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S Sarkar

Publications and source records attributed to S Sarkar.

At least 73 records · Page 4Linked to original sources
PubMed2001

Six and twelve month changes in bone turnover are related to reduction in vertebral fracture risk during 3 years of raloxifene treatment in postmenopausal osteoporosis.

We studied the relationship between change in bone turnover and vertebral fracture risk during raloxifene therapy using 3-year data from the MORE trial, where 2622 of the 7705 randomized women had measurement of bone markers at baseline and after 6 and 12 months participation. Change in bone turnover was significantly related to future risk of vertebral fracture, also after adjusting for baseline vertebral fracture status and BMD. Thus, for a decrease of 9.3 pg/l in serum osteocalcin after 1 year's raloxifene therapy, the odds ratio (OR) for a new vertebral fracture during 3 years was 0.69 (0.54-0.88), p = 0.003. Similarly, for a decrease of 5.91 microg/l in serum bone alkaline phosphatase, OR was 0.75 (0.62-0.92), p = 0.005. The change in BMD over 12 and 24 months was not related to fracture risk in any of the analyses. The strongest predictor for vertebral fracture was prevalent vertebral fracture--even during therapy. The predictive value of baseline BMD was in the same order of magnitude as bone turnover change during raloxifene treatment. In conclusion, the change in bone turnover is related to fracture risk during raloxifene therapy. In contrast the change in BMD is not related to fracture risk. The strongest predictor for vertebral fracture is prevalent vertebral fracture.

Alkaline Phosphatase↗
PubMed2001

Effect of raloxifene on serum triglycerides in postmenopausal women: influence of predisposing factors for hypertriglyceridemia.

BACKGROUND: Estrogen increases serum triglyceride (TG) levels and induces hypertriglyceridemia in susceptible women. The effect of raloxifene (RLX), a selective estrogen-receptor modulator, on serum TG has not been studied in detail. OBJECTIVE: The purpose of this study was to examine the effect of RLX on serum TG levels in postmenopausal women with and without osteoporosis, including those with predisposing factors for hypertriglyceridemia. METHODS: Fasting serum TG levels were assessed over 36 months in 2738 osteoporotic postmenopausal women (mean age, 67 years) assigned to placebo or RLX (60 or 120 mg/d) in an osteoporosis treatment trial and over 24 months in 1318 postmenopausal women without osteoporosis (mean age, 54 years) assigned to placebo or RLX (60 or 150 mg/d) in 3 osteoporosis prevention trials. RESULTS: In the osteoporosis treatment trial, the median serum TG concentration decreased in all groups, but significantly more in the placebo group (placebo, -3.4%; RLX 60 mg/d, -1.4%; RLX 120 mg/d, -1.3%; P = 0.002). In the osteoporosis prevention trials, the percentage change in median serum TG concentration was not significantly different among treatments (P = 0.22). Among women with varying degrees of hypertriglyceridemia at baseline (>2.82, >3.39, and >4.51 mmol/L), the median serum TG level at the end of the study decreased from baseline in all groups, with no significant differences among treatments (P > or = 0.13). The effect of RLX on serum TG level was not influenced by age, smoking status, use of alcohol, or presence of diabetes (P > or = 0.10 for all interactions). Among women in the highest tertile of body mass index (>26.4 kg/m2), RLX increased serum TG levels significantly compared with placebo (placebo, -3%; RLX 60 mg/d, 6%: RLX 120 mg/d, 4%; P < 0.05); the absolute increase from baseline with RLX in this subgroup was 0.05 mmol/L (4.4 mg/dL). CONCLUSIONS: RLX did not increase serum TG in postmenopausal women overall or among women with elevated TG levels or evidence of diabetes at baseline. TG levels increased slightly but statistically significantly in women in the upper tertile of body mass index who were treated with RLX.

Adult↗
PubMed2001

Activation detection in event-related fMRI data based on spatio-temporal properties.

Template-based activation detection methods, such as cross-correlation, could be difficult to apply in event-related functional MRI data because accurate a priori knowledge about the activation signal patterns is often not available. As a result, several categories of template-free data analysis techniques have been introduced in the fMRI literature. One previously described template-free activation detection technique is based on the feature that activated voxels yield reproducible time course patterns as the subject undergoes the same simulation in repeated epochs. In this paper, spatial information is incorporated as a second feature and a combined univariate measure is formed. The resulting method is shown to offer measurable improvement in detecting activation regions in simulated data in a highly computationally efficient manner. Its practical utility is demonstrated with an experimental data set obtained with a visually guided motor paradigm.

Algorithms↗
PubMed2001

Production of terbium-152 by heavy ion reactions and proton induced spallation.

Terbium-152 (Tb-152) is of potential value as a radiotracer for radiolanthanides in positron emission tomography. We report the production of Tb-152 by heavy ion reactions at the ANU Tandem accelerator, and by the spallation method at the CERN proton accelerator using the on-line ISOLDE separator, obtaining microcurie and millicurie yields, respectively. After purification, a phantom image in PET is obtained which shows the feasibility of using Tb-152 for monitoring the kinetics of Tb-149 and other radiolanthanides. However, the current availability of this radioisotope will be restricted to major nuclear physics research centres.

Kinetics↗
PubMed2001

Conductive hearing loss in preterm infants with bronchopulmonary dysplasia.

OBJECTIVE: To determine the risk of conductive hearing loss in preterm infants with bronchopulmonary dysplasia (BPD) and preterm controls. METHODOLOGY: The study population consisted of 78 infants with BPD of 26-33 weeks gestation and 78 controls of similar gestational age matched for broad-based birthweight categories. An auditory brainstem response (ABR) audiology was performed shortly before hospital discharge. Visual reinforcement orientation audiometry (VROA) and impedance audiometry were performed at 8-12 months corrected for prematurity. Infants with persistent audiological abnormalities were referred for evaluation to paediatric ENT surgeons. RESULTS: Infants with BPD had a significantly higher rate of ABR abnormalities (BPD: 22%, controls: 9%; P = 0.028). On VROA and impedance audiometry, the infants with BPD also had a higher rate of persistent abnormalities. Following ENT assessment, 22.1% of infants with BPD and 7.7% of controls had persistent conductive dysfunction requiring myringotomy and grommet tube insertion (P = 0.03). Most of these infants had normal ABR audiometry at hospital discharge. CONCLUSIONS: Preterm infants with BPD are at high risk of persistent conductive hearing loss late in the first year of life compared to controls. An ABR audiology conducted at the time of hospital discharge does not predict accurately later conductive hearing problems. Infants with BPD should have routine audiological evaluation toward the end of the first year of life.

Audiometry↗
PubMed2001

In vitro and preclinical studies of targeted alpha therapy (TAT) for colorectal cancer.

INTRODUCTION: Effective targeted cancer therapy requires high selectivity and cytotoxicity of the labelled product. We report the preparation and testing of anticolorectal cancer monoclonal antibody c30.6 radioimmunoconjugates (RIC) labelled with alpha-emitting Bismuth-213 and positron emitting Terbium-152 using two chelators, viz. Cyclic dianhydride of diethylenetriaminepentacetic acid (DTPA) and CHX-A" (a DTPA derivative). METHODS: Selectivity and stability of the RIC were tested in vitro (flow cytometry) and in vivo (biodistribution, organ/tumour uptake and retention). Cytotoxicity assays were carried out using tritiated thymidine uptake (inhibition of DNA synthesis) and MTS assay. RESULTS: High labelling efficiency (ranging between 89 and 91%) and stability over 2-5 half-lives of the isotopes were seen. Kidney retention was not seen in contrast to high uptake and retention of both conjugates in tumours. Flow cytometry studies showed high specificity of the antibody before and after labelling and this unchanged targeting behaviour was reflected in cytotoxicity assays. These assays showed that only alpha-labelled antibody could selectively kill the cancer cells for activities as low as 2-3 microCi. The study also revealed that free isotopes or isotopes bound to nonspecific antibodies did not kill cancer cells. CONCLUSION: The stability of the RICs and outstanding cytotoxicity of the alpha emitter, together with no kidney retention and high tumour uptake and retention of the radiolabel, offers a new approach for the potential control of colorectal cancer.

Journal Article↗
PubMed2001

Role of nuclear pools of aminoacyl-tRNA synthetases in tRNA nuclear export.

Reports of nuclear tRNA aminoacylation and its role in tRNA nuclear export (Lund and Dahlberg, 1998; Sarkar et al., 1999; Grosshans et al., 20001) have led to the prediction that there should be nuclear pools of aminoacyl-tRNA synthetases. We report that in budding yeast there are nuclear pools of tyrosyl-tRNA synthetase, Tys1p. By sequence alignments we predicted a Tys1p nuclear localization sequence and showed it to be sufficient for nuclear location of a passenger protein. Mutations of this nuclear localization sequence in endogenous Tys1p reduce nuclear Tys1p pools, indicating that the motif is also important for nucleus location. The mutations do not significantly affect catalytic activity, but they do cause defects in export of tRNAs to the cytosol. Despite export defects, the cells are viable, indicating that nuclear tRNA aminoacylation is not required for all tRNA nuclear export paths. Because the tRNA nuclear exportin, Los1p, is also unessential, we tested whether tRNA aminoacylation and Los1p operate in alternative tRNA nuclear export paths. No genetic interactions between aminoacyl-tRNA synthetases and Los1p were detected, indicating that tRNA nuclear aminoacylation and Los1p operate in the same export pathway or there are more than two pathways for tRNA nuclear export.

Active Transport, Cell Nucleus↗
PubMed2001

Central neural mechanisms mediating human visceral hypersensitivity.

Although visceral hypersensitivity is thought to be important in generating symptoms in functional gastrointestinal disorders, the neural mechanisms involved are poorly understood. We recently showed that central sensitization (hyperexcitability of spinal cord sensory neurones) may play an important role. In this study, we demonstrate that after a 30-min infusion of 0.15 M HCl acid into the healthy human distal esophagus, we see a reduction in the pain threshold to electrical stimulation of the non-acid-exposed proximal esophagus (9.6 +/- 2.4 mA) and a concurrent reduction in the latency of the N1 and P2 components of the esophageal evoked potentials (EEP) from this region (10.4 +/- 2.3 and 15.8 +/- 5.3 ms, respectively). This reduced EEP latency indicates a central increase in afferent pathway velocity and therefore suggests that hyperexcitability within the central visceral pain pathway contributes to the hypersensitivity within the proximal, non-acid-exposed esophagus (secondary hyperalgesia/allodynia). These findings provide the first electrophysiological evidence that central sensitization contributes to human visceral hypersensitivity.

Adult↗
PubMed2001

Inhibition of placental 11beta-hydroxysteroid dehydrogenase type 2 by catecholamines via alpha-adrenergic signaling.

The placenta expresses high levels of 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) that converts cortisol into inactive 11-keto metabolites and effectively protects the developing fetus from maternal cortisol during pregnancy. Impairment of this glucocorticoid barrier has adverse effects on fetal outcomes. A similar spectrum of adverse fetal effects is induced by antenatal stress during pregnancy. To examine the hypothesis that physiological stress may regulate placental 11betaHSD2 gene expression, we examined the effects of the catecholamines norepinephrine (NE) and epinephrine (E) on 11betaHSD2 expression in human trophoblastic cells. With the use of Northern blotting and semiquantitative RT-PCR, we determined that NE and E rapidly downregulate 11betaHSD2 steady-state mRNA levels in early- and late-gestation human trophoblasts and BeWo trophoblastic cells. Experiments using different adrenoceptor subtype-selective agonists and antagonists demonstrated that this catecholamine suppression of 11betaHSD2 mRNA expression is mediated via both alpha(1)- and alpha(2)-adrenoceptors and is independent of beta-adrenergic stimulation. To examine transcriptional regulation, BeWo cells were transiently transfected with a reporter construct in which an 11betaHSD2 human promoter sequence was inserted upstream of the luciferase gene. Treatment with 10(-7) M NE decreased luciferase activity by ~60% (n = 3, P < 0.01). These results suggest the NE/E-mediated decrease in placental 11betaHSD2 gene expression is an instance of alpha-adrenoceptor-specific rapid transcriptional inhibition of an adrenergic target gene. This molecular mechanism may be involved in the deleterious effects of antenatal physiological stress on fetoplacental growth and development.

Adrenergic alpha-Antagonists↗
PubMed2001

Role of myocytes in myocardial collagen production.

