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Biomedical subjects

A Pathak

Publications and source records attributed to A Pathak.

At least 19 recordsLinked to original sources
PubMed2007

NMR and cDNA array analysis prior to heart failure reveals an increase of unsaturated lipids, a glutamine/glutamate ratio decrease and a specific transcriptome adaptation in obese rat heart.

Obesity is a risk factor for heart failure through a set of hemodynamic and hormonal adaptations, but its contribution at the molecular level is not clearly known. Therefore, we investigated the kinetic cardiac transcriptome and metabolome in the Spontaneous Hypertensive Heart Failure (SHHF) rat. The SHHF rat is devoid of leptin signaling when homozygous for a mutation of the leptin receptor (ObR) gene. The ObR-/- SHHF rat is obese at 4 months of age and prone to heart failure after 14 months whereas its lean counterpart ObR-/+ is prone to heart failure after 16 months. We used a set of rat pangenomic high-density macroarrays to monitor left ventricle cardiac transcriptome regulation in 4- and 10-month-old, lean and obese animals. Comparative analysis of left ventricle of 4- and 10-month-old lean rat revealed 222 differentially expressed genes while 4- and 10-month-old obese rats showed 293 differentially expressed genes. (1)H NMR analysis of the metabolome of left ventricular extracts displayed a global decrease of metabolites, except for taurine, and lipid concentration. This may be attributed to gene expression regulation and likely increased extracellular mass. The glutamine to glutamate ratio was significantly lower in the obese group. The relative unsaturation of lipids increased in the obese heart; in particular, omega-3 lipid concentration was higher in the 10-month-old obese heart. Overall, several specific kinetic molecular patterns act as a prelude to heart failure in the leptin signaling deficient SHHF obese rat.

Adaptation, Biological↗
PubMed2006

A Monte-Carlo code for the detailed simulation of electron and light-ion tracks in condensed matter.

In an effort to understand the basic mechanism of the action of charged particles in solid radiation dosimeters, we extend our Monte-Carlo code (MC4) to condensed media (liquids/solids) and present new track-structure calculations for electrons and protons. Modeling the energy dissipation process is based on a model dielectric function, which accounts in a semi-empirical and self-consistent way for condensed-phase effects which are computationally intractable. Importantly, these effects mostly influence track-structure characteristics at the nanometer scale, which is the focus of radiation action models. Since the event-by-event scheme for electron transport is impractical above several kilo-electron volts, a condensed-history random-walk scheme has been implemented to transport the energetic delta rays produced by energetic ions. Based on the above developments, new track-structure calculations are presented for two representative dosimetric materials, namely, liquid water and silicon. Results include radial dose distributions in cylindrical and spherical geometries, as well as, clustering distributions, which, among other things, are important in predicting irreparable damage in biological systems and prompt electric-fields in microelectronics.

Algorithms↗
PubMed2006

Valvular heart disease in a patient taking benfluorex.

The authors describe a case of valvular heart disease in a 48-year-old woman receiving benfluorex (150 mg t.i.d. for 8 years) and leading to surgical mitral valve replacement. Examination showed severe dyspnea with severe mitral regurgitation associated with tricuspid regurgitation. No other common disease known to affect mitral valves nor intake of other drugs (ergot derivatives or appetite suppressant drugs) was found. The paper discusses the imputability of benfluorex, a drug used as an adjuvant in hypercholesterolemia, structurally related to amphetamines.

Female↗
PubMed2006

Thrombin generation in vascular tissue.

BACKGROUND: Classically, it is thought that the vast majority of thrombin is generated on the surface of platelets, however, thrombotic events occur in patients despite treatment with potent antiplatelet agents. METHODS AND RESULTS: In freshly harvested left internal mammary artery (IMA) sections, addition of CaCl2 and platelet-poor plasma (PPP) were sufficient to stimulate a profound burst of thrombin and this effect was inhibited by antitissue factor antibodies. Ultracentrifugation of PPP to remove platelet microparticles had no effect on thrombin generation. Both the extrinsic and factor VIII-dependent pathways were necessary for IMA-supported thrombin generation as PPP derived from individuals deficient in factors V, VII, VIII or X did not support thrombin production. Small amounts of thrombin were generated utilizing factor IX (FIX)-deficient plasma, however, thrombin was not generated by aorta from FIX-deficient mice when FIX-deficient plasma was used. The addition of non-lipidated tissue factor (0.6 pM) and CaCl2 to actively proliferating cultured human aortic smooth muscle cells (SMC) resulted in a pronounced burst of thrombin generation occurring between 3 and 15 min after treatment. In the absence of tissue factor, thrombin was generated but at a slower rate and with a peak value 26% of that observed in the presence of tissue factor. CONCLUSION: Significant thrombin generation can occur on vascular tissue in the absence of platelets or platelet microparticles and on the surface of non-apoptotic SMC.

