basic sciences mrcp1

7/27/2019 Basic Sciences MRCP1

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Basic Sciences


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Immunology


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Complement

Complement pathway

C1qrs

C2,4

C3

Classic pathway

Properdin,

Factor B, D(C3bBb)

Alternate pathway

Mannose + lectinfrom bact cell wall

proteases

C5,6,7,8,9

(MAC) cell lysis

- C1 inhibitor, + immune complex

- C4 binding protein

+ bact. LipopolysacC3 nephritic factor

- Decay accelerating factor

(DAF), factor H.

- Membrane inhibitorof reactive lysis (MIRL)

C3a, 5 a

chemotaxis

C3b

opsonization


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Complement deficiency Def of Complement components;1. Congenital def. of C2,4IC clearance SLE, vasculitis, polymyositis.

2. C3 def Life threatening infection with encapsulated org. e.g. pneumococci.3. MAC (C5,6,7,8,9) disseminated neisserial infection.

4. Acquired consumption occur in SLE, cryo, IEC, post infectious GN, MPGN.

Def of regulatory proteins;1. Def of C1 inhibitor hereditary angioneurotic edema dt vasoactive C2

fragment, ttt with epinephrine in the acute attack & danazole for preventionas it hepatic synthesis of C1 inhibitor & C4, SLE dt consumption of C2, 4.

2. PNH; def of membrane GP (GPI) which bind the inhibitory comp DAF.

3. HUS; familial type dt def of Factor H compl activation & end. Injury.

4. MPGN type 2; C3 nephritic factor, def factor H.

5. ACEI C1 inhibitor def angioedema.

6. Cryo; C4, preserved C3 dt C4 binding protein inact of C3.


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Immunoglobulin

Fab

Fc

Ig G;- Monomer formed of a divalent molecule ( 2Fab) 2 light and 2

heavy chains.

- Most abundant.

- 2ry immune response.

- The only Ig that cross the placenta.

- MW; 150.000 dalton (25 for each LC & 50 for HC).

- 4 subclasses according to Fc.

The reference range is 8-20 g/l.

Ig A;- Monomer in serum, dimeric in secretion.

- Def chronic diarrhea, respiratory infection, autoimmune dis.

- IgA1 contain hinge region.- Level undetectable at birth, reach adult level at puberty.

Ig M- pentameric.

- 1ry immune response.

- Secretion do not need Th2.

- Include Bl group Ab.- Against bacteria.

- Level undetectable at birth, reach adult level at 1 yr.

Ig D on B cell surface.

Ig E;produced by plasma cell, attach to mast cell & basophils,

responsible for type 1 hypersensitivity reaction.


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Hypersensitivity reactions Type 1; anaphylactic or immediate

- Ag+ Ig E on mast cell

- diagnosed by plasma tryptase ( protease released from mast cell).- e.g. asthma, atopy, drugs as latex, peanut.

Type 2; Ab-dependent cytotoxicity

- cell bound Ag + circulating Ig

- e.g. transfusion react, Rh, Goodpasture, ITP, Coomb's positive haemolyticanaemia.

Type 3; IC-mediated or arthus reaction- free Ag + free Ig

- e.g. excess Ig farmer lung, bird fancier, pulm aspergillosis.

excess AgGn, serum sickness.

Type4; cell-mediated or delayed hypersensitivity

- Ag on APC + T memory cells- tuberculin, contact dermatitis, GVHD, graft rejection.

Type 5; stimulatory.

-Ab + cell surface receptor e.e. Graves.


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Cells of the immune system

PMN;

1. Neutrophilsphagocytosis, bacteria.

- Phagocytes have a role in recognition and eliminationof microbes by reactive oxygen species or antigens by

opsonisation.2. basophils & mast cells; type 1 hypersensitivity,parasites.

3. Eosinophils; allergy, helminthes, phagocytose IC.

Mononuclear;1. Lymphocytes,

2. monocytes.


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Chronic granulomatous disease;

- It is a defect in the production of NADPH H

peroxide phagocytic function of neutrophils

(normal phagocytosis but defective intracellularkilling) chronic granulomas & microabcesses

in skin, bone & liver.

- Diagnosed by nitroblue tetrazolium test

(screening for reduced phagocytic capacity).

- Ttt; INF


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blood lymphocytes1.5-3.5.000

20-40% of WBCs

T-cells

60 to 80 %

B-cells10 to 20 %

natural killer (NK)

5 to 10 %.

Helper T-cells

60 to 70 %

(CD4+ cells)

Suppressor/

cytotoxic T-cells

30 to 40 %(CD8+ cells). Bind to

class 2 MHC Ag

on APC as MQ

IL1,6, TNF

Bind toclass 1 MHC Ag

On viral infected cells, cancer cells

Active

CD4 Th

IL2

th1 th2

IL12, 18 IL4

IL10

IFNTh1

(-)


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T lymphocytes;- The predominant cell type in the paracortical region of LN.

- Role; intracellular infections, tumour surveilance, graftrejection.

- Arise in BM, mature in thymus.

- Types;

Cytotoxic (CD8) T cells recognise MHC class Imolecule antigens

T helper (CD4) cells recognise MHC class II molecule

antigens.


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Thymus- independent Ag;

- theses are mainly carbohydrate Ag

- e.g. pneumoccocal polysaccarides,- activate B lymphocyte without TH cells

- polyclonal Ab mainly Ig M with poor affinity

& no memory.


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B lymphocytes;

- The predominant cell type in the germinal

follicle of LN.

- Arise in BM, mature in the spleen & LN.

NB:

- B cells usually require T cell help for full

activation. B cells are activated in primary

immune response which initially produce

IgM. CD40 & CD 40L are required forcostimulation of T cells, if either is

deficient impair Ig class switching.


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Natural killer cells;

- destroy viral infected & tumour cells.- Rather than T cell receptors, natural killer

cells express adhesion molecules which

allow adhesion to target cells.

- CD94 receptor is located in Natural Killer

(NK) cells and is bound to the cell

membrane. It enables NK cells to

discriminate between healthy cells and

pathogen infected cells


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Major histocompatibility complex

MHC is a group of genes on chr 6 that form HLA Ag & some CC.

