Biomedical subjects
Publications and source records attributed to A K Shah.
Extraadrenal paragangliomas are very rare tumors arising from cells derived from the neural crest. These tumors are encountered only as case reports, and as a result, little is known of their natural history. We present a case of pancreatic paraganglioma and review all previously reported cases.
A virulent strain of pigeon pea wilt pathogen was isolated from wilted pigeon pea plants and was identified as Fusarium oxysporum f. sp. udum. Many bacterial cultures showing antagonism to the pathogen were isolated from various ecological niches. When tested under pot and field conditions, development of fusarial wilt symptoms was prevented in pigeon pea seeds treated with one such antagonist, Bacillus brevis. A formulation of B. brevis with vermiculite as a carrier had a shelf life of at least 6 months. Bacillus brevis produced an extracellular antagonistic substance which induced swelling of the pathogen's hyphal tips, and cells were bulbous and swollen with shrunken and granulated cytoplasm. The antagonistic substance also inhibited germination of conidia, and was fungicidal to the vegetative mycelia of the pathogen. Comparison of the properties of our antagonistic substance with that of known antibiotics produced by B. brevis suggests that our antagonistic substance is a novel compound. The observations reported here indicate that this strain of B. brevis may have potential as a biocontrol agent against fusarial wilt in pigeon pea.
Gastric stromal tumors display a bewildering array of immunohistological and ultrastructural features as well as variable biological behavior. These tumors are rare as compared with ones that arise from the gastric epithelium. Moreover, they have been the subjects of controversy because of their uncertain histogenesis. We report the pathological features of gastric stromal tumors we recently encountered in three patients.
Peripartum seizure is a serious disease with significant morbidity and mortality for women and their unborn children. The underlying etiologies are varied, with eclampsia and venous stroke being the most common causes. T2 weighted MR images of the brain show hyperintense lesions in either condition. Diffusion weighted MR images (DWI) of the brain is abnormal in strokes. We report three cases of eclampsia with abnormal T2 weighted images, but normal DWI. Diffusion weighted MR images in association with T2 weighted MR images can be extremely helpful in evaluation of women with new onset peripartum seizures.
Clotrimazole, a specific inhibitor of the Ca(2+) activated potassium (Gardos) channel, and the antioxidant N-acetylcysteine were found to inhibit the in vitro formation of high-density sickle cells induced by treatment with 1-chloro-2,4-dinitrobenzene (CDNB). The CDNB induced leakage of K(+) can be inhibited by treatment of SS erythrocytes with 20 mM N-acetylcysteine. We conclude that the effect of N-acetylcysteine in preventing K(+) efflux and formation of high-density sickle cells is related to its ability to protect the Gardos channel from oxidative damage caused by diminished levels of reduced glutathione. This effect is due to the ability of N-acetylcysteine to maintain an appropriate level of reduced glutathione and its direct antioxidant activity.
Cell adhesion is dependent on many factors, including the repertoire of extracellular matrix (ECM) proteins and their receptors, e.g. integrins, synthesized by the cell, the composition of the ECM adsorbed to the surface, and the intrinsic chemistry of the surface. Factors that govern bone cell, i.e. osteoblast, adhesion and ECM elaboration significantly influence its re-modeling into mature bone, and ultimately its ability to integrate with biomaterials used for orthopedic prostheses. In this study, we have investigated how treatment with bone morphogenetic protein-2 (BMP-2), a member of the transforming growth factor-beta (TGF-beta) superfamily that promotes ectopic bone formation, modulates the organization and expression of osteoblastic cell proteins. Specifically, we analyzed how BMP-2 treatment affects cytoskeletal components, ECM, and alpha 5 and beta 1 integrin receptor subunits in osteoblastic cells plated on Ti6A14V, a titanium alloy widely used for orthopedic implants that interacts with bone cells in vitro and in vivo. Osteoblastic cells were pre-treated with BMP-2 for 12 h prior to plating; BMP-2 treatment stimulated adhesion and proliferation of osteoblastic cells and this adhesive advantage was reflected in enhanced long-term matrix mineralization in the BMP-2 pretreated cultures. Confocal laser scanning microscopic analysis of BMP-2 treated cells showed that enhanced cytoskeletal organization and focal contact formation occurred. These changes were accompanied by a concomitant increase in the spatial organization of fibronectin, whereas vitronectin, collagen type I, osteopontin, and osteocalcin showed little change. The changes in ECM organization correlated with increased fibronectin, alpha 5 and beta 1 integrin subunit, and focal adhesion kinase (p125FAK) expression, as well as increased p125FAK phosphorylation. By confocal microscopy, the alpha 5 integrin subunit was more concentrated in lamellipodia after BMP-2 treatment. These results demonstrate that BMP-2 significantly altered osteoblastic cytoskeletal and ECM organization and enhanced expression of fibronectin and of specific integrin receptor subunits, with concomitant changes in the levels and phosphorylation of p125FAK. These effects may contribute to downstream cellular responses important for bone cell function, and growth.
