TAUOPATHIES :-

 TAUOPATHIES :-

• class of neurodegenerative diseases associated with the pathological aggregation of TAU PROTEIN in the human brain.
• tau protein is deposited within neurons in form of neurofibrillary tangles (NFTs).
• Tangles (NFT=a/k/a---PHF or "paired helical filaments") are formed by hyperphosphorylation of a microtubule-associated protein known as tau, causing it to aggregate in an insoluble form (also referred to as ).
• It consists of following disorder:-

1. Alzheimer disease
2. Pick's disease
3. corticobasal degeneration
4. progressive supranuclear palsy
5. Dementia pugilistica (chronic traumatic encephalopathy)
6. Frontotemporal dementia and parkinsonism linked to chromosome 17,
7. Lytico-Bodig disease (Parkinson-dementia complex of Guam)
8. Ganglioglioma and gangliocytoma
9. Meningioangiomatosis
10. Subacute sclerosing panencephalitis
11. Frontotemporal dementia
12. Frontotemporal lobar degeneration
13. lead encephalopathy,
14. tuberous sclerosis, Hallervorden-Spatz disease, and lipofuscinosis

SYNUCLEINOPATHIES:-
• group of neurodegenerative disorders characterized by fibrillary aggregates of ALPHA-SYNUCLEIN PROTEIN in the cytoplasm of neurons and glia.
• These disorders include:-
• Parkinson's disease (PD)
• dementia with Lewy bodies (DLB)
• pure autonomic failure (PAF)
• multiple system atrophy (MSA)

Lung development

Lung development: REMEMBER  the sequence as Entering [Embryonic], Professional [Pseudoglandular], Course [Canalicular],  So [Saccular] Amazing [Alveolar]....
--Develops from median diverticulum of foregut, lining epithelium is endodermal origin.
Stages:-
5 overlapping stages
1.Embryonic –D26-7thwk- lung buds.
2.Pseudo glandular-5thwk-16thwk-Terminal bronchiole.
3.Canalicular-16th-26thwk-Alv.duct.
4.Saccular-26thw-birth-Primitive alveoli.
5.Alveolar-36w-18m-Prominent alveoli.

PDE Inhibitors

Approved PDE3 inhibitors include the following:
amrinone
cilostazol
milrinone
enoximone
Pimobendane
PDE4
Apremilast, a phthalimide derivative being developed for inflammatory disorders, including psoriasis, psoriatic arthritis and ankylosing spondylitis.
Cilomilast, in clinical development
for treatment of COPD.
Diazepam, a benzodiazepine anxiolytic, amnesic, hypnotic, sedative and muscle relaxant.
Ibudilast, a neuroprotective and bronchodilator drug used mainly in the treatment of asthma and stroke. It inhibits PDE4 to the greatest extent, but also shows significant inhibition of other PDE subtypes, and so acts as a selective PDE4 inhibitor or a non-selective phosphodiesterase inhibitor, depending on the dose.
Luteolin, supplement extracted from peanuts that also possesses IGF-1 properties.
Mesembrenone, an alkaloid from the herb Sceletium tortuosum (Kanna).
Piclamilast, a more potent inhibitor than rolipram.
Roflumilast, licensed for the treatment of severe chronic obstructive pulmonary disease
Rolipram, used as investigative tool in pharmacological research.
PDE5
Sildenafil, tadalafil, vardenafil, and the newer udenafil and avanafil selectively inhibit PDE5, which is cGMP-specific and responsible for the degradation of cGMP in the corpus cavernosum. These phosphodiesterase inhibitors are used primarily as remedies for erectile dysfunction, as well as having some other medical applications such as treatment of pulmonary hypertension.
Dipyridamole also inhibits PDE5. This results in added benefit when given together with NO or statins.
Claimed newer and more-selective inhibitors are icariin, an active component of Epimedium grandiflorum,
PDE10
Papaverine, an opium alkaloid, has been reported to act as a PDE10 inhibitor. PDE10A is almost exclusively expressed in the striatum and subsequent increase in cAMP and cGMP after PDE10A inhibition
Nonselective phosphodiesterase inhibitors
Methylated xanthines and derivatives:

