen sensitivity might accurately be termed "partial" or "incomplete" AIS. However, it was not understood until the 1980s that Reifenstein syndrome and the other male problems described below were also due to androgen receptor mutations, and the term incomplete or partial androgen insensitivity syndrome (PAIS) had already been used for decades for the condition "almost" like CAIS.

    3. Reifenstein syndrome

    Androgen receptor mutations associated with more intermediate degrees of androgen responsiveness can result in more intermediate degrees of masculinization before birth and obvious ambiguity of the genitalia. Of the five clinical forms of AIS described here, this is the only one likely to result in uncertainty about a baby's sex at birth, and the most likely to be diagnosed in infancy. The clinical diagnostic and management problems are those common to many other intersex disorders. Puberty can produce secondary sex characteristics of both sexes, though not fertility as the spermatogenic tissue requires androgen support as well as scrotal location. The amounts of androgenic body hair and breast development are variable.

    Neonatal manifestations

    As described above, the testes of a 46,XY fetus produce AMH and testosterone. In Reifenstein syndrome, as in CAIS, PAIS, and normal males, the AMH suppresses development of a uterus, fallopian tubes, and upper vagina. However, unlike CAIS and PAIS, fetal testosterone has a significant effect on the external genitalia, producing a phallus smaller than a typical penis but larger than a typical clitoris. The labioscrotal folds are almost but not completely fused in the midline of the perineum, producing a small perineal pouch termed a "pseudovagina". Instead of being on the tip of the phallus, the urethra remains in this pseudovagina of the perineum (a position termed a 3rd degree hypospadias). The labioscrotal skin flanking the pseudovagina remains less prominent than labia but less thinned, rugated, and fused than a scrotum. The testes usually remain in the abdomen but occasionally can be felt in the inguinal canal. This genital configuration has traditionally been referred to as a pseudovaginal perineoscrotal hypospadias (PPSH) and can occur in other intersex conditions.

    Variants of Reifenstein syndrome occur with greater or less androgen sensitivity and correspondingly more or less genital masculinization. The common feature is that they have enough ambiguity that they are not simply assumed to be normal female infants, as is usual in CAIS and PAIS.

    This most obvious birth defect, somewhat midway between male and female, nearly always leads to referral to a pediatric endocrinologist and a full genetic, anatomic, and hormonal evaluation.

    Diagnostic issues

    Evaluation of neonatal ambiguity is described in more detail in the intersex article. It typically consists of pelvic ultrasound to determine presence or absence of uterus and gonads, karyotype, and measurement of testosterone, DHT, AMH, and one or more adrenal steroids. Commercial androgen receptor assays have recently become available.

    AIS is one of the more common forms of male undervirilization. Even after absence of the uterus and a 46,XY karyotype have been demonstrated, a number of other conditions, including Leydig cell hypoplasia, several uncommon defects of testosterone synthesis, and 5α-reductase deficiency which can produce similar genital Anatomy must be excluded.

    One of the most important aspects of evaluation of suspected AIS is the potential tissue responsiveness to testosterone, since future growth of the penis and other male secondary sex characteristics are dependent on it. After one or more injections of testosterone are given to the infant, measurable growth of the penis and noticeably increased erection frequency over the next two weeks suggests (though not infallibly) a capacity for further growth and virilization at puberty.

    Aspects of management

    The first major management decision is the sex of assignment: will the baby be a boy or girl? Assignment depends partly on predicting likely pubertal development, potential response of the phallus to testosterone, and likely outcome of surgical reconstruction attempts. The Reifenstein form of AIS can present one of the most challenging sets of decisions imaginable as parents and physicians try to choose the "least bad" of several undesirable options.

    * Male assignment is usually followed by one or more operations in infancy by a pediatric urologist to completely repair the hypospadias, close the midline pouch, and (if possible) place the testes in the scrotum. Gonadal status and potential testosterone responsiveness is reassessed around age 12. Breast tissue can be removed surgically in adolescence if excessive. Gonads should be removed if scrotal placement is impossible. High dose testosterone replacement will sometimes achieve further virilization. An advantage of this choice commonly cited by parents is consistency with karyotype. A survey of adults brought up this way reported that nearly all were comfortable with the gender assignment made at birth and the sexual function of their genitalia, but many were dissatisfied with the size.[citation needed]

    * Female assignment is usually followed by gonadectomy in childhood to prevent further masculinization, especially at puberty; sometimes by surgery to enlarge the vaginal opening and reduce clitoral size. Estrogen is replaced at puberty. This course has the advantage that future tissue sensitivity to testosterone is irrelevant for a girl.[citation needed] This course may involve fewer surgical procedures than male assignment and surgery, and may produce a better cosmetic outcome, but a higher percentage of women raised with early surgical repair describe impairment of sexual sensation or function.[citation needed]

    * A third option has been advocated in the last decade by some: to tentatively assign male or female sex but postpone all surgery until early adolescence. This approach is intended to make it easier for an adolescent to reject or confirm the gender assigned in infancy by parents and doctors, and to choose or refuse reconstructive surgery.[citation needed]

    Over the last 40–50 years, the second path, female assignment with reconstructive surgery in infancy, has been the course most often chosen by parents and physicians, and the hazards of this course are most familiar. Since 1997, male assignment with early surgery is increasing in popularity, and even the third course of delaying surgery is sometimes followed. Advantages and disadvantages of this course will become apparent over the next two decades. See the intersex article for more detail on this important management shift.

    Yet another note on history and terminology

    One might fairly call Reifenstein syndrome "even more partial" AIS, but when E.C. Reifenstein described the features of a new syndrome of male "familial hypogonadism" in 1947, it was not known that this condition was due to an abnormal androgen receptor and related to the female conditions of CAIS or PAIS. Additional familial intersex and hypogonadal conditions described by Lubs, Gilbert, Dreyfus, Rosewater, Walker, and others are now considered variants of the Reifenstein syndrome form of AIS.

    4. Infertile male syndrome

    Androgen receptor mutations have also been discovered in men with normal internal and external genitalia but infertility due to absence of sperm (azoospermia). Androgenic body hair is normal and gynecomastia uncommon. Some have mildly elevated testosterone and LH levels but this is not invariable. Several surveys suggest that androgen receptor mutations can be found in 30-40% of men with infertility due to otherwise unexplained oligospermia or azoospermia. AIS may also explain most cases of a rarer form of male infertility, the Del Castillo or Sertoli-cell-only syndrome.

    5. Undervirilized fertile male syndrome

    Some AR mutations with mildly reduced sensitivity cause mild undervirilization. These men have normally formed internal and external genitalia but a small penis. Androgenic body hair may be sparser than unaffected relatives. Ejaculate volume may be reduced, though sperm density is normal. Few examples of this variant of AIS have been reported, but unlike the previously listed phenotypes, many of these men are fertile.

    6. X-linked spinal and bulbar atrophy syndrome

    Kennedy disease is an X-linked spinal-bulbar muscle atrophy syndrome associated with mutations of the androgen receptor. Like the other forms of AIS described above, it affects only males.

    Since the neuromuscular disease was first described in 1968 many kindreds have been reported. Ages of onset and severity of manifestations in affected males vary from adolescence to old age, but most commonly develop in middle adult life. Early signs often include weakness of tongue and mouth muscles, fasciculations, and gradually increasing weakness of proximal limb muscles. In some cases, premature muscle exhaustion began in adolescence. Neuromuscular management is supportive, and the disease progresses very slowly and often does not lead to extreme disability.

    Endocrine manifestations of this disorder are variable and only rarely include undervirilization of internal or external genitalia. In the majority evidence of altered androgen sensitivity is restricted to exaggerated or persistent adolescent gynecomastia, and the mildly high LH, testosterone, and estradiol levels characteristic of other forms of AIS. In other words, most people affected with Kennedy disease are relatively normal XY men with normal fertility and normal or minimally reduced virilization.

    The distinctive AR mutation of Kennedy disease, reported in 1991, involves multiplied CAG repeats in the first exon. The mechanism by which this type of mutation causes neuromuscular disease, while complete insensitivity does not, is not yet understood.
  29. Dr. Tara

    Dr. Tara Guest

    Q which of the following is true about diagnosis of ectopic pregnancy
    a) TVS
    b) cudocentesis
    c) serial hcg

    ans TVS
  30. Dr. Tara

    Dr. Tara Guest

    .11What is true about Histoplasmosis?
    a)in early stages it is indistinguishable from TB
    b)Blood culture is not diagnostic
    c)Hyphal forms are infectious form
    d)antibody detection is useful in early stages

    ans is a)in early stages it is indistinguishable from TB

    REF: Robbins/7th ed/page no.754

    As this Q was a direct pick from robbins.I am quoting exact lines from robbins:


    Histoplasma capsulatum infection is acquired by inhalation of dust particles from soil contaminated with bird or bat droppings that contain small spores(microconidia),the infectious form of the fungus(NOT HYPHAL FORM,OPTION C).
    The clinical presentation & morphologic lesions of histoplasmosis strikingly resembles those of TB(OPTION A).



    The diagnosis of histoplasmosis is firmly established by culture of the fungus(OPTION B)
    Antigen detection in body fluids is most useful in early stages because antibodies are formed 2-6 wk after infection(OPTION D)
  31. Dr. Tara

    Dr. Tara Guest

    steroid receptors bind to a/e:
    a) steroid hormones
    b) transcription repressors
    c) transcription enhancers
    d) hormone response elements

    Ans: (b) transcription repressors....most probably
    Ref: Harper's 25th (Pg- 536-537..Chapter 44)

    If we look at diagram on Pg 537, u will see that Steroid receptor & hormone both bind to HRE..so steroid receptor is definitely binding to it.

    Pg- 536 says that HRE resembles transcription enhancer elements found in other genes

    Steroids definitely bind to steroid receptors..guess no need for reference on that one.
  32. Dr. Tara

    Dr. Tara Guest

    chloroma, or granulocytic sarcoma, or most appropriately, extramedullary myeloid tumor, is a solid tumor composed of immature malignant white blood cells called myeloblasts. A chloroma is an extramedullary manifestion of acute myeloid leukemia; in other words, it is a solid collection of leukemic cells occurring outside of the bone marrow.


    diagnosis of chloroma

    Diagnosis

    Definitive diagnosis of a chloroma usually requires a biopsy of the lesion in question. Historically, even with a tissue biopsy, pathologic misdiagnosis was an important problem, particularly in patients without a clear pre-existing diagnosis of acute myeloid leukemia to guide the pathologist. In one published series on chloroma, the authors stated that 47% of the patients were initially misdiagnosed, most often as having a malignant lymphoma.[7]

    However, with advances in diagnostic techniques, the diagnosis of chloromas can be made more reliable. Traweek et al. described the use of a commercially available panel of monoclonal antibodies, against myeloperoxidase, CD68, CD43, and CD20, to accurately diagnose chloroma via immunohistochemistry and differentiate it from lymphoma.[8] Nowadays, immunohistochemical staining using monoclonal antibodies against CD34 and CD117 would be the mainstay of diagnosis. The increasingly refined use of flow cytometry has also facilitated more accurate diagnosis of these lesions.

    devita p2256
    B. Commonly used markers for flow immunophenotyping in acute leukemia:
    General: CD34, HLA-DR, TdT, CD45
    B-cell markers: CD10, CD19, cCD22, CD20, CD79A, CD24
    T-cell markers: CD1a, CD2, cCD3, CD4, CD8, CD5, CD7
    Myeloid: MPO, CD117, CD13, CD33, CD11c, CD14, CD15
    C. B-lineage acute lymphoblastic leukemia


    devita p2381

    Patients with predominant abdominal masses and a diagnosis of carcinoma or sarcoma (particularly leiomyosarcoma) of unknown primary site should have their biopsy specimen stained for c-kit (CD117).
  33. Dr. Tara

    Dr. Tara Guest

    As compared to embryo adult cell does not divide bcoz?

    a. CDK inhibitors are present in adults which prevents cell from entering in s phase
    ?
    Ans is CDK inhibitors are present in adults which prevents cell from entering in s phase
  34. Dr. Tara

    Dr. Tara Guest

    Rituximab is used in a/e?

    A.NHL
    B.PNH
    C.RA
    D.SLE

    Ans B.PNH

    REF:goodman & gilman/10th ed/p.1444,
    Harrison/16th ed/p.482,net ref= http://en.wikipedia.org/wiki/Rituximab

    Rituximab, sold under the trade names Rituxan and MabThera, is a chimeric monoclonal antibody used in the treatment of B cell non-Hodgkin's lymphoma, B cell leukemia, and some autoimmune disorders.

    Uses
    Rituximab depletes B cells, and therefore is used to treat diseases which are characterized by having too many B cells, overactive B cells or dysfunctional B cells.
    Neoplastic diseases
    Most patients taking rituximab have a neoplastic disease such as leukemia or lymphoma.
    Autoimmune diseases
    Rituximab has been shown to be an effective rheumatoid arthritis treatment in three randomised controlled trials and is now licensed for use in refractory rheumatoid disease.[2] (FDA-approved for use in combination with methotrexate (MTX) for reducing signs and symptoms in adult patients with moderately- to severely-active rheumatoid arthritis (RA) who have had an inadequate response to one or more anti-TNF-alpha therapies.) There is evidence for efficacy in a range of other autoimmune diseases, including idiopathic autoimmune hemolytic anemia, Pure red cell aplasia, idiopathic thrombocytopenic purpura (ITP)[3][4], Evans syndrome[5], vasculitis, multiple sclerosis,[6] [bleep] skin disorders (for example pemphigus, pemphigoid), type 1 diabetes mellitus, Sjogren's syndrome, Devic's Syndrome and systemic lupus erythematosus, although there are significant concerns about PML infection in SLE patients
  35. Dr. Raina

    Dr. Raina Guest

    Villous adenomata arise mainly in the rectum and the rectosigmoid, with equal sex distribution, usually in persons over the age of 50 years.2 Malignancy is a common complication in these tumours and multiple histological sections may be required to exclude this possibility in any given patient. Diarrhoea of varying duration (3 months to 15 years) and volume (0.3-3.4 l/24 h) is commonly seen with these tumours; an average of 120, 44 and 123 mmol/l of sodium (range 40-120), potassium (range 15-107) and chloride (80-163), respectively, has been described in the faecal fluid.3 Vague abdominal pain, anorexia, weight loss, excessive thirst, nausea and vomiting may have been present for some time prior to total collapse.1 Not all of these tumours produce fluid and electrolyte depletion4 but those that do may cause marked dehydration, lethargy, weakness, oliguria, metabolic acidosis, mental confusion, and hypotension. Ability to compensate for loss of fluid and electrolytes may extend over many years until the tumour enlarges sufficiently, intake is decreased or fluid loss increased to the point that compensatory mechanisms become ineffectual; inability to compensate may develop rapidly and dramatically, the previously asymptomatic patient presenting as an emergency.1 Symptoms such as rectal bleeding, change in bowel habit, tenesmus, prolapse of the tumour, and elimination of tumour tissue have also been described.1 Lesions can be overlooked on rectal palpation because of their softness or a more proximal location. These tumours are usually single and located within reach of a sigmoidoscope, as was the case in our patient, although multiple and more proximal lesions have been described.5 Typically the tumour arises in the rectum, is sessile, reddish-grey, bulky and may involve the entire circumference of the bowel. Barium enema studies are helpful, as seen in our patient, in outlining the extent of the lesions as well as establishing the presence or absence of multiple lesions. Definitive diagnosis must be confirmed by histological examination.5 6 Lack of awareness has been credited with fatal outcome, up to 20% in some series1 3; such fatal outcome is invariably secondary to the incomplete correction of fluid and electrolyte imbalance produced by these tumours. Complete excision of the lesion with a margin of normal tissue is curative and the treatment of choice in benign lesions. If the tumour is shown to be malignant, the type of surgery should be the same as for any other carcinoma of colon or rectum.



    REFERENCE IS:http://pmj.bmj.com/cgi/content/full/75/881/185
  36. Dr. Raina

    Dr. Raina Guest

    Q on G protein was
    which is true about g protein
    a. g protein acts as inhibitory and excietatory as alpha subunit exists in two forms
    b. GTP binds to G protein in resting state
    c. all the three subunits alpha, beta, gamma should bind to eachother for g protein to act
    d. G protien binds to hormone on cell surface

    Ans: a.. G protein acts as inhibitory and excietatory as alpha units exist in two forms.

    Dragonlivesforever CAN U PLEASE QUOTE A REF FOR YOUR ANSWER

    Ref Biochemistry by Stayanarayan2001 edition pg 471 ( Chapter on hormones)
    'Adenylate cyclase system
    A series of events occur at the membrane level that influence the activity of adenylate cyclase leading to the synthesis of cAMP. The process is mediated by G proteins. The mechanism of cAmp sysnthesis is briefly described here
    1. The hormone (Hs) binds to a stimulatory receptor (Rs) on the membrane which in turn stimulates the G protein (Gs)2. The G protein is a trimer consisting of α, β, γ subunits (45, 37 and 7 KD respectively). The α subunit is in a bound form to GDP in the native G protein structure.
    3. The hormone receptor complex causes exchange of GDP with GTP on α subunit and dissociates it from Gβγ. The resultant α subunit bound to GTP stimulates (hence called αs ) the adenylate cyclase.
    4. ATP is converted to cAMP by activated adenylate cyclase.
    5. The GTP bound to αs is hydrolysed to GDP and this αs-GDP combines with Gβγ to regenerate the original G α, β, γ proteins.
    6. Some hormones inhibit (Hi) the adenylate cyclase activity. This effect is mediated through inhibitory G proteins (Gi). The structure of β and γ subunits of Gi is similar to that of G protein with stimulatory effect (Gs). However, α subunit (Gαi) differs in structure with a molecular weight of 41,000.
    The dissociation of inhibitory G protein and role of GTP in releasing αi is almost similar to that described above for αs. The striking difference is that αi inhibits adenylate cyclase activity.
    It therefore appears that there are 2 families of G proteins- stimulatory and inhibitory- through which the hormones affecting adenylate cyclase act.'
  37. Dr. Raina

    Dr. Raina Guest

    Causes of Metabolic Acidosis

    High anion gap

    Ketoacidosis (diabetes, chronic alcoholism, malnutrition, fasting)

    Lactic acidosis

    Renal failure

    Toxins metabolized to acids

    Methanol (formate)

    Ethylene glycol (oxalate)

    Paraldehyde (acetate, chloracetate)

    Salicylates

    Toxins causing lactic acidosis

    CO2

    Cyanide

    Iron

    Isoniazid Some Trade Names
    INH
    NYDRAZID
    Click for Drug Monograph

    Toluene (initially high gap, subsequent excretion of metabolites normalizes gap)

    Rhabdomyolysis (rare)

    Normal anion gap (hyperchloremic acidosis)

    GI HCO3 − loss (diarrhea, ileostomy, colostomy, enteric fistulas, use of ion-exchange resins)

    Ureterosigmoidostomy, ureteroileal conduit

    Renal HCO3 − loss

    Tubulointerstitial renal disease

    Renal tubular acidosis, types 1, 2, 4

    Hyperparathyroidism

    Ingestions ( acetazolamide Some Trade Names
    DIAMOX
    Click for Drug Monograph
    , CaCl2, MgSO4) Others

    Hypoaldosteronism

    Hyperkalemia

    Parenteral infusion of arginine Some Trade Names
    R-GENE
    Click for Drug Monograph
    , lysine, NH4Cl

    Rapid NaCl infusion

    Toluene (late)


    http://www.merck.com/mmpe/sec12/ch157/ch157c.html
  38. Dr. Raina

    Dr. Raina Guest

    THER WAS A QUESTION ABOUT A LADY WITH PREVIOUS C/S,PRESENTED IN LABOR WITH HEMATURIA
    A.SCAR RUPTURE
    B.CYSTITIS
    C..
    D..

