Islet Xenotransplantation: Are We Really Ready for Clinical Trials?

Four clinical trials of porcine islet transplantation have been reported, and there are verbal reports that clinical trials on much larger scales are continuing in centers in China and Russia. The four reported trials are briefly reviewed and, in the light of the present status of experimental islet xenotransplantation, consideration is given to whether such trials are currently justified. The Ethics Committee of the International Xenotransplantation Association has (1) emphasized the need for encouraging studies in non-human primates before clinical trials should be undertaken, (2) mandatory monitoring for the transfer of porcine microorganisms, and (3) careful regulation and oversight by recognized bodies. Other aspects of the topic, such as the need for informed consent, are briefly discussed. We conclude that, at the present time, more data documenting convincing efficacy, focused on clinically applicable immunosuppressive regimens, are needed to justify the initiation of closely monitored clinical trials. A clinical trial may then be justified even though the potential risk to the patients, and possibly for society, will not be zero.     

Intravenous cidofovir treatment for recalcitrant warts in the setting of a patient with myelodysplastic syndrome

Cidofovir is an acyclic nucleoside phosphonate with broad-spectrum activity against DNA viruses, including human papilloma virus (HPV). However, data on the efficacy of cidofovir in an immunosuppressive setting remain contradictory. We report for the first time on the promotion of the healing of recalcitrant warts in a patient with myelodysplastic syndrome with intravenous cidofovir treatment.     

The effect of individual HLA-A and -B mismatches on the generation of cytotoxic T lymphocyte precursors

In order to study the correlation between HLA mismatches and the cytotoxic T lymphocyte precursor frequency, we used a limiting dilution analysis to determine the CTLp frequencies against individual mismatched HLA-A and -B alloantigens in 21 patients waiting for a renal transplant. Altogether, thirty-three mismatched HLA-A antigens and 55 HLA-B antigens were tested. The CTLp frequencies against mismatches of HLA-B locus antigens were found to be significantly higher than those against HLA-A antigens (P less than 0.002). This may explain why matching for HLA-B antigens is more important for a good renal allograft survival than matching for HLA-A antigens.     

Magnesium hydroxide: new insights into the mechanism of its laxative effect and the potential involvement of prostaglandin E2.

The mechanism by which Mg(OH)2 acts as a laxative is unknown. To explore the mechanism, six volunteers more than 55 years old, with normal bowel habits, were enrolled in a dose-response, randomized, placebo-controlled, double-blind, crossover design study. Each subject was studied for four inpatient periods of 5 days each on a metabolic ward with 9 days off of all medication between studies. In the hospital, all patients were on a diet fixed in calories, fluid volume, Na+, fiber, and Ca2+. At 8 p.m. on each study day, each subject took 45 ml containing either placebo or 1,200, 2,400, or 3,600 mg of Mg(OH)2 plus 240 ml of water. On the fourth and fifth hospital days of each period, 24-h stool output was quantified and analyses performed. Compared to placebo, Mg(OH)2 caused the following dose-dependent results: (a) increased number of bowel movements; (b) increased percentage of stool water; (c) increased stool volume; (d) increased stool Mg2+; and (e) increased total stool 24-h prostaglandin E2 (PGE2), with mean 24-h excretions as follow: placebo, 95 +/- 18 pg/24 h; 1,200 mg Mg(OH)2, 260 +/- 100; 2,400 mg Mg(OH)2, 357 +/- 117; and 3,600 mg Mg(OH)2, 525 +/- 196. There was a significant correlation between stool PGE2 excretion and stool water consistent with a causative relationship. However, the concentration of stool prostaglandin was lower than the concentration found to alter intestinal electrolyte transport in vitro. In summary, the laxative effect of Mg(OH)2 is associated with increased output of stool PGE2. The contribution of the stool PGE2 to the laxative effect of Mg(OH)2 is unknown.     

Drug-Induced Antibodies: Interaction of the Drug with a Polymorphic Platelet-Antigen

Preincubation of donor platelets with ticarcillin will prevent the reactivity of a platelet antibody against these platelets, whereas no influence was observed on antisera against HLA, 5A, 5b and ZWa. The implications for the mechanism of drug-induced antibodies with restricted specificity will be discussed.     

Glial cell line-derived neurotrophic factor-dependent recruitment of Ret into lipid rafts enhances signaling by partitioning Ret from proteasome-dependent degradation

The receptor tyrosine kinase (RTK) Ret is activated by the formation of a complex consisting of ligands such as glial cell line-derived neurotrophic factor (GDNF) and glycerophosphatidylinositol-anchored coreceptors termed GFRalphas. During activation, Ret translocates into lipid rafts, which is critical for functional responses to GDNF. We found that Ret was rapidly ubiquitinated and degraded in sympathetic neurons when activated with GDNF, but, unlike other RTKs that are trafficked to lysosomes for degradation, Ret was degraded predominantly by the proteasome. After GDNF stimulation, the majority of ubiquitinated Ret was located outside of lipid rafts and Ret was lost predominantly from nonraft membrane domains. Consistent with the predominance of Ret degradation outside of rafts, disruption of lipid rafts in neurons did not alter either the GDNF-dependent ubiquitination or degradation of Ret. GDNF-mediated survival of sympathetic neurons was inhibited by lipid raft depletion, and this inhibitory effect of raft disruption on GDNF-mediated survival was reversed if Ret degradation was blocked via proteasome inhibition. Therefore, lipid rafts sequester Ret away from the degradation machinery located in nonraft membrane domains, such as Cbl family E3 ligases, thereby sustaining Ret signaling.     

Late side-effects with cosmetic relevance following soft X-ray therapy of cutaneous neoplasias

Background Cosmetic changes are to be expected after radiotherapy for skin tumours. Objectives This study aimed to answer the questions: How frequent are cosmetic changes after soft X‐ray therapy? Do treatment parameters, tumour thickness, localization and size of the irradiated field have a major influence? Were patients irritated by the visual appearance of the irradiated field? Methods In total, 2474 examinations of 1149 irradiated fields were performed. Results Hypopigmentation was found in 64.7% of examinations more than 90 days after therapy, teleangiectases in 43.1%, erythema in 24.8%, and hyperpigmentation in 16.8%. The frequency of hypopigmentation, teleangiectases and hyperpigmentation increased with time from X‐ray exposure; more than 4 years after therapy hypopigmentation was diagnosed in 91.8% and teleangiectases in 82.2% of examinations. Total dose, the time–dose–fractionation factor (TDF), field size and dose per fraction were significantly related to the frequency of cosmetic changes. Incidence rates of cosmetic changes differed by less than 15% if different treatment conditions were compared: thicker vs. thinner tumours, larger vs. smaller fields, higher vs. lower total doses, doses per fraction, and TDF. Frequencies of hypopigmentation, teleangiectases, erythema and hyperpigmentation differed by more than 15% between some localizations on the head. Women reported irritation by the visual appearance of the irradiated field in 12.6% of 1116 interviews, and men in 4.4% of 1284 interviews. Conclusions Cosmetic changes after soft X‐ray therapy are relatively frequent. Treatment parameters, tumour thickness and field size have only a minor influence. Few patients, but more women than men, were irritated by the visual appearance of the irradiated field.