caffeine, a minor stimulant
aminophylline
IBMX (3-isobutyl-1-methylxanthine), used as investigative tool in pharmacological research
paraxanthine
pentoxifylline, a drug that has the potential to enhance circulation and may have applicability in treatment of diabetes, fibrotic disorders, peripheral nerve damage, and microvascular injuries
theobromine
theophylline, a bronchodilator
PDE1 selective inhibitors
Vinpocetine
Cilastatin

"MOST COMMON" FACTS -

MC invasive gynecologic malignancy : Endometrial malignancy
MC islet cell tumor in MEN 1 : Gastrinoma
MC islet cell tumor of the pancreas : Insulinoma.
MC joint involved in synovial osteochondromatosis : Knee
MC lesion to cause expansion of paranasal sinus : Mucocele
MC lethal bone dysplasia : Osteogenesis imperfecta
MC lobe affected in bronchial atresia : Left upper lobe.
MC location for a cephalhematoma : Parietal
MC location for a gastric diverticulum : Posterior wall of the gastric fundus.
MC location for a pilocytic astrocytoma : Cerebellum
MC location for a solitary myeloma of the bone : Spine
MC location for a synovial sarcoma : Knee

Psychiatry

Othello syndrome (conjugal paranoia)
A psychosis in which the content of delusions is predominantly jealousy (infidelity) involving spouse.

Clerambault’s syndrome (erotomania)
A psychosis in which the content of delusions is erotic.
Most often in women with erotic conviction that a person with higher status is in love with the
patient.

Kadinsky-Clerambault’s syndrome
A syndrome of mental automatism

Folie a deux
Induced delusional disorder c/b sharing of delusions b/w 2 persons.
So is folie a trios, folie a quatre, folie a famille

Capgras’ syndrome (delusion of doubles)
C/b delusional conviction that other persons in environment are not their real selves but are their
own doubles.
There are 4 types
1. Typical Capgras’ syndrome(illusion des sosies)-pt sees a familiar person as a stranger who is
imposing as the familiar person.
2. Illusion de Fregoli pt falsely identifies strangers as familiar persons.
3. Syndrome of subjective doubles pt’s own self is perceived as being replaced by a double.
4. Intermetamorphosis pt’s misidentification is complete including both external appearance & personality.

Fregoli’s phenomenon
Delusion that a persecutor is taking on a variety of faces like an actor.

One liners

1. Cardiotoxic anticancer drug:
Adriamycin /  Doxorubicin, Donorubicin,  Cyclophosphamide,  5 - Fluorouracil

[Dilated Cardiomypathy is caused by.......:-
DoxoRubicin, DonoRubicin ---- (Rubi Dil le gayi)]

2. Digoxin is excreted Through which route (organ): Renal

3. Digitoxin is excreted mainly by which organ:Liver

4. DOC for PSVT:
1. Adenosine
2. Verapamil

5. Effect on calcium levels of Furosemide:Hypercalemia

6. DOC for motion sickness: Hyoscine (transdermal)[Hyoscine aka Scopolamine: 

also Prescribed to 'Prevent' nausea & vomiting caused by Motion Sickness & Vertigo.]

