Biomedical subjects

A Tandon

Publications and source records attributed to A Tandon.

At least 19 recordsLinked to original sources

PubMed2000

Carboxyl-terminal fragments of Alzheimer beta-amyloid precursor protein accumulate in restricted and unpredicted intracellular compartments in presenilin 1-deficient cells.

Absence of functional presenilin 1 (PS1) protein leads to loss of gamma-secretase cleavage of the amyloid precursor protein (betaAPP), resulting in a dramatic reduction in amyloid beta peptide (Abeta) production and accumulation of alpha- or beta-secretase-cleaved COOH-terminal fragments of betaAPP (alpha- or beta-CTFs). The major COOH-terminal fragment (CTF) in brain was identified as betaAPP-CTF-(11-98), which is consistent with the observation that cultured neurons generate primarily Abeta-(11-40). In PS1(-/-) murine neurons and fibroblasts expressing the loss-of-function PS1(D385A) mutant, CTFs accumulated in the endoplasmic reticulum, Golgi, and lysosomes, but not late endosomes. There were some subtle differences in the subcellular distribution of CTFs in PS1(-/-) neurons as compared with PS1(D385A) mutant fibroblasts. However, there was no obvious redistribution of full-length betaAPP or of markers of other organelles in either mutant. Blockade of endoplasmic reticulum-to-Golgi trafficking indicated that in PS1(-/-) neurons (as in normal cells) trafficking of betaAPP to the Golgi compartment is necessary before alpha- and beta-secretase cleavages occur. Thus, although we cannot exclude a specific role for PS1 in trafficking of CTFs, these data argue against a major role in general protein trafficking. These results are more compatible with a role for PS1 either as the actual gamma-secretase catalytic activity or in other functions indirectly related to gamma-secretase catalysis (e.g. an activator of gamma-secretase, a substrate adaptor for gamma-secretase, or delivery of gamma-secretase to betaAPP-containing compartments).

Alzheimer Disease↗

PubMed2000

Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing.

Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2. Suppression of nicastrin expression in Caenorhabditis elegans embryos induces a subset of notch/glp-1 phenotypes similar to those induced by simultaneous null mutations in both presenilin homologues of C. elegans (sel-12 and hop-1). Nicastrin also binds carboxy-terminal derivatives of beta-amyloid precursor protein (betaAPP), and modulates the production of the amyloid beta-peptide (A beta) from these derivatives. Missense mutations in a conserved hydrophilic domain of nicastrin increase A beta42 and A beta40 peptide secretion. Deletions in this domain inhibit A beta production. Nicastrin and presenilins are therefore likely to be functional components of a multimeric complex necessary for the intramembranous proteolysis of proteins such as Notch/GLP-1 and betaAPP.

Amino Acid Sequence↗

PubMed2000

Mutation of conserved aspartates affects maturation of both aspartate mutant and endogenous presenilin 1 and presenilin 2 complexes.

Presenilin (PS1 and PS2) holoproteins are transiently incorporated into low molecular weight (MW) complexes. During subsequent incorporation into a higher MW complex, they undergo endoproteolysis to generate stable N- and C-terminal fragments. Mutation of either of two conserved aspartate residues in transmembrane domains inhibits both presenilin-endoproteolysis and the proteolytic processing of beta-amyloid precursor protein and Notch. We show that although PS1/PS2 endoproteolysis is not required for inclusion into the higher MW N- and C-terminal fragment-containing complex, aspartate mutant holoprotein presenilins are not incorporated into the high MW complexes. Aspartate mutant presenilin holoproteins also preclude entry of endogenous wild type PS1/PS2 into the high MW complexes but do not affect the incorporation of wild type holoproteins into lower MW holoprotein complexes. These data suggest that the loss of function effects of the aspartate mutants result in altered PS complex maturation and argue that the functional presenilin moieties are contained in the high molecular weight complexes.

Aspartic Acid↗

PubMed2000

Molecular genetics of Alzheimer's disease: the role of beta-amyloid and the presenilins.

Alzheimer's disease is the most common neurodegenerative disorder of aging, accounting for an estimated two-thirds of all cases of senile dementia. Epidemiologic studies have failed to resolve any single cause of Alzheimer's disease and suggest a complex etiology, with environmental and genetic factors influencing the pathogenesis. Although the majority of cases are sporadic, a small number display familial clustering. Genetic analyses of these pedigrees have identified four genes that are involved in the development of Alzheimer's disease.