    ANS-SCAR RUPTURE
  39. Dr. Raina

    Dr. Raina Guest

    Indian reference- man a/e:
    a) 60Kg
    b) spends 8 hrs in bed
    c) 20-39 years
    d) consumes 2200Kcal/day

    Ans: (d) consumes...
    Ref: Park18th (Pg-457)

    1)weighs 60 kg
    2)spends 8hrs in bed, 4-6 hrs sitting & moving around and 2 hrs in walking & in active recreation or household duties
    3)20-39 years
    4)free from disease & physically fit for active work
    on each working day, employed for 8 hrs that involves moderate activity
  40. R. Saha

    R. Saha Guest

    condition which causes choroidal neovascularisation,all except
    a.angiod streak
    b.myopia
    c.hypermetropia

    ANS-HYPERMETROPIA


    Neovascularization, Choroidal


    Virtually any pathologic process that involves the RPE and damages the Bruch membrane can be complicated by CNV.



    Degenerative conditions


    ARMD

    Myopia

    Angioid streaks

    Inflammatory or infectious conditions


    Histoplasmosis

    Sarcoidosis

    Multifocal choroiditis

    PIC

    Choroidal tumors


    Nevi

    Melanoma

    Hemangioma

    Osteoma

    Trauma


    Choroidal rupture

    Laser photocoagulation

    Idiopathic
  41. Sanjay.

    Sanjay. Guest

    Liver transplant

    Introduction

    A liver transplant is surgery to remove an unhealthy liver from the body and replace it with a healthy liver from a donor. The donor liver is usually from a person who has died, but has given permission for their organs to be donated. This is called orthotopic liver transportation.

    It is also possible for a living person to donate part of their liver for transplant. This is known as a living donor transplant or split-liver transplant, and is a less common form of liver transplant. It can be used to make new liver tissue in the unhealthy liver, as it will help the growth of new liver cells.

    The first liver transplant was carried out in 1963. There are currently around 650 liver transplants every year in the UK.

    Most people who have a liver transplant take around three months to recover, but then have a full and active life. Many will have to take drugs for the rest of their lives to ensure that their body does not reject the replacement liver.
  42. Sanjay.

    Sanjay. Guest

    ISTINCTIVE PHENOTYPIC EFFECTS

    •
    Nose hypoplasia in Warfarin-exposed
    •
    Ear malformations in retinoic acid (Accutane)-exposed
    •
    Severe nail hypoplasia and fused interphalangeal joints in phenytoin-exposed
    •
    Vascular disruption defects in CVS-exposed and misoprostol-exposed
  43. Sanjay.

    Sanjay. Guest

    Steroid hormone receptor

    Steroid hormone receptors are intracellular receptors (typically cytoplasmic) that perform signal transduction for steroid hormones. Steroid hormone receptors are part of the nuclear receptor family that include a group of homologous structured receptors (type II receptors) that bind to non-steroid ligands such as thyroid hormones and vitamin A, as well as to vitamin D, and orphan receptors. All these receptors are transcription factors. Depending upon the steroid hormone that they bind, they are either located in the cytosol and move to the cell nucleus upon activation, or spend their life in the nucleus waiting for the the steroid hormone to enter and activate them. This uptake into the nucleus has to do with Nuclear Localization Signals (NLS) found in a region of the receptor. In most cases this signal is covered up by heat shock proteins which bind the receptor until the hormone is present. Upon binding by the hormone the receptor undergoes a conformational change, the heat shock proteins come off, and the receptor together the with bound hormone enter the nucleus to act upon transcription.

    Contents


    * 1 Types
    * 2 Structure
    * 3 Functioning
    * 4 Action on DNA
    * 5 See also
    * 6 References
    * 7 External links

    Types

    * Type I Receptors
    o Sex hormone receptors (sex hormones)
    + Androgen receptor
    + Estrogen receptor
    + Progesterone receptor
    o Glucocorticoid receptor (glucocorticoids)
    o Mineralocorticoid receptor (mineralocorticoids)
    * Type II Receptors
    o Vitamin A receptor (Vitamin A)
    o Vitamin D receptor (Vitamin D)
    o Retinoid receptor
    o Thyroid hormone receptor
    * Orphan receptors

    Structure

    Steroid hormone receptors share a common structure of four units that are functionally homologous, so-called "domains":

    1. Variable domain: It begins at the N-terminal and is the most variable domain between the different receptors.
    2. DNA binding domain: This centrally located highly conserved DNA binding domain (DBD) consists of two non-repetitive globular motifs (PDB: 1HCQ) where zinc is coordinated with four cysteine and no histidine residues. Their secondary and tertiary structure is distinct from that of classic zinc fingers.[1] This region controls which gene will be activated. On DNA it interacts with the hormone response element (HRE).
    3. Hinge region: This area controls the movement of the receptor to the nucleus.
    4. Hormone binding domain: The moderately conserved ligand-binding domain (LBD) can include a nuclear localization signal, amino-acid sequences capable of binding chaperones and parts of dimerization interfaces. Such receptors are closely related to chaperones (namely heat shock proteins hsp90 and hsp56), which are required to maintain their inactive (but receptive) cytoplasmic conformation. At the end of this domain is the C-terminal. The terminal connects the molecule to its pair in the homodimer or heterodimer. It may affect the magnitude of the response.

    Only type I receptors have a heat shock protein (hsp) associated with the inactive receptor that will be released when the receptor interacts with the ligand. Type I receptors may be found in homodimer or heterodimer forms. Type II receptors have no hsp, and in contrast to the classical type I receptor are located in the cell nucleus.

    There is some evidence that certain steroid hormone receptors can extend through lipid bilayer membranes at the surface of cells and might be able to interact with hormones that remain outside of cells.[2]

    Steroid hormone receptors can also function outside of the nucleus and couple to cytoplasmic signal transduction proteins such as PI3k and Akt kinase.[3]

    Functioning

    Free (that is, unbound) steroids enter the cell cytoplasm and interact with their receptor. In this process heat shock protein is dissociated, and the activated receptor-ligand complex is translocated into the nucleus.

    After binding to the ligand (steroid hormone), steroid receptors often form dimers. In the nucleus the complex acts as transcription factors, augmenting or suppressing transcription of particular genes by its action on DNA. As a result messenger RNA is produced that exits the nucleus and interacts with ribosomes. There, after translation of the genetic message, specific proteins are produced. These specific proteins perform a biological task.

    Type II receptors are located in the nucleus. Thus their ligands pass through the cell wall and cytoplasm and enter the nucleus, where they activated the receptor without release of hsp. The activated receptor interacts with the hormone response element, and the transcription process is initiated as with type I receptors.

    Action on DNA

    The hormone response elements (HRE) for steroid hormone receptors are DNA sequences with the structure of a pair of palindrome or tandem sequences often separated by three nucleotides. These elements resemble each other in their length and arrangement but differ in their sequences.

    A given hormone-receptor complex's ability to cause a change in the expression of the gene it regulates depends on the specific HRE sequence, the distance of HRE from the gene and the number of HRE affecting the gene.[4]

    The biological response is influenced by the amount of hormones available, the available receptor population, the dissociation rate of the hormone-receptor complex with the specific DNA site, and the replenishment of the receptor population.
  44. Sanjay.

    Sanjay. Guest

    IN ULCERATIVE COLITIS THERE IS

    a)crypt loss
    b)cryptitis
    c)crypt abcess
    -----------------------------------------

    The Pathology in ulcerative colitis typically involves distortion of crypt architecture, inflammation of crypts (cryptitis), frank crypt abscesses, and hemorrhage or inflammatory cells in the lamina propria. In cases where the clinical picture is unclear, the histomorphologic analysis often plays a pivotal role in determining the management.


    -----------------------------------------
    Ulcerative colitis
    From Wikipedia, the free encyclopedia
    • Ten things you may not know about images on Wikipedia •
    Jump to: navigation, search
    Ulcerative colitis
    Classification and external resources
    Endoscopic image of a sigmoid colon afflicted with ulcerative colitis. Note the vascular pattern of the colon granularity and focal friability of the mucosa.
    ICD-10 K51.
    ICD-9 556
    OMIM 191390
    DiseasesDB 13495
    MedlinePlus 000250
    eMedicine med/2336
    MeSH D003093

    Ulcerative colitis (Colitis ulcerosa, UC) is a form of inflammatory bowel disease (IBD). Ulcerative colitis is a form of colitis, a disease of the intestine, specifically the large intestine or colon, that includes characteristic ulcers, or open sores, in the colon. The main symptom of active disease is usually diarrhea mixed with blood, of gradual onset. Ulcerative colitis is, however, a systemic disease that affects many parts of the body outside the intestine. Because of the name, IBD is often confused with irritable bowel syndrome ("IBS"), a troublesome, but much less serious condition. Ulcerative colitis has similarities to Crohn's disease, another form of IBD. Ulcerative colitis is an intermittent disease, with periods of exacerbated symptoms, and periods that are relatively symptom-free. Although the symptoms of ulcerative colitis can sometimes diminish on their own, the disease usually requires treatment to go into remission.

    Ulcerative colitis is a fairly common disease, with an incidence of about one person per 600 in the United States[citation needed]. The disease tends to be more common in northern areas. Although ulcerative colitis has no known cause, there is a presumed genetic component to susceptibility. The disease may be triggered in a susceptible person by environmental factors. Although dietary modification may reduce the discomfort of a person with the disease, ulcerative colitis is not thought to be caused by dietary factors. Although ulcerative colitis is treated as though it were an autoimmune disease, there is no consensus that it is such. Treatment is with anti-inflammatory drugs, immunosuppression, and biological therapy targeting specific components of the immune response. Colectomy (partial or total removal of the large bowel through surgery) is occasionally necessary, and is considered to be a cure for the disease.

    Contents


    * 1 Causes
    o 1.1 Genetic factors
    o 1.2 Environmental factors
    o 1.3 Autoimmune disease
    o 1.4 Alternative theories
    * 2 Epidemiology
    * 3 Clinical presentation
    o 3.1 GI symptoms
    + 3.1.1 Extent of involvement
    + 3.1.2 Severity of disease
    o 3.2 Extraintestinal features
    o 3.3 Similar conditions
    o 3.4 Comparison to Crohn's Disease
    * 4 Diagnosis and workup
    o 4.1 General
    o 4.2 Endoscopic
    o 4.3 Histologic
    * 5 Course and complications
    o 5.1 Progression or remission
    o 5.2 Ulcerative colitis and colorectal cancer
    o 5.3 Primary sclerosing cholangitis
    o 5.4 Mortality
    * 6 Treatment
    o 6.1 Drugs used
    + 6.1.1 Aminosalicylates
    + 6.1.2 Corticosteroids
    + 6.1.3 Immunosuppressive drugs
    + 6.1.4 Biological treatment
    o 6.2 Surgery
    o 6.3 Alternative treatments
    + 6.3.1 Smoking
    + 6.3.2 Dietary modification
    + 6.3.3 Fats and oils
    + 6.3.4 Herbals
    + 6.3.5 Bacterial recolonization
    + 6.3.6 Intestinal parasites
    * 7 Ongoing research
    * 8 See also
    * 9 External links
    * 10 References

    Causes

    While the cause of ulcerative colitis is unknown, several, possibly interrelated, causes have been suggested.

    Genetic factors

    A genetic component to the etiology of ulcerative colitis can be hypothesized based on the following:

    * Aggregation of ulcerative colitis in families.
    * Identical twin concordance rate of 10% and dizygotic twin concordance rate of 3%
    * Ethnic differences in incidence
    * Genetic markers and linkages

    There are 12 regions of the genome which may be linked to ulcerative colitis. This includes chromosomes 16, 12, 6, 14, 5, 19, 1, 16, and 3 in the order of their discovery. However, none of these loci has been consistently shown to be at fault, suggesting that the disorder arises from the combination of multiple genes. For example, chromosome band 1p36 is one such region thought to be linked to inflammatory bowel disease. Some of the putative regions encode transporter proteins such as OCTN1 and OCTN2. Other potential regions involve cell scaffolding proteins such as the MAGUK family. There are even HLA associations which may be at work. In fact, this linkage on chromosome 6 may be the most convincing and consistent of the genetic candidates.

    Multiple autoimmune disorders have been recorded with the neurovisceral and cutaneous genetic porphyrias including ulcerative colitis, Crohn's disease, celiac disease, dermatitis herpetiformis, systemic and discoid lupus, rheumatoid arthritis, ankylosing spondylitis, scleroderma, Sjogren's disease and scleritis. Physicians should be on high alert for porphyrias in families with autoimmune disorders and care must be taken with potential porphyrinogenic drugs, including sulfasalazine.

    Environmental factors

    Many hypotheses have been raised for environmental contributants to the pathogenesis of ulcerative colitis. They include the following:

    * Diet: as the colon is exposed to many different dietary substances which may encourage inflammation, dietary factors have been hypothesized to play a role in the pathogenesis of both ulcerative colitis and Crohn's disease. There have been few studies to investigate such an association, but one study showed no association of refined sugar on the prevalence of ulcerative colitis.
    * Diet: A diet low in fermentable dietary fiber may affect ulcerative colitis incidence.
    * Breastfeeding: There have been conflicting reports of the protection of breastfeeding in the development of inflammatory bowel disease. One Italian study showed a potential protective effect.
    * Other childhood exposures, or infections[citation needed]

    Autoimmune disease

    Some sources list ulcerative colitis as an autoimmune disease, a disease in which the immune system malfunctions, attacking some part of the body. As discussed above, ulcerative colitis is a systemic disease that affects many areas of the body outside the digestive system. Surgical removal of the large intestine often cures the disease, including the manifestations outside the digestive system. This suggests that the cause of the disease is in the colon itself, and not in the immune system or some other part of the body.

    Alternative theories

    Levels of sulfate-reducing bacteria tend to be higher in persons with ulcerative colitis. This could mean that there are higher levels of hydrogen sulfide in the intestine. An alternative theory suggests that the symptoms of the disease may be caused by toxic effects of the hydrogen sulfide on the cells lining the intestine. It may be caused occlusions in the capillaries of the subepithelial linings, degenerated fibers beneath the mucosa and infiltration of the lamina propria with plasma cells

    Epidemiology

    The incidence of ulcerative colitis in North America is 10-12 cases per 100,000, with a peak incidence of ulcerative colitis occurring between the ages of 15 and 25. There is thought to be a bimodal distribution in age of onset, with a second peak in incidence occurring in the 6th decade of life. The disease affects females more than males.

    The geographic distribution of ulcerative colitis and Crohn's disease is similar worldwide, with highest incidences in the United States, Canada , the United Kingdom, and Scandinavia. Higher incidences are seen in northern locations compared to southern locations in Europe and the United States.

    As with Crohn's disease, ulcerative colitis is thought to occur more commonly among Ashkenazi Jewish people than non-Jewish people.

    Clinical presentation

    GI symptoms

    The clinical presentation of ulcerative colitis depends on the extent of the disease process. Patients usually present with diarrhea mixed with blood and mucus, of gradual onset. They also may have signs of weight loss, and blood on rectal examination. The disease is usually accompanied with different degrees of abdominal pain, from mild discomfort to severely painful cramps.

    Ulcerative colitis is a systemic disease that affects many parts of the body. Sometimes the extra-intestinal manifestations of the disease are the initial signs, such as painful, arthritic knees in a teenager. It is, however, unlikely that the disease will be correctly diagnosed until the onset of the intestinal manifestations.

    Extent of involvement

    Diagram of the Human Intestine
    Diagram of the Human Intestine

    Ulcerative colitis is normally continuous from the rectum up the colon. The disease is classified by the extent of involvement, depending on how far up the colon the disease extends:

    * Distal colitis, potentially treatable with enemas:
    o Proctitis: Involvement limited to the rectum.
    o Proctosigmoiditis: Involvement of the rectosigmoid colon, the portion of the colon adjacent to the rectum.
    o Left-sided colitis: Involvement of the descending colon, which runs along the patient's left side, up to the splenic flexure and the beginning of the transverse colon.
    * Extensive colitis, inflammation extending beyond the reach of enemas:
    o Pancolitis: Involvement of the entire colon, extending from the rectum to the cecum, beyond which the small intestine begins.

    Severity of disease

    In addition to the extent of involvement, UC patients may also be characterized by the severity of their disease.

    * Mild disease correlates with fewer than four stools daily, with or without blood, no systemic signs of toxicity, and a normal erythrocyte sedimentation rate (ESR). There may be mild abdominal pain or cramping. Patients may believe they are constipated when in fact they are experiencing tenesmus, which is a constant feeling of the need to empty the bowel accompanied by involuntary straining efforts, pain, and cramping with little or no fecal output. Rectal pain is uncommon.

    Colonic pseudopolyps of a patient with intractable ulcerative colitis. Colectomy specimen.
    Colonic pseudopolyps of a patient with intractable ulcerative colitis. Colectomy specimen.

    * Moderate disease correlates with more than four stools daily, but with minimal signs of toxicity. Patients may display anemia (not requiring transfusions), moderate abdominal pain, and low grade fever, 38 to 39 °C (99.5 to 102.2 °F).

    * Severe disease, correlates with more than six bloody stools a day, and evidence of toxicity as demonstrated by fever, tachycardia, anemia or an elevated ESR.

    * Fulminant disease correlates with more than ten bowel movements daily, continuous bleeding, toxicity, abdominal tenderness and distension, blood transfusion requirement and colonic dilation (expansion). Patients in this category may have inflammation extending beyond just the mucosal layer, causing impaired colonic motility and leading to toxic megacolon. If the serous membrane is involved, colonic perforation may ensue. Unless treated, fulminant disease will soon lead to death.

    Extraintestinal features

    As ulcerative colitis is a systemic disease, patients may present with symptoms and complications outside the colon. These include the following:
    Patients with ulcerative colitis can occasionally have aphthous ulcers involving the tongue, lips, palate and pharynx
    Patients with ulcerative colitis can occasionally have aphthous ulcers involving the tongue, lips, palate and pharynx

    * aphthous ulcers of the mouth
    * Ophthalmic (involving the eyes):
    o Iritis or uveitis, which is inflammation of the iris
    o Episcleritis
    * Musculoskeletal:
    o Seronegative arthritis, which can be a large-joint oligoarthritis (affecting one or two joints), or may affect many small joints of the hands and feet
    o Ankylosing spondylitis, arthritis of the spine
    o Sacroiliitis, arthritis of the lower spine
    * Cutaneous (related to the skin):
    o Erythema nodosum, which is a panniculitis, or inflammation of subcutaneous tissue involving the lower extremities
    o Pyoderma gangrenosum, which is a painful ulcerating lesion involving the skin
    * Deep venous thrombosis and pulmonary embolism
    * Autoimmune hemolytic anemia
    * clubbing, a deformity of the ends of the fingers
    * Primary sclerosing cholangitis, or inflammation of the bile ducts

    Similar conditions

    Endoscopic image of ulcerative colitis affecting the left side of the colon. The image shows confluent superficial ulceration and loss of mucosal architecture. Crohn's disease may be similar in appearance, a fact that can make diagnosing UC a challenge.
    Endoscopic image of ulcerative colitis affecting the left side of the colon. The image shows confluent superficial ulceration and loss of mucosal architecture. Crohn's disease may be similar in appearance, a fact that can make diagnosing UC a challenge.