7. Commonest sife-effect of Cisapride is: Diarrhea

8. Common side-effect of Clofazimine: Red brown discoloration of skin

9. DOC for taenia: Praziquantel

10. Drug inhibiting DNA -dependent RNA polymerase in Mycobacteria is: Rifampicin

11. Common  side-effect of Cisplatin: Vomiting

12. Vitamin deficiency noticed with phenytoin use: Folic acid,Vitamin D, and some says vitamin K as well.

13. DOC for lithium induced Polyuria:  Amiloride

14. Concentration of Lidocaine used in Spinal anaesthesia: 5%

15. Local anaesthetic causing methemoglobinemia: Prilocaine

16. Longest acting local anaesthetic: Dibucaine

17. Anaesthetic agent with LEAST analgesic property: Halothane

18. Post spinal headache can last for: 7-10 days

19. Common site of post spinal headache: Occipital

20. Therapeutic index of a drug is an indicator of its: Safety 

21. Common side-effect of Captopril: Dry cough

22. Active metabolite of Enalapril: Enalaprilat

23. Which steroid can be administered by inhalation: Beclomethasone

24. Drug used for heparin induced thrombocytopenia: Argatroban, Lepirudin 

25. Estrogen acts on which receptors:  Cytoplasmic receptors

26. Mydriasis without cycloplegia: Phenyl-ephrine

27. Buprenorphine is: Partial agonist (mu) & antagonist (k) receptors

28. Drug for maintenance therapy for opioids withdrawl: Methadone 

29. DOC for diabetes inspidus: Desmopressin

30. MOA of minoxidil: Potassium Channel OPENER

31. Beta blocker with shortest plasma half-life: Esmolol

32. Pancreatitis is a common side effect of which anti-HIV: Didanosine

33. Anticancer Drug which causes pulmonary fibrosis: Busulfan, Bleomycin.

34. Drug which is used for treating brady-arrythmias: Atropine

35. MOA of Cholestyramine: Binds to bile acids

36. Antifungal which disrupts fungal cell membrane: Griseofulvin

37. Advantage of 3rd generation cephalosporins over 1st and 2nd generation cephalosporins is that they are: Effective against Gram Negative bacteria.

38. Fluoroquinolone banned in India: Gatifloxacin

39. Anti-malarial drug effective in pre-erythrocytic phase in liver is: Proguanil

40. Effect of chloroquine on eye: Bulls eye maculopathy

41. DOC for herpes simplex: Acyclovir

42. ACE inhibitors causes hyperkalemia so they should not be used with:
Potassium Sparing Diuretics

43. Anticoagulant of choice in pregnancy: Heparin

44. Antidote of heparin: Protamine sulphate

45. Profound Analgesia is related to which anaesthetic agent:  Ketamine

46. Best way to prevent hypotension during spinal anaesthesia:  Preloading with Crystalloids

47. Post spinal headache is due to:  CSF leak

48. Agent causing Malignant Hyperthermia: Succinylcholine.

[DOC for MH - Dantrolene]