Understanding the cellular basis of osteoblastic cell-biomaterial interaction is crucial to the analysis of the mechanism of osseointegration, a requirement of long-term orthopedic implant stability. Clinically, the amount of bone ingrowth is variable, and cellular parameters that influence ingrowth have yet to be clearly determined. In this study, two clinically relevant orthopedic alloys, titanium Ti6A14V (Ti) and cobalt-chrome-molybdenum (CC), were used for a comparative analysis of primary human osteoblastic cell adhesion and spreading, where cell adhesion represents the initial interaction between cellular elements and the biomaterial surface. The kinetic profile of adhesion revealed enhanced cell attachment upon rough Ti surfaces relative to rough CC. Using confocal laser scanning microscopy (CLSM), we observed that, during the first 12 h of contact with the substratum, osteoblastic cells were relatively less spread on rough Ti, whereas cells appeared elongated with multiple cellular extensions on rough CC. Focal adhesion contacts, as indicated by vinculin immunostaining, were distributed throughout the cells adhering to Ti, but were relatively sparse and localized to cellular processes on CC. Furthermore, three-dimensional CLSM reconstruction analysis indicated the presence of vinculin at all membrane-to-surface contact points on both Ti and CC. On Ti, these contact points closely followed the surface contour, whereas, on CC, they were restricted to relative topographic peaks only. Actin cytoskeletal reorganization was prominent in cells cultured on Ti, with stress fibers arranged throughout the cell body, whereas, on CC, actin filaments were sparse and localized primarily to cellular extensions. Because cell attachment mechanisms are likely to influence signal transduction and regulation of gene expression, these early differential responses of osteoblastic cells on Ti and CC may have functional implications on subsequent extracellular matrix mineralization and bone ingrowth at the cell-biomaterial interface.
Analysis of an exopolysaccharide of Sphingomonas paucimobilis GS-1 (EPS/GS-1) with respect to its rheological properties, cross-linking ability with chrome alum and performance test at 75 +/- 5 degrees C revealed its strong suspending ability, shear thinning property, and thixotrophic nature which are required to impart desirable rheology to drilling mud. The organism fulfilled all the specified requirements and its properties were superior to those of currently-used XC polymer (a xanthan product) for oil drilling applications. However, EPS/GS-1 was unstable in the presence of bentonite at 100 +/- 5 degrees C during performance tests, in contrast to XC polymer.
We are reporting an interesting case of pituitary macroadenoma. The patient presented with sudden, bifrontal, pulsating headache; photophobia; and an abducens nerve palsy, due to extension of the tumor into the cavernous sinus region. The headache resolved completely after a subcutaneous injection of sumatriptan.
