Dominant T-cell clones of unknown significance in patients with idiopathic sensory neuropathies

The aim of this study was to describe an high-performance liquid chromatographic assay for the simultaneous determination of two HIV protease inhibitors, saquinavir and ritonavir, in human serum. The method involved extraction of ritonavir and saquinavir from serum with the aid of solid-phase extraction C18 cartridges followed by high-performance liquid chromatography with a C8 column and ultraviolet detection set at a wavelength of 240 nm. The assay was linear and has been validated over the concentrations range of 0.5-32 microg/ml for ritonavir and 0.075-4.8 microg/ml for saquinavir, from 600 microl serum extracted. In future, the assay will be used to support human population pharmacokinetic studies, and therapeutic drug monitoring for ritonavir and saquinavir.     

Genetic transformation of germinated conidia of the thermophilic fungus Humicola grisea var. thermoidea to hygromycin B resistance

Dihydrotestosterone decreased alcohol dehydrogenase (ADH) activity and enzyme-protein in rat hepatocytes in culture. This effect was observed after the hepatocytes had been exposed to dihydrotestosterone for 3 days at concentrations of 0.5 micromol/L or higher. Dihydrotestosterone did not decrease alcohol dehydrogenase messenger RNA (mRNA) but, rather, resulted in small increases in ADH mRNA after 3 days of exposure. To further determine the mechanism for the effects of dihydrotestosterone in decreasing the enzyme, the turnover of ADH was determined after incorporation of [3H]-leucine into the enzyme protein. Dihydrotestosterone did not alter the initial 2-hour incorporation of [3H]-leucine into the enzyme protein. Dihydrotestosterone, however, resulted in an increase in the fractional rate of degradation (Kd) of the enzyme from 0.12 +/- 0.013 to 0.23 +/- 0.004 per hour (P < .001) accompanied by a much smaller increase in the fractional rate of synthesis (Ks) from 0.12 +/- 0.028 to 0.17 +/- 0.031 per hour (P > .05). Hence, the mechanism for the fall in ADH in the presence of dihydrotestosterone is an increase in enzyme degradation which is not accompanied by a sufficient increase in enzyme synthesis.     

The effect of plasma drug concentrations on HIV-1 clearance rate during quadruple drug therapy

OBJECTIVE: To investigate the relationship between exposure to antiretroviral drugs and the initial decline of plasma HIV-1 RNA. DESIGN: Open-label study in antiretroviral-naive HIV-1 infected patients using a quadruple drug regimen [nelfinavir (NFV), saquinavir (SQV), stavudine, and lamivudine]. METHODS: The elimination rate constant (k) for HIV-1 clearance was calculated during the first 2 weeks of treatment in 29 patients. Exposure to NFV and SQV was quantified on each study visit. Observed NFV and SQV concentrations were related to those expected in a reference population and a concentration ratio was calculated. The median concentration ratios for NFV and SQV, the baseline CD4+ lymphocyte count and baseline log10 HIV-1 RNA were correlated with k. RESULTS: A significant positive correlation was observed between k and the median NFV (P = 0.001) or SQV concentration ratio (P = 0.016) in univariate analysis. In multivariate analyses, the median NFV concentration ratio remained significantly correlated with k. CONCLUSIONS: The variation in the rate of decline of plasma HIV-1 RNA between patients after the initiation of a quadruple drug regimen could be explained by differences in exposure to NFV or SQV. Determination of k could be used to optimise further antiretroviral drug therapy and may be a first tool to assess antiretroviral activities of new or increasing doses of drugs administered in combination regimens. Furthermore, our data suggest that exposure to antiretroviral drugs should be incorporated in mathematical models to describe HIV-1 dynamics in more detail.     

Outcomes of high-dose unilateral kidney irradiation in patients with gastric lymphoma

PURPOSE: To review the long-term clinical effects of unilateral kidney irradiation on overall renal function and blood pressure in patients with gastric lymphoma. METHODS AND MATERIALS: In the study were 27 patients with Stage I or II gastric lymphoma who had undergone irradiation of at least 24 Gy to > or = 1/3 of the left kidney. They include 16 women and 11 men, aged 31 to 77, with a mean age of 57.6 years (median 56). Fifteen patients had Stage I and 12 had Stage II disease. In 13 patients the whole kidney had been irradiated, and 14 had had partial kidney irradiation, at doses ranging between 24 and 40.5 Gy. All patients received combined chemotherapy with various drugs: all patients received corticosteroids, and five received cis-platinum. Their follow-up ranged between 0.7 and 7.8 years (mean 3.4 years). Data on possible effects of the treatment on blood pressure, renal function as assessed by blood urea and creatinine, and kidney shrinkage as seen by serial computed tomography scanning were collected on all patients. RESULTS: Three patients had persistent, mild elevations of urea and creatinine levels, which did not require special treatment. All three also received cis-platinum. Ipsilateral kidney shrinkage was evident in most patients. In 19 patients the craniocaudal measurement of the kidney shrank by > or = 1.6 cm. Shrinkage in other dimensions was also evident. The degree of atrophy was related to the volume of kidney irradiated. Only two patients developed hypertension, both at a low level of 150/90; one patient had had 40 Gy to the whole kidney, the other 40 Gy to half the kidney. Neither patient had elevated urea or creatinine. CONCLUSIONS: Notwithstanding the shrinkage to the irradiated part of the kidney, the treatment did not lead to clinically significant hypertension or renal dysfunction. The administration of cis-platinum to patients with gastric lymphoma that requires kidney irradiation should be further evaluated.     

