Biomedical subjects

V Balasubramanian

Publications and source records attributed to V Balasubramanian.

At least 19 recordsLinked to original sources

PubMed2006

A distributed model of carbohydrate transport and metabolism in the liver during rest and high-intensity exercise.

A model of reaction and transport in the liver was developed that describes the metabolite concentration and reaction flux dynamics separately within the tissue and blood domains. The blood domain contains equations for convection, axial dispersion, and transport to the surrounding tissue; and the tissue domain consists of reactions representing key carbohydrate metabolic pathways. The model includes the metabolic heterogeneity of the liver by incorporating spatial variation of key enzymatic maximal activities. Simulation results of the overnight fasted, resting state agree closely with experimental values of overall glucose uptake and lactate output by the liver. The incorporation of zonation of glycolytic and gluconeogenic enzyme activities causes the expected increase in glycolysis and decrease in gluconeogenesis along the sinusoid length from periportal to perivenous regions, while fluxes are nearly constant along the sinusoid length in the absence of enzyme zonation. These results confirm that transport limitations are not sufficient to account for the observed tissue heterogeneity of metabolic fluxes. Model results indicate that changes in arterial substrate concentrations and hepatic blood flow rate, which occur in the high-intensity exercise state, are not sufficient to shift the liver metabolism enough to account for the 5-fold increase in hepatic glucose production measured during exercise. Changes in maximal activities, whether caused by exercise-induced changes in insulin, glucagon, or other hormones are shown to be needed to achieve the expected glucose output. This model provides a framework for evaluating the relative importance to hepatic function of various phenomenological changes that occur during exercise. The model can also be used to assess the potential effect of metabolic heterogeneity on metabolism.

Carbohydrate Metabolism↗

PubMed2006

Moxifloxacin, ofloxacin, sparfloxacin, and ciprofloxacin against Mycobacterium tuberculosis: evaluation of in vitro and pharmacodynamic indices that best predict in vivo efficacy.

Members of the fluoroquinolone class are being actively evaluated for inclusion in tuberculosis chemotherapy regimens, and we sought to determine the best in vitro and pharmacodynamic predictors of in vivo efficacy in mice. MICs for Mycobacterium tuberculosis H37Rv were 0.1 mg/liter (sparfloxacin [SPX]) and 0.5 mg/liter (moxifloxacin [MXF], ciprofloxacin [CIP], and ofloxacin [OFX]). The unbound fraction in the presence of murine serum was concentration dependent for MXF, OFX, SPX, and CIP. In vitro time-kill studies revealed a time-dependent effect, with the CFU reduction on day 7 similar for all four drugs. However, with a J774A.1 murine macrophage tuberculosis infection model, CIP was ineffective at up to 32x MIC. In addition, MXF, OFX, and SPX exhibited less activity than had been seen in the in vitro time-kill study. After demonstrating that the area under the concentration-time curve (AUC) and maximum concentration of drug in plasma were proportional to the dose in vivo, dose fractionation studies with total oral doses of 37.5 to 19,200 mg/kg of body weight (MXF), 225 to 115,200 mg/kg (OFX), 30 to 50,000 mg/kg (SPX), and 38 to 100,000 mg/kg (CIP) were performed with a murine aerosol infection model. MXF was the most efficacious agent (3.0+/-0.2 log10 CFU/lung reduction), followed by SPX (1.4+/-0.1) and OFX (1.5+/-0.1). CIP showed no effect. The ratio of the AUC to the MIC was the pharmacodynamic parameter that best described the in vivo efficacy. In summary, a lack of intracellular killing predicted the lack of in vivo activity of CIP. The in vivo rank order for maximal efficacy of the three active fluoroquinolones was not clearly predicted by the in vitro assays, however.

Animals↗

PubMed2005

Texture analysis of foot sole soft tissue images in diabetic neuropathy using wavelet transform.

The paper presents a new method of characterisation of texture changes in foot sole soft tissue ultrasound (US) images, as observed to occur in diabetic subjects, using wavelet transforms. US images of the soft tissue subcutaneous layer were taken with a 7.5 MHz linear transducer probe placed parallel to the skin surface. The foot sole hardness was characterised by Shore level. A 2D discrete wavelet transform was performed on the US images to extract features that encode the internal state of the foot sole soft tissue. The global energy feature computed at the output of each wavelet channel was found to achieve excellent delineation between the normal and the diabetic groups. An important finding was a strong correlation, in the order of 0.84 and above, between the feature values that reflect changes in the internal arrangement of the tissue, and the externally measurable hardening of the skin, characterised by the Shore levels, with the latter known to be high for diabetics. A comparison drawn between diabetic ulcer and non-ulcer groups established a change in the order of 122-311% in the textural parameter, as influenced by a corresponding 66.7-200% change in the respective Shore values. Thus US examination of foot sole soft tissue and its texture analysis may serve as sources of valuable information regarding the internal changes taking place with progressive hardening of the soft tissue and thereby help the clinician in taking appropriate preventive measures.