Alzheimer Disease↗

PubMed1999

Effect of lithium on hepatic and serum elemental status under different dietary protein regimens.

Lithium carbonate at the dose level of 1.1 g/kg was administered in diet to normal (18% protein), low-protein- (LP; 8%) and high-protein (HP; 30% diet)-fed rats for a period of 1 mo. The LP diet resulted in a significant decrease in the hepatic levels of zinc, iron, copper, manganese, calcium, and serum levels of calcium and sodium. The HP diet caused a marked decrease in copper and calcium levels in liver, but an increase in potassium levels in serum was observed. Lithium treatment to normal rats led to a significant reduction in the hepatic contents of zinc, copper, potassium, calcium, and serum contents of potassium and sodium, whereas an elevation in serum contents of calcium was noticed. Administration of lithium to protein-deficient rats increased the hepatic concentration of manganese and serum concentration of calcium and the levels almost reached the normal limits. On the other hand, there was a marked depression in potassium contents in the serum of LP- as well as HP-fed rats following lithium treatment when compared to LP and HP groups, respectively.

Animals↗

PubMed1999

Status of lipid peroxidation and antioxidant enzymes in hypoxic ischemic encephalopathy.

OBJECTIVE: To compare the activities of key antioxidant enzymes [superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase] and the level of malonyl dialdehyde (MDA) in neonates with hypoxic ischemic encephalopathy (HIE) and controls. DESIGN: Prospective cross sectional study. SETTING: Tertiary care level II neonatal unit of teaching hospital. METHODS: Fifteen term new borns with HIE were registered for the study whereas normal term appropriate for gestational age babies were enrolled as controls. Clinical features were recorded. Activities of SOD, GPx, catalase and the content of MDA were estimated at 24 hours of age. The results obtained were statistically analyzed. RESULTS: Activities of SOD and Catalase and the level of MDA were significantly higher in cases as compared to the controls. There was however no significant alternation in the activity of GPx levels in both the groups. CONCLUSION: The increased activities of antioxidant enzymes are unable to counteract the excessively generated oxidants in vivo, as is evident from the increased MDA levels. Hence, oxygen free radicals may play a significant role in the pathogenesis of HIE.

Case-Control Studies↗

PubMed1998

Neurotransmitter release from semi-intact synaptosomes.

We have developed a secretion assay composed of semi-intact synaptosomes from which transmitter release is optimally evoked by micromolar Ca2+ in the presence of cytosol. Transmitter release from this preparation reconstitutes known characteristics of regulated exocytosis and is accompanied by a marked decrease in synaptic vesicles. The assay is useful in characterizing the components known to be involved in transmitter release, and should also facilitate the identification of additional factors that are important for this process.

Animals↗

PubMed1998

Differential regulation of exocytosis by calcium and CAPS in semi-intact synaptosomes.

Using a novel approach to measure exocytosis in vitro from semi-intact synaptosomes, we establish that the Ca2+-dependent release of glutamate requires cytosolic factors for mobilization from the reserve pool. The cytosolic activity for glutamate release was not satisfied by CAPS, a soluble component required for norepinephrine (NE) release. Moreover, the CAPS-independent glutamate release from synaptic vesicles (SVs) was 200-fold less sensitive to Ca2+ than that required for dense core vesicles (DCVs). The differential regulation of exocytosis by CAPS, Ca2+, and potential novel cytosolic factor(s) suggests that the docking and fusion machinery controlling DCVs has diverged from that regulating glutamate-containing SVs.

Animals↗

PubMed1998

Mutations in GDI1 are responsible for X-linked non-specific mental retardation.

Rab GDP-dissociation inhibitors (GDI) are evolutionarily conserved proteins that play an essential role in the recycling of Rab GTPases required for vesicular transport through the secretory pathway. We have found mutations in the GDI1 gene (which encodes uGDI) in two families affected with X-linked non-specific mental retardation. One of the mutations caused a non-conservative substitution (L92P) which reduced binding and recycling of RAB3A, the second was a null mutation. Our results show that both functional and developmental alterations in the neuron may account for the severe impairment of learning abilities as a consequence of mutations in GDI1, emphasizing its critical role in development of human intellectual and learning abilities.

Brain↗

PubMed1998

Clinical assessment of nutritional status at birth.

OBJECTIVE: Clinical assessment of nutritional status of neonate using CAN score and comparison with other methods of determining intrauterine growth. DESIGN: Cross sectional study. SETTING: Tertiary care hospital. SUBJECTS: 637 consecutive, liveborn singleton neonates with known gestational age and no major congenital malformation. METHODS: Birth weight, length, midarm circumference and head circumference recorded in newborns. Ponderal index and mid arm to head circumference ratio was calculated. Clinical assessment of nutritional status was done on the basis of CAN score and compared with other methods. RESULTS: CAN score < 25 separated 60% of the babies as well nourished and 40% as malnourished. Weight for age and Ponderal Index classified 70-75% of babies as well nourished (AGA) and 25-30% as malnourished. Also MAC/HC classified nearly half the babies as well nourished and half as malnourished. CONCLUSION: CAN score may be a simple clinical index for identifying fetal malnutrition and for prediction of neonatal morbidity associated with it, without the aid of any sophisticated equipments.

Anthropometry↗

PubMed1998

Cognitive abilities of asphyxiated survivors beyond 5 years of age.

OBJECTIVE: To evaluate the intellectual, psychoeducational and social maturity of a cohort of unimpaired asphyxiated survivors beyond 5 years of age. DESIGN: Case control study on hospital based cohorts on a longitudinal follow up at High Risk and Well Baby Clinics of a teaching hospital. METHODS: The demographic data of these children was recorded. A detailed physical examination was performed. The tests of cognition included the Stanford Binet and the Raven's Progressive matrices. Academic achievement was evaluated by the Wide range achievement test-Revised (WRAT-R). Assessment of visuo-motor integration was done by the Bender Gestalt Test. The proportion of children having soft neurological signs was determined. Vineland Social Maturity Scale was performed on all children. RESULTS: Fifty-four asphyxiated and 57 matched control children participated in the study. Of the 54 asphyxiated children, 27 were tested at a mean age of 7.2 +/- 1.6 years (Group 1) and 27 were tested at a mean age of 10.9 +/- 1.52 years (Group 2). The asphyxiated children as a group performed in the normal range on tests of cognition and academic achievement but were significantly disadvantaged (p < 0.005) as compared to controls. A higher percentage of asphyxiated children had low scores on the Bender Gestalt Test as compared to controls but the difference was not significant. A significantly higher proportion of asphyxiated children of both the groups showed the presence of soft neurological signs as compared to controls. Approximately 11% of the asphyxiated children performed in the abnormal range in the Vineland Social Maturity Scale. CONCLUSION: Cognitive abilities of asphyxiated children beyond the age of 5 years are impaired in comparison to controls, emphasizing the need for early detection and referral for special education.

Adolescent↗

PubMed1997

Effect of lithium on hepatic drug-metabolizing enzymes of protein-deficient rats.

Protein deficiency was produced by feeding synthetic 8%-protein diet. Lithium carbonate at the dose level of 1.1g/kg diet was administered to normal and protein-deficient rats for a period of one mo. A significant inhibition in the levels of cytochrome (cyt) P450, cyt b5, glutathione (GSH), glutathione S-transferase (GST) and glutathione peroxidase (GPx), but an increase in gamma-glutamyl transpeptidase (gamma-GT), was observed in low-protein LP-fed rats. Lithium treatment to normal rats caused no significant change in the activities of cyt P450, cyt b5, GST, and GSH levels, whereas there was elevation in the activities of gamma-GT and GPx and suppression in glutathione reductase (GRd) activity. Lithium administration to LP-fed rats resulted in significant increases in the hepatic gamma-GT and GPx activities.

Animals↗

PubMed1996

Structure and mutational analysis of Rab GDP-dissociation inhibitor.

The crystal structure of the bovine alpha-isoform of Rab GDP-dissociation inhibitor (GDI), which functions in vesicle-membrane transport to recycle and regulate Rab GTPases, has been determined to a resolution of 1.81 A. GDI is constructed of two main structural units, a large complex multisheet domain I and a smaller alpha-helical domain II. The structural organization of domain I is surprisingly closely related to FAD-containing monooxygenases and oxidases. Sequence-conserved regions common to GDI and the choroideraemia gene product, which delivers Rab to catalytic subunits of Rab geranylgeranyltransferase II, are clustered on one face of the molecule. The two most sequence-conserved regions, which form a compact structure at the apex of GDI, are shown by site-directed mutagenesis to play a critical role in the binding of Rab proteins.

Adaptor Proteins, Signal Transducing↗

PubMed1996

Fulminant hepatitis in a tropical population: clinical course, cause, and early predictors of outcome.