49. Nerve fibre affected by Local anaesthesia first: Type C

50. Zero order kinetics at higher dose is seen with: Phenytoin

51. DOC for Scabies: 5% Permethrin ('Oral' DOC - Ivermectin)

52. Lithium monitoring is done because of:  Very low Therapeutic Index

53. MOA of pralidoxime: Cholinesterae enzyme reactivator

54. Drug used in BPH: Prazosin, Tamsulosin

55. DOC for Acute Migraine: Sumitriptan

56. Test for Myasthenia Gravis: Edrophonium Test

57. If Theophylline is used with Ciprofloxacin:  Toxicity of theophylline Increases

58. Steroid with equal Gluco-corticoid & mineralocorticoid activity: Hydrocortisone

59. Flumazenil is: Benzodiazepine Antagonist

60. Fomepizole is used in which poisoning: Methanol Poisoning.

61. MC side-effect of chronic use of Phenothiazines is: Tardive Dyskinesia

62. Side effect of Clozapine: Agranuocytosis

63. MOA of Clonidine:  Alpha2 Agonist  & Decreasing Central sympathetic outflow

64. MOA of Digoxin: Na K ATPase inhibition

65. DOC for meningitis due to listeria:  Ampicillin

66. Mode if metabolism of INH: Acetylation

67. Most common side effect of long term use of lithium: Hypothyroidism

68. DOC for MRSA infection: Vancomycin 69. ADH acts on which part of kidney:  Collecting Duct

70. Hemorrhagic Cystitis may be a side effect of: Cyclophosphamide (Rx. Of Hmg Cystitis: MESNA)

71. Metrifonate is used for: Schistosoma 

72. Anticholinergic drug used in peptic ulcer: Pirenzipine

73. Postural hypotension is commoner with which adrenergic blocker: Prazosin

74. Organ toxicity seen with bupivacaine: Cardiotoxicity.

75. LEAST cardiotoxic anaesthetic agent: Isoflurane

76. Dissociative anaesthesia is seen with: Ketamine

77. Sodium Thiopentone is Ultra-short acting due to: Rapid redistribution

78. Dipyradimole acts by inhibiting  PDE-5 79 Beta 1 agonist drug: Dobutamine

80. Beta1 selective adrenergic blocker which can be used as anti-glaucom: Betaxolol

81. Anti-adrenergic drug which crosses blood-brain-barrier minimally: Atenolol

82. Abacavir belongs to which group: NRTI

83. Prostaglandin analogue used in peptic ulcer: E1

84. Prostaglandin analogue used in glaucoma: F2alpha

85. Shortest acting neuromuscular blocking agent: Mivacurium

86. Anaethetic Drug which increase intracranial pressure: Ketamine

87. Anti-epileptic drug which acts by release of the inhibiting transmitter GABA:   Valproic Acid

88. Furosemide & thiazides have similar properties that they both are:  Well absorbed orally

89. MOA of ciprofloxacin: Inhibits DNA gyrase

90. DOC for WPW syndrome: Pracainamide/ Amiodarone

91. Anti-hypertensive which acts by producing NO Sodium: Nitroprusside

92. MOA of Dantrolene:  Sodium Acts on RyR1 receptors resulting in Decreased Calcium.

93. Interstitial nephritis is MC seen with which antibiotic: Methicillin

94. DOC for dermatitis herpetiformis:  Dapsone

95. Neuro-psychiatric symptoms can be seen with: Cycloserine

96. Oral contraceptive failure may be seen with: Rifampicin 

97. MC side-effect of 5-Fluoro-Uracil: Gastro-Intestinal toxicity

98.  MOA of omeprazole: H K ATPase inhibition

99. Prolonged use of steroids may cause: Decrease in bone matrix proteins

100. First drug to be used in anaphylactic shock: Adrenaline (Subcutaneous / IM )

HIV

high yield (HIV):
HUMAN IMMUNODEFICIENCY VIRUS (HIV) :
• LENTIVIRUS (slowly replicating RETROVIRUS)
that causes the acquired immunodeficiency
syndrome(AIDS)
• a/k/a---“ Slim’s disease “ ( d/t weight loss)
• Commonest secondary immunodeficiency
disorder
• Most patients with HIV infection progress to
AIDS after a chronic phase lasting from 7 to 10
years.
• Exceptions to this typical course are :-
1) RAPID PROGRESSORS
