Biomedical subjects
Publications and source records attributed to S Joshi.
Opioids are widely and successfully used for control of pain, including pain arising from the viscera. Constipating, sedating, respiratory depressant and other effects of opioids, however, often limit their long-term use in the treatment of a variety of visceral pain states. Accordingly, understanding visceral pain mechanisms and its modulation is important to developing improved strategies for pain control.
PROBLEM: Conventional immunization using whole sperm containing multiple antigens as the immunogen followed by hybridoma technology usually gives antibodies to antigens invariably of testicular origin, probably because of the strong immunogenic nature of these antigens. Therefore, an alternate approach of neonatal tolerization or subtractive immunization has been utilized to raise antibodies specific to epididymis by suppressing immune response to testicular antigens. METHOD OF STUDY: Neonatal mice were tolerized with testicular sperm proteins on days 0 and 5. These animals were then immunized with epididymal sperm proteins on day 21, followed by two boosters at biweekly intervals. Sera from these mice were used to localize epididymis-specific antigens. RESULTS: Sera from mice that were tolerized to testicular sperm proteins and later immunized with epididymal sperm proteins reacted only with epididymal proteins. CONCLUSION: The results of this study demonstrate that neonatal tolerization with testicular sperm proteins, followed by immunization with epididymal sperm proteins, enhances the production of antibodies to proteins exclusively of epididymal origin.
In five patients with mesial temporal sclerosis, the authors verified the precision and reproducibility of hippocampal segmentations with deformation-based magnetic resonance (MR) imaging. The overall percentage overlap between automated segmentations was 92.8% (SD, 3.5%), between manual segmentations was 73.1% (SD, 9.5%), and between automated and manual segmentations was 74.8% (SD, 10.3%). Deformation-based hippocampal segmentations provided a precise method of hippocampal volume measurement in this patient population.
Vascular networks adapt structurally in response to local pressure and flow and functionally in response to the changing needs of tissue. Whereas most research has either focused on adaptation of the macrocirculation, which primarily transports blood, or the microcirculation, which primarily controls flow, the present work addresses adaptation of the small conductance vessels in between, which both conduct blood and resist flow. A simple hemodynamic model is introduced consisting of three parts: 1) bifurcating arterial and venous trees, 2) an empirical description of the microvasculature, and 3) a target shear stress depending on pressure. This simple model has the minimum requirements to explain qualitatively the observed structure in normotensive conditions. It illustrates that flow regulation in the microvasculature makes adaptation in the larger conductance vessels stable. Furthermore, it suggests that structural changes in response to hypotension can account for the observed decrease in the lower limit of autoregulation in chronically hypotensive vasculature. Independent adaptation to local conditions thus yields a coordinated set of structural changes that ultimately adapts supply to demand.
The anti-inflammatory activity of sodium pyruvate was evaluated in acute and chronic models of inflammation in rats. Oral administration of sodium pyruvate at three different dose levels of 125, 250 and 500 mg/kg body weight significantly inhibited the carrageenan induced acute paw edema in a dose dependent manner. The effect of 500 mg/kg sodium pyruvate was comparable to that of 12.5 mg/kg of standard diclofence. In Freund's adjuvant arthritis model, oral administration of sodium pyruvate at the submaximal dose of 250 mg/kg once daily upto one week before Freund's adjuvant injection and immediately by the same route on the 7th day of adjuvant injection significantly reduced the edema at 18 hours after the challenge. The treatment was continued for 14 days thereafter in two divided doses of 125 mg/kg in the morning and 125 mg/kg in the evening. Sodium pyruvate showed significant anti-inflammatory activity at the 14th day (chronic phase) also. To conclude, sodium pyruvate exhibited significant anti-inflammatory activity in both the models of inflammation which could be attributed to its antioxidant properties.