DR/DP

Class 2A, B, C

class1

Class 3= C2,4, factor B

Class 2class1

HLA DR, DP, DQHLA A,B,C transmemb peptide with B2

microglobulin

form

Immune cells; B cell, MQ &

some endothelial cells

All cells, allow self recognition.on

CD4 Th, (class2 Ag on APC

present foreign Ag to Th

cells & protect their cells

from T cytot)

CD8 cytotoxic cells (which are activated

when they see foreign class 1 Ag as

graft, virally infected cell, tumor cell.)

Signal to


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Cytokines Cytokines are low MW peptides produced by

lymphocytes, MQ and fibroblasts & have non

enzymatic biological activity,( local or systemic). They include;

- Interleukins

- interferons- CSFs

Certain patterns of Cytokine production;

-Acute phase reactants(IL1, 6, TNF ) derived from MQ.

- cell-mediated immunity; (IL2,INF) by Th1.

Ab-mediated immunity; (IL4,5,6,10) by Th2 & stimulate Blymphocytes, maturation of dendritic cells .

- Antiinflammatory; (IL4, 10) by Th2.


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IL-1;

Released by MQ B &T stimulation, acute phase reactant,osteoclastic bone resorption.

Involved in;

- Rh arthritis IL-1 + collagenase, phospholipase,cyclooxygenese (facilitator of damage).

- Atherosclerosis; endo uptake of LDL IL-1 PDGF.

- Septic shock IL1NO, PG, PAF VD.- Infection, acute graft rejection IL1 T & B lymph.

IL2; from Th1 growth of activated T cells, NK cells.

IL4, IL10; from Th2inhibit cell mediated immunity, INF(antiinflammatory cytokines), stimulate Ig production.

IL-5; from mast cells chemotaxis for esinophils.

IL6; from MQ acute phase reactant, stimulate Ig production.


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Tumour necrosis factor (TNF) ;

MQ, esinoph, NK.

T lymph .

TNF is procoagulant & lead to thrombosis.

dis associated; Rheumatoid, MS, MOF. So,neutralizing Abs = anti-TNF are used.

not used in cancer highly toxic, + tumor

growth.


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INF,; from WBC, fibroblasts antiviral

effects

. IFN and IFN (not ) bind to the same

receptor known as type I receptors. IFN is

used therapeutically in multiple sclerosis.

INF; Th1 activate MQ, inhibit Th2.

.


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Therapeutic uses;

* INF HBV, HCV, hairy cell Keuk, cut T cell lymphoma, Kaposi

sarcoma in AIDs, RCC, condyloma acuminata.

* INF MS.

* INF chronic granulomatous dis.

* IL2 RCC, acute leukemia.

* GM-CSF correction of cytopenias e.g. during chemotherapy.

* interleukin receptor antagonists (IL-1Ra) are useful as diseasemodifying drugs in rheumatoid arthritis (Anakinra).

* anti- TNF (infliximab, etanercept) are used in Rheumatoid,IBD.


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Eicosanoids Def; are biologically active lipids, derived from the cellular

membrane phospholipids by the enzyme phospholipase

releasing arachydonic acid (or Omega 3 FA as anexogenous source);

Lipooxygenase act upon arachydonic acid leukotrienes;

- LTB4neutrophil chemotaxis, mucous secretion,modulate cell growth.

- LTC4,D4,E4 (slow reacting substance of anaphylaxis)vascular permeability, sm contraction, mucous secretion,modulate cell growth.NB; LT receptor antagonists are usedin asthma.

Cyclooxygenase act upon arachydonic acid PG &

thromboxane.- PG I2 (prostacyclin) released from endothelium VD, (-)plat aggregation.used in 1ry pul HTN, HUS, Raynaulds.

- PGE2; immunomodulator, (-) lymphocyte proliferation,cytokinr production, neutrophil function.

- PGD2; from mast cells anaphylaxis.


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Immune deficiencyCongenital

Complement def.; encap org- C3 life threatening pneumoc inf.

- MAC disseminated neisseria. Neutrophil def Bact, candida.- chronic granulomatous dis.

- Chediak Higashi

- lazy leukocyte S.

T cell def

viral, mycobact, fungal, malig, parasites, fatal BCG & yellowfever vaccine.

- Di George; non familial, def in thymus & 3rd & 4th branchial arches immun def,absent PTH, aortic arch abn., cleft palate

B cell def Bact.- common variable; non familial, failure of B cell maturation

- X linked agammagiardia.- Ig A def. giardia, allergic, autoimmune dis, fatal transfusion react.

Combined B & T def;- severe combined immune def.; AR.

- ataxia telangectasia; AR, ataxia, telangiectasia, malignancy, cell mediated im,Ig A.

- Wischott Aldriech; XLR, CMI, IgM, thrombocytopenia, eczema, malignancy.


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Acquired; Causes of neutropenia

Causes of acquired hypogammaglob (B cells)- synthesis; malnutrition, uremia, viral infection, immunosuppdrugs.

- catabolic dis; thyrotoxicosis, myotonia.

- lost; prot loosing enteropathy, nephrotic S, ovarianhyperstimulation.

- lymphoproliferative dis; CLL, NHL, MM.

Causes of acquired CMI def (T cells)

- alcohol- drugs; cyclosporin, cyclophosphamide, steroids.

- lymphomas,

- AIDS,

- medical dis; DM, RA.


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Vaccination Passive; (Ig)

- used for post exposure, immunocompromized.

- HAV, HBV, ZIG, DT, Rabies, Botulinum.

Active;1. Subunit vaccines;

- used for patients with CRF, before splenectomy, hypocomplementimics.

- e.g. pneumoccoccal, Meningeococcal, H influenza, HBV

2. Killed;

- used for patients with chronic illness.

- e.g. pertussis, TAB, influenza, cholera.

3. Live attenuated;

- used for healthy individual.

- contraindicated for HIV, patients taking steroids 40mg/d for one week orlong term smaller dose .

