Subarachnoid hemorrhage (SAH) implies the presence of blood within the subarachnoid space from some pathologic process. The common medical use of the term SAH refers to the nontraumatic types of hemorrhages, usually from rupture of a berry aneurysm or arteriovenous malformation (AVM). The scope of this article is limited to these nontraumatic hemorrhages.
Workup
Complete blood count
Prothrombin time, activated partial thromboplastin time
Blood typing and screening
Blood bank typing is indicated when SAH is identified or a severe bleed is suspected.
Intraoperative transfusions may be required.
Troponin I (cTnI): cTnI measurement is a powerful predictor for the occurrence of pulmonary and cardiac complications, but it does not carry additional prognostic value for clinical outcome in patients with aneurysmal SAH (Schuiling, 2005).
Imaging Studies
The initial study of choice is an urgent CT scan without contrast (see Picture 1).
Sensitivity decreases with time from onset and with older resolution scanners.
In one recent study published by New England Journal of Medicine, good quality CT scanning revealed subarachnoid hemorrhage in 100% of cases within 12 hours of onset and 93% within 24 hours of onset (Suarez, 2006). Other studies traditionally report 90-95% sensitivity within 24 hours of onset of bleeding, 80% at 3 days, and 50% at 1 week.
CT also can detect intracerebral hemorrhage, mass effect, and hydrocephalus.
A falsely negative CT scan can result from severe anemia or small-volume SAH.
Distribution of SAH can provide information about the location of an aneurysm and prognosis.
Intraparenchymal hemorrhage may occur with middle communicating artery and posterior communicating artery aneurysms. Interhemispheric and intraventricular hemorrhages may occur with anterior communicating artery aneurysms.
Outcome is worse for patients with extensive clots in basal cisterns than for those with a thin, diffuse hemorrhage.
Cerebral angiography is performed once the SAH diagnosis is made.
This study assesses the following:
Vascular anatomy
Current bleeding site
Presence of other aneurysms
This study helps plan operative options.
Angiography findings are negative in 10-20% of patients with SAHs.
If negative, some advocate repeating angiography a few weeks later.
Magnetic resonance imaging (MRI) is performed if no lesion is found on angiography.
Its sensitivity in detecting blood is considered equal or inferior to that of CT scan.
The higher cost, lower availability, and longer study time make it less optimal for detecting SAH.
MRI mostly is used to identify possible AVMs that are not visible on angiography.
MRI may miss small symptomatic lesions that have not yet ruptured.
Magnetic resonance angiography (MRA) is less sensitive than angiography in detecting vascular lesions; however, many believe CT angiography and/or MRA one day will play a more central role.
Multidetector computed tomography angiography (MD-CTA) of the intracranial vessels is now a routine examination, and it is becoming fully integrated into the imaging and treatment algorithm of patients presenting with acute subarachnoid hemorrhage in many centers in the United Kingdom and Europe (Goddard, 2005). Digital-subtraction cerebral angiography has been the criterion standard for the detection of cerebral aneurysm, but CT angiography has gained more popularity and is frequently used owing to its noninvasiveness and a sensitivity and specificity comparable to that of cerebral angiography (Jayaraman, 2004).
Other Tests
Electrocardiogram
About 20% of SAH cases have myocardial ischemia from the increased circulation of catecholamines.
Typical results are nonspecific ST-and T-wave changes, prolonged QRS segments, U waves, and increased QT intervals.
ECG changes reflect myocardial ischemia or infarction and should be treated in the usual manner. Suspicion of SAH is a contraindication to thrombolytic and anticoagulant therapy.
Lumbar puncture
Lumbar puncture (LP) is indicated if the patient has possible SAH and negative CT scan findings.
Perform CT scan prior to LP to exclude any significant intracranial mass effect or obvious intracranial bleed.
LP may be negative less than 2 hours after the bleed; LP is most sensitive at 12 hours after symptom onset.
Red blood cells (RBCs) in the cerebrospinal fluid (CSF) remain consistently elevated in 2 sequential tubes or punctures in SAH, whereas the number of RBCs in technically traumatic punctures decrease over time.
Xanthochromia (yellow-to-pink CSF supernatant) usually is seen by 12 hours after the onset of bleeding; ideally this is measured spectrographically, although many laboratories rely on visual inspection.
LP findings were thought to be positive in 5-15% of all SAH presentations that are not evident on the CT scan. This number may be no longer valid with the advent of newer generations of CT scans. A recent small retrospective chart review about patients presenting to the emergency department undergoing fifth generation CT scans and LP showed no patients with positive LP and negative CT scan (Boesiger, 2005).
REFERENCE: http://emedicine.medscape.com/article/794076-overview
December 29, 2008
November 21, 2008
PHARMACOLOGY MOCK TEST
Full marks 40 Time – 2 hours
Attempt all questions. Supplement your answer with charts and diagrams as needed.
1. Name the drugs that can be administered by rotahaler. What is the basic difference between a rotahaler and a metered dose inhaler (MDI)? What are the advantages and disadvantages of nebuliser over MDI? Discuss the management of acute severe asthma indicating the doses of individual drugs. [2 + 1 + 2 + 5]
Or, Classify β adrenoceptor antagonists. State the contraindications of non-selective β adrenoceptor antagonists. What is the role of β blockers in AMI? Name the drugs used in the management of hypertension in pregnancy with their doses. [3 + 2 + 2 + 3]
2. Explain why: (Any FIVE) [2 x 5]
a) Neostigmine is preferred over Physostigmine for the treatment of myasthenia gravis
b) Omeprazole is not given concurrently with antacids
c) Spironolactone is used in cirrhosis of liver
d) Atropine substitutes are used in Haloperidol induced acute dystonias
e) Acetazolamide should be avoided in hepatic failure
f) Enalapril is contraindicated in bilateral renal artery stenosis
g) Class III anti-arrhythmic drugs can themselves precipitate arrhythmias
h) Pirenzepine is not used in treatment of peptic ulcer
3. Describe the mechanism of action of: (Any 4) [2 x 4]
a) Castor oil as purgative
b) Adenosine in PSVT
c) Ketotifen in asthma
d) Thiazide in diabetes insipidus
e) Glucocorticoids in chemotherapy induced vomiting
f) Pralidoxime in organophosphate compound poisoning
g) Propranolol in hyperthyroidism
4. Write short notes on: [4 x 3]
a) Management of acute angle closure glaucoma OR Management of mushroom poisoning
b) Classification of drugs used in diarrhea OR Classification of drugs used in peptic ulcer
c) Glyceryl trinitrate OR Digoxin (Mechanism of action, Use, Dose, Adverse effect)
Full marks 40 Time – 2 hours
Attempt all questions. Supplement your answer with charts and diagrams as needed.
1. Name the drugs that can be administered by rotahaler. What is the basic difference between a rotahaler and a metered dose inhaler (MDI)? What are the advantages and disadvantages of nebuliser over MDI? Discuss the management of acute severe asthma indicating the doses of individual drugs. [2 + 1 + 2 + 5]
Or, Classify β adrenoceptor antagonists. State the contraindications of non-selective β adrenoceptor antagonists. What is the role of β blockers in AMI? Name the drugs used in the management of hypertension in pregnancy with their doses. [3 + 2 + 2 + 3]
2. Explain why: (Any FIVE) [2 x 5]
a) Neostigmine is preferred over Physostigmine for the treatment of myasthenia gravis
b) Omeprazole is not given concurrently with antacids
c) Spironolactone is used in cirrhosis of liver
d) Atropine substitutes are used in Haloperidol induced acute dystonias
e) Acetazolamide should be avoided in hepatic failure
f) Enalapril is contraindicated in bilateral renal artery stenosis
g) Class III anti-arrhythmic drugs can themselves precipitate arrhythmias
h) Pirenzepine is not used in treatment of peptic ulcer
3. Describe the mechanism of action of: (Any 4) [2 x 4]
a) Castor oil as purgative
b) Adenosine in PSVT
c) Ketotifen in asthma
d) Thiazide in diabetes insipidus
e) Glucocorticoids in chemotherapy induced vomiting
f) Pralidoxime in organophosphate compound poisoning
g) Propranolol in hyperthyroidism
4. Write short notes on: [4 x 3]
a) Management of acute angle closure glaucoma OR Management of mushroom poisoning
b) Classification of drugs used in diarrhea OR Classification of drugs used in peptic ulcer
c) Glyceryl trinitrate OR Digoxin (Mechanism of action, Use, Dose, Adverse effect)
Mock test on Bacteriology (General and Systemic)
MICROBIOLOGY (BACTERIOLOGY) MOCK TEST
Full marks 40 Time – 2 hours
Attempt all questions. Supplement your answer with charts and diagrams as needed.
1. A middle aged lady attended the skin OPD with complaints of hypopigmented patch over the right elbow with progressive loss of sensation. What is your provisional diagnosis? How would you proceed to confirm the clinical diagnosis in the laboratory? How is the efficacy of treatment evaluated in such cases? [1 + 7 + 2]
Or, A middle aged person attended the STD clinic with a solitary painless ulcer with hard base on the glans penis. What is the commonest organism that causes such a lesion? What are the methods of isolation and demonstration of the organism in the laboratory? Discuss the role of serological tests in diagnosing late stages of the disease. [1 + 4 + 5]
Or, Name the bacteria responsible for diarrheal diseases in man. How would you proceed to investigate a case of bacterial diarrhea in the laboratory if you are supplied with the fresh fecal matter of the infected individual collected in a sterile plastic bottle? [2 + 8]
2. Write short notes on any THREE: [3 x 4 = 12]
a) Acid fast stain OR Bacterial growth curve
b) Plasmids OR Bacterial flagella
c) El Tor Vibrio OR Shiga toxin producing E. coli
d) Importance of ASO titer OR Interpretation of Mantoux test
3. Comment on any THREE: [3 x 4 = 12]
a) The choice of specimen for diagnosis depends on the stage of Enteric fever.
b) Koch’s postulates have many exceptions.
c) Morphology of the colonies of motile bacteria depends on the concentration of agar agar in Nutrient agar medium.
d) Bacteriological profile of purulent meningitis varies with the age of the patient.
e) Slide and tube coagulase tests are based on different biological principles.
f) Both chromosomal and extra-chromosomal factors are involved in the origin of bacterial drug resistance.
4. Differentiate between any THREE: [3 x 2 = 6]
a) Staphylococcus aureus and S. saprophyticus
b) Autoclaving and Tyndallisation
c) Streptococcus pneumoniae and Streptococcus pyogenes
d) Chlamydia and bacteria
e) Blood agar and chocolate agar
Full marks 40 Time – 2 hours
Attempt all questions. Supplement your answer with charts and diagrams as needed.
1. A middle aged lady attended the skin OPD with complaints of hypopigmented patch over the right elbow with progressive loss of sensation. What is your provisional diagnosis? How would you proceed to confirm the clinical diagnosis in the laboratory? How is the efficacy of treatment evaluated in such cases? [1 + 7 + 2]
Or, A middle aged person attended the STD clinic with a solitary painless ulcer with hard base on the glans penis. What is the commonest organism that causes such a lesion? What are the methods of isolation and demonstration of the organism in the laboratory? Discuss the role of serological tests in diagnosing late stages of the disease. [1 + 4 + 5]
Or, Name the bacteria responsible for diarrheal diseases in man. How would you proceed to investigate a case of bacterial diarrhea in the laboratory if you are supplied with the fresh fecal matter of the infected individual collected in a sterile plastic bottle? [2 + 8]
2. Write short notes on any THREE: [3 x 4 = 12]
a) Acid fast stain OR Bacterial growth curve
b) Plasmids OR Bacterial flagella
c) El Tor Vibrio OR Shiga toxin producing E. coli
d) Importance of ASO titer OR Interpretation of Mantoux test
3. Comment on any THREE: [3 x 4 = 12]
a) The choice of specimen for diagnosis depends on the stage of Enteric fever.
b) Koch’s postulates have many exceptions.
c) Morphology of the colonies of motile bacteria depends on the concentration of agar agar in Nutrient agar medium.
d) Bacteriological profile of purulent meningitis varies with the age of the patient.
e) Slide and tube coagulase tests are based on different biological principles.
f) Both chromosomal and extra-chromosomal factors are involved in the origin of bacterial drug resistance.
4. Differentiate between any THREE: [3 x 2 = 6]
a) Staphylococcus aureus and S. saprophyticus
b) Autoclaving and Tyndallisation
c) Streptococcus pneumoniae and Streptococcus pyogenes
d) Chlamydia and bacteria
e) Blood agar and chocolate agar
Mock test on Pathology Paper I
PATHOLOGY PAPER I
Full marks 40 Time – 2 hours
Attempt all questions. Supplement your answer with charts and diagrams as needed.
