AIIMS nov07 Q & A with explanation

Discussion in 'AIIMS Nov 2013' started by DR.KAVISH CHOUHAN, Nov 6, 2007.

  1. Manisha.

    Manisha. Guest

    LYSOSOMAL STORAGE DISEASE
    .........DEFECT IN LYSOSOMAL MEMBRANE.......INABILITY OF LYSOSME TO BIND WITH GOLGI BODIES............?


    ANS-DEFECT IN LYSOSOMAL MEMBRANE
    www.biochemsoctrans.org/bst/028/0150/0280150.pdf
    ochemical Society Transactions (2000) Volume 28, part 2
    The molecular basis of lysosomal storage diseases and their treatment
    B. Winchester, A. Vellodi and E. Young
    Biochemistry , Endocrinology and Metabolism Unit, Institute of Child Health (University College London) and
    Great Ormond Street Hospital, 30 Guilford Street, London WC1N 1EH, U. K.
    Abstract
    The lysosomal system is the main intracellular
    mechanism for the catabolism of naturally oc-
    curring endogenous and exogenous macromol-
    ecules and the subsequent recycling of their
    constituent monomeric components. It also plays
    an important part in processing essential metab-
    olites. A genetic defect in a protein responsible for
    maintaining the lysosomal system results in the
    accumulation within lysosomes of partially de-
    graded molecules, the initial step in the process
    leading to a lysosomal storage disease. The de-
    fective protein can be a luminal lysosomal enzyme
    or protein cofactor, a lysosomal membrane pro-
    tein or a protein involved in the post-translational
    modification or transport of lysosomal proteins.
    Over 40 lysosomal storage diseases are known and
    they have a collective incidence of $1 in 7000–
    8000 live births. Most of the genes for the
    lysosomal proteins have been cloned, permitting
    mutation analysis in individual cases. This in-
    formation can be used for genotype\phenotype
    correlation, genetic counselling and the selection
    of patients for novel forms of therapy, such as
    substrate deprivation or dispersal, enzyme re-
    placement,bone-marrowtransplantationandgene
    transfer.
    Introduction
    The lysosomal system is the main intracellu-
    lar mechanism in eukaryotic cells for the catab-
    olism of naturally occurring macromolecules,
    which may arise from within or outside a cell (for
    a comprehensive review of the biology of lyso-
    somes see [1]). It also plays an important part in
    processing several essential metabolites. Material
    to be catabolized or processed is delivered to the
    lysosomes either by direct engulfment or by fusion
    of digestive vacuoles with the lysosomes. Catab-
    olism takes place within the lumen of the lyso-
    somes at an acidic pH, which is maintained by a
    Key words: enzyme replacement therapy, substrate deprivation.
    Abbreviations used: MPR, mannose 6-phosphate receptor; MPS,
    mucopolysaccharide; ERT, enzyme-replacement therapy; BMT,
    bone-marrow transplantation.
    specific proton pump in the lysosomal membrane.
    This catabolism is catalysed by a mixture of
    enzymes, which collectively have the capacity to
    degrade all naturally occurring macromolecules
    totheirconstituentmonomericcomponents,which
    can then pass through the lysosomal membrane
    for reutilization by the cell. The pathways for the
    lysosomal catabolism of most macromolecules
    have been established [1]. The enzymes in these
    pathways are predominantly soluble hydrolases,
    whichhavecharacteristicacidicpHoptimaandare
    localized in the lumen of the lysosome. They
    are all glycoproteins and are synthesized on ribo-
    somes associated with the rough endoplasmic
    reticulum as inactive precursors and transported
    to the lysosomes via the endoplasmic reticulum
    and the Golgi compartment. During their trans-
    port from their site of synthesis to their site of