    The following conditions may present in a similar manner as ulcerative colitis, and should be excluded:

    * Crohn's disease
    * Infectious colitis, which is typically detected on stool cultures
    o Pseudomembranous colitis, or Clostridium difficile-associated colitis, bacterial upsets often seen following administration of antibiotics
    * Ischemic colitis, inadequate blood supply to the intestine, which typically affects the elderly
    * Radiation colitis in patients with previous pelvic radiotherapy
    * Chemical colitis resulting from introduction of harsh chemicals into the colon from an enema or other procedure.

    Comparison to Crohn's Disease

    The most common disease that mimics the symptoms of ulcerative colitis is Crohn's disease, as both are inflammatory bowel diseases that can affect the colon with similar symptoms. It is important to differentiate these diseases, since the course of the diseases and treatments may be different. In some cases, however, it may not be possible to tell the difference, in which case the disease is classified as indeterminate colitis.
    Comparisons of various factors in Crohn's disease and ulcerative colitis Crohn's Disease Ulcerative Colitis
    Involves terminal ileum? Commonly Seldom
    Involves colon? Usually Always
    Involves rectum? Seldom Usually
    Peri-anal involvement? Commonly Seldom
    Bile duct involvement? Not associated Higher rate of Primary sclerosing cholangitis
    Distribution of Disease Patchy areas of inflammation Continuous area of inflammation
    Endoscopy Linear and serpiginous (snake-like) ulcers Continuous ulcer
    Depth of inflammation May be transmural, deep into tissues Shallow, mucosal
    Fistulae, abnormal passageways between organs Commonly Seldom
    Biopsy Can have granulomata Crypt abscesses and cryptitis
    Surgical cure? Often returns following removal of affected part Usually cured by removal of colon, can be followed by pouchitis
    Smoking Higher risk for smokers Lower risk for smokers
    Autoimmune disease? Generally regarded as an autoimmune disease No consensus
    Cancer risk? Lower than ulcerative colitis Higher than Crohn's

    Diagnosis and workup

    General
    H&E stain of a colonic biopsy showing a crypt abscess, a classic finding in ulcerative colitis
    H&E stain of a colonic biopsy showing a crypt abscess, a classic finding in ulcerative colitis

    The initial diagnostic workup for ulcerative colitis includes the following:

    * A complete blood count is done to check for anemia; thrombocytosis, a high platelet count, is occasionally seen
    * Electrolyte studies and renal function tests are done, as chronic diarrhea may be associated with hypokalemia, hypomagnesemia and pre-renal failure.
    * Liver function tests are performed to screen for bile duct involvement: primary sclerosing cholangitis.
    * X-ray
    * Urinalysis
    * Stool culture, to rule out parasites and infectious causes.
    * Erythrocyte sedimentation rate can be measured, with an elevated sedimentation rate indicating that an inflammatory process is present.
    * C-reactive protein can be measured, with an elevated level being another indication of inflammation.

    Although ulcerative colitis is a disease of unknown causation, inquiry should be made as to unusual factors believed to trigger the disease. Factors may include: recent cessation of tobacco smoking; recent administration of large doses of iron or vitamin B6; hydrogen peroxide in enemas or other procedures.

    Endoscopic
    Biopsy sample (H&E stain) that demonstrates marked lymphocytic infiltration (blue/purple) of the intestinal mucosa and architectural distortion of the crypts.
    Biopsy sample (H&E stain) that demonstrates marked lymphocytic infiltration (blue/purple) of the intestinal mucosa and architectural distortion of the crypts.

    The best test for diagnosis of ulcerative colitis remains endoscopy. Full colonoscopy to the cecum and entry into the terminal ileum is attempted only if diagnosis of UC is unclear. Otherwise, a flexible sigmoidoscopy is sufficient to support the diagnosis. The physician may elect to limit the extent of the exam if severe colitis is encountered to minimize the risk of perforation of the colon. Endoscopic findings in ulcerative colitis include the following:

    * Loss of the vascular appearance of the colon
    * Erythema (or redness of the mucosa) and friability of the mucosa
    * Superficial ulceration, which may be confluent, and
    * Pseudopolyps.

    Ulcerative colitis is usually continuous from the rectum, with the rectum almost universally being involved. There is rarely peri-anal disease, but cases have been reported. The degree of involvement endoscopically ranges from proctitis or inflammation of the rectum, to left sided colitis, to pancolitis, which is inflammation involving the ascending colon.

    Histologic

    Biopsies of the mucosa are taken to definitively diagnose UC and differentiate it from Crohn's disease, which is managed differently clinically. Microbiological samples are typically taken at the time of endoscopy. The Pathology in ulcerative colitis typically involves distortion of crypt architecture, inflammation of crypts (cryptitis), frank crypt abscesses, and hemorrhage or inflammatory cells in the lamina propria. In cases where the clinical picture is unclear, the histomorphologic analysis often plays a pivotal role in determining the management.

    Course and complications

    Progression or remission

    Patients with ulcerative colitis usually have an intermittent course, with periods of disease inactivity alternating with "flares" of disease. Patients with proctitis or left-sided colitis usually have a more benign course: only 15% progress proximally with their disease, and up to 20% can have sustained remission in the absence of any therapy. Patients with more extensive disease are less likely to sustain remission, but the rate of remission is independent of the severity of disease.

    Ulcerative colitis and colorectal cancer

    There is a significantly increased risk of colorectal cancer in patients with ulcerative colitis after 10 years if involvement is beyond the splenic flexure. Those with only proctitis or rectosigmoiditis usually have no increased risk. It is recommended that patients have screening colonoscopies with random biopsies to look for dysplasia after eight years of disease activity

    Primary sclerosing cholangitis

    Ulcerative colitis has a significant association with primary sclerosing cholangitis (PSC), a progressive inflammatory disorder of small and large bile ducts. As many as 5% of patients with ulcerative colitis may progress to develop primary sclerosing cholangitis.

    Mortality

    The effect of ulcerative colitis on mortality is unclear, but it is thought that the disease primarily affects quality of life, and not lifespan.

    Treatment

    Main article: Treatment of ulcerative colitis
    Main article: Biological therapy for inflammatory bowel disease

    Standard treatment for ulcerative colitis depends on extent of involvement and disease severity. The goal is to induce remission initially with medications, followed by the administration of maintenance medications to prevent a relapse of the disease. The concept of induction of remission and maintenance of remission is very important. The medications used to induce and maintain a remission somewhat overlap, but the treatments are different. Physicians first direct treatment to inducing a remission which involves relief of symptoms and mucosal healing of the lining of the colon and then longer term treatment to maintan the remission.

    Drugs used

    Aminosalicylates

    Sulfasalazine has been a major agent in the therapy of mild to moderate UC for over 50 years. In 1977 Mastan S.Kalsi et al determined that 5-aminosalicyclic acid (5-ASA and mesalazine) was the therapeutically active compound in sulfasalazine. Since then many 5-ASA compounds have been developed with the aim of maintaining efficacy but reducing the common side effects associated with the sulfapyridine moiety in sulfasalazine.

    * Mesalazine, also known as 5-aminosalicylic acid, mesalamine, or 5-ASA. Brand name formulations include Asacol, Pentasa, Mezavant, Lialda, and Salofalk.
    * Sulfasalazine, also known as Azulfidine.
    * Balsalazide - Disodium, also known as Colazal.
    * Olsalazine, also known as Dipentum.

    Corticosteroids

    * Cortisone
    * Prednisone
    * Prednisolone
    * Hydrocortisone
    * Methylprednisolone
    * Beclometasone
    * Budesonide - under the brand name of Entocort

    Immunosuppressive drugs

    * Mercaptopurine, also known as 6-Mercaptopurine, 6-MP and Purinethol.
    * Azathioprine, also known as Imuran, Azasan or Azamun, which metabolises to 6-MP.
    * Methotrexate, which inhibits folic acid
    * Tacrolimus

    Biological treatment

    * Infliximab
    * Visilizumab

    Surgery

    Unlike Crohn's disease, ulcerative colitis can generally be cured by surgical removal of the large intestine. This procedure is necessary in the event of: exsanguinating hemorrhage, frank perforation or documented or strongly suspected carcinoma. Surgery is also indicated for patients with severe colitis or toxic megacolon. Patients with symptoms that are disabling and do not respond to drugs may wish to consider whether surgery would improve the quality of life.

    Ulcerative colitis is a disease that affects many parts of the body outside the intestinal tract. In rare cases the extra-intestinal manifestations of the disease may require removal of the colon.

    Alternative treatments

    Smoking

    Unlike Crohn's disease, ulcerative colitis has a lesser prevalence in smokers than non-smokers.

    Dietary modification

    This article does not cite any references or sources. (January 2008)
    Please help improve this article by adding citations to reliable sources. Unverifiable material may be challenged and removed.

    Dietary modification may reduce the symptoms of the disease.

    * Lactose intolerance is noted in many ulcerative colitis patients. Those with suspicious symptoms should get a lactose breath hydrogen test.
    * Patients with abdominal cramping or diarrhea may find relief or a reduction in symptoms by avoiding fresh fruits and vegetables, caffeine, carbonated drinks and sorbitol-containing foods.
    * Many dietary approaches have purported to treat UC, including the Elaine Gottschall's specific carbohydrate diet and the "anti-fungal diet" (Holland/Kaufmann).
    * The use of elemental and semi-elemental formula has been successful in pediatric patients.

    Fats and oils

    * Fish oil. Eicosapentaenoic acid (EPA), derived from fish oil. This is an Eicosanoid that inhibits leukotriene activity. It is effective as an adjunct therapy. There is no recommended dosage for ulcerative colitis. Dosages of EPA of 180 to 1500 mg/day are recommended for other conditions. [1]
    * Short chain fatty acid (butyrate) enema. The colon utilizes butyrate from the contents of the intestine as an energy source. The amount of butyrate available decreases toward the rectum. Inadequate butyrate levels in the lower intestine have been suggested as a contributing factor for the disease. This might be addressed through butyrate enemas. The results however are not conclusive.

    Herbals

    * Herbal medications are used by patients with ulcerative colitis. Compounds that contain sulphydryl may have an effect in ulcerative colitis (under a similar hypothesis that the sulpha moiety of sulfasalazine may have activity in addition to the active 5-ASA component).[19] One randomized control trial evaluated the over-the-counter medication methionine-methyl sulphonium chloride (abbreviated MMSC, but more commonly referred to as Vitamin U) and found a significant decreased rate of relapse when the medication was used in conjunction with oral sulfasalazine.

    Bacterial recolonization

    * Probiotics may have benefit. One study which looked at a probiotic known as VSL#3 has shown promise for people with ulcerative colitis.

    * Fecal bacteriotherapy involves the infusion of human probiotics through fecal enemas.[22] It suggests that the cause of ulcerative colitis may be a previous infection by a still unknown pathogen. This initial infection resolves itself naturally, but somehow causes an imbalance in the colonic bacterial flora, leading to a cycle of inflammation which can be broken by "recolonizing" the colon with bacteria from a healthy bowel. There have been several reported cases of patients who have remained in remission for up to 13 years.

    Intestinal parasites

    Inflammatory bowel disease is less common in the developing world. Some have suggested that this may be because intestinal parasites are more common in underdeveloped countries. Some parasites are able to reduce the immune response of the intestine, an adaptation that helps the parasite colonize the intestine. The decrease in immune response could reduce or eliminate the inflammatory bowel disease

    Helminthic therapy using the whipworm Trichuris suis has been shown in a randomized control trial from Iowa to show benefit in patients with ulcerative colitis. The therapy tests the hygiene hypothesis which argues that the absence of helminths in the colons of patients in the developed world may lead to inflammation. Both helminthic therapy and fecal bacteriotherapy induce a characteristic Th2 white cell response in the diseased areas, which is somewhat paradoxical given that ulcerative colitis immunology was thought to classically involve Th2 overproduction

    Nicotine It has been shown that smokers on a dose-based schedule have their ulcerative colitis symptoms effectively reduced by cigarettes. The effect disappears if the user quits.

    Ongoing research

    Recent evidence from the ACT-1 trial suggests that infliximab may have a greater role in inducing and maintaining disease remission.

    An increased amount of colonic sulfate-reducing bacteria has been observed in some patients with ulcerative colitis, resulting in higher concentrations of the toxic gas hydrogen sulfide. The role of hydrogen sulfide in pathogenesis is unclear. It has been suggested that the protective benefit of smoking that some patients report is due to hydrogen cyanide from cigarette smoke reacting with hydrogen sulfide to produce the nontoxic isothiocyanate. Another unrelated study suggested sulphur contained in red meats and alcohol may lead to an increased risk of relapse for patients in remission

    There is much research currently being done to elucidate further genetic markers in ulcerative colitis. Linkage with Human Leukocyte Antigen B-27, associated with other autoimmune diseases, has been proposed.

    Low dose naltrexone is under study for treatment of Crohn's disease and ulcerative colitis.

    See also

    * Crohn's disease
    * Ileo-anal pouch
    * Ileostomy
    * Inflammatory bowel disease
    * Primary sclerosing cholangitis
  45. Aman.

    Aman. Guest

    Cystinosis is an autosomal recessive genetic disorder of the renal tubules, characterized by the presence of carbohydrates and amino acids in the urine, excessive urination, and low blood levels of potassium and phosphates.

    Contents


    * 1 Diagnosis
    o 1.1 Symptoms
    * 2 Genetics
    * 3 Types
    * 4 See also
    * 5 References
    * 6 External links

    Diagnosis

    Cystinosis causes an accumulation of the amino acid cystine within cells, forming crystals that can build up and damage the cells. These crystals negatively affect many systems in the body, especially the kidneys and eyes.

    The accumulation is caused by abnormal transport of cystine from lysosomes, resulting in a massive intra-lysosomal cystine accumulation in tissues. Via an as yet unknown mechanism, lysosomal cystine appears to amplify and alter apoptosis in such a way that cells die inappropriately, leading to loss of renal epithelial cells. This results in renal Fanconi syndrome, and similar loss in other tissues can account for the short stature, retinopathy, and other features of the disease.

    Symptoms

    There are three distinct types of cystinosis each with slightly different symptoms: nephropathic cystinosis, intermediate cystinosis, and non-nephropathic or ocular cystinosis. Infants affected by nephropathic cystinosis initially exhibit poor growth and particular kidney problems (sometimes called renal Fanconi syndrome). The kidney problems lead to the loss of important minerals, salts, fluids, and other nutrients. The loss of nutrients not only impairs growth, but may result in soft, bowed bones (hypophosphatemic rickets), especially in the legs. The nutrient imbalances in the body lead to increased urination, thirst, dehydration, and abnormally acidic blood (acidosis).

    By about age two, cystine crystals may also be present in the cornea. The buildup of these crystals in the eye causes an increased sensitivity to light (photophobia). Untreated children will experience complete kidney failure by about age ten. Other signs and symptoms that may occur in untreated patients include muscle deterioration, blindness, inability to swallow, diabetes, and thyroid and nervous system problems.

    The signs and symptoms of intermediate cystinosis are the same as nephropathic cystinosis, but they occur at a later age. Intermediate cystinosis typically begins to affect individuals around age twelve to fifteen. Malfunctioning kidneys and corneal crystals are the main initial features of this disorder. If intermediate cystinosis is left untreated, complete kidney failure will occur, but usually not until the late teens to mid twenties.

    People with non-nephropathic or ocular cystinosis do not usually experience growth impairment or kidney malfunction. The only symptom is photophobia due to cystine crystals in the cornea.

    It is currently being researched at UC San Diego, Tulane University School of Medicine, and at the National Institutes of Health in Bethesda, Maryland as well as at Robert Gordon University in Aberdeen and in Sunderland, UK.

    Genetics
    Cystinosis has an autosomal recessive pattern of inheritance.
    Cystinosis has an autosomal recessive pattern of inheritance.

    Cystinosis is due to a mutation in the gene CTNS which codes for cystinosin, the lysosomal cystine transporter. Symptoms are first seen at about 3 to 18 months of age with profound polyuria (excessive urination), followed by poor growth, photophobia, and ultimately kidney failure by age 6 years in the nephropathic form. It is important for the child to see a biochemical geneticist and pediatric nephrologist to begin treatment with cysteamine as early as possible. Cysteamine decreases the amount of cystine stored in lysosomes and correlates with conservation of renal function and improved growth. Cysteamine eyedrops remove the cystine crystals in the cornea that can cause photophobia if left unchecked.

    All forms of cystinosis (nephropathic, juvenile and ocular) are autosomal recessive, which means that the trait is located on an autosomal gene, and an individual who inherits two copies of the gene - one from both parents - will have the disorder. There is a 25% risk of having a child with the disorder, when both parents are carriers of an autosomal recessive trait.

    Cystinosis "breeds true", indicating that parents of a child with the juvenile variety of cystinosis will not have another child with the nephropathic form, etc. Cystinosis affects approximately 1 in 100,000 to 200,000 newborns. The incidence is higher in the province of Brittany, France, where the disorder affects 1 in 26,000 individuals.

    Types

    * Online 'Mendelian Inheritance in Man' (OMIM) 219800 - Infantile nephropathic
    * Online 'Mendelian Inheritance in Man' (OMIM) 219900 - Adolescent nephropathic
    * Online 'Mendelian Inheritance in Man' (OMIM) 219750 - Adult nonnephropathic

    See also

    * Hartnup disease
    * Cystinuria
    * Fanconi syndrome

    References

    * Overview of condition at NLM Genetics Home Reference

    External links

    * BC Health Guide
    * Cystinosis Foundation UK - a UK Charity Supporting Families & Research
    * Cystinosis Research Foundation - a US research support and education foundation


    v • d • e
    Inborn errors of amino acid metabolism (E70-72, 270)
    K
    Lysine/straight chain

    Glutaric acidemia type 1 - type 2 - Hyperlysinemia - Pipecolic acidemia - Saccharopinuria
    Leucine

    Isovaleric acidemia - 3-Methylcrotonyl-CoA carboxylase deficiency
    G
    Glycine

    Sarcosinemia - D-Glyceric acidemia - Glutathione synthetase deficiency
    Glutamate/glutamine

    SSADHD
    Proline

    Hyperprolinemia - Prolidase deficiency
    Histidine

    Carnosinemia - Histidinemia - Urocanic aciduria
    Sulfur: methionine/cysteine

    Hypermethioninemia - Homocystinuria - Cystathioninuria
    Valine

    Hypervalinemia - Isobutyryl-CoA dehydrogenase deficiency
    Urea cycle disorder
    (arginine, aspartate)

    N-Acetylglutamate synthase deficiency - Carbamoyl phosphate synthetase I deficiency - Ornithine transcarbamylase deficiency/translocase deficiency - Citrullinemia - Argininosuccinic aciduria - Argininemia - Hyperammonemia
    KG
    Phenylalanine/tyrosine

    Phenylketonuria - Alkaptonuria - Ochronosis - Tyrosinemia (Hawkinsinuria)

    Albinism
    Tetrahydrobiopterin deficiency
    Isoleucine

    Beta-ketothiolase deficiency - 2-Methylbutyryl-CoA dehydrogenase deficiency
    General BC/OA
    Maple syrup urine disease - Propionic acidemia - Methylmalonic acidemia
    Transport
    Cystinuria - Hartnup disease - Oculocerebrorenal syndrome - Lysinuric protein intolerance - Inborn errors of renal tubular transport (Cystinosis, Fanconi syndrome)
    Other
    GAMT deficiency - Trimethylaminuria - 2-Hydroxyglutaric aciduria
    see also enzymes
    Retrieved from "http://en.wikipedia.org/wiki/Cystinosis"
    Categories: Metabolic disorders | Genetic disorders | Autosomal recessive disorders | Lysosomal storage diseases
  46. Aman.

