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Biomedical subjects

S Srinivasan

Publications and source records attributed to S Srinivasan.

At least 91 records · Page 5Linked to original sources
PubMed2001

Molecular mechanisms for the antiapoptotic action of gastrin.

Gastrin (G17) has a CCK-B receptor-mediated growth-promoting effect on the AR42J rat acinar cell line. We examined whether G17 inhibits apoptosis induced by serum withdrawal of AR42J cells and CHO-K1 cells stably expressing CCK-B receptors (CHO-K1/CCK-B cells). Cellular apoptosis was measured by flow cytometry and the terminal deoxynucleotidyltransferase-mediated dUTP-FITC nick end-labeling method. Serum withdrawal induced AR42J and CHO-K1/CCK-B cell apoptosis. Addition of 10 nM G17 reversed these effects. We examined the action of G17 (10 nM) on phosphorylation and activation of protein kinase B/Akt, a kinase known to promote cell survival. Akt phosphorylation and activation were measured by kinase assays and Western blots with an anti-phospho-Akt antibody. G17 stimulated Akt phosphorylation and activation. G17 induction of Akt phosphorylation was inhibited by the phosphoinositide 3-kinase (PI 3-kinase) inhibitors LY-294002 (10 microM) and wortmannin (200 nM) but not by the mitogen-activated protein kinase kinase 1 inhibitor PD-98059 (50 microM). To study the role of p38 kinase in G17 signaling to Akt, we examined the effect of G17 on p38 kinase activation and phosphorylation using kinase assays and Western blots with an anti-phospho-p38 kinase antibody. G17 induced p38 kinase activity at doses and with kinetics similar to those observed for Akt induction. The p38 kinase inhibitor SB-203580 inhibited G17 induction of Akt phosphorylation and activation at a concentration (10 microM) 10-fold higher than necessary to block p38 kinase (1 microM), suggesting the possible involvement of kinase activities other than p38 kinase. Transduction of AR42J cells with the adenoviral vector Adeno-dn Akt, which overexpresses an inhibitor of Akt, reversed the antiapoptotic action of G17. In conclusion, G17 promotes AR42J cell survival through the induction of Akt via PI 3-kinase and SB-203580-sensitive kinase activities.

Animals↗
PubMed2001

Selected Contribution: Osteocytes upregulate HIF-1alpha in response to acute disuse and oxygen deprivation.

Loss of mechanical loading, or disuse, rapidly precipitates locally mediated bone resorption. However, the pathway by which this process is initiated and mediated is poorly understood. In this study, we used a complementary in vivo and in vitro approach to determine whether disuse-induced osteocyte hypoxia resulted in upregulation of the hypoxia-dependent transcription factor HIF-1alpha. We found that acute disuse (1-5 days) resulted in a significant increase in the percentage of osteocytes staining positive for HIF-1alpha vs. normal bone (30.9 +/- 6.1 vs. 14.1 +/- 3.8%) and that this response was uniform around the cortex. In addition, we found that acute oxygen deprivation (4-12 h of 2% O2) resulted in a 2.1- to 3.7-fold upregulation of HIF-1alpha protein expression in MLO-Y4 osteocyte-like cells compared with cells cultured in parallel under normal oxygen conditions. Given known HIF-1alpha targets genes, we suggest that osteocyte hypoxia and subsequent upregulation of hypoxia-dependent pathways may serve to initiate and mediate disuse-induced bone resorption.

Animals↗
PubMed2001

A new method of analysis of standing foot pressure images for detection of the plantar ulcers in early-stage diabetic neuropathy.

In this paper, studies are performed on a large number of diabetic patients belonging to different levels of plantar sensation loss, by analyzing the standing foot pressure images in the frequency domain. A new parameter, the power ratio (PR, the ratio of high frequency power to the total power in an image), is used to distinguish between foot pressure image patterns of diabetic neuropathic subjects (at different levels of sensation loss) and those of normal feet. The foot areas of the diabetic subjects are scanned in 10 specified areas using Semmes Weinstein's nylon monofilaments to quantify the diabetic neuropathy. A statistical study of the mean values of this parameter in different plantar areas of the feet for different levels of diabetic neuropathy indicates distinguishing trends. The result could help in the early detection of low-level sensation loss by establishing the threshold of the PR in a particular area above which there could be the possibility of plantar ulcer formation. This information could be utilized by orthopedic surgeons to devise early corrective methods to protect the feet from further damage due to plantar ulcers.