CP-101,606 is a postsynaptic antagonist of the glutamate-mediated NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor. When administered intravenously (i.v.) at the time of injury, CP-101,606 is neuroprotective in animal models of traumatic brain injury (TBI) and ischemia. Minimal adverse effects have been observed in normal human volunteers given i.v. doses of up to 3 mg/kg/hr for 72 hours. The objective of the present clinical trial was to assess the safety, pharmacokinetics, and tolerability of CP-101,606 infused for various times in patients who had suffered either an acute moderate or mild TBI (Glasgow Coma Score 9-14) or hemorrhagic stroke. Patients began receiving treatment within 12 hours of brain injury. A total of 53 subjects (45 with TBI and 8 with stroke) were randomized in a double-blind fashion to receive CP-101,606 or placebo (4 drug: 1 placebo). Drug/placebo was administered by i.v. infusion (0.75 mg/kg/hr) for 2 hours and then stopped (n = 25) or continued for 22 hours (n = 4) or 70 hours (n = 24) at a rate of 0.37 mg/kg/hr. Mean plasma drug concentrations were well above the predicted therapeutic concentration of 200 ng/ml within two hours of initiating treatment and were sustained as long as drug was infused. All the patients tolerated their drug/placebo treatment, and there were no clinically significant cardiovascular or hematological abnormalities in either group. A Neurobehavioral Rating Scale, used to detect personality changes and behavioral disturbances, indicated that all subjects showed an improvement from their postinjury, predosing baseline but did not significantly differ from each other with respect to type of head injury and/or treatment with drug or placebo. Modified Kurtzke Scoring also showed a similar pattern of improvement irrespective of type of head injury or drug/placebo treatment. This study suggests that CP-101,606, infused for up to 72 hours has no psychotropic effects and is well-tolerated in patients who have sustained a mild or moderate TBI or hemorrhagic stroke.
CP-101,606 is a postsynaptic antagonist of N-methyl-D-aspartate (NMDA) receptors bearing the NR2B subunit. When administered intravenously (i.v.), it decreases the effects of traumatic brain injury (TBI) and focal ischemia in animal models. Therapeutic plasma concentrations (200 ng/ml) in animals, have been well tolerated in healthy human volunteers. The purpose of the present dose escalation study was to assess the safety, tolerability, and pharmacokinetics of CP-101,606 in subjects who had suffered either an acute severe TBI (Glasgow Coma Scale 3-8) or spontaneous intracerebral hemorrhage. Thirty patients, 20 with a TBI and 10 with a stroke, were enrolled in the trial and began receiving an i.v. infusion of CP-101,606 for 2 hours, 24 hours, or 72 hours within 12 hours of brain injury. For the first two hours, the drug was given a rate of 0.75 mg/kg/hr and then stopped (n = 17) or continued for 22 (n = 2) or 70 hours (n = 11) at 0.37 mg/kg/hr. Plasma and cerebrospinal fluid (CSF) were collected at serial times during and after treatment. There were no consistent changes in blood pressure or pulse nor any clinically significant hematological or electrocardiogram (ECG) abnormalities attributable to CP-101,606. No adverse events or behavioral changes were considered to be related to the drug. Plasma concentrations of CP-101,606 over 200 ng/ml were rapidly achieved in the blood and CSF within two hours and were sustained there as long as the drug was infused. CSF concentrations were slightly higher than that in plasma by the end of infusion suggesting good penetration of CP-101,606 into the CSF. Outcome in the severe TBI patients, as measured by the Glasgow Outcome Score at six months, suggested that a two-hour infusion yielded a range of scores similar to contemporary patients with a severe TBI treated at our hospital while the outcomes of the patients treated with either a 24- or 72-hour infusion were better on average. Thus, these results indicate that CP-101,606 infused for up to 72 hours is well tolerated, penetrates the CSF and brain, and may improve outcome in the brain-injured patient.
We present a case of an in-situ lobular carcinoma within an otherwise benign fibroadenoma in a 45-year-old woman.
