In the search of a 'fitness gene': an analysis of ACTN gene polymorphisms in serving soldiers.

BACKGROUND: Genetic polymorphisms in the exon 15 and exon 16 of the ACTN3 gene are believed to be associated with athletic performance. Paratroopers are some of the fittest soldiers in the Indian Armed Forces. This study was taken up to assess if there was a significant difference in the genetic profile between paratroopers and non-paratroopers. METHOD: Polymerase chain reaction (PCR) followed by restriction length fragment polymorphism (RFLP) was used to analyse the genetic polymorphisms in the exon 15 and 16 of the ACTN3 gene. RESULTS: There was a significant difference between paratroopers and non-paratroopers in the polymorphic loci at codon 15 and 16. CONCLUSIONS: The study suggests that there is a significant difference in the genotype between paratroopers and non-paratroopers. It is likely that the differences in muscle fibres as a result of these genotypic changes confer a 'survival advantage'; people with a homozygous genotype are more likely to pass the harsh probation and qualify for the Parachute Regiment.

Autopsy in dengue encephalitis: An analysis of three cases.

Dengue viral infection with unusual presentations has been described in literature, but autopsy is rarely done and is only limited to some cases, based on the literature review. Here, we present the autopsy findings in three cases of dengue encephalitis. All the three patients clinically presented with signs of meningoencephalitis and were positive for dengue non-structural (NS) 1 antigen (Ag) in the serum and cerebrospinal fluid. The postmortem findings revealed cerebral edema, inflammation, hemorrhage, and microinfarcts in all the three cases with herniation of the brain in one case. Sub-massive hepatocellular necrosis was seen in one case. The renal findings included hemorrhage into the Bowman's capsule with red cell cast in two of three cases. The pulmonary findings included a diffuse destruction of the alveoli and hemorrhage into the alveolar spaces in all the three cases.

Bullous erythema nodosum leprosum manifesting in the post partum period with unusual features.

A 30 year old woman who presented with multiple numb patches on the body was initially diagnosed as borderline lepromatous leprosy and started on multidrug therapy for leprosy. She had an episode of Type 1 reaction during the fifth month of pregnancy. After delivery, she stopped therapy fearing harm to her child and developed an episode of Type 2 reaction. The reaction was unusual in that bullous lesions developed over previous leprosy patches which had initially become indurated, with associated neuritis. Histopathology revealed bullae with intense neutrophilic reaction and strong positivity for acid fast bacilli. There was no response to steroid therapy which was started for the reaction. Thalidomide had to be prescribed after stopping lactation by medical means. She responded dramatically to Thalidomide with regression of cutaneous lesions and neuritis. This patient is being reported as a very unusual manifestation of bullous erythema nodosum leprosum in the postpartum period responding dramatically to thalidomide.

Vitamin D Deficiency After Oral Retinoid Therapy for Ichthyosis.

Oral retinoids are being increasingly used to treat ichthyotic disorders in children. We report on two children with ichthyotic disorders who developed unusual manifestations after they were started on oral retinoids. The first case is a 10-year-old girl with nonbullous ichthyosiform erythroderma and the second is a 2-year-old girl with lamellar ichthyosis. The child with ichthyosiform erythroderma developed features of rickets within months of initiation of systemic retinoids. Her baseline examination before initiation of oral retinoids was normal. The second patient with lamellar ichthyosis was found to have low vitamin D levels after 6 months of retinoid therapy, and prompt supplementation reversed the levels in 2 months. These cases are being reported to bring attention to the probable need for initiation of vitamin D supplementation with systemic retinoid therapy in ichthyotic disorders in children.

Genetics of non syndromic hearing loss.

Non Syndromic Hearing Loss is an important cause for hearing loss. One in 1000 newborns have some hearing impairment. Over 400 genetic syndromes have been described. Non Syndromic Hearing Loss (NSHL) can be inherited in an Autosomal Dominant, Autosomal Recessive or a Sex Linked fashion. There are several reasons why genetic testing should be done in cases of NSHL, the main reasons being for genetic screening and for planning treatment. This review describes the genes involved in NSHL and the genetic mechanisms involved in the pathogenesis of the disease.