    Aman. Guest

    cystinosis has all the following EXCEPT

    a)cysteine stones in urine common
    b)Corneal crystals
    c)Fanconi syndrome
    d)---------


    ans-------------


    -----------------------------------------------

    Urine testing reveals low osmolality, glucosuria, and tubular proteinuria (including generalized amino aciduria).



    ------------------------------------------------
    background

    Nephropathic cystinosis is an inherited (autosomal recessive) lysosomal storage disorder caused by defective transport of the amino acid cystine out of lysosomes. The stored cystine is poorly soluble and crystallizes within the lysosomes of many cell types, leading to widespread tissue and organ damage.

    Three types of cystinosis have been described based on the age at diagnosis and magnitude of cellular cystine deposition: infantile onset, adolescent onset, and adult onset. Patients with the infantile nephropathic form of cystinosis (the most common and the most severe) develop symptoms early in life and develop end-stage kidney failure by late childhood, if untreated.

    Specific therapy with a drug that allows for removal of cystine from its lysosomal accumulation has been associated with marked improvement in the outlook for kidney function and quality of life in patients with nephropathic cystinosis.

    Pathophysiology

    Ingested protein enters the lysosome, where acid hydrolases degrade it to its component amino acids, including cysteine. Within the lysosome, cysteine is readily oxidized to cystine (a disulfide of the amino acid cysteine). In healthy individuals, both cystine and cysteine can normally enter the cytoplasm, where cystine is rapidly converted to cysteine by the reducing agent glutathione. Cytoplasmic cysteine is incorporated into protein or degraded to inorganic sulfate for excretion.

    Cystinosis is caused by one of several mutations in the gene that encodes cystinosin, the cystine-lysomal exporter. Because of the defect in cystinosin, cystine cannot leave the lysosomes and is accumulated there as birefringent, hexagonal, or rectangular crystals within cells of various organ systems.

    In the infantile nephropathic form of cystinosis, the kidney is affected early in life by cystine crystals deposited in proximal tubule cells. This leads eventually to a Fanconi syndrome, characterized by wasting of substances reabsorbed in this nephron segment, including sodium, potassium, phosphate, calcium, magnesium, bicarbonate, and others. Metabolic acidosis and electrolyte disturbances ensue and contribute to the stunting of growth in children with cystinosis. Cystinosis is the most common inherited cause of Fanconi syndrome.

    Frequency
    United States

    In North America, the incidence of infantile nephropathic cystinosis is 1 case per 100,000-200,000 live births; an estimated 300-400 children in the United States have cystinosis.
    International

    The incidence of cystinosis is higher in certain subpopulations. France's Brittany province has an estimated incidence of 1 case per 26,000 population; the incidence in the rest of France is 1 case per 326,440 population. The incidence rate of infantile and adolescent cystinosis in the former Federal Republic of Germany was reported to be approximately 1 case per 179,000 live births.
    Mortality/Morbidity

    Medical perceptions regarding the complications and outcome of cystinosis have changed over the years. Prior to the availability of renal transplantation, infantile cystinosis was considered a fatal disease. By the early 1970s, the salutary effects of renal transplants had been recognized.

    Cysteamine, introduced in the early 1980s, was shown to blunt the decline in renal function and improve linear growth in these children, despite the fact that it does not ameliorate the defect in renal tubule transport. However, the increased life expectancy afforded by the progress in medical and surgical treatment was accompanied by the development of serious complications due to the continuous accumulation of cystine in nonrenal organs, including the eye, thyroid, brain, liver, pancreas, and muscle. However, many patients survive into the third or fourth decade of life and are able to pursue fulfilling lifestyles.
    Race

    Cystinosis is often considered a disease of fair-skinned individuals of European descent; however, it is known to occur in blacks, Hispanics, and people of Middle Eastern descent. It has also been described in at least one Chinese patient and in several Japanese patients.
    Sex

    The male-to-female ratio among cystinotic children has been reported to be 1.4:1.
    Age

    Patients with infantile nephropathic cystinosis develop initial symptoms in infancy, frequently when younger than 1 year. In the adolescent form, symptoms are evident by age 8-12 years, and the progression is slow. The adult form of cystinosis does not include renal involvement and is limited to the eye (ocular cystinosis).

    CLINICAL
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    * Authors and Editors
    * Introduction
    * Clinical
    * Differentials
    * Workup
    * Treatment
    * Medication
    * Follow-up
    * Miscellaneous
    * Multimedia
    * References


    History

    Cystinosis is classified into 2 general phenotypes: nephropathic and nonnephropathic cystinosis (benign variant).

    * Nephropathic cystinosis is further subdivided into infantile and late-onset (intermediate cystinosis), based on the age at presentation.
    *
    o Nephropathic infantile cystinosis is the most common and most severe variant.
    o
    + Symptoms of multiorgan involvement may be mild to severe, depending on the patient's age at diagnosis, the age when treatment was instituted, and genetic factors.
    + Early in the natural history of infantile nephropathic cystinosis, clinical involvement follows a fairly predictable chronology. Patients usually present during the first year of life with polyuria, polydipsia, dehydration, metabolic acidosis (normal anion gap hyperchloremic acidosis), hypophosphatemic rickets, failure to thrive, and laboratory findings consistent with Fanconi syndrome. If untreated, renal failure develops by age 7-10 years.
    + Oral cysteamine therapy postpones the need for renal transplantation.
    + Renal transplantation has prolonged the lives of children with cystinosis. Renal transplantation is highly successful, disease does not recur in the graft, but cystine continues to accumulate in other tissues, resulting in such complications as eye disease (eg, severe photophobia, corneal ulcerations, retinal blindness), delayed puberty, hypothyroidism, pancreatic disease (eg, exocrine insufficiency, insulin-dependent diabetes mellitus), liver disease (eg, hepatosplenomegaly, nodular degenerative hyperplasia), distal vacuolar myopathy, swallowing difficulties, and CNS involvement (eg, calcifications, atrophy, pseudotumor cerebri).
    o Late-onset (intermediate) nephropathic cystinosis is a more indolent form of the disease. The first symptoms most commonly appear at age 8-12 years. The features of Fanconi syndrome are less severe, and end-stage renal disease occurs after age 15 years.
    * Nonnephropathic cystinosis is considered a benign variant and is usually diagnosed by an ophthalmologist treating patients for photophobia. Photophobia may not begin until middle age and is not usually as debilitating as in the nephropathic form of the disease. Slit-lamp examination reveals corneal crystal deposits. In addition to the eye, cystine crystals are present in the bone marrow and leukocytes but are absent in the kidney and the retina.

    Physical

    A typical cystinotic patient has pale blond hair and blue eyes, although the disease also occurs among dark-haired individuals.

    * Initial presentation of infantile nephropathic cystinosis
    *
    o The initial symptoms include polydipsia, polyuria, vomiting, loss of appetite, constipation, and failure to thrive.
    o The first signs may go unrecognized for several months until the patient develops severe dehydration, electrolyte imbalance, and metabolic acidosis during a mild illness. Some children may have recurrent bouts of fever and manifestations of heat intolerance (becoming red like beets) caused by a defect in sweat production.
    o Patients typically have short stature and renal Fanconi syndrome.
    o They have poor appetite, crave salty and hot and spicy foods, and prefer specific food textures. Each patient has specific preferences that may already be evident by age 2 years.
    * Initial presentation of late-onset nephropathic (intermediate) cystinosis
    *
    o Most cases are diagnosed by age 12 years.
    o Complete Fanconi syndrome often does not develop in late-onset cystinosis, but renal function deteriorates as in infantile nephropathic cystinosis, and patients often experience end-stage renal failure within a few years of diagnosis.
    * Nephropathic cystinosis (progressive disease)
    *
    o Children younger than 1 year usually show growth retardation, rickets, metabolic acidosis, and other chemical evidence of renal tubular abnormalities, such as increased renal excretion of glucose, amino acids, phosphate, and potassium. They may require frequent hospital admissions because of dehydration.
    o As children age, failure to thrive is prominent. Without specific therapy, children remain below the third percentile in both height and weight throughout life.
    o Corneal crystals are apparent by age 1-2 years. The untreated cornea is packed with crystals by age 3-4 years, leading to photophobia in early childhood.
    o By age 7-10 years, previously noted symptoms become more severe, and patients develop renal failure, increased photophobia, and thyroid insufficiency.
    o Sexual maturation is almost always late.
    o Retinal damage does not occur until the second or third decade of life.
    o Cerebral calcifications and muscular and swallowing difficulties cluster around the third decade of life.
    o The major complication of cystinosis in patients older than 20 years is legal blindness, distal myopathy, cerebral calcifications or atrophy, swallowing dysfunction, diabetes mellitus, and liver disease (eg, hepatomegaly, nodular degenerative hyperplasia).

    Causes

    All forms of cystinosis have autosomal recessive patterns of inheritance. Cystinosis is caused by a defect in transport of cystine across the lysosomal membrane due to defective function of the lysosomal membrane protein cystinosin, resulting from mutations of the cystinosis gene (CTNS). CTNS has been mapped to chromosome arm 17p13. The CTNS gene has 12 exons, the last 10 of which code for cystinosin.

    Cystinosin (an integral lysosomal membrane protein) has 367 amino acids and 7 transmembrane domains. In nephropathic cystinosis patients, CTNS mutations can cause either an absence of cystinosin or a disruption of transmembrane domains and loss of protein function, leading to inhibition of cystine transport through the lysosomal membrane (which is carrier-dependent). More than 80 different CTNS mutations (missense, nonsense, splice-site, deletion, and promoter mutations) are described in patients with nephropathic cystinosis; the most common are 57 kilobases (kb) (approximately 60% of the mutations in US patients).1

    Patients with a mild form of cystinosis that is diagnosed when patients are younger than 7 years or patients with late-onset (intermediate) cystinosis have mutations of CTNS that affect functionally unimportant regions of cystinosin, accounting for a milder clinical course. The various CTNS mutations can explain why patients have a wide spectrum of clinical symptomatology.

    The parents of patients with cystinosis are obligate heterozygotes for cystinosis; they each carry a single gene for the disease. Individuals heterozygous for cystinosis have never been reported to have cystine crystals in any tissue or cell. Despite the clinically normal appearance of individuals who are heterozygous for cystinosis, their polymorphonuclear cells contain an increased amount of cystine.

    Late-onset (intermediate) cystinosis appears to be due to the inheritance of a mutation known to cause infantile disease in one allele and a relatively less clinically severe mutation in the other or due to the inheritance of a relatively less severe mutation in both alleles.


    DIFFERENTIALS
    Section 4 of 11 Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic -

    * Authors and Editors
    * Introduction
    * Clinical
    * Differentials
    * Workup
    * Treatment
    * Medication
    * Follow-up
    * Miscellaneous
    * Multimedia
    * References


    Other Problems to be Considered

    Cystinosis may initially be misdiagnosed as dehydration caused by vomiting and diarrhea, failure to thrive, fever of unknown origin, Bartter syndrome, diabetes mellitus, diabetes insipidus, dwarfism, rickets, or brain tumor.

    WORKUP
    Section 5 of 11 Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic -

    * Authors and Editors
    * Introduction
    * Clinical
    * Differentials
    * Workup
    * Treatment
    * Medication
    * Follow-up
    * Miscellaneous
    * Multimedia
    * References


    Lab Studies

    * Serum electrolyte measurements are used to detect the presence of acidosis (hyperchloremic, normal anion gap) and severity of hypokalemia, hyponatremia, hypophosphatemia, and low bicarbonate concentration.
    * Blood gases may be used to detect metabolic acidosis and the degree of respiratory compensation.
    * Urine testing reveals low osmolality, glucosuria, and tubular proteinuria (including generalized amino aciduria).
    * Measurements of urine electrolytes serve to detect the loss of bicarbonate and phosphaturia.
    * Diagnosis of cystinosis is confirmed by measuring cystine levels in polymorphonuclear leukocytes or cultured fibroblasts. Cystine concentrations in individuals who are homozygous for cystinosis are 5-10 nmol half-cystine/mg cell protein; in heterozygous individuals, the levels are less than 1 nmol half-cystine/mg cell protein. Reference range levels are below 0.2 nmol half-cystine/mg cell protein.
    * When a fetus is at risk for cystinosis, the cystine level can be measured in chorionic villi or cultured amniotic fluid cells.

    Imaging Studies

    * Renal ultrasonography should be obtained in patients with elevated urine calcium excretion to rule out nephrocalcinosis.
    * Radiography for kidneys, ureters, and bladder (KUB) may be needed to evaluate possible urinary tract calcifications in patients with hypercalciuria or as a diagnostic evaluation of severe abdominal pain.
    * CT scanning and MRI are used to evaluate adult patients with infantile nephropathic cystinosis who have CNS symptoms.

    Other Tests

    * Slit-lamp examination of the eyes reveals corneal and conjunctival cystine crystals (pathognomonic for cystinosis) as early as age 1 year, although photophobia does not usually become apparent until age 3-6 years.
    * Examination of the eye fundi may reveal the presence of peripheral retinopathy that is more severe on the temporal than on the nasal side. In some patients, retinopathy may lead to blindness.

    Histologic Findings

    The kidney appears particularly susceptible to the adverse effects of cystine accumulation in cystinosis. The morphologic changes in the kidney vary with the stage of the disease.

    Early in the course of the disease, renal tubules are disorganized and poorly developed, even before the clinical onset of Fanconi syndrome. A "swan neck" deformity, or thinning of the first part of proximal convoluted tubule, becomes apparent during the first years of life and correlates with the clinical onset of the Fanconi syndrome, although this finding is not unique to cystinosis. A cystinotic kidney manifests different stages of destruction, with giant cell transformation of the glomerular visceral epithelium and occasional peculiar "dark" cells (unique to the cystinotic kidney) and cytoplasmic inclusions. Hyperplasia and hypertrophy of the juxtaglomerular apparatus may correlate with functional alterations of the renin-angiotensin system. With the help of polarizer attachment to the light microscope, birefringent rectangular to polygonal crystals of cystine are readily apparent, especially in interstitial cells, but they have also been observed in glomerular and tubular cells.

    Later in the course of cystinosis, in the uremic phase, varying degrees of global and segmental sclerosis, tubular atrophy and degeneration, chronic interstitial nephritis, interstitial fibrosis, and abundant crystal deposition are pronounced. The kidneys are small, echodense, and have a tendency to form cysts. Kidneys from patients with late-onset nephropathic disease resemble those with advanced changes in the infantile form.

    Kidneys from patients with benign adult cystinosis do not demonstrate any abnormalities.

    TREATMENT
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    * Authors and Editors
    * Introduction
    * Clinical
    * Differentials
    * Workup
    * Treatment
    * Medication
    * Follow-up
    * Miscellaneous
    * Multimedia
    * References


    Medical Care

    In the past, the treatment of cystinosis was limited to treating metabolic acidosis and, often, replacing electrolytes lost in the urine; later during the course of the disease, chronic kidney disease (CKD) was treated. Today, the wide availability of an effective drug, phosphocysteamine, and kidney replacement therapy with transplantation has dramatically improved the outlook for patients and altered management strategies.

    * Replacement of urinary losses: The child must be well-hydrated and administered supplements of potassium and bicarbonate, as needed. Rickets should be treated with vitamin D and phosphate supplementation. Carnitine may also be needed because its excretion is particularly elevated in the urine, and muscle levels have been documented to be reduced. Particular care should be given to fluid and electrolyte therapy during intercurrent episodes of fever, vomiting, or diarrhea.
    * Management of volume depletion/dehydration states
    *
    o Initial management of volume depletion in a child with cystinosis requires administration of large amounts of fluids and electrolytes, often exceeding conventionally defined limits. Fluid requirements may be more than twice that expected for the patient's size.
    o Urinary losses must be carefully monitored and replaced during hospitalization.
    o The rehydration fluid should contain glucose, sodium, potassium, and bicarbonate (in amounts generously exceeding the standard IV fluid composition). The concentration of these substances should be adjusted on the basis of frequently measured serum laboratory values.
    o After rehydration is accomplished, maintaining free access to water or other fluids is important because patients with cystinosis easily become dehydrated. For example, place a water container at the bedside during the night.
    o When the patient becomes free of acute GI symptoms (ie, no longer having frequent episodes of vomiting, gagging, abdominal pain, or diarrhea) and is able to eat well, restart the patient on a regular diet, supplementing individually determined amounts of sodium, potassium, bicarbonate, and phosphate to achieve reference range serum levels.
    * Indomethacin therapy
    *
    o Indomethacin may limit water losses in patients with nephropathic cystinosis by both reducing the glomerular filtration rate (GFR) and by sensitizing the collecting duct to the effects of antidiuretic hormone. It has been used to treat patients with cystinosis more commonly in Europe than in the United States. In uncontrolled clinical reports, indomethacin has been shown to relieve polyuria and polydipsia and to improve appetite, energy, and general well-being by reducing urinary losses of water and other various substances.
    o Indomethacin therapy requires careful monitoring of kidney function because the GFR may be worsened by the administration of this drug.
    o The ulcerogenic potential of indomethacin is its major drawback for treating cystinosis.
    * Growth hormone therapy
    *
    o Treatment with recombinant human growth hormone improves growth velocity. Long-term recombinant human growth hormone treatment in young children with nephropathic cystinosis prior to renal replacement therapy is safe and efficient.
    o Growth hormone treatment is less effective for peripubertal or adolescent patients on renal replacement therapy.
    o Treatment with recombinant human growth hormone does not accelerate a decline in kidney function in children with chronic kidney disease.
    * Thyroid replacement: This is indicated in patients diagnosed with hypothyroidism.
    * Kidney transplantation: Kidney transplantation in patients with infantile cystinosis corrects kidney failure and prolongs survival (the donor parenchymal cells are not homozygous for the genetic defect and are therefore able to transport cystine from the lysosomes). However, transplantation does not prevent progression of the disease in other nonrenal organs, and therapy with phosphocysteamine is indicated in patients after kidney transplantation.

    Surgical Care

    Some patients with severe gastroesophageal reflux may require gastric/jejunal tube placement or Nissen fundoplication to achieve optimal nutrition.
    Consultations

    * Nephrologists usually diagnose cystinosis as the cause of Fanconi syndrome.
    * The patient must be referred to an ophthalmologist upon initial evaluation and at subsequent regular intervals.
    * A pediatric endocrinologist may provide follow-up care for the patient related to growth hormone therapy, thyroid insufficiency, or diabetes mellitus.
    * Patients with recurrent abdominal pain, poor feeding, or vomiting and/or diarrhea should be evaluated by a gastroenterologist to diagnose the nature of GI abnormalities (eg, swallowing dysfunction, gastroesophageal reflux, delayed gastric emptying, gastric/duodenal ulcer, pseudo-obstruction).
    * Some children may require follow-up care by a behavioral therapist or a dietitian, depending on the child's needs.
    * Because of various neuromuscular problems, patients in late adolescence require follow-up by a neurologist.