    action they undergo essential post-translational
    modification, including proteolysis, glycosylation
    and phosphorylation [2]. In particular they ac-
    quire a specific lysosomal-recognition marker,
    mannose 6-phosphate, which is recognized by
    specific mannose 6-phosphate receptors (MPRs)
    in the Golgi compartment. Binding to the MPRs
    segregates the proteins destined for the lumen of
    the lysosome from other glycoproteins. The
    MPR–lysosome enzyme-precursor complex is de-
    livered to a pre-lysosomal compartment, where
    dissociation occurs. The receptor recycles to the
    trans-Golgi network or the plasma membrane and
    the lysosomal enzyme precursors are transported
    to lysosomes where the final steps in their matu-
    ration occur. These include proteolysis, folding,
    aggregation and possibly dephosphorylation. The
    lysosomal sulphatases undergo a novel oxidation
    of the thiol group of a conserved cysteine to an
    aldehyde in the endoplasmic reticulum [3]. Some
    lysosomalenzymesthatactonlipophilicsubstrates
    require a non-enzymic protein co-factor, a sphin-
    golipid activator protein or saposin, to function
    [4]. Four saposins are derived from a common
    precursor, prosaposin, which is also transported
    to the lysosomes by the mannose 6-phosphate-
    recognition pathway. A few lysosomal enzymes
    are associated with the lysosomal membrane. Al-
    though they are glycoproteins they are transported
    # 2000 Biochemical Society
    150
    Page 2
    Organisms, Organs, Cells and Organelles
    to the lysosomes by an alternative route that does
    not utilize the mannose 6-phosphate marker. An
    alternative delivery route may also exist for the
    luminal enzymes in certain cells [2].
    The low-molecular-mass products of lyso-
    somal digestion can pass through the lysosomal
    membrane, whereas the membrane is imper-
    meable to undigested or partially digested ma-
    terial. Egress from the lysosomes is either by
    passive diffusion or by specific metabolite tran-
    sporters [5]. Two transporters, for cystine [6] and
    sialic acid [7], have recently been cloned. Several
    other lysosomal membrane proteins have been
    isolated and cloned but their functions are not
    known [8]. They are not transported to the
    lysosomes by the mannose 6-phosphate pathway
    but are either delivered to the endosomal\
    lysosomal system directly in clathrin-coated vesi-
    cles or indirectly via the plasma membrane after
    following the default secretory pathway for glyco-
    proteins. Signals in the short cytosolic domain of
    these proteins mediate their sorting and delivery
    to the lysosomes.
    A genetic defect in a lysosomal enzyme, its
    protein cofactor, a lysosomal membrane protein or
    in a protein involved in the post-translational
    modification or transport of lysosomal proteins
    will disrupt lysosomal function. In consequence,
    partially digested molecules, or in the case of a
    transporter defect, the substrate, will accumulate
    progressively within lysosomes. This is the patho-
    logical condition called a lysosomal storage
    disease. The progressive hypertrophy of the lyso-
    somal system leads to a wide range of clinical
    symptoms that depend on the protein defect, the
    nature of the stored material and the cells in which
    the material is stored. The pathogenesis of lyso-
    somal storage diseases is poorly understood [9].
    Over 40 different lysosomal storage diseases have
    been described in humans [10], with an overall
    prevalence of approximately 1 in 7000–8000 live
    births [11]. Diagnosis is based on clinical symp-
    tomsfollowedbydemonstrationofadeficiencyofa
    specific enzyme activity or transporter. Most of
    thegenesfortheproteinsinvolvedinthelysosomal