- given after ;

3 wks of another live v. 3 m of Ig or stopping steroids , 6 mths fromchemo.

- BCG, Yellow fever, MMR, oral polio.


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Genetics


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Prokaryotes(microorganisms)circular DNA,

no nuclear membrane .

Eukaryotes (higher

organisms) have multiplechromosomes , nuclearmembranes.

Histones allow DNA to twirlround it to form stablenucleoprotein complexes.


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Chromosomes

The human karyotypeconsists of22 pairs ofautosomes and 1 pair of

sex chromosomes totalling23 pairs altogether.

Telomeres are DNAsequence at distalextremities of chromosomalarms, become progressivelyshorter with each celldivision when it is reducedto a critical length, the cell is

not capable of dividing. The enzyme telomeraselengthen it.

centromeres provide apoint of attachment for the

mitotic spindle.


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Lyonization is the process whereby in a cell containing > 1x chr, only one is active. A Barr body is an inactivated Xchromosome.

Haploid= cell with 23 chromosome as gametes.

Diploid= cell with 46 chromosome

Triploid= cell with 3 copies of each chr.

Aneupoid= contain a number of chr not a multiple of 23.


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- Bases are paired withhydrogen bonds

- In DNA;

- Deoxyribose sugar

- A+T by 2 H bonds

- G + C by 3 H bonds

In RNA,

- uracil instead of thymine

- Ribose

- Single-stranded.


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Cell cycle:

G1 phase ; enzymes for the production of RNA and protein, are produced. S phase ; DNA is synthesized by replication of the existing strand.

G2 phase ; RNA and protein are synthesized.

M phase mitosis occur:

Cell division results in 2 daughter cells, each of which can enter its own G1 phase

become an inactive resting (G0) or die (cell loss fraction).

cyclins= are proteins key regulators of cell

cycles which can bind to enzymes known as

cyclin dependent kinases. These regulate the

progression of the cell cycle.


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Stages of

Mitosis

Prophase:

chromosomes condense Metaphase:

chromosomes are lined up on cell equator,

attached to the spindle at the centromeres

Anaphase: centromeres divide.

the chromosomes are pulled to opposite poles by the spindle.

Telophase: cytoplasm divided into 2 separate cells


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Chromozomal aneuploidy Turner S (45,X0);

-1:2500 live birth females.- Streak ovaries, E, failure of menstruation, 2ry sexual ccc

- short stature, normal intelligence.

- Associations;

- CVS; coarctation- renal; hoarseshoe, agenesis, double ureter.

Kleinfelter;47; XXY

- Hypergonadotrophic hypogonadism

- Male, tall stature.- Azospermia, testosterone, Gn.

- Gynecomastia, male breast cancer.

- normal intelligence.


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Down syndrome (trisomy 21)- 2ry to non dysjunction during oogenesis (with increasing

maternal age)

- 5% Translocation bet. Chr 14 & 21.

- 3% mosaism.

- Complication;

- CVS; VSD

- hematologic malig; ALL, AML.

- Alzeheimer disease.

- Duodenal atresia (Double bubble sign), hirshsprung.

Edwards (trisomy 18);


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Edwards (trisomy 18);

- overlapping fingers

- renal abn- CHD

- MR

- diaphragmatic hernia-mortality early infancy.

Patau S (trisomy 13);

- CNS,

-scalp defect, microphthalmia, cleft lip & palate.

Genome


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Genome = DNA. Only about 5% of DNA codes for proteins.

Human genome = 30.000 gene.

Each cell express 16.000 gene.

Housekeeping genes =genes expressed in all cells to provide basicfunction for cell survival (constitutive).

Southern blotting detects DNA.

Transcriptome = m RNA.

Microarray analysis of transcriptome identify the expressed genes.

Northern blotting detects RNA

Proteome = protein.

Analysis of the proteome is better as it detects changes at the proteinlevel, not reflected at transcriptome level dt Post translationprocessing.(bioinformatics).

Western blotting can be used to detect and quantify proteins


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Gene

Transforming factor

binding sitesTATA

box

RNA polymerase

binding site

ex exin in

ATG

Translation

Starting site

Translation

termination code

Promotor elements

53

Coding sequences (exons) are interspersed with introns.

Both coding (exons) and non coding regions (introns) exist on RNA.

E t f th t i t d i t RNA th t l t d i t


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Exons= segment of the gene transcripted into m RNA then translated intoproteins.

Introns= segment of the gene transcripted then removed by splicing (nottranslated).

Promotor elements = binding sites for initiation of transcription complex at

5. TF can activate any gene that has a TATA box.

TATA box=

- a promotor element.

- at 25-30 base pairs from the start of transcription.

- anchor to RNA polymerase II. Enhancers=

- present at 5 or3.

- not obligatory for initiation.

- but gene expression.

TF;- basal = constitutive - Housekeeping genes.

- inducible = temporal, spatial expression of genes for tissue phenotype.

Application of TF;

1- many cong malformation are dt inherited mutation of TF.

2- can be oncogenic e.g. CMyC, P53.

3- steroids affect TF.


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DNA is transcribed into RNA by mRNApolymerase II

mRNA is translated into proteins in the cytoplasm atthe ribosomes.

mRNA contain codon which bind to anticodons ontRNA.

Transfer RNA (tRNA) is a small RNA chain that hassites for amino-acid attachment & transfers a specificamino acid to the growing polypeptide chain accordingto the RNA codon.

the anticodon region of tRNA, contains thecomplementary bases to the ones encountered on themRNA.

Process of protein synthesis


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Reverse transcription involves transcription of

RNA to DNA (used by retroviruses).

Restriction enzymes cut DNA at nucleotide

sequences specific to each restriction

enzyme.

DNA ligase and polymerase are involved injoining and linking DNA together.

Plasmids are circular molecules of bacterial

DNA separate from the bacterial chromosome.

DNA l i


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DNA analysis

Direct testing;

= identify abnormality within a well knownspecific gene.

- PCR

- restriction enzymes digestion

- Southern blotting

Indirect testing; (linkage analysis)

used when the gene in question has notbeen identified before. It involves tracingDNA markers in more than generation withina family.