    Diet

    Dietary recommendations should follow daily adult (RDA) requirements (ie, 60% carbohydrate, 10% protein, 30% lipids), and caloric intake should aim to achieve weight gain. If the patient is a poor eater and oral feeding is unsuccessful, high-calorie oral supplements should be administered. If the patient does not take supplements or has an inappropriately low intake because of poor appetite or vomiting, gastric tube placement can help.

    Total parenteral nutrition is indicated if a cystinotic patient cannot tolerate any form of enteral feeding. Some patients may need additional therapy with agents improving GI kinetics or antagonists of acid production.
    Activity

    Because of the chronic nature of the disorder, parents should try to accommodate the child's medical needs, while allowing the child to grow and develop similar to healthy children. Parents should encourage play and group participation.

    Cysteamine, introduced in the 1980s, blunts the decline in renal function and improves the linear growth of these children, despite the fact that it does not ameliorate the defect in renal tubule transport.

    Oral cysteamine (Cystagon) therapy should be initiated within days of diagnosis. Topical cysteamine therapy to the anterior segment of the eye now is undergoing clinical trials.

    Drug Category: Cystine-depleting agents

    Cysteamine is an aminothiol compound used to treat cystinosis. Various cysteamine salts are used. Cysteamine HCl has an unpleasant taste and odor, and, therefore, other forms have been developed. Cysteamine bitartrate (Cystagon) is available in the United States. Another form, phosphocysteamine, is the phosphorothioester of cysteamine and is rapidly converted to cysteamine in the gut. Phosphocysteamine is designated as an orphan drug in the United States. Much of the clinical data refers to cysteamine HCl or phosphocysteamine.

    In addition to the oral product that is available, an ophthalmic product is currently investigational. Topical cysteamine therapy administered to the anterior segment of the eye is being studied to observe the results of decreasing corneal cystine crystals, which develop with nephropathic cystinosis.
    Drug Name Cysteamine bitartrate (Cystagon)
    Description Approved by the FDA in August 1994, the sole distributor of this drug in the United States is CVS Procare (888-700-0024).
    Used as a cystine-depleting agent in cystinosis. It is a weak base that enters the cystinotic lysosome and reacts with cystine, forming a mixed disulfide of half-cystine and cysteamine. This mixed disulfide rapidly exits the lysosome via the transport system for cationic amino acids, which is normal in cystinosis. Cysteamine and its prodrug analog, phosphocysteamine, are very beneficial to patients with cystinosis, especially when started early in life. Therapy does not prevent or affect Fanconi syndrome. Diagnosis of cystinosis as early as possible is important because efficacy of cysteamine or phosphocysteamine treatment clearly relates to age at which the drugs are started.
    Goal of therapy is to keep leukocyte cystine levels <1 nmol/half-cystine/mg protein measured 5-6 h following administration of cysteamine. Check cystine levels after maintenance dose is achieved; then check every 3 mo; if cysteamine is poorly tolerated initially because of GI tract symptoms or transient rashes, temporarily stop therapy; restart at lower dose and gradually increase to proper dose. Dose is expressed as free base of drug.
    Available as 50-mg and 150-mg cap.
    Adult Dose Maintenance dose (>50 kg): 500 mg/dose PO q6h
    Administer one fourth to one sixth of maintenance dose initially; then increase gradually over 4-6 wk to avoid intolerance and achieve a leukocyte cystine level <1.0 nmol half-cystine/mg protein
    Pediatric Dose Maintenance dose:
    <12 years: 1.3-1.95 g/m2/d (about 60–90 mg/kg/d) PO divided q6h
    May sprinkle cysteamine cap contents over food
    >12 years and >50 kg: Administer as in adults
    Contraindications Documented hypersensitivity
    Interactions None reported; can be administered with electrolyte and mineral and vitamin D and thyroid hormone replacements necessary for management
    Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
    Precautions Can cause occasional reversible leukopenia (reduces by almost 80%), monitor blood counts and perform liver function studies; because of adverse GI effects (eg, nausea, vomiting, duodenal ulcer), therapy may have to be interrupted and the dose adjusted; may cause CNS symptoms (eg, seizures, lethargy, somnolence, depression, encephalopathy); may also cause abnormal liver function values (monitor liver function) and rash; because of offensive smell and taste, some patients are unable to tolerate cysteamine treatment


    FOLLOW-UP
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    Further Inpatient Care

    * Patients with nephropathic cystinosis may require many hospitalizations as a result of severe electrolyte imbalance during recurrent episodes of dehydration from vomiting, diarrhea, or infection. Some patients may also have severe failure to thrive, requiring total parenteral nutrition if gastric tube feedings are not tolerated.

    Further Outpatient Care

    * Most patients receive follow-up care by a pediatric nephrologist, who usually undertakes the role of primary care provider because of the complexity of problems.
    * Patients should be seen on a regular basis, depending on the age of the patient and the spectrum of multisystem involvement. The visits should be coordinated with other subspecialists involved in the care.
    *
    o The leukocyte cystine content should be measured every 3 months, depending on the previous levels.
    o Blood chemistry should be monitored initially every other week for the first month and then monthly for 6 months; when chemistry remains stable, laboratory follow-up testing can be done less frequently, every 2-3 months.
    o During the office visits, the patient should be monitored for growth and weight gain, possible electrolyte abnormalities, renal function, and for nonrenal complications of cystinosis.
    o Ophthalmic examination should be performed every year to monitor corneal crystals and to rule out idiopathic intracranial hypertension.
    o If the linear growth velocity is not improved within a year of therapy and the height remains below the third percentile, recombinant human growth hormone therapy should be considered.
    o Thyroid function should be monitored to detect hypothyroidism.

    In/Out Patient Meds

    * A typical patient with cystinosis takes 2-11 medications daily. Most severely affected patients are treated with the following agents:
    *
    o Cysteamine (oral form, ophthalmic drops - investigational)
    o Sodium chloride
    o Sodium bicarbonate
    o Potassium chloride
    o Phosphate supplements
    o Prokinetic agents and/or H2 blockers and/or dyspeptic agents
    o Vitamin D
    o Indomethacin
    o Growth hormone
    o Thyroid compounds

    Complications

    * Before renal transplantation, nonrenal complications of infantile cystinosis include photophobia, corneal crystals, hypothyroidism, and short stature.
    * After renal transplantation, nonrenal complications include photophobia, corneal crystals, hypothyroidism, polyneuropathy, distal myopathy, CNS abnormalities, renal stones, and diabetes mellitus. Among the more unusual complications noted in the literature are pulmonary fibrosis, nodular degenerative hyperplasia of the liver, and hearing loss.

    Prognosis

    * In the early 1960s, nephropathic cystinosis was considered a fatal renal disease of childhood; patients died of progressive renal failure before age 10 years. The natural history of the disease has changed dramatically since the introduction of cysteamine and renal transplantation. Patients with infantile cystinosis now survive into the second and third decades of life. Cysteamine markedly slows the progression of renal failure.

    Patient Education

    * Because of the chronic and rare nature of the disease, allowing the parents of patients with cystinosis full access (eg, handouts to take home, library card) to current articles on the disease is critical. Parents may also join the Cystinosis Research Network or Cystinosis Foundation to become familiar with the disease, to exchange their knowledge, and to bond their children with peers who also have cystinosis.
  47. Aman.

    Aman. Guest

    MORE ABOUT HUS (Hemolytic uremic syndrome)


    ackground

    Hemolytic uremic syndrome (HUS) is a disease primarily of infancy and early childhood. It is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Diarrhea and upper respiratory infection are the most common precipitating factors. HUS is the most common cause of acute renal failure in children. The term HUS was first used by Gasser and coworkers in 1955, when they described an acute fatal syndrome in children that featured hemolytic anemia, thrombocytopenia, and severe renal failure.
    Pathophysiology

    In children, HUS often follows a prodromal infectious disease, usually diarrhea (90%) and less often an upper respiratory infection (10%). Use of antimotility drugs may increase the risk of developing HUS. The most common cause of HUS is a toxin produced by Escherichia coli serotype O157:H7. Additional agents include Shigella, Salmonella, Yersinia, and Campylobacter species. The shiga and shigalike toxins, produced by some strains of Shigella dysenteriae and E coli O157:H7, respectively, have been associated with approximately 70% of cases of HUS in children. Because of the cytotoxic activity of these toxins on vero cells, they are referred to as verotoxins. Transmission of E coli O157:H7 appears to be caused by contaminated food, such as ground beef and other cattle products that are undercooked, and unpasteurized dairy products. Food contaminated with E coli does not look, smell, or taste bad.

    Person-to-person contact, as well as contamination of public water supplies, may also have a role in the transmission of this bacterium. E coli is normal flora in the gastrointestinal tracts of some healthy cattle, and children can contract it by petting a cow.

    HUS is also associated with viruses, including varicella, echovirus, and coxsackie A and B, as well as other infectious agents such as Streptococcus pneumoniae and Clostridium difficile. HUS has also been associated with AIDS, cancer, and the administration of chemotherapeutic agents. Mitomycin C is the most common chemotherapeutic agent associated with HUS. Malignancies found in conjunction with HUS include prostatic, gastric, and pancreatic malignancies. Some have suggested that HUS is mediated by immune complexes. Some cases of HUS are familial, which may reflect a genetic or human leukocyte antigen (HLA)–type predisposition.

    HUS is subdivided into 2 forms, depending on whether the patient has had diarrhea (D+ HUS and D- HUS). D- HUS, which accounts for 10% of HUS cases, is sometimes referred to as atypical HUS. Although it is not associated with shiga toxin-producing E coli, it is still characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure.

    HUS and thrombotic thrombocytopenic purpura (TTP) represent different ends of what is probably the same disease continuum. Endothelial cell injury appears to be the primary event in the pathogenesis of these disorders. The endothelial damage triggers a cascade of events that result in microvascular lesions with platelet-fibrin hyaline microthrombi that occlude arterioles and capillaries. The platelet aggregation results in a consumptive thrombocytopenia. The epithelial damage may result from toxins released by bacteria or viruses. In TTP, the hyaline microthrombi occur throughout the microcirculation, and microvascular thromboses may be found in the brain, skin, intestines, skeletal muscle, pancreas, spleen, adrenals, and heart. On the other hand, in HUS, microthrombi are essentially confined to the kidneys. Many of the infectious agents and drugs implicated in HUS/TTP are toxic to the vascular endothelium.

    Although the vascular lesions are identical in HUS and TTP, involvement of the CNS predominates in TTP. As in TTP, DIC is not found. In contrast to TTP, the Pathology remains essentially localized to the kidney, where hyaline thrombi are seen in the afferent arterioles and glomerular capillaries. Thrombi are not present in other vessels, and neurologic symptoms, other than those associated with uremia, are uncommon. Hence, renal involvement is the defining feature of HUS. On gross examination, the kidneys are swollen and pale; many fleabite hemorrhages are on the surface. Vasculitis is usually absent.

    More recently, attention has focused on ADAMTS13 levels, which are normal in HUS but depressed in TTP. ADAMTS13 is a Von Willebrand factor-cleaving protease and, in the future, assay for this enzyme may be useful in distinguishing between TTP and HUS.

    Recurrences of HUS have been reported, and they are noted to have a mortality rate of 30%.

    Comparisons Between HUS, TTP, and Disseminated Intravascular Coagulation (DIC)

    � HUS TTP DIC
    Age Children Adults Adults
    CBC Anemia Anemia and
    thrombocytopenia Anemia and
    thrombocytopenia
    Peripheral smear MAHA* MAHA MAHA
    Clinical manifestation Predominantly renal Predominantly CNS Reflects the underlying illness
    Treatment Supportive Plasmapheresis, steroids Heparin and blood components
    Prognosis Good Poor Generally poor

    *MAHA = microangiopathic hemolytic anemia
    Frequency
    United States

    HUS is characteristically a disease of young children. In individuals aged 5 years and younger, the average annual incidence is 2.65 cases per 100,000; in individuals aged 18 and younger, the average annual incidence is 0.97 cases per 100,000. Incidence tends to parallel the seasonal fluctuation of E coli O157:H7 infections, which peaks between June and September.
    Mortality/Morbidity

    * The mortality rate is 5-15%.
    * Older children and adults have poorer prognoses.
    * Approximately 85% of children recover if given supportive care.

    Age

    * HUS is typically observed in infants and children, especially those aged 6 months to 4 years.
    * HUS is reported less often in adults than in children. Most adult patients are women who have been taking oral contraceptives, are postpartum, or are having obstetric complications (eg, preeclampsia, eclampsia).


    CLINICAL
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    * Medication
    * Follow-up
    * Miscellaneous
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    History

    * Children usually present following an acute diarrheal illness. The GI prodrome occurs a few days to a few weeks before the onset of HUS and may mimic ulcerative colitis, various enteric infections, and appendicitis.
    * Risk factors for children include eating rare hamburgers, recent visits to a petting zoo, or even a nursing home visit to a relative with diarrhea.
    * The clinical picture can suggest a GI bleed, as opposed to a toxic gastroenteritis, because the stool may be grossly bloody. The finding of grossly bloody stools in children is a strong indicator for E coli disease. Fever is often absent in these cases.
    * Urine output is reduced or absent.
    * Neurologic symptoms may be observed in some patients and may result from uremia. Seizures may occur, in some cases secondary to the development of a hypertensive encephalopathy.
    * On the other hand, neurologic dysfunction is a key feature of TTP.

    Physical

    * Findings reflect those of the inciting prodromal illness.
    * Petechiae, purpura, and fever are common.
    * GI bleeding is often found.
    * GI involvement may lead to symptoms of an acute abdomen, with occasional perforation.
    * Cardiac involvement may lead to congestive heart failure (CHF) and arrhythmias.
    * Microinfarcts in the pancreas may cause pancreatitis or, rarely, insulin-dependent diabetes mellitus.
    * Ocular involvement may lead to retinal or vitreous hemorrhage.
    * Hypertension and oliguria may be observed.

    Causes

    See Pathophysiology.

    DIFFERENTIALS
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    Henoch-Sch�nlein Purpura

    Other Problems to be Considered

    Vasculitis

    WORKUP
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    * Medication
    * Follow-up
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    Lab Studies

    * As in TTP, HUS is primarily a clinical diagnosis coupled with consistent laboratory findings.
    * HUS produces a microangiopathic hemolytic anemia (hemoglobin typically less than 8 g/dL). This is the hallmark finding and is necessary to establish the diagnosis.
    *
    o The hallmark of HUS in the peripheral smear is the presence of schistocytes. These consist of fragmented, deformed, irregular, or helmet-shaped RBCs (see Image 1). They reflect the fragmentation of RBCs that occurs as the RBCs traverse vessels partially occluded by platelet and hyaline microthrombi. The peripheral smear may also contain giant platelets. This is a reflection of the reduced platelet survival time resulting from the peripheral consumption/destruction of platelets.
    o Thrombocytopenia is present but is mild to moderate in severity, typically less than 60,000 per mL. In spite of this, there is usually no purpura or active bleeding. As with the anemia, the degree of thrombocytopenia is unrelated to the severity of the renal dysfunction.
    o Prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen are within the reference ranges, thus differentiating HUS/TTP from DIC.
    o No consumptive coagulopathy is present.
    * Elevation of lactate dehydrogenase (LDH) and indirect bilirubin reflects intravascular hemolysis. The bilirubin rarely exceeds 2-3 mg/dL. Haptoglobin is very low.
    * Blood urea nitrogen (BUN) and creatinine are markedly elevated. However, there is no correlation between the severity of anemia and the severity of the renal disease.
    * Urine, if present, may contain protein and RBCs.
    * Results of DIC panel (D-dimer, fibrinogen) usually are within the reference range.
    * The reticulocyte count is elevated.
    * Coombs test results are negative, indicating that the anemia is not immunologically mediated.
    * A moderate leukocytosis may be present, but rarely more than 20,000 per mL.
    * There may be mild fibrinolysis with slight elevation in fibrin degradation products.
    * Plasma contains free hemoglobin that can often be observed with the naked eye. The degree correlates with the severity of the anemia.
    * The urine contains hemoglobin, hemosiderin, albumin, RBCs, WBCs, and casts.
    * Bone marrow reveals erythroid hyperplasia and increased megakaryocytes.
    * Normal stool culturing does not reveal E coli O157:H7. The laboratory order must specifically request this analysis.
    * Blood cultures are negative in E coli disease.


    TREATMENT
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    Emergency Department Care

    ED care should focus on supportive management, treatment of blood pressure elevation, blood transfusions, and admission with arrangement for prompt dialysis.

    * Avoid fluid overload. Watch for and treat hyperkalemia.
    * Plasma exchange (plasmapheresis combined with fresh-frozen plasma replacement) is currently the treatment of choice. Plasma exchange is performed daily until remission is obtained. However, because 85% of children with HUS recover after supportive therapy alone, plasma exchange is generally reserved for the most severe cases.
    * In HUS associated with diarrhea, maintain adequate fluid balance and bowel rest.
    * Antibiotics are not effective except for certain forms caused by Shigella dysenteriae. In fact, antibiotic therapy may increase the risk of developing HUS in children with E coli O157:H7 colitis. Trimethoprim-sulfamethoxazole may increase verotoxin production by E coli O157:H7.

    Consultations

    Consult a hematologist and a nephrologist; in severe cases, consider consulting the Renal Transplant Service.
  48. Aman.

    Aman. Guest

    A patient with chest pain ,ST depression in ....,which is not given?

    a)thrombolytic therapy
    b)aspirin
    c)Ca channel blocker
    d)beta blocker


    ans-

    During an attack of angina pectoris, 50% of patients with normal findings after resting ECG show abnormalities. A 1-mm or greater depression of the ST segment below the baseline, measured 80 milliseconds from the J point, is the most characteristic change. Reversible ST-segment elevation occurs with Prinzmetal angina. Some patients with coronary artery disease may show pseudonormalization of the resting ECG ST-T–wave abnormalities during episodes of chest pain.

    -----------------------------------------------------

    ackground

    Angina pectoris is the result of myocardial ischemia caused by an imbalance between myocardial blood supply and oxygen demand. Angina is a common presenting symptom (typically, chest pain) among patients with coronary artery disease. A comprehensive approach to diagnosis and to medical management of angina pectoris is an integral part of the daily responsibilities of physicians.
    Pathophysiology

    Myocardial ischemia develops when coronary blood flow becomes inadequate to meet myocardial oxygen demand. This causes myocardial cells to switch from aerobic to anaerobic metabolism, with a progressive impairment of metabolic, mechanical, and electrical functions. Angina pectoris is the most common clinical manifestation of myocardial ischemia. It is caused by chemical and mechanical stimulation of sensory afferent nerve endings in the coronary vessels and myocardium. These nerve fibers extend from the first to fourth thoracic spinal nerves, ascending via the spinal cord to the thalamus, and from there to the cerebral cortex.

    Recent studies have shown that adenosine may be the main chemical mediator of anginal pain. During ischemia, ATP is degraded to adenosine, which, after diffusion to the extracellular space, causes arteriolar dilation and anginal pain. Adenosine induces angina mainly by stimulating the A1 receptors in cardiac afferent nerve endings.

    Heart rate, myocardial inotropic state, and myocardial wall tension are the major determinants of myocardial metabolic activity and myocardial oxygen demand. Increases in the heart rate and myocardial contractile state result in increased myocardial oxygen demand. Increases in both afterload (ie, aortic pressure) and preload (ie, ventricular end-diastolic volume) result in a proportional elevation of myocardial wall tension and, therefore, increased myocardial oxygen demand. Oxygen supply to any organ system is determined by blood flow and oxygen extraction. Because the resting coronary venous oxygen saturation is already at a relatively low level (approximately 30%), the myocardium has a limited ability to increase its oxygen extraction during episodes of increased demand. Thus, an increase in myocardial oxygen demand (eg, during exercise) must be met by a proportional increase in coronary blood flow.