Excessive collagen deposition may cause abnormal stiffness of the heart during hypertrophy and heart failure. The potent vasoconstrictor angiotensin II seems, via an unknown mechanism, to stimulate collagen production. This study describes the in vitro and ex vivo effects of [Sar(1)]Ang II on collagen production by fibroblasts in culture and in beating, nonworking heart preparations. The effects of [Sar(1)]Ang II on isolated rat hearts or rat heart fibroblasts were determined by quantifying transcript levels of collagen phenotypes I and III through videodensitometry after Northern blot analysis with specific cDNA probes (collagen [P alpha( 2)r(2)] rat alpha( 2)[I] probe for type I and human skin fibroblast alpha(1)[III] probe for type III). When [Sar(1)]Ang II was added in vitro to neonatal or adult 28-week-old Wistar-Kyoto rat heart fibroblasts, questionable stimulation in the mRNAs of types I and III occurred. In contrast, when 10(-8) mol/L [Sar(1)]Ang II was added to beating, nonworking Wistar-Kyoto rat heart preparation ex vivo, a 1.5- to 2.5-fold stimulation of collagen mRNAs of phenotypes I and III was observed. When neonatal fibroblasts were cocultured with neonatal myocytes in vitro, with 10(-10) mol/L [Sar(1)]Ang II added, there was no stimulation of either phenotype. However, significant stimulation of both collagen transcripts was recorded when 10(-10) mol/L [Sar(1)]Ang II was added to adult fibroblasts cocultured with either neonatal or adult myocytes. Our data suggest that factors produced by myocytes are necessary for upregulation of collagen genes in vitro and demonstrate that fibroblast-myocyte cross-talk is required for Ang II-induced collagen upregulation.

Angiotensin II↗
PubMed2001

Neuropeptide Y has a central inhibitory action on the hypothalamic-pituitary-thyroid axis.

Recent evidence suggests that neuropeptide Y (NPY), originating in neurons in the hypothalamic arcuate nucleus, is an important mediator of the effects of leptin on the central nervous system. As these NPY neurons innervate hypophysiotropic neurons in the hypothalamic paraventricular nucleus (PVN) that produce the tripeptide, TRH, we raised the possibility that NPY may be responsible for resetting of the hypothalamic-pituitary-thyroid (HPT) axis during fasting. To test this hypothesis, the effects of intracerebroventricularly administered NPY on circulating thyroid hormone levels and proTRH messenger RNA in the PVN were studied by RIA and in situ hybridization histochemistry, respectively. NPY administration suppressed circulating levels of thyroid hormone (T(3) and T(4)) and resulted in an inappropriately normal or low TSH. These alterations were associated with a significant suppression of proTRH messenger RNA in the PVN, indicating that NPY infusion had resulted in a state of central hypothyroidism. Similar observations were made in NPY-infused animals pair fed to the vehicle-treated controls. These data are reminiscent of the effect of fasting on the thyroid axis and indicate that NPY may play a major role in the inhibition of HPT axis during fasting.

Adipose Tissue↗
PubMed2001

FGF2 promotes skeletogenic differentiation of cranial neural crest cells.

The cranial neural crest gives rise to most of the skeletal tissues of the skull. Matrix-mediated tissue interactions have been implicated in the skeletogenic differentiation of crest cells, but little is known of the role that growth factors might play in this process. The discovery that mutations in fibroblast growth factor receptors (FGFRs) cause the major craniosynostosis syndromes implicates FGF-mediated signalling in the skeletogenic differentiation of the cranial neural crest. We now show that, in vitro, mesencephalic neural crest cells respond to exogenous FGF2 in a dose-dependent manner, with 0.1 and 1 ng/ml causing enhanced proliferation, and 10 ng/ml inducing cartilage differentiation. In longer-term cultures, both endochondral and membrane bone are formed. FGFR1, FGFR2 and FGFR3 are all detectable by immunohistochemistry in the mesencephalic region, with particularly intense expression at the apices of the neural folds from which the neural crest arises. FGFRs are also expressed by subpopulations of neural crest cells in culture. Collectively, these findings suggest that FGFs are involved in the skeletogenic differentiation of the cranial neural crest.

Animals↗
PubMed2001

Bilateral ovarian hydatid disease--an unusual case.

Hydatid disease is caused by parasitic tapeworm Echinococcus. The larval stage of this parasite can thrive in many parts of the body, most frequently in the liver. Primary ovarian location is very rare. In our case the patient had bilateral ovarian cysts which on histopathological study was found to be hydatid cysts. Moreover one of the cysts was multilocular which is also unusual.

Adult↗
PubMed2000

Inherited infantile dilated cardiomyopathy in dogs: genetic, clinical, biochemical, and morphologic findings.