Adult↗
PubMed2001

Furano pyrimidines as novel potent and selective anti-VZV agents.

Bicyclic furano pyrimidine nucleosides have been found to be highly potent and selective inhibitors of varicella zoster virus (VZV). They are inactive against herpes simplex virus and have been known for several decades as (unwanted) synthetic by-products in the Pd-catalysed coupling of acetylenes to 5-iodo nucleosides. These fluorescent bicyclic nucleosides are now established as a new family of potent antivirals. They are unusual in that they exhibit complete specificity for VZV and require an alkyl (or alkylaryl) side-chain for biological activity. The latter requirement confers extremely high lipophilicities on these compounds, unknown amongst chemotherapeutic nucleosides, which may be of considerable importance in formulation, dosing and tissue distribution. The most potent compounds reported are p-alkylaryl compounds, with EC50 values below 1 nM versus VZV and selectivity index values of around 1,000,000. Here, we review the discovery, synthesis, characterization, antiviral profile, SAR, mechanism of action and development prospects for this new family of antivirals.

Antiviral Agents↗
PubMed2001

Multiple genetic changes are required for efficient immortalization of different subtypes of normal human mammary epithelial cells.

Multiple Genetic Changes Are Required for Efficient Immortalization of Different Subtypes of Normal Human Mammary Epithelial Cells. Breast cancer is the second leading cause of cancer-related deaths of women in the U.S. About 180,000 new cases of breast cancer are diagnosed each year, a quarter of them fatal. Early detection is the key to the survival of these patients. However, there are no molecular markers to detect breast cancer at very early stages. A hurdle in understanding the early molecular changes in breast cancer has been the difficulty in establishing premalignant lesions and primary breast tumors as in vitro cell cultures. Normal epithelial cells grow for a finite life span and then senesce. Immortalization is defined by continuous growth of otherwise senescing cells and is believed to represent an early stage in tumor progression. To examine these early stages, we and others have developed in vitro models of mammary epithelial cell immortalization. These models have been extremely important in understanding the role of various tumor suppressor pathways that maintain the normal phenotypes of mammary epithelial cells. In this paper, we describe the establishment of these models and their relevance to understanding the molecular changes that occur in early breast cancer. These models have helped to identify molecular changes that occur in early breast cancers and appear to be well suited to identify novel markers for early diagnosis of breast cancer.

Breast↗
PubMed2001

Fish hook injury to the eyelid - an unusual case.

Fishing is recreational activity enjoyed by millions of people worldwide. Although uncommon in developing countries it is a popular pastime in the Western world. and, given this popularity, a number of associated personal injuries are probably inevitable. We report a case of fish hook injury to the eyelid and discuss the various techniques available for removal of fish hooks. The terminologies associated with various parts of the fish hook are also illustrated.

Eye Foreign Bodies↗
PubMed2000

Resistance-modifying agents. 9. Synthesis and biological properties of benzimidazole inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase.

