Indrajeet Singh Gambhir

Molecular genetics of essential hypertension.

ABSTRACT Hypertension is a major public health problem in the developing as well as in developed countries due to its high prevalence and its association with coronary heart disease, renal disease, stroke, peripheral vascular disease, and related disorders. Essential hypertension (EH) is the most common diagnosis in this disease, suggesting that a monocausal etiology has not been identified. However, a number of risk factors associated with EH have also been identified such as age, sex, demographic, environmental, genetic, and vascular factors. Recent advances in molecular biological research had achieved clarifying the molecular basis of Mendelian hypertensive disorders. Molecular genetic studies have now identified mutations in several genes that cause Mendelian forms of hypertension in humans. However, none of the single genetic variants has emerged from linkage or association analyses as consistently related to the blood pressure level in every sample and in all populations. Besides, a number of polymorphisms in candidate genes have been associated with differences in blood pressure. The most prominent candidate has been the polymorphisms in the renin–angiotensin–aldosterone system. In total, EH is likely to be a polygenic disorder that results from inheritance of a number of susceptibility genes and involves multiple environmental determinants. These determinants complicate the study of blood pressure variations in the general population. The complex nature of the hypertension phenotype makes large-scale studies indispensable, when screening of familial and genetic factors was intended. In this review, recent genetic studies exploring the molecular basis of EH, including different molecular pathways, are highlighted.

Angiotensin-converting enzyme gene I/D polymorphism increases the susceptibility to hypertension and additive diseases: A study on North Indian patients

ABSTRACT Angiotensin-converting enzyme (ACE) is the key enzyme of the renin angiotensin system (RAS) which maintains the blood pressure homeostasis in our body. The association of the ACE insertion/deletion (I/D) polymorphism with essential hypertension has been demonstrated by many studies. The purpose of the present study is to investigate the association of the insertion/deletion polymorphism of the ACE gene with hypertension and additive diseases in North Indian population. In total, 222 hypertensive and 218 normotensive adults participated in this hospital-based study. Anthropometric measures, lipids profiles, blood glucose, and blood pressure (BP) measures were collected from participants. ACE I/D polymorphism was determined by using insertion-specific amplification. The mean ages of study groups were 50.35 ± 12.40 and 47.32 ± 11.94 for cases and controls, respectively. Significant differences were observed in the frequencies of DD, ID, and II genotypes among the hypertensive and normotensive groups which were found to be 29.7%, 38.7%, and 31.5% vs. 53.7%, 23.4%, and 22.9%, respectively. It has been observed that the ACE ID genotype was significantly (p < 0.05) higher in hypertensive subjects, whereas, the DD genotype was significantly (p < 0.05) higher in control subjects. A strong association was found between cardiovascular diseases (CVDs) and ID genotype [p = 0.017, odds ratio (OR) = 3.091, 95% confidence interval (CI) = 1.224–7.807]. ID [p = 0.002, OR = 2.020, 95% CI = 1.281–3.185] and II [p = 0.032, OR = 1.677, 95% CI = 1.044–2.694] genotypes are more prone to diabetes with hypertension. This finding suggests that ACE insertion/deletion polymorphism is associated with hypertension and additive diseases in North Indians.

The see-saw of Keap1-Nrf2 pathway in Cancer

Keap1-Nrf2 pathway is continuously involved in the cytoprotection from oxidative stress generated due to various factors either extrinsic or intrinsic in origin. This role of Nrf2 in the response to oxidative stress is well established. Following oxidative insult, Nrf2 mediates the regulation of the inducible expression of cytoprotective genes. The level and functional capacity of Nrf2 is regulated at the post-transcriptional level, mainly through its association with an actin-associated protein, Keap1. Various studies reported that any discrepancy from their routine may lead to promotion of tumor as well. So there is need to explore their role in cytoprotection and tumor promotion if any. This review is an attempt to critically analyze the available data that may lighten up the present knowledge and unveil the new regime for cancer prevention and treatment.