Several reports have indicated that cortical resection is effective in alleviating intractable epilepsy in children with tuberous sclerosis complex (TSC). Because of the multitude of cortical lesions, however, identifying the epileptogenic tuber(s) is difficult and often requires invasive intracranial electroencephalographic (EEG) monitoring. As increased concentrations of serotonin and serotonin-immunoreactive processes have been reported in resected human epileptic cortex, we used alpha-[11C]methyl-L-tryptophan ([11C]AMT) positron emission tomography (PET) to test the hypothesis that serotonin synthesis is increased interictally in epileptogenic tubers in patients with TSC. Nine children with TSC and epilepsy, aged 1 to 9 years (mean, 4 years 1 month), were studied. All children underwent scalp video-EEG monitoring, PET scans of glucose metabolism and serotonin synthesis, and EEG monitoring during both PET studies. [11C]AMT scans were coregistered with magnetic resonance imaging and with glucose metabolism scans. Whereas glucose metabolism PET showed multifocal cortical hypometabolism corresponding to the locations of tubers in all 9 children, [11C]AMT uptake was increased in one tuber (n=3), two tubers (n=3), three tubers (n=1), and four tubers (n=1) in 8 of the 9 children. All other tubers showed decreased [11C]AMT uptake. Ictal EEG data available in 8 children showed seizure onset corresponding to foci of increased [11C]AMT uptake in 4 children (including 2 with intracranial EEG recordings). In 2 children, ictal EEG was nonlocalizing, and in 1 child there was discordance between the region of increased [11C]AMT uptake and the region of ictal onset on EEG. The only child whose [11C]AMT scan showed no regions of increased uptake had a left frontal seizure focus on EEG; however, at the time of his [11C]AMT PET scan, his seizures had come under control. [11C]AMT PET may be a powerful tool in differentiating between epileptogenic and nonepileptogenic tubers in patients with TSC.
The QVIEW image-processing software package provides a graphical user interface for interactive and rapid selection of particles from digital electron micrographs. This package was developed to facilitate the selection of elliptical, hydrophobic, and aggregating particles, which present complications for other particle selection packages. Speed improvements have been attained by using the fast graphics routines available in the Tc1/Tk toolkit and by separating the time consuming image-processing procedures from the interactive selection steps. The software is based on C++ and Tc1/Tk, both of which are readily available on many computer platforms. Processing features include removal of oversaturated pixels, planar subtraction using three or more background regions, exclusion of unwanted density such as nearby particles, and application of a circular or elliptical mask. Particles, along with their corresponding background and exclude regions, may be selected interactively from multiple digital micrographs, and the selection parameters are saved in a disk file for later processing. C shell processing scripts are easily modified and customized for specific applications. In summary, this software package enables the user-friendly, rapid selection of particles suitable for input into three-dimensional reconstruction packages.
Most frequently, placental glycogen has been studied as an index of fetal nutrition. There are no published studies of placental glycogen as an index of fetal stress. In this study of 1573 samples from 71 placentae, glycogen levels in the placental disk, fetal membranes and umbilical cord of normal uncomplicated pregnancies were compared with those in complicated pregnancies. The complicated pregnancies included preterm delivery, hypertensive disorders, inadequate prenatal care, substance abuse, maternal fever or infection, obesity, diabetes mellitus, premature rupture of membranes, intrauterine growth retardation, sickle cell trait, and acute meconium staining of amniotic fluid at delivery. The data showed that the only significant differences were in the subgroup complicated by meconium-stained amniotic fluid in which the placental disks and umbilical cords had significantly lower (P=0.0006) glycogen levels. This finding suggests a relatively specific association. It is interesting to speculate that the passage of meconium with its vasoconstrictive effect increases utilization of local glycogen stores, decreases local glycogen reserves needed for the work of further vasoconstriction, and, in the event of subsequent acute stress, impairs vascular perfusion of tissues. In this way, meconium could predispose the infant to asphyxia.
