Biomedical subjects
Publications and source records attributed to A Tandon.
Meleney's gangrene is almost exclusively postoperative and is caused by multiple bacteria. This case review describes the conservative management of Meleney's gangrene in a young patient following a Caesarean section.
OBJECTIVE: To improve the evidence base for health policy by devising a method to measure and monitor the performance of health systems. DESIGN: Estimation of the relation between levels of population health and the inputs used to produce health. SETTING: 191 countries. MAIN OUTCOME MEASURE: Health system efficiency (performance). RESULTS: Estimated efficiency varied from nearly fully efficient to nearly fully inefficient. Countries with a history of civil conflict or high prevalence of HIV and AIDS were less efficient. Performance increased with health expenditure per capita. CONCLUSIONS: Increasing the resources for health systems is critical to improving health in poor countries, but important gains can be made in most countries by using existing resources more efficiently.
Subacute hepatitis is a common and distinct clinicopathological entity due to Hepatitis B and E viruses in India. Lamivudine has been established as a safe and effective antiviral agent for the treatment of chronic HBV hepatitis. This drug was administered orally along with intravenous (I/V) Glycyrrhizin, an immunomodulator drug, in an open pilot trial to assess its efficacy in the treatment of subacute hepatitis. The results establish the safety and efficacy of Lamivudine in combination with I.V. Glycyrrhizin in subacute Hepatitis.
The presenilins and nicastrin, a type 1 transmembrane glycoprotein, form high molecular weight complexes that are involved in cleaving the beta-amyloid precursor protein (betaAPP) and Notch in their transmembrane domains. The former process (termed gamma-secretase cleavage) generates amyloid beta-peptide (Abeta), which is involved in the pathogenesis of Alzheimer's disease. The latter process (termed S3-site cleavage) generates Notch intracellular domain (NICD), which is involved in intercellular signalling. Nicastrin binds both full-length betaAPP and the substrates of gamma-secretase (C99- and C83-betaAPP fragments), and modulates the activity of gamma-secretase. Although absence of the Caenorhabditis elegans nicastrin homologue (aph-2) is known to cause an embryonic-lethal glp-1 phenotype, the role of nicastrin in this process has not been explored. Here we report that nicastrin binds to membrane-tethered forms of Notch (substrates for S3-site cleavage of Notch), and that, although mutations in the conserved 312-369 domain of nicastrin strongly modulate gamma-secretase, they only weakly modulate the S3-site cleavage of Notch. Thus, nicastrin has a similar role in processing Notch and betaAPP, but the 312-369 domain may have differential effects on these activities. In addition, we report that the Notch and betaAPP pathways do not significantly compete with each other.
An 80-year-old woman presented with right endophthalmitis, characterized by chalky white deposits covering her posterior capsule. This occurred 17 months after uncomplicated right cataract surgery. A three-port pars plana vitrectomy and partial posterior capsulectomy isolated Bacillus circulans, and the patient made a rapid and full recovery on topical cephalothin and prednisolone acetate 1%. The case demonstrates that, unlike endophthalmitis due to other Bacillus spp., B. circulans endophthalmitis does not necessarily follow a fulminant course. It is the first report describing a subacute presentation, and response to posterior capsulectomy and simple antibiotic therapy It is also the first description of B. circulans causing white plaques in the posterior capsule, a finding characteristic of chronic endophthalmitis and previously considered pathognomonic of Proprionibacterium acnes endophthalmitis.
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).
The presenilin proteins are involved in the proteolytic processing of transmembrane proteins such as Notch/lin-12 and the beta-amyloid precursor protein (betaAPP). Mutation of a conserved cysteine (Cys60Ser) in the C. elegans presenilin sel-12 has a loss-of-function effect on Notch/lin-12 processing similar to that of null mutations in sel-12. In contrast, in mammalian cells, most missense mutations increase gamma-secretase cleavage of betaAPP. We report here that mutation of this conserved cysteine (Cys92Ser) in human presenilin 1 confers a loss-of-function effect in C. elegans, but causes increased A beta42 secretion in mammalian cells. These data suggest that the role of presenilins in Notch/lin-12 signalling and betaAPP processing are either separately regulated activities or independent activities of the presenilins.
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.
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.
To determine the intellectual, psycho-educational and functional status of low birth weight (LBW) survivors (birth weight < or = 2000 gms) beyond 5 years of age and to compare their status with normal birth weight counterparts. This was cross-sectional study. On hospital based cohort on longitudinal follow-up at the High Risk and Well Baby Clinics of a teaching hospital. 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. Fifty-nine LBW children and fifty-seven matched control children participated in the study. 27 of LBW children were examined at a mean age of 7.0 +/- 1.1 years (group I) and 32 were examined at a mean age of 10.6 +/- 1.2 years (group II). The LBW children as a group performed in the normal range on the tests of cognition and academic achievement, but were significantly disadvantaged (p < 0.005) as compared to controls. A higher percentage of LBW children had low scores on the Bender Gestalt. Test as compared to controls but the difference was not significant. A significantly higher proportion of LBW children of both the groups showed the presence of soft neurological signs as compared to controls. The social quotient as assessed by the vineland Social Maturity Scale was significantly lower in the LBW children as compared to controls. Thus, though the LBW children were performing in the normal range on various measures, comparison with the control group showed that they were clearly disadvantaged on nearly every measure tested, emphasizing the need for early detection and referral for special education.
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 (NTF/CTF). Mutation of either of two conserved aspartate residues in transmembrane domains inhibits both presenilin-endoproteolysis and the proteolytic processing of APP and Notch. We show that aspartate-mutant holoprotein presenilins are not incorporated into the high molecular weight, NTF/CTF-containing complexes. Aspartate-mutant presenilin holoproteins also preclude entry of endogenous wild-type PS1/PS2 into the high molecular weight complexes, but do not affect the incorporation of wild-type holoproteins into lower molecular weight holoprotein complexes. These data suggest that the loss-of-function aspartate-mutants cause altered PS complex maturation, and argue that the functional presenilin moieties are contained in the high molecular weight presenilin NTF/CTF-containing complexes.
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.
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.
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.
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.
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.
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.
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.