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Biomedical subjects

S Saxena

Publications and source records attributed to S Saxena.

At least 73 records · Page 4Linked to original sources
PubMed2000

Interaction of syntaxins with epithelial ion channels.

Recent evidence suggests that some of the syntaxin isoforms may physically interact with and regulate the transport activity of a defined set of membrane transport proteins. This review examines recent studies of the cystic fibrosis transmembrane conductance regulator and the epithelial sodium channel which define distinct roles of syntaxin 1A and syntaxin 3 in the regulation of surface expression as well as intrinsic properties of these epithelial ion transporters.

Cystic Fibrosis Transmembrane Conductance Regulato↗
PubMed2000

Personality changes in adult subjects with major depressive disorder or obsessive-compulsive disorder treated with paroxetine.

BACKGROUND: Human and animal studies point to 3 dimensions of personality that change during pharmacotherapy with a selective serotonin reuptake inhibitor (SSRI). Specifically, harm avoidance has been found to decrease, social dominance has been found to increase, and hostility in social situations has been found to decrease with SSRI treatment. We sought to determine personality changes in subjects with either major depressive disorder (MDD) or obsessive-compulsive disorder (OCD) treated with paroxetine. We also sought to determine whether or not these personality changes were associated with disease state (MDD vs. OCD) or treatment response (responders vs. nonresponders). METHOD: Thirty-seven subjects diagnosed with either MDD or OCD (according to DSM-IV criteria) completed the Cattell 16 Personality Factor Inventory (16-PF) before and after treatment with paroxetine. Treatment response was defined as a Clinical Global Impressions-Improvement rating of "much" or "very much" improved and a drop in Hamilton Rating Scale for Depression score of at least 50% for MDD or Yale-Brown Obsessive Compulsive Scale score of at least 30% for OCD. RESULTS: No significant differences were found between subjects with MDD and OCD in personality change with treatment. In the whole group, treatment responders had a greater decrease than nonresponders in 16-PF factors relating to harm avoidance. An increase in social dominance factors and a decrease in factors relating to hostility in social situations were found, but these changes were not significantly different between responders and nonresponders. CONCLUSION: These findings indicate that certain personality dimensions change with SSRI treatment and that some of these changes are independent of clinical treatment response.

Adult↗
PubMed2000

Towards a global alcohol policy: alcohol, public health and the role of WHO.

In 1983 the World Health Assembly declared alcohol-related problems to be among the world's major health concerns. Since then, alcohol consumption has risen in developing countries, where it takes a heavy toll. Alcohol-related problems are at epidemic levels in the successor states of the Soviet Union and are responsible for 3.5% of disability-adjusted life years (DALYs) lost globally. Substantial evidence exists of the relationship between the levels and patterns of alcohol consumption on the one hand and the incidence of alcohol-related problems on the other. Over the past 20 years, research has demonstrated the effectiveness of public policies involving, for example, taxation and restrictions on alcohol availability, in reducing alcohol-related problems. In the wake of rapid economic globalization, many of these policies at national and subnational levels have been eroded, often with the support of international financial and development organizations. Development agencies and international trade agreements have treated alcohol as a normal commodity, overlooking the adverse consequences of its consumption on productivity and health. WHO is in a strong position to take the lead in developing a global alcohol policy aimed at reducing alcohol-related problems, providing scientific and statistical support, capacity-building, disseminating effective strategies and collaborating with other international organizations. Such leadership can play a significant part in diminishing the health and social problems associated with alcohol use.

Alcohol Drinking↗
PubMed2000

Eye tracking disturbances in schizophrenia.

PURPOSE: To study the frequency of different types of eye tracking disturbances in schizophrenia. MATERIALS AND METHODS: Smooth pursuit eye movements were studied by electro-oculography (EOG) in 22 schizophrenic patients (ICD-10 criteria) and 15 age and sex-matched controls. The studied parameters included average pursuit gain, number of saccades, the frequency of different types of saccades (catch-up, back-up, anticipatory saccades), and disturbances during fixation. The results were analysed statistically. RESULTS: The average pursuit gain was significantly affected in patients for target velocity of 30 degrees/sec (p = 0.007). The catch-up and back-up saccades were more common in cases than controls but the difference was not significant (p = 0.39 and 0.36 respectively). The anticipatory saccades were significantly more frequent in cases than controls (p < 0.0001) for both 15 degrees/sec and 30 degrees/sec target velocities. This was also correlated with the duration of illness. CONCLUSION: Anticipatory saccades are significantly more frequent during eye tracking in schizophrenia and appear to be an objective marker for the disease.

Adult↗
PubMed2000

Raised platelet thiobarbituric acid-reacting substances in proliferative Eales' disease.

BACKGROUND: Platelets are an elective site for oxidative stress owing to their high content of polyunsaturated fatty acid. Increased lipid peroxidation and elevated platelet thiobarbituric acid-reacting substances (TBARS) signal oxidative stress. This possibly leads to retinal neovascularization in Eales' disease. METHODS: TBARS levels were estimated in consecutive cases of Eales' disease with neovascularisation (n = 26), Eales' disease without neovascularisation (n = 17) and healthy controls (n = 17). RESULTS: Platelet TBARS levels in the cases of Eales' disease with neovascularisation, Eales' disease without neovascularisation, and healthy controls were 0.66 +/- 0.1, 0.57 +/- 0.11 and 0.42 +/- 0.14 n moles TBARS formed/hour/10(8) platelets respectively. Student's t-test showed a significant increase in platelet TBARS levels in cases with neovascularisation as compared to cases without neovascularization (p < 0.05) and healthy controls (p < 0.01). CONCLUSION: The increase in platelet TBARS levels in proliferative Eales' disease is consistent with an emerging view that lipid peroxides may be associated with retinal neovascularisation.

Adolescent↗
PubMed2000

Management of diabetic retinopathy.

Diabetic retinopathy remains a major cause of blindness despite increased understanding of this disease and identification of successful treatments. The Diabetic Retinopathy Study identified risk factors associated with a high risk of blindness and confirmed the benefits of panretinal photocoagulation. The Early Treatment Diabetic Retinopathy Study defined the retinal characteristics, indications of treatment and results of laser treatment of clinically significant macular oedema. The Diabetic Retinopathy Vitrectomy study established the benefits and timing of vitrectomy for non-clearing vitreous haemorrhage and severe proliferative diabetic retinopathy. The Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study have also demonstrated the value of tight control of blood sugar and blood pressure in diabetic retinopathy. These studies developed specific recommendations for the management of diabetic retinopathy. Optimum use of this information can minimize visual loss due to diabetic retinopathy.

Diabetic Retinopathy↗
PubMed1999

Parental review.

Explore the source record for details and available documents.

Journal Article↗
PubMed1999

Effect of amphotericin B lipid formulation on immune response in aspergillosis.

The immune response against Aspergillus fumigatus has been studied during infection and therapy in order to understand the mechanism of pathogenesis and the effect of treatment with amphotericin B. With this in view an animal model of aspergillosis was developed in Balb/c mice by intravenous injection of an optimized dose of 3. 6x10(6) A. fumigatus spores. Infection due to Aspergillus was well established by histopathological examination and fungal load in the animal. Lesions and eosinophil infiltration was observed in the infected tissues which indicated the involvement of a Type I hypersensitivity response. Evaluation of serological parameters indicated high levels of interleukin-4 (IL-4) and A. fumigatus specific IgG antibodies. The reduction in fungal load and modulation of immune response in the infected mice was studied following treatment with amphotericin B/cholesterol hemisuccinate vesicles (ABCV). The results clearly indicated significant reduction in the fungal load, disappearance of eosinophils and lesions with the appearance of macrophages and neutrophils in the infected lung tissue, a decrease in IL-4 (fourfold) and a concomitant increase of interferon-gamma (IFN-gamma; twofold) with an improvement in general condition of mice. In the non-treated mice, the rise of IL-4 level indicated the association of T(H)2 cell response with susceptibility to infection while the increase of IFN-gamma in the treated group suggested that T(H)1 cell response may be involved in resistance to Aspergillus infection.

Amphotericin B↗
PubMed1999

Brain metabolic changes in major depressive disorder from pre- to post-treatment with paroxetine.

Functional brain imaging studies of subjects with Major Depressive Disorder (MDD) have suggested that decreased dorsolateral (DLPFC) and increased ventrolateral (VLPFC) prefrontal cortical activity mediate the depressed state. Pre- to post-treatment studies indicate that these abnormalities normalize with successful treatment. We performed [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) scans on 16 outpatients with MDD before and after treatment with paroxetine (target dose = 40 mg/day). Regions of interest (ROIs) for this analysis were drawn by a rater blind to subject identity on the magnetic resonance image of each subject and transferred onto their coregistered PET scans. We hypothesized that DLPFC metabolism would increase, while ventral frontal metabolism [in the VLPFC, the orbitofrontal cortex (OFC), and the inferior frontal gyrus (IFG)] would decrease with successful treatment. Treatment response was defined as a decrease in the Hamilton Depression Rating Scale of > 50% and a Clinical Global Improvement Scale rating of 'much' or 'very much' improved. By these criteria, nine of the subjects were classified as treatment responders. These responders had significantly greater decreases in normalized VLPFC and OFC metabolism than did non-responders. There were no significant effects of treatment response on change in the DLPFC or IFG in this sample. However, there was a positive correlation between change in HAM-D scores and change in normalized IFG and VLPFC metabolism. There were no significant interactions with laterality. On pre-treatment scans, lower metabolism in the left ventral anterior cingulate gyrus was associated with better treatment response. These findings implicate ventral prefrontal-subcortical brain circuitry in the mediation of response to serotonin reuptake inhibitors in MDD.