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southern blot; electrophoresis of DNA fragment through gel


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southern blot; electrophoresis ofDNA fragment through gel solid memb as nitrocellulose+ labelled probe visualised under x ray film.

Northern blot is a mean to detect RNA (uracil instead of

thymine in m RNA). Somatic cell hybridization;

- method for gene maping.

- using 2 diff species, chr from 1 species is selectively lostresulting in clones of certain chr of the another species.

FISH; fluorescence in situ hybridization, labeled probes arehybridized to chromosomes, and the hybridized probes aredetected with fluorochromes. visualised underflorescentmicroscope, This technique is a rapid and sensitive meansof detecting recurring numerical and structural

abnormalities. for microdeletions & trisomy. SSCP (single strand conformation polymorphism analysis); is

a technique for detecting variation in DNA sequence byrunning single stranded DNA fragments through a non

denaturating gel.


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Gene mutations;

- mismatch = change in the nucleotide.

- inversion= nucleotide base removed,reverse directed & reinserted.

- point mutation; single base pair substitution.


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Dominant vs. Recessive

A dominant allele is expressed even if it is

paired with a recessive allele.

A recessive allele is only visible when

paired with another recessive allele.

Recessive alleles are not expressed in the

presence of a dominant allele

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Expression

Homozygous Both alleles alike

AA or aa

Heterozygous

Alleles are different Aa

Codominant Two different alleles are both dominant

A = allele for type A blood B = allele for type B blood

AB = results in type AB blood


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Marfan's syndrome

AD

associated with;

1. ocular abnormalities ; upwards lens dislocationand retinal detachment.

2. Aortic regurgitation due to aneurysmaldilatation, MVP.

3. Upper to lower body ratio is decreased ,arachnodactyly, high arched palate.

4. Spontanoeus pneumothorax.


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As if a male Turner


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Autosomal recessive Metabolic; alkaptonuria, galactosaemia, glycogen storage disease ,

homocystinuria, phenylketonuria, mucopolysaccharidoses exceptHunter, oculocutaneous albinism, G6 phosphatase dedficiency (Vongierkes),

Liver; crigler, DJS, Rotor, hemochromatosis, Wilson's disease,Gaucher's disease

Blood; B thalathemia, Fanconi anemia, Sickle cell disease, pyruvatekinase def.

Neuro; ataxia telangiectasia, spinal ms atrophy, Renal; Bartter's syndrome,

Endocrine; congenital adrenal hyperplasia ,

endemic goitrous cretinism

cystic fibrosis

xeroderma pigmentosa


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Most metabolic disorders are AR except;

1. XLR; MPS 2 (Hunter), G6PD def ,

adrenoleuckodystrophy.

2. AD; AIP, Familial hypercholesterolaemia


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X li k d d i t ( )


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X linked dominant (rare)

Daughters of affected males will all be

affected.

All offsprings of an affected female have a50% chance of being affected.

e.g.

X linked Hypophosphataemic VDR rickets .Fragile X syndrome


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Codominant inheritance

Two different versions (alleles) of a gene

can be expressed, and each version makes

a slightly different protein.

E.g. ABO locus

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mitochondrial inheritance


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mitochondrial inheritance

Mitochondria contain certain genes & are exclusivelymaternally inherited (from oval cytoplasm).

Mitochondrial DNA codes for proteins in the oxidativephosphorylation .

In Mitochondrial Diseases , all offsprings of affected womenbut no offsprings of affected men.

Kearn Sayre's

MELAS (mitochondrial encephalopathy, lactic acidosis,stroke)

MERRF (myoclonic epilepsy, ragged red fibres) progressive external opthalmoplegia

Leber's optic atrophy


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Genomic imprinting refers to the difference

in phenotypic presentation depending on

the origin of the diseased chromosome

from either maternal or paternal.Conditions with genomic imprinting:

Albright hereditary osteodystrophy

Prader Willi syndrome

Angelman syndrome


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Trinucleotide repeat


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Trinucleotide repeat

Affected pts has increased number of repeated units

of 3 nucleotides in affected gene (expansion),become more severe over successive generations(anticipation).

Myotonic dystrophy (AD)

Huntington dis (AD) Fragile X S (XLR)

Freidreich ataxia (AR)

Spinocerebellar ataxia (AD)

Anticipation refers to increase in the number oftrinucleotide repeats


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Enzyme deficiencies

Gauchers disease Glucocerebrosidase

deficiency

Niemann Pick disease - Sphingomyelinase

deficiency

Alkaptonuria homogentisic acid oxidase

Homocystinuriacystathionine B synthase.

Ochronosis;


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Ochronosis;

Alkaptinuria)(

AR Dt deficiency of homogentisic acid oxidase

accumulation of homogentisic acidpolymerize

to alkaptondeposit in different tissues.

C/P; pigmentation of ear, arthritis, intervertebral

disc calcification, dark sweat-stained clothes,

urine darken on standing,renal stone, ocular

comp.

TTT; symptomatic non specific.


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cong hyperhomocysteinemia

AR

Reduced activity ofcystathionine synthase.

accumulation of homocysteine & methionine.

C/P; Marfanoid + Mental Ret. + thrombosis

( downward dislocation of the lens, high arched

palate, Osteoporosis , livido reticularis,

atherogenic, thrombogenic).

Diagnosis; Na cyanide/nitroprusside test

Ttt; vit B6, B12, folic acid, methionine

restriction, cystine supplemented diet.


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Liver transplantation before renal


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Fabry's disease is an X-linked lysosomal storagedisorder. It is caused by a deficiency ofalpha-galactosidase A. Ceramide accumulation occursin various organs including the heart, skin and

nerves. The skin lesion is known asangiokeratoma corporis diffusum.

Gaucher's disease is associated with the enzymeglucocerebrosidase. As a result,

glucocerebroside accumulates, principally in thephagocytic cells of the body but also sometimesin the central nervous system neurones.