    The ability of the coronary arteries to increase blood flow in response to increased cardiac metabolic demand is referred to as coronary flow reserve (CFR). In healthy people, the maximal coronary blood flow after full dilation of the coronary arteries is roughly 4-6 times the resting coronary blood flow. CFR depends on at least 3 factors: large and small coronary artery resistance, extravascular (ie, myocardial and interstitial) resistance, and blood composition.

    Myocardial ischemia can result from (1) a reduction of coronary blood flow caused by fixed and/or dynamic epicardial coronary artery (ie, conductive vessel) stenosis, (2) abnormal constriction or deficient relaxation of coronary microcirculation (ie, resistance vessels), or (3) reduced oxygen-carrying capacity of the blood.

    Atherosclerosis is the most common cause of epicardial coronary artery stenosis and, hence, angina pectoris. Patients with a fixed coronary atherosclerotic lesion of at least 50% show myocardial ischemia during increased myocardial metabolic demand as the result of a significant reduction in CFR. These patients are not able to increase their coronary blood flow during stress to match the increased myocardial metabolic demand, thus they experience angina. Fixed atherosclerotic lesions of at least 90% almost completely abolish the flow reserve; patients with these lesions may experience angina at rest.

    Coronary spasm can also reduce CFR significantly by causing dynamic stenosis of coronary arteries. Prinzmetal angina is defined as resting angina associated with ST-segment elevation caused by focal coronary artery spasm. Although most patients with Prinzmetal angina have underlying fixed coronary lesions, some have angiographically normal coronary arteries. Several mechanisms have been proposed for Prinzmetal angina: focal deficiency of nitric oxide production, hyperinsulinemia, low intracellular magnesium levels, smoking cigarettes, and using cocaine.

    Approximately 30% of patients with chest pain referred for cardiac catheterization have normal or minimal atherosclerosis of coronary arteries. A subset of these patients demonstrates reduced CFR that is believed to be caused by functional and structural alterations of small coronary arteries and arterioles (ie, resistance vessels). Under normal conditions, resistance vessels are responsible for as much as 95% of coronary artery resistance, with the remaining 5% being from epicardial coronary arteries (ie, conductive vessels). The former is not visualized during regular coronary catheterization. Angina due to dysfunction of small coronary arteries and arterioles is called microvascular angina. Several diseases, such as diabetes mellitus, hypertension, and systemic collagen vascular diseases (eg, systemic lupus erythematosus, polyarteritis nodosa), are believed to cause microvascular abnormalities with subsequent reduction in CFR.

    The syndrome that includes angina pectoris, ischemialike ST-segment changes and/or myocardial perfusion defects during stress testing, and angiographically normal coronary arteries is referred to as syndrome X. Most patients with this syndrome are postmenopausal women, and they usually have an excellent prognosis. Syndrome X is believed to be caused by microvascular angina. Multiple mechanisms may be responsible for this syndrome, including (1) impaired endothelial dysfunction, (2) increased release of local vasoconstrictors, (3) fibrosis and medial hypertrophy of the microcirculation, (4) abnormal cardiac adrenergic nerve function, and/or (5) estrogen deficiency.

    A number of extravascular forces produced by contraction of adjacent myocardium and intraventricular pressures can influence coronary microcirculation resistance and thus reduce CFR. Extravascular compressive forces are highest in the subendocardium and decrease toward the subepicardium. Left ventricular (LV) hypertrophy together with a higher myocardial oxygen demand (eg, during tachycardia) cause greater susceptibility to ischemia in subendocardial layers.

    Myocardial ischemia can also be the result of factors affecting blood composition, such as reduced oxygen-carrying capacity of blood, as is observed with severe anemia (hemoglobin, <8 g/dL), or elevated levels of carboxyhemoglobin. The latter may be the result of inhalation of carbon monoxide in a closed area or of long-term smoking.

    Recently, ambulatory ECG monitoring has shown that silent ischemia is a common phenomenon among patients with established coronary artery disease. In one study, as many as 75% of episodes of ischemia (defined as transient ST depression of >1 mm persisting for at least 1 min) occurring in patients with stable angina were clinically silent. Silent ischemia occurs most frequently in early morning hours and may result in transient myocardial contractile dysfunction (ie, stunning). The exact mechanism(s) for silent ischemia is not known. However, autonomic dysfunction (especially in patients with diabetes), a higher pain threshold in some individuals, and the production of excessive quantities of endorphins are among the more popular hypotheses.

    Frequency
    United States

    Approximately 6.3 million Americans are estimated to experience angina. An estimated 350,000 new cases of angina occur every year. Each year, 1.1 million new and recurrent cases of an acute coronary event occur in this country, of which more than 40% are fatal. Roughly, more than 12 million Americans had a history of myocardial infarction (MI) and/or angina pectoris in the year 2000.
    Mortality/Morbidity

    Coronary artery disease is the single most common cause of death in the United States, accounting for almost one death per minute. More than half of those who die suddenly from coronary artery disease have no previous symptoms.
    Race

    The rate of angina pectoris in women older than 20 years ranges from 3.9% in non-Hispanic white women to 6.2% in non-Hispanic black women and 5.5% in Mexican American women. The rates of angina pectoris for men in the same ethnic groups are 2.6%, 3.1%, and 4.1%, respectively. Among American Indians aged 65-74 years, the rates (per 1000 persons) of new and recurrent heart attacks are 25.1% for men and 9.1% for women.
    Sex

    Angina pectoris is more often the presenting symptom of coronary artery disease in women than in men, with a female-to-male ratio of 1.7:1. It has a prevalence of 3.9 million in women and 2.3 million in men. The frequency of atypical presentations is also more common among women compared with men. Women have a slightly higher rate of mortality from coronary artery disease compared with men, in part because of an older age at presentation and a frequent lack of classic anginal symptoms. The estimated age-adjusted prevalence of angina is greater in women than in men.
    Age

    The prevalence of angina pectoris increases with age. Age is a strong independent risk factor for mortality.

    CLINICAL
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    * Workup
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    * Medication
    * Follow-up
    * Miscellaneous
    * References


    History

    Most patients with angina pectoris report of retrosternal chest discomfort rather than frank pain. The former is usually described as a pressure, heaviness, squeezing, burning, or choking sensation. Anginal pain may be localized primarily in the epigastrium, back, neck, jaw, or shoulders. Typical locations for radiation of pain are arms, shoulders, and neck. Typically, angina is precipitated by exertion, eating, exposure to cold, or emotional stress. It lasts for approximately 1-5 minutes and is relieved by rest or nitroglycerin. Chest pain lasting only a few seconds is not usually angina pectoris. The intensity of angina does not change with respiration, cough, or change in position. Pain above the mandible and below the epigastrium is rarely anginal in nature.

    * Ask patients about the frequency of angina, severity of pain, and number of nitroglycerin pills used during angina episodes.
    * Angina decubitus is a variant of angina pectoris that occurs at night while the patient is recumbent. Some have suggested that it is induced by an increase in myocardial oxygen demand caused by expansion of the blood volume with increased venous return during recumbency.
    * The Canadian Cardiovascular Society grading scale is used for classification of angina severity, as follows:
    *
    o Class I - Angina only during strenuous or prolonged physical activity
    o Class II - Slight limitation, with angina only during vigorous physical activity
    o Class III - Symptoms with everyday living activities, ie, moderate limitation
    o Class IV - Inability to perform any activity without angina or angina at rest, ie, severe limitation
    * The New York Heart Association classification is also used to quantify the functional limitation imposed by patients' symptoms, as follows:
    *
    o Class I - No limitation of physical activity (Ordinary physical activity does not cause symptoms.)
    o Class II - Slight limitation of physical activity (Ordinary physical activity does cause symptoms.)
    o Class III - Moderate limitation of activity (Patient is comfortable at rest, but less than ordinary activities cause symptoms.)
    o Class IV - Unable to perform any physical activity without discomfort, therefore severe limitation (Patient may be symptomatic even at rest.)
    * Unstable angina is defined as new-onset angina (ie, within 2 mo of initial presentation) of at least class III severity, significant recent increase in frequency and severity of angina, or angina at rest.

    Physical

    * For most patients with stable angina, physical examination findings are normal. Diagnosing secondary causes of angina, such as aortic stenosis, is important.
    * A positive Levine sign (characterized by the patient's fist clenched over the sternum when describing the discomfort) is suggestive of angina pectoris.
    * Look for physical signs of abnormal lipid metabolism (eg, xanthelasma, xanthoma) or of diffuse atherosclerosis (eg, absence or diminished peripheral pulses, increased light reflexes or arteriovenous nicking upon ophthalmic examination, carotid bruit).
    * Examination of patients during the angina attack may be more helpful. Useful physical findings include third and/or fourth heart sounds due to LV systolic and/or diastolic dysfunction and mitral regurgitation secondary to papillary muscle dysfunction.
    * Pain produced by chest wall pressure is usually of chest wall origin.

    Causes

    * Decrease in myocardial blood supply due to increased coronary resistance in large and small coronary arteries
    *
    o Significant coronary atherosclerotic lesion in the large epicardial coronary arteries (ie, conductive vessels) with at least a 50% reduction in arterial diameter
    o Coronary spasm (ie, Prinzmetal angina)
    o Abnormal constriction or deficient endothelial-dependent relaxation of resistant vessels associated with diffuse vascular disease (ie, microvascular angina)
    o Syndrome X
    o Systemic inflammatory or collagen vascular disease, such as scleroderma, systemic lupus erythematous, Kawasaki disease, polyarteritis nodosa, and Takayasu arteritis
    * Increased extravascular forces, such as severe LV hypertrophy caused by hypertension, aortic stenosis, or hypertrophic cardiomyopathy, or increased LV diastolic pressures
    * Reduction in the oxygen-carrying capacity of blood, such as elevated carboxyhemoglobin or severe anemia (hemoglobin, <8 g/dL)
    * Congenital anomalies of the origin and/or course of the major epicardial coronary arteries
    * Structural abnormalities of the coronary arteries
    *
    o Congenital coronary artery aneurysm or fistula
    o Coronary artery ectasia
    o Coronary artery fibrosis after chest radiation
    o Coronary intimal fibrosis following cardiac transplantation
    * Risk factors
    *
    o Major risk factors for atherosclerosis: These include a family history of premature coronary artery disease, cigarette smoking, diabetes mellitus, hypercholesterolemia, or systemic hypertension.
    o Other risk factors: These include LV hypertrophy, obesity, and elevated serum levels of homocysteine, lipoprotein (a), plasminogen activator inhibitor, fibrinogen, serum triglycerides, or low high-density lipoprotein (HDL).
    o Metabolic syndrome: This has recently been characterized by the presence of hyperinsulinemia (fasting glucose level, ³110 mg/dL), abdominal obesity (waist circumference, >40 in for men or >35 in for women), decreased HDL cholesterol levels (<40 mg/dL for men or <50 mg/dL for women), hypertriglyceridemia (>150 mg/dL), and hypertension (³130/85 mm Hg). Based on data from the 2000 US census, an estimated 47 million Americans have the metabolic syndrome. Patients with the metabolic syndrome have a 3-fold increased risk for coronary atherosclerosis and stroke compared with those without this syndrome.
    * Precipitating factors: These include factors such as severe anemia, fever, tachyarrhythmias, catecholamines, emotional stress, and hyperthyroidism, which increase myocardial oxygen demand.
    * Preventive factors: Factors associated with reduced risk of atherosclerosis are a high serum HDL cholesterol level, physical activity, estrogen, and moderate alcohol intake (1-2 drinks/d).


    DIFFERENTIALS
    Section 4 of 10 Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic -

    * Authors and Editors
    * Introduction
    * Clinical
    * Differentials
    * Workup
    * Treatment
    * Medication
    * Follow-up
    * Miscellaneous
    * References


    Anemia
    Anxiety Disorders
    Aortic Dissection
    Aortic Stenosis
    Biliary Colic
    Cardiomyopathy, Hypertrophic
    Cholecystitis
    Coronary Artery Atherosclerosis
    Coronary Artery Vasospasm
    Diabetes Mellitus, Type 1
    Diabetes Mellitus, Type 2
    Gastric Ulcers
    Gastritis, Acute
    Gastroesophageal Reflux Disease
    Hiatal Hernia
    Hypercholesterolemia, Familial
    Hypercholesterolemia, Polygenic
    Hypertension
    Hyperthyroidism
    Isolated Coronary Artery Anomalies
    Kawasaki Disease
    Mitral Regurgitation
    Mitral Valve Prolapse
    Panic Disorder
    Pericarditis, Acute
    Pleurodynia
    Pneumothorax
    Polyarteritis Nodosa
    Pott Disease (Tuberculous Spondylitis)
    Pulmonary Embolism
    Pulmonary Hypertension, Primary
    Pulmonary Hypertension, Secondary
    Scleroderma
    Systemic Lupus Erythematosus
    Takayasu Arteritis
    Toxicity, Cocaine
    Varicella-Zoster Virus

    Other Problems to be Considered

    Esophageal spasm
    Esophageal rupture
    Costochondritis
    Herpes zoster
    Pneumonia with pleural involvement

    WORKUP
    Section 5 of 10 Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic -

    * Authors and Editors
    * Introduction
    * Clinical
    * Differentials
    * Workup
    * Treatment
    * Medication
    * Follow-up
    * Miscellaneous
    * References


    Imaging Studies

    * Chest radiograph findings are usually normal in patients with angina pectoris. However, they may show cardiomegaly in patients with previous MI, ischemic cardiomyopathy, pericardial effusion, or acute pulmonary edema. Calcification of coronary arteries frequently correlates with major coronary artery disease.
    * Graded exercise stress testing is the most widely used test for the evaluation of patients presenting with chest pain. In patients with established stable angina pectoris, it also can provide prognostic information about the extent of disease.
    *
    o Exercise stress testing can be performed alone and in conjunction with echocardiography or myocardial perfusion scintigraphy tests. Stress echocardiography has an overall sensitivity of 78% and specificity of 86%; myocardial perfusion scintigraphy has an overall sensitivity of 83% and specificity of 77%. Exercise stress testing alone generally has somewhat lower sensitivity and specificity, but it is cheaper and therefore is a reasonable choice in those with a low probability of disease.
    o These test results must be interpreted in the context of the likelihood of the presence of coronary artery disease determined from the patient's history and physical examination findings. In a population with low prevalence, the predictive abilities of these tests are low; however, in patients with a high likelihood of coronary artery disease, the predictive value is much higher.
    * Stress echocardiography can be used to evaluate segmental wall motion during exercise. It detects changes in regional wall motion that occur during myocardial ischemia. Normal myocardium becomes hyperdynamic during exercise; ischemic segments become hypokinetic or akinetic.
    *
    o Stress echocardiography has the advantage of simultaneous evaluation of LV function, cardiac dimensions, and valvular disease. It is especially useful in patients with baseline ECG abnormalities and those with systolic murmurs suggestive of aortic stenosis or hypertrophic cardiomyopathy.
    o It is also helpful for localizing ischemia and evaluating its severity.
    o Signs of severe coronary artery disease during exercise stress echocardiography include LV dilation, a decrease in global systolic function, and new or worsening mitral regurgitation. However, with dobutamine stress echocardiography, even in patients with severe coronary artery disease, the LV cavity may not dilate and global systolic function may improve.
    o A major problem with stress echocardiography is the technical difficulty with obtaining adequate images in some patients.
    * Thallium Tl 201 and technetium Tc 99m sestamibi are the most frequently used myocardial perfusion scintigraphy tests. These tests are especially useful in patients with baseline ECG abnormalities, to localize the region of ischemia, and as prognostic indicators. The presence of increased lung uptake upon thallium imaging is associated with a poor prognosis. Increased lung uptake, together with poststress dilation of the LV and multiple perfusion defects, is suggestive of either left main coronary artery disease or severe 3-vessel disease. The number of affected myocardial segments is predictive of long-term survival. Smaller perfusion defects are usually associated with peripheral coronary artery lesions, which are associated with a better prognosis. The absence of perfusion defects even in the presence of symptoms indicates an excellent prognosis.
    * The frequency of infarction or death is 1 case per 10,000 stress tests. Absolute contraindications include symptomatic cardiac arrhythmias, severe aortic stenosis, acute MI within the previous 2 days, acute myocarditis, or pericarditis. Discontinue the exercise stress test in the presence of chest pain, a drop in systolic blood pressure of more than 10 mm Hg, severe shortness of breath, fatigue, dizziness or near syncope, ST depression of more than 2 mm, ST elevation of at least 1 mm without diagnostic Q waves, or development of ventricular tachyarrhythmia.
    * In recent years, coronary artery calcium (CAC) scoring by fast computed tomography (CT) has become more popular in clinical practice for risk assessment of patients with chest pain. Currently, electron-beam computed tomography (EBCT) and multi-detector computed tomography (MDCT) are the primary fast CT methods for CAC measurement. However, some controversy exists about the usefulness of this test.
    *
    o In asymptomatic patients, analysis of the data from CAC scoring in patients with an intermediate Framingham risk score reveals that for a score of 400 or more, the patient's 10-year CAD risk would achieve a risk equivalent status similar to that noted with diabetes or peripheral arterial disease. Thus, finding a high CAC score in asymptomatic patients with an intermediate Framingham risk score (10-20% risk of CAD in 10 y) could be useful by resulting in a more aggressive management approach. However, unselected screening is of limited clinical value in asymptomatic patients who have a low Framingham risk score. On the other hand, assessment of CAC in asymptomatic patients with a high Framingham risk score (>20% risk of CAD in 10 y) has limited value since, based on current guidelines, these patients should be treated aggressively irrespective of their CAC scoring.
    o In symptomatic patients, exclusion of measurable CAC may be an effective tool before undertaking invasive diagnostic procedures or hospital admission. Patients with CAC scores of less than 100 have a low probability (<2%) of abnormal perfusion on nuclear stress tests, and a low probability (<3%) of obstructive CAD (>50% stenosis) on cardiac catheterization. Studies of large numbers of symptomatic patients demonstrated that the absence of CAC has a high negative predictive value of 96-100%. Thus, an individual with no coronary calcium (score _ 0) can be told with a high level of confidence that he or she has no obstructive angiographic coronary disease.
    o In patients with documented CAD, clinical monitoring of CAC progression through serial fast CT scanning to assess progression or regression of CAD is not recommended at this time.
    o Since most of current data regarding CAC are collected from patient population of mostly Caucasian men, the guidelines suggest caution in applying these findings to women and ethnic minorities.

    Other Tests

    * ECG is useful for evaluating persons with angina pectoris; however, findings are variable among patients.
    *
    o Approximately 50% of patients with angina pectoris have normal findings after a resting ECG. However, abnormalities such as evidence for prior MI, intraventricular conduction delay, various degrees of atrioventricular block, arrhythmias, or ST-T–wave changes may be seen.
    o During an attack of angina pectoris, 50% of patients with normal findings after resting ECG show abnormalities. A 1-mm or greater depression of the ST segment below the baseline, measured 80 milliseconds from the J point, is the most characteristic change. Reversible ST-segment elevation occurs with Prinzmetal angina. Some patients with coronary artery disease may show pseudonormalization of the resting ECG ST-T–wave abnormalities during episodes of chest pain.
    * Exercise with ECG monitoring alone is the initial procedure of choice in patients without baseline ST-segment abnormalities or in whom anatomic localization of ischemia is not a consideration.
    *
    o Horizontal or down-sloping ST-segment depression of at least 1 mm, measured 80 milliseconds from the J point, is considered the characteristic ischemic response.
    o ST-segment depression of more than 2 mm at a low workload or that persists for more than 5 minutes after termination of exercise and a failure of blood pressure to rise or an actual drop in blood pressure are signs of severe ischemic heart disease and a poor prognosis.
    o Withhold beta-blockers for approximately 48 hours before the stress test, whenever possible. Patients on digoxin and those with LV hypertrophy with repolarization abnormalities more often show positive results. Exercise stress tests have lower sensitivity and specificity in women and in patients with left bundle-branch block.
    o Pharmacologic agents (eg, dobutamine, dipyridamole, adenosine) can be used in patients who are unable to exercise.
    * Ambulatory ECG monitoring can be used for diagnostic purposes in patients with chest pain suggestive of Prinzmetal angina but is primarily used to evaluate the frequency of silent ischemia. Silent ischemia has been shown to be an independent predictor of mortality in patients with angina pectoris.

    Procedures

    * Selective coronary angiography is the definitive diagnostic test for evaluating the anatomic extent and severity of coronary artery disease.
    *
    o Consider coronary angiography in symptomatic patients with inconclusive noninvasive study results, in survivors of sudden cardiac death, in those who are considered to have a poor prognosis based on the results of noninvasive studies, in those with occupational requirements for a definite diagnosis (eg, pilots), or in patients with coronary artery disease who are severely symptomatic despite maximal medical therapy.
    o In patients in whom Prinzmetal angina is suggested, provocative testing with ergonovine maleate during coronary angiography may be useful.
    * Intra-aortic balloon counterpulsation can be used in patients who continue to have unstable angina pectoris despite maximal medical treatment. This procedure should be followed promptly by coronary angiography with possible coronary revascularization.
    * In patients whose angina is refractory to medical therapy who are not suitable candidates for either percutaneous or surgical revascularization, enhanced external counterpulsation is a safe and noninvasive alternative therapy. It increases coronary perfusion and reduces myocardial oxygen demand by diastolic augmentation of the central aortic pressure. Several studies have shown that patients treated with enhanced external counterpulsation have a significantly reduced number of anginal episodes, improved exercise tolerance, and decreased daily use of nitroglycerin tablets. Its therapeutic effects on quality of life are noted to remain at 1-year follow-up.


    TREATMENT
    Section 6 of 10 Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic -

    * Authors and Editors
    * Introduction
    * Clinical
    * Differentials
    * Workup
    * Treatment
    * Medication
    * Follow-up
    * Miscellaneous
    * References


    Medical Care

    The main goals of treatment in angina pectoris are to relieve the symptoms, slow the progression of disease, and reduce the possibility of future events, especially MI and premature death.

    * General measures
    *
    o Smoking cessation results in a significant reduction of acute adverse effects on the heart and may reverse, or at least slow, atherosclerosis. Strongly encourage patients to quit smoking, and take an active role in helping them to achieve this goal.
    o Treat risk factors, including hypertension, diabetes mellitus, obesity, and hyperlipidemia.
    o Several clinical trials have shown that in patients with established coronary artery disease, reduction of low-density lipoprotein (LDL) level with a beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitor (ie, statin) is associated with significant reductions in both mortality rate and major cardiac events.
    o
    + These benefits are present even in patients with mild-to-moderate elevations of LDL cholesterol level.
    + Recent trials with cholesterol-lowering agents have confirmed the benefits of the therapeutic LDL lowering in older persons.
    + Angiographic studies demonstrate that a reduction of the LDL level in patients with coronary artery disease could cause slowing of progression, stabilization, or even regression of coronary artery lesions.
    + A recent study demonstrates a significant reduction of symptomatic myocardial ischemia in patients with unstable angina or non–Q-wave infarction with the administration of a statin during the early acute phase.
    + In a study of 10,001 patients with stable coronary artery disease, an aggressive cholesterol-lowering approach with atorvastatin 80 mg daily (mean cholesterol level of 77 mg/dL) compared to a less-aggressive approach with atorvastatin 10 mg daily (mean cholesterol level of 101 mg/dL) resulted in a 2.2% absolute reduction and a 22% relative reduction in the occurrence of a first major cardiovascular event (defined as death from coronary heart disease; nonfatal, non–procedure-related myocardial infarction; resuscitation from cardiac arrest; or fatal or nonfatal stroke).1 This occurred with a greater incidence of elevated aminotransferase levels with the aggressive cholesterol-lowering approach (1.2% vs 0.2%, p <0.001).
    o Based on several recent studies that have demonstrated the benefits of more aggressive LDL-lowering therapies in high-risk patients with coronary artery disease, the Committee of the National Cholesterol Education Program recently made the following modifications to the Adult Treatment Panel III (ATP III) guidelines.
    o
    + In high-risk patients, a serum LDL cholesterol level of less than 100 mg/dL is the goal.
    + In very high-risk patients, an LDL cholesterol level goal of less than 70 mg/dL is a therapeutic option. Patients in the category of very high risk are those with established coronary artery disease with one of the following: multiple major risk factors (especially diabetes), severe and poorly controlled risk factors (especially continued cigarette smoking), multiple risk factors of the metabolic syndrome (especially high triglyceride levels [³200 mg/dL] plus non-HDL cholesterol level [³130 mg/dL] with low HDL cholesterol level [<40 mg/dL]), and patients with acute coronary syndromes.
    + For moderately high-risk persons (2+ risk factors), the recommended LDL cholesterol level is less than130 mg/dL, but an LDL cholesterol level of 100 mg/dL is a therapeutic option.
    o Some triglyceride-rich lipoproteins, including partially degraded very LDL levels, are believed to be independent risk factors for coronary artery disease. In daily practice, non-HDL cholesterol level (ie, LDL + very LDL cholesterol [total cholesterol - HDL cholesterol]) is the most readily available measure of the total pool of these atherogenic lipoproteins. Thus, the ATP III has identified non-HDL cholesterol level as a secondary target of therapy in persons with high triglyceride levels (>200 mg/dL). The goal for non-HDL cholesterol level (for persons with serum triglyceride levels >200 mg/dL) is 30 mg/dL higher than the identified LDL cholesterol level goal.
    o Patients with established coronary disease and low HDL cholesterol levels are at high risk for recurrent events and should be targeted for aggressive nonpharmacological (ie, dietary modification, weight loss, physical exercise) and pharmacological treatment.
    o Several large epidemiologic studies demonstrated that HDL cholesterol levels are inversely related to cardiovascular risk. Thus, developing pharmaceutical agents to increase the HDL level has been an attractive target for prevention and treatment of CAD. Cholesteryl ester transfer protein (CETP) inhibitors have been shown to have the effect of increasing HDL cholesterol levels by blocking this CETP. Torcetrapib has been one of CETP agents that has been used in large randomized trials.
    o
    + Investigation of Lipid Level management using coronary UltraSound To assess Reduction of Atherosclerosis by CETP inhibition and HDL Elevation (ILLUSTRATE) was a randomized study that looked at the effect of torecetrapib in 1188 patients with CAD who underwent intravascular ultrasonography at baseline.2 After treatment with atorvastatin to reduce levels of LDL cholesterol to less than 100 mg/dL, patients were randomly assigned to receive atorvastatin monotherapy or atorvastatin plus 60 mg of torcetrapib daily.

    Intravascular ultrasonography was repeated in 910 of these patients (77%) after 24 months of treatment to evaluate the disease progression. Compared with atorvastatin monotherapy, torcetrapib–atorvastatin therapy was associated with an impressive 61% relative increase in HDL levels and a 20% relative decrease in LDL levels resulting in an LDL to HDL ratio of less than 1.0 in this group of patients. Despite this favorable change in the HDL and LDL levels, among patients who underwent repeat intravascular ultrasonography, the percent atheroma volume between the 2 groups was not different. Torcetrapib did not result in significant decrease in the progression of coronary atherosclerosis, but it was associated with an increase in blood pressure.
    + Rating Atherosclerotic Disease change by Imaging with A New Cholesteryl-Ester-transfer protein inhibitor (RADIANCE) 2, a more recent trial, looked into the effect of torcetrapib on carotid atherosclerosis progression in patients with mixed dyslipidaemia.3 Although similar to the ILLUSTRATE trial, torcetrapib also substantially raised HDL levels and lowered LDL levels in this study; it did not affect the progression of carotid atherosclerosis. Similar to the ILLUSTRATE trial, torcetrapib also significantly increased systolic blood pressure.
    + Investigation of Lipid Level management to Understand its iMpact IN ATherosclerotic Events (ILLUMINATE), an international phase 3 study of 15,000 patients, was terminated early because it had already recorded 82 deaths in the patients taking torcetrapib-atorvastatin compared with 51 deaths in patients taking atorvastatin alone. In addition, the rates of MI, revascularization, angina, and heart failure were higher in the torcetrapib-atorvastatin arm. Due to the disappointing results of these studies, torcetrapib will not be developed further. Whether this failure represents a problem unique to torcetrapib or is common among the entire class of CETP inhibitors remains to be determined.
    o A recent study demonstrated that in patients with established coronary artery disease who have low HDL levels and low-risk LDL levels, drug therapy with medications that raise HDL levels and lower triglyceride levels but have no effect on LDL levels (eg, gemfibrozil) could significantly reduce the risk of major cardiac events.
    o Currently, the accepted approach to the management of patients with coronary artery disease and low HDL levels is as follows:
    o
    + In all persons with low HDL cholesterol levels, the primary target of therapy is to achieve the ATP III guideline LDL cholesterol level goals with diet, exercise, and drug therapy as needed.
    + After reaching the targeted LDL level goal, emphasis shifts to other issues. That is, in patients with low HDL cholesterol levels who have associated high triglyceride levels (>200 mg/dL), the secondary priority is to achieve the non-HDL cholesterol level goal of 30 mg/dL higher than the identified LDL cholesterol level goal. In patients with isolated low HDL cholesterol levels (triglycerides <200 mg/dL), drugs to raise the HDL cholesterol level (eg, gemfibrozil, nicotinic acid) can be considered.
    o Exercise training results in improvement of symptoms, increase in the threshold of ischemia, and improvement of patients' sense of well-being. However, before enrolling a patient in an exercise-training program, perform an exercise tolerance test to establish the safety of such a program.
    o Consider enteric-coated aspirin at a dose of 80-325 mg/d for all patients with stable angina who have no contraindications to its use. In patients in whom aspirin cannot be used because of allergy or gastrointestinal complications, consider clopidogrel.
    o Although early observational studies suggested a cardiovascular protective effect with the use of hormone replacement therapy, recent large randomized trials failed to demonstrate any benefit with hormone replacement therapy in the primary or secondary prevention of cardiovascular disease.
    o
    + In fact, these studies even demonstrated an increased risk of coronary artery disease and stroke in patients on hormone replacement therapy.
    + The Women's Health Initiative study demonstrated that the use of hormone replacement therapy for 1 year in 10,000 healthy postmenopausal women is associated with 7 more instances of coronary artery disease, 8 more strokes, 8 more pulmonary emboli, 8 more invasive breast cancers, 5 fewer hip fractures, and 6 fewer colorectal cancers.
    + Based on these data, the risks and benefits of hormone replacement therapy must be assessed on an individual basis for each patient.
    * Sublingual nitroglycerin has been the mainstay of treatment for angina pectoris. Sublingual nitroglycerin can be used for acute relief of angina and prophylactically before activities that may precipitate angina. No evidence indicates that long-acting nitrates improve survival in patients with coronary artery disease.
    * Beta-blockers are also used for symptomatic relief of angina and prevention of ischemic events. They work by reducing myocardial oxygen demand and by decreasing the heart rate and myocardial contractility. Beta-blockers have been shown to reduce the rates of mortality and morbidity following acute MI.
    * Long-acting heart rate–slowing calcium channel blockers can be used to control anginal symptoms in patients with a contraindication to beta-blockers and in those in whom symptomatic relief of angina cannot be achieved with the use of beta-blockers, nitrates, or both. Avoid short-acting dihydropyridine calcium channel blockers because they have been shown to increase the risk of adverse cardiac events.
    * Anginal symptoms in patients with Prinzmetal angina can be treated with calcium channel blockers with or without nitrates. In one study, supplemental vitamin E added to a calcium channel blocker significantly reduced anginal symptoms among such patients.
    * In patients with syndrome X and hypertension, ACE inhibitors may normalize thallium perfusion defects and increase exercise capacity.

    Surgical Care

    * Revascularization therapy (ie, coronary revascularization) can be considered in patients with left main artery stenosis greater than 50%, 2- or 3-vessel disease and LV dysfunction (ejection fraction, <45%), poor prognostic signs during noninvasive studies, or severe symptoms despite maximum medical therapy. The 2 main coronary revascularization procedures are percutaneous transluminal coronary angioplasty, with or without coronary stenting, and coronary artery bypass grafting.
    * Patients with 1- or 2-vessel disease and normal LV function who have anatomically suitable lesions are candidates for percutaneous transluminal coronary angioplasty and coronary stenting. Restenosis is the major complication, with symptomatic restenosis occurring in 20-25% of patients. Restenosis mostly occurs during the first 6 months after the procedure and can be managed by repeat angioplasty. Several trials have demonstrated that the use of drug-eluting stents (eg, sirolimus-eluting stents, paclitaxel-coated stents) can remarkably reduce the rate of in-stent restenosis. With the introduction of these drug-coated stents, patients with multivessel coronary artery disease are more frequently treated with percutaneous revascularization as opposed to the surgical revascularization.

    More recently, some concerns have arisen that instead of improving the long-term prognosis, drug-eluting stents might actually worsen it. In addition, stent thrombosis is a major concern with the use of drug-eluting stents. A meta-analysis of individual data on 4958 patients enrolled in 14 randomized trials comparing sirolimus-eluting stents with bare-metal stents looked at the long-term effect of these stents.4 The mean follow-up interval was 12.1-58.9 months. The primary end point was death from any cause. The secondary end points were stent thrombosis, the composite end point of death or myocardial infarction, and the composite of death, MI, or a revascularization. The overall risk of death and the combined risk of death or MI were not significantly different for patients receiving sirolimus-eluting stents versus bare-metal stents. A sustained reduction in the need for revascularization occurred after the use of sirolimus-eluting stents compared with bare-metal stents. The overall risk ofstentthrombosis with sirolimus-eluting stents was not significantly higher than bare-metal stents. However, evidence showed an increase in the risk of stent thrombosis associated with sirolimus-eluting stents after the first year.
    * Patients with single-vessel disease and normal ventricular function treated with percutaneous transluminal coronary angioplasty show improved exercise tolerance and fewer episodes of angina compared with those who receive medical treatment. However, no difference in the frequency of MI or death has been shown between these two groups.
    * The Clinical Outcomes Utilizing Revascularization and AGgressive Drug Evaluation (COURAGE) trial looked at the benefits of PCI as an initial management strategy in patients with stable CAD. This trial was a randomized and involved 2287 patients who had objective evidence of myocardial ischemia and significant CAD.5 Of these, 1149 patients were randomized to undergo PCI with optimal medical therapy (PCI group) and 1138 were to receive optimal medical therapy alone (medical-therapy group). They were observed for 2.5-7 years (median, 4.6 y). During the follow-up, no difference was reported in the primary outcome of death from any cause and nonfatal MI between the PCI group and the medical-therapy group. In addition, no significant differences were noted between the 2 groups in the secondary end points of the composite of death, MI, and stroke; hospitalization for acute coronary syndrome; or MI.
    * Patients with significant left main coronary artery disease, 2- or 3-vessel disease and LV dysfunction, diabetes mellitus, or lesions anatomically unsuitable for percutaneous transluminal coronary angioplasty have better results with coronary artery bypass grafting. The overall operative mortality rate for coronary artery bypass grafting is approximately 1.3%. The rate of graft patency 10 years after surgery is less than 50% for vein grafting, although more than 90% of grafts using internal mammary arteries are patent at 10 years. In recent years, interest has increased regarding surgery without cardiopulmonary bypass (ie, off-pump) in an attempt to avoid the morbidity associated with cardiopulmonary bypass. A recent randomized study demonstrated that off-pump coronary surgery was as safe as on-pump surgery and caused less myocardial damage. However, the graft-patency rate was lower at 3 months in the off-pump group than in the on-pump group.
    * Recently, laser transmyocardial revascularization has been used as an experimental therapy for the treatment of severe, chronic, stable angina refractory to medical or other therapies. This technique has been performed with either an epicardial surgical technique or by a percutaneous approach. In both approaches, a series of transmural endomyocardial channels are created to improve myocardial perfusion. The surgical transmyocardial revascularization technique has been associated with symptomatic relief for end-stage chronic angina in the short term. However, no published data address the long-term efficacy of surgical transmyocardial revascularization. Nonetheless, this technique appears to provide at least symptomatic relief for end-stage chronic angina in the short term.

    Diet

    A diet low in saturated fat and dietary cholesterol is the mainstay of the Step I and Step II diet from the American Heart Association.
    Activity

    The level of activity that aggravates anginal symptoms is different for each patient. However, most patients with stable angina can avoid symptoms during daily activities simply by reducing the speed of activity.
  49. Aman.

    Aman. Guest

    Fulminant hepatic failure (FHF) is defined as a syndrome of acute liver failure with the development of hepatic encephalopathy and severe hypoprothrombinemia occurring within 2 months of the onset of symptoms or jaundice in a person without preexisting liver disease.1 Total orthotopic liver transplantation (OLTX) is a lifesaving therapeutic option for patients with FHF, but currently requires lifelong immunosuppression to maintain the graft.2 Auxiliary partial orthotopic liver transplantation (A-OLTX) is a procedure whereby only a portion of the native liver is removed, and the remainder of the native liver is left in situ.3 A-OLTX provides temporary support until the native liver recovers and immunosuppression can be withdrawn.

    Liver transplantation for FHF has been well-accepted in recent years, accounting for 5% to 10% of indications for OLTX.4 Survival rates have varied substantially between centers ranging from 50% to over 90%.4 This variation has been due in large part to the difficulty in finding donors within the short time span before irreversible brain injury, and the use of marginal donors with poor initial graft function in this context. Progress in recent years has included the development of improved prognostic scores for the selection of patients for OLTX and the use of intracranial pressure monitoring for selection of viable candidates and perioperative monitoring.

    Despite improvements in transplantation therapy, recovery of the native liver obviating the need for lifetime immunosuppression is the optimum outcome for patients with acute liver failure. To achieve this end, artificial liver support and the use of auxiliary liver grafts with preservation of the native liver have been introduced.3 Although artificial liver devices have had limited success to date, up to 40% of patients supported with auxiliary liver transplants may have recovery of their own liver with subsequent withdrawal of immunosuppression.

    FHF caused by acute toxic ingestions offer an ideal setting in which to perform A-OLTX. The insult is discrete, structural damage may be minimal, and no infectious agent is involved.

