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Biomedical subjects

S Saxena

Publications and source records attributed to S Saxena.

At least 55 records · Page 3Linked to original sources
PubMed2001

Targeting of the c-Abl tyrosine kinase to mitochondria in endoplasmic reticulum stress-induced apoptosis.

The ubiquitously expressed c-Abl tyrosine kinase localizes to the nucleus and cytoplasm. Using confocal microscopy, we demonstrated that c-Abl colocalizes with the endoplasmic reticulum (ER)-associated protein grp78. Expression of c-Abl in the ER was confirmed by immunoelectron microscopy. Subcellular fractionation studies further indicate that over 20% of cellular c-Abl is detectable in the ER. The results also demonstrate that induction of ER stress with calcium ionophore A23187, brefeldin A, or tunicamycin is associated with translocation of ER-associated c-Abl to mitochondria. In concert with targeting of c-Abl to mitochondria, cytochrome c is released in the response to ER stress by a c-Abl-dependent mechanism, and ER stress-induced apoptosis is attenuated in c-Abl-deficient cells. These findings indicate that c-Abl is involved in signaling from the ER to mitochondria and thereby the apoptotic response to ER stress.

Animals↗
PubMed2001

Effect of Leishmania donovani lipophosphoglycan on ornithine decarboxylase activity in macrophages.

Lipophosphoglycan (LPG), a major surface molecule from Leishmania donovani, stimulated ornithine decarboxylase (ODC) activity in macrophages in a dose- and time-dependent manner. LPG stimulated the rapid increase in ODC activity within 30 min after exposure, suggesting that the interaction of LPG with its receptor stimulated a specific signal transduction pathway. However, LPG-induced ODC activity was a transient event because 3 hr after exposure to LPG, no stimulation of ODC activity was detectable. ODC activity appeared to be coupled to the activation of protein kinase C (PKC) in macrophages, as activators of PKC caused a rapid increase in the ODC activity. Macrophages pretreated with LPG for 1 hr became unresponsive to subsequent stimulation by the PKC activators 1-oleoyl-2-acetyl-glycerol and the calcium ionophore A23187. In contrast, the ability of macrophages to express ODC activity in response to the cyclic AMP analogue dibutyryl cyclic AMP was not impaired by LPG.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2001

A retrospective review of clinical characteristics and treatment response in body dysmorphic disorder versus obsessive-compulsive disorder.

BACKGROUND: Although body dysmorphic disorder (BDD) has many features in common with obsessive-compulsive disorder (OCD) and is frequently comorbid with OCD, few studies have directly compared the 2 disorders. Although BDD and OCD respond to similar medications and cognitive-behavioral therapy (CBT), their response to treatment has never been directly compared. METHOD: We studied 107 consecutive patients with DSM-III-R OCD (N = 96) or BDD (N = 11) treated openly for 6 weeks with intensive CBT, medication, and psychosocial rehabilitation, in a specialized partial hospitalization program for severely ill OCD patients. All patients were assessed, before and after treatment, with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), Hamilton Rating Scale for Depression (HAM-D), Hamilton Rating Scale for Anxiety (HAM-A), and Global Assessment Scale (GAS). Retrospectively, we compared the clinical characteristics, symptom severity, and response to treatment of BDD patients with those of OCD patients. RESULTS: BDD patients and OCD patients had similar sex ratio, age, treatment duration, prevalence of comorbid major depression, and pretreatment Y-BOCS and GAS scores. BDD patients had significantly higher pretreatment HAM-D and HAM-A scores. The proportions of patients treated with serotonin reuptake inhibitors and antipsychotics did not differ between groups. Both groups improved with treatment, with significant (p < .001) changes in Y-BOCS, HAM-D, HAM-A, and GAS scores. Change in Y-BOCS did not differ between groups, but changes in HAM-D and HAM-A were significantly greater in BDD patients than in OCD patients. CONCLUSION: While BDD may be associated with greater severity of depressive and anxiety symptoms than OCD, this study suggests that BDD may respond to intensive, multimodal treatment.

Adult↗
PubMed2001

Targeting of protein kinase C delta to mitochondria in the oxidative stress response.

The cellular response to oxidative stress includes the release of mitochondrial cytochrome c and the induction of apoptosis. Here we show that treatment of diverse cells with hydrogen peroxide (H2O2) induces the targeting of protein kinase C delta (PKCdelta) to mitochondria. The results demonstrate that H2O2-induced activation of PKCdelta is necessary for translocation of PKCdelta from the cytoplasm to the mitochondria. The results also show that mitochondrial targeting of PKCdelta is associated with the loss of mitochondrial transmembrane potential and release of cytochrome c. The functional importance of this event is also supported by the demonstration that H2O2-induced apoptosis is blocked by the inhibition of PKCdelta activation and translocation to mitochondria. These findings indicate that mitochondrial targeting of PKCdelta is required, at least in part, for the apoptotic response of cells to oxidative stress.

3T3 Cells↗
PubMed2001

Dialytic support in acute renal failure.

Acute renal failure is the sudden failure on the part of the kidney to maintain normal biochemical homeostasis in the body. Medical causes of acute renal failure are fluid and electrolyte depletion, infectious diarrhoea, non-diarrhoeal infections, glomerulonephritis, poisoning with heavy metals, G-6-PD deficiency, snake bite and nephrotoxic drugs. Septic abortion is the most common cause of obstetric acute renal failure. Obstructive uropathy is an important cause of surgical acute renal failure. Guidelines to non-dialytic management of acute renal failure depend on the patient's condition which includes volume status, hyperkalaemia, acidaemia, uraemia and whether he/she is receiving medication and having adequate nutrition. Several dialytic methods are currently available for renal replacement therapy--intermittent haemodialysis and peritoneal dialysis are to name a few. Dialytic intervention in acute renal failure is usually considered when there is dinical evidence of uraemic symptoms or biochemical features of solute and fluid imbalance. Continuous renal replacement therapy implies to continuous replacement of renal function and it is limited to only a few big centres.

Acute Kidney Injury↗
PubMed2001

Detection of tubercle bacilli in sputum: application of sodium hypochlorite concentration method.

Tuberculosis has emerged as the leading cause of death due to single infectious agent. Sputum microscopy forms mainstay of diagnosis as it is most reliable, specific and objective method available especially in developing countries. However, this method is hampered by lack of sensitivity. Liquefaction and concentration of sputum before Ziehl Neelsen staining improves yield and also makes examination of smears rapid and convenient. A total of 304 sputum samples were studied by direct staining and after sodium hypochlorite treatment and centrifugation. Direct smears stained with Auramine-Phenol were also examined. Use of sodium hypochlorite method increased the number of positive samples from 52 to 96. No false positives were detected by either method. The method is simple as the only extra reagent required is sodium hypochlorite that is easily available. Additional advantage is that sodium hypochlorite, being a potent disinfectant, reduces the risk of laboratory acquired infections.

Humans↗
PubMed2001

Finding the retinal break in rhegmatogenous retinal detachment.

The development of subretinal fluid is governed by a limited number of anatomical factors and gravity. As a result, rhegmatogenous retinal detachments form in a predictable manner around the retinal break of their origin. The shape of the detachments points to the position of the break. The purpose of this review is to describe the characterstic contours of subretinal fluid in rhegmatogenous retinal detachments, and to highlight some rules and methodology which can help in the detection of the retinal break in phakic, psuedophakic and recurrent retinal detachments.

Cryosurgery↗
PubMed2000

Mitochondrial translocation of protein kinase C delta in phorbol ester-induced cytochrome c release and apoptosis.

Apoptosis is induced by the release of cytochrome c from mitochondria to the cytoplasm. The present studies demonstrate that the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) induces translocation of protein kinase C (PKC) delta from the cytoplasm to mitochondria. The results also show that translocation of PKCdelta results in release of cytochrome c. The functional significance of this event is further supported by the demonstration that PKCdelta translocation is required for TPA-induced apoptosis. These findings demonstrate that translocation of PKCdelta to mitochondria is responsible, at least in part, for inducing cytochrome c release and apoptosis.

Apoptosis↗
PubMed2000

Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease.

The major known genetic risk for Alzheimer's disease (AD), apolipoprotein E-4 (APOE-4), is associated with lowered parietal, temporal, and posterior cingulate cerebral glucose metabolism in patients with a clinical diagnosis of AD. To determine cognitive and metabolic decline patterns according to genetic risk, we investigated cerebral metabolic rates by using positron emission tomography in middle-aged and older nondemented persons with normal memory performance. A single copy of the APOE-4 allele was associated with lowered inferior parietal, lateral temporal, and posterior cingulate metabolism, which predicted cognitive decline after 2 years of longitudinal follow-up. For the 20 nondemented subjects followed longitudinally, memory performance scores did not decline significantly, but cortical metabolic rates did. In APOE-4 carriers, a 4% left posterior cingulate metabolic decline was observed, and inferior parietal and lateral temporal regions demonstrated the greatest magnitude (5%) of metabolic decline after 2 years. These results indicate that the combination of cerebral metabolic rates and genetic risk factors provides a means for preclinical AD detection that will assist in response monitoring during experimental treatments.

Aged↗
PubMed2000

Translocation of SAPK/JNK to mitochondria and interaction with Bcl-x(L) in response to DNA damage.

Activation of the stress-activated protein kinase (SAPK/JNK) by genotoxic agents is necessary for induction of apoptosis. We report here that ionizing radiation ionizing radiation exposure induces translocation of SAPK to mitochondria and association of SAPK with the anti-apoptotic Bcl-x(L) protein. SAPK phosphorylates Bcl-x(L) on threonine 47 (Thr-47) and threonine 115 (Thr-115) in vitro and in vivo. In contrast to wild-type Bcl-x(L), a mutant Bcl-x(L) with the two threonines substituted by alanines (Ala-47, Ala-115) is a more potent inhibitor of ionizing radiation-induced apoptosis. These findings indicate that translocation of SAPK to mitochondria is functionally important for interactions with Bcl-x(L) in the apoptotic response to genotoxic stress.

Apoptosis↗
PubMed2000

Autonomic studies in hypertensive patient with unusual sexual dysfunction: response to reserpine.

The authors examined a 48-year-old man with a history of hypertension (6 years) and a history of erection and ejaculation during cold exposure and confrontation with fear (20 years). Exposing the foot to cold water induced ejaculation in 10 seconds. A variety of antihypertensive medications resulted in control of hypertension, without improvement in ejaculatory dysfunction. Similarly, prazosin controlled the blood pressure, but not the episodes of ejaculation. Treatment with reserpine resulted in gradual reduction in blood pressure and an improvement in ejaculatory dysfunction.

Autonomic Nervous System↗
PubMed2000

Dominant late-onset retinal degeneration with regional variation of sub-retinal pigment epithelium deposits, retinal function, and photoreceptor degeneration.

PURPOSE: To clarify the pathogenesis of late-onset retinal degeneration (L-ORD), an autosomal dominant disorder characterized by thick deposits of lipid-rich material between the retinal pigment epithelium (RPE) and Bruch's membrane. STUDY DESIGN: Comparative clinicopathologic case report and case series. TISSUES: Eyes of an 82-year-old L-ORD eye donor and an age-matched control. SUBJECTS: Five descendants of the eye donor and his affected sister. METHODS: The eyes were processed for histopathologic examination, including electron microscopy and immunohistochemistry. Family members were examined clinically and with retinal function tests. RESULTS: The L-ORD eye had sub-RPE deposits that were positive for lipid, including esterified and unesterified cholesterol. The deposits were thinnest in the macula, which retained the highest percentage of photoreceptors. In the periphery, RPE thinning and photoreceptor loss correlated with thickness of the sub-RPE deposits. The eye donor was asymptomatic until his late 50s, when he developed problems with adapting to darkness. At age 68, the eye donor had normal acuity but a midperipheral scotoma and subnormal electroretinograms (ERGs); visual loss was progressive. The five descendants (at the time of examination ages 44-58) of the eye donor and his affected sister, who were at 50/50 risk of inheriting L-ORD, had normal ERGs, but four showed defects in dark adaptation. The dark adaptation abnormalities had a distribution similar to the thickness of the sub-RPE deposits in the eye donor, with slow kinetics in the midperiphery and normal kinetics centrally. CONCLUSIONS: The L-ORD donor eye differed from a previous case in the regional distribution of sub-RPE deposits and photoreceptors. In the next generation of this L-ORD family, the first expression of disease, abnormal dark adaptation, mirrored the regional distribution of the deposits in the donor eye. The fine structure and staining characteristics of the sub-RPE deposits in L-ORD resemble those in age-related macular degeneration and Sorsby fundus dystrophy.