Adult↗

PubMed2004

Isoniazid pharmacokinetics-pharmacodynamics in an aerosol infection model of tuberculosis.

Limited data exist on the pharmacokinetic-pharmacodynamic (PK-PD) parameters of the bactericidal activities of the available antimycobacterial drugs. We report on the PK-PD relationships for isoniazid. Isoniazid exhibited concentration (C)-dependent killing of Mycobacterium tuberculosis H37Rv in vitro, with a maximum reduction of 4 log10 CFU/ml. In these studies, 50% of the maximum effect was achieved at a C/MIC ratio of 0.5, and the maximum effect did not increase with exposure times of up to 21 days. Conversely, isoniazid produced less than a 0.5-log10 CFU/ml reduction in two different intracellular infection models (J774A.1 murine macrophages and whole human blood). In a murine model of aerosol infection, isoniazid therapy for 6 days produced a reduction of 1.4 log10 CFU/lung. Dose fractionation studies demonstrated that the 24-h area under the concentration-time curve/MIC (r2 = 0.83) correlated best with the bactericidal efficacy, followed by the maximum concentration of drug in serum/MIC (r2 = 0.73).

Aerosols↗

PubMed2003

Pharmacokinetics-pharmacodynamics of rifampin in an aerosol infection model of tuberculosis.

Limited information exists on the pharmacokinetic (PK)-pharmacodynamic (PD) relationships of drugs against Mycobacterium tuberculosis. Our aim was to identify the PK-PD parameter that best describes the efficacy of rifampin on the basis of in vitro and PK properties. Consistent with 83.8% protein binding by equilibrium dialysis, the rifampin MIC for M. tuberculosis strain H37Rv rose from 0.1 in a serum-free system to 1.0 mg/ml when it was tested in the presence of 50% serum. In time-kill studies, rifampin exhibited area under the concentration-time curve (AUC)-dependent killing in vitro, with maximal killing seen on all days and with the potency increasing steadily over a 9-day exposure period. MIC and time-kill studies performed with intracellular organisms in a macrophage monolayer model yielded similar results. By use of a murine aerosol infection model with dose ranging and dose fractionation over 6 days, the PD parameter that best correlated with a reduction in bacterial counts was found to be AUC/MIC (r(2) = 0.95), whereas the maximum concentration in serum/MIC (r(2) = 0.86) and the time that the concentration remained above the MIC (r(2) = 0.44) showed lesser degrees of correlation.

Aerosols↗

PubMed2002

Oxidative stress and tumor markers in cervical cancer patients.

Cervical carcinoma is the second most common cancer worldwide. The extent of free radical induced oxidative stress can be exacerbated by the decreased efficiency of antioxidant defense mechanisms. Low levels of essential antioxidants in the circulation have been found to be associated with an increased risk of cancer. The aim of our study was to assess the extent of oxidative stress, the levels of antioxidants like superoxide dismutase (SOD), catalase (CAT), ceruloplasmin and to evaluate tumor markers such as aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) and total sialic acid (TSA) levels in circulation of women with cervical carcinoma and to compare our findings with age matched controls. Low levels of SOD and CAT observed in the circulation of cervical cancer patients may be due to their increased utilization to scavenge lipid peroxides as well as sequestration by tumor cells. Higher levels of TSA, AST, ALT and ALP, in the circulation of cervical cancer patients may be used in the diagnosis and treatment monitoring of patients with cervical carcinoma.

Adult↗

PubMed2002

The effect of fluid shear and co-adsorbed proteins on the stability of immobilized fibrinogen and subsequent platelet interactions.

The conformation adopted by the plasma protein fibrinogen upon its adsorption onto synthetic surfaces has been implicated to play an important role in determining the blood compatibility of biomaterials. It has recently been shown that adsorbed fibrinogen undergoes biologically significant conformational changes with increasing residence time on the surface of selected biomaterials. The purpose of this study was to examine the effects of co-adsorbed proteins and shear forces on such time-dependent functional changes in fibrinogen adsorbed onto polyethylene (PE), polytetrafluoroethylene (PTFE), and silicone rubber (SR). Fibrinogen was adsorbed onto these materials for 1 min and then allowed to 'reside' on these surfaces for up to 2 h prior to assessing its biological activity. Changes in fibrinogen reactivity were determined by measuring the adhesion of 51Cr-labeled platelets and the ability of blood plasma to displace previously adsorbed fibrinogen. The magnitude of platelet adhesion to substrates adsorbed with pure fibrinogen increased in the presence of shear, compared with static conditions; at the lowest shear rate of 200 s(-1), samples exhibited a 20-fold increase in adhered platelet levels. In contrast, at a higher shear rate of 1000 s(-1), the three polymers supported minimal levels of platelet attachment. Surfaces pre-adsorbed with 10% plasma did not promote a significant increase in the number of adherent platelets with increasing shear when compared with the pure fibrinogen-coated substrates. The presence of shear also significantly altered the materials' ability to retain fibrinogen. Under static conditions, the amount of fibrinogen retained following incubation in blood plasma increased on all materials with increasing fibrinogen residence time. However, the materials varied distinctly in their ability to retain adsorbed fibrinogen with increasing fibrinogen residence time, shear rate, and nature of the co-adsorbed proteins. Thus, the results from this study indicate that fluid shear, residence time of the adsorbed protein, nature of the co-adsorbed proteins, and surface chemistry of the material all play important roles in influencing platelet-surface interactions and that they act in a complex manner to influence the biocompatibility of a material.

Adsorption↗

PubMed2001

Aminonaphthoquinones--a novel class of compounds with potent antimalarial activity against Plasmodium falciparum.

Malaria is a major tropical disease, which kills two million people annually. The population at risk from this disease has increased because of the difficulties in eradicating the mosquito vector in the endemic regions and the emergence and spread of parasite resistance to all the commonly used antimalarials. Since antimalarials are the major arsenal for treatment of the disease, there is an urgent need for newer drugs with novel mechanisms of action, which will be effective against all strains of the parasite. As a part of our anti-infective drug discovery program, we have investigated 18 compounds including several synthetic and natural naphthoquinones as potential antimalarial agents. We have identified aminonaphthoquinones, as a class of antimalarial compounds with antimalarial activity against Plasmodium falciparum. Among these compounds, 2-amino-3-chloro-1,4-naphthoquinone is the most potent. It had an IC(50)of 0.18 micro M (37.3 ng ml(-1)) against the W2 clone, and is more potent than chloroquine, which had an IC(50)of 0.23 micro M (72 ng ml(-1)). It was also active against the D6 clone. In general, 2-amino-1,4-naphthoquinone analogs and the 4-amino-1,2-napthoquinone analog showed promising antimalarial activity in the bioassay. In contrast, a number of 2-hydroxy-1,4-naphthoquinones and dimeric quinones were less active.

Animals↗

PubMed2001

Metabolically efficient information processing.

Energy-efficient information transmission may be relevant to biological sensory signal processing as well as to low-power electronic devices. We explore its consequences in two different regimes. In an "immediate" regime, we argue that the information rate should be maximized subject to a power constraint, and in an "exploratory" regime, the transmission rate per power cost should be maximized. In the absence of noise, discrete inputs are optimally encoded into Boltzmann distributed output symbols. In the exploratory regime, the partition function of this distribution is numerically equal to 1. The structure of the optimal code is strongly affected by noise in the transmission channel. The Arimoto-Blahut algorithm, generalized for cost constraints, can be used to derive and interpret the distribution of symbols for optimal energy-efficient coding in the presence of noise. We outline the possibilities and problems in extending our results to information coding and transmission in neurobiological systems.

Action Potentials↗

PubMed2000

Counting probability distributions: differential geometry and model selection.

A central problem in science is deciding among competing explanations of data containing random errors. We argue that assessing the "complexity" of explanations is essential to a theoretically well-founded model selection procedure. We formulate model complexity in terms of the geometry of the space of probability distributions. Geometric complexity provides a clear intuitive understanding of several extant notions of model complexity. This approach allows us to reconceptualize the model selection problem as one of counting explanations that lie close to the "truth." We demonstrate the usefulness of the approach by applying it to the recovery of models in psychophysics.

Models, Theoretical↗

PubMed2000

Glycosaminoglycans alter the conformation of interferon-gamma.

