Bioethics for clinicians.

The author introduces the Bioethics for Clinicians series, which begins in this issue with an article on patient consent to medical care (see pages 177 to 180). This 14-part series is intended to elucidate key concepts in bioethics and to help clinicians to integrate bioethical knowledge into daily practice. In educational terms, the goal is to support performance: what clinicians actually do.     

Treatment-refractory schizophrenia

Treatment-refractory schizophrenia is common. Refinements in pharmacologic and psychosocial treatments of schizophrenia offer the expectation of superior outcomes for this disadvantaged patient group. This article critically reviews those articles that were published during the year 2000 that address this treatment-refractory population.     

The enzymatic basis for the rat liver 6-hydroxymelatonin sulfotransferase activity

Abstract: Understanding 6-hydroxymelatonin (6HM) sulfation is deemed impor-tant to explaining normal and oncostatic actions of the pineal gland. Here we identify the enzymatic basis for this sulfation in rats. First, a quantitative assay was designed for measuring hepatic 6HM sulfotransferase (6HMST) activity. The as-say was then used to identify a male dominant sexual dimorphism wherein liver from males contains double the 6HMST per g or per 100 g body weight seen in fe-males. Examination of other rat tissues showed that most in vivo 6HM sulfation was likely to occur in liver. In addition, DEAE-Sephadex chromatography of liver cytosol indicated that 80–90% of the 6HMST activity in both sexes was due to an enzyme we named 6HMST II. A minor 6HM sulfotransferase (6HMST I) eluted from the columns prior to the main enzyme. 6HMST II, purified additionally, was shown to convert 6HM to a product that appeared to be 6HM sulfate (6-sulfa-toxymelatonin). The enzyme was inhibited by Na⁺, K⁺, Zn²⁺, and Cd²⁺. Its pH op-timum was 7.80 ± 0.30. Comparisons are made between 6HMST II, dopamine sulfotransferase II, and aryl sulfotransferase IV.     

The mildly abnormal cervical smear: patient anxiety and choice of management.

Argument continues over the best management of women with a first mildly dyskaryotic cervical smear: should they be referred for prompt colposcopy, or should they be kept under cytological review, with recourse to colposcopy if the abnormality persists? One consideration is the amount of anxiety generated. We measured anxiety, retrospectively, in two groups of women who had been managed by one or other method. Colposcopy caused more anxiety than cytological surveillance. When told that their smear was mildly abnormal, 47% of the immediate-colposcopy group (n = 182), compared with 33% of the surveillance group (n = 163), thought they had cancer. None the less, there was a general preference for immediate colposcopy. Whatever the relative merits of these two strategies for clinical management, it is clear that both forms of screening, and especially colposcopy, demand better information for patients.     

A yeast glutamine tRNA signals nitrogen status for regulation of dimorphic growth and sporulation

Dimorphic growth of the budding yeast Saccharomyces cerevisiae is regulated by the quality of the nitrogen supply. On a preferred nitrogen source diploid cells grow as ellipsoidal cells by using a bipolar pattern of budding, whereas on a poor nitrogen source a unipolar pattern of budding is adopted, resulting in extended pseudohyphal chains of filamentous cells. Here we report that the quality of the nitrogen source is signaled by the glutamine tRNA isoform with a 5′-CUG anticodon (tRNA_CUG). Mutations that alter this tRNA impair assessment of the nitrogen supply without measurably affecting protein synthesis, so that mutant cells display pseudohyphal growth even on a preferred nitrogen source. The nitrogen status for other nitrogen-responsive processes such as catabolic gene expression and sporulation also is signaled by this tRNA: mutant cells inappropriately induce the nitrogen-repressed gene CAR1 and undergo precocious sporulation in nitrogen-rich media. Therefore, in addition to its role in mRNA translation, this tRNA also transduces nitrogen signals that regulate development.     

Isoform of Fibronectin Mediates Bone Loss in Patients With Primary Biliary Cirrhosis by Suppressing Bone Formation

Osteoporosis is a major cause of morbidity and decreased quality of life in patients with chronic cholestatic liver disease. It is established that this osteoporosis results from decreased bone formation, but the mechanisms for the interaction between liver and bone remain elusive. The aim of this study was to test the hypothesis that an increase in the production of cellular fibronectins during liver disease may result in decreased osteoblast‐mediated mineralization and thus explain the decrease in bone formation. We performed a prospective cross‐sectional study in patients with primary biliary cirrhosis and matched controls, followed by experiments on human and mouse osteoblasts in culture and injections in mice in vivo. In patients with primary biliary cirrhosis, the oncofetal domain of fibronectin correlated significantly with the decrease in osteocalcin, a marker of bone formation (r = ?0.57, p < 0.05). In vitro, amniotic fluid fibronectin (aFN) containing mainly the oncofetal domain and EIIIA domain resulted in decreased osteoblast‐mediated mineralization in human osteoblasts (69% decrease at 100 μg/ml; p < 0.01) and mouse osteoblasts (71% decrease; p < 0.05). Removing the EIIIA domain from aFN similarly suppressed mineralization by osteoblasts (78% decrease; p < 0.05). Injection of labeled aFN in mice showed that it infiltrates the bone, and its administration over 10 days resulted in decreased trabecular BMD (17% drop; p < 0.05), mineralizing surface (30% drop; p < 0.005), and number of osteoