Biomedical subjects
A Verma
Publications and source records attributed to A Verma.
Poly(ADP-ribosyl)ation basally activated by DNA strand breaks reflects glutamate-nitric oxide neurotransmission.
Poly(ADP-ribose) polymerase (PARP) transfers ADP ribose groups from NAD(+) to nuclear proteins after activation by DNA strand breaks. PARP overactivation by massive DNA damage causes cell death via NAD(+) and ATP depletion. Heretofore, PARP has been thought to be inactive under basal physiologic conditions. We now report high basal levels of PARP activity and DNA strand breaks in discrete neuronal populations of the brain, in ventricular ependymal and subependymal cells and in peripheral tissues. In some peripheral tissues, such as skeletal muscle, spleen, heart, and kidney, PARP activity is reduced only partially in mice with PARP-1 gene deletion (PARP-1(-/-)), implicating activity of alternative forms of PARP. Glutamate neurotransmission involving N-methyl-d-aspartate (NMDA) receptors and neuronal nitric oxide synthase (nNOS) activity in part mediates neuronal DNA strand breaks and PARP activity, which are diminished by NMDA antagonists and NOS inhibitors and also diminished in mice with targeted deletion of nNOS gene (nNOS(-/-)). An increase in NAD(+) levels after treatment with NMDA antagonists or NOS inhibitors, as well as in nNOS(-/-) mice, indicates that basal glutamate-PARP activity regulates neuronal energy dynamics.
Interleukin 10-induced thrombocytopenia in normal healthy adult volunteers: evidence for decreased platelet production.
Recombinant human interleukin 10 (rhuIL-10) inhibits the production of proinflammatory cytokines and has shown promise in the treatment of inflammatory bowel disease. Clinical trials have been accompanied by a reversible decline in platelet counts. We conducted a randomized, double-blinded, placebo-controlled, parallel group trial in 12 healthy volunteers to investigate the aetiology of rhuIL-10-induced thrombocytopenia. Eight volunteers received 8 microg/kg/d of rhuIL-10 subcutaneously, while four subjects received a placebo alone for 10 d. A reversible decline in the platelet counts from a mean of 275 x 10(9)/l to 164 x 10(9)/l was observed in the IL-10-treated cohort (P = 0.012). A fall in the haemoglobin mean levels was also observed in the IL-10-treated cohort from 13.7 to 11.7 g/dl (P = 0.011). No significant change was observed in the bone marrow cellularity or myeloid/erythroid ratio or in the number of megakaryocytes per high-powered field (HPF). A fall was observed in the number of megakaryocyte colony-forming units (CFU-MKs) after the administration of IL-10 compared with those receiving the placebo (P = 0.068). No difference in the change in granulocyte-macrophage CFUs (CFU-GMs), mixed lineage CFUs (CFU-GEMMs) or erythroid burst-forming units (BFU-Es) was observed when comparing the IL-10- vs. placebo-treated groups (P > 0.465). Serum cytokine levels of thrombopoietin (TPO). IL-6 and granulocyte-macrophage colony stimulating factor (GM-CSF) were not decreased following IL-10 administration. In fact, both TPO and GM-CSF appeared to be slightly increased in the serum. All subjects underwent In111-labelled platelet survival studies with liver/spleen scans to assess splenic sequestration prior to and then on day 7 of treatment. A significant reduction in splenic sequestration of platelets (P =0.012) was observed in the IL-10-treated group, but not in the placebo-treated subjects.
Alzheimer's: no pain or no complain?
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Opportunities for neuroprotection in traumatic brain injury.
Traumatic injury of the brain in man is normally followed by little or no recovery of function by the lesioned tissue. Neuroprotective strategies employed in the acute period after traumatic CNS injury attempt to use pharmacological tools to reduce the progressive secondary injury processes that follow after the initial lesion occurs to limit overall tissue damage. Results from experimental animal studies using a variety of drugs that modulate neurotransmitter function, scavenge free radicals, or interfere with cell death cascades point toward many new opportunities for pharmacological intervention in the acute and subacute period after traumatic brain injury.