    system have been cloned, permitting mutation
    analysis in individual cases. This information is
    very useful for carrier detection and genetic
    counselling within families and for investigating
    the relationship between genotype and phenotype.
    The lysosomal storage diseases are very hetero-
    geneous genetically. A full understanding of the
    molecular basis of a lysosomal storage disease is
    becoming increasingly important for the selection
    ofpatientsforthenovelformsoftherapybecoming
    available.
    Many naturally occurring lysosomal storage
    diseases have also been reported in animals [12]
    and they have been used to investigate the patho-
    genesis of the disorders and therapeutic strategies.
    More recently many mouse models of the cor-
    responding human disease have been created by
    targeted disruption of specific genes [13,14].
    Approaches to therapy can be considered at
    two levels, dispersal or restriction of the storage
    material and replacement of the defective protein
    (Figure 1). Dispersal of the storage products is
    probably only applicable to transport defects in
    which low-molecular-mass material has accumu-
    lated within the lysosomes. The intralysosomal
    accumulation of cystine in cystinosis can be de-
    creased by high oral doses of the drug cysteamine,
    which is a weak base that accumulates naturally
    within lysosomes. There it reacts with the accu-
    mulated cystine to form a mixed disulphide, which
    bears a strong structural resemblance to lysine and
    is transported out of the lysosomes by the lysine
    transporter. If used early, in high doses, cyste-
    amine can prevent renal deterioration and lead to
    improvement in growth but does not alter other
    aspects of the disease [15]. The cloning of the
    cystine transporter, cystinosin, raises the possi-
    bility of correction by gene therapy.
    Restricting the flow of substrates to the
    lysosomes or substrate deprivation has been achi-
    eved in cells in culture and in mouse models of
    glycolipid storage diseases [16]. N-Butyldeoxy-
    nojirimycin, which was originally developed as an
    anti-HIV drug, is an effective inhibitor in vitro
    and in vivo of glucosyltransferase, the first enzyme
    in the pathway for the assembly of the oligo-
    saccharide chains of glycolipids (Figure 2). There-
    fore it can decrease the rate of synthesis of all the
    glycolipids based on glucosylceramide and is
    potentially a generic drug for the glycosphingo-
    lipidoses, including those with central-nervous-
    system involvement. It is currently in clinical trial
    in patients with Fabry and Gaucher type-1 dis-
    eases. The galactose analogue, N-butyldeoxy-
    galactonojirimycin, is a more selective inhibitor
    andpotentially maybe a superiordrug for therapy.
    Replacement of the defective protein can be
    achieved by direct administration of the puri-
    fied protein, transplant of cells producing the
    normal protein or by transfer of the gene encoding
    the protein (Figure 1).
    Endocytosis provides a natural mechanism
    for delivery of exogenous enzyme to the storage
    # 2000 Biochemical Society
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    Biochemical Society Transactions (2000) Volume 28, part 2
    material in the lysosomes. As all lysosomal en-
    zymes are glycoproteins, it is possible to exploit
    endocytosis mediated by the carbohydrate-recog-
    nizing receptors to enhance the uptake of circu-
    lating enzyme and to target the enzyme to different
    cells. Enzyme-replacement therapy (ERT) is an
    established and effective treatment for the non-
    neuronopathic form of Gaucher disease (type 1),
    which results from a deficiency of β--gluco-
    cerebrosidase [17]. The N-linked oligosaccharides
    on recombinant β--glucocerebrosidase are modi-
    fied enzymically to terminate in mannose, which is
    recognized by the mannose receptor on macro-
    phages, the major target cell for the replacement
    enzyme. Exogenous lysosomal enzymes carrying
    the lysosomal tag, mannose 6-phosphate, can be
    delivered to a wide range of cells via the ubiquitous
    MPRs on cell surfaces. Over-production of re-
    combinant human lysosomal enzymes in mam-
    malian cells can be controlled to produce secreted
    phosphorylated enzymes. Trials of ERT using
    such material are in progress for mucopoly-
    saccharidosis I (MPSI), glycogen storage disease
    Figure 1
    Strategies for treatment of lysosomal storage diseases
    Figure 2
    Use of sugar mimic, N-butyldeoxynojirimycin (DNJ), to decrease synthesis of
    glycolipids in lysosomal storage diseases
    type II and Fabry disease. Although ERT may
    disperse the storage material in systemic tissues
    and organs, it is unlikely to be beneficial in those
    disorders with involvement of the central nervous
    system because of the blood–brain barrier. Other
    sanctuaries from the replacement enzyme may
    also exist, e.g. bone and joints. Development of
    antibodies against the exogenous enzyme may be a
    problem in patients who do not produce any
    endogenous protein.
    In bone-marrow transplantation (BMT),
    normal donor stem cells differentiate to different
    lineages that colonize many organs and tissues.
    Secretion of the normal enzyme by these cells
    followed by uptake by other cells or perhaps direct
    transfer of the normal enzyme mediated by cell-
    to-cell contact [18] results in wide distribution of
    the therapeutic enzyme. Again, BMT has been
    most successful for disorders that are primarily
    systemic, e.g. non-neuronopathic Gaucher disease
    (type 1) [19]. Although donor-derived microglia
    and macrophages can enter the central nervous
    system they do not seem to provide enough
    # 2000 Biochemical Society
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    Organisms, Organs, Cells and Organelles
    enzyme for correction, especially if neurological
    symptoms are present at the time of transplant.
    However, BMT is considered for patients with
    mucopolysaccharidosis I, a neurological disorder,
    if the patient has a genotype expected to lead to the
    severe Hurler phenotype and is less than 2 years of
    age [20].
    The transfer of lysosomal enzyme genes into a
    variety of cells in culture using retroviral vectors
    leads to expression, correct processing and de-
    livery of the enzyme to the lysosomes and conse-
    quent metabolic correction. Gene transfer into the
    patient’s own haematopoietic cells is equivalent to
    autologous BMT. The success of this approach in
    several mouse models of lysosomal storage dis-
    eases led to human clinical trials in Gaucher [21]
    andHurlerdiseases[22].TransductionofCD34j
    peripheral blood stem cells with retrovirus con-
    taining the β-glucocerebrosidase cDNA has also
    been used for Gaucher disease. Although the full
    results of these trials have not been published the
    reported lack of persistence of expression and
    antigenic responses are disappointing.
    It had been anticipated from the animal
    experiments that visceral organ storage would be
    cleared but the brain and some of the skeletal
    Pathology would not be corrected by procedures
    that depend upon enzyme secretion. However,
    BMT in some animal models had shown donor
    enzyme activity and localized correction in the
    brain, suggesting that neurotransplantation of
    enzyme-secreting cells might be therapeutic [23].
    Injection of murine neural progenitor cells
