Challenges and recommendations for conducting epidemiological studies in the field of epilepsy pharmacogenetics.

Epilepsy is one of the most prevalent neurological disorders, afflicting approximately 50 million Indians. Owing to affordability and easy availability, use of first-generation antiepileptic drugs (AEDs) is heavily encouraged for the treatment of epilepsy in resource-limited countries such as India. Although first-generation AEDs are at par with second-generation AEDs in terms of efficacy, adverse drug reactions (ADRs) are quite common with them. This could be attributed to the inferior pharmacokinetic parameters such as nonlinear metabolism, narrow therapeutic index and formation of toxic intermediates. In addition, epilepsy patients may differ in the pharmacokinetic and pharmacodynamic profiles, with about 1/3rd of the population failing to respond to treatment. A proportion of this interindividual variability in response may be explained by genetic heterogeneity in the activity and expression of the network of proteins such as metabolizing enzymes, transporters and targets of AEDs. Over the last two decades, a considerable effort has been made by the scientific community for unraveling this genetic basis of variable response to AEDs. However, there have been inconsistencies in such genetic association studies conducted across different territories of the world. There could be several reasons underlying the poor replicability of these studies, mainly nonuniform phenotypic definitions, poor sample size and interethnic variability. In the present review article, we provide an overview of heterogeneity in study designs for conducting pharmacogenetic studies. In addition, critical recommendations required for overcoming such challenges imposed by pharmacogenetic epidemiological studies have been briefly discussed.

Angiogenesis in myelodysplastic syndromes (MDS) in Indian patients.

Angiogenesis plays an important role in the pathogenesis of haematological neoplasms and may be correlated with the prognosis. We recently evaluated the microvessel densities in trephine biopsy sections of seventeen patients of myelodysplastic syndromes (MDS). Of the 17 cases, 2 were RAEB-t, 3 were RAEB, one was RARS and 11 were of the subtype RA (FAB subtyping). The microvessel counts were measured in the bone marrow biopsy sections by immunohistochemical staining, using CD34 reactive monoclonal antibodies. MVD was significantly higher in the cases of RAEB and RAEB-t as compared to the cases of RA. The average MVD per x400 in the cases of RA was 5.7 +/- 4.7 with a median value of 4.65 (range 19) whereas it was 45.4 +/- 10.0 and 44.0 (range 27.3) respectively in RAEB and RAEB-t (p <.001), the 95% confidence interval being (2.94, 8.5) and (36.6, 54.3), for the two groups respectively. This finding may imply that subtypes of MDS with a higher tendency for converting to acute leukaemia are associated with increased angiogenesis as compared to other subtypes where the risk of progression to acute leukaemia is much lower.

Inherited heterogenous defect in platelet aggregation selectively with ADP and epinephrine--a series of 25 cases.

Inherited heterogeneous defects of platelet function caused by impairment of platelet responses to weak agonists as ADP, epinephrine and others as low concentration collagen and platelet activating factor (PAF) have been described, though quite rarely. We describe here 25 cases of this defect with impairment in response to ADP and epinephrine. Subjects with a history of generalized bleeding and a prolonged bleeding time, PF3 availability or prothrombin consumption index and a normal platelet count, prothrombin time, activated partial thromboplastin time and clot solubility were subjected to platelet aggregation. Those of these which showed a normal aggregation with collagen and arachidonic acid and an absent or reduced aggregation with ADP and epinephrine were included in our study group. Subjects with history or findings suggestive of antiplatelet drug intake or any acquired condition affecting platelet functions were excluded from this study. 76% of the patients had onset of recurrent bleeding manifestations since childhood with a mean age at onset of 9.2 years. A positive family history was present in 36% of the patients. Majority of the patients (88%) presented with mild bleeding manifestations, the commonest symptom being appearance of recurrent ecchymotic spots. We present here a series of patients with a hereditary platelet aggregation defect selectively with ADP and epinephrine.

Comparative protein profiles of Salmonella and Escherichia coli.

Protein profiles of selected Salmonella serovars were compared with E. coli to identify genus specific protein(s) for Salmonella. The PDP formed of different Salmonella serovars were compared with E. coli O78 when subjected to SDS-PAGE yielded 11, 15, 15, 11 and 14 bands in S. Bareilly, S. Gallinarum, S. Typhimurium and S. Weltevreden and E. coli O78 respectively. The bands produced were compared with each other. It was found that S. Weltevreden shared 7 bands with E. coli O78, A protein of molecular weight 20.89 kDa was found in all Salmonella serovars, but not in E. coli O78 suggesting its genus specific attribute.

An unusual platelet function defect: report of 19 cases.

Selective impairment in platelet responsiveness to epinephrine has been seen in certain acquired conditions and very rarely as a hereditary disorder. To the best of our knowledge this hereditary defect has been described in a single family and in two other individuals. We describe here 19 cases of this defect. Subjects with history of generalized bleeding with a prolonged bleeding time, PF3 availability or prothrombin consumption index and a normal platelet count, prothrombin time, activated partial thromboplastin time, clot solubility were subjected to platelet aggregation. Those of these who showed a normal aggregation with ADP, collagen, arachidonic acid and an absent aggregation with epinephrine were included in our study group. Subjects with history or findings suggestive of antiplatelet drug intake or any acquired condition giving rise to this abnormality were excluded from this study. 74% of the patients had onset of bleeding manifestations since childhood (<14 years) with a mean age at onset of 10.4 years. All patients presented with mild bleeding manifestations, the commonest symptom being appearance of recurrent ecchymotic spots. In females, menorrhagia was the commonest symptom. We present here probably the first report of the occurrence of hereditary platelet aggregation defect selectively with epinephrine in Indian patients.

Contribution of iron deficiency to anemia in chronic renal failure.

Prevalence of iron deficiency in anemia of chronic renal failure (CRF) has long been the subject of interest, because the patients of CRF with coexistent iron deficiency anemia need to be treated with iron preparations before starting erythropoietin therapy. Prevalence of iron deficiency in CRF is higher in Indian patients as compared to the West. Diagnosis of iron deficiency in patients with CRF is difficult. Bone marrow iron which is considered to be the gold standard is a painful and invasive procedure. In the present study we used serum transferrin receptor and serum ferritin levels, since not much Indian data is available on this.