Zoledronate Induced Hypocalcemia and Hypophosphatemia in Osteoporosis: A Cause of Concern

Zoledronate is a Nitrogen containing bisphosphonate (NBP) used in many conditions like osteoporosis, Pagets disease and hypercalcemia of malignancy. Unlike oral bisphosphonates, Zoledronate is not seen to be associated with gastroesophageal side effects but the drug is not free of certain rare but life threatening adverse effects like hypocalcemia and renal deterioration. Majority of cases of hypocalcemia with Zoledronate are seen in patients with underlying malignancy and are asymptomatic. Here we present a case of severe symptomatic hypocalcemia along with hypophosphatemia following zoledronate administration in an elderly male with a history of osteoporotic fracture.

Isoniazid Induced Metabolic Acidosis and Renal Dysfunction in an Elderly Patient with Chronic Renal Disease.

Metabolic acidosis is one of the common manifestations of Isoniazid toxicity but rare with normally used doses of the drug. Among anti tubercular drugs, rifampicin, streptomycin and capreomycin are commonly implicated in renal injury. Here we report the first case of metabolic acidosis and renal injury caused by isoniazid at normal prescribed dose.

Effect of Immunosenescence on the Induction of Cardiovascular Disease Pathogenesis: Role of Peripheral Blood Mononuclear Cells

It is well established that the immune potential declines with age. However, there is a great paucity of information regarding role of monocytes in elderly suffering from cerebrovascular accident. This present study was undertaken to investigate if the functions of peripheral blood mononuclear cells have any correlation to the manifestation of an age-associated cerebrovascular disorders: myocardial infraction, cerebrovascular (infract & hemorrhage). An age-associated inhibition in the production of interleukin-1 (IL-1) by monocytes was observed while the production of nitric oxide (NO) remained unaltered in the response of monocytes, obtained from normal elderly donors, to Lipopolysaccharide (LPS) treatment in vitro. Cerebrovascular pathologies were found to be associated with an augmentation of IL-1 production by monocyte, while NO production was augmented in case of CVA (hemorrhage) and MI. Trace element copper was found to be lower in the serum of patients suffering from CVA, while concentration of zinc was found to be elevated in serum compared to these trace elements in normal adults. Thus these factors are likely to play a role in the pathogenesis of age-related cerebrovascular disorders.

Morvan’s syndrome—is a pathogen behind the curtain?

Morvan’s syndrome is a rare syndrome of likely autoimmune etiology characterized by peripheral nerve hyperexcitability, dysautonomia, insomnia, and fluctuating delirium with prominent hallucinations. Since its first mention in 1890, less than 100 cases have been described in literature. The largest existing review includes details of 29 cases. This case series describes 4 cases (M = 4) of Morvan’s syndrome which presented between May and November 2017 to a single tertiary care referral teaching hospital in north India. All the four patients manifested behavioral abnormalities, sleep disturbances, hallucinations, autonomic dysfunction, and clinical signs of peripheral nerve hyperexcitability, mostly as myokymia. Two of the patients had Anti-CASPR2 (contactin-associated protein 2) antibodies. Three of them had electromyography features of peripheral nerve hyperexcitability and only one had elevated cerebrospinal fluid protein level. We hypothesize that Morvan’s syndrome and other less characterized autoimmune encephalitis/peripheral nervous system syndromes may have infectious triggers. A possible viral trigger may result in generation of autoantibodies which result in the typical manifestations. We base these hypotheses on the finding of four cases of an orphan disease within a short period of time in a limited geographical distribution.

Striatal hand in an elderly man with disseminated tuberculosis: An unusual first case: Letters to the Editor

1 Llinas R, Galen MD, Henderson GV. Images in clinical medicine. Tremor as a cause of pseudo-ventricular tachycardia.N Engl J Med 1999; 341: 1275. 2 Knight BP, Pelosi F, Michaud GF, Strickberger SA, Morady F. Clinical consequences of electrocardiographic artifact mimicking ventricular tachycardia. N Engl J Med 1999; 341: 1270–1274. 3 Robottom BJ, Weiner WJ. Teaching neuroImages: rest tremor mimicking ventricular tachycardia. Neurology 2010; 75: 2134. 4 Perez-Riera A, Barbosa-Barros R, Daminello-Raimundo R, de Abreu LC. Main artifacts in electrocardiography. Ann Noninvasive Electrocardiol 2017: e12494. 5 Hwang W, Chen J, Sung PS, Lee JC. Parkinsonian tremor-induced electrocardiographic artifacts mimicking atrial flutter/fibrillation or ventricular tachycardia. Int J Cardiol 2014; 173: 597–600.