The nuclear enzyme poly(ADP-ribose) polymerase (PARP) facilitates the repair of DNA strand breaks and is implicated in the resistance of cancer cells to certain DNA-damaging agents. Inhibitors of PARP have clinical potential as resistance-modifying agents capable of potentiating radiotherapy and the cytotoxicity of some forms of cancer chemotherapy. The preclinical development of 2-aryl-1H-benzimidazole-4-carboxamides as resistance-modifying agents in cancer chemotherapy is described. 1H-Benzimidazole-4-carboxamides, particularly 2-aryl derivatives, are identified as a class of potent PARP inhibitors. Derivatives of 2-phenyl-1H-benzimidazole-4-carboxamide (23, K(i) = 15 nM), in which the phenyl ring contains substituents, have been synthesized. Many of these derivatives exhibit K(i) values for PARP inhibition < 10 nM, with 2-(4-hydroxymethylphenyl)-1H-benzimidazole-4-carboxamide (78, K(i) = 1.6 nM) being one of the most potent. Insight into structure-activity relationships (SAR) for 2-aryl-1H-benzimidazole-4-carboxamides has been enhanced by studying the complex formed between 2-(3-methoxyphenyl)-1H-benzimidazole-4-carboxamide (44, K(i) = 6 nM) and the catalytic domain of chicken PARP. Important hydrogen-bonding and hydrophobic interactions with the protein have been identified for this inhibitor. 2-(4-Hydroxyphenyl)-1H-benzimidazole-4-carboxamide (45, K(i) = 6 nM) potentiates the cytotoxicity of both temozolomide and topotecan against A2780 cells in vitro (by 2.8- and 2.9-fold, respectively).

Antineoplastic Agents↗
PubMed2000

PKN binds and phosphorylates human papillomavirus E6 oncoprotein.

The high risk human papillomaviruses (HPVs) are associated with carcinomas of cervix and other genital tumors. Previous studies have identified two viral oncoproteins E6 and E7, which are expressed in the majority of HPV-associated carcinomas. The ability of high risk HPV E6 protein to immortalize human mammary epithelial cells has provided a single gene model to study the mechanisms of E6-induced oncogenic transformation. In recent years, it has become clear that in addition to E6-induced degradation of p53 tumor suppressor protein, other targets of E6 are required for mammary epithelial cells immortalization. Using the yeast two-hybrid system, we have identified a novel interaction of HPV16 E6 with protein kinase PKN, a fatty acid- and Rho small G protein-activated serine/threonine kinase with a catalytic domain highly homologous to protein kinase C. We demonstrate direct binding of high risk HPV E6 proteins to PKN in wheat-germ lysate in vitro and in 293T cells in vivo. Importantly, E6 proteins of high risk HPVs but not low risk HPVs were able to bind PKN. Furthermore, all the immortalization-competent and many immortalization-non-competent E6 mutants bind PKN. These data suggest that binding to PKN may be required but not sufficient for immortalizing normal mammary epithelial cells. Finally, we show that PKN phosphorylates E6, demonstrating for the first time that HPV E6 is a phosphoprotein. Our finding suggests a novel link between HPV E6 mediated oncogenesis and regulation of a well known phosphorylation cascade.

Amino Acid Substitution↗
PubMed2000

Relation of abdominal height to cardiovascular risk factors in young adults: the Bogalusa heart study.

Obesity and fat patterns are important predictors of coronary heart disease risk. The relations of abdominal height (sagittal diameter) and various obesity measures to coronary heart disease risk factors were examined in a community-based sample of 409 Blacks and 1,011 Whites aged 20-38 years in Bogalusa, Louisiana (1995-1996). Obesity measures used included weight, waist circumference, waist:hip ratio, waist:height ratio, abdominal height, triceps and subscapular skinfold thicknesses, body mass index, and conicity index. Abdominal height was highly correlated with other obesity measures, especially waist circumference (0.937-0.944, p < 0.001), and was least correlated with height. In multivariate analysis, abdominal height was an independent predictor of levels of total cholesterol, triglycerides, very low density lipoprotein cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, glucose, and insulin and of systolic and diastolic blood pressures (p < 0.05 to p < 0.001), with total R2 values ranging from 0.13 to 0.52. Abdominal height contributed more to the prediction of blood pressure than did other measures of central obesity. In canonical analysis, abdominal height was correlated more strongly with the coronary disease risk factor variables as a group than were other obesity measures. These results suggest that abdominal height adds another dimension to measures of obesity in that it may help to assess a component of visceral fat that other measures miss.

Abdomen↗
PubMed2000

Multiple O-glycoforms on the spore coat protein SP96 in Dictyostelium discoideum. Fuc(alpha1-3)GlcNAc-alpha-1-P-Ser is the major modification.