    into the ventricles of new-born MPS VII (β-
    glucuronidase-deficient) mice led to widespread
    engraftment and clearage of storage material [24].
    Transplantation of fibroblasts overproducing β-
    glucuronidase into the brain of the MPS VII mice
    also resulted in local clearance of preformed stor-
    age material [25]. Adult bone-marrow stroma
    cells may be another potential source of cells for
    treatment of the central nervous system [26]
    because direct injection of human bone-marrow
    stroma cells into rat brain led to engraftment and
    migration of the cells [27].
    The β-glucuronidase gene has been intro-
    duced directly into the central nervous system of
    the MPS VII mouse using herpes simplex virus
    [28], adenovirus [29] or adeno-associated virus
    [30] with expression of activity and localized
    clearance of storage products. Intravenous in-
    jection of the adeno-associated virus neonatally
    prevented storage in the brain, indicating a less
    invasive route to the brain [31].
    We have been investigating the use of non-
    viral vectors that exploit receptor-mediated endo-
    cytosis to transfect cells from patients with lyso-
    somal storage diseases [32].
    Many of these experimental forms of therapy
    will become available for human use, perhaps in
    combination to target different rates or sites of
    storage. Selection of the appropriate therapy will
    depend on a full knowledge of the molecular basis
    and cellular Pathology in the individual case.
    We thank the Society for Mucopolysaccharide Diseases for their
    support.
    References
    1 Lloyd, J. B. and Mason, R. W. (eds.) (1996) Biology of the
    Lysosome, Subcellular Biochemistry vol. 27, Plenum Press,
    New York
    2 Braulke, T. (1996) in Biology of the Lysosome, Subcellular
    Biochemistry vol. 27 (Lloyd, J. B. and Mason, R. W., eds.),
    pp. 15–49, Plenum Press, New York
    3 Schmidt, B., Selmer, T., Ingendoh, A. and von Figura, K
    (1995) Cell 82, 217–278
    4 Suzuki, K. (1995) in Essays in Biochemistry , vol. 29 (Apps,
    D. K. and Tipton, K. F., eds.), pp. 25–37, Portland Press,
    London
    5 Lloyd, J. (1996) in Biology of the Lysosome, Subcellular
    Biochemistry vol. 27 (Lloyd, J. B. and Mason, R. W., eds.),
    pp. 361–386, Plenum Press, New York
    6 Town, M., Jean, G., Cherqui, S., Attard, M., Forestier, L.,
    Whitmore, S. A., Callen, D. F., Gribouval, O., Bryoer, M.,
    Bates, G. P., van’t Hoff, W. and Antignac, C. (1998) Nat.
    Genet. 18, 319–324
    7 Verheijen, F. W., Verbeek, E., Aula, N. et al. (1999)
    Nat. Genet., in the press
    8 Hunziker, W. and Geuze, H. J. (1996) BioEssays 18,
    379–389
    9 Walkley, S. U. (1998) Brain Pathol. 8, 175–193
    10 Gieselmann, V. (1995) Biochim. Biophys. Acta 1270,
    103–136
    11 Meikle, P. J., Hopwood, J. J., Clague, A. E. and Carey, W. F.
    (1999) J. Am. Med. Assoc. 281, 249–254
    12 Jolly, R. D. and Walkley, S. U. (1997) Vet. Pathol. 34,
    527–548
    13 Vogler, C., Sands, M. S., Galvin, N., Levy, B., Thorpe, C.,
    Barker, J. and Sly, W. S. (1998) J. Inher. Metab. Dis. 21,
    575–586
    14 Suzuki, K., Proia, R. L. and Suzuki, K. (1998) Brain Pathol. 8,
    195–215
    15 Markello, T. C., Bernardini, I. M. and Gahl, W. A. (1993)
    N. Engl. J. Med. 328, 1157–1162
    16 Platt, F. M., Neises, G. R., Reinkensmeier, G., Townsend,
    M. J., Perry, H., Proia, R. L., Winchester, B., Dwek, R. A. and
    Butters, T. D. (1997) Science 276, 428–431
    17 Barton, N. W., Brady, R. O., Dambrosia, J. M. et al. (1991)
    N. Engl. J. Med. 324, 1464–1470
    18 Abraham, D., Muir, H., Olsen, I. and Winchester, B. G.
    (1985) Biochem. Biophys. Res. Commun. 129, 417–425
    19 Hoogerbrugge, P. M. and Valerio, D. (1998) Bone Marrow
    Transplant Suppl. 2, S34–S36
  2. John.