Interferon-gamma (IFN-gamma) is a potent immunomodulatory cytokine whose physiological roles are modulated by the extracellular matrix. Here, circular dichroism and fluorescence spectroscopic techniques are used to demonstrate that low molecular weight heparin and chondroitin sulfate cause significant changes in secondary and tertiary structure of IFN-gamma. The results suggest that heparin and chondroitin sulfate modulate IFN-gamma activity by causing structural changes in the IFN-gamma dimer.

Animals↗

PubMed2000

A rapid spectrofluorimetric technique for determining drug-serum protein binding suitable for high-throughput screening.

PURPOSE: To develop and validate a rapid method for determining the dissociation constants with which pharmaceutical candidates and drugs bind to serum albumin and to alpha1-acid glycoprotein with the goal of deducing the extent of binding. METHODS: The quenching of the intrinsic tryptophan fluorescence of serum albumin and alpha1-acid glycoprotein was monitored by spectrofluorimetry and the data were used to calculate the apparent dissociation constant. Sodium warfarin was used to probe the warfarin-binding site of serum albumin and diazepam was used to probe the benzodiazepine binding site. Additionally, the binding of sodium salicylate, phenylbutazone, sulfinpyrazone, iophenoxic acid, theophylline, chloramphenicol, acetaminophen, lithium chloride and ampicillin were also investigated. Chlorpromazine hydrochloride and imipramine hydrochloride were used as probes for alpha1-acid glycoprotein. The assays were also extended to the multiwell format. The quenching curves were fitted to the quadratic binding equation to determine the dissociation constants. RESULTS: Intrinsic fluorescence measurements are an excellent predictor of the drug binding to human serum albumin and to alpha1-acid glycoprotein. These measurements detect binding to the warfarin and benzodiazepine binding sites of human serum albumin. The dissociation constants estimated using the method compare favorably to the dissociation constants previously reported by Epps et al. using extrinsic fluorescence methodology, and the results correlate well with equilibrium dialysis using drug displacement endpoints. CONCLUSIONS: These measurements can be carried out with small samples and do not require separation of the bound and unbound species. Additionally, the proposed methods eliminate membrane separations, are not compound specific and do not require analytical chromatography or mass spectrometry for quantitation. Spectrofluorimetry may prove to be a useful method for rapidly determining the protein binding of combinatorial libraries.

Anticoagulants↗

PubMed2000

Animal models for experimental tuberculosis.

Animal models for tuberculosis vaccine assays have evolved through a series of sequential experiments aimed at optimizing the activity of a particular vaccine product. As a result, studies that use different animal models do not agree on the potency ranking of antituberculosis vaccines, and each major test-system variable contributes to the disagreement. Disagreements among laboratories about the efficacy of vaccines are in part due to differences in test systems. A survey of potency assays of tuberculosis vaccines suggests that, based on the choice of a specific combination of variables in the test model, an investigator can show that any given vaccine product has superior potency. In view of these problems with animal models for research on tuberculosis vaccines, we recommend that attention should be focused on those animal models that replicate the key aspects of the natural history of human tuberculosis. The development of vaccines by means of new technologies requires animal models to assay the protective potency of vaccines that, ideally, inhibit tubercle bacilli at the point of infection. The development of new tuberculosis vaccines may be handled most efficiently in a joint venture that includes both laboratories involved in vaccine production and laboratories concerned with animal models.

Animals↗

PubMed2000

An analysis of some hypotheses related to the Chingelput bacille Calmette-Guérin trial.

Investigation of several hypotheses related to the outcome of the Chingelput Bacille Calmette-Guérin (BCG) Trial suggests at least 2 factors that might explain the major scientific puzzle of a protective effect expected of 80% and a protective effect observed of 0% (i.e., equivalent protection for BCG and placebo). One factor that explains some of the low efficacy observed for BCG in this trial is the virtual saturation level of exposure to environmental mycobacteria (EM). Studies in animal models demonstrated that the protection afforded by infection with EM was equivalent to the protection that resulted from BCG vaccination. The second factor, pathogenetic pathway, explains why there was still a high case rate for tuberculosis, even though the population was fully vaccinated by EM. This hypothesis states that tuberculosis in India, as well as in most developing countries, results primarily from exogenous reinfection, a pathway against which BCG (or EM) exerts no protective effect beyond that induced by the first episode of infection with Mycobacterium tuberculosis.

BCG Vaccine↗

PubMed1999

Residence-time dependent changes in fibrinogen adsorbed to polymeric biomaterials.