Cytokines and the microcirculation in ischemia and reperfusion

The intense inflammatory reaction following reperfusion of the infarcted myocardium has been implicated as a factor in extension of injury. However, this inflammatory reaction is also critical to tissue repair. The cellular responses that mediate these functions are orchestrated by sequential induction and/or release of cytokines resulting in a closely regulated cytokine cascade. This paper reviews research on these cytokine cascades, their cellular origin, and factors which control the cellular response to their presence. Factors examined include leukotaxis, phenotypic transition of leukocytes, adhesion molecule induction and the role of cytokines in tissue repair and scar formation.     

Comparative studies of specific acquired systemic tolerance induced by intrathymic inoculation of a single synthetic Wistar-Furth (RT1U) allo-MHC class I (RT1.AU) peptide or WAG (RT1U)-derived class I peptide

Research on public opinion has seldom been incorporated into the debate about appropriate coverage of mental health and substance abuse treatment services in health insurance plans. However, several surveys have been conducted to probe for voters' awareness of and attitudes toward persons with mental illness and insurance coverage of their treatment needs. Given the current debate over mandating parity for coverage of mental health and substance abuse treatment services, these data promise to be particularly useful to politicians and health policy analysts. The author reviews reports of survey research conducted between 1989 and 1994 to assess American voters' support for expansions of mental health and substance abuse treatment coverage, including their knowledge about the origins and implications of mental illness and their willingness to pay for more generous benefits. The results suggest widespread support for such benefit expansions, but voters express concern about potential increases in their taxes or in their health insurance premiums. To facilitate the passage of meaningful reforms for mental health and substance abuse treatment benefits, policy makers must present realistic estimates of the costs of such expansions and of the benefits to be delivered to those in need.     

Effects of ovarian source, patient age, and menstrual cycle phase on in vitro maturation of immature human oocytes

OBJECTIVE: To determine the efficiency of in vitro maturation, expressed by nuclear maturation, of oocytes aspirated during gynecologic surgeries or collected from excised ovaries. To assess the effect of patient age and cycle phase at collection on the oocyte's ability to mature in vitro. To examine the time course of oocyte maturation in vitro. DESIGN: Nuclear maturation based on patient criteria compared. SETTING: University-based IVF program and research center. PATIENT(S): Consented patients undergoing gynecologic surgeries or patients undergoing oophorectomy. INTERVENTION(S): Oocytes were maintained in culture for 48 hours and evaluated for maturation. MAIN OUTCOME MEASURE(S): Nuclear maturation evaluated as germinal vesicle breakdown (GVBD) or progression to the metaphase II (MII) stage. RESULT(S): A significantly higher percentage of oocytes collected during the follicular phase of the menstrual cycle underwent GVBD than did oocytes collected during the luteal phase (60% versus 48%, respectively). The percentage of oocytes reaching the MII stage, from these two groups, was not different. No statistically significant differences in maturation were observed in oocytes from different ovarian sources or from patients >40 or <40 years of age. CONCLUSION(S): These data suggest that oocytes collected during the follicular phase are more likely to undergo GVBD than oocytes collected during the luteal phase. In this study, ovarian source, age, or cycle phase did not influence the final meiotic maturation of oocytes to metaphase II.     

Rational management of cardiac arrest

When immediate defibrillation fails, successful cardiac resuscitation is contingent on prompt reestablishment of myocardial blood flow. Conventional methods of closed-chest resuscitation generates only critical levels of myocardial blood flow and therefore are of limited value for successful resuscitation. Methods that optimize the site, depth, rate and duration of precordial compression may increase myocardial blood flow, however, the lack of objective measurements of their hemodynamic effects limits the optimal performance of this resuscitation method. With the recognition that elimination of CO2 is flow limited, measurement of end-expired PCO2 has emerged as a practical option for continuous assessment of systemic blood flow and coronary perfusion pressure. With measurement of the end-expired PCO2, operator fatigue may be recognized, the technique of precordial compression may be optimized, and the likelihood of restoring spontaneous circulation may be estimated. When conventional cardiac resuscitation fails or is predicted to fail by measurements of end-tidal PCO2, more effective interventions such as open-chest direct cardiac massage may be instituted. Regarding the vast resuscitation polypharmacy, only agents that act by selectively augmenting coronary perfusion pressure and myocardial blood flow are of proven benefit for successful resuscitation.