Adult↗
PubMed1999

A multisubunit complex of outer and inner mitochondrial membrane protein translocases stabilized in vivo by translocation intermediates.

Translocation of nuclear encoded preproteins into the mitochondrial matrix requires the coordinated action of two translocases: one (Tom) located in the outer mitochondrial membrane and the other (Tim) located in the inner membrane. These translocases reversibly cooperate during protein import. We have previously constructed a chimeric precursor (pPGPrA) consisting of an authentic mitochondrial precursor at the N terminus (Delta(1)-pyrroline-5-carboxylate dehydrogenase, pPut) linked, through glutathione S-transferase, to protein A. When pPGPrA is expressed in yeast, it becomes irreversibly arrested during translocation across the outer and inner mitochondrial membranes. Consequently, the two membranes of mitochondria become progressively "zippered" together, forming long stretches in which they are in close contact (Schülke, N., Sepuri, N. B. V., and Pain, D. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 7314-7319). We now demonstrate that trapped PGPrA intermediates hold the import channels stably together and inhibit mitochondrial protein import and cell growth. Using IgG-Sepharose affinity chromatography of solubilized zippered membranes, we have isolated a multisubunit complex that contains all Tom and Tim components known to be essential for import of matrix-targeted proteins, namely Tom40, Tom22, Tim17, Tim23, Tim44, and matrix-localized Hsp70. Further characterization of this complex may shed light on structural features of the complete mitochondrial import machinery.

Biological Transport↗
PubMed1999

Interaction of syntaxins with the amiloride-sensitive epithelial sodium channel.

Amiloride-sensitive sodium channels mediate sodium entry across the apical membrane of epithelial cells in variety of tissues. The rate of Na(+) entry is controlled by the regulation of the epithelial sodium channel (ENaC) complex. Insertion/retrieval of the ENaC complex into the apical membrane as well as direct kinetic effects at the single channel level are recognized mechanisms of regulation. Recent data suggest that the syntaxin family of targeting proteins interact with and functionally regulate a number of ion channels and pumps. To evaluate the role of these proteins in regulating ENaC activity, we co-expressed rat ENaC cRNA (alpha, beta, gamma subunits) with syntaxin 1A or 3 cRNAs in Xenopus oocytes. Basal ENaC currents were inhibited by syntaxin 1A and stimulated by syntaxin 3. Both syntaxin 1A and syntaxin 3 could be co-immunoprecipitated with ENaC subunit proteins, suggesting physical interaction. Interestingly, immunofluorescence data suggest that with either syntaxin isoform the ENaC-associated epifluorescence on the oocyte surface is enhanced. These data indicate that (i) both syntaxin isoforms increase the net externalization of the ENaC channel complex, (ii) that the functional regulation is isoform specific, and (iii) suggest that ENaC may be regulated through mechanisms involving protein-protein interactions.

Animals↗
PubMed1999

Multiple-informant ranking of the disabling effects of different health conditions in 14 countries. WHO/NIH Joint Project CAR Study Group.

BACKGROUND: The Global Burden of Disease study provided international statistics on the burden of diseases, combining mortality and disability, that can be used for priority setting and policy making. However, there are concerns about the universality of the disability weights used. We undertook a study to investigate the stability of such weighting in different countries and informant groups. METHODS: 241 key informants (health professionals, policy makers, people with disabilities, and their carers) from 14 countries were asked to rank 17 health conditions from most disabling to least disabling. Kruskal-Wallis ANOVA was used to test for differences in ranking between countries or informant groups and Kendall tau-B correlations to measure association between different rank orders. FINDINGS: For 13 of 17 health conditions, there were significant (p<0.05) differences in ranking between countries; in the comparison of informant groups, there were significant differences for five of the 17 health conditions. The overall rank order in the present study was, however, almost identical to the ranking of the Global Burden of Disease study, which used a different method. Most of the rank correlations between countries were between 0.50 and 0.70 (average 0.61 [95% CI 0.59-0.64]). The average correlation of rank orders between different informant groups was 0.76. INTERPRETATION: Rank order of disabling effects of health conditions is relatively stable across countries, informant groups, and methods. However, the differences are large enough to cast doubt on the assumption of universality of experts' judgments about disability weights. Further studies are needed because disability weights are central to the calculation of disability-adjusted life years.

Analysis of Variance↗
PubMed1999

Apoptosis in heart failure: release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy.