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Molecular


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Apoptosis

Def; is the morphological changes that accompagny

the programmed cell death e.g. cell shrinkage,

compaction of chromatin, nuclear & cytoplasmic

apoptotic bodies phagocytosed by MQ, laddering ofDNA on electrophoresis gel by activation of

intracellular nucleases.

programmed cell death= naturally occurring cell

death dt activation of a set of genes in response toext signals e.g. from neighbour or extracellular

matrix.


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Signals for cell death

+

+

+

P53

Fas, CD 95

TF

_bcl2

+

caspases

endonucleases

+


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Cancer resists apoptosis by;

- Mutation of P53.

- Causing apoptosis of cytotoxic T cells

(TNF like + Fas).

- Over-expression of Bcl2.


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Apoptosis;

- non-inflammatory process.

- no proteolytic enzymes.- no free radicals.

- no damage of neighbouring cells.

E.g.

apopt of finger web, selection of neurons ( normal apopt in embrio).

- apopt of excess or autoreactive T lymphocytes ( normal apopt in adult).

- neurodegenerative dis, HIV (dis).

- insufficient apoptosis e.g. cancer, autoimmune dis, viral dis.

Factors that + apoptosis; P53, P27, Fas or CD95 (receptor for TNF),withdrawal of GF.

Factors that - apoptosis; bcl2 (survival signals), B catenin accumulation

adenoma. Apoptosis occur through proteases called caspases (e.g. ICE= IL-1B

converting enzyme) that + endonuleases.

Caspases = cysteine aspartate specific proteases.

Molecular pathogenesis of cancer


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Molecular pathogenesis of cancer

Oncogenes Proto-oncogenes and oncogenes encode growth factors. A single

aa mutation is enough to change the proto-oncogene into anoncogene.

Mutated proto-oncogenes that cause cancer are called oncogenes.

Examples of oncogenes are:

Ras is the commonest oncogene is involved in sporadic tumours

(colon and lung) and rhabdomyosarcomas. c-myc translocation occurs in Burkitt's lymphoma.

N-myc proto-oncogene is seen in neuroblastoma.

SRC oncogene is associated with sarcoma.

Mutations of protein kinasesTF (Fos & Jun)+ Myctumor.

Philadelphia chr bcr + abl (9;22) fusion protein tumor growth.

Bcl-2 inhibits apoptosis, preventing p53 mediated cell destructionand prevent cell death.

Fas ligands and caspases trigger apoptosis. Bax, Bad and Bak aremembers of the oncogenes which promote cell death (of immunecell).

Tumour suppressor genes ;


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Tumour suppressor genes;NF-1 gene in neurofibromatosis

BRCA-1 in breast and ovarian cancer

Rb gene in retinoblastomaVHL gene in von Hippel Lindau

P53 Li Fraumeni syndrome

p53 : The p53 Gene is a tumor suppressor gene. If aperson inherits only one functional copy of the p53 gene

from their parents, they are predisposed to cancer andusually develop several independent tumors in a varietyof tissues in early adulthood. This condition is rare, andis known as Li-Fraumeni syndrome. Li Fraumenisyndrome predisposes patients to breast cancer and

sarcoma. p53 is also a transcription factor and is notfound only in malignant cells. It has a role indownregulating cell division and apoptosis.

P27 Tumor suppressor gene through down regulation ofcell cycle (cyclin dependent kinase inhibitor), ifdownregulated sporadic Cancer colon.

Nitric oxide


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Nitric oxide

(NO) Endothelial derived relaxation factor Produced from L arginine by oxidation of Nitrogen NO + citrulin.

C GMP (2ry mess) in neighboring cells.

Produced in;

1. Constitutive..Vascular end & Nervous systemVD, smhyperplasia, plat agg. new memory.

2. Inducible.. in MQ, PNL, plat, hepatocytecytotoxic.

Clinical application;- So used as nitrates or inhaled NO in pulm HTN.

- endothelial dysf in DM, HTN, smokers & hypercholestrolemia is dtloss of NO bioavailability.

- NO in atherosclerosis, HTN dt CRF, HRS, Alzeheimer.

- NO in septic shock, ARDS, acute inflammation.

Endothelin I (VC)


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Endothelin I (VC)

ET-1 (end, sm, coronary, GIT).

Related to dis;

- HTN, HRS, ARF, CHF, Raynaulds. (VC)

- VC following subarachnoid Hge.

ET1 receptor blockers & CEI used as anti HTN.

P i fl t t ki


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Pro-inflammatory cytokines

Il-1, TNF, TGF-B, Heat shock protein, free radicals.

TGF-

action;

- tissue repair.

- extracellular matrix.- fibrosis.

tissue injury + plat release of TGF-B chemotaxis monocytes (+ fibroblast GF, TNF, IL-1)

involved in glomerulosclerosis, hep fibrosis, pulmfibrosis, bleomycin lung.

NB;

HSPs (Heat shock proteins)


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HSPs (Heat shock proteins)

heat, chemicals, free radicals damage of

intracellular proteins HSP cellresistance to stress through;

- prot folding & unfolding.

- degrad of prot ( by ubiquitination).dis associated; if mutated cataract, motor

neuron deg.

bact HSP + immune syst.

Free radicals


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Any molecule with 1or more unpaired electron (morereactive); peroxide, super, hydroxyl, NO.

NB; hydroxyl is the most reactive.

action;- lysosomes.

- lipid peroxidation of memb.

- mutations (by attaching purines & pyrimidine).

Diseases athero, cancer, neurodeg ( MND).Free radical scavengers;

- tocopherol (Vit E).

- ascorbate (Vit C).

- glutathione.

- Beta carotene.

- Flavenoids.

Adhesion Molecules


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Def; Molecules that interact as receptors & ligand.

4 groups;

- Ig ( CD2, CD3, NCA (neural cell adh), ICAM (intercellular)bind to LFA ( lymph funct ass)to recruit lymphocytes.

- integrin ( cell to matrix) Integrins are surface receptors bywhich cells are attached to extracellular matrix..

- Cadherins (Nerve & Muscle ).- selectins ( leukocytes to endoth in inflam, over expressed

in autoimmune viral hepatitis, organ rejection).