OBJECTIVE: To evaluate the safety, tolerance, and pharmacokinetics of dolasetron mesylate and its active metabolite hydrodolasetron when dolasetron mesylate was administered intravenously at increasing infusion rates. DESIGN: A double-blind, placebo-controlled, parallel-group study. METHODS: Forty-nine healthy nonsmoking male volunteers were randomly assigned to receive intravenous doses of dolasetron mesylate 100 mg or placebo. Three groups of 16 subjects each (12 dolasetron mesylate, 4 placebo) received escalating infusion rates (50, 100, then 200 mg/min). Physical examinations, vital signs, laboratory tests, and adverse events were recorded before and after administration of the study drug. Serial blood samples and 12-lead electrocardiogram measurements were obtained for 24 hours after the infusion. Plasma samples were analyzed for dolasetron and hydrodolasetron. RESULTS: Dolasetron mesylate was well tolerated, with no apparent differences in vital signs or adverse event profiles among the different rates of infusion. In general, the pharmacokinetics of dolasetron and hydrodolasetron were superimposable among the three infusion rate groups. Plasma dolasetron concentrations declined rapidly in all three infusion rate groups, with mean elimination half-life (t1/2) of less than 10 minutes. The reduced metabolite hydrodolasetron, which accounts for most pharmacologic activity, formed rapidly, with maximum concentrations occurring between 0.4 and 0.5 hours and disappeared with a mean t1/2 of 8-9 hours. The correlation coefficients of least-squares regression analysis between the pharmacokinetic parameters and the infusion rate of dolasetron were less than 0.083 and the slopes were not significantly different from 0, suggesting that none of the hydrodolasetron pharmacokinetic parameters were affected by rate of infusion. CONCLUSIONS: The intravenous administration of dolasetron 100 mg over 0.5-2 minutes did not significantly alter the pharmacokinetic profiles of either dolasetron or hydrodolasetron. In addition, the safety profile of dolasetron did not change with increasing rate of infusion. Therefore, the rate of infusion of dolasetron mesylate appears to have no pharmacokinetic or clinical implications when assessed over a 0.5-2-minute time period.
In an open-label, randomized, two-way complete crossover study, the influence of renal impairment on the pharmacokinetics of dolasetron and its primary active metabolite, hydrodolasetron, were evaluated. Patients with renal impairment were stratified into three groups of 12 based on their 24-hour creatinine clearance (Cl(cr)): group 1, mild impairment (Cl(cr) between 41 and 80 mL/min); group 2, moderate impairment (Cl(cr) between 11 and 40 mL/min); and group 3, endstage renal impairment (Cl(cr) < or = 10 mL/min). Twenty-four healthy volunteers from a previous study served as the control group. Each participant received a single intravenous or oral 200-mg dose of dolasetron mesylate on separate occasions. Serial blood samples were collected up to 60 hours after dose for determination of dolasetron and hydrodolasetron, and urine samples were collected in intervals up to 72 hours for determination of dolasetron, hydrodolasetron, and the 5' and 6'-hydroxy metabolites of hydrodolasetron. Because plasma concentrations were low and sporadic, pharmacokinetic parameters of dolasetron were not calculated after oral administration. Although some significant differences in area under the concentration-time curve (AUC0-infinity), volume of distribution (Vd), systemic clearance (Cl), and elimination half-life (t1/2) of the parent drug were observed between control subjects and patients with renal impairment, there were no systematic findings related to degree of renal dysfunction. The elimination pathways of hydrodolasetron include both hepatic metabolism and renal excretion. Consistent increases in mean Cmax, AUC0-infinity, and t1/2 and decreases in renal and total apparent clearance of hydrodolasetron were seen with diminishing renal function after intravenous administration of dolasetron mesylate. No consistent changes were found after oral administration. Urinary excretion of hydrodolasetron and its metabolites decreased with decreasing renal function, but the profile of metabolites remained constant. Dolasetron was well tolerated in all three groups of patients. Based on these findings, no dosage adjustment for dolasetron is recommended in patients with renal impairment.
It has been demonstrated that cysteine modification in irreversibly sickled cell beta-actin slows down the remodeling of membrane skeletons [Shartava et al.: J Cell Biol 128:805-812, 1995]. This slow remodeling can be due to alterations in spectrin-actin binding and/or actin-actin interactions in irreversibly sickled cell (ISC) membrane skeletons. In these studies we demonstrate that ISC actin binds spectrin normally. However, ISC beta-actin polymerizes and depolymerizes more slowly than control beta-actin, and forms unusual aggregates when placed under polymerizing conditions. Electron microscopic analysis of actin polymers indicated that ISC actin generates a large amount of aggregates which we conclude are due to the structural modification caused by the disulfide bridge between cysteine284 and cysteine373 in beta-actin.