Aorta↗
PubMed2006

Novel conjugate of moxifloxacin and carboxymethylated glucan with enhanced activity against Mycobacterium tuberculosis.

Mycobacterium tuberculosis is an intracellular pathogen that persists within macrophages of the human host. One approach to improving the treatment of tuberculosis (TB) is the targeted delivery of antibiotics to macrophages using ligands to macrophage receptors. The moxifloxacin-conjugated dansylated carboxymethylglucan (M-DCMG) conjugate was prepared by chemically linking dansylcadaverine (D) and moxifloxacin (M) to carboxymethylglucan (CMG), a known ligand of macrophage scavenger receptors. The targeted delivery to macrophages and the antituberculosis activity of the conjugate M-DCMG were studied in vitro and in vivo. Using fluorescence microscopy, fluorimetry, and the J774 macrophage cell line, M-DCMG was shown to accumulate in macrophages through scavenger receptors in a dose-dependent (1 to 50 microg/ml) manner. After intravenous administration of M-DCMG into C57BL/6 mice, the fluorescent conjugate was concentrated in the macrophages of the lungs and spleen. Analyses of the pharmacokinetics of the conjugate demonstrated that M-DCMG was more rapidly accumulated and more persistent in tissues than free moxifloxacin. Importantly, therapeutic studies of mycobacterial growth in C57BL/6 mice showed that the M-DCMG conjugate was significantly more potent than free moxifloxacin.

Animals↗
PubMed2005

"Medicamentation" of society, non-diseases and non-medications: a point of view from social pharmacology.

This review presents the definition and goals of "social pharmacology", a new branch of clinical pharmacology, investigating relationships between drugs and society through the example of "medicamentation", defined as the use of drugs for social problems previously not requiring drug utilisation (ageing, smoking cessation, vigilance troubles, sleep synchronisation, loss of libido, etc.). The involvement of the different "actors" from our society (patients, physicians, pharmaceutical industries, clinical pharmacologists, regulatory agencies, etc.) in this phenomenon is also discussed.

Aging↗
PubMed2005

Insulin downregulates M(2)-muscarinic receptors in adult rat atrial cardiomyocytes: a link between obesity and cardiovascular complications.

OBJECTIVE: To determine whether decreased cardiac parasympathetic activity observed in obesity is due to insulin-induced alterations in cardiac M(2)-muscarinic receptors and/or adenylyl cyclase activity. DESIGN AND METHODS: After incubation with increasing concentrations of insulin, adult rat atrial cardiomyocytes were assayed for M(2)-muscarinic receptor binding density and affinity, and for M(2)R mRNA expression using RT-PCR analysis. Forskolin-stimulated adenylyl cyclase activity and its inhibition by carbachol were also assayed, as was endothelial nitric oxide synthase mRNA expression. The effects of insulin on M(2)-muscarinic receptor density and mRNA expression levels were analyzed using the insulin signaling inhibitors rapamycin, wortmanin and PD 098059. RESULTS: Insulin induces a concentration- and time-dependent decrease in expression of the M(2)R mRNA, and in [(3)H]N-methylscopolamine binding by the receptor. These effects on the M(2)R mRNA levels and on [(3)H]N-methylscopolamine binding were prevented by PD 98059, but not by wortmanin or rapamycin. Basal and forskolin-induced cAMP production did not differ, but the inhibition of forskolin-simulated enzyme activity by carbachol was blunted by insulin. No change in the mRNA levels for endothelial nitric oxide synthase was observed. CONCLUSION: In rat atrial cardiomyocytes, insulin markedly alters both the M(2)-muscarinic receptor density, and its mRNA expression through transcriptional regulation and adenylyl cyclase activity. These data suggest that the obesity-associated decrease in cardiac parasympathetic tone may be related to hyperinsulinemia, which could directly contribute to cardiovascular morbidity in obese patients.

Adenylyl Cyclases↗
PubMed2005

Pituitary apoplexy: an unusual cause of frontal lobe syndrome.

Pituitary apoplexy presenting as frontal lobe syndrome is rare. Interestingly, in our patient the frontal lobe infarct was as a result of intense anterior cerebral artery spasm consequent to nonaneurysmal subarachnoid haemorrhage. The mechanisms of cerebral infarct associated with pituitary apoplexy are discussed.

Adenoma↗
PubMed2005

Change in tissue thromboplastin content of brain following trauma.

BACKGROUND: Tissue thromboplastin (TTP) is an integral membrane protein contributing to coagulopathy after trauma of brain, which is a rich source of TTP. AIMS: A study was undertaken to establish the TTP content of various areas of normal brain and estimate the changes in TTP activity of brain in response to varying degrees of trauma. MATERIALS AND METHODS: Samples from different areas of brain of ten cadavers were used as controls and they were compared with contused brain tissue obtained after surgery in 25 head injury (HI) patients of varying severity. RESULTS: In the study group, the TTP activity of the frontal, parietal, and temporal lobes after HI was significantly raised in contrast to that of the control group. The TTP activity was also significantly higher in the severe HI patients than those having moderate HI. The mode of injury and the time lapse after HI had no significant bearing on the TTP activity. Subjects above 40 years of age demonstrated a higher mean TTP activity after HI, though it was not statistically significant. CONCLUSION: The study provides quantitative data on TTP activity of normal brain and highlights the role of TTP in coagulopathy following HI through its increased activity after HI, more so in the severe HI group.

Adolescent↗
PubMed2005

[Obesity and cardiac failure].

Obesity alone is the cause of 11% of cases of cardiac failure in men and 14% of cases in women in the United States. The frequency of obesity continues to rise in our country, 41% of our compatriots being obese or overweight. It is expected that obesity will become an important cause of cardiac failure in the coming years. The Framingham study showed that, after correction for other risk factors, for every point increase in body mass index, the increase in risk of developing cardiac failure was 5% in men and 7% in women. There are three physiopathological mechanisms to explain the adverse effects of obesity on left ventricular function: an increase in ventricular preload secondary to increased plasma volume induced by the high fatty mass; an increase in left ventricular afterload due to the common association of hypertension generated by activation of the sympathetic nervous system by hyperinsulinism; and systolic and diastolic dysfunction due to changes in the myocardial genome and coronary artery disease induced by risk factors of atherosclerosis aggravated by obesity. The adipocyte also secretes a number of hormones which act directly or indirectly on the myocardium: angiotensin II, leptin, resistin, adrenomedulin, cytokines. These haemodynamic and hormonal changes profoundly modify the genetic expression of the myocardium in obesity, favourising hypertrophy of the myocyte and the development of interstitial fibrosis. Whether it be eccentric in the absence of hypertension or concentric when hypertension is associated with obesity, left ventricular hypertrophy, although normalising left ventricular wall stress, has adverse consequences causing abnormal relaxation and decreased left ventricular compliance. Therefore, in obese patients, two forms of cardiac failure may be observed. The more common is due to diastolic dysfunction, obesity being one of the principal causes of cardiac failure with preserved systolic function. Cardiac failure due to systolic dysfunction is less common and may be observed in cases with inappropriate left ventricular hypertrophy which does not normalise abnormal left ventricular wall stress leading to cardiomyopathy, and in cases with associated coronary artery disease. Whatever the underlying mechanism, the diagnosis of cardiac failure is made more difficult by obesity. From the prognostic point of view, in the global population of patients with cardiac failure, obesity improves survival because it counteracts the adverse effect of cachexia; however, obesity increases the risk of sudden death. In fact, obesity is associated with dynamic change in QT interval. In cases of cardiac failure secondary to obesity-related cardiomyopathy, loss of weight leads to an improved functional status and a reduction of left ventricular remodelling and an increase of the ejection fraction.

Cardiomyopathy, Dilated↗
PubMed2005

Influence of zinc on the status of hepatic trace elements and biokinetics of 65Zn in ethanol treated rats.

Whole body counting studies of 65Zn indicated that the Tb1 (the faster component) was significantly decreased while the slower component (Tb2) was increased significantly following ethanol treatment. Interestingly, following zinc treatment to ethanol treated rats, slower component (Tb2) of 65Zn came back to within normal limits while the faster component (Tb1) got significantly elevated in comparison to ethanol treatment. Percent uptake values of 65Zn were found to be increased in liver, intestine, muscle, brain and kidney, and decreased in bone under alcoholic conditions. Interestingly, the uptake values of 65Zn in all the organs except muscle were reverted back to within normal limits upon zinc supplementation to these ethanol intoxicated animals. A significant decrease in zinc contents was noticed in ethanol treated rats, which, however, were raised to normal levels upon zinc supplementation: Copper levels, on the other hand, were significantly enhanced in both ethanol fed and combined ethanol + zinc treated rats. Calcium levels were significantly decreased in both ethanol and zinc treated rats, which however were further reduced upon zinc supplementation to ethanol fed rats. However, no significant change was observed in the concentrations of sodium and potassium in any of the treatment groups. In conclusion, zinc appears to play a protective role by normalizing the turnover of 65Zn in whole body as well as in its uptake in different organs under alcoholic conditions.

Animals↗
PubMed2005

[Cardiac cellular therapy: from cells to the first clinical uses].

Despite the improvement in revascularisation techniques, coronary artery disease remains the principal aetiology of cardiac failure in developed countries. The therapeutic management of cardiac failure has been improved over recent years, yet cardiac failure is still associated with significant morbidity and mortality. As cardiac transplantation lacks donors, techniques that allow myocardial regeneration represent an attractive alternative. To date, several types of cells are under study and are suitable for implantation into infarcted myocardium (myoblasts, medullary stem cells...). Following good preclinical study results, the first human cell therapy trials, using the intramyocardial route, have begun, in the course of aorto-coronary bypass surgery in patients with chronic ischaemic cardiopathy and little altered left ventricular function, and then in those with ventricular dysfunction. Different modes of administration of these cell therapy products are under study and could be envisaged in clinical situations such as just after infarction in order to improve ventricular remodelling with an intracoronary injection technique. As for every new treatment, there are numerous problems to resolve, from understanding the relevant mechanisms of cellular transplantation, to the secondary effects that it could entail. Nevertheless, cardiac cellular transplantation is expanding rapidly and with the evolution of techniques it allows a glimpse of a new field of treatment for cardiac failure.

Cell Transplantation↗
PubMed2004

Idiopathic granulomatous hypophysitis presenting as non-functioning pituitary adenoma: description of six cases and review of literature.

The aim of this study was to analyse the complete profile and outcome of patients with idiopathic giant cell granulomatous hypophysitis. Six consecutive cases of idiopathic giant cell granulomatous hypophysitis were studied from 1993 to 2002. Headache and visual disturbances were the most frequent presenting symptoms. All patients had hypogonadism, four had hypoadrenalism and three were hypothyroid at presentation. None of them had diabetes insipidus preoperatively. A sellar mass with suprasellar extension on MRI with loss of the posterior pituitary 'bright spot' was a consistent observation in all patients. All patients underwent surgical excision of the mass lesion with histopathological confirmation of giant cell granulomatous hypophysitis. Other systemic granulomatous diseases were excluded by appropriate investigations. Postoperatively, all patients became hypothyroid and hypogonad, five patients had adrenal insufficiency, while two developed permanent diabetes insipidus. The clinical presentation of giant cell granulomatous hypophysitis is that of an expanding sellar mass lesion with a varying degree of endocrine dysfunction. Preoperative diagnosis of 'hypophysitis' is usually difficult; however, stalk thickening and loss of posterior pituitary 'bright spot' on MR imaging are clues to the diagnosis.

Adenoma↗
PubMed2004

Nonsteroidal anti-inflammatory drug-induced liver injury: a case-control study in primary care.

Several nonsteroidal anti-inflammatory drugs (NSAIDs) have been withdrawn from the market because of hepatic adverse drug reactions (ADRs). Moreover, some cases of liver diseases have been reported in patients taking NSAIDs (arylcarboxylic NSAIDs, piroxicam, sulindac, nimesulide, etc.). Pharmacoepidemiological studies have shown a risk of hepatic ADRs with NSAIDs used in association with other hepatotoxic drugs. In contrast, other studies performed in hospitalized patients did not found any association. The aim of this study was to assess the hepatic risk associated with the use of NSAID in the setting of primary care. The study design was a case-control study where cases and controls were all recruited among patients seen in the context of medical community care. Eighty-eight cases and 178 controls were included between January 1998 and December 2000. Cases used more drugs than controls in the 15 days before index day (2.9 +/- 2.2 vs. 1.8 +/- 1.8 different consumed drugs; P < 10(-4)). After adjustment, we found a significant association between liver injury and NSAID exposure in women [odds ratio (OR) = 6.49 (1.67-25.16)] but not in men [OR = 1.06 (0.36-3.12)]. A total of 22 cases were exposed to NSAIDs. Of them, seven patients were exposed to salicylates, five to diclofenac, four to ibuprofen, four to ketoprofen, two to niflumic acid, one to flurbiprofen and one to meloxicam (two patients were simultaneously exposed to two different NSAIDs: salicylate + niflumic acid and salicylate + diclofenac). These patients suffered from hepatocellular (53.3%), cholestatic (20%) or mixed (26.7%) injury. In 18 cases, liver enzymes returned to normal values after discontinuation of drug. No case had a fatal outcome. This study shows the existence of a significant association between liver disturbances and NSAID use in women.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

Role of zinc on lipid peroxidation and antioxidative enzymes in intestines of ethanol-fed rats.

This study was undertaken to investigate the effects of zinc on lipid peroxidation and various antioxidative enzymes in the intestines of male Wistar rats fed on ethanol. It was observed that NADPH-dependent lipid peroxidation (LP) was significantly increased upon ethanol treatment for 4 and 8 wk. The concentration of glutathione as well as the activities of catalase, superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR) were also found to be significantly increased upon ethanol feeding at all of the treatment intervals. The glutathione levels were found to be further elevated upon combined zinc and ethanol treatments. Interestingly, the administration of zinc to ethanol-fed rats was able to bring down the elevated levels of LP, catalase, SOD, and GPx, thus indicating the antiperoxidative potential of zinc under such conditions.

Administration, Oral↗