Mycobacterium tuberculosis infection in pediatric liver transplant recipients.
OBJECTIVES: To study the incidence, clinical presentation, management, complications and outcome of tuberculosis in pediatric liver transplant recipients. METHODS: A retrospective review of the medical records of children who underwent liver transplantation between 1991 and 1998. RESULTS: Mycobacterium tuberculosis infection occurred in 6 of 254 (2.4%) children undergoing liver transplantation between 1991 and 1998. Cough, pyrexia and poor appetite were common presentations; one-half had normal chest radiographs. The median time to confirmation of diagnosis was 8 months (range, 1 to 17 months). Tests contributing to diagnosis included: Ziehl-Neelsen (ZN) stain (2 patients), M. tuberculosis polymerase chain reaction (1 patient), Mantoux test (1 patient) and histopathology (4 patients). Family health screening was productive for 4 patients. Duration of treatment varied from 9 to 18 months. Isoniazid-induced hepatitis was observed in 2 patients but resolved with dose reduction. Two patients died while receiving treatment, one of Klebsiella spp. septicemia and the other of pulmonary hemorrhage. CONCLUSIONS: Tuberculosis after liver transplantation has a significant morbidity and mortality. Pretransplantation a personal and family history of tuberculosis must be sought, and screening of patients and their families should be considered. Standard regimens incorporating isoniazid and rifampin are effective, but regular monitoring of liver function is essential to detect drug-induced hepatotoxicity.
Infection of human endothelial cells with Bartonella bacilliformis is dependent on Rho and results in activation of Rho.
Bartonella bacilliformis was continuously internalized into human endothelial cells beginning shortly after addition of the bacteria and continuing for at least 24 h after infection in vitro, with a major increase in uptake occurring between 16 and 24 h. Preincubation of endothelial cells with C3 exoenzyme, which inactivated intracellular Rho-GTPase, blocked internalization of the bacteria. Addition of C3 exoenzyme at any time after addition of the bacteria blocked further internalization of bacteria, including the major uptake of bacteria internalized at 16 to 24 h. Rho, a key signaling protein in pathways involving actin organization, was directly shown to be activated in endothelial cells undergoing infection with B. bacilliformis, with maximal activation and translocation to the plasma membrane at 12 to 16 h. At late times of infection, most of the bacteria were found in a perinuclear location. Staining of the Golgi complex with specific markers, anti-human Golgin-97, anti-KDEL receptor, and BODIPY-TR ceramide, showed colocalization of bacteria in the Golgi complex region. Disruption of the Golgi complex with brefeldin A scattered the bacteria from this perinuclear location and resulted in inhibition of internalization of the bacteria in endothelial cells.
Myocardial postischemic injury is reduced by polyADPripose polymerase-1 gene disruption.
BACKGROUND: PolyADPribose polymerase (PARP) is activated by DNA strand breaks to catalyze the addition of ADPribose groups to nuclear proteins, especially PARP-1. Excessive polyADPribosylation leads to cell death through depletion of NAD+ and ATP. MATERIALS AND METHODS: In vivo PARP activation in heart tissue slices was assayed through conversion of [33P]NAD+ into polyADPribose (PAR) following ischemia-reperfusion (I/R) and also monitored by immunohistochemical staining for PAR. Cardiac contractility, nitric oxide (NO), reactive oxygen species (ROS), NAD+ and ATP levels were examined in wild type (WT) and in PARP-1 gene-deleted (PARP-1(-/-)) isolated, perfused mouse hearts. Myocardial infarct size was assessed following coronary artery occlusion in rats treated with PARP inhibitors. RESULTS: Ischemia-reperfusion (I/R) augmented formation of nitric oxide, oxygen free radicals and PARP activity. I/R induced decreases in cardiac contractility and NAD+ levels were attenuated in PARP-1(-/-) mouse hearts. PARP inhibitors reduced myocardial infarct size in rats. Residual polyADPribosylation in PARP-1(-/-) hearts may reflect alternative forms of PARP. CONCLUSIONS: PolyADPribosylation from PARP-1 and other sources of enzymatic PAR synthesis is associated with cardiac damage following myocardial ischemia. PARP inhibitors may have therapeutic utility in myocardial disease.
Nasopharyngeal cyst of branchiogenic origin: report of a case and review of the literature.
To date, only 22 cases of nasopharyngeal cyst of branchiogenic origin have been reported in the literature. In this article, we report a new case in a 35-year-old woman. We also present a review of the literature and a discussion of the sites of origin, histopathology, and treatment modalities.
Status of vitamin E and reduced glutathione in semen of oligozoospermic and azoospermic patients.
AIM: To investigate the status of seminal plasma reduced glutathione (GSH) and vitamin E in three different conditions of spermatogenesis: azoospermia, oligozoospermia and normospermia. METHODS: Reduced glutathione was measured in the seminal plasma by the method of Moron et al (1979), and vitamin E estimation was performed by the method of Taylor et al (1976). RESULTS: Vitamin E levels in seminal plasma of oligospermic and azoospermic samples were significantly decreased to 65.54% and 66.04% respectively as compared to the normospermic group. Levels of reduced glutathione were also significantly decreased in oligospermic and azoospermic group, and the reduction in azoospermic group (76.73%) was more pronounced than oligozoospermic group (62.07%). CONCLUSION: The decrease in reduced glutathione, an endogenous antioxidant, levels in azoospermic and oligozoospermic conditions may cause disruption in the membrane integrity of spermatozoa as a consequence of increased oxidative stress.
Fulminant neuropathy and lactic acidosis associated with nucleoside analog therapy.
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Poly(ADP-ribose) polymerase-deficient mice are protected from streptozotocin-induced diabetes.
Streptozotocin (STZ) selectively destroys insulin-producing beta islet cells of the pancreas providing a model of type I diabetes. Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme whose overactivation by DNA strand breaks depletes its substrate NAD+ and then ATP, leading to cellular death from energy depletion. We demonstrate DNA damage and a major activation of PARP in pancreatic islets of STZ-treated mice. These mice display a 500% increase in blood glucose and major pancreatic islet damage. In mice with homozygous targeted deletion of PARP (PARP -/-), blood glucose and pancreatic islet structure are normal, indicating virtually total protection from STZ diabetes. Partial protection occurs in PARP +/- animals. Thus, PARP activation may participate in the pathophysiology of type I diabetes, for which PARP inhibitors might afford therapeutic benefit.
Morbidity assessment index for newborns: a composite tool for measuring newborn health.
OBJECTIVE: The objective was to develop, validate, and recommend a scaling model for a discriminative obstetric outcome measure named the Morbidity Assessment Index for Newborns. The purpose of this tool is to allow comparison of obstetric therapeutic strategies on neonatal morbidity, particularly in the mild to moderate morbidity range. STUDY DESIGN: A list of 66 check-mark (yes or no) items of readily available clinical and laboratory data from the early neonatal period was compiled by a panel of obstetric and neonatal experts. These data were collected on 411 neonates born at >/=28 weeks' gestation and representing all grades of morbidity. Detailed psychometric testing included dimensionality testing and item analysis with the item response theory. The scores obtained with this new assessment tool were correlated with newborn and maternal disease conditions or events and with other measures of newborn morbidity. RESULTS: The Morbidity Assessment Index for Newborns is easy to apply in prospective or retrospective studies. Detailed psychometric evaluation resulted in modification of the list to 47 items, each item with a relative scale value according to severity of morbidity. The test was demonstrated to be a reliable and generalizable scaled index that performs optimally for the mild to moderate neonatal morbidity range. CONCLUSION: The Morbidity Assessment Index for Newborns is a validated outcome measurement scale of neonatal morbidity. This new tool may facilitate the conduct of obstetric clinical trials or epidemiologic population-based studies in obstetrics.
Ultrasound guided aspiration of endometrioma--a new therapeutic modality to improve reproductive outcome.
OBJECTIVE: To evaluate the therapeutic efficacy and reproductive outcome following ultrasound guided aspiration (UGA) of endometrioma in infertile patients. METHOD: This is a prospective non-randomized clinical report of UGA in 22 infertile patients with endometrioma. The aspiration of endometriotic cysts was carried out transvaginally in nine and transabdominally in 13 patients. Following aspiration intranasal buserilin was given to eight and danazol to 14 patients. In the case of recurrence a reaspiration was done. Patients were allowed to conceive following medical therapy. Recurrence of endometrioma and conception rate was recorded and correlated with endometrioma size and volume aspirated. RESULT: A total of 47 aspirations were done. There were no procedure related complications. Reaspiration was required in six patients and one was operated (total recurrence 7/22--31.8%). During a mean follow-up of 20+/-8.4 months nine patients (40.9%) conceived and eight have already delivered at term. The recurrence risk and the conception rate was not affected by the cyst size or volume aspirated. CONCLUSION: UGA of endometrioma can be an effective and safe alternative therapeutic procedure in infertile patients with endometrioma to improve their reproductive outcome.
Poly (ADP-ribose) polymerase, nitric oxide and cell death.
Poly (ADP-ribose) polymerase (PARP) is a nuclear enzyme that is activated by DNA strand breaks to participate in DNA repair. Excessive activation of PARP, however, can deplete tissue stores of nicotinamide adenine dinucleotide (NAD), the PARP substrate which, with the resultant depletion of ATP, leads to cell death. In many cases of CNS damage, for example vascular stroke, nitric oxide release is a key stimulus to DNA damage and PARP activation. In conditions as diverse as focal cerebral ischaemia, myocardial infarction and toxin-induced diabetes, PARP inhibitors and PARP gene deletion afford dramatic protection from tissue damage. Accordingly, PARP inhibitors could provide novel therapeutic approaches in a wide range of clinical disorders.
Demonstration and partial characterisation of phospholipid methyltransferase activity in bile canalicular membrane from hamster liver.
BACKGROUND/AIMS: Methylation of phosphatidylethanolamine to phosphatidylcholine predominantly takes place in mitochondrial-associated membrane and the endoplasmic reticulum of the liver. The transport of the phospholipids from endoplasmic reticulum to the bile canalicular membrane is via vesicular and protein transporters. In the bile canalicular membrane a flippase enzyme helps to transport phosphatidylcholine specifically to the biliary leaflet. The phosphatidylcholine then enters the bile where it accounts for about 95% of the phospholipids. We postulated that the increased proportion of phosphatidylcholine in the bile canalicular membrane and the bile compared to the transport vesicles may be due to a methyltransferase activity in the bile canalicular membrane which, using s-adenosyl methionine as the substrate, converts phosphatidylethanolamine on the cytoplasmic leaflet to phosphatidylcholine, which is transported to the biliary leaflet. The aim of our study was to demonstrate and partially characterise methyltransferase activity in the bile canalicular membrane. METHODS: Organelles were obtained from hamster liver by homogenisation and separation by sucrose gradient ultracentrifugation. These, along with phosphatidylethanolamine, were incubated with radiolabelled s-adenosyl methionine. Phospholipids were separated by thin-layer chromatography and radioactivity was counted by scintigraphy. RESULTS: We demonstrated methyltransferase activity (nmol of SAMe converted/mg of protein/h at 37 degrees C) in the bile canalicular membrane of 0.442 (SEM 0.077, n=8), which is more than twice that found in the microsomes at 0.195 (SEM 0.013, n=8). The Km and pH optimum for the methyltransferase in the bile canalicular membrane and the microsomes were similar (Km 25 and 28 microM, respectively, pH 9.9 for both). The Vmax was different at 0.358 and 0.168 nmol of SAMe converted/mg of protein/h for the bile canalicular membrane and the microsomes, respectively. CONCLUSION: The presence of the methyltransferase activity in the bile canalicular membrane may be amenable to therapeutic manipulation.