Group A
1. A 30 year old lady presented with multiple petechial spots on skin and easy bruisability for the last one year. On examination, temperature, pulse and BP were within normal limits. How would you proceed to investigate the case in the laboratory? [10]
Group B (Answer any ONE)
2. Classify Diabetes Mellitus according to causes. What are the acute complications of DM? Enumerate the investigations that you may use to evaluate the glycemic control in a patient of DM who is under treatment. Discuss the diagnostic importance of oral glucose tolerance test. [3 + 2 + 2 + 3]
3. Classify acute leukemia based on bone marrow findings and cytochemistry. What may be the causes of dry tap in acute leukemia? Enumerate the clinical conditions caused by organ infiltration in acute leukemia. [5 + 2 + 3]
Group C (Answer any ONE)
4. Discuss the various routes of spread of a malignant tumor. Name 4 occupational cancers with their associated occupations. Name 4 premalignant conditions and their resultant cancers. Name 4 tumors that can present with Cushing’s syndrome.
[4 + 2 + 2 + 2]
5. Discuss the steps of healing of a clean surgical incision well apposed by sutures. Mention four complications that may develop due to infection of the surgical wound. Discuss the pathogenesis of septic shock. [4 + 2 + 4]
Group D
6. Write short notes on: (Any FIVE) [5 x 2]
a) Peripheral blood picture in vitamin B-12 deficiency
b) Myeloid leukemoid reaction
c) Plummer Vinson syndrome
d) Target cells
e) Staining of amyloid
f) Turner’s syndrome
g) Reed Sternberg cells
Full marks 40 Time – 2 hours
Attempt all questions. Supplement your answer with charts and diagrams as needed.
Group A
1. A 30 year old lady presented with multiple petechial spots on skin and easy bruisability for the last one year. On examination, temperature, pulse and BP were within normal limits. How would you proceed to investigate the case in the laboratory? [10]
Group B (Answer any ONE)
2. Classify Diabetes Mellitus according to causes. What are the acute complications of DM? Enumerate the investigations that you may use to evaluate the glycemic control in a patient of DM who is under treatment. Discuss the diagnostic importance of oral glucose tolerance test. [3 + 2 + 2 + 3]
3. Classify acute leukemia based on bone marrow findings and cytochemistry. What may be the causes of dry tap in acute leukemia? Enumerate the clinical conditions caused by organ infiltration in acute leukemia. [5 + 2 + 3]
Group C (Answer any ONE)
4. Discuss the various routes of spread of a malignant tumor. Name 4 occupational cancers with their associated occupations. Name 4 premalignant conditions and their resultant cancers. Name 4 tumors that can present with Cushing’s syndrome.
[4 + 2 + 2 + 2]
5. Discuss the steps of healing of a clean surgical incision well apposed by sutures. Mention four complications that may develop due to infection of the surgical wound. Discuss the pathogenesis of septic shock. [4 + 2 + 4]
Group D
6. Write short notes on: (Any FIVE) [5 x 2]
a) Peripheral blood picture in vitamin B-12 deficiency
b) Myeloid leukemoid reaction
c) Plummer Vinson syndrome
d) Target cells
e) Staining of amyloid
f) Turner’s syndrome
g) Reed Sternberg cells
November 10, 2008
October 15, 2008
Web snippets about Japanese B Encephalitis
JAPANENE ENCEPHALITIS
Japanese encephalitis (Japanese: , Nihon-nōen; previously known as Japanese B encephalitis to distinguish it from von Economo's A encephalitis) is a disease caused by the mosquito-borne Japanese encephalitis virus. The Japanese encephalitis virus is a virus from the family Flaviviridae. Domestic pigs and wild birds are reservoirs of the virus; transmission to humans may cause severe symptoms. One of the most important vectors of this disease is the mosquito Culex tritaeniorhynchus. This disease is most prevalent in Southeast Asia and the Far East.
Epidemiology:
Japanese encephalitis is the leading cause of viral encephalitis in Asia, with 30,000–50,000 cases reported annually. Case-fatality rates range from 0.3% to 60% and depends on the population and on age. Rare outbreaks in U.S. territories in Western Pacific have occurred. Residents of rural areas in endemic locations are at highest risk; Japanese encephalitis does not usually occur in urban areas. Countries which have had major epidemics in the past, but which have controlled the disease primarily by vaccination, include China, Korea, Japan, Taiwan and Thailand. Other countries that still have periodic epidemics include Vietnam, Cambodia, Myanmar, India, Nepal, and Malaysia. Japanese encephalitis has been reported on the Torres Strait Islands and two fatal cases were reported in mainland northern Australia in 1998. The spread of the virus in Australia is of particular concern to Australian health officials due to the unplanned introduction of Culex gelidus, a potential vector of the virus, from Asia. However, the current presence on mainland Australia is minimal.[1]
Human, cattle and horses are dead-end hosts and disease manifests as fatal encephalitis. Swine acts as amplifying host and has very important role in epidemiology of the disease. Infection in swine is asymptomatic, except in pregnant sows, when abortion and fetal abnormalities are common sequelae. Infection in Humans occur in the ear, particularly the cochlea. The most important vector is C. tritaeniorhynchus, which feeds on cattle in preference to humans, it has been proposed that moving swine away from human habitation can divert the mosquito away from humans and swine.[2] The natural host of the Japanese encephalitis virus is bird, not human, and many believe the virus will therefore never be completely eliminated.
Clinical features:
Japanese encephalitis has an incubation period of 5 to 15 days and the vast majority of infections are asymptomatic: only 1 in 250 infections develop into encephalitis.
Severe rigors mark the onset of this disease in humans. Fever, headache and malaise are other non-specific symptoms of this disease which may last for a period of between 1 and 6 days. Signs which develop during the acute encephalitic stage include neck rigidity, cachexia, hemiparesis, convulsions and a raised body temperature between 38 and 41 degrees Celsius. Mental retardation developed from this disease usually leads to coma. Mortality of this disease varies but is generally much higher in children. Transplacental spread has been noted. Life-long neurological defects such as deafness, emotional lability and hemiparesis may occur in those who have had central nervous system involvement. In known cases some effects also include, nausea, headache, fever, vomiting and sometimes swelling of the testicles.
Virology:
The causative agent Japanese encephalitis virus is an enveloped virus of the genus flavivirus; it is closely related to the West Nile virus and St. Louis encephalitis virus. Positive sense single stranded RNA genome is packaged in the capsid, formed by the capsid protein. The outer envelope is formed by envelope (E) protein and is the protective antigen. It aids in entry of the virus to the inside of the cell. The genome also encodes several nonstructural proteins also (NS1,NS2a,NS2b,NS3,N4a,NS4b,NS5). NS1 is produced as secretory form also. NS3 is a putative helicase, and NS5 is the viral polymerase. It has been noted that the Japanese encephalitis virus (JEV) infects the lumen of the endoplasmic reticulum (ER)[3][4] and rapidly accumulates substantial amounts of viral proteins for the JEV.
Japanese Encephalitis is diagnosed by detection of antibodies in serum and CSF (cerebrospinal fluid) by IgM capture ELISA.
Prevention:
Infection with JEV confers life-long immunity. All current vaccines are based on the genotype III virus. A formalin-inactivated mouse-brain derived vaccine was first produced in Japan in the 1930s and was validated for use in Taiwan in the 1960s and in Thailand in the 1980s. The widespread use of vaccine and urbanisation has led to control of the disease in Japan, Korea, Taiwan and Singapore. The high cost of the vaccine, which is grown in live mice, means that poorer countries have not been able to afford to give it as part of a routine immunisation programme.
In the UK, the two vaccines used (but which are unlicensed) are JE-Vax and Green Cross. Three doses are given at 0, 7–14 and 28–30 days. The dose is 1ml for children and adult, and 0.5ml for infants under 36 months of age.
The most common adverse effects are redness and pain at the injection site. Uncommonly, an urticarial reaction can develop about four days after injection. Because the vaccine is produced from mouse brain,[6] there is a risk of autoimmune neurological complications of around 1 per million vaccinations.
Neutralising antibody persists in the circulation for at least two to three years, and perhaps longer.[7][8] The total duration of protection is unknown, but because there is no firm evidence for protection beyond three years, boosters are recommended every two years for people who remain at risk.
There are a number of new vaccines under development. The mouse-brain derived vaccine is likely to be replaced by a cell-culture derived vaccine that is both safer and cheaper to produce. China licensed a live attenuated vaccine in 1988 and more than 200 million doses have been given; this vaccine is available in Nepal, Sri Lanka, South Korea and India. There is also a new chimeric vaccine based on the yellow fever 17D vaccine that is currently under development.Treatment:
There is no specific treatment for Japanese encephalitis and treatment is supportive. There is no transmission from person to person and therefore patients do not need to be isolated.
The use of arctigenin has been proposed.[9]
Reference:
http://en.wikipedia.org/wiki/Japanese_Encephalitis
Article 2:
JAPANESE ENCEPHALITIS: CLINICAL FEATURES AND LABORATORY DIAGNOSIS
(Japanese B encephalitis)
Definition
Japanese encephalitis (JE) is an arthropod-borne virus disease affecting the central nervous system (CNS) of human beings and, less frequently, horses. The infection also results in the birth of litters of pigs with a high percentage of stillbirths or pigs affected with encephalitis.
Etiology
The JE virus is a member of the family Flaviviridae and is in the genus Flavivirus. Host range and other characteristics are described in detail in the International Catalogue of Arboviruses (1).
Host Range
People and horses are victims of the JE virus infection but appear to be dead-end hosts from an epidemiologic standpoint. Viremia levels in infected human beings and equine species are generally too low to provide potential mosquito vectors with an infective blood meal. Under experimental conditions, however, Gould et al. (9) demonstrated horse to horse transmission by Culex tritaeniorhynchus. Cattle are frequently infected in enzootic areas (24) but do not develop sickness or viremia (14).
Swine in Japan and Taiwan are both victims of disease as well as amplifiers of infection in nature. This is particularly true when swine are bred to farrow at a time when infected mosquitoes make their first appearance. This type of breeding program is practiced in Japan where, because of immunity or natural seasonal lows in transmission, gilts resist infection during pregnancy, and thus losses due to abnormal litters resulting from JE infection are reduced. However, normal newborn piglets soon lose maternally acquired antibody and are fully susceptible to infection from arthropod vectors.
Although JE infection in shoats is subclinical, viremias are sufficiently high to provide emerging broods of Cu. tritaeniorhynchus, which feed readily on swine, with a plentiful source of virus-containing blood. Following a period of extrinsic incubation of virus, the mosquitoes are able to transmit the infection to susceptible vertebrate hosts.
In Japan, herons and egrets play a role in the spread of infection to man and other vertebrates and may be responsible for carrying the virus from rural to urban areas. Cu. tritaeniorhynchus feeds readily on herons and egrets and ranges sufficiently high off the ground to feed on the young nesting birds.
Geographic Distribution
Human encephalitis in Japan was recognized as early as 1871, and Japanese encephalitis in epidemic form has been known since 1924 when 4,000 human deaths were recorded in Japan. The epidemiology of the disease was studied extensively after World War II in Japan by scientists of the U.S. Army's 406th Medical General Laboratory (2). Concurrent with vaccination of people and extensive use of agricultural pesticides in the last three decades, the disease has practically disappeared from Japan.
Japanese encephalitis virus infection is widespread throughout temperate and tropical Asia; increasing numbers of human and equine cases have appeared in India, Nepal, China, Philippines, Sri Lanka, and northern Thailand. The disease in humans is sporadic in Indonesia and northern Australia but is not known in the rest of the world.
Transmission
The virus is maintained in nature in a cycle involving Culex mosquitoes of the genera tritaeniorhynchus, annulus, fuscocephala, gelidus, and vishnui complex. Mosquitoes transmit the virus to many species of birds and to swine (2,25).
The sequence of events in temperate Asia is initiated by appearance of virus in mosquitoes in late spring followed by the infection and disease in susceptible horses and swine. This is followed by the appearance of disease in man in August and September. In tropical and semitropical areas of Asia, the seasonal nature of the disease is less marked.
Basically, however, it appears the Culex mosquitoes and birds are common factors in the epidemiology of JE, regardless of the region of occurrence, and that swine are involved where they are numerous in Asia (15).
The mechanism of maintaining the virus over the winter in temperate areas has not been elucidated. Overwintering in mosquitoes is a possibility either in infected hibernating mosquitoes or by transovarial passage (23). It is also possible that bats may carry the virus for prolonged periods (18,6).
Incubation Period
In horses, the incubation period is 8 to 10 days. The time between exposure of pregnant swine to an infectious dose of JE virus and delivery of abnormal litters does not seem to be clearly established, although exposure early in gestation appears more likely to result in abnormal litters than later exposure.