Deep Venous Thrombosis Associated with Thalidomide use in a Case of Steroid Dependent Erythema Nodosum Leprosum-a Management Conundrum

Thalidomide, previously banned owing to the issues of teratogenicity is being used and tested for a variety of dermatological and non dermatological conditions. The drug has been approved for the management of erythema nodosum leprosum [ENL] and multiple myeloma [MM]. The drug is commonly known to produce adverse effects like peripheral neuropathy and constipation. Deep vein thrombosis [DVT] is one of the serious adverse effects seen with thalidomide use, especially in malignancies and is relatively uncommon in non cancer settings like ENL. Method: Here we report a case of DVT occurring after 8 months of use of thalidomide in a young patient of 22 years age suffering from ENL. Result: The case highlights the problems faced in the management of refractory ENL and the treatment of DVT in the setting of multiple drug interactions and financial constraints. Conclusion: New guidelines are required regarding the prophylaxis and management of DVT associated with thalidomide use in non-malignant conditionsThalidomide, previously banned owing to the issues of teratogenicity is being used and tested for a variety of dermatological and non dermatological conditions. The drug has been approved for the management of ENL and Multiple myeloma. The drug is commonly known to produce adverse effects like peripheral neuropathy and constipation. Deep vein thrombosis (DVT) is one of the serious adverse effects seen with thalidomide use, especially in malignancies and is relatively uncommon in non cancer settings like ENL. Here we report a case of DVT induced after 8 months of use of thalidomide in a young patient of 22 years age suffering from ENL. The case also highlights the problems faced in the management of refractory ENL and the treatment of DVT in the setting of multiple drug interactions and financial constraints.

Free radicals hasten head and neck cancer risk: A study of total oxidant, total antioxidant, DNA damage, and histological grade

Background: Free radicals such as reactive oxygen species (ROS), which induce oxidative stress, are the main contributors to head and neck carcinogenesis (HNC). The present study was conducted with the aim to assess the oxidant/antioxidant status and DNA damage analysis in head and neck cancer/control patients. Materials and Methods: This prospective study was conducted on 60 patients with biopsy-proven HNC and 17 patients of head and neck disease (HND). The total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI) were determined by novel automatic colorimetric methods from tissue homogenate. DNA damage analysis was determined by single cell gel electrophoresis (SCGE). Results: The mean age of the study cohort was 46.65 ± 14.84 years for HNC patients, while it was 49.41 ± 13.00 years for HND patients. There were no significant differences found between the two groups with respect to demographic presentation except tobacco addiction. The association between oxidative stress parameters and DNA damage analysis with study group revealed the following. (A) DNA damage - tissue homogenate TOS and OSI were significantly higher in HNC subjects than in HND (16.06 ± 1.78 AU vs 7.86 ± 5.97 AU, P < 0.001; 53.00 ± 40.61 vs 19.67 ± 21.90, P < 0.01; 7.221 ± 5.80 vs 2.40 ± 2.54, P < 0.01, respectively), while TAS was significantly decreased. (B) Aggressive histological features were identified, more commonly with higher TOS and lower TAS [probability (P) = 0.002, relative risk (RR) = 11.838, 95% confidence interval CI = 2.514-55.730 and P = 0.043, RR = 0.271, 95% CI = 0.077-0.960, respectively]. Conclusion: The increase in free radicals may be the event that led to the reduction of antioxidant status in HNC, thus explaining the oxidative damage of DNA and the severity of disease. Increased OSI represents a general mechanism in its pathogenesis.