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Biomedical subjects

R Lewis

Publications and source records attributed to R Lewis.

At least 361 records · Page 20Linked to original sources
PubMedDate not supplied

Structure-activity relationships of omega-conotoxins at N-type voltage-sensitive calcium channels.

Due to their selectivity towards voltage-sensitive calcium channels (VSCCs) omega-conotoxins are being exploited as a new class of therapeutics in pain management and may also have potential application in ischaemic brain injury. Here, the structure-activity relationships (SARs) of several omega-conotoxins including GVIA, MVIIA, CVID and MVIIC are explored. In addition, the three-dimensional structures of these omega-conotoxins and some structurally related peptides that form the cysteine knot are compared, and the effects of the solution environment on structure discussed. The diversity of binding and functional assays used to measure omega-conotoxin potencies at the N-type VSCC warranted a re-evaluation of the relationship between these assays. With one exception, [A22]-GVIA, this analysis revealed a linear correlation between functional (peripheral N-type VSCCs) and radioligand binding assays (central N-type VSCCs) for the omega-conotoxins and analogues that were tested over three studies. The binding and functional results of several studies are compared in an attempt to identify and distinguish those residues that are important in omega-conotoxin function as opposed to those that form part of the structural scaffold. Further to determining what omega-conotoxin residues are important for VSCC binding, the range of possible interactions between the ligand and channel are considered and the factors that influence the selectivity of MVIIA, GVIA and CVID towards N-type VSCCs examined.

Amino Acid Sequence↗
PubMedDate not supplied

Recent advances in the management of preeclampsia.

The past decade has been characterized by few advances regarding the pathophysiology and prevention but many changes in the clinical treatment of patients with preeclampsia. Specifically, recommendations have been made for home or day-care management of a select group of patients with mild gestational hypertension or preeclampsia. Moreover, three randomized clinical trials revealed that expectant management with close monitoring of maternal and fetal conditions is possible in a select group of patients with severe preeclampsia at less than 34 weeks' gestation. In addition, the efficacy of magnesium sulfate in the prevention and control of eclamptic convulsion has been validated in randomized controlled trials performed worldwide. In contrast, recent randomized trials failed to demonstrate any major benefit from the routine use of low-dose aspirin in pregnancy, whereas a recent meta-analysis found calcium supplementation during pregnancy to be effective in reducing the risk of hypertension.

Anticonvulsants↗
PubMedDate not supplied

Analysis of potential phosphorylation sites in human T cell leukemia virus type 1 Tax.

The human T cell leukemia virus type 1 (HTLV-1) Tax is a phosphoprotein, however, the contribution of phosphorylation to Tax activity is unknown. Previous studies have shown that phosphorylation of Tax occurs on serine residue(s), within one tryptic fragment, in response to 4beta-phorbol-12beta-myristate-13alpha-acetate, in both mouse and human cells. Studies were conducted in multiple cell lines to identify the specific phosphorylated serines as a prelude to functional analysis. The phosphorylation pattern of Tax was found to be different in 293T and COS-7 cells in comparison with MT-4 and Px-1 cells. However, one tryptic fragment remained consistent in comigration analyses among all cell lines. Using selected Tax serine mutants a tryptic fragment containing a serine at residue 113 believed to be the site of phosphorylation of Tax did not comigrate with the common phosphorylated tryptic fragment. Analysis of selected Tax mutants for ability to trans-activate the cytomegalovirus promoter demonstrated mutation of serine 77 to alanine reduced trans-activation by 90% compared to wild-type Tax. However, examination of the phosphorylation pattern of the serine 77 mutant demonstrated that it is not the site of phosphorylation. These studies demonstrate the importance of using relevant cell lines to characterize the role of phosphorylation in protein function.

Amino Acid Sequence↗
PubMedDate not supplied

Three-dimensional quantitative structure-permeability relationship analysis for a series of inhibitors of rhinovirus replication.

Multiple three-dimensional quantitative structure-activity relationship (3D-QSAR) approaches were applied to predicting passive Caco-2 permeability for a series of 28 inhibitors of rhinovirus replication. Catalyst, genetic function approximation (GFA) with MS-WHIM descriptors, CoMFA, and VolSurf were all used for generating 3D-quantitative structure permeability relationships utilizing a training set of 19 molecules. Each of these approaches was then compared using a test set of nine molecules not present in the training set. Statistical parameters for the test set predictions (r(2) and leave-one-out q(2)) were used to compare the models. It was found that the Catalyst pharmacophore model was the most predictive (test set of predicted versus observed permeability, r(2) = 0.94). This model consisted of a hydrogen bond acceptor, hydrogen bond donor, and ring aromatic feature with a training set correlation of r(2) = 0.83. The CoMFA model consisted of three components with an r(2) value of 0.96 and produced good predictions for the test set (r(2) = 0.84). VolSurf resulted in an r(2) value of 0.76 and good predictions for the test set (r(2) = 0.83). Test set predictions with GFA/WHIM descriptors (r(2) = 0.46) were inferior when compared with the Catalyst, CoMFA, and VolSurf model predictions in this evaluation. In summary it would appear that the 3D techniques have considerable value in predicting passive permeability for a congeneric series of molecules, representing a valuable asset for drug discovery.

Antiviral Agents↗
PubMedDate not supplied

Chronic, inhalation exposure of rats, rabbits, and monkeys to 1,2,4-trichlorobenzene.