Apoptosis has been shown to contribute to loss of cardiomyocytes in cardiomyopathy, progressive decline in left ventricular function, and congestive heart failure. Because the molecular mechanisms involved in apoptosis of cardiocytes are not completely understood, we studied the biochemical and ultrastructural characteristics of upstream regulators of apoptosis in hearts explanted from patients undergoing transplantation. Sixteen explanted hearts from patients undergoing heart transplantation were studied by electron microscopy or immunoblotting to detect release of mitochondrial cytochrome c and activation of caspase-3. The hearts explanted from five victims of motor vehicle accidents or myocardial ventricular tissues from three donor hearts were used as controls. Evidence of apoptosis was observed only in endstage cardiomyopathy. There was significant accumulation of cytochrome c in the cytosol, over myofibrils, and near intercalated discs of cardiomyocytes in failing hearts. The release of mitochondrial cytochrome c was associated with activation of caspase-3 and cleavage of its substrate protein kinase C delta but not poly(ADP-ribose) polymerase. By contrast, there was no apparent accumulation of cytosolic cytochrome c or caspase-3 activation in the hearts used as controls. The present study provides in vivo evidence of cytochrome c-dependent activation of cysteine proteases in human cardiomyopathy. Activation of proteases supports the phenomenon of apoptosis in myopathic process. Because loss of myocytes contributes to myocardial dysfunction and is a predictor of adverse outcomes in the patients with congestive heart failure, the present demonstration of an activated apoptotic cascade in cardiomyopathy could provide the basis for novel interventional strategies.

Animals↗
PubMed1999

Bcl-xL blocks activation of related adhesion focal tyrosine kinase/proline-rich tyrosine kinase 2 and stress-activated protein kinase/c-Jun N-terminal protein kinase in the cellular response to methylmethane sulfonate.

The stress-activated protein kinase/c-Jun N-terminal protein kinase (JNK) is induced in response to ionizing radiation and other DNA-damaging agents. Recent studies indicate that activation of JNK is necessary for induction of apoptosis in response to diverse agents. Here we demonstrate that methylmethane sulfonate (MMS)-induced activation of JNK is inhibited by overexpression of the anti-apoptotic protein Bcl-xL, but not by caspase inhibitors CrmA and p35. By contrast, UV-induced JNK activity is insensitive to Bcl-xL. The results demonstrate that treatment with MMS is associated with an increase in tyrosine phosphorylation of related adhesion focal tyrosine kinase (RAFTK)/proline-rich tyrosine kinase 2 (PYK2), an upstream effector of JNK and that this phosphorylation is inhibited by overexpression of Bcl-xL. Furthermore, overexpression of a dominant-negative mutant of RAFTK (RAFTK K-M) inhibits MMS-induced JNK activation. The results indicate that inhibition of RAFTK phosphorylation by MMS in Bcl-xL cells is attributed to an increase in tyrosine phosphatase activity in these cells. Hence, treatment of Bcl-xL cells with sodium vanadate, a tyrosine phosphatase inhibitor, restores MMS-induced activation of RAFTK and JNK. These findings indicate that RAFTK-dependent induction of JNK in response to MMS is sensitive to Bcl-xL, but not to CrmA and p35, by a mechanism that inhibits tyrosine phosphorylation and thereby activation of RAFTK. Taken together, these findings support a novel role for Bcl-xL that is independent of the caspase cascade.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1999

Socioeconomic differences in childhood consultation rates in general practice in England and Wales: prospective cohort study.

OBJECTIVE: To establish how consultation rates in children for episodes of illness, preventive activities, and home visits vary by social class. DESIGN: Analysis of prospectively collected data from the fourth national survey of morbidity in general practice, carried out between September 1991 and August 1992. SETTING: 60 general practices in England and Wales. SUBJECTS: 106 102 children aged 0 to 15 years registered with the participating practices. MAIN OUTCOME MEASURES: Mean overall consultation rates for any reason, illness by severity of underlying disease, preventive episodes, home visits, and specific diagnostic category (infections, asthma, and injuries). RESULTS: Overall consultation rates increased from registrar general's social classes I-II to classes IV-V in a linear pattern (for IV-V v I-II rate ratio 1.18; 95% confidence interval 1.14 to 1. 22). Children from social classes IV-V consulted more frequently than children from classes I-II for illnesses (rate ratio 1.23; 1.15 to 1.30), including infections, asthma, and injuries and poisonings. They also had significantly higher consultation rates for minor, moderate, and serious illnesses and higher home visiting rates (rate ratio 2.00; 1.81 to 2.18). Consultations for preventive activities were lower in children from social classes IV-V than in children from social classes I-II (rate ratio 0.95; 0.86 to 1.05). CONCLUSIONS: Childhood consultation rates for episodes of illness increase from social classes I-II through to classes IV-V. The findings on severity of underlying illness suggest the health of children from lower social classes is worse than that of children from higher social classes. These results reinforce the need to identify and target children for preventive health care in their socioeconomic context.

Adolescent↗