Cytokine gene polymorphisms in type I and type II reactions in Hansen's disease.

INTRODUCTION: Leprosy or Hansen's disease is a chronic debilitating disease caused by Mycobacterium leprae. Host genetics are believed to strongly influence the course of the disease. It is known that cytokines play an important role in leprosy and cytokine gene polymorphisms probably influence the course of the disease. METHODS: In the present study, we evaluated 70 patients with leprosy and 243 controls. DNA was extracted from the peripheral blood and genotyping was done for the following polymorphisms: IL-1 RA intron 2, IL-1ß-511 C/T and TNF-α A/G. RESULTS: A strong association of TNF-α-308 G/A polymorphism with Hansen's disease with both genotypes and alleles was found. However, no correlation was identified between the other two polymorphisms and Hansen's disease. A strong association between the IL-1ß gene polymorphisms and the type of reactions seen in leprosy was found. In contrast, the other two polymorphisms did not show any such association. LIMITATIONS: Genetic polymorphisms are association studies. They are not a direct reflection of the transcriptome or proteome and this is a major limitation of this study. CONCLUSION: In conclusion, cytokine gene polymorphisms appear to influence the susceptibility and course of Hansen's disease. An evaluation of the cytokine levels in the skin during lepra reactions would confirm this observation. Possibly, in future, this would be a guide to therapeutic decisions in cases of lepra reactions.

Correlation between transbronchial lung biopsy and lung cytology.

Respiratory diseases are an important cause of morbidity and mortality worldwide. Although conventional histopathology is the gold standard for their diagnosis, cytology is a useful adjunctive diagnostic test. In the present study we evaluated the efficacy of cytology in providing a rapid diagnosis. We included lesions which were both visible and not visible on bronchoscopy. We evaluated the role of bronchoalveolar lavage (BAL), brush cytology and imprint smears both separately and in combination, and compared them with the histopathological findings of transbronchial lung biopsy (TBLB). Among 100 cases the highest concordance was seen between imprint cytology (77.78%) and biopsy for malignancy, followed by bronchoalveolar lavage (40.91%) and brush cytology (40.00%). The concordance and level of agreement between cytology and biopsy was very poor in general for non-neoplastic lesions. However, it increased when BAL and imprint smears (42.50%) were performed together, compared to other combinations. We recommend a combination of cytological techniques in suspected cases of malignancy, as more useful than a single test, and to include imprint smears in all cases. However, biopsy remains the gold standard for diagnosis in non-neoplastic lung disease.

Role of cyclooxygenase-2 functional gene polymorphisms in Helicobacter pylori induced gastritis and gastric atrophy.

In India, the role of host genetic factors is poorly studied for Helicobacter pylori associated diseases. Therefore, we evaluated the association of functionally relevant COX-2 gene polymorphisms (-765 G>C and +8473 T>C) in gastritis and precancerous lesions susceptibility. After upper GI endoscopy, 130 rapid urease test positive patients with non-ulcer dyspepsia, also showed positivity for H. pylori using modified Geimsa staining and anti-CagA IgG serology were included. All patients and 260 asymptomatic controls were genotyped for COX-2 variations using PCR-RFLP. COX-2 -765 (GC+CC) genotypes, -765 C allele, +8473 CC genotype, +8473 (TC+CC) genotypes, +8473 C allele, and variant haplotypes imparted high risk for gastritis (P = 0.036, OR = 1.82; P = 0.007, 1.92; P = 0.025, OR = 2.13; P = 0.017, OR = 1.80; P = 0.017, OR = 1.45; P = 0.010, OR = 2.40; P = 0.023, OR = 1.50 and P = 0.012, OR = 2.20 folds, respectively). In contrast, COX-2 -765 C allele carriers had low risk for lymphocyte (P = 0.020, OR = 0.35), plasma cell infiltrations (P = 0.016, OR = 0.33), and gastric atrophy (GA) development (P = 0.019, OR = 0.35). In conclusion, COX-2 variant allele/genotype/haplotype carriers may be at high risk for gastritis. However, COX-2 -765 C allele carriers may be at low risk for GA development.