It has generally been accepted that biomaterials adsorbing the least amount of the plasma protein fibrinogen following exposure to blood will support less platelet adhesion and therefore exhibit less thrombogenicity. Several studies suggest, however, that the conformation or orientation of immobilized fibrinogen rather than the total amount adsorbed plays an important role in determining the blood compatibility of biomaterials. The purpose of this study was to investigate time-dependent functional changes in fibrinogen adsorbed to polytetrafluoroethylene (PTFE), polyethylene (PE), and silicone rubber (SR). Fibrinogen was adsorbed to these materials for 1 min and then allowed to 'reside" on the surfaces for up to 2 h prior to assessing its biological activity. Changes in fibrinogen reactivity were determined by measuring the adhesion of 51Cr-labeled platelets, the binding of a monoclonal antibody (mAb) directed against an important functional region of the fibrinogen molecule (the gamma-chain dodecapeptide sequence 400-411), and the ability of blood plasma to displace previously adsorbed fibrinogen. Platelet adhesion differed among the polymeric materials studied, and PTFE and PE samples exhibited a small decrease in adhesion with increasing fibrinogen residence time. Platelet adhesion to SR was the least among all materials studied and showed no variation with residence time. When using PTFE and SR as substrates, mAb recognition of adsorbed fibrinogen did not change with residence time whereas that on PE decreased slightly. The mAb binding was least to fibrinogen adsorbed to SR, which is in agreement with the platelet adhesion results. Finally, the ability of plasma to displace previously adsorbed fibrinogen decreased dramatically with increasing residence time on all materials. These in vitro studies support the hypothesis that fibrinogen undergoes biologically significant conformational changes upon adsorption to polymeric biomaterials, a phenomenon that may contribute to the hemocompatibility of the materials following implantation in the body.

Adsorption↗

PubMed1999

Rapid Solubility Determination Using Vapor-Phase Osmometry.

Because of the need for resource-sparing assays of the solubility of new drug candidates, we sought to develop and validate a rapid method for determining the solubility of nonvolatile pharmaceutical solids in water. Vapor-phase osmometry was used to determine the concentration of drugs in saturated solutions prepared by a rapid ultrasound-mediated dissolution protocol. The osmolality of saturated solutions as measured by the vapor-phase osmometer is an excellent predictor of the solubility of pharmaceutical solids in water. Each osmolality measurement requires less than 10 µl of saturated solution and takes less than 2 min to complete. For small-molecule drugs with solubilities greater than 10 g/kg, osmometry may prove to be a rapid and accurate method for determining the water solubilities of drugs.

Journal Article↗

PubMed1998

Cancer chemopreventive activity of synthetic colorants used in foods, pharmaceuticals and cosmetic preparations.

In continuation with our studies to uncover cancer chemopreventive effects of non-toxic natural colorants and other products of biologic and synthetic origin, we tested several Food and Drug Administration-approved synthetic colorants for antitumor promoting potential by the in vitro Epstein-Barr virus early antigen activation in Raji cells in response to the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Among 29 such colorants used in foods, pharmaceuticals and cosmetics and evaluated in vitro, six of the 10 most effective had an azo group. Three structurally unrelated colorants tested in this assay were also studied in vivo for chemoprevention of 7,12-dimethylbenz[a]anthracene (DMBA)-induced TPA-promoted mouse skin carcinogenesis. The results indicate that tartrazine, indigo carmine and erythrosine are potent inhibitors of skin tumor promotion in mice treated with DMBA and TPA.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1998

Vascular cell attachment and procoagulant activity on metal alloys.

The attachment and growth of vascular smooth muscle cells on biomaterials used as components of devices implanted in the vascular space may influence the biocompatibility of such materials. The nature of the materials may affect the attachment and/or the activation of these cells' procoagulant responses. Therefore, the main objective of this study was to measure the strength of adhesion of these vascular cells to potential biomaterials (titanium, zirconium alloys, and stainless steel) by exposing them to a range of shear stresses (50-300 dyn cm(-2)) in a parallel plate flow chamber. The procoagulant responses of the cells were evaluated by measuring the tissue factor (TF) activity promoted by the different materials under flow conditions. The materials supported distinctly different levels of initial cell adhesion in static culture. However, the fraction of adherent cells did not decline significantly with incrementally increasing shear stress within the range tested. TF expression, as measured by factor Xa (FXa) production. was material-dependent. For example, cells cultured on Ti1313 exhibited more FXa production (13.2 nM 10(-5) cells) than Ti1313(DH) (8.5 nM 10(-5) cells) or stainless steel (2 nM 10(-5) cells). Thus, our studies indicate that the level of adhesion, strength of attachment and the expression of procoagulant activity of adherent vascular cells depend strongly on the nature of the underlying biomaterial.

Alloys↗