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Biomedical subjects

Pankaj Sharma

Publications and source records attributed to Pankaj Sharma.

At least 19 recordsLinked to original sources
PubMed2006

Interleukins and STAT signaling.

Metazoan cells secrete small proteins termed cytokines that execute a variety of biological functions essential for the survival of organisms. Binding of cytokines that belong to the hematopoietin- or interferon-family, to their cognate receptors on the surface of target cells, induces receptor aggregation, which in turn sequentially triggers tyrosine-phosphorylation-dependent activation of receptor-associated Janus-family tyrosine kinases (JAKs), receptors, and signal transducers and activators of transcription (STATs). Phosphorylated STATs form dimers that migrate to the nucleus, bind to cognate enhancer elements and activate transcription of target genes. Each cytokine activates a specific set of genes to execute its biological functions with a certain degree of redundancy. Cytokine signals are, in general, transient in nature. Therefore, under normal physiological conditions, initiation and attenuation of cytokine signals are tightly controlled via multiple cellular and molecular mechanisms. Aberrant activation of cytokine signaling pathways is, however, found under a variety of patho-physiological conditions including cancer and immune diseases.

Animals↗
PubMed2006

Heritability of left ventricular mass in a large cohort of twins.

INTRODUCTION: Left ventricular hypertrophy is recognized as one of the most important independent predictors of adverse cardiovascular outcome. The aetiology of LVH includes a number of well-recognized causes but there is considerable interest in the genetics of cardiac muscle hypertrophy. We used a large prospective twin database in order to establish the heritability of left ventricular mass (LVM). METHODS: Normotensive twins were prospectively recruited. Demographic data were collected. The LVM was determined using the Penn formulae derived from data collected from echocardiography. RESULTS: A total of 376 Caucasian twin pairs (182 monozygotic and 194 dizygotic) aged 25-79 years were recruited. All subjects were normotensive with no significant differences in blood pressure (mean blood pressure: monozygotic twins, 132/83 mmHg; dizygotic twins, 131/82 mmHg) or body mass index between the monozygotic and dizygotic twins. The mean LVM for monozygotic twins was 140.9 g, compared with 140.2 g for dizygotic twins. Heritability estimates suggest that the genetic variance of LVM is 0.59 (95% confidence interval, 0.5-0.67). No common shared environmental effects were identified under this model. CONCLUSION: Our data from the largest set of twin pairs studied to date show that LVM has a sizeable genetic basis that is probably polygenic. This result has important implications for the understanding of normal and abnormal cardiac morphology at the molecular level.

Adult↗
PubMed2005

PI3K-AKT pathway negatively controls EGFR-dependent DNA-binding activity of Stat3 in glioblastoma multiforme cells.

Glioblastoma multiforme (GBM) cells frequently harbor amplification and/or gain-of-function mutation of the EGFR gene leading to the activation of multiple signaling pathways. Blockade of EGFR activation inhibited the activation of both AKT and Stat3 in U87 and D54 GBM cells and induced spontaneous apoptosis, which were associated with reduction in the steady-state level of Mcl-1. Surprisingly, inhibition of PI3 kinase (PI3K) activity, which in turn inhibited AKT activation, significantly increased the DNA-binding activity of Stat3 in U87 and D54 cells. This was not due to an increase in the level of tyrosine-phosphorylated Stat3. Conversely, ectopic expression of constitutively activated AKT significantly decreased the DNA-binding activity of Stat3 in 293T cells. Interestingly, blockade of protein phosphatase 2A activity in GBM or 293T cells by calyculin A, which activated AKT, stabilized the phosphorylation of multiple Ser/Thr residues that were located in the transactivation domain (TAD) of Stat3 and this in turn completely ablated the DNA-binding activity of Stat3. Collectively, these results suggest that both Stat3 and AKT provide survival signals in U87 and D54 cells, and Ser/Thr phosphorylation of Stat3-TAD by the PI3K-AKT pathway negatively controls the DNA-binding function of Stat3.

Apoptosis↗
PubMed2005

Pharmacological treatment of ischemic stroke.