Dilated cardiomyopathy, a lethal disease characterized by left ventricular dilation and systolic dysfunction, is relatively common in humans and other mammals. Idiopathic dilated cardiomyopathy (IDCM) is a primary myocardial disease of unknown cause and can be a familial disorder. This report describes autosomal recessive IDCM in dogs. It occurs in Portuguese Water Dog (PWD) pups and is manifested by acute, vague clinical signs and sudden death. Affected pups have progressive reduction of fractional shortening that can be demonstrated by echocardiography prior to the development of clinical signs. Furthermore, these pups have low plasma taurine levels when consuming certain diets. Affected pups had dilation of the left ventricle and alterations in the sarcomere appearance, while immunohistochemical and biochemical studies demonstrate an increase in desmin, a cytoskeleton protein. The clinical and morphologic findings of IDCM in PWDs are distinct from those reported in adult IDCM. Finally, the clinical and echocardiographic manifestations were reversible in some pups following oral taurine supplementation for 2 months. These results suggest that IDCM in PWDs is correlated with low plasma taurine levels.

Animals↗
PubMed2000

Chronic toxicity of arsenic in goats: clinicobiochemical changes, pathomorphology and tissue residues.

Chronic inorganic arsenic toxicity was induced in goats by oral administration of one-fifth of the acute lethal dose 50 (ALD(50)) of sodium arsenite (25mgkg(-1) body weight) packed in gelatin capsules and given daily for 12 weeks. Clinical signs of toxicity developed from 3 week post-exposure, consisting of gastrointestinal disturbances and renal insufficiency with 100% mortality in all animals. There were significant (p<0.01) decreases in total serum protein and the albumin: globulin ratio, and increases in blood glucose and various enzymatic activities of treated animals. Toxicity also induced severe pathomorphological changes, indicative of haemorrhagic and degenerative and/or necrotic lesions in most organs. In addition, proliferative pneumonia in lungs, hyperplastic goitre in thyroid and chronic proliferative lesions in skin were observed. Liver contained the largest residues of arsenic, followed by intestine, kidneys, thyroid, abomasum, spleen, skin, lungs and lowest in brain. The intensity of pathomorphological changes was proportional to the accumulated amount of arsenic in tissues/organs.

Journal Article↗
PubMed2000

The cloning of a new peroxidase found in lignocellulose cultures of Pleurotus eryngii and sequence comparison with other fungal peroxidases.

We report cloning and sequencing of gene ps1 encoding a versatile peroxidase combining catalytic properties of lignin peroxidase (LiP) and manganese peroxidase (MnP) isolated from lignocellulose cultures of the white-rot fungus Pleurotus eryngii. The gene contains 15 putative introns, and the deduced amino acid sequence consists of a 339-residue mature protein with a 31-residue signal peptide. Several putative response elements were identified in the promoter region. Amino acid residues involved in oxidation of Mn(2+) and aromatic substrates by direct electron transfer to heme and long-range electron transfer from superficial residues as predicted by analogy with Phanerochaete chrysosporium MnP and LiP, respectively. A dendrogram is presented illustrating sequence relationships between 29 fungal peroxidases.

Amino Acid Sequence↗
PubMed2000

Contribution of central sensitisation to the development of non-cardiac chest pain.

BACKGROUND: Non-cardiac chest pain mimics angina pectoris but generally originates from the oesophagus. Visceral hypersensitivity may contribute, but its neurophysiological basis is unclear. We investigated whether central sensitisation, an activity-dependent amplification of sensory transfer in the central nervous system, underlies visceral pain hypersensitivity and non-cardiac chest pain. METHODS: We studied 19 healthy volunteers and seven patients with non-cardiac chest pain. Acid was infused into the lower oesophagus. Sensory responses to electrical stimulation were monitored within the acid-exposed lower oesophagus, the non-exposed upper oesophagus, and the cutaneous area of pain referral, before and after the infusion. FINDINGS: In healthy volunteers, acid infusion into the lower oesophagus lowered the pain threshold in the upper oesophagus (mean decrease 18.2% [95% CI 10.4 to 26.0]; p=0.01) and on the chest wall (24.5% [10.2 to 38.7]; p=0.01). Patients with non-cardiac chest pain had a lower resting oesophageal pain threshold than healthy controls (45 [30 to 58] vs 64 [49 to 81] mA; p=0.04). In response to acid infusion, their pain threshold in the upper oesophagus fell further and for longer (mean fall in area under threshold/time curve 26.7 [11.0 to 42.3] vs 5.8 [2.8 to 8.8] units; p=0.04). INTERPRETATION: The finding of secondary viscerovisceral and viscerosomatic pain hypersensitivity suggests that central sensitisation may contribute to visceral pain disorders. The prolonged visceral pain hypersensitivity in patients with non-cardiac chest pain suggests a central enhancement of sensory transfer. New therapeutic opportunities are therefore possible.

Adult↗