Recurrent pregnancy loss: can factor V Leiden mutations be a cause.

The role of Factor V Leiden (FVL) mutation in recurrent miscarriages has been disputed. It has been hypothesized that FVL mutation in patients with recurrent miscarriages is treatable. In this study, we evaluated 78 pregnant women for FVL mutations, among whom 50 had a history of recurrent miscarriages. Only 1 (2%) of the woman was positive for heterozygous FVL mutation. The incidence of FVL mutations in patients with recurrent pregnancy loss had an odds ratio of 1.72 (95% confidence interval, 0.0681-43.8257; P>0.05). However, the findings were not statistically significant. Thus, we suggest that FVL mutation study may not be included in the battery of tests for recurrent miscarriages in the Indian population.

Is Crush Cytology of Central Nervous System Lesions Relevant in Surgical Practice Today?

BACKGROUND: Intraoperative crush cytology is a useful tool for diagnosing the lesions of the central nervous system (CNS). However, because of the development of newer and better imaging techniques, it is important to evaluate if crush cytology is still relevant in neurosurgical practice. AIMS: We evaluated the crush cytology smears in a series of cases where neurosurgical intervention was performed. We studied the role of crush cytology in the intraoperative diagnosis. We report a series of cases where intraoperative crush cytology helped the surgeon revise the surgery during the operation. MATERIALS AND METHODS: A small portion of all CNS lesions was taken intraoperatively and the tissue was crushed between two slides. The slide was stained using the toluidine blue, Leishman stain, Pap stain and a routine H & E stain. The slides were the evaluated. RESULTS: We evaluated the 50 cases of CNS lesions. We found that intraoperative crush cytology is particularly important in differentiating between neoplastic and nonneoplastic CNS lesions. It may also help in differentiating lymphomas from high-grade gliomas. Finally, crush cytology may help the surgeon in delineating the lesions during surgery. CONCLUSION: We conclude that crush cytology remains relevant in neurosurgical practice today and it should be adopted in all neurosurgical centers as a routine diagnostic technique.

Fatal meningococcal septicemia without meningeal signs, contribution of the peripheral smear in diagnosis: Report of a case.

Acute meningococcemia is characterized by extensive purpurae consisting of both petechiae and ecchymoses. This condition can be rapidly fatal without treatment due to shock and severe consumptive coagulopathy. We report a case of fatal meningococcal septicemia in a military recruit who presented with fever and associated rapidly progressive purpuric rash (purpura fulminans) without any meningeal signs. Evaluation revealed evidence of disseminated intravascular coagulopathy and multiorgan failure. Diplococci were demonstrated in peripheral blood neutrophils and monocytes. On autopsy, extensive hemorrhages were found in both adrenals, lungs, liver, skin, and kidneys with secondary hemophagocytic lymphohistiocytosis in bone marrow. This report highlights useful information obtained from examination of peripheral blood smear in purpura fulminans.

A 37-year-old male with extensive cerebral venous thrombosis: Clinicopathological correlation of a rare case.

We present the autopsy findings and differential diagnosis of a 37-year-old immunocompetent male patient who presented primarily with extensive cerebral vein thrombosis and was found to have a rare association with JAK2V617F mutation positivity.

Association of Toll-like receptor-4 (Asp299Gly and Thr399Ileu) gene polymorphisms with gastritis and precancerous lesions.