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We examine the life cycles of gasoline, diesel, compressed natural gas (CNG), and ethanol (C2H5OH)-fueled internal combustion engine (ICE) automobiles. Port and direct injection and spark and compression ignition engines are examined. We investigate diesel fuel from both petroleum and biosources as well as C2H5OH from corn, herbaceous bio-mass, and woody biomass. The baseline vehicle is a gasoline-fueled 1998 Ford Taurus. We optimize the other fuel/powertrain combinations for each specific fuel as a part of making the vehicles comparable to the baseline in terms of range, emissions level, and vehicle lifetime. Life-cycle calculations are done using the economic input-output life-cycle analysis (EIO-LCA) software; fuel cycles and vehicle end-of-life stages are based on published model results. We find that recent advances in gasoline vehicles, the low petroleum price, and the extensive gasoline infrastructure make it difficult for any alternative fuel to become commercially viable. The most attractive alternative fuel is compressed natural gas because it is less expensive than gasoline, has lower regulated pollutant and toxics emissions, produces less greenhouse gas (GHG) emissions, and is available in North America in large quantities. However, the bulk and weight of gas storage cylinders required for the vehicle to attain a range comparable to that of gasoline vehicles necessitates a redesign of the engine and chassis. Additional natural gas transportation and distribution infrastructure is required for large-scale use of natural gas for transportation. Diesel engines are extremely attractive in terms of energy efficiency, but expert judgment is divided on whether these engines will be able to meet strict emissions standards, even with reformulated fuel. The attractiveness of direct injection engines depends on their being able to meet strict emissions standards without losing their greater efficiency. Biofuels offer lower GHG emissions, are sustainable, and reduce the demand for imported fuels. Fuels from food sources, such as biodiesel from soybeans and C2H5OH from corn, can be attractive only if the co-products are in high demand and if the fuel production does not diminish the food supply. C2H5OH from herbaceous or woody biomass could replace the gasoline burned in the light-duty fleet while supplying electricity as a co-product. While it costs more than gasoline, bioethanol would be attractive if the price of gasoline doubled, if significant reductions in GHG emissions were required, or if fuel economy regulations for gasoline vehicles were tightened.
In the present study MRSA prevalence increased from 12% in 1992 to 80.83% in 1999. Indian literature shows that MRSA incidence was as low as 6.9% in 1988 and reached to 24% and 32.6% in Vellore and Lucknow in 1994 and was of the same order in Mumbai, Delhi and Bangalore in 1996 and in Rohtak and Mangalore in 1999. However, in some of the centres it was as high as 87%. All the MRSA isolates in India including in the present study were sensitive to vancomycin and resistance to netilmycin appears to be low among MRSA isolates in India. All the MRSA isolates were also found to be sensitive to teicoplanin in the present study. Like in other Indian studies, resistance to cotrimoxazole, erythromycin, gentamicin, other penicillins and cephalosporins appeared to be a common feature for MRSA isolates in the present study.
A 49-year-old woman presenting with recurrent, reversible brainstem symptoms and a distal basilar artery aneurysm underwent balloon test occlusion. Five minutes after balloon inflation she developed a reversible isolated dysarthria. Despite failing the test occlusion (and after an additional brainstem event), the patient underwent surgery with placement of a clip across the basilar artery. The operation was tolerated without complication. The authors conclude that 1) pure dysarthria may be a symptom of temporary basilar artery occlusion and 2) balloon testing may overestimate the risk of basilar artery clipping.
A hammerhead ribozyme targeted against the HIV-1 env coding region was expressed as part of the anticodon loop of human tRNA3Lys without sacrificing tRNA stability or ribozyme catalytic activity. These tRNA-ribozymes were isolated from a library which was designed to contain linkers (sequences connecting the ribozyme to the anticodon loop) of random sequence and variable length. The ribozyme target site was provided in cis during selection and in trans during subsequent characterization. tRNA-ribozymes that possessed ideal combinations of linkers were expected to recognize the cis target site more freely and undergo cleavage. The cleaved molecules were isolated, cloned and characterized. Active tRNA-ribozymes were identified and the structural features conducive to cleavage were defined. The selected tRNA-ribozymes were stable, possessed cleavage rates lower or similar to the linear hammerhead ribozyme, and could be transcribed by an extract containing RNA polymerase III. Retroviral vectors expressing tRNA-ribozymes were tested in a human CD4+ T cell line and were shown to inhibit HIV-1 replication. These tRNA3Lys-based hammerhead ribozymes should therefore prove to be valuable for both basic and applied research. Special application is sought in HIV-1 or HIV-2 gene therapy.
This paper describes methods for white matter segmentation in brain images and the generation of cortical surfaces from the segmentations. We have developed a system that allows a user to start with a brain volume, obtained by modalities such as MRI or cryosection, and constructs a complete digital representation of the cortical surface. The methodology consists of three basic components: local parametric modeling and Bayesian segmentation; surface generation and local quadratic coordinate fitting; and surface editing. Segmentations are computed by parametrically fitting known density functions to the histogram of the image using the expectation maximization algorithm [DLR77]. The parametric fits are obtained locally rather than globally over the whole volume to overcome local variations in gray levels. To represent the boundary of the gray and white matter we use triangulated meshes generated using isosurface generation algorithms [GH95]. A complete system of local parametric quadratic charts [JWM+95] is superimposed on the triangulated graph to facilitate smoothing and geodesic curve tracking. Algorithms for surface editing include extraction of the largest closed surface. Results for several macaque brains are presented comparing automated and hand surface generation.
A targeted RNase would be ideal for gene therapy of several acquired and inherited disorders. Such an RNase may be engineered to contain a ribonucleolytic domain and a specific target RNA binding domain. To demonstrate the feasibility of this approach, an RNase targeted against human immunodeficiency virus (HIV) RNA--Tev-RNase T1--was designed and tested for its use in HIV-1 gene therapy. A human CD4+ T lymphoid (MT4) cell line and human peripheral blood lymphocytes (PBLs) were transduced with retroviral vectors lacking or expressing the tevT1 gene. Expression of enzymatically functional Tev-RNase T1 protein and its lack of toxicity was demonstrated in stable MT4 transductants. Compared with control cells lacking this protein, both transduced MT4 cells and PBLs expressing Tev-RNase T1 delayed HIV-1 replication. Tev-RNase T1 was shown to act after integration, since HIV-1 proviral DNA could be detected, but the amount of HIV-1 RNA produced in MT4 cells and PBLs was significantly decreased. This study demonstrates the feasibility of a targeted RNase strategy for therapeutic use.
BACKGROUND: Hepatitis E virus (HEV) is responsible for most of the hepatitis epidemics in the developing world and it frequently affects young adults. Therefore, common perception is that it does not affect children. METHODS: A group of 20 school children (13 years old) were possibly exposed to hepatitis E virus infection during a 2 day trekking trip. Epidemiological and clinical information was correlated to the presence of the hepatitis E virus genome and antibodies to HEV structural and non-structural proteins found in the blood of the children, using polymerase chain reaction and line immunoassay techniques. RESULTS: Ten children developed icteric hepatitis, seven prodrome-like illness without jaundice while three remained asymptomatic. Immunoglobulin M (IgM) antibodies to open reading frame (ORF)2 protein (pORF2) were detected in all 19 children tested, whereas 11 and 10 of the children were positive for IgM antibodies against ORF1 (pORF1) and ORF3 (pORF3) proteins, respectively. The rate of HEV infection was found to be 85%. Viraemia was observed in 11 children and was present in four of the seven anicteric patients (55%) compared with six of the nine (66%) icteric patients. One child without any symptom also had viraemia. CONCLUSIONS: The data obtained indicate a high susceptibility of children for HEV infection and a frequently prolonged viraemia in those infected.