    Emergency A-OLTX for FHF has the distinct advantages of permanently stopping immunosuppressive therapy with withdrawal of the auxiliary graft and allowing recovery of full native liver function as demonstrated in the present case. Obviously, A-OLTX is not appropriate therapy for all patients. Criteria for prediction of those patients who are expected to have complete native liver regeneration and who could benefit from A-OLTX are not established. For FHF, young age, viral hepatitis or acetaminophen overdose as etiologies of FHF, and a delay between the onset of jaundice and encephalopathy less than 7 days are recognized predictors of a favorable outcome for patients with FHF.1,5 Amanita phalloides ingestion is a rare enough condition such that prognostic criteria are not well recognized. The extent of hepatic injury might be expected to influence outcome because liver regeneration is required for ultimate recovery. Our patient had extensive diffuse centrilobular necrosis in her native liver at the time of emergency A-OLTX, and her native liver recovered completely. This finding is in agreement with other reports indicating that the extent of hepatocyte necrosis on liver biopsy is of no value in predicting the survival of patients with FHF.3,6 Surviving hepatocytes, even if few in number but if relatively damage-free, have the potential for extensive regeneration with time and the potential for ultimate complete recovery of the native liver. Situations where there is injury from a limited single hepatotoxin exposure, as in the current case, may theoretically be the most appropriate candidates for emergency A-OLTX. Based on our successful case, application of emergency A-OLTX should be considered a therapeutic option for children with FHF from Amanita phalloides ingestion or other hepatotoxins when the native liver has the potential to regenerate and recover.

    ans: drug induced fulminant liver failure
  50. Meena.

    Meena. Guest

    williams syndrome
    -----------------------------



    Background

    Originally described independently by Williams and Beuren in 1961, Williams syndrome (WS) is a rare genetic condition whose clinical manifestations include a distinct facial appearance, cardiovascular anomalies, hypercalcemia, and a characteristic neurodevelopmental/behavioral profile.
    Pathophysiology

    Haploinsufficiency (loss of 1 out of 2 copies) due to a deletion at chromosome band 7q11.23 involving the elastin gene, ELN, is implicated in virtually all cases of Williams syndrome. Most deletions are not detected through standard karyotyping but rather through fluorescent in situ hybridization (FISH) for a 2-Mb deletion (Ewart, 1993; Lowery, 1995; Nickerson, 1995). The size of the deletion can be variable (Urban, 1996; Hockenhull, 1999; Heller, 2003).

    Williams syndrome is not caused solely by elastin haploinsufficiency; the deletion involves a region spanning over 20 genes and, hence, is considered a contiguous gene deletion syndrome (Urban, 1996; Merla, 2002). The cardiovascular and connective tissue Pathology , as well as facial dysmorphology, is attributed to the elastin gene haploinsufficiency (Mari, 1995; Dridi, 1999).

    Other genes being investigated for their role in the cognitive profile of Williams syndrome include LIMK1, GTF1IRD1, and GTF2I (Frangiskakis, 1996; Tassabehji, 1996; Hirota, 2003). However, genotype-phenotype correlations with genes other than elastin are not yet fully elucidated (Osborne, 1999; Merla, 2002).
    Frequency
    United States

    Williams syndrome occurs in 1 per 20,000 births; cases are largely sporadic.
    International

    Frequency worldwide is the same as in the United States.
    Mortality/Morbidity

    Cardiovascular disease accounts for most early mortality associated with Williams syndrome. Overall, unexpected death is rare, but it is 25- to 100-fold higher than in age-matched control subjects (Wessel, 2004). Factors implicated in sudden death have included supravalvar aortic stenosis (SVAS), severe pulmonary stenosis, and myocardial ischemia secondary to either coronary insufficiency or biventricular outflow tract obstruction with ventricular hypertrophy. Coronary insufficiency appears most likely because of stenosis resulting from intimal fibrosis and muscular hypertrophy.

    Deaths have been reported after induction of anesthesia for minor surgical procedures, during cardiac catheterization and heart surgery, and with progressive heart failure and respiratory infection (Bird, 1996; Wessel, 2004; Bragg, 2005). Sudden deaths with no apparent instigating event have also been reported but with apparent underlying myocardial injury (Bird, 1996). Patients with a higher risk of sudden death may show signs of myocardial ischemia on electrocardiogram (such as ST segment depression). Echocardiography, Holter monitoring, and careful evaluation should be considered before the use of anesthesia, sedation, or both or prior to an invasive procedure. Patients have also presented with syncope related to SVAS who died during diagnostic cardiac catheterization. Calcified valvular aortic stenosis has also been reported (Horowitz, 2002), but not with sudden death (Yetkin, 2004).

    Sigmoid diverticulitis in adults is reported at a higher frequency in the Williams syndrome population than in the general population (Partsch, 2005).

    Williams syndrome is a multisystem condition with other potential consequences, including mental retardation, motor delay, hearing loss, severe dental disease, ocular problems, progressive joint contractures, and bowel and bladder diverticula.
    Race

    Williams syndrome is panethnic. The prevalence of particular features may vary among populations, for instance peripheral pulmonary stenosis is more common than SVAS in the Hong Kong Chinese population (Yau, 2004), and people living in Greece have a lower rate of cardiovascular anomalies (Amenta, 2005).
    Sex

    The deletion is equally prevalent in males and females. A greater severity and earlier presentation of cardiovascular disease may exist in males (Sadler, 2001; Bruno, 2003).
    Age

    Clinical manifestations of Williams syndrome are evident from birth through adulthood. However, features that may be detected antenatally include the characteristic cardiovascular lesions. In addition, fetal ultrasounds of neonates with Williams syndrome have revealed multicystic dysplastic kidney in addition to the congenital heart lesions (Zaghloul, 2002). Associated findings on prenatal screening that have been reported include an increased fetal nuchal translucency (Gicquel, 1998) and low maternal serum alpha fetoprotein (MSAFP) (Bernard, 1997), although none of the prenatal findings has been proven to be a diagnostic marker of Williams syndrome.

    CLINICAL
    Section 3 of 9 Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic �

    * Authors and Editors
    * Introduction
    * Clinical
    * Differentials
    * Workup
    * Treatment
    * Follow-up
    * Miscellaneous
    * References


    History

    The history obtained from caregivers of patients with Williams syndrome is variable and reflects the wide phenotypic spectrum observed in the syndrome. The neurodevelopmental profile primarily involves 4 areas: cognitive development, language, auditory function, and visuospatial function (Mervis, 2000).

    * Children with Williams syndrome are described as overly friendly, hyperactive, inattentive, and hypersensitive to loud sounds or certain types of sounds (Blomberg, 2005).
    * Intellectual, motor, and language skills are typically delayed. Children with Williams syndrome typically have mild-to-moderate mental retardation, but the range includes severe mental retardation to average intelligence (Mervis, 2000). Abilities should be considered on an individual basis due to the wide variability among individuals (Porter, 2005).
    * Older children have relative strengths in language and auditory memory with significant weaknesses in visual-spatial cognition.
    * Visual-spatial problems may present as gait apraxia, especially on uneven or sandy surfaces (Withers, 1996).
    * A history of hearing deficits and visual disturbances is possible.
    * Adults may have a high rate of emotional and behavioral problems, poor social relationships and anxiety, preoccupations and obsessions, and communication disturbances. Few adults achieve complete independence (Einfeld, 2001; Davies, 1997; Davies, 1998).
    * In children, a history of increased urinary frequency and daytime wetting is possible (Schulman, 1996). A history of renal abnormalities is also possible.
    * Children may have a history of postnatal growth delay including short stature with delayed bone age (Partsch, 1999), growth hormone deficiency (Spadoni, 1983), and decreased insulinlike growth factor–1 (IGF1) levels (Kuijpers, 1999; Xekouki, 2005).
    * A history of hypertension may exist.
    * A history of connective tissue abnormalities, such as abnormal joint mobility, hernias, and diverticula, is possible.

    Physical

    A wide variation occurs in the phenotypic expression of Williams syndrome. Virtually all cases have typical facial features that can be recognized even at birth.

    * Children with Williams syndrome are generally full-term infants.
    * Microcephaly in one third of children (Pankau, 1994) and postnatal failure to thrive is typical.
    * The diagnosis of Williams syndrome should also be considered after an incidental finding of idiopathic hypercalcemia or a characteristic cardiac lesion such as SVAS. Other cardiac lesions in patients with Williams syndrome can include pulmonary stenosis and mitral valve regurgitation (Eronen, 2002; Bruno, 2003). Arterial hypertension may be present. If the distinct facial features are not evident, consider referral to a practitioner experienced in examining the facial features of Williams syndrome, such as a clinical geneticist or cardiologist experienced in dysmorphology.
    * Virtually all children and adults with Williams syndrome have some combination of the following facial features: short upturned nose, flat nasal bridge, long philtrum, flat malar area, wide mouth, full lips, dental malocclusion and widely spaced teeth, micrognathia, stellate irides, and periorbital fullness. The voice may be harsh. Nails tend to be hypoplastic and the skin soft and lax, and the hallices have a valgus deviation. "Elfin facies" is considered a pejorative term, and its use should be discouraged.
    * Ocular findings can include strabismus (usually due to esotropia), a stellate iris, cataract, retinal vascular tortuosity, and reduced binocular vision; a case of Reiger anomaly has even been reported (Greenberg, 1988; Kapp, 1995; Sadler, 1996).
    * Sensorineural hearing loss can be present and is likely underdiagnosed (Marler, 2005). It can be aggravated by conductive loss due to middle ear effusions.
    * Examine patients for signs of precocious puberty.
    * Other findings include hyperacusis (despite hearing loss), hoarse voice, joint hyperelasticity, contractures, kyphoscoliosis, and lordosis.
    * Monitor for hypertension at every visit.

    Causes

    A deletion on band 7q11.23 near the elastin gene is identified in virtually all individuals with Williams syndrome. The underlying etiology is believed to be unequal meiotic crossover events leading to interstitial deletions (Dutly, 1996; Baumer, 1998). These deletions may result in unbalanced interchromosomal and, to a lesser extent, intrachromosomal rearrangements. Mechanisms whereby chromosomes paired during meiosis may undergo unequal crossover resulting in Williams syndrome have typically been thought to result from an unequal overlap of repetitive Alu sequences flanking the region resulting in a type of misalignment of the chromosomal regions during a crossover event (Robinson, 1996). In addition, another mechanism that has recently been shown includes a familial inversion polymorphism in the Williams syndrome region that may predispose to unequal crossover during meiosis (Osborne, 2001).

    DIFFERENTIALS
    Section 4 of 9 Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic �

    * Authors and Editors
    * Introduction
    * Clinical
    * Differentials
    * Workup
    * Treatment
    * Follow-up
    * Miscellaneous
    * References


    Aortic Stenosis, Supravalvar
    Attention Deficit Hyperactivity Disorder
    Failure to Thrive
    Hypercalcemia

    WORKUP
    Section 5 of 9 Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic �

    * Authors and Editors
    * Introduction
    * Clinical
    * Differentials
    * Workup
    * Treatment
    * Follow-up
    * Miscellaneous
    * References


    Lab Studies

    * Fluorescent in situ hybridization (FISH) for the 7q11.23 elastin gene deletion should be performed in patients in whom Williams syndrome is suspected, in addition to a routine chromosomal analysis (karyotype). Testing is routinely performed on peripheral blood leukocytes. FISH testing and karyotype are performed in cytogenetics laboratories. An international list of laboratories offering FISH testing for Williams syndrome is available through GeneTests or the European Directory of DNA Diagnostic Laboratories.
    *
    o A standard karyotype should always be performed since a negative FISH result for Williams syndrome does not exclude the possibility of an underlying chromosomal abnormality, and chromosomal translocation in the region affected by Williams syndrome has been reported (von Dadelszen, 2000).
    o Since atypical cases of Williams syndrome may have other chromosomal rearrangements not detected by the standard FISH test, further studies, such as high resolution chromosome analysis and testing for ELN gene mutations should be coordinated through a clinical geneticist
    * FISH testing and chromosomal analysis in the parents is not routinely indicated, unless either parent has associated physical features or other findings for which Williams syndrome is suspected, a positive family history of Williams syndrome, or other affected children with Williams syndrome.
    * Plasma creatine phosphokinase (CPK) levels may be elevated, but the clinical significance is not clear in incidental cases (Amenta, 2005). Further studies are needed to see if this may relate to an underlying myopathy (Voit, 1991).
    * Obtain baseline measurements of serum calcium, blood urea nitrogen (BUN), and serum creatinine levels. Perform routine urinalysis and obtain spot urine calcium/creatinine ratios. Serum calcium can be checked in suspected cases before genetic confirmation of the diagnosis.
    * Obtain a baseline thyroid-stimulating hormone (TSH) levels.

    Imaging Studies

    * Perform a baseline echocardiogram in all patients diagnosed with Williams syndrome, regardless of cardiac physical examination findings. Approximately one half of all children with Williams syndrome have a significant cardiac lesion.
    * Cardiovascular management is dependent on the specific cardiac lesion present. In addition to ECGs and echocardiograms, children with SVAS may require cardiac catheterization as part of their presurgical evaluation.
    * Obtain a renal ultrasound in the initial workup to look not only for anatomic abnormalities but also for nephrolithiasis caused by hypercalcemia. The incidence of renal abnormalities in Williams syndrome is significantly higher than that in the general population (Sforzini, 2002). Further management may require referral to a urologist, nephrologist, or both.

    Other Tests

    * Full neurodevelopmental testing may aid the general practitioner in identifying suspected cases of Williams syndrome, and it may help tailor schooling and supplemental developmental assistance for children already diagnosed with Williams syndrome.


    TREATMENT
    Section 6 of 9 Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic �

    * Authors and Editors
    * Introduction
    * Clinical
    * Differentials
    * Workup
    * Treatment
    * Follow-up
    * Miscellaneous
    * References


    Medical Care

    Williams syndrome is a complex multisystem medical condition that requires the attention of multiple health care professionals. A few large tertiary care centers have Williams syndrome clinics, which help organize and coordinate the care of Williams syndrome patients. Williams Syndrome Associations exist in the United States and Canada and are a valuable resource for both parents and health care professionals.

    Tailor specific management of Williams syndrome to the presenting clinical spectrum. Initial care often centers on failure to thrive, hypercalcemia, or repair of the cardiac lesion. School performance, physical therapy, hyperactivity, and the child's eventual role in society are long-term issues that need to be addressed on an ongoing basis. Anticipatory guidance is essential to help parents prepare for future needs of children with Williams syndrome. Anticipatory care guidelines and growth curves for children with Williams syndrome are available through the American Academy of Pediatrics.

    * Hypercalcemia is frequently asymptomatic and resolves in the first few years of life but can be lifelong.
    *
    o Signs and symptoms of hypercalcemia, in addition to blood calcium levels, should be monitored periodically throughout life and prior to the administration of any anesthetic or sedative agent and prior to any invasive procedure. Symptomatic hypercalcemia can present with decreased feeding, irritability, and severe colic in infants and may require multidisciplinary management through restriction of calcium, vitamin D intakes (including vitamin formulations), specialized formulas and some patients may require bisphosphonates to control elevated calcium levels (Cagle, 2004; Oliveri, 2004).
    o The goal of managing calcium and vitamin D levels is to monitor and achieve levels in the normal range for age at intakes adequate for bone growth. The need for dietary manipulation and medication to control hypercalcemia should be monitored frequently since long-term unrestricted use of low calcium, low vitamin D formula has been reported to lead to rickets in a patient with Williams syndrome (Mathias, 2000).
    o Nephrocalcinosis and sclerosis of the long bones are occasionally observed.
    * Systemic hypertension should be treated when identified.
    * Periodically assess visual problems and hearing loss. Middle ear infusions should be done periodically. Acoustic-visual-behavioral training has been reported to improve symptoms of hyperacusis in an adult (Miani, 2001).
    * Patients with short stature should have a bone age assessment and be referred to an endocrinologist for assessment and management of growth hormone deficiency.
    * Monitor for signs of precocious puberty and arrange referrals with an endocrinologist as necessary (Partsch, 2002).
    * Feeding difficulties in children are common, and referral to a gastroenterologist should be considered.
    * Early involvement of dentist is suggested.

    Surgical Care

    For cardiac findings in children with Williams syndrome, early involvement with a pediatric cardiologist and cardiothoracic surgeon is essential.

    * SVAS is the most frequently observed operable cardiac lesion in Williams syndrome. SVAS may be progressive in some individuals and life-long cardiac follow-up is recommended (Wessel, 1994).
    * Timing of the operative repair depends on the presence of cardiac symptoms, the gradient across the supraaortic obstruction, or if ischemic changes are noted on a stress test. Peripheral branch pulmonary stenosis usually resolves spontaneously and generally should not be treated with catheter or surgical intervention.
    * In general, the degree of supraaortic obstruction in Williams syndrome patients tends to progress with time, whereas peripheral branch pulmonary stenosis improves with time.

    Consultations

    Williams syndrome requires the attention of multiple health care professionals, depending on the specific phenotypic manifestations. Many large tertiary care centers have Williams syndrome clinics that help organize and coordinate the care of patients with Williams syndrome.

    * For cardiac findings in children with Williams syndrome, early involvement of a pediatric cardiologist and cardiothoracic surgeon is essential.
    * An anesthesiologist should be consulted prior to administration of anesthetics. Sedation should be administered only by physicians experienced in pediatric procedural sedation.
    * Geneticists, dentists, ophthalmologists, orthopedists, physical and occupational therapists, and psychologists all contribute to the care of the patient with Williams syndrome.
    * Parents of children with Williams syndrome should be offered genetic counseling to review their recurrence risks and options for prenatal diagnosis. If neither parent is affected with Williams syndrome, the risk of having another affected child with Williams syndrome is usually less than 1%. However, recurrences of Williams syndrome have been reported even with unaffected parents due to apparent germline mosaicism (Kara-Mostefa, 1999). If one parent is affected with Williams syndrome, the risk for having an affected child is typically 50% since the deletion behaves in an autosomal dominant manner. When of appropriate age, affected children should receive genetic counseling prior to considering having children of their own.
    * Women with Williams syndrome considering pregnancy or who are pregnant should be referred to a maternal-fetal medicine specialist for close monitoring. In particular, a pregnant woman with Williams syndrome should be monitored for hypertension, hypercalcemia, and cardiovascular and other complications (Mulik, 2004).

    urther Outpatient Care

    * School performance, hyperactivity, and the child's eventual role in society are long-term issues that need to be addressed on an ongoing basis.
    * Anticipatory guidance is essential to help parents prepare for future needs of children with Williams syndrome.

    Prognosis

    * Medical complications may occur, especially related to the cardiovascular system. However, most individuals with Williams syndrome are healthy and lead active full lives.
    * Most adults with Williams syndrome are employed in a variety of settings and can perform self-care tasks.
    * Some adults with Williams syndrome require the daily care of parents or caregivers; however, others may live with less supervision and care.

    Patient Education

    * Inform parents or caregivers of the Williams Syndrome Association (WSA) for supporting resources and education. WSAs are located in the United States and Canada . They provide valuable resources for parents and caregivers. The WSA can be contacted by phone (248-541-3630) or through the Williams Syndrome Association Web site.


    MISCELLANEOUS
    Section 8 of 9 Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic �

    * Authors and Editors
    * Introduction
    * Clinical
    * Differentials
    * Workup
    * Treatment
    * Follow-up
    * Miscellaneous
    * References


    Medical/Legal Pitfalls

    * Failure to perform an echocardiogram or to refer patients to a pediatric cardiologist in the presence of any cardiac history or findings
    * Failure to consider risks in a patient with Williams syndrome who is pregnant
    * Failure to discuss the options of prenatal care and recurrence risks
    * Failure to screen and manage high-risk patients prior to anesthetic and sedation procedures, cardiac catheterization, or surgery

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