Clinical application;

1. leuk adhesions deficiency recc bact sepsis.

2. integrin IIb IIIa ( plat receptor to fibrinogen)

deficiency Glansman thrombathenia.

Ab (abciximab)antithrombotic in coronary Ht.

St ll


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Stem cells

progenitor cells.

present in certain tissues e.g. BM, embrionic.

embryonic totipotent (any tissue).

BM Bl. cells only, can be recruited by Ag

sorting with CD34 Ab & undergo

transdifferentiation to non hematologic cells.


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Physiology

O2 Hb di i ti


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O2-Hb dissociation curve

is shifted to the right when there is:- an increase in CO2

- increase in hydrogen ions (fall in pH)

- increase in temperature- increase in lactate

The curve is shifted to the left by

- increased carboxyhaemoglobin

- methaemoglobin

- fetal haemoglobin.


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B) Intracellular receptors;

- cytoplasmic= steroids.

- Nuclear= thyroid.

- no 2 ry mess.

- intracytoplasmic receptors.

- the complex travel to the nucleus &bind to hormone responsive elements.

Stimulation of receptors leads to:


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Stimulation of receptors leads to:

- Vasoconstriction

- decrease in gut motility- uterus contraction

- decrease in pancreatic exocrine secretion

Cholera toxin: activates G protein, whichactivates adenylate cyclase. Elevated

cAMP results in unrestricted chloridesecretion from villous crypts.


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H pylori


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H pylori Campylobacterpyloridis, is a gram-negative microaerophilic rod

Pathologic mech;

1. produce urease. Urease produces ammonia from urea, an essential stepin alkalinizing the surrounding pH epithelial damage.

2. Produce protease, lipase damage of mucosal gel.

3. Increase HCl directly or indirectly through cytokines on G, D, parietal cellsresulting in gastrin & somatostatin.

4. Chemotactic factors PNL.

Incidence; 80% in developing countries, 20% in industrialized.

Complications;

1. Chronic active gastritis.

2. PUD3. MALT lymphomas

4. Adenocarcinoma

5. Extragastric; IsHD, enteropathic arthropathy, hep enceph, acne rosesea,alopecia, urticaria, Raynaulds.

Gut Hormones


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Gut Hormones

Gastrin;

- is secreted by the G cells of gastric antrum.

- It stimulates parietal cells produce hydrochloric acid.- Its production is stimulated by;

- gastric distension, certain aa (phenylalanine, tryptophan).HCL.

- vagal stimulation

- S.Ca

- epinephrine.- Its production is inhibited by;

- HCL

- secretin, GIP, VIP

- glucagon, calcitonin

- effects; gastric motility & secretionmucosal growth

pancreatic secretion; insulin, glucagon, bicarbonate.

Cholecystokinin


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Cholecystokinin.

- is produced by the duodenum & jejunum.

- Its production is stimulated by fat, aa, peptides.

- stimulates GB contraction, pancreatic enzyme secretion, delaygastric empting.

Secretin ;

- is produced by the jejunum.

- Its production is stimulated by HCL

- stimulates pancreatic enzyme secretion(HCO3).- It relaxes the oesophageal sphincter , delay gastric empting.

Motilin;

- is produced by the duodenum & jejunum.

- Its production is stimulated by acid- increase motility.

Vasoactive intestinal peptide (VIP)

i d d b SI


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- is produced by SI

- Its production is under neural stimulation

- promotes intestinal & pancreatic water and electrolyte secretion.

Gastric inhibitory peptide;

- produced by duodenum & jej.

- Its production is stimulated by glucose, fat &aa

- inhibit gastric acid secretion, stimulate insulin secretion, motility.

Somatostatin;

- produced by D cells of pancreas.

- stimulated by vagal & B adrenergic stimulation.

- stimulate gastric empting & inhibit everything else (gastric & pancsecretion).

Pancreatic polypeptide;

- produced by PP cells in pancreas.

- stimulated by protein rich diet

- inhibit pancreatic & biliary secretion.

Q


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Q

The following statements regarding gastrointestinal hormones arecorrect:

A gastrin increases gastric motility.

B somatostatin decreases gastric motility.

C pancreatic polypeptide stimulates pancreatic bicarbonatesecretion.

D enteroglucagon decreases the small bowel transit time. E secretin maintains mucosal growth.

True= abd

Comments:

Pancreatic Polypeptide inhibits exocrine pancreatic secretions.

Secretin is important in stimulating pancreatic secretion. The role ofenteroglucagon is not well defined but includes villous hypertrophyand hence reduction in transit time. Somatostatin inhibits manymany GI functions including gastric motility.


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Contributing Factors to

Deficiency

Clinical FindingNutrient


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Alcoholism, chronic diuretic

use, hyperemesis

Beriberi: neuropathy, muscle weakness and wasting,

cardiomegaly, edema, ophthalmoplegia, confabulation

Thiamine

Magenta tongue, angular stomatitis, seborrhea,

cheilosis

Riboflavin

Alcoholism,

vitamin B 6deficiency,

riboflavin deficiency,

tryptophan deficiency

Pellagra: pigmented rash of sun-exposed areas, bright

red tongue, diarrhea, apathy, memory loss,

disorientation

Niacin

Alcoholism, isoniazidSeborrhea, glossitis convulsions, neuropathy,

depression, confusion, microcytic anemia

Vitamin B6

Alcoholism, sulfasalazine,

pyrimethamine, triamterene

Megaloblastic anemia, atrophic glossitis, depression ,

homocysteine

Folate

Gastric atrophy (pernicious

anemia),

terminal ileal disease,

strict vegetarianism, acidreducing drugs (e.g., H 2blockers)

Megaloblastic anemia, loss of vibratory and position

sense, abnormal gait, dementia, impotence, loss of

bladder and bowel control, homocysteine ,

methylmalonic acid

Vitamin B12

Smoking, alcoholismScurvy: petechiae, ecchymosis, coiled hairs, inflamed

and bleeding gums, joint effusion, poor wound

healing, fatigue

Vitamin C

ToxicityDeficiencyElement

Renal insufficiency (milk-alkalai syndrome),Reduced bone mass, osteoporosisCalcium