Clinical Signs
In horses, initial signs are fever, impaired locomotion, stupor, and grinding of teeth. Blindness, coma, and death follow in more severe cases. Although the clinical signs resemble those seen in horses with Western equine encephalomyelitis and Eastern equine encephalomyelitis, mortality is relatively low. Inapparent or subclinical infections in horses are far more common than cases of recognizable encephalitis.
The principal manifestation of disease in swine is the expulsion of litters of stillborn or mummified fetuses, usually at term. Viable piglets frequently die shortly after birth and exhibit tremor and convulsions before expiring. Experimental infection of boars leads to diminished sperm count and decreased mobility of sperm. Virus has been transmitted to gilts by way of infected semen (11).
Gross Lesions
In horses, gross lesions are similar to those observed in animals dying from Eastern equine encephalomyelitis and Western equine encephalomyelitis virus infections and are not specific enough to establish an etiologic diagnosis. Litters from infected pigs contain fetuses that are mummified and dark in appearance (24,4). Hydrocephalus, cerebellar hypoplasia, and spinal hypomyelinogenesis have been noted (20).
Morbidity and Mortality
The equine mortality caused by JE has been reported at about 5 percent in Japan and may actually be less than this in Southeast Asia. Mortality in adult pigs is close to zero. Litters of pigs from infected sows may be dead at delivery or, if living, may be quite weak and apt to succumb to encephalitis shortly after birth.
Diagnosis
Field Diagnosis
Presumptive diagnosis can be made in horses that manifest CNS disease accompanied by fever, particularly in an epizootic period. It has been observed that illness in horses at race tracks in Malaysia is frequently due to JE infection. The infection is manifested only by fever and a short period of lethargy (16,12,22). In temperate zones, the disease appears during late summer and early fall.
A presumptive diagnosis in swine is based on the birth of litters with a high percentage of stillborn or weak piglets.
Specimens for Laboratory
One half of a brain from animals having signs of encephalitis should be submitted unfixed and the other half fixed in 10 percent formalin. Paired serum samples collected at least 14 days apart should be submitted from animals that survive. Cerebrospinal fluid from horses with CNS signs should be submitted for detection of JE-specific IgM.
Laboratory Diagnosis
Confirmation of JE can be accomplished by demonstrating seroconversion in animals that survive long enough to yield properly spaced blood samples. Neutralization, complement fixation, hemagglutination inhibition, immunofluorescence, and enzyme-linked immonosorbent assay tests are used to show a rise in titer from the acute stage to death or recovery. Reliance on seroconversion or IgM as a means of diagnosis in horses is not definitive because seroconversion may have resulted from exposure to another nonpathogenic Flavivirus.
Demonstration of JE-specific IgM in serum of an encephalitic equine is presumptive evidence of the diagnosis.
Further confirmation of JE in horses can be obtained by examination of the cerebrospinal fluid and the brain. Specific IgM in the spinal fluid is excellent evidence of CNS infection. Although microscopic lesions of the brain are of value, definitive confirmation is based on isolation and identification of the virus from the brain. Virus isolations are more likely to be successful from brains of animals that died after a short course of the disease.
Confirmation of JE in diseased litters of pigs is accomplished by isolation of the virus from fetal brains or brains of piglets that die after manifesting signs of encephalitis. Demonstration of antibody increase in dams bearing affected litters is probably not a reliable measure because seroconversion in such animals would probably have occurred earlier in infection.
Differential Diagnosis
The disease in horses must be differentiated from other viral encephalitides. In Asia, JE is the only recognized arboviral infection causing encephalitis in horses. Because there are many mild or subclinical infections, laboratory confirmation is essential.
Various forms of toxic encephalitis must be considered in differential diagnosis. In temperate-zone Asia, the midsummer seasonal occurrence of JE in horses aids in differential diagnosis.
Japanese encephalitis in pigs must be differentiated from a hemagglutinating DNA virus infection that appears to be as commonplace in Japan as JE (21) and causes the same pattern of disease. There is evidence that the DNA virus infection is established in gilts in the middle or last trimester of pregnancy. Seasonal patterns of DNA virus infection need more complete study, but the disease does appear concurrently with Japanese encephalitis and therefore requires laboratory tests for differentiation.
Another hemagglutinating virus, myxovirus parainfluenza 1 (Sendai), has been shown capable of producing stillbirth in swine under experimental conditions (20). Encephalitis in neonatal pigs is also associated with a coronavirus infection. This agent is known to cause encephalitis in piglets in at least North America and Europe (19).
Vaccination
A live attenuated vaccine produced in hamster kidney tissue culture is in widespread use in horses in China (13). This vaccine reduced disease by about 85 percent. An inactivated vaccine prepared in mouse brain is licensed in Japan, Korea, Taiwan, India, and Thailand for use in humans. A similar inactivated product made in hamster kidney tissue culture has been used to immunize children annually in China since 1965. Live attenuated vaccines are used to immunize pigs in Japan and Taiwan (8) and humans in China (13A).
Control and Eradication
Options for control include elimination of the vectors, prevention of amplification of the infection cycle in birds and pigs, or immunization of horses, pigs, and people. Although some success in vector control was achieved by modification of irrigation methods to minimize breeding of Cu. tritaeniorhynchus in Southeast Asia and coincidentally by the use of agricultural pesticides, vector control has never been more than marginally successful. Reduction of the avian reservoir hosts does not appear feasible.
The most promising approach to reducing livestock losses and at the same time reducing the totality of infection in nature is widespread immunization of swine. Live attenuated vaccines are in use in Japan and Taiwan (8). Immunization of shoats prevents infection in vaccinees and neutralizes their role as amplifiers of infection in nature. It is anticipated that those animals retained for breeding will remain immune, and, because of immunity or natural seasonal lows in transmission resist infection during pregnancy and therefore bear normal litters. Although controlling the disease in swine dampens the spread of infection in nature, there is a continued threat to horses and human beings from other sources.
The introduction of JE virus into the United States is always a possibility, but whether the infection, once introduced, would become established in nature is difficult to assess. Animal health authorities must continue to be alert to detecting and identifying agents associated with encephalitis in horses and with abnormal litters of pigs. The means for rapid diagnosis and identification of JE are available, although it is doubtful that control of the disease in Asia will be achieved in the near future.
Japanese encephalitis (Japanese: , Nihon-nōen; previously known as Japanese B encephalitis to distinguish it from von Economo's A encephalitis) is a disease caused by the mosquito-borne Japanese encephalitis virus. The Japanese encephalitis virus is a virus from the family Flaviviridae. Domestic pigs and wild birds are reservoirs of the virus; transmission to humans may cause severe symptoms. One of the most important vectors of this disease is the mosquito Culex tritaeniorhynchus. This disease is most prevalent in Southeast Asia and the Far East.
Epidemiology:
Japanese encephalitis is the leading cause of viral encephalitis in Asia, with 30,000–50,000 cases reported annually. Case-fatality rates range from 0.3% to 60% and depends on the population and on age. Rare outbreaks in U.S. territories in Western Pacific have occurred. Residents of rural areas in endemic locations are at highest risk; Japanese encephalitis does not usually occur in urban areas. Countries which have had major epidemics in the past, but which have controlled the disease primarily by vaccination, include China, Korea, Japan, Taiwan and Thailand. Other countries that still have periodic epidemics include Vietnam, Cambodia, Myanmar, India, Nepal, and Malaysia. Japanese encephalitis has been reported on the Torres Strait Islands and two fatal cases were reported in mainland northern Australia in 1998. The spread of the virus in Australia is of particular concern to Australian health officials due to the unplanned introduction of Culex gelidus, a potential vector of the virus, from Asia. However, the current presence on mainland Australia is minimal.[1]
Human, cattle and horses are dead-end hosts and disease manifests as fatal encephalitis. Swine acts as amplifying host and has very important role in epidemiology of the disease. Infection in swine is asymptomatic, except in pregnant sows, when abortion and fetal abnormalities are common sequelae. Infection in Humans occur in the ear, particularly the cochlea. The most important vector is C. tritaeniorhynchus, which feeds on cattle in preference to humans, it has been proposed that moving swine away from human habitation can divert the mosquito away from humans and swine.[2] The natural host of the Japanese encephalitis virus is bird, not human, and many believe the virus will therefore never be completely eliminated.
Clinical features:
Japanese encephalitis has an incubation period of 5 to 15 days and the vast majority of infections are asymptomatic: only 1 in 250 infections develop into encephalitis.
Severe rigors mark the onset of this disease in humans. Fever, headache and malaise are other non-specific symptoms of this disease which may last for a period of between 1 and 6 days. Signs which develop during the acute encephalitic stage include neck rigidity, cachexia, hemiparesis, convulsions and a raised body temperature between 38 and 41 degrees Celsius. Mental retardation developed from this disease usually leads to coma. Mortality of this disease varies but is generally much higher in children. Transplacental spread has been noted. Life-long neurological defects such as deafness, emotional lability and hemiparesis may occur in those who have had central nervous system involvement. In known cases some effects also include, nausea, headache, fever, vomiting and sometimes swelling of the testicles.
Virology:
The causative agent Japanese encephalitis virus is an enveloped virus of the genus flavivirus; it is closely related to the West Nile virus and St. Louis encephalitis virus. Positive sense single stranded RNA genome is packaged in the capsid, formed by the capsid protein. The outer envelope is formed by envelope (E) protein and is the protective antigen. It aids in entry of the virus to the inside of the cell. The genome also encodes several nonstructural proteins also (NS1,NS2a,NS2b,NS3,N4a,NS4b,NS5). NS1 is produced as secretory form also. NS3 is a putative helicase, and NS5 is the viral polymerase. It has been noted that the Japanese encephalitis virus (JEV) infects the lumen of the endoplasmic reticulum (ER)[3][4] and rapidly accumulates substantial amounts of viral proteins for the JEV.
Japanese Encephalitis is diagnosed by detection of antibodies in serum and CSF (cerebrospinal fluid) by IgM capture ELISA.
Prevention:
Infection with JEV confers life-long immunity. All current vaccines are based on the genotype III virus. A formalin-inactivated mouse-brain derived vaccine was first produced in Japan in the 1930s and was validated for use in Taiwan in the 1960s and in Thailand in the 1980s. The widespread use of vaccine and urbanisation has led to control of the disease in Japan, Korea, Taiwan and Singapore. The high cost of the vaccine, which is grown in live mice, means that poorer countries have not been able to afford to give it as part of a routine immunisation programme.
In the UK, the two vaccines used (but which are unlicensed) are JE-Vax and Green Cross. Three doses are given at 0, 7–14 and 28–30 days. The dose is 1ml for children and adult, and 0.5ml for infants under 36 months of age.
The most common adverse effects are redness and pain at the injection site. Uncommonly, an urticarial reaction can develop about four days after injection. Because the vaccine is produced from mouse brain,[6] there is a risk of autoimmune neurological complications of around 1 per million vaccinations.
Neutralising antibody persists in the circulation for at least two to three years, and perhaps longer.[7][8] The total duration of protection is unknown, but because there is no firm evidence for protection beyond three years, boosters are recommended every two years for people who remain at risk.
There are a number of new vaccines under development. The mouse-brain derived vaccine is likely to be replaced by a cell-culture derived vaccine that is both safer and cheaper to produce. China licensed a live attenuated vaccine in 1988 and more than 200 million doses have been given; this vaccine is available in Nepal, Sri Lanka, South Korea and India. There is also a new chimeric vaccine based on the yellow fever 17D vaccine that is currently under development.Treatment:
There is no specific treatment for Japanese encephalitis and treatment is supportive. There is no transmission from person to person and therefore patients do not need to be isolated.
The use of arctigenin has been proposed.[9]
Reference:
http://en.wikipedia.org/wiki/Japanese_Encephalitis
Article 2:
JAPANESE ENCEPHALITIS: CLINICAL FEATURES AND LABORATORY DIAGNOSIS
(Japanese B encephalitis)
Definition
Japanese encephalitis (JE) is an arthropod-borne virus disease affecting the central nervous system (CNS) of human beings and, less frequently, horses. The infection also results in the birth of litters of pigs with a high percentage of stillbirths or pigs affected with encephalitis.
Etiology
The JE virus is a member of the family Flaviviridae and is in the genus Flavivirus. Host range and other characteristics are described in detail in the International Catalogue of Arboviruses (1).
Host Range
People and horses are victims of the JE virus infection but appear to be dead-end hosts from an epidemiologic standpoint. Viremia levels in infected human beings and equine species are generally too low to provide potential mosquito vectors with an infective blood meal. Under experimental conditions, however, Gould et al. (9) demonstrated horse to horse transmission by Culex tritaeniorhynchus. Cattle are frequently infected in enzootic areas (24) but do not develop sickness or viremia (14).
