Selection for donor-specific cytotoxic T lymphocytes within the allografted human heart.

Lymphocytes were cultured from cardiac biopsies following heart transplantation using interleukin-2-conditioned medium. Using the technique of limiting dilution analysis the frequency of donor specific cytotoxic T lymphocytes was measured in cells cultured from biopsies and compared with that in peripheral blood lymphocytes taken at the same time as the biopsy. The graft cell population showed a considerably higher frequency of donor-specific CTL when compared with the PBL. CTL frequencies in the graft cells were always higher against the donor than against third-party cells. These data demonstrate that there was either selective sequestration or selective expansion of donor-reactive T cells in the heart following cardiac transplantation. These results emphasize the need to investigate more closely the events occurring in the heart, and may explain the lack of specificity and sensitivity in immune monitoring (IM) or cytoimmune monitoring (CIM) seen in many centers.     

Production of epidermal growth factor and transforming growth factor-alpha by the androgen-responsive LNCaP human prostate cancer cell line

Epidermal growth factor (EGF)-related polypeptides may be involved in the growth of human prostate cancer cells, and in the androgen stimulation of hormone-responsive prostatic carcinomas. We have shown that androgen-responsive LNCaP cells, like the autonomous DU 145 human prostate cancer cell line, synthesize and secrete EGF and related polypeptides, including immunoreactive transforming growth factor-alpha (TGF-alpha). As determined by radioimmunoassay, intracellular EGF levels were approximately 100 times those of TGF-alpha, but together these accounted for less than half of the total EGF-like polypeptides detected in a radioreceptor assay. Although LNCaP cell growth was stimulated by dihydrotestosterone (DHT), there was no evident effect on immunoreactive EGF levels in the medium after correction for cell number. Moreover, metabolic labeling experiments showed no effect of the androgen on EGF synthesis by LNCaP cells. Gel filtration chromatography of conditioned medium showed both high molecular weight species and the mature 6,000 dalton form of immunoreactive EGF. We conclude that although LNCaP prostate cancer cell growth is stimulated by DHT, it is unlikely that it is mediated directly via increased EGF synthesis by the tumor cells.     

A pharmacokinetic comparison of cyclosporin oral solution and cyclosporin capsules in heart and lung transplant recipients

Pharmacokinetic profiles were obtained for 16 heart or lung recipients following the administration of identical doses of cyclosporin as oral solution and capsules on consecutive days. A comparison of pharmacokinetic parameters (AUC, C_max, C_min and t_max) showed that there were no significant differences between the two formulations except for the t_max, which was significantly longer for the capsules. The mean variation in day-to-day trough levels produced by the two different forms was 25.6%. A retrospective study was carried out of consecutive cyclosporin levels in patients at steady state on oral solution. The mean variation in day-to-day trough levels was 32.3%. This was not significantly different from the variation in consecutive trough levels seen in the oral solution/capsule comparison. This study shows that cyclosporin capsules can be substituted for oral solution without causing acute changes in cyclosporin blood levels, and that the pharmacokinetics of the two formulations are similar.This work was carried out in partial fulfillment of the requirements for the Master of Science Degree in Clinical Pharmacy, University of London     

The Effect of High-Dose Ascorbate Supplementation on Plasma Lipoprotein(a) Levels in Patients With Premature Coronary Heart Disease

Study Objective . To determine the efficacy of high-dose ascorbate supplementation in lowering lipoprotein(a) [Lp(a)] levels in patients with premature coronary heart disease (CHD). Design . Randomized, double-blind, placebo-controlled trial. Setting . Outpatient clinic. Patients . Forty-four patients with documented premature CHD. defined as confirmed myocardial infarction and/or angiographically determined stenosis of 50% or greater in at least one major coronary artery before age 60 years. Interventions . Patients were block randomized on the basis of age, gender, and screening Lp(a) concentrations to receive ascorbate 4.5 g/day or placebo for 12 weeks. Measurements and Main Results . High-dose ascorbate was well tolerated and produced a marked elevation in mean plasma ascorbate levels (+1.2 mg/dl; p<0.001). Multiple linear regression analysis revealed no significant effect of supplementation on postintervention Lp(a) levels (p=0.39) in a model that included treatment group assignment, and baseline Lp(a) levels. Conclusions . Our findings do not support a clinically important lowering effect of high-dose ascorbate on plasma Lp(a) in patients with premature CHD.     