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nephrolithiasis, impaired iron absorption

Nausea, vomiting, diarrhea, hepatic failure,

tremor, mental deterioration, hemolytic anemia,

renal dysfunction

Anemia, growth retardation, defective

keratinization and pigmentation of hair,

hypothermia, degenerative changes in aortic

elastin, osteopenia, mental deterioration

Copper

Dental and skeletal fluorosis, osteosclerosisDental cariesFluoride

Thyroid dysfunction, acne-like eruptionsThyroid enlargement ,cretinismIodine

Gastrointestinal effects (nausea, vomiting,

diarrhea, constipation), iron overload with

organ damage, acute systemic toxicity

kilonychia, pica, anemia,, impaired cognitive

development,

Iron

Neurotoxicity, Parkinson-like symptoms

Encephalitis-like syndrome, Parkinson-like

syndrome, psychosis, pneumoconiosis

Impaired growth and skeletal development,

reproduction, lipid and carbohydrate

metabolism; upper body rash

Manganese

Alopecia, nausea, vomiting, abnormal nails,

emotional lability, peripheral neuropathy,

lassitude, garlic odor to breath, dermatitis

Lung and nasal carcinomas, liver necrosis,

pulmonary inflammation

Cardiomyopathy, heart failure, striated muscle

degeneration

Selenium

Hyperphosphatemiaosteomalacia, proximal muscle weakness,

rhabdomyolysis, paresthesia, ataxia, seizure,

confusion, heart failure, hemolysis, acidosis

Phosphorou

s

Reduced copper absorption, gastritis,

sweating, fever, nausea, vomiting, Respiratory

distress, pulmonary fibrosis

Growth retardation,taste and smell, alopecia,

dermatitis, diarrhea, immune dysfunction,

gonadal atrophy, congenital malformations

Zinc


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Iron is absorbed in upper small intestine.Iron absorption is increased with ascorbic

acid. The sulfate form contains more

elemental iron per dosage unit thangluconate.

Q


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Q

The following may be found in the event ofa prolonged bout of vomiting except

A tetany

B hypochlorhydriaC megaloblastic anaemia

D hypokalaemia

E high serum aldosterone .C


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Renal physiology

The glomerular filtration barrier;


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The glomerular filtration barrier;

1. Fenestrated endothelial cells.

2. Glom BM

3. Visceral epith cells (podocytes) & filtration slit diaphragm.

GBM is composed of3, 4, 5 type IV collagen.

Juxta glomerular apparatus;

1. Modified aff arteriolar cells.

2. Macula densa in DCT3. Lacis cells in extraglom. Mesangium.

Stimuli for renin secretion;

1. RBFNa delivery to the macula densa

2. BP (baroreceptor mech)renin from aff cells.3. B adrenergic stimulation.

Renin catalyse the conversion of angiotensinogen intoA I


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Ang I.

Angiotensin II;- thirst sensation

- systemic VC

- VC of efferent arteriole mainlyGFR.

- stimulate aldosterone secretion

- stimulate ADH- direct stimulation of Na reabsorption from PCT bystimulation of Na/H exchanger.

Andosterone;- stimulate Na-K ATPase,

- luminal memb permeab to K

- H secretion by collecting duct

ADH;


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Stimulated by plasma osmolarity > 285,plasma volume.

V1 receptor VC V2water permeability in the collecting ducts

by stimulation of adenylate cyclaseCAMPStimulate memb fusion of vesicle

containing water channels.

ANP;

Inhibit Na reab in the collecting duct

GFR Inhibit ADH & Ald secretion

Tubular function


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PCT;

- Absorption of all glucose, aa.

- 90% of HCO3- 60% Na, Cl, K, Ca

- Phophate absorption inhibitesd by PTH.

LOH;

- countercurrent multiplier (NaK2Cl in thick ascending limb) #frusemide.

- 70% of Mg absorption

DCT; Na/Cl cotransport # thiazide.

CD;

principle cellsamiloride sensitive channelsaldosterone on NaK ATPase

ADH on aquaporins

intercalated cells H or HCO3 secretion


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In pre renal failure / Acute TubularNecrosis (hypovolaemia, dehydration),

the kidney attempts to retain sodium,

hence urine sodium is


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Sweat chloride test

False +ve conc of sweat electrolytes;

1. Endocrine; hypo-adrenal, parath, thyr,

cong nephr DI.

2. Metabolic; G6PD, MPS

3. Ectodermal dysplasia, familial

cholestasis, pancreatitis, malnutrition.

Falseve; nephrotic S.

Q


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Q

Atrial natriuretic peptide

A inhibits distal tubular reabsorption of sodium

B promotes excretion of potassium in the urine

C levels in the blood are independent of leftventricular function

D inhibits vasoconstriction mediated by

angiotensin II

E is a vasodilator without causing reflex

tachycardia

Neuro


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Neuro

Myosin is involved in striated musclecontraction. It forms filaments in a

hexameric array of 2 heavy chains and 2

pairs of light chains. Myosin heavy chain mutation is implicated

in familial hypertrophic cardiomyopathy.

HOCM and Carney complex are forms ofmyosin chain disorders.


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Weakness of small ms of thehand;

- lower trunk of Br plexus injuryallsmall ms of the hand (T1) + longflex & ext of fingers (C8).

- T1 root e.g. cervical rib, pancoat,sub art aneurysm.all small ms ofthe hand.

- ulnar nall small ms of the handexcept 2 lateral lumbricals & thenargroup (T1 through median n).


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Cord compression


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Upper 4 cervical;

- neck pain

- quadriplegia, wasting UL.

- cr n 5 spinal root; dissociated sensory loss of face.

C5,6;

- pain in shoulder, outer arm, FA, thumb

- wasting of romboids, deltoid, biceps, supinator, brakioradialis.

- lost biceps, exagerated triceps, inverted supinator reflexes.

C8,T1;

- pain medial side

- wasting of flexors of wrist, hand.