Swine in Japan and Taiwan are both victims of disease as well as amplifiers of infection in nature. This is particularly true when swine are bred to farrow at a time when infected mosquitoes make their first appearance. This type of breeding program is practiced in Japan where, because of immunity or natural seasonal lows in transmission, gilts resist infection during pregnancy, and thus losses due to abnormal litters resulting from JE infection are reduced. However, normal newborn piglets soon lose maternally acquired antibody and are fully susceptible to infection from arthropod vectors.
Although JE infection in shoats is subclinical, viremias are sufficiently high to provide emerging broods of Cu. tritaeniorhynchus, which feed readily on swine, with a plentiful source of virus-containing blood. Following a period of extrinsic incubation of virus, the mosquitoes are able to transmit the infection to susceptible vertebrate hosts.
In Japan, herons and egrets play a role in the spread of infection to man and other vertebrates and may be responsible for carrying the virus from rural to urban areas. Cu. tritaeniorhynchus feeds readily on herons and egrets and ranges sufficiently high off the ground to feed on the young nesting birds.
Geographic Distribution
Human encephalitis in Japan was recognized as early as 1871, and Japanese encephalitis in epidemic form has been known since 1924 when 4,000 human deaths were recorded in Japan. The epidemiology of the disease was studied extensively after World War II in Japan by scientists of the U.S. Army's 406th Medical General Laboratory (2). Concurrent with vaccination of people and extensive use of agricultural pesticides in the last three decades, the disease has practically disappeared from Japan.
Japanese encephalitis virus infection is widespread throughout temperate and tropical Asia; increasing numbers of human and equine cases have appeared in India, Nepal, China, Philippines, Sri Lanka, and northern Thailand. The disease in humans is sporadic in Indonesia and northern Australia but is not known in the rest of the world.
Transmission
The virus is maintained in nature in a cycle involving Culex mosquitoes of the genera tritaeniorhynchus, annulus, fuscocephala, gelidus, and vishnui complex. Mosquitoes transmit the virus to many species of birds and to swine (2,25).
The sequence of events in temperate Asia is initiated by appearance of virus in mosquitoes in late spring followed by the infection and disease in susceptible horses and swine. This is followed by the appearance of disease in man in August and September. In tropical and semitropical areas of Asia, the seasonal nature of the disease is less marked.
Basically, however, it appears the Culex mosquitoes and birds are common factors in the epidemiology of JE, regardless of the region of occurrence, and that swine are involved where they are numerous in Asia (15).
The mechanism of maintaining the virus over the winter in temperate areas has not been elucidated. Overwintering in mosquitoes is a possibility either in infected hibernating mosquitoes or by transovarial passage (23). It is also possible that bats may carry the virus for prolonged periods (18,6).
Incubation Period
In horses, the incubation period is 8 to 10 days. The time between exposure of pregnant swine to an infectious dose of JE virus and delivery of abnormal litters does not seem to be clearly established, although exposure early in gestation appears more likely to result in abnormal litters than later exposure.
Clinical Signs
In horses, initial signs are fever, impaired locomotion, stupor, and grinding of teeth. Blindness, coma, and death follow in more severe cases. Although the clinical signs resemble those seen in horses with Western equine encephalomyelitis and Eastern equine encephalomyelitis, mortality is relatively low. Inapparent or subclinical infections in horses are far more common than cases of recognizable encephalitis.
The principal manifestation of disease in swine is the expulsion of litters of stillborn or mummified fetuses, usually at term. Viable piglets frequently die shortly after birth and exhibit tremor and convulsions before expiring. Experimental infection of boars leads to diminished sperm count and decreased mobility of sperm. Virus has been transmitted to gilts by way of infected semen (11).
Gross Lesions
In horses, gross lesions are similar to those observed in animals dying from Eastern equine encephalomyelitis and Western equine encephalomyelitis virus infections and are not specific enough to establish an etiologic diagnosis. Litters from infected pigs contain fetuses that are mummified and dark in appearance (24,4). Hydrocephalus, cerebellar hypoplasia, and spinal hypomyelinogenesis have been noted (20).
Morbidity and Mortality
The equine mortality caused by JE has been reported at about 5 percent in Japan and may actually be less than this in Southeast Asia. Mortality in adult pigs is close to zero. Litters of pigs from infected sows may be dead at delivery or, if living, may be quite weak and apt to succumb to encephalitis shortly after birth.
Diagnosis
Field Diagnosis
Presumptive diagnosis can be made in horses that manifest CNS disease accompanied by fever, particularly in an epizootic period. It has been observed that illness in horses at race tracks in Malaysia is frequently due to JE infection. The infection is manifested only by fever and a short period of lethargy (16,12,22). In temperate zones, the disease appears during late summer and early fall.
A presumptive diagnosis in swine is based on the birth of litters with a high percentage of stillborn or weak piglets.
Specimens for Laboratory
One half of a brain from animals having signs of encephalitis should be submitted unfixed and the other half fixed in 10 percent formalin. Paired serum samples collected at least 14 days apart should be submitted from animals that survive. Cerebrospinal fluid from horses with CNS signs should be submitted for detection of JE-specific IgM.
Laboratory Diagnosis
Confirmation of JE can be accomplished by demonstrating seroconversion in animals that survive long enough to yield properly spaced blood samples. Neutralization, complement fixation, hemagglutination inhibition, immunofluorescence, and enzyme-linked immonosorbent assay tests are used to show a rise in titer from the acute stage to death or recovery. Reliance on seroconversion or IgM as a means of diagnosis in horses is not definitive because seroconversion may have resulted from exposure to another nonpathogenic Flavivirus.
Demonstration of JE-specific IgM in serum of an encephalitic equine is presumptive evidence of the diagnosis.
Further confirmation of JE in horses can be obtained by examination of the cerebrospinal fluid and the brain. Specific IgM in the spinal fluid is excellent evidence of CNS infection. Although microscopic lesions of the brain are of value, definitive confirmation is based on isolation and identification of the virus from the brain. Virus isolations are more likely to be successful from brains of animals that died after a short course of the disease.
Confirmation of JE in diseased litters of pigs is accomplished by isolation of the virus from fetal brains or brains of piglets that die after manifesting signs of encephalitis. Demonstration of antibody increase in dams bearing affected litters is probably not a reliable measure because seroconversion in such animals would probably have occurred earlier in infection.
Differential Diagnosis
The disease in horses must be differentiated from other viral encephalitides. In Asia, JE is the only recognized arboviral infection causing encephalitis in horses. Because there are many mild or subclinical infections, laboratory confirmation is essential.
Various forms of toxic encephalitis must be considered in differential diagnosis. In temperate-zone Asia, the midsummer seasonal occurrence of JE in horses aids in differential diagnosis.
Japanese encephalitis in pigs must be differentiated from a hemagglutinating DNA virus infection that appears to be as commonplace in Japan as JE (21) and causes the same pattern of disease. There is evidence that the DNA virus infection is established in gilts in the middle or last trimester of pregnancy. Seasonal patterns of DNA virus infection need more complete study, but the disease does appear concurrently with Japanese encephalitis and therefore requires laboratory tests for differentiation.
Another hemagglutinating virus, myxovirus parainfluenza 1 (Sendai), has been shown capable of producing stillbirth in swine under experimental conditions (20). Encephalitis in neonatal pigs is also associated with a coronavirus infection. This agent is known to cause encephalitis in piglets in at least North America and Europe (19).
Vaccination
A live attenuated vaccine produced in hamster kidney tissue culture is in widespread use in horses in China (13). This vaccine reduced disease by about 85 percent. An inactivated vaccine prepared in mouse brain is licensed in Japan, Korea, Taiwan, India, and Thailand for use in humans. A similar inactivated product made in hamster kidney tissue culture has been used to immunize children annually in China since 1965. Live attenuated vaccines are used to immunize pigs in Japan and Taiwan (8) and humans in China (13A).
Control and Eradication
Options for control include elimination of the vectors, prevention of amplification of the infection cycle in birds and pigs, or immunization of horses, pigs, and people. Although some success in vector control was achieved by modification of irrigation methods to minimize breeding of Cu. tritaeniorhynchus in Southeast Asia and coincidentally by the use of agricultural pesticides, vector control has never been more than marginally successful. Reduction of the avian reservoir hosts does not appear feasible.
The most promising approach to reducing livestock losses and at the same time reducing the totality of infection in nature is widespread immunization of swine. Live attenuated vaccines are in use in Japan and Taiwan (8). Immunization of shoats prevents infection in vaccinees and neutralizes their role as amplifiers of infection in nature. It is anticipated that those animals retained for breeding will remain immune, and, because of immunity or natural seasonal lows in transmission resist infection during pregnancy and therefore bear normal litters. Although controlling the disease in swine dampens the spread of infection in nature, there is a continued threat to horses and human beings from other sources.
The introduction of JE virus into the United States is always a possibility, but whether the infection, once introduced, would become established in nature is difficult to assess. Animal health authorities must continue to be alert to detecting and identifying agents associated with encephalitis in horses and with abnormal litters of pigs. The means for rapid diagnosis and identification of JE are available, although it is doubtful that control of the disease in Asia will be achieved in the near future.
September 05, 2008
Selected Images on Infective Endocarditis
FIG 1. Infective vegetations on heart valves (diagrammatic)
FIG 2. Vegetations in Infective endocarditis
FIG 3. Uninfected prosthetic heart valves
FIG 4. Roth spots: pale center with red periphery; Right (The one on top and left are splinter hemorrhage)
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FIG 5. Osler's node
Topic of the month September 2008: Infective Endocarditis
INFECTIVE ENDOCARDITIS: A RAPID REVIEW
What is Infective endocarditis (IE)?
-Infection of the endocardium, valve cusps or prosthetic valves
-May occur as acute infection (e.g. <24hrs after surgery)
-More commonly runs an insidious course : Subacute Bacterial Endocarditis (SBE)
Endocarditis is an infection that invades the innermost lining of the heart - the endothelium. It can damage the heart valves, the rings of connective tissue that surround the valves, as well as the inner linings of the heart chambers themselves.
In some congenital cardiac diseases, infection can also occur in the lining of the arteries that come out of the heart.
CONDITIONS PREDISPOSING TO IE
1. Structural cardiac abnormalities:
• AS
• AR
• MR
• VSD
2. Factors altering immunity:
• Immunosuppression
• AIDS
• Diabetes
• Chronic alcoholism
3. External factors:
• Prosthetic valves
• Indwelling vascular catheters
• Pacing wires (IV)
4. Factors causing bacteraemia:
• Oral/Dental surgery
• IV drug use
• Urogenital/GI operations
CARDIAC DISEASES IMMUNE TO IE
-ASD
-Heart failure
-VSD with reversal of shunt
-MS
WHAT ARE THE SIGNS AND SYMPTOMS?
The signs and symptoms of infective endocarditis depend on the causative organism. Symptoms may include fever, fatigue, weight loss, new rashes (either painful or painless), headaches, backaches, joint pains, and confusion.
A new heart murmur as well as new skin, fingernail, and retinal lesions are typical physical findings in endocarditis. We can make the diagnosis by finding microbial organisms in the blood and by performing an echocardiogram that shows evidence of endocarditis in the heart.
WHAT ARE THE COMPLICATIONS?
If not treated, most patients with infective endocarditis will die. Depending on when treatment is begun, there can be various complications. The infection can destroy the heart valves, resulting in congestive heart failure.
Small masses of bacteria or fungus, as well as platelets and fibrin can flick off the valves and cause problems throughout the body. These are called emboli. They can result in strokes, kidney failure, heart attacks, and damage to the gastrointestinal organs. Endocarditis can also result in heart arrhythmias and inflammation of heart tissue.
Finally, infective endocarditis can result in abscesses in the heart that are very hard to treat.
SUMMARY OF CLINICAL FEATURES AND COMPLICATIONS
A. General
1. Malaise
2. Fever
3. Night sweats
4. Anaemia
5. Clubbing
6. Weight loss
B. Eyes
1. Roth spots
2. Conjunctival splinter haemorrhages
C. Arthralgia
D. Splenomegaly
E. Skin
1. Osler’s nodes
2. Janeway lesions
3. Splinter haemorrhages
4. Petechiae
F. Cardiac
1. Murmurs
2. Cardiac failure
G. Cerebral emboli/abscess
H. Kidney
1. Glomerulonephritis
2. Haematuria
HOW IS INFECTIVE ENDOCARDITIS DIAGNOSED USING DUKE’S CRITERIA?