A decreased level of fucosylation on certain spore coat proteins of Dictyostelium discoideum alters the permeability of the spore coat. Here the post-translational modifications of a major spore coat protein, SP96, are studied in a wild type strain (X22) and a fucosylation-defective mutant (HU2470). A novel phosphoglycan structure on SP96 of the wild type strain, consisting of Fuc(alpha1-3)GlcNAc-alpha-1-P-Ser(,) was identified by electrospray ionization mass spectrometry and NMR. It was shown using monosaccharide and gas chromatography mass spectrometry analysis that SP96 in the mutant HU2470 contained approximately 20% of wild type levels of fucose, as a result of a missing terminal fucose on the novel glycan structure. The results support previous predictions, based on inhibition studies on different fucose-deficient strains, about the nature of monoclonal antibody epitopes identified by monoclonal antibodies MUD62 and MUD166, which are known to identify O-linked glycans (Champion, A., Griffiths, K., Gooley, A. A., Gonzalez, B. Y., Gritzali, M., West, C. M., and Williams, K. L. (1995) Microbiology 141, 785-797). Quantitative studies on wild type SP96 indicated that there were approximately 60 sites with phosphodiester-linked N-acetylglucosamine-fucose disaccharide units and a further approximately 20 sites with fucose directly linked to the protein. Over 70% of the serine sites are modified, with less than 1% of these sites as phosphoserine. Threonine and tyrosine residues were not found to be modified.

Amino Acids↗
PubMed2000

Enhancing the aqueous solubility of d4T-based phosphoramidate prodrugs.

A range of polyether para-substituted phosphoramidates were synthesised and found to have substantially elevated aqueous solubilities compared to the underivatised parent prodrug. A 30-fold increase in aqueous solubility could be achieved without a substantial decrease of in vitro activity against HIV-1. Replacement of the aryl (i.e. phenolic) moiety by tyrosine led to a substantial enhancement in aqueous solubility but also to a decrease in antiviral potency. A previously unobserved trend was identified, relating increased aryl substituent steric bulk to decreased antiviral activity.

Amides↗
PubMed2000

Factors predicting occult bacteremia in young children.

A febrile child without a definite localizing sign of infection may be in initial phase of bacteremia which unless treated would result in systemic complication. These instances are referred to as "Occult bacteremia". The common pathogens isolated in these children are Streptococcus pneumoniae, Hemophilus influenzae and Neisseria meningitidis. A hundred consecutive children in the age group of 3-36 months attending pediatric outpatient department and casualty were clinically evaluated using AIOS (acute illness observation scale) score and were subjected to complete blood counts, smear for malarial parasites, ESR and blood culture. In the 19-month study period, 4 instances of occult bacteremia were identified. Streptococcus pneumoniae was cultured in 3 cases and H. influenzae in one. A febrile and toxic child in the age group of 3-36 months has a high risk of occult bacteremia. High fever of temperature > or = 102 degrees F, ESR > or = 15 mm/hour, and total leukocyte count > or = 15,000/mm3, in a child with AIOS score of > or = 10 may be considered for more detailed investigations and early intervention with antimicrobial therapy.

Bacteremia↗
PubMed2000

Fetal echocardiography.