The profiles of patients with fulminant hepatic failure (FHF) from developing countries have not been reported earlier. The current study was conducted prospectively, at a single tertiary care center in India, to document the demographic and clinical characteristics, natural course, and causative profile of patients with FHF as well as to define simple prognostic markers in these patients. Four hundred twenty-three consecutive patients with FHF admitted from January 1987 to June 1993 were included in the study. Each patient's serum was tested for various hepatotropic viruses. Univariate Cox's regression for 28 variables, multivariate Cox's proportional hazard regression, stepwise logistic regression, and Kaplan-Meier survival analysis were done to identify independent predictors of outcome at admission. All patients presented with encephalopathy within 4 weeks of onset of symptoms. Hepatotropic viruses were the likely cause in most of these patients. Hepatitis A (HAV), hepatitis B (HBV), hepatitis D (HDV) viruses, and antitubercular drugs could be implicated as the cause of FHF in 1.7% (n= 7), 28% (n= 117), 3.8% (n= 16), and 4.5% (n= 19) patients, respectively. In the remaining 62% (n= 264) of patients the serological evidence of HAV, HBV, or HDV infection was lacking, and none of them had ingested hepatotoxins. FHF was presumed to be caused by non-A, non-B virus(es) infection. Sera of 50 patients from the latter group were tested for hepatitis E virus (HEV) RNA and HCV RNA. In 31 (62%), HEV could be implicated as the causative agent, and isolated HCV RNA could be detected in 7 (19%). Two hundred eighty eight (66%) patients died. Approximately 75% of those who died did so within 72 hours of hospitalisation. One quarter of the female patients with FHF were pregnant. Mortality among pregnant females, nonpregnant females, and male patients with FHF was similar (P > .1). Univariate analysis showed that age, size of the liver assessed by percussion, grade of coma, presence of clinical features of cerebral edema, presence of infection, serum bilirubin, and prothrombin time prolongation over controls at admission were related to survival (P < .01). The rapidity of onset of encephalopathy and cause of FHF did not influence the outcome. Cox's proportional hazard regression showed age > or = 40 years, presence of cerebral edema, serum bilirubin > or = 15 mg/dL, and prothrombin time prolongation of 25 seconds or more over controls were independent predictors of outcome. Ninety-three percent of the patients with three or more of the above prognostic markers died. The sensitivity, specificity, positive predictive value, and the negative predictive value of the presence of three or more of these prognostic factors for mortality was 93%, 80%, 86%, and 89.5%, respectively, with a diagnostic accuracy of 87.3%. We conclude that most of our patients with FHF might have been caused by hepatotropic viral infection, and non-A, non-B virus(es) seems to be the dominant hepatotropic viral infection among these patients. They presented with encephalopathy within 4 weeks of the onset of symptoms. Pregnancy, cause, and rapidity of onset of encephalopathy did not influence survival. The prognostic model developed in the current study is simple and can be performed at admission.

Adolescent↗

PubMed1996

Effects of colchicine application to preganglionic axons on choline acetyltransferase activity and acetylcholine content and release in the superior cervical ganglion.

These experiments investigate the effect of block, by colchicine, of fast axonal transport in the cat's cervical sympathetic trunk (CST) on the superior cervical ganglion's choline acetyltransferase (ChAT) enzyme activity, acetylcholine (ACh) content, and ACh release. Electron microscopy on the segment of the CST exposed to colchicine 1 or 4 days earlier showed disappearance of microtubules and accumulation of vesicles and smooth membrane tubules but no disruption of the axonal cytomatrix. At 4 days following colchicine treatment, the number and size of synaptic boutons per grid square in the ganglion ipsilateral to the colchicine-treated CST were similar to those in the control ganglion. At 2 and 4 days following exposure of the CST to colchicine, ChAT activity in the ipsilateral ganglion was reduced to 78 +/- 8 and 54 +/- 8% of control values, respectively. ACh stores in the ganglia were also reduced (to 81 +/- 6% of control values at 2 days and to 51 +/- 5% of control values at 4 days). Ganglionic transmission and its sensitivity to blockade by hexamethonium during 2-Hz CST stimulation were not impaired at day 4 postcolchicine. ACh release evoked by 2-Hz stimulation of colchicine-treated axons was similar to release from untreated axons, despite the decrease in the ganglionic ACh content. In contrast, ACh release evoked by 20-Hz stimulation was depressed. The amount of ACh released during 5-Hz stimulation in the presence of vesamicol by the terminals of colchicine-treated axons was similar to that released by the terminals of untreated axons. These results suggest the following conclusions: (a) Colchicine-sensitive fast axonal transport contributes significantly to maintaining ChAT stores in preganglionic axon terminals. (b) The half-life of ChAT in sympathetic preganglionic terminals is approximately 4 days. (c) One consequence of colchicine-induced block of axonal transport is a reduced ACh content of preganglionic nerve terminals. (d) This decrease in ACh content appears to be the result of a loss in a reserve transmitter pool, whereas the size of the readily releasable compartment is maintained.