chronic phase shortened to 2 to 3 years after
primary infection.
CD4T cell count < 200 /microL.
2) LONG-TERM NON-PROGRESSORS.
untreated HIV-1-infected individuals who
remain asymptomatic for 10 years or more
with stable CD4+ T-cell counts and low levels
of plasma viremia (usually less than 500 viral
RNA copies per milliliter).
3) ELITE CONTROLLERS.
infected individuals have undetectable plasma
virus (50-75 RNA copies/mL)
• Most common mode of spread --- (75% of all
cases)Sexual contact ( most commonly from
Male to female ).
• Risk of transmission with needle stick
injury--- 0.3%.
• Commonest cause of AIDS in children ---
Vertical transmission
• BLOOD BANK and HIV ( Harrison18/e page no
– 1513 ):-
Blood collected for transfusion is routinely
screened for both HIV-1 and HIV-2
A) HIV transmission is by-------
1) whole blood
2) packed rbc
3) platelets
4) leucocytes
5) plasma
B) No-HIV –Transmission is seen with
( processing procedure will inactivate virus in all
given products) ---
1) hyperimmune gammaglobulin
2) hepatitis B immune globulin
3) plasma derived hepatitis B vaccine
4) Rh0 immune globulin
HIV Epidemiology:-
• HIV-1 ---- most common type a/w AIDS in
the United States, Europe, and Central Africa
• HIV-2----- in West Africa and India.
• HIV-1 three subgroups
1) M(major)
2) O (outlier)
3) N (neither M nor O)
• Group M ( subtypes or clades ;A to K ) ----
most common form worldwide
1) Subtype B --- most common in western
Europe and United States
2) Subtype E --- most common in Thailand.
3) Subtype C (fastest-spreading type
worldwide) --- most common in India, Ethiopia,
and Southern Africa.
• most common cause of AIDS in India---
HIV-1 group-M , Subtype-C.
life cycle of HIV:-
• HIV infects cells by using ---- CD4 molecule
as receptor and various chemokine receptors as
coreceptors.
• CD4 receptors are required for entry of HIV in
Brain
a) macrophages /monocytes
b) dendritic cell
c) CD4T cells (worse affected cells)
• Chemokine receptors:-
HIV isolates and their chemokine receptors:-
1) R5 strains use CCR5--- expressed on
monocytes / macrophage and T-cells both
2) X4 strains use CXCR4 --- expressed on T-
cells only.
3) R5X4-- dual-tropic.
early in course of infection R5 (M-tropic) type
of HIV is the dominant virus (90%).
T-tropic viruses gradually accumulates ( R5
replaced by X4).
T-tropic viruses are “MORE
VIRULENT” ( because capable of infecting many
T cells and even thymic T-cell precursors and
cause greater T-cell depletion and
impairment) .
• infection leads to low levels of CD4+ T cells
through a number of mechanisms including:
1) Apoptosis of uninfected bystander cells
2) Direct viral killing of infected cells
3) Killing of infected CD4+ T cells by CD8
cytotoxic lymphocytes that recognize infected
cells.
HIV and GENETICS:-
• Very high genetic variability ( difference from
other viruses) due to :-
a) Fast replication cycle with generation of
about 1010 virions every day
b) High mutation rate of approximately 3 x 10−5
per nucleotide base per cycle of replication and
c) Recombinogenic properties of REVERSE
TRANSCRIPTASE
• high mutation rate of the human
immunodeficiency virus (HIV) is due to host cell
“DNA-POLYMERASE”
CD4 count and HIV:-
• Normal CD4 count ---- 500 cells/mm3 to
1,000 cells/mm3.
• Treatment is recommended for opportunistic
infections at CD4 count levels:
1) less than 500/mm3 ----- ART start
2) Less than 200/ mm3---- pneumocystis
pneumonia (PCP).
3) Less than 50 mm3/: mycobacterium avium
complex (MAC).
• Some circumstances, it is recommended to
start treatment when CD4 count is higher.
These include:
a) hepatitis B or hepatitis C
b) heart problems or kidney disease
c) having treatment for cancer