Current pharmacological strategies for acute ischemic stroke largely mirror those employed in acute coronary syndromes. However, important differences in the effectiveness and versatility of the principal agents have emerged between these 2 clinical settings. In general, the level of success achieved with drugs in acute coronary syndromes has not carried over to the same extent when the same drug types are used in stroke. The principal reason is that reperfusion or anticoagulant therapies in the setting of brain infarction run a significant risk of hemorrhagic transformation that has no direct equivalent in myocardial infarction. Consequently, a significant challenge in acute stroke therapeutics is the ability to select patients for drugs where only a narrow therapeutic margin exists and to identify methods that can minimize hemorrhage risk. Other brain-specific vascular factors also pertain in explaining differences in outcome of drugs generally regarded as having a broad cardiovascular remit. The relatively limited efficacy of antiplatelets in stroke might relate to the composition and heterogeneity of the cerebrovascular lesion, while the poor outcome associated with acute anti-hypertensive use is partly due to loss of cerebrovascular autoregulation. Finally, downstream consequences of arterial occlusion within the brain such as excitotoxicity and plasticity are organ specific and, as such, deserve their own pharmacological approaches. In this review, we describe the general mechanism of each drug class used in ischemic stroke and then report on the clinical experience and application for each.

Animals↗
PubMed2005

Human pol II promoter prediction: time series descriptors and machine learning.

Although several in silico promoter prediction methods have been developed to date, they are still limited in predictive performance. The limitations are due to the challenge of selecting appropriate features of promoters that distinguish them from non-promoters and the generalization or predictive ability of the machine-learning algorithms. In this paper we attempt to define a novel approach by using unique descriptors and machine-learning methods for the recognition of eukaryotic polymerase II promoters. In this study, non-linear time series descriptors along with non-linear machine-learning algorithms, such as support vector machine (SVM), are used to discriminate between promoter and non-promoter regions. The basic idea here is to use descriptors that do not depend on the primary DNA sequence and provide a clear distinction between promoter and non-promoter regions. The classification model built on a set of 1000 promoter and 1500 non-promoter sequences, showed a 10-fold cross-validation accuracy of 87% and an independent test set had an accuracy >85% in both promoter and non-promoter identification. This approach correctly identified all 20 experimentally verified promoters of human chromosome 22. The high sensitivity and selectivity indicates that n-mer frequencies along with non-linear time series descriptors, such as Lyapunov component stability and Tsallis entropy, and supervised machine-learning methods, such as SVMs, can be useful in the identification of pol II promoters.

Algorithms↗
PubMed2005

The future: rehabilitation, gene therapy, optimization of healing.

Tendon disorders can be debilitating for patients and are difficult to manage. Current management strategies offer symptomatic relief, but may not result in definitive disease resolution. Despite remodeling, the biochemical and mechanical properties of healed tendon tissue never match those of intact tendon. This article outlines the stages of tendon healing, and reviews the possible strategies for optimizing tendon healing and repair, such as cytokine therapy, gene therapy, and tissue engineering.

Animals↗
PubMed2005

Serine phosphorylation of Stat6 negatively controls its DNA-binding function.

In response to interleukin-4 (IL-4) or IL-13 stimulation of cells, Stat6 becomes phosphorylated on Tyr(641) and forms homodimers that migrate to the nucleus, bind to cognate DNA elements, and drive the transcription of target genes. Here, we show that phosphorylation of multiple serine residues ablates its DNA-binding activity in IL-4 stimulated cells. The phosphorylation sites are mapped to the transactivation domain (TAD) of Stat6. Importantly, serine phosphorylation of Stat6 TAD does not affect the phosphorylation of Tyr(641), nor does it affect the dimer formation or the ability of translocating to the nucleus in IL-4-stimulated cells. Collectively, these data suggest that phosphorylation of multiple serine residues in the TAD possibly induces conformational changes in Stat6 dimers that cause the loss of DNA binding and, thus, negatively control the expression of IL-4-responsive genes.

Cell Line↗
PubMed2005

The unique role of diamorphine in British medical practice: a survey of general practitioners and hospital doctors.

AIMS: Diamorphine (heroin) is one of the longest established medications with a 130-year history. In British medicine diamorphine is sometimes used as a maintenance treatment for opiate addiction but is also routinely used in clinical practice to treat a number of general medical conditions. These uses are very different but are often confused by observers of the British system. The routine clinical use of diamorphine in medicine is unique to the UK, but this is not well known outside the UK. The present study investigates the use of diamorphine to treat medical conditions by general practitioners and by hospital doctors. METHOD: In a survey of 141 medical practitioners who had prescribed diamorphine for the treatment of a medical condition, data were collected on conditions prescribed for, numbers of patients, dosage, routes of administration, duration of treatment, worries about prescribing diamorphine and observed adverse effects. FINDINGS: Many doctors had prescribed diamorphine to a large number of patients. The four main conditions for which diamorphine had been prescribed in the previous year were myocardial infarction, palliative care, pulmonary oedema, and post-operative pain. More than half of the sample (57%) reported no reservations about prescribing diamorphine. Of the doctors (n = 60, 43%) who expressed worries, this was most often about possible problems of respiratory depression or respiratory arrest. Respiratory arrest/failure was also the most frequent observed adverse effect. Relatively few doctors reported worries about addiction. CONCLUSIONS: Although diamorphine was widely used and most doctors regarded it as a useful medication, there remains insufficient research information about current clinical practice. At a time when diamorphine may be coming under increased scrutiny, more detailed information is required of its uses and applications.

Analgesics, Opioid↗
PubMed2005

Tendon injury and tendinopathy: healing and repair.

Tendon disorders are frequent and are responsible for substantial morbidity both in sports and in the workplace. Tendinopathy, as opposed to tendinitis or tendinosis, is the best generic descriptive term for the clinical conditions in and around tendons arising from overuse. Tendinopathy is a difficult problem requiring lengthy management, and patients often respond poorly to treatment. Preexisting degeneration has been implicated as a risk factor for acute tendon rupture. Several physical modalities have been developed to treat tendinopathy. There is limited and mixed high-level evidence to support the, albeit common, clinical use of these modalities. Further research and scientific evaluation are required before biological solutions become realistic options.

Genetic Therapy↗
PubMed2005

Immunoprophylactic effects of the anti-leprosy Mw vaccine in household contacts of leprosy patients: clinical field trials with a follow up of 8-10 years.

We report here a large scale, double blind immunoprophylactic trial of a leprosy vaccine based on Mycobacterium w (Mw) in an endemic area of Kanpur Dehat, Uttar Pradesh, India. A population of 420,823 spread over 272 villages was screened where 1226 multibacillary (MB) and 3757 paucibacillary (PB) cases of leprosy were detected. A total of 29,420 household contacts (HHC) of these patients were screened for evidence of active or inactive leprosy. After exclusion of 1622 contacts for any of the different exclusion criteria, a total of 24,060 HHC could be vaccinated for vaccine or placebo under coding (20,194 administered two doses and 3866 received single dose). The vaccine consisted of 1 x 10(9) heat killed bacilli (Mw) in normal saline for the first dose and half of the first dose, i.e. 5 x 10(8) bacilli for the second dose, given 6 months after the first dose. The placebo consisted of 1/8th dose of the normal dose of tetanous toxoid. Both placebo and vaccine were given under double-blind coding, The contacts were followed up during three surveys at 3, 6 and 9 years after the initial vaccination, for detection of post-vaccination cases (PVCs) and observing any side-effects caused as a result of vaccination. The codes were opened on 24th January 2001, after the analysis of the data following completion of the third and final follow-up survey. When only contacts received the vaccine, Mw vaccine showed a protective efficacy (PE) of 68-6% at the end of first, 59% at the end of the second and 39.3% at the end of the third follow-up survey. When both patients and contacts received the vaccine, the protective efficacy observed was 68%, 60% and 28% at the end of the first, second and third surveys, respectively. When patients, and not the contacts, received the vaccine, a PE of 42.9% in the first, 31% in the second and 3% in the third survey was shown. These results suggest that the vaccination of the contacts is more valuable in achieving the objective of immunoprophylaxis than that of patients, and the vaccine effects are noted maximally in children (as compared to adolescents and adults) who constitute the most responsive group The effect of vaccine is sustained for a period of about 7-8 years, following which there is a need to provide a booster vaccination for the sustained protection.

Adolescent↗
PubMed2004

Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls.

Ischemic stroke is thought to have a polygenic basis, but identification of stroke susceptibility genes and quantification of associated risks have been hampered by conflicting results from underpowered case-control studies. We performed a meta-analysis of all candidate gene association studies in ischemic stroke. Electronic databases were searched up until January 2003 for all case-control and nested case-control studies in English-language journals relating to the investigation of any candidate gene for ischemic stroke in humans. Cases were required to have neuroimaging evidence of the diagnosis. To maintain genetic homogeneity, only studies in white adults were included. Studies that evaluated quantitative traits or intermediate phenotypes were excluded. Data from 120 case-control studies were included. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) from random- and fixed-effects models were calculated. Of 32 genes studied, 15 polymorphisms were identified for which at least 3 studies had been conducted. Statistically significant associations with ischemic stroke were identified for factor V Leiden Arg506Gln (OR, 1.33; 95% CI, 1.12-1.58), methylenetetrahydrofolate reductase C677T (OR, 1.24; 95% CI, 1.08-1.42), prothrombin G20210A (OR, 1.44; 95% CI, 1.11-1.86), and angiotensin-converting enzyme insertion/deletion (OR, 1.21; 95% CI, 1.08-1.35). These were also the most investigated candidate genes, including 4588, 3387, 3028, and 2990 cases, respectively. No statistically significant association with ischemic stroke was detected for the 3 next most investigated genes (factor XIII, apolipoprotein E, and human platelet antigen type 1). There is a genetic component to common stroke. No single gene with major effect was identified; rather, common variants in several genes, each exerting a modest effect, contribute to the risk of stroke. These findings have important implications for the design of future genetic studies and for predictive genetic testing for stroke and other multifactorial diseases.