Acetylcholine↗

PubMed1996

Epidemiology of hepatitis B virus infection in India.

The average estimated carrier rate of hepatitis B virus (HBV) in India is 4%, with a total pool of approximately 36 million carriers. Wide variations in social, economic, and health factors in different regions may explain variations in carrier rates from one part of the country to another. Professional blood donors constitute the major high risk group for HBV infection in India, with a hepatitis B surface antigen positivity rate of 14%. Blood transfusions represent the most important route of HBV transmission among adults. However, most of India's carrier pool is established in early childhood, predominantly by horizontal spread due to crowded living conditions and poor hygiene. Acute and subacute liver failure are common complications of viral hepatitis in India and HBV is reckoned to be the aetiological agent in 42% and 45% of adult cases, respectively. HBV is reported to be responsible for 70% of cases of chronic hepatitis and 80% of cases of cirrhosis of the liver. About 60% of patients with hepatocellular carcinoma are HBV marker positive. Small numbers of patients have been reported to be infected with the pre-core mutant virus but none with the S mutant. Coinfection with hepatitis C virus or hepatitis delta virus is comparatively uncommon. In conclusion, hepatitis B is a major public health problem in India and will continue to be until appropriate nationwide vaccination programmes and other control measures are established.

Hepatitis B↗

PubMed1995

Increased acetylcholine content induced by antidromic stimulation of a sympathetic ganglion: a possible retrograde action of adenosine.

Prolonged high-frequency orthodromic stimulation of superior cervical ganglia is known to result in increased acetylcholine (ACh) synthesis and ACh content after the period of stimulation. In a previous study, we provided evidence to suggest that adenosine acts as an extracellular signal to activate this increased ACh synthesis and we proposed that the source of that adenosine might be postsynaptic. Thus, the purpose of the present study was to test whether direct stimulation of the post-ganglionic nerves could affect ganglionic ACh content. Antidromic conditioning of ganglia (15 Hz, 45 min) did not affect significantly their ACh content. However, if ganglia were allowed a 15-min rest period after this antidromic conditioning, their ACh stores were increased by 20%; a similar increase was induced by 4-Hz stimulation before the rest period. During the 15-Hz antidromic stimulation, ACh release was not clearly increased above the basal level, suggesting that preganglionic nerve endings were not stimulated to an extent that could explain the increased ACh content. Orthodromic stimulation (5 Hz) of ganglia 15 min after they had been subjected to antidromic conditioning (15 Hz, 45 min) showed increased ACh release in comparison with that from control unconditioned ganglia. Moreover, the extra ACh released by the conditioned ganglia was quantitatively similar to the increase in the ACh stores, as if most, or all, of the additional ACh was released by preganglionic stimulation. If the antidromic conditioning and the rest period were done during perfusion with Ca(2+)-free medium, the ganglia did not accumulate extra ACh.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1995

p53 and human papilloma virus type 16 in cervical intraepithelial neoplasia and carcinoma.

A series of cervical biopsies and excision specimens representing normal cervical epithelium, metaplastic epithelium, cervical intraepithelial neoplasia and cervical carcinoma were examined for the presence of p53 in relation to the human papillomavirus type 16 (HPV 16). The results show that p53 accumulation in premalignant cervical lesions is almost identical to the low levels detected in normal endo- and ectocervical epithelia, reserve cells, immature and mature squamous metaplastic epithelium. p53 levels were low and seem to be independent of the grade in cervical intraepithelial neoplasia (CIN). However, carcinomas of the cervix contained high levels of immunohistochemically detectable p53. Apparently, a p53 mutation is not an early factor in cervical carcinogenesis. Furthermore, our studies demonstrate that alterations in p53 levels and the presence of HPV 16 are not mutually exclusive markers of cervical tumorigenesis. This contrasts with several reports in the literature and underlines the observation that p53 expression is probably an inadequate prognosticator for estimating progression or regression of CIN lesions.

DNA, Viral↗