Three groups composed of rats, rabbits, and monkeys were exposed for 26 weeks to 1,2,4-trichlorobenzene (-TCB), and one group of each species was used as a control group. The nominal exposure concentrations of 1,2,4-TCB were 25.0, 50.0, and 100.0 ppm. Pulmonary function and operant behavior tests in monkeys, ophthalmoscopic examinations in rabbits and monkeys, and measurement of body weights and hematologic and serum biochemical determinations in all species were conducted before and during the exposure period. At termination of 1, 3, and 6 months of exposure, microscopic examination of selected rat tissues was performed. Microscopic changes were seen in the parenchymal of livers and kidneys from all groups of rats exposed to 1,2,4-TCB when sacrificed after 4 and 13 weeks of exposure, but no exposure-related abnormalities or other effects were seen after 26 weeks of exposure in any species.

Animals↗
PubMedDate not supplied

Trash and brush burning: an underappreciated mechanism of thermal injury in a rural community.

Open-fire injuries associated with burning trash or brush result in a significant number of burn admissions annually. Trash- and brush-burning injuries are more prevalent in rural environments where open burning is an acceptable practice of waste disposal. These injuries are not "unavoidable accidents" but follow a predictable injury pattern. Understanding this injury pattern is paramount to effective prevention. The purpose of this work is to describe the epidemiology of burn injuries associated with burning trash or brush. Charts were retrospectively reviewed for all trash and brush burning injuries from July 1989 to December 2000. One hundred ninety-four injuries were identified, accounting for one fifth of all flame admissions for the study period. Persons most at risk for these burn injuries were males between the ages of 25 to 45, followed by males ages 16 to 24. Accelerant use was identified in over 80% of these injuries. The median cost for admission was $9,363.00 US dollars. Cost was significantly related to age, percent body surface area burned, and operative intervention. Brush and trash burning can lead to costly injuries especially when accelerants are used. Additional research is needed to explore the cultural and social influences associated with these injuries to target effective prevention.

Adolescent↗
PubMedDate not supplied

Corticotropin-releasing hormone: potentiation of cocaine-kindled seizures and lethality.

Carbamazepine (CBZ) blocks the development of local anesthetic seizures kindled by cocaine and lidocaine. Cocaine and lidocaine release corticotropin-releasing hormone (CRH) in hypothalamic cell cultures, and this effect is also blocked by CBZ. Because CRH administered intracerebroventricularly (i.c.v.) can produce seizures, its potential role in the development of cocaine seizures and in the anticonvulsant effects of CBZ was studied. CRH (at doses of 5, 10, and 100 micrograms) potentiated cocaine-kindled seizure development and lethality in a dose-related fashion. CRH also reversed the effects of CBZ on cocaine kindling and lethality, but only at the highest doses, which also affected cocaine kindling. Thus, a selective role for CRH in the anticonvulsant effects of CBZ was not demonstrated. The findings suggest a potentially important role for CRH in exacerbating cocaine-seizure evolution and its associated lethality and confirm the inhibition of cocaine kindling and lethality by CBZ.

Animals↗
PubMedDate not supplied

Hyper- and hyponatremia among geropsychiatric inpatients.

We report our experience treating 14 elderly psychiatric patients with altered sodium states. Hypernatremia occurs more commonly among elderly psychiatric patients than among their younger counterparts, and elderly hypernatremic psychiatric patients suffer most commonly from dementia. Dilutional hyponatremia is less common and less severe among elderly schizophrenic patients compared with younger patients with schizophrenia. Central nervous system changes induced by altered sodium states among elderly psychiatric patients are sufficiently similar whether hyper- or hyponatremia is present; therefore, the clinician must not wait for specific features to develop, but must quickly measure serum sodium concentration in elderly psychiatric patients with altered mental states. Treatment of hypernatremia involves rehydration with normal saline or hypotonic solutions, and treatment of dilutional hyponatremia largely involves fluid restriction.

Age Factors↗
PubMedDate not supplied

Comparative CD4 T-cell responses of reverse transcriptase inhibitor therapy with or without nelfinavir matched for viral exposure.

BACKGROUND: Therapy of HIV infection with protease inhibitors (PIs) may be associated with improvements in CD4 T-cell number via a mechanism that is independent of effects on plasma viral load (VL). PURPOSE: To compare CD4 responses of patients who receive reverse transcriptase inhibitor (RTI) therapies with or without a PI, matched for viral exposure. METHODS: Patient data were analyzed from two prospective randomized trials of antiviral therapy with or without nelfinavir. Total viral exposure over 24 weeks was estimated by viral area under the curve (AUC), which reflects baseline viral load, slope of virologic decay, viral nadir, and duration of suppression. Patients were stratified into quartiles on the basis of viral AUC, and CD4 T-cell responses were evaluated between PI-containing and RTI-only treatment groups within each quartile. RESULTS: In both trials, patients receiving nelfinavir had greater CD4 T-cell increases than patients receiving RTI alone. Analysis of variance modeling revealed increased CD4 T-cell responses in PI-treated groups at all time points after the second week. These differences were significant (p <.05) at weeks 12, 24, 28, 32, 36, 40, and 48 in one study, and weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, and 44 in the other. Within quartiles matched for viral AUC, absolute CD4 T-cell change from baseline was greater in the PI-treated patients at 84% (101/120) of time points analyzed. CONCLUSION: Nelfinavir-containing therapy is associated with enhanced increases in CD4 T-cell number compared to RTI therapy alone with equivalent antiviral effect. These data suggest that PIs influence CD4 T-cell number through a nonvirologic effect.

Anti-HIV Agents↗