d) age over 50
• Viral load (= level of HIV in body) is measured
by------- number of copies of HIV-1 per
milliliter of blood plasma (copies/mL).
• GOAL OF HIV-THERAPY ---- to lower viral
load below 50 copies/mL within 6 months of
treatment.
• DIAGNOSES OF AIDS:-
is made in anyone with HIV infection and a “CD
4-T cell count <200 /Microlitres.”
“AIDS-RELATED COMPLEX (ARC)”:-
• Clinically recognized syndromes seen in HIV
infected patients at the end of clinical latency
• Clinical criteria to define ARC :-
1) Generalised lymphadenopathy (>2 non
inguinal sites)
2) Fatigue /malaise
3) Weight loss ( > 7kg or >10% of normal body
weight)
4) Fever
5) Diarrhoea
6) Night sweats
NOTE:- OPPORTUNISTIC INFECTIONS and
CANCERS a/w AIDS are not included in this
criteria.
CD4 -COUNT SIGNIFICANCE :-
• During asymptomatic period of HIV infection,
average rate of CD4T cell decline is ---50
cells /mm3/year.
• High risk of opportunistic infections --- CD4T
cells < 200/mm3.
• Cardiovascular diseases risk --- CD4T cells <
500/mm3.
• CD4T-cells and infections :-
1) > 350 cells/mm3 ---- HIV- associated
dementia
2) > 300 cells/mm3 – T.B.( Mycobaterium
Tuberculosis)
3) < 300 cells/mm3 –Thrush (Candidiasis); Oral
hairy leukoplakia (EBV-infections );Protozoans
(cryptosporidia; microsporidia and isospora
belli)
4) < 200 cells/mm3 ----Pnuemocystis Jirovecii
(Carinii) Pneumonia (PCP); HIV –Associated
Nephropathy ( HIVAN).; trypanosomiasis
(Chagas disease); Toxoplasmosis; Lymphomas
5) < 100 cells/mm3 – Cryptococcus
neoformans; Bartonella henselae (Bacillary
Angiomatosis);
6) < 50cells /mm3--- Cytomegalovirus (CMV-
retinitis); Mycobaterium Aviam Complex (MAC);
Histoplasmosis; IRIS (Immune Reconstitution
Inflammatory Syndrome ---parodoxical
worsening of preexisting symptoms after
starting ART treatment ); Primary CNS
Lymphomas
HIV- IMPORTANT-INFO:-
1) Most common opportunistic infection in
AIDS---- PNEUMOCYSTIS JIROVECI
2) Most common opportunistic infection in AIDS
pneumonia --- PNEUMOCYSTIS JIROVECI
3) Most common opoortunististic infection in
AIDS in INDIA--- TUBERCULOSIS
4) Most common FUNGAL infection in HIV/AIDS
in INDIA/world both----- CANDIDIASIS
5) Most common cancer in AIDS---KAPOSI-
SARCOMA
6) Most common neurological manifestation in
HIV infection--- “AIDS-DEMENTIA COMPLEX”
7) Most common skeletal muscle disorder ----
INFLAMMATORY MYOPATHY.
8) Most common organism to cause pneumonia
in HIV is---- streptococcus pneumonia
(HARRISON 18/E PAGE 1547)
HIV and LYMPHOMAS:-
• Lymphoma occurs in HIV infection when CD4T
CELL COUNT < 200 cells/mm3 .
• AIDS-DEFINING LYMPHOMAS are NON-
HODGKINS LYMPHOMAS (NHL) only .
(HODGKINS LYMPHOMA are not AIDS-
DEFINING LYMPHOMAS).
• AIDS-DEFINING NON HODGKINS LYMPHOMAS
(NHL)-
1) Immunoblastic lymphomas (60%--Most
common Lymphoma in HIV)---consists of –a)
diffuse large b cell lymphoma b) primary
effusion lymphoma
2) Burkitts lymphomas (small non cleaved cell
lymphomas)
3) Primary CNS lymphomas.
• HIV associated HODGKINS LYMPHOMA :-
1) Mixed cellularity (most common)
2) Nodular sclerosis
3) Lymphocyte depleted
• Most common type of lymphoma in HIV -----
(60%) IMMUNOBLASTIC LYMPHOMA ( diffuse
large b cell lymphoma) .(Primary CNS
Lymphoma -- 20% in HIV cases (HARRISON 18/
e page 1566.)
• Most common extranodal site for non
hodgkins lymphoma in HIV ----CNS.
(Most common extranodal site for NON
HODGKINS LYMPHOMA-------- stomach)
DIAGNOSIS OF HIV-INFECTIONS:-
• Most sensitive (=best screening method)-----
ELISA
• Most specific (=confirmatory)---- WESTERN
BLOT (positive if antibodies exist against 2 out
of 3 HIV-proteins i.e. p24; gp 41; gp120/60 )
• Window period ( 2-4 weeks)--- by PCR.

Compiled by Devesh Mishra sir