A Toll-like receptor-4 (TLR-4) Asp299Gly and Thr399Ileu substitution reduces responsiveness to Helicobacter pylori (H. pylori) lipopolysaccharide. CagA+ strains of H. pylori are known to be associated with gastroduodenal diseases. Therefore we aimed to evaluate association of TLR-4 substitutions and CagA seropositivity with gastritis and precancerous lesions in a northern Indian population. After upper gastrointestinal endoscopy, 130 rapid urease test (RUT)-positive patients with nonulcer dyspepsia (NUD) were included. Patients with NUD were also screened for H. pylori infection using modified Giemsa staining and anti-CagA IgG enzyme-linked immunoabsorbent assay. All patients and 200 asymptomatic control subjects were genotyped for TLR-4 substitutions using polymerase chain reaction-restriction fragment length polymorphism. We observed that frequencies of TLR-4 Asp299Gly variants were comparable between patients and control subjects, and also between positive and negative groups of precancerous lesions in patients. Frequencies of TLR-4 399Ileu allele (8% vs 3%, p = 0.008) and Asp299-Ileu399 haplotype (6.5% vs 3%, p = 0.022) were higher in patients than in control subjects at risk for gastritis (OR = 2.6 and 2.5, respectively). TLR-4 399Ileu allele carriers had higher risk for plasma cell infiltration (p = 0.023, OR = 10.6) that led to atrophy (p = 0.028, OR = 4.2) and intestinal metaplasia (p = 0.009, OR = 4.7). CagA positivity was more frequently associated with lymphoid follicle formation (p = 0.033, OR = 2.53). In conclusion TLR-4 Thr399Ileu substitution may be a risk factor for gastritis and precancerous lesions. CagA positivity may be a risk factor for lymphoid follicle development but not for other precancerous lesions in a northern Indian population.

The histopathology of chronic gastritis.

Chronic gastritis is a multifactorial disorder thought to be influenced by bacterial and host genetic factors. Histopathological examination is the mainstay of diagnosis, however features like the presence of Helicobacter pylori are difficult to evaluate on biopsy. We evaluated 120 gastric antral biopsies using the revised Sydney system. The density of the inflammatory infiltrate, H pylori and mast cells were evaluated. It was seen that the presence of H pylori is strongly associated with an acute and a chronic inflammatory infiltrate. The presence of neutrophils on biopsy is strongly associated with the presence of H pylori and with the density and the grade of the chronic inflammatory infiltrate. The chronic inflammatory response is an intermediary between the acute inflammatory process and glandular atrophy. The lymphocytic infiltrate is also a precursor lesion of the lymphoid follicles. The presence of mast cells does not appear to be related to any of the other inflammatory parameters. The presence of one feature is a strong indicator for the presence of other inflammatory features.

A 54-year-old male with rapidly progressive neurologic syndrome: Clinicopathologic correlation of a rare diagnosis.

Diagnosis of systemic lupus erythematosus (SLE) as primary presentation with central nervous system involvement as a rapidly progressive neurologic syndrome is extremely rare. We present a rare case of a 54-year-old hypertensive male patient, who presented with a fulminant neurologic syndrome. He presented with cerebellar and meningeal signs, aseptic meningitis and had a rapid downhill course following admission. A postmortem revealed feature of systemic connective tissue fulfilling diagnostic criteria of SLE with lupus cerebritis.

Modifier genes and oligogenic disease.

It is now increasingly apparent that modifier genes have a considerable role to play in phenotypic variations of single-gene disorders. Intrafamilial variations, altered penetrance, and altered severity are now common features of single gene disorders because of the involvement of several genes in the expression of the disease phenotype. Oligogenic disorders occur because of a second gene modifying the action of a dominant gene. It is now certain that cancer occurs due to the action of the environment acting in combination with several genes. Although modifier genes make it impossible to predict phenotype from the genotype and cause considerable difficulties in genetic counseling, they have their uses. In the future, it is hoped that modifier genes will allow us to understand cell and protein interactions and thus allow us to understand the pathogenesis of disease.

Expression of apoptosis regulating proteins p53 and bcl-2 in psoriasis.