    John. Guest

    III cranial nerve supplies :
    a- Superior oblique
    b- Inferior oblique
    c- Medial rectus
    d- Superior rectus
    e- Lateral rectus
  3. Joseph.

    Joseph. Guest

    Ans: B, C, D.
    IIIrd cranial nerve supplies:
    - Medial rectus
    - Inferior rectus
    - Inferior oblique
    [Pneumonic : SO4LR6]
    - Superior oblique - 4th Nv.
    - Lateral rectus - 6th Nv.
  4. Joseph.

    Joseph. Guest

    Isthmus of thyroid gland lies against following tracheal rings :
    a- 2 - 4
    b- 2, 3
    c- 2 - 5
    d- 1 - 3
    e- 3- 5
  5. Joseph.

    Joseph. Guest

    Ans: B.
    - Isthmus of thyroid gland extends from second to the third tracheal ring.
    Extent of thyroid gland
    - Gland: C5, 6, 7 and T1
    - Each lobe: Middle of thyroid cartilage 4th or 5th traceal ring.
  6. Joseph.

    Joseph. Guest

    Superficial perineal muscles include :
    a- Iliococcygeus
    b- Ischiococcygeus
    c- bulbospongiosus
    d- Levator ani
    e- Pubococcygeus

    Ans: C. bulbospongiosus
  7. Joseph.

    Joseph. Guest

    Intracellular receptors are found in :
    a- Insulin
    b- Glucagon
    c- Corticosteroids
    d- Androgen
    e- Thyroxine

    Ans: C, D, E.
    Steroids, androgen, thyroxin, vit. D receptor, retinoid X - Receptor (R x R) - are intra cellular receptors.
  8. Joseph.

    Joseph. Guest

    Insulin is secreted along with the following molecule in a 1: 1 ratio :
    a- Pancreatic polypeptide
    b- Glucagon
    c- GLP-1
    d- Somatostatin
    e- C-peptide

    Ans: C.
    - Insulin and C-peptide are secreted in equimolar amounts.
  9. Joseph.

    Joseph. Guest

    Antigen presenting cells are :
    a- Langerhans cell
    b- Macrophage
    c- Cytotoxic T cells
    d- Helper T cells
    e- B lymphocyte

    Ans: A, B, E.
  10. Joseph.

    Joseph. Guest

    Features of innate immunity A/E :
    a- Recognizes foreign antigen in bacteria
    b- C reactive protein
  11. Joseph.

    Joseph. Guest

    Ans: A. Recognizes foreign antigen in bacteria.
    Mechanism of Innate Immunity
    - Epithelial surface
    - Antibacterial substances in blood and body tissues
    - Microbiological antagonisms
    - Cellular factor in innate immunity
    - Fever
    - Acute phase proteins
    * CRP and other acute phase proteins activate the alternative pathway of complement and they enhance the host resistance.
  12. Joseph.

    Joseph. Guest

    Before sensitizing T-cells slight modification in antigen is induced by :
    a- Langerhans cell
    b- NK cell
    c- Dendritic cells
  13. Joseph.

    Joseph. Guest

    Ans: A, C.
    * Dendritic and langerhans cells present antigen to T-cells for recognition and activation. The properties of the dendritic cells are :
    - They are in right place to capture antigen e.g. under epithelia.
    - Express many receptors for capturing and responding to microbes e.g. TLRs, mannose receptors.
    - Express high level of MHC-II molecules and costimulatory molecules.
    - Express chemokine receptors in response to microbes.
    Thus, they possess all the machinery needed for antigen presentation and activating CD4+ cells.
  14. Joseph.

    Joseph. Guest

    Interleukin produced characteristically by TH1 :
    a- Interleukin 2
    b- IL 5
    c- IL γ
    d- IFN γ
    e- IL 10

    Ans: A. Interleukin-2, D. IFN gamma.
  15. Joseph.

    Joseph. Guest

    Correctly matched pairs in Amyloids :
    a- Multiple myeloma - light chain
    b- Chronic inflammation - AA
    c- Cardiac - ATTR
    d- Neural - β2 microglobulin

    Ans: All.
    * Multiple myeloma - AL Type
    * Chronic inflammation - AA Type
    * Hereditary polyneuropathies - ATTR
    * Familial Mediterranean fever - AA
    * Senile cardiac - ATTR
    * Senile cerebral - A beta, APrP.
    * Medullary carcinoma - Procalcitonine.
  16. Joseph.

    Joseph. Guest

    Stop codon :
    a- UAG
    b- UCA
    c- UAC
    d- AUG

    Ans: A. UAG.
    - Stop codons are : UAA, UAG, UGA.
    - AUG - is initiation codon.

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