Adult↗
PubMed2000

Functional neuroimaging and the neuroanatomy of obsessive-compulsive disorder.

Functional neuroimaging studies have advanced the understanding of the brain mediation of OCD by orbitofrontal-subcortical circuitry, but much is still unknown. Phenotypic heterogeneity could account for many of the inconsistencies among previous neuroimaging studies of OCD. Current studies are seeking to find the neurobiological basis of OCD symptom subtypes and predictors of treatment response. Future studies combining genetics and basic neuroanatomic research with neuroimaging may clarify the cause and pathophysiology of OCD. Although many lines of evidence point to dysfunction of orbitofrontal-subcortical circuitry in patients with OCD, many questions remain unanswered. Some have suggested that orbitofrontal-subcortical hyperactivity in OCD may be the result of abnormal neuroanatomic development of these structures or a failure of pruning of neuronal connections between them, as occurs in normal development, but no postmortem neuroanatomic studies of OCD exist to delineate its pathophysiology. Interventions that directly alter the indirect-direct pathway balance within frontal-subcortical circuits will allow for direct testing of the pathophysiologic hypotheses presented here. The roles of various neurochemical systems in OCD are similarly unclear. Although an abundance of indirect evidence suggests serotonergic abnormalities in patients with OCD, no direct evidence demonstrates what those abnormalities are or whether they are primary or secondary phenomena in patients with OCD. Ongoing studies of 5-HT synthesis in the brains of patients with OCD may shed light on this question.

Brain↗
PubMed2000

Biodistribution of amphotericin B when delivered through cholesterol hemisuccinate vesicles in normal and A. fumigatus infected mice.

PURPOSE: This study compared the biodistribution of two amphotericin B formulations in normal and Aspergillus infected mice. Amphotericin B cholesterol hemisuccinate vesicles (ABCV) which reduces the toxicity of amphotericin B and thereby enhances its therapeutic efficacy in a murine model of aspergillosis was compared with conventional amphotericin B deoxycholate suspension (AmB(DOC)). METHODS: ABCV (12 mg/kg wt) and AmB(DOC) (2 mg/kg wt) were intravenously administered to normal and A. fumigatus infected mice. The concentration of amphotericin B in plasma and other organs was determined at different time points. RESULTS: It was observed that ABCV had a significantly different pharmacokinetic profile compared to conventional amphotericin B. In comparison to AmB(DOC) significantly lower levels of amphotericin B were observed in kidneys and plasma, the major target organs of toxicity. Animals receiving ABCV demonstrated high levels of amphotericin B in liver (38% retention till 48 h) and spleen (2.6% retention till 48 h) in comparison to AmB(DOC) (7.3% and 0.21% retention in liver and spleen respectively till 48 h). Biodistribution studies of ABCV in infected mice demonstrated that there was a moderate enhancement in levels of amphotericin B in liver, spleen, lungs and kidneys as compared to normal mice and the plasma levels were reduced. However, such observations were not made after AmB(DOC) administration to infected mice except for kidneys in which there was a marked increase in uptake as compared to normal mice. CONCLUSIONS: Our results suggest that prolonged retention of high concentrations of ABCV in reticuloendothelial system organs is the reason for its reduced toxicity. Enhanced localization of the drug at the infected site may lead to improvement in therapeutic efficacy.

Amphotericin B↗