Duke clinical criteria
2 major criteria
Or
1 major & 3 minor criteria
Or
5 minor criteria
Major
i) Typical organism in 2 separate cultures or persistently +ve blood cultures (>3, >12 hrs apart)
ii) +ve echocardiogram (vegetation, abscess) or new valvular regurgitation
Minor
i) Predisposition
ii) Fever >38˚C
iii) Vascular/ immunological phenomena (splinter haemorrhages, Osler’s nodes)
iv) +ve blood cultures (not meeting major criteria)
v) +ve echocardiogram (not meeting major criteria)
INVESTIGATIONS FOR THE DIAGNOSIS OF IE
A. Routine – Blood, Urine, Ur, Cr, CXR, ECG
B. Special –
a. Blood culture
b. Echo-cardiography
c. Rheumatoid factor
HOW IS ENDOCARDITIS TREATED?
Infective endocarditis is treated with antibiotics and with surgery in some situations. Intravenous antibiotics are used for several weeks to eradicate the organism that caused the condition. But in more serious cases, urgent cardiac surgery is indicated to treat some patients.
Surgery is considered particularly when a patient has an artificial heart valve. However, there is new evidence to suggest that certain kinds of bacterial infections of prosthetic valves can be treated with just antibiotics.
IS ENDOCARDITIS PREVENTABLE?
Yes. As described above, infective endocarditis occurs when there is an infection in the blood. Antibiotics can prevent such an infection from occurring in the first place. Antibiotic prophylaxis is recommended before medical procedures with a high probability of introducing bacteria into the blood.
Dental procedures that cause bleeding from the gums (even a simple cleaning); rigid bronchoscopy; and surgery of the upper respiratory tract, urinary tract procedures, and gastrointestinal procedures all confer an increased risk of bacteremia, and therefore, an increased risk of infective endocarditis in those individuals with predisposing cardiac lesions.
BASIC MECHANISMS UNDERLYING SEIZURES AND THEIR PHARMACOLOGIC MANAGEMENT
THIS ARTICLE WILL HELP YOU TO:
- 1. Define and distinguish between seizure and epilepsy
2. Classify seizures
3.Explain the physiology of excitatory and inhibitory neurotransmitters in CNS
4.Explain the molecular mechanism of seizure initiation and propagation
5.Explain the mechanism of epileptogenesis
6.Discuss the basic pharmacology of antiepileptic drugs
· Seizure: the clinical manifestation of an abnormal and excessive excitation and synchronization of a population of cortical neurons
· Epilepsy: two or more recurrent seizures unprovoked by systemic or acute neurologic insults
Definitions and Epidemiology
A. Seizure
A seizure is the manifestation of an abnormal, hypersynchronous discharge of a population of cortical neurons. This discharge may produce subjective symptoms or objective signs, in which case it is a clinical seizure, or it may be apparent only on an electroencephalogram (EEG), in which case it is an electrographic (or subclinical) seizure. Clinical seizures are usually classified according to the International Classification of Epileptic Seizures. Although all classification schemes have limitations, this is the best one currently available. The incidence of new-onset seizures in the general population is approximately 80 per 100,000 per year; approximately 60% of these patients will have epilepsy, a tendency toward recurrent unprovoked seizures. The diagnosis of a particular seizure type, and of a specific type of epilepsy (epilepsy syndrome), directs the diagnostic workup of these patients and their initial therapy.
B. Epilepsy
At least two unprovoked seizures are required for the diagnosis of epilepsy. In the past, physicians were reluctant to make this diagnosis even after repeated seizures, because of the adverse consequences including social stigmatization and limitations on driving and employment. Despite advances in public understanding of the condition, these issues remain active.
Epilepsy is an umbrella term, under which many types of diseases and syndromes are included. The current classification of the epilepsies and epileptic syndromes attempts to separate these disorders according to their putative brain origins, that is, whether they arise in a circumscribed portion of the brain (partial), or appear to begin diffusely in the cortex and its deeper connections (generalized).
The syndrome is idiopathic when the disorder is not associated with other neurologic or neuropsychologic abnormalities; symptomatic indicates that such an abnormality is present and the cause is known. Cryptogenic refers to syndromes that are presumed to be symptomatic but the cause in a specific patient is unknown. Many idiopathic epilepsies occur in children and adolescents, and often remit in adolescence or adulthood. There is evidence that most or all of these syndromes have a genetic basis, and that when this basis becomes known, they will move from the idiopathic to the symptomatic category.
Some authors distinguish between epilepsies and epileptic syndromes, depending on whether seizures are the only neurologic disorder (an epilepsy) or are one of a group of symptoms (an epileptic syndrome). Some of the epilepsies (e.g., juvenile myoclonic epilepsy) have well-defined genetics, clinical courses, and responses to medication. Others (e.g., temporal lobe epilepsy) have natural histories which are highly variable, and which reflect differences in pathology as well as in host response to that pathologic process and to the treatments administered.
CLASSIFICATION OF SEIZURES
I. Partial seizures (seizures beginning locally)
A. Simple partial seizures (consciousness not impaired)
1.with motor symptoms
2.with somatosensory or special sensory symptoms
3.with autonomic symptoms
4.with psychic symptoms
B. Complex partial seizures (with impairment of consciousness)
1.beginning as simple partial seizures and progressing to impairment of consciousness
a.without automatisms
b.with automatisms
2.with impairment of consciousness at onset
a.without automatisms
b.with automatisms
C. Partial seizures (simple or complex), secondarily generalized
II. Generalized seizures (bilaterally symmetric, without localized onset)
1.Absence seizures
a.true absence (`petit mal')
b.atypical absence
2.Myoclonic seizures
3.Clonic seizures
4.Tonic seizures
5.Tonic-clonic seizures (`grand mal')
6.Atonic seizures
III.Unclassified seizures
CELLULAR MECHANISMS OF SEIZURE GENERATION
· Excitation (too much)
o Ionic-inward Na+, Ca++ currents
o Neurotransmitter: glutamate, aspartate
· Inhibition (too little)
o Ionic-inward CI-, outward K+ currents
o Neurotransmitter: GABA
The cortex includes two general classes of neurons. The projection, or principal, neurons (e.g., pyramidal neurons) are cells that "project" or send information to neurons located in distant areas of the brain. Interneurons (e.g., basket cells) are generally considered to be local-circuit cells which influence the activity of nearby neurons. Most principal neurons form excitatory synapses on post-synaptic neurons, while most interneurons form inhibitory synapses on principal cells or other inhibitory neurons. Recurrent inhibition can occur when a principal neuron forms synapses on an inhibitory neuron, which in turn forms synapses back on the principal cells to achieve a negative feedback loop.
Recent work suggests that some interneurons appear to have rather extensive axonal projections, rather than the local, confined axonal structures previously suggested. In some cases, such interneurons may provide a very strong synchronization or pacer activity to large groups of neurons.
BASIC NEUROPHYSIOLOGY AND NEUROCHEMISTRY GOVERNING EXCITABILITY
Given that the basic mechanism of neuronal excitability is the action potential, a hyperexcitable state can result from increased excitatory synaptic neurotransmission, decreased inhibitory neurotransmission, an alteration in voltage-gated ion channels, or an alteration of intra- or extra-cellular ion concentrations in favor of membrane depolarization. A hyperexcitable state can also result when several synchronous subthreshold excitatory stimuli occur, allowing their temporal summation in the post synaptic neurons.
Neurotransmitters are substances that are released by the presynaptic nerve terminal at a synapse and subsequently bind to specific postsynaptic receptors for that ligand. Ligand binding results in channel activation and passage of ions into or out of the cells. The major neurotransmitters in the brain are glutamate, gamma-amino-butyric acid (GABA), acetylcholine (ACh), norepinephrine, dopamine, serotonin, and histamine. Other molecules, such as neuropeptides and hormones, play modulatory roles that modify neurotransmission over longer time periods.
The major excitatory neurotransmitter is the amino acid glutamate. There are several subtypes of glutamate receptors. Glutamate receptors can be found postsynaptically on excitatory principal cells as well as on inhibitory interneurons, and have been demonstrated on certain types of glial cells. The ionotropic subclasses are the alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid (AMPA), kainate receptors, and N-methyl-D-aspartate (NMDA); these allow ion influx upon activation by glutamate. They are differentiated from one another by cation permeability as well as differential sensitivity to pharmacological agonists/antagonists. All ionotropic glutamate receptors are permeable to Na+ and K+, and it is the influx of Na+ and outflow of K+ through these channels that contribute to membrane depolarization and generation of the action potential. The NMDA receptor also has a Ca++ channel that is blocked by Mg++ ions in the resting state, but under conditions of local membrane depolarization, Mg++ is displaced and the channel becomes permeable to Ca++; influx of Ca++ tends to further depolarize the cell, and is thought also to contribute to Ca++ mediated neuronal injury under conditions of excessive neuronal activation (such as status epilepticus and ischemia), potentially leading to cell death, a process termed excitotoxicity. The other major type of glutamate receptor is the metabotropic receptor, which functions by means of receptor-activated signal transduction involving membrane-associated G-proteins
There are at least 3 subtypes of metabotropic receptors, based on differential agonist potency, mechanism of signal transduction, and pre- versus post-synaptic localization.
Experimental studies using animal epilepsy models have shown that NMDA, AMPA and kainate agonists induce seizure activity, whereas their antagonists suppress seizure activity. Metabotropic agonists appear to have variable effects likely dependent upon their different location and mechanisms of signal transduction.
The major inhibitory neurotransmitter, GABA, interacts with 2 major subtypes of receptor: GABAA and GABAB receptors. GABAA receptors are found postsynaptically, while GABAB receptors are found presynaptically, and can thereby modulate synaptic release. In the adult brain, GABAA receptors are permeable to Cl− ions; upon activation Cl− influx hyperpolarizes the membrane and inhibits action potentials. Therefore, substances which are GABAA receptor agonists, such as barbiturates and benzodiazepines, are well known to suppress seizure activity. GABAB receptors are associated with second messenger systems rather than Cl− channels, and lead to attenuation of transmitter release due to their presynaptic location. The second messenger systems often result in opening of K+ channels, leading to a hyperpolarizing current. Certain GABAB agonists, such as baclofen, have been reported to exacerbate hyperexcitability and seizures.
Relevant to epilepsy, glutamate and GABA both require active reuptake to be cleared from the synaptic cleft. Transporters for both glutamate and GABA exist on both neurons and glia (primarily astrocytes). Interference with transporter function has also been shown to activate or suppress epileptiform activity in animal models, depending on which transporter is being blocked.
FACTORS GOVERNING EXCITABILITY OF INDIVIDUAL NEURONS
· Intrinsic factors
· Extrinsic factors
The complexity of neuronal activity is partly due to various mechanisms controlling the level of electrical activation in one or more cellular regions. These mechanisms may act inside the neuron or in the cellular environment, including other cells (e.g., neighboring neurons, glia, and vascular endothelial cells) as well as the extracellular space, to modify neuronal excitability. The former may be termed "neuronal" or "intrinsic," and the latter "extra-neuronal" or "extrinsic."
1. Examples of neuronal (intrinsic) factors include:
The type, number and distribution of voltage- and ligand-gated channels. Such channels determine the direction, degree, and rate of changes in the transmembrane potential, which in turn determine whether an action potential occurs. Voltage-gated sodium channels, for example, form the basis of the rapid depolarization constituting the action potential. Among ligand-gated channels, the GABA receptor complex mediates inflow of chloride ions which hyperpolarize the cell, forming the basis of neuronal inhibition, as described previously.
Biochemical modification of receptors. For example, phosphorylation of the NMDA receptor increases permeability to Ca++, resulting in increased excitability.
Activation of second-messenger systems. Binding of norepinephrine to its alpha receptor, for example, activates cyclic GMP, in turn activating G-proteins which open K+ channels, thereby decreasing excitability.
Modulating gene expression, as by RNA editing. For example, editing a single base pair of mRNA encoding a specific glutamate receptor subunit can change the ion selectivity of the assembled channel.
2. Examples of extra-neuronal (extrinsic) factors include:
Changes in extracellular ion concentration due to variations in the volume of the extracellular space. For example, decreased extracellular volume leads to increased extracellular K+ concentration, resisting the outward movement of K+ ions needed to repolarize the cell, thereby effectively increasing excitability.
Remodeling of synaptic contacts. For example, movement of an afferent axon terminal closer to the target cell body increases the likelihood that inward ionic currents at the synapse will bring the target neuron to threshold. The coupling between the pre- and post-synaptic elements can be made more efficient by shortening of the spine neck. In addition, previous synaptic experience such as a brief burst of high frequency stimulation (e.g., long-term potentiation-LTP) also increases the efficacy of such synapses, increasing their excitability.
Modulating transmitter metabolism by glial cells. Excitability increases, for example, if glial metabolism or uptake of excitatory transmitters such as glutamate or ACh decreases.
PATHOPHYSIOLOGY OF SEIZURES: AN ALTERATION IN THE NORMAL BALANCE OF INHIBITION AND EXCITATION
A. Basic Mechanisms of Focal Seizure Initiation and Propagation
The hypersynchronous discharges that occur during a seizure may begin in a very discrete region of cortex and then spread to neighboring regions. Seizure initiation is characterized by two concurrent events: 1) high-frequency bursts of action potentials, and 2) hypersynchronization of a neuronal population. The synchronized bursts from a sufficient number of neurons result in a so-called spike discharge on the EEG. At the level of single neurons, epileptiform activity consists of sustained neuronal depolarization resulting in a burst of action potentials, a plateau-like depolarization associated with completion of the action potential burst, and then a rapid repolarization followed by hyperpolarization. This sequence is called the paroxysmal depolarizing shift.
The bursting activity resulting from the relatively prolonged depolarization of the neuronal membrane is due to influx of extracellular Ca++, which leads to the opening of voltage-dependent Na+ channels, influx of Na+, and generation of repetitive action potentials. The subsequent hyperpolarizing afterpotential is mediated by GABA receptors and Cl− influx, or by K+ efflux, depending on the cell type.
Seizure propagation, the process by which a partial seizure spreads within the brain, occurs when there is sufficient activation to recruit surrounding neurons. This leads to a loss of surround inhibition and spread of seizure activity into contiguous areas via local cortical connections, and to more distant areas via long association pathways such as the corpus callosum.
The propagation of bursting activity is normally prevented by intact hyperpolarization and a region of surrounding inhibition created by inhibitory neurons. With sufficient activation there is a recruitment of surrounding neurons via a number of mechanisms. Repetitive discharges lead to: 1) an increase in extracellular K+, which blunts the extent of hyperpolarizing outward K+ currents, tending to depolarize neighboring neurons; 2) accumulation of Ca++ in presynaptic terminals, leading to enhanced neurotransmitter release; and 3) depolarization-induced activation of the NMDA subtype of the excitatory amino acid receptor, which causes more Ca++ influx and neuronal activation. Of equal interest, but less well understood, is the process by which seizures typically end, usually after seconds or minutes, and what underlies the failure of this spontaneous seizure termination in the life-threatening condition known as status epilepticus.
B. Current Theories as to How Inhibition and Excitation Can Be Altered at the Network Level
Our understanding of the CNS abnormalities causing patients to have recurrent seizures remains limited. It is important to understand that seizures and epilepsy can result from many different pathologic processes that upset the balance between excitation and inhibition. Epilepsy can result from processes which disturb extracellular ion homeostasis, alter energy metabolism, change receptor function, or alter transmitter uptake. Despite major differences in etiology, the outcome of synchronous bursting of cortical neurons may superficially appear to have a similar phenotype. Seizure phenotype may be modified more by the location and function of the neuronal network recruited into the synchronous bursting than by the underlying pathophysiology.
Because of the well organized and relatively simple circuits within the entorhinal-dentate-hippocampal loop, the limbic system has been intensively studied in experimental models of epilepsy. These investigations have led to two theories regarding the cellular network changes which cause the hippocampus, among the most common sites of origin of partial seizures, to become hyperexcitable. The first proposes that a selective loss of interneurons decreases the normal feed-forward and feedback inhibition of the dentate granule cells, an important group of principal neurons. The other theory suggests that synaptic reorganization follows injury and creates recurrent excitatory connections, via axonal "sprouting," between neighboring dentate granule cells. More recently, it has been proposed that the loss, rather than being of GABAergic inhibitory neurons, is actually of excitatory neurons which normally stimulate the inhibitory interneurons to, in turn, inhibit the dentate granule cells. These mechanisms of hyperexcitability of the neuronal network are not mutually exclusive, could act synergistically, and may coexist in the human epileptic brain.
Seizures may also appear to arise from widespread cortical areas virtually simultaneously. The mechanisms underlying such generalized seizures are uncertain. One type of generalized seizure, the absence seizure, (also called petit mal) is a generalized seizure consisting clinically of a brief staring spell in conjunction with a characteristic burst of spike-wave complexes on the EEG. Generalized spike-wave discharges in absence seizures may result from aberrations of oscillatory rhythms that are normally generated during sleep by circuits connecting the cortex and thalamus. This oscillatory behavior involves an interaction between GABAB receptors, Ca++ channels and K+ channels located within the thalamus. Pharmacologic modulation of these receptors and channels can induce absence seizures, and there is speculation that genetic forms of absence epilepsy may be associated with mutations of components of this system.
C. Epileptogenesis: The Transformation of a Normal Network Into a Hyperexcitable Network
Clinical observations suggest that certain forms of epilepsy are caused by particular events. For example, approximately 50% of patients who suffer a severe head injury will develop a seizure disorder. However, in a significant number of these patients, the seizures will not become clinically evident for months or years. This "silent period" after the initial injury indicates that in some cases the epileptogenic process involves a gradual transformation of the neural network over time. Changes occurring during this period could include delayed necrosis of inhibitory interneurons (or the excitatory interneurons driving them), or sprouting of axonal collaterals leading to reverberating, or self-reinforcing, circuits. In the future, patients at risk for developing epilepsy due to an acquired lesion may benefit from treatment with "anti-epileptogenic" compounds that could prevent these network changes.
An important experimental model of epileptogenesis is kindling, discovered by Goddard and coworkers in the 1960s. Daily, subconvulsive stimulation (electrical or chemical) of certain brain regions such as the hippocampus or amygdala result in electrical afterdischarges, eventually leading to stimulation-induced clinical seizures, and in some instances, spontaneous seizures. This change in excitability is permanent and presumably involves long-lasting biochemical and/or structural changes in the CNS. A variety of changes have been measured in kindling models, including alterations in glutamate channel properties, selective loss of neurons, and axonal reorganization.
MECHANISMS OF ANTI-EPILEPTIC DRUG (AED) ACTIVITY
A seizure is the clinical manifestation of a hyperexcitable neuronal network, in which the electrical balance underlying normal neuronal activity is pathologically altered—excitation predominates over inhibition (see Basic Mechanisms syllabus). Effective seizure treatment generally augments inhibitory processes or opposes excitatory processes. Since the normal resting neuronal membrane potential is intracellularly negative, inhibitory processes make the neuron more electrically negative, hyperpolarizing the membrane, while excitatory processes make the intracellular potential less negative or more positive, depolarizing the cell. On an ionic level, inhibition is typically mediated by inward chloride or outward potassium currents, and excitation by inward sodium or calcium currents. Drugs can directly affect specific ion channels or indirectly influence synthesis, metabolism, or function of neurotransmitters or receptors that control channel opening and closing. The most important central nervous system inhibitory neurotransmitter is gamma-amino-butyric acid (GABA). The most important excitatory neurotransmitter is glutamate, acting through several receptor subtypes.
Blocking voltage-gated sodium channels during rapid rates of neuronal discharge appears to be the primary mechanism of action of several AEDs, particularly the two first-line drugs for partial epilepsies, phenytoin and carbamazepine; this mechanism also appears to be at least partly responsible for the antiepileptic effects of newer drugs such as lamotrigine and topiramate. This rate-dependent action is crucial, addressing the requirement that AEDs should affect pathologic more than physiologic neuronal excitation, since a drug with similar effects on all excitation would produce deep coma as an inevitable side effect.
The GABA system and its associated chloride channel is a target of many old and new AEDs effective against many seizure types. Barbiturates and benzodiazepines act directly on subunits of the GABA receptor-chloride channel complex. Barbiturates increase the duration of chloride channel openings, while benzodiazepines increase the frequency of these openings. Tiagabine inhibits GABA re-uptake from synapses. Vigabatrin, a drug not available in the U.S., elevates GABA levels by irreversibly inhibiting its main catabolic enzyme, GABA-transaminase. Gabapentin was designed as a lipophilic GABA analogue, but does not function as a receptor agonist; its mechanism of action is unknown.
Calcium current into the neuron is another important excitatory mechanism. There are several different calcium channel types, but nonselective calcium channel blockers have low antiepileptic efficacy. Ethosuximide selectively blocks transient ("T-type") calcium currents in thalamic neurons, which inhibits the thalamocortical circuits responsible for generating the EEG spike-wave complex underlying absence seizures.
Excitatory neurotransmission mediated by calcium and sodium currents through glutamate receptors has been a tempting target for new AEDs, because these currents may contribute not only to seizure generation but also to neuronal damage from status epilepticus and stroke. Direct glutamate receptor antagonists are effective against experimental seizures, but frequently cause psychosis and other neuropsychiatric adverse effects, preventing clinical use. However, several newer, better tolerated drugs, including lamotrigine and topiramate, may act on this system indirectly.
AED PHARMACOKINETICS
Pharmacokinetics is the quantitative description of what happens to a drug when it enters the body, including drug absorption, distribution, metabolism and elimination/excretion).
A. Absorption
This is determined by route of intake. Most AEDs are available for oral administration, although some have formulations that are also available for intravenous, intramuscular or rectal administration.
Oral Absorption:
Most AEDs undergo complete or nearly complete absorption when given orally. Most often, administration of AEDs with food slows absorption and can help avert peak dose related side effects. Calcium containing antacids may interfere with phenytoin absorption. Gabapentin is absorbed by a saturable amino acid transport system and does not get absorbed after a certain dose.
Intramuscular Administration:
Fosphenytoin may be administered intramuscularly if intravenous access cannot be established in cases of frequent repetitive seizures.
Rectal administration:
Diazepam (available as a rectal gel) has been shown to terminate repetitive seizures and can be administered by family members at home.
Intravenous administration:
This route is used for emergencies. Phenytoin, fosphenytoin, phenobarbital, diazepam, lorazepam and valproic acid are available as IV preparations (see section on status epileptics for side effects related to intravenous use).
B. Distribution
Following absorption into the bloodstream, the drug is distributed throughout the body. Lipid solubility and protein binding affect CNS availability. Drugs can displace others from albumin and protein binding is responsible for many pharmacokinetic interactions between AEDs. An example of this is the interaction between phenytoin and valproic acid. If valproic acid is added to a patient who is already taking phenytoin, the phenytoin is displaced from albumin binding sites, resulting in a higher free fraction and toxicity.
C. Metabolism
Most AEDs are metabolized in the liver by hydroxylation or conjugation. These metabolites are then excreted by the kidney. Some metabolites are themselves active (carbamazepine, oxcarbazepine, primidone). Gabapentin undergoes no metabolism and is excreted unchanged by the kidney.
Most AEDs are metabolized by the P450 enzyme system in the liver. Different AEDs either induce or inhibit certain isoenzymes of this system and can result in changes of the pharmacokinetic properties of different medications
In general enzyme inducers decrease the serum concentrations of other drugs metabolized by the system and enzyme inhibitors have the opposite affect. Valproic acid is metabolized by a combination of conjugation by uridine glucuronate (UDP)-Glucuronyltranferase (UGT) via conjugation and by mitochondrial beta-oxidation.
D. Elimination
Drug elimination rate is usually expressed as the biological half-life and is defined as the time required for the serum concentration to decrease by 50% following absorption and distribution.
This changes for some drugs based on serum concentration e.g. phenytoin has a longer half-life at high serum levels. The half-life also determines the dosing frequency required for a drug to be maintained at a steady state in the serum. Most drugs are eliminated by the kidneys and dosage adjustments are required in cases of renal impairment.
ADDITIONAL PHARMACOKINETIC AND PHARMACODYNAMIC ASPECTS OF AEDs
A. Therapeutic Index
AEDs can have a narrow range within which seizures are controlled without toxicity. This concept is quantified as the "therapeutic index" (TI). TI is the ratio of the drug concentration effective for 50% of subjects (ED50) to the concentration toxic to 50% of subjects (TD50) – TI=ED50/TD50. The "therapeutic range" of AED serum concentrations is an attempt to translate the experimental concept of therapeutic index to the clinic. These ranges are broad generalizations which are of limited use and can be misleading when applied to individual patients. Many patients tolerate and need serum concentrations above the usual therapeutic range, while others achieve complete seizure control, or even experience adverse effects, at concentrations below it.
B. Pharmacodynamic Interactions
Drug interactions based on pharmacokinetics, or "what the body does to the drug," must be distinguished from those based on pharmacodynamics, or "what the drug does to the body." Pharmacodynamic effects include both wanted and unwanted drug effects on the brain and other organs. Gabapentin, for example, has no important pharmacokinetic interactions with other AEDs. Because gabapentin and many other drugs can cause sedation and dizziness, however, pharmacodynamic interactions can occur. Ideally, drug combinations should produce additive or synergistic (supra-additive) therapeutic effects and sub-additive toxicities. Drug combinations with different mechanisms of action may help achieve this goal.
C. Adverse Effects
Most AEDs have a narrow therapeutic window—a small range of serum concentrations within which seizure prevention is achievable without significant toxicity or side effects. This concept applies primarily to dose-related, reversible, short-term side effects. However, risk of idiosyncratic effects such as allergic reactions and organ damage must also be considered. Serious idiosyncratic effects are rare but can be life threatening. They generally occur within several weeks or months of starting the drug, tend to be dose-independent (except possibly for skin rash with lamotrigine), and unpredictable.
Intermittent or frequent monitoring of biochemical (e.g., liver functions such as ALT, AST) or hematologic (e.g., CBC) laboratory tests may not detect changes in time to alter prognosis. In addition, frequent monitoring may detect changes or abnormalities which are not clinically significant (e.g., usually transient alterations in liver function tests associated with valproate therapy or commonly-observed, usually transient reductions in leukocyte counts associated with carbamazepine). Education of patients or caregivers to promptly report relevant symptoms of possibly serious idiosyncratic effects accompanied by appropriate laboratory follow-up are currently regarded as mainstays of detection.
Many idiosyncratic reactions likely result from inherited genetic susceptibilities to a particular drug or metabolite. The most common target organs are skin, liver, bone marrow, and occasionally pancreas. Skin rashes are common, immunologically mediated, and usually minor and reversible. Skin rashes, can however, progress to Stevens-Johnson syndrome. The more serious organ toxicities occur in less than 1 in 10,000–100,000 treated patients. Felbamate-related aplastic anemia appears to occur more commonly (approximately 1:5,000). For some AEDs, the presence of predisposing risk factors may increase the risk of serious idiosyncratic reactions. Valproate-related hepatotoxicity is more common in very young children receiving multiple AEDs; lamotrigine-induced skin rashes are more common in patients receiving valproate and/or who are treated with aggressively-titrated lamotrigine doses.
The third type of adverse drug effect is cumulative toxicity, usually occuring over years of treatment. Because most AEDs other than phenobarbital and phenytoin have been in use for less than 25 years, data regarding these types of adverse effects are limited.
May 01, 2008
Approach to pathological diagnosis of diseases
How do I approach a question on laboratory diagnosis in pathology?
Dear friends,
As part of your second professional examination, all of you will face a compulsory question on laboratory diagnosis of a particular condition. Here is a basic guide to how to approach such a question.
The questions on laboratory diagnosis may be placed in two ways. Study the following questions carefully:
1. How do you approach to diagnose acute leukemia in the laboratory?
2. A 17 yr boy came to the outdoor with complaints of fever and nodular swellings over neck. On examination, he had marked pallor. How do you approach to diagnose the case in the laboratory?
A quick look will reveal that the approaches of the two questions are different. The first question points to a specific diagnosis and asks about the relevant laboratory investigations needed to establish the diagnosis. The second question gives you a constellation of symptoms and signs and asks you to make a clinico-pathological diagnosis.
Let us first pick up the second question and try to solve it. For all practical purpose, your answer can be divided into the following parts:
- Case summary
- Provisional diagnosis
- Differential diagnosis
- Approach to diagnosis
Case summary:
This means you summarise the history and clinical features mentioned in the question in a logical manner so that it can point to a specific diagnosis.
For Q.2 it can be written as follows –
History: a boy aged 17 yrs came with a chief complaint of – a) fever, b) nodular swellings over neck.
Physical examination: marked pallor
Provisional diagnosis (PD):
This means, you write down the most appropriate diagnosis that matches with the given symptoms. The appropriateness will depend on –
- The prevalence of the disease. The commoner the disease more is the chance of the person suffering from it. Remember, rare diagnoses are rarely correct.
- The disease that you choose as your PD should logically explain all the symptoms and signs mentioned in the question.
- Your PD can be different from your friend’s PD. There is no rule of thumb that all PD has to be the same.
For examination purpose, try to choose the PD from the diseases that are important in your syllabus. This is because examiners will expect you to answer from the chapters you have read. Moreover, the diseases that you read in your syllabus are also the commoner diseases.
For Q2, I can write my provisional diagnosis as follows:
Provisional diagnosis: Acute leukemia, probably ALL
Differential diagnoses (DD):
This means, you list all the diseases (or their complications) that can mimic the signs and symptoms of your PD. Please remember that this is the most important part of your answer. Follow these simple rules to find out the probable DDs:
- Keep your mind open to all possibilities (including relatively rare diagnosis) while searching for DD
Search for the diseases systemically, i.e. follow a pattern of going through different systems of the body. This will ensure that you never miss a DD - You can also include complications of a primary disease as a DD
- Remember, your DD can be someone else’s PD!
As for example, let me list the DDs for Q2.
Differential diagnoses:
a) Hematological:
1. Acute lymphatic leukaemia ( your PD is always your first DD)
2. Juvenile CML (in blast crisis phase)
3. Hodgkin’s lymphoma
4. Infectious mononucleosis
b) Respiratory:
1. Pulmonary tuberculosis ( anemia is due to chronic disease)
c) Multisystemic:
1. Septicemia
2. Metastatic carcinoma ( with Lymph Node and Bone Marrow metastasis)
This is how you list your DDs.
Now you might wonder why at all should we bother about the DDs? Because, we need to investigate only when there is some confusion in the diagnosis and we want to rule out the other causes. If we are already sure about a single diagnosis, there will be no need to investigate at all!
Differential diagnosis is a scientific approach by which we can reach at a single diagnosis by clinical and laboratory tests (very much like testing for the acid and basic radicals of an unknown salt in the chemistry lab).
Approach to diagnosis:
This can be done by following four simple steps:
1.Find out the systems of the body that your DDs cover
2.Note down the routine investigations that you do for each systems
3.Note down the specific or confirmatory diagnosis for each of the DDs
4.Now make a chart with the left-most column reading “steps of diagnosis”, and the rest of the columns dedicated to each individual disease. Point down the list of all investigations that you have listed in the above steps. Write down the findings of each disease against each point. If the test is in no way related to the disease, you can expect the finding to be normal. Mention if the finding may change with a complication.
For Q.2, the left column may include the following points:
1) History
2) Clinical features
3) Routine blood examination
· Hb
· TLC
· DLC
· Platelets
· Reticulocytes
· Abnormal cells
4) Bone marrow examination
· Cellurarity
· Nature of myelopoiesis
· Nature of erythropoiesis
· M:E ratio
· Megakaryocytes
· Plasma cells
· Abnormal cells/ parasites
5) Biopsy from the nodular tissue
· HE stain
6) FNAC from nodular tissue
· Pap stain
· Gram stain
· Acid fast stain
7) Blood culture
8) Chest X ray
9) Abdominal CT scan/ USG (to rule out occult neoplasm)
Now in case of Q.1, where the question is straight and simple, (Lab diagnosis of Acute leukemia), follow these steps:
1.List all the pathological types of the disease ( In this case, ALL and AML)
2.Jot out the points for diagnosis as before
3.Jot out the points for diagnosis of complications
4.Now make a chart with the left-most column reading “steps of diagnosis”, and the rest of the columns dedicated to each type. Point down the list of all investigations that you have listed. Write down the findings of each disease against each point. If the test is in no way related to the disease, you can expect the finding to be normal. Mention if the finding may change with a complication.
So, here you go… try and write the entire approach yourselves, and get back to us if you face any problem. You can also email your completed answers to tirthankar82@yahoo.co.in which we can publish with your names.
Till then, take care.
Cheers!
Question bank on Autonomic Pharmacology
Dear friends,
Here is list of theory questions that are often asked from autonomic pharmacology. Hope you will find it useful.
Cholinergic system
1. Briefly discuss the synthesis and metabolism of acetyl choline
2. Enumerate the differences between true and pseudo- cholinesterase
3. Outline the cause, pathogenesis, clinical features and treatment of succinyl choline apnea
4. Classify cholinergic receptors
5. Classify Cholinergic drugs
6. Discuss the pathogenesis and treatment of myasthenia gravis
7. How will you distinguish between myasthenic and cholinergic crisis?
8. Classify anti-cholinergic drugs (Atropine substitutes) according to therapeutic use
9. Write short notes on:
a) Pilocarpine
b) Physostigmine
c) Neostigmine
d) Edrophonium challenge test
e) Atropine
f) Hyoscine (Scopolamine)
g) Treatment of acute congestive glaucoma
10. Discuss the steps of management of Organophosphate poisoning.
11. Write briefly on cholinesterase reactivators and aging of AChE enzyme
Noradrenergic system
1. Briefly discuss the synthesis and metabolism of Catecholamines.
2. Enumerate the differences between uptake I and uptake II of catecholamines.
3. Classify noradrenergic receptors.
4. Classify adrenergic drugs.
5. Discuss the drugs used in the treatment of Glaucoma.
6. Explain why:
a) Dopamine is used in cardiogenic shock
b) Noradrenalione is not used in cardiogenic shock
c) Beta blockers are contraindicated in asthma
d) Clonidine and alpha methyl dopa is used to treat hypertension
e) Beta blockers alone should not be used in pheochromocytoma
7. Classify beta blockers. Mention the cardiovascular and non-cardiovascular uses of beta blockers.
8. How do beta blockers act as antihypertensive agents?
9. Write briefly on autonomic ganglionic blockers and their uses.
Here is list of theory questions that are often asked from autonomic pharmacology. Hope you will find it useful.
Cholinergic system
1. Briefly discuss the synthesis and metabolism of acetyl choline
2. Enumerate the differences between true and pseudo- cholinesterase
3. Outline the cause, pathogenesis, clinical features and treatment of succinyl choline apnea
4. Classify cholinergic receptors
5. Classify Cholinergic drugs
6. Discuss the pathogenesis and treatment of myasthenia gravis
7. How will you distinguish between myasthenic and cholinergic crisis?
8. Classify anti-cholinergic drugs (Atropine substitutes) according to therapeutic use
9. Write short notes on:
a) Pilocarpine
b) Physostigmine
c) Neostigmine
d) Edrophonium challenge test
e) Atropine
f) Hyoscine (Scopolamine)
g) Treatment of acute congestive glaucoma
10. Discuss the steps of management of Organophosphate poisoning.
11. Write briefly on cholinesterase reactivators and aging of AChE enzyme
Noradrenergic system
1. Briefly discuss the synthesis and metabolism of Catecholamines.
2. Enumerate the differences between uptake I and uptake II of catecholamines.
3. Classify noradrenergic receptors.
4. Classify adrenergic drugs.
5. Discuss the drugs used in the treatment of Glaucoma.
6. Explain why:
a) Dopamine is used in cardiogenic shock
b) Noradrenalione is not used in cardiogenic shock
c) Beta blockers are contraindicated in asthma
d) Clonidine and alpha methyl dopa is used to treat hypertension
e) Beta blockers alone should not be used in pheochromocytoma
7. Classify beta blockers. Mention the cardiovascular and non-cardiovascular uses of beta blockers.
8. How do beta blockers act as antihypertensive agents?
9. Write briefly on autonomic ganglionic blockers and their uses.
April 12, 2008
Overview of Acute Inflammation - in a FAQ style
This chapter will help you to:
- answer the frequently asked questions on acute inflammation
- prepare for the theory and viva exams in pathology
- get an easy refence tool for mediators of inflammation which might prove useful in pharmacology (autacoids) and microbiology (immunity) as well
General Considerations
1. Define inflammation.
Inflammation is defined as the protective response of a living vascularised tissue to a sub-lethal injury.
2. What are the different types of inflammation?
Inflammation may be of two types:
a) Acute inflammation
b) Chronic inflammation
3. State the cardinal signs of inflammation.
The cardinal signs of inflammation are:
Rubor (redness)
Tumor (swelling)
Calor (heat)
Dolor (pain)
Functio laesa (loss of function)
4. Compare acute & chronic inflammation.
Acute inflammation
It is of short duration
Characterized by tissue destruction followed by repair
Principal cells of inflammation are neutrophils (microphage)
Exudate formation is a hallmark
Chronic inflammation
It is of longer duration
Characterised by the simultaneous progress of tissue destruction and repair
Principal cells of inflammation are macrophages, lymphocytes and plasma cells.
Exudate formation is not so promine
5. What are the mechanisms underlying the genesis of the cardinal signs of inflammation?
Rubor – Due to increased vasodilation
Dolor – Due to local injury & release of pain producing mediators of inflammation
Tumor – Due to transudation & exudation of fluids into tissue spaces
Calor – Due to increased rate of oxygen utilization in the local tissue (respiratory burst) and vasodilatation.
ACUTE INFLAMMATION
6. Enumerate different events of acute inflammation.
The different events of acute inflammation are:
A. Vascular changes:
a) Changes in vascular flow & caliber
b) Increased vascular permeability
B. Leukocyte cellular events
a. Margination & rolling
b. Adhesion & transmigration
c. Chemotaxis & activation
d. Phagocytosis & degranulation
e. Leukocyte induced tissue injury
7. Write a short note on Phagocytosis.
Definition: It is a process of endocytosis by which a cell engulfs a semisolid material with subsequent formation of a phagocytic vacuole.
Mechanism:
A) FORMATION OF ENDOSOME
Phagocytosis can be basically of two types - Constitutive phagocytosis and receptor mediated phagocytosis. Costitutive phagocytosis is a continuous process that is not induced by any agent. Receptors meditative phagocytosis is produced in most cases by specialized clathrin-coated pits on the cell membrane. The latter is triggered by various ligands binding to their receptors on the cell surface. After the pit is full of ligands, the pit pinches off, forming a coated vesicle. This coated vesicle is now called early endosome. Now the endosome gets separated from the membrane and moves into the cytosol. This is now called a late endosome.
B) TRANSPORT OF ENDOSOME
The transport of vesicles is guided by different groups of targeting and docking proteins. On the surface of the endosome (vesicle) there is a specific V-snare protein that latches with its corresponding T-snare protein on the target.
Various small GTP-binding proteins of the Rab family are associated with acceleration of the transport, where as proteins of Sec 1 family slow down the transport process.
C) FATE OF THE ENDOSOME
The late endosome fuses with lysosomes and lysosomal enzymes digest their contents.
Importance of Phagocytosis:
- It helps to kill bacteria. Bacteria can be killed by ROS-mediated, non-ROS-mediated (enzymatic) & NO-mediated mechanisms
- Phagocytosis of dead tissue by scavenger cells (macrophages) helps in clearing tissue debris
- Receptors mediated endocytosis helps in internalization of LDL, insulin, epidermal growth factor, nerve growth factor, diphtheria toxin and a no. of viruses.
8. What are the morphological patterns, which an acute inflammatory process can present?
Morphological patterns of acute inflammation:
- Catarrhal – Superficial inflammation of mucous surfaces with hyper secretion of mucus by goblet cells.
E.g. Common cold, Inflammation of bowel
- Serous – Formation of protein rich fluid exudates with minor cellular exudation
E.g. Peritonitis, Synovitis - Fibrinous – Here, exudates contains abundant fibrinogen which is precipitated as a thick fibrin coating
E.g. Fibrinous pericarditis, lobar pneumonia - Pseudo-membranous – Formation of a membrane made of fibrin, necrotic epithelium and inflammatory cells
E.g. Pseudo-membrane of diphtheria - Hemorrhagic – Associated with frank hemorrhage due to vascular damage by bacterial toxins
E.g. Secondary bacterial infection in viral pneumonia - Gangrenous – Inflammation associated with wide spread necrosis of the organ, probably resulting from superimposed thrombosis or vascular occlusion
E.g. Strangulated hernia - Purulent – Production of pus which is creamy yellow in color, high specific gravity, alkaline in reaction & semi fluid in consistency
E.g. Abscess, Empyema - Phlegmatous – Diffuse spread of exudates through loose and lax tissue spaces by virulent bacteria
E.g. Erysipelas of face - Allergic – Hyper sensitivity of the host immune system to an antigen which was previously introduced to the body
E.g. Bronchial asthma
NOTE: Q. Why is diphtheric inflammation called Pseudo-membranous?
In diphtheria the membrane that is formed does not contain any basement membrane. It is composed entirely of fibrin, necrotic tissue &cellular exudates; hence it is called pseudo-membranous.
9. What are the fates of acute inflammation?
The fates of acute inflammation are:
- Resolution
- Progression to suppuration
- Progression to chronic phase with fibrosis
10. What are the cells taking part in host immunity? State their roles in the process of inflammation?
Natural cytolytic cells
a) Natural killer cells – Large granular lymphocytes, having Fc receptors for antibodies and kill anti body coated cells and virus infected tumor cells
Phagocytic cells
a) Neutrophils – Granulocytes with multilobed nucleus; help in phagocytosis and kill bacteria
b) Eosinophils – Granulocytes with bilobed nucleus and coarse brick-red cytoplasmic granules; take part in parasite defense and allergic response
c) Macrophages – Present in tissue, spleen, lymph nodes; bears Fc and C3 receptors on cell surface; takes part in inflammatory response anti-viral and anti-tumor activities
Antigen-presenting cells (APCs)
a) Monocytes – agranulocytes with Horse-shoe shaped nucleus that modulates immune response by releasing various cytokines
b) Macrophages – as above
Antigen -responsive cells
a) CD4 T cells – Mature in thymus, characterized by large nucleus, small cytoplasm; contains CD2, CD3, TCR, CD4 molecules on cell surface; Secretes IL-1 and other lymphokines and stimulate T and B cell growth
b) CD8 T killer cells – Involved in recognition of antigen; bears CD2, CD3, TCR, CD8 molecules on surface; Kill viral, tumor, transplant cells and secretes IL-2, IFN-gamma
Antibody producing cells
a) B cells – Mature in bursal equivalent; presents surface antibodies and class II MHC molecules and involved in Antibody production
b) Plasma cells – Activated B cells with eccentric small nucleus with Russel bodies in the cytoplasm that serve as antibody factories
Other cells
a) Basophils / mast cells – Granulocytes with coarse blue cytoplasmic granules; bears Fc-receptor of Ig E on surface; involved in Histamine release and allergic reactions
11. Enumerate the chemical mediators of acute inflammation.
The different chemical mediators of acute inflammation are classified into:
- Cell-derived mediators
- Plasma-derived mediators
The cell derived mediators include:
a) Preformed mediators, like Histamine, Serotonin & Lysosomal enzymes
b) Newly synthesized mediators, like Prostaglandins, Leukotrienes, PAF, ROS, NO, Cytokines, etc
The plasma derived mediators include:
Active by-products of the clotting system, fibrinolytic system, kinin system & complement system
12. Mention the functions of the mediators of inflammation with examples.
The most likely mediators involved in the following inflammatory changes are:
Vasodilatation:
a) Prostaglandins
b) Nitric oxide
Increased vascular permeability:
a) Vasoactive amines
b) C3a and C 5a
c) Bradykinin
d) LT C4, D4, E4
e) PAF
Chemotaxis and leukocyte activation:
a) C5a
b) LT B4
c) Bacterial products
d) Chemokines
Fever:
a) IL1, IL6s
b) TNF-alpha
c) Prostaglandins
Pain:
a) Prostaglandins
b) Bradykinin
Tissue damage:
a) Lysosomal enzymes
b) ROS
c) NO
A BRIEF DISCUSSION ON SOME IMPORTANT MEDIATORS OF INFLAMMATION:
Histamine: -
Derived from the amino acid histidine by decarboxylation
Present in mast cells
Released in response to physical injury, typeI hypersensitivity, C3a and C5a of complement, leukocyte-derived histamine-releasing proteins, neuropeptides and some cytokines.
Causes arteriolar dilatation and increased vascular permeability, venular endothelial contraction and widening of inter-endothelial cell junction.
Inactivated by histaminase
Serotonin: -
Derived from amino acid tryptophan by 5-hydroxylation and decarboxylation. Also called 5-hydroxytryptamine or 5HT
Found within platelet- dense body granules
Release is stimulated by platelet aggregation
Function is similar to histamine
Arachidonic acid metabolites (Eicosanoids): -
These are derivatives of eicosa-tetra-eneoic acid (20carbon unsaturated fatty acid) viz. arachidonic acid
Arachidonic acid is liberated from membrane-phospholipid during cell injury by the enzyme phospholipase A2. This enzyme is inhibited by glucocorticoids
From arachidonic acid, by cycloxygenase enzyme (COX) the prostaglandins (PG) & thromboxanes (TX) are produced. This enzyme is inhibited by NSAIDs
From arachidonic acid by lipoxygenase enzyme (LOX) the leukotrienes (LT) are produced. This enzymes is inhibited by zileuton
Functions of eicosanoids are:
1. PG I2 (prostacyclin)
Vasodilatation
Inhibits platelet aggregation
2. TX-A2 (thromboxane)
Vasoconstriction
Promotes platelet aggregation
3. PG-D2, PG-E2, PG-F2 alpha
Vasodilation
Edema
4. LT-B4
Chemotaxis
5. LT-C4, LT-D4, LT-E4
Vasoconstriction
Bronchospasm
Increased vascular permeability
Platelet-activating factor (PAF): -
It is a phospholipid- derived mediator. Chemically it is acetyl glycerol ether phosphocholine
Obtained from membrane phospholipids of leukocytes and other cells by the action of phospholipase-A2
It causes vasoconstriction in high doses and vasodilation at low doses .in addition it also causes broncho-constriction, increased leukocyte adhesion, chemotaxis, leukocyte degranulation and oxidative burst. It can also stimulate synthesis of eicosanoids
Nitric oxide (NO): -
It is a short acting soluble gaseous free radical
It was initially called EDRF (endothelium-derived relaxation factor)
It is synthesized from L-Arginine with the help of NO-synthase
L-Arginine + O2 + NADPH = Citrulline + NO + NADP
The reaction is catalysed by NO-synthase
The enzyme NO synthase has 3 isoforms:
I. Neuronal isoform, present in neurons, and constitutive in nature. It is also called nc NOS
II. An inducible isoform present in cardiac myocytes, hepatocytes and respiratory epithelium, called i NOS
III. Another constitutive isoform present in endothelium, called ec NOS
Of these, the function of the constitutive iso-enzymes (I and III) depends on the cytosolic Ca++ level.
Functions of NO include:
a. Smooth muscle relaxation by stimulating soluble Guanylyl cyclase enzyme
b. Formation of peroxynitrite radical by combining with super oxide radical. This radical breaks into toxic NO2 and OH- radical
c. It can combine with iron in presence of thio-compounds (R-SH) to form di-thio di-nitroso complex with iron. This depletes iron and leads to inhibition of several bacterial enzymes.
Complement system: -
It is a group of about 20 plasma proteins that help in non specific immune response
It comprises of 2 distinct pathways – the classical pathway and the alternate pathway
Classical pathway comprises of sequential activation of number of plasma proteases following activation by immune-complex
Alternate pathway is activated by the cell wall lipo-polysaccharide of bacteria
Both the systems converge into a final common pathway leading to the formation of a Membrane Attack Complex (MAC) that induces pore formation in the membrane of cells and leads to osmotic lysis
Role of complement components in inflammation are:
a) C 3a and C5a increases vascular permeability (anaphylatoxin)
b) C5a is chemotactic to leukocytes
c) C3b is an important opsonin
d) C5b- C7 complex is a chemo tactic agent
e) C5b-9 is the MAC
Kinin system: -
This system comprises of 2 vasoactive peptides- bradykinin and lysyl-bradykinin (kalidin)
Bradykinin is a Nona peptide whereas lysyl-bradykinin is a deca peptide having an extra lysine residue at the amino-terminal
They are derived from the High and the Low molecular weight kininogens (HMWK and LMWK)
They are inactivated by kininase I and kininase II.Kininase II is identical with ACE
Function of kinins are:
a) Contraction of smooth muscle
b) Dilatation of arterioles
c) Production of pain
d) Chemotaxis
e) Increased vascular permeability
Clotting system: -
The coagulation system plays important roles in the mediation of inflammation
Activation of the Hageman factor (factor XII) is the key process leading to activation of the plasma proteases
Fibrino-peptides formed due to conversion of fibrinogen to fibrin leads to increased vascular permeability
The fibrino-peptides are also chemotactic to neutrophils
Fibrinolytic system: -
Converts fibrin into fibrinopeptides which lead to:
a) Increased vascular permeability
b) Chemotaxis
c) Generation of C 3a
d) Activation of kinin system
Lysosomal products: -
Lysosomal granules of neutrophils and monocytes contain different inflammatory mediators
The proteolytic substances include acid proteases and neutral proteases
Acid proteases have acidic pH optima and active only in phagolysosomes
Neutral proteases include elastase, collagenase and cathepsin, which degrade extra-cellular matrix (ECM). It can generate C3a and C5a, and stimulate kinin system
To counteract the uncontrolled effects of proteases, a number of anti-proteases are present in serum and ECM
References:
- Pathologic Basis of Disease – 7th ed, Robbins & Cotran
- General Pathology – Walter Israel
- Review of Medical physiology – 19th ed, W F Ganong
- Harper’s Biochemistry – 25th ed, Murray et al
- Immunology – Roitt
- Medical microbiology – 22nd Jawetz, Melnick & Adelberg
- Pharmacology – 6th ed, Rang, Dale, Ritter
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