- horner

L3,4;

- medial side of LL pain.

- wasting of quadriceps, abductors

- lost knee, extensor planter reflexes.

Epiconus= L4,5, S1,2 segments of SC.

lesions;


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lesions;

- lost anckle, preserved knee reflexes

- motor;extension of hip, flexor of knee, dorsi & planter flexion of foot,

toes.- sensory; most of leg

- micturition disturbance.

Conus medullaris= S3,4,5 segments of SC.

lesions;

- no motor or sensory of LL.- dissociated sensory loss of saddle area.

- early urinary incontinence.

- impotence.

Cauda equina= all lumbar & sacral roots.

lesions;- early radical pain.

- sphincters late (retension then autonomic)

- LMNL in LL.

NB; siatica= roots of epiconus (L4,5, S1,2,3)

Root compression


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C5; deltoid

C6; biceps & brakioradialis

C7; wrist extensor, triceps C8; finger flexors, thumb abductors

T1; small ms of the hand

L1,2; iliopsoas (flexion of hip)

L3; quadriceps (knee exten

L4; ant. Tibial (dorsiflexion & inversion)

L5; ant. Tibial & glutei.

S1; calf ms, glutei

S2; hamstring

S3-5; saddle area.

Biceps reflexes= C5,6 Triceps reflexes; C7,8

Supinator reflexes;C6

Knee reflexes L3,4

Anckle reflexes; S1,2.

ExaminationPpitating ActsSymptoms- Sensory loss in thumb, 2nd,3rd

fingers

Sleep or repetitive

hand activity

Numbness, pain

or paresthesias in

Carpal

tunnel


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g

- Weakness in thenar muscles;

-Tinel and Phalen signs

yp

fingerssyndrome

Sensory loss in the little fingerand ulnar half of ring finger

Weakness of the interossei and

thumb adductor; claw-hand

Elbow flexionduring sleep;

elbow resting on

desk

Numbness orparesthesias in

ulnar aspect of

hand

Ulnarnerveentrapment

at the elbow

Like UNE but sensory

examination spares dorsum of

the hand, and selected handmuscles affected

Unusual hand

activities with

tools, bicycling

Numbness or

weakness in the

ulnar distributionin the hand

Ulnarnerve

entrapment

at the wrist

Wrist drop with sparing of elbow

extension (triceps sparing);

finger and thumb extensors

paralyzed; sensory loss inradialregion of wrist

Sleeping on arm

after inebriation

with alcohol

"Saturday nightpalsy"

Wrist dropRadial

neuropathy

at the spiral

groove

Sensory loss resembles ulnar

nerveand motor loss resembles

mediannerve

Lifting heavy

objects with the

hand

Numbness,

paresthesias in

medial arm,

forearm, hand,

and fingers

Thoracic

outlet

syndrome

ExaminationPrecipitating

Activities

Symptoms

W ti d k fAbd i lB kli f kF l


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Wasting and weakness of

quadriceps; absent knee jerk;

sensory loss in medial thigh and

lower leg

Abdominal

hysterectomy;

lithotomy position;

hematoma, DM

Buckling of knee,

numbness or

tingling in

thigh/medial leg

Femoral

neuropathy

Weakness of hip adductors;

sensory loss in upper medial

thigh

Stretch during hip

surgery; pelvic

fracture; childbirth

Weakness of the

leg, thigh

numbness

Obturator

neuropathy

Sensory loss in the pocket of the

pant distribution

- Standing /walking

-Recent weightgain

Pain or numbness

in the anteriorlateral thigh

Meralgia

paresthetica

Weak dorsiflexion, eversion of

the foot

Sensory loss in the anterolateral

leg and dorsum of the foot

Usually an acute

compressive

episode

identifiable; wt loss

Foot dropPeronealn.

entrapment

at the fibular

head

Weakness of hamstring, plantar

and dorsiflexion of foot; sensory

loss in tibial and peronealnerve

distribution

Injection injury;

fracture/dislocation

/ prolonged

pressure on hip

(comatose patient)

Flail foot and

numbness in foot

Sciatic

neuropathy

Q


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Q

A lesion of the facial nerve in the internal auditory meatus will affect

A taste

B sensation over cheek

C lacrimation

D sweating over cheek

E blinkingTrue=ace

Comments:

The extent of dysfunction depends on the level of injury. If it is proximal togeniculate ganglion eg internal auditory meatus, taste is lost in the anterior2/3 of tongue. Also secretion from submandibular, sublingual and lacrimalglands is impaired. Hyperacusis is due to paralysis of stapedius. Orbicularisoculi is affected causing inability to blink/close eyelids. Sensation over facesupplied by trigeminal nerve, and sweat glands controlled by sympatheticnervous system eg anhydriosis in Horner's syndrome.

Q


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Q

The following associations of muscles andnerve supply are true except

A triceps and C7

B deltoid and C5

C gastroenemius and S1D quadriceps and L3

E long flexors of fingers and C6

E

Comments:Finger flexors and extensors are supplied by C8.

QThe following are true of lipoprotein metabolism:


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The following are true of lipoprotein metabolism:

A Large LDL particles are most atherogenic

B LDL concentrations can be calculated from total cholesterol,

triglyceride and HDL concentrationsC VLDL is secreted by the liver

D hyperchylomicronaemia may cause pancreatitis

E dietary lipid is absorbed into the blood as chylomicrons

The true= bcd

Comments:

LDL concentrations can be calculated from HDL, total cholesterol andtriglyceride using the Friedwald equation. Small, high density LDL

particles are the most atherogenic. Cholesterol and triglycerides thatare absorbed from the gut are transported on chylomicrons into theblood through the lymphatic system and thoracic duct.Hyperchylomicronaemia, associated with type I hyperlipidaemia is

rare and is associated with hypertriglyceridaemia and pancreatitis.VLDL is secreted by the liver.


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Causes of Retinitis pigmentosa are:

Kearn Sayre's syndrome

Usher's disease

Refsum's disease

Lawrence Moon Biedl syndrome

Alports's syndromeFriedrich's ataxia

basic sciences mrcp1

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