Since the first report of fetal echocardiography in 1972 by Winsberg, several advances in ultrasound technology have occurred allowing detailed evaluation of cardiac anatomy in the second trimester fetus. Fetal echo is indicated in high risk pregnancies where the chances of fetus having a congenital heart disease (CHD) are likely to be high e.g., in fetus with extracardiac anomalies picked up on obstetric ultrasound, those with a history of CHD in family, maternal diabetes (especially insulin dependent), maternal connective tissue disorder etc. The reported sensitivity of fetal echo has ranged from 4-96% in various series depending upon the equipment, level of training, study design and examination technique. Although many CHD can be detected in four chamber view, an important group malformations that would need early intervention are likely to be missed. Hence a detailed echocardiographic examination including the outflow views must be done. Defects like atrial septal defect and patent ductus arteriosus cannot be diagnosed in fetal echo, as these are part of normal fetal physiology. Other CHD like coarctation of aorta, small ventricular septal defects, mild valvular stenosis, partial anomalous pulmonary venous drainage are also difficult to diagnose. Ultrasound assessment of fetus, however, has a clear role in the diagnosis, monitoring and management of fetuses with sustained arrhythmias. Prenatal diagnosis of CHD helps in planning the optimal management of the baby e.g. a fetus with a ductus dependent lesion can be planned to be delivered in a tertially care centre for stabilisation and early initiation of prostaglandin therapy to avoid acidosis and organ damage. Future of fetal medicine lies in fetal cardiac surgery for which echocardiography will play a very important role.

Fetal Diseases↗
PubMed2000

Structural response and relative strength of a laminated composite hip prosthesis: effects of functional activity.

To obtain a better appreciation for the structural performance of a laminated composite hip prosthesis (CP), we examined in situ prosthesis structural response and relative strengths as a function of walking and stair climbing using our previously developed analysis guidelines. Accordingly, we examined overall prosthesis structural response utilizing a global continuum level modeling approach and prosthesis relative strengths using a local microstructural (or ply-level) modeling approach. As a reference and control, we examined the structural performance of the intact natural femur (NAT) and a titanium alloy (Ti) based hip prosthesis. In terms of the overall structural response, i.e., the femur/prosthesis deformational response, stem/bone interfacial stress transfer, and calcar strain energy density restored, the performance of the CP prosthesis was moderately improved over that of the control Ti prosthesis and better approximates the NAT response. In terms of relative strength, we found that the neck of the CP prosthesis failed for all activities with the exception of the mid-stance phase of level walking. However, the prosthesis appears to have sufficient relative strength for function at positions distal to the neck of the prosthesis. While these results dampen enthusiasm for consideration of laminated composite hip prostheses designed with a shape based on a metal alloy implant, they indirectly support consideration of alternate hip prosthesis structural designs such as using a better supported prosthesis neck or utilizing metal/composite hybrid constructions. Importantly, our simulation and analysis approach could be utilized in the design of other laminated composite biomedical structural components.

Alloys↗
PubMed2000

Crossing the finish line of development: regulated secretion of Dictyostelium proteins.

The genesis of the spore coat of Dictyostelium represents an exquisite example of developmentally regulated protein secretion. The proteins that are destined to be assembled into the extracellular matrix of the spore coat are stored in unique prespore vesicles that are triggered to secrete their contents at terminal differentiation. The regulation of this process is being revealed by the identification of the individual proteins in these vesicles.

Animals↗
PubMed2000

Canalicular fluid flow induced by bending of a long bone.

Interstitial fluid flow has been hypothesized to underly mechanotransduction within bone. Here, we present an analytical model of fluid flows induced at the level of osteocyte canaliculi when a long bone is subject to functionally relevant bending loads. Dynamic bending of cortical bone results in a non-uniform longitudinal normal strain environment in which strain magnitude varies both temporally (i.e., at a given location, strain varies as a function of time) and spatio-temporally (i.e., at each given point in time, strain varies between locations). To account for the complexity posed by these two aspects of the strain environment, canalicular fluid flows were decomposed into temporal and spatio-temporal components. In terms of distribution around the cortex, temporal and spatio-temporal flows in the radial direction were both maximal near sites of peak strain magnitude. Spatio-temporal flows in the circumferential direction, in contrast, were maximal near locations of minimal strain magnitude (i.e. near the neutral axis). All fluid flow components were maximal during the first load cycle and reached markedly reduced steady state levels during subsequent load cycles. The novelty of the described model is that it provides the first estimate of canalicular fluid flows induced within a complexly loaded long bone. As the model may be readily extended to provide a simplistic accounting of the fluid flow profiles induced during functional loading and other exogenous loading regimes, the approach will enhance the ability to examine fluid flow related mechanotransduction within bone.

Adaptation, Physiological↗