Brain Ischemia↗
PubMed2004

Bulk femoral-head autografting in uncemented total hip arthroplasty for acetabular dysplasia: results at 8 to 11 years follow-up.

Acetabular dysplasia causes difficulty in achieving adequate coverage of the acetabular component during total hip arthroplasty (THA). Bulk femoral-head autografting is one technique that has been used to achieve better coverage of the acetabular component. Long-term follow-up studies have shown a significant failure rate when this technique has been used in conjunction with a cemented acetabular component; however, with uncemented components, early results have been encouraging. In our study, 15 patients with acetabular dysplasia underwent uncemented THA, during which bulk femoral-head autografts were used. At an average follow-up of 10 years, no cases required revision, and radiologically, the bone graft had united. Our results support the use of bulk femoral-head autografting in patients with acetabular dysplasia requiring hip arthroplasty.

Acetabulum↗
PubMed2004

A comparative study of small incision trabeculectomy avoiding Tenon's capsule vis-à-vis trabeculectomy with Mitomycin-C.

PURPOSE: To compare the results of small incision trabeculectomy avoiding Tenon's capsule (SIT) vis-à-vis intraoperative use of Mitomycin-C (MMC) in primary chronic angle closure glaucoma. METHODS: A controlled prospective study was conducted on 60 consecutive primary chronic angle closure glaucoma patients requiring glaucoma filtration surgery. Patients were divided into two groups, Group I (n = 30): those undergoing SIT and Group II (n = 30): those undergoing trabeculectomy with MMC. Patients were followed up serially for 24 months and their intraocular pressure (IOP) was monitored. Success was defined as IOP < or = 22 mm Hg with no additional anti-glaucoma medication or laser/surgical intervention. Success was also defined as a 30% reduction from the initial IOP at which optic disc cupping and/or visual field changes occurred. RESULTS: The final mean IOP with SIT was 16.80 +/- 4.20 mm Hg as against 17.84 +/- 3.80 mm Hg with trabeculectomy with MMC. Final success rate of 93.3% was obtained with SIT versus 90% with trabeculectomy with MMC. No major complications were seen with either procedure. CONCLUSION: Small incision trabeculectomy safely and effectively reduces the IOP in over 90% cases. The advantages of this procedure over trabeculectomy with MMC are its low cost, use of a small (2.5 mm) limbal incision which obviates the dissection of Tenon's capsule and absence of any major complication.

Adult↗
PubMed2003

Human CRP gene polymorphism influences CRP levels: implications for the prediction and pathogenesis of coronary heart disease.

OBJECTIVE: C-reactive protein (CRP) concentrations are predictive of cardiovascular disease, and levels are heritable, in part. We identified novel polymorphisms in the CRP gene and assessed their influence on CRP level. METHODS AND RESULTS: CRP was measured in 250 male army recruits before and after strenuous exercise and perioperatively in 193 coronary artery bypass graft (CABG) patients. Two novel polymorphisms were identified in the CRP gene, -717G>A in the promoter and +1444C>T in the 3'UTR. Among army recruits, CRP was higher in +1444TT homozygotes than +1444 C-allele carriers at baseline (1.04+/-0.38 versus 0.55+/-0.06, P=0.014) and at all time points after exercise (2.35+/-0.68 versus 1.07+/-0.12, 2.11+/-0.53 versus 0.88+/-0.09, and 1.77+/-0.44 versus 0.71+/-0.09, P=0.034, P=0.007, and P=0.013, at 2, 48, and 96 hours after exercise, respectively). In the CABG patients, mean CRP (mg/L) rose from 1.97+/-0.36 at baseline to 167.2+/-5.0 72 hours postoperatively. Genotype did not influence CRP at baseline; however, peak post-CABG CRP levels were higher in +1444TT homozygotes compared with +1444C-allele carriers (198+/-17 versus 164+/-5, P=0.03). CONCLUSIONS: The CRP gene +1444C>T variant influences basal and stimulated CRP level. These findings have implications both for the prediction and pathogenesis of coronary heart disease.

Acute-Phase Reaction↗