Opioid receptors (mu, delta and kappa) are known to regulate diverse physiological functions and yet, at the molecular level, they are coupled to a seemingly identical set of G proteins. A recent study has discerned subtle differences between the opioid receptors in their ability to activate the pertussis toxin-insensitive G16. Differences in microarchitecture might be magnified when these receptors are provided with 'non-native' partners. Here, we examined whether the opioid receptors can interact productively with a set of chimeric Galphaq subunits which are known to link many Gi-coupled receptors to phosphoinositide-specific phospholipase C (PI-PLC). The qi5, qo5 and qz5 chimeras have the last five residues of Galphaq replaced by those of Galphai, Galphao and Galphaz, respectively. Except for mu-receptor and qo5, each pair of opioid receptor and Galphaq chimera allowed opioid agonists to stimulate PI-PLC in transfected COS-7 cells. The Galphaq chimera-mediated responses were ligand selective, agonist dose dependent and saturable. The most robust responses were obtained with kappa-receptor and qi5 or qz5, whereas the coupling of delta- and mu-receptors to Galphaq chimeras produced much weaker responses. Among the Galphaq chimeras, qo5 was less efficiently coupled to the opioid receptors. As revealed by radioligand binding assays and immunoblot analysis, differences in the efficiency of coupling were not due to variations in the expression of receptors and Galphaq chimeras. Differences in the magnitude of PI-PLC responses are thus likely to represent structural incompatibility between opioid receptors and Galphaq chimeras, suggesting that each opioid receptor possesses unique structural surfaces for the binding of G proteins.
OBJECTIVE: Extremely high flow through arteriovenous malformations (AVMs) may limit the safety and effectiveness of endovascular glue therapy. To achieve a more controlled deposition of glue, we used transient but profound systemic hypotension afforded by an intravenously administered bolus of adenosine to induce rapidly reversible high-degree atrioventricular block. METHODS AND CASE REPORT: A patient with a large high-flow occipital AVM fed primarily by the posterior cerebral artery underwent n-butyl cyanoacrylate glue embolization. Nitroprusside-induced systemic hypotension did not adequately reduce flow through the nidus, as determined by contrast injection in the feeding artery. In a dose-escalation fashion, boluses of adenosine were administered to optimize the dose and verify that there was no flow reversal in the AVM and no other unexpected hemodynamic abnormalities by arterial pressure measurements and transcranial Doppler monitoring of the posterior cerebral artery feeding the AVM. Thereafter, 64 mg of adenosine was rapidly injected as a bolus to provide 10 to 15 seconds of systemic hypotension (approximately 20 mm Hg). Although there were conducted beats and some residual forward flow through the AVM during this time, the mean systemic and feeding artery pressures were roughly similar and remained relatively constant. A slow controlled injection of n-butyl cyanoacrylate glue was then performed, with excellent filling of the nidus. CONCLUSION: Adenosine-induced cardiac pause may be a viable method of partial flow arrest in the treatment of cerebral AVMs. Safe, deep, and complete embolization with a permanent agent may increase the likelihood of endovascular therapy's being curative or may further improve the safety of microsurgical resection.
OBJECTIVES: Measures capable of detecting early alterations of brain function during acute cerebral ischaemia have not been adequately defined. Internal carotid artery (ICA) test occlusions provide a well controlled environment to investigate the effects of reversible acute hemispheric hypoperfusion on brain function. A continuous time estimation task was developed that reliably demonstrated alterations in higher cerebral function before development of any deficits in elementary neurological function during ICA balloon catheter test occlusions. In the present study, we hypothesised that alterations in our behavioural task would correlate significantly with absolute level of ipsilateral CBF. METHODS: Twenty five patients underwent awake ICA test occlusions during which sustained attention and ipsilateral CBF were measured simultaneously using our time estimation task and the intracarotid 133Xe washout method. Alteration in sustained attention was correlated with CBF after occlusion using Fisher's exact test. RESULTS: Deterioration in sustained attention was significantly associated with ipsilateral CBF below 30 ml/g/min (Fisher's exact test, p=0.047). Changes in individual patients' performance on the behavioural task correlated in real time with changes occurring either at the point of occlusion or at a specific threshold of induced hypotension. Sensitivity for our behavioural test in predicting CBF was 75%; specificity 70%. CONCLUSIONS: Monitoring sustained attention during carotid balloon test occlusions seems to be a sensitive means to detect decreases in CBF as measured by 133Xe washout. Correlation between higher cerebral function and CBF can allow more detailed investigations of physiological relations between cerebral haemodynamics and brain function in human conditions of cerebral ischaemia.