Assessing quality of life in primary biliary cirrhosis.

BACKGROUND AND AIMS: Assessment of health-related quality of life (HRQOL) is not routinely reported in the literature on chronic liver disease (CLD). Few studies have examined quality of life (QOL) in patients with primary biliary cirrhosis (PBC) despite its significant functional impact. One of the reasons for the lack of HRQOL measurement in patients with PBC may be the absence of a well-recognized and widely used measure that clinicians can use in ordinary clinical practice. The aim of this study is to evaluate HRQOL measures used in patients with PBC and examine the suitability of the measures for these patients. METHODS: A literature search identified reports that focused on any aspect of QOL in patients with PBC. Key texts were identified containing generic, domain-specific, and condition-specific measures. The identified measures were systematically evaluated for appropriateness, acceptability, reliability, validity, precision, and responsiveness. RESULTS: Twenty measures were identified from 9 key texts. Six of the measures were previously validated generic measures; 10 were domain-specific measures previously used to measure fatigue, depression, and psychological distress in general and psychiatric populations; and 4 measures had been developed in patients with CLD. Reporting of reliability and validity generally was consistent for all measures used. However, reporting of the remaining criteria was variable, particularly in relation to responsiveness over time and acceptability of the measures to patients with PBC. CONCLUSIONS: A clearer and more rigorous approach is needed in reporting the properties of HRQOL measures used in patients with PBC to help clinicians decide which measures are most suitable for these patients.     

Diagnosis and management of anaphylaxis

ANAPHYLAXIS IS A SEVERE SYSTEMIC ALLERGIC reaction that is potentially fatal. It requires prompt recognition and immediate management. Anaphylaxis has a rapid onset with multiple organ–system involvement and is mostly caused by specific antigens in sensitized individuals. Reactions typically follow a uniphasic course, however, 20% will be biphasic in nature. The second phase usually occurs after an asymptomatic period of 1–8 hours, but there may be a 24-hour delay. Protracted anaphylaxis may persist beyond 24 hours. Concurrent β-blocker therapy may adversely affect the response to management. Epinephrine is the treatment of choice and should be administered immediately. Secondary measures include circulatory support, H₁ and H₂ antagonists, corticosteroids and, occasionally, bronchodilators. Post-treatment observation of these patients is necessary, and they should remain within ready access of emergency care for the following 48 hours.     

Transient depletion of nucleus accumbens dopamine content may contribute to initial akinesia induced by MPTP in common marmosets

Acute treatment of common marmosets with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused an initial profound akinesia and other motor deficits. However, over the following months akinesia gradually disappeared although the animals remained clumsy and poorly coordinated. At 10 days following MPTP treatment there was a profound decrease in the dopamine, HVA and DOPAC content of the caudate nucleus, putamen and nucleus accumbens. By 3-4 months following MPTP treatment the animals had largely recovered from their akinesia, but the caudate nucleus and putamen dopamine, HVA and DOPAC content remained low. In contrast, the dopamine content of the nucleus accumbens had returned towards normal and the metabolite levels were higher than at 10 days. No overall alterations in 5HT or 5HIAA levels were observed at either time point. The transient and reversible nature of dopamine loss in the nucleus accumbens may contribute to the initial profound akinesia exhibited by common marmosets treated with MPTP. The restoration of dopamine levels in the nucleus accumbens may be partially responsible for the subsequent recovery of motor function that occurs in MPTP-treated marmosets.