BACKGROUND: Dysfunctional apoptosis has an important role in the development of several skin diseases. Psoriatic keratinocytes possess an enhanced ability to resist apoptosis, which might be one of the key pathogenetic mechanisms in psoriasis. P53 and bcl-2 are two proteins which control apoptosis. Several studies have evaluated the expression of these two proteins in the psoriatic skin, but the results are controversial. METHODS: Fifty-eight cases of psoriatic skin biopsies were studied, and the grade of p53 and bcl-2 immunostaining was correlated with the histopathological indices of severity. RESULTS: Bcl-2 expression in the epidermis strongly correlated with the expression in the basal cells and lymphocytes (P--0.001 and 0.035). There was no correlation with epidermal hyperplasia or with p53 expression in the three compartments. Bcl-2 expression in the basal layer correlated with the p53 expression in the epidermis (P--0.027), basal layer (P--0.015) and the lymphocytes (P--0.034). There was a strong correlation among the p53 expression in all the compartments. There was also a weak correlation of the p53 expression in the epidermis with the epidermal hyperplasia (P--0.042). CONCLUSIONS: Bcl-2 does not appear to play an important role in the apoptotic process in psoriasis. In contrast, it is likely that p53 has a far more important role to play. Mutation analysis of the p53 protein is necessary to evaluate if the protein has mutated or if it is of the wild type.

Interleukin-1 Gene Polymorphisms and their Relation with NFκB Expression and Histopathological Features in Psoriasis.

BACKGROUND: Psoriasis is a chronic inflammatory disease driven by exaggerated production of pro-inflammatory cytokines and interleukins. Various genetic polymorphisms including IL-1 are implicated in pathogenesis of psoriasis. The exact role of IL-1 gene polymorphisms and their interaction with NFκB is not yet determined. We aimed to study various genetic polymorphisms of IL-1 in psoriasis and their influence on NFκB and histopathological features. MATERIALS AND METHODS: 112 newly diagnosed cases of psoriasis vulgaris were included in this prospective study. Histology was done on sections and genotyping was done for the IL-1ß and IL-1 receptor antagonist (IL-1RA) genetic polymorphisms. In addition, NFκB immunostaining was performed on 89 sections and the intensity of staining was evaluated in the epidermis, basal cells, and the lymphocytes. RESULTS: A strong association of IL-1ß 511 C/T polymorphism was found with both genotypes and alleles in psoriasis. A strong correlation was also detected between the IL-1ß genotype and the grade of NFκB immunostaining in the epidermis (P = 0.012). The grade of NFκB lymphocyte staining showed a strong correlation with the IL-1RA genotype (P = 0.025) but not with the IL-1ß genotype (P = 0.226). The genetic polymorphisms did not show any correlation with the histological features. CONCLUSIONS: IL-1 genetic polymorphisms may not play a very direct role in pathogenesis of psoriasis. However, their interaction with NFκB appears to be a significant factor in this direction as NFκB is activated by pro-inflammatory genetic polymorphisms and therefore may influence the severity of psoriasis.

A Comprehensive Study of Tumor Necrosis Factor-Alpha Genetic Polymorphisms, its Expression in Skin and Relation to Histopathological Features in Psoriasis.

BACKGROUND: Tumor necrosis factor-alpha (TNFα) is an important inflammatory mediator in psoriasis and several genetic polymorphisms of this cytokine have been reported. Majority of studies have focused on the increased G- A polymorphism at the -308 position in psoriasis. There has been no comprehensive study evaluating the genetic polymorphisms, TNFα expression in the skin and histopathology. We are undertaking this study to outline TNFα genetic polymorphisms, its skin expression and histopathological correlation to help determine its role at the genetic and protein level. MATERIALS AND METHODS: 112 patients of psoriasis and 243 healthy controls were included in this prospective study. 5 ml of peripheral blood was collected to study the TNFα genetic polymorphisms by polymerase chain reaction and restriction fragment length polymorphism analysis. Histopathological analysis of biopsies from the 112 patients were done using visual analogue scale and correlated with the findings. 61 of these cases were analyzed for TNFα expression by immunohistochemistry. The results of study were statistically analyzed using SPSS 13.0 statistical package program. RESULTS: A strong association of TNFα -308 G/A polymorphism in psoriasis cases was detected. The A allele of the TNFα -308 G/A polymorphism occurs rarely in the Indian population, however there is an over representation of this allele in psoriatic patients. There was no association seen between TNFα genotype and histopathological severity of psoriasis. CONCLUSION: The study emphasized the central role of TNFα in the pathogenesis of psoriasis. TNFα genotyping may be helpful in identifying subjects in whom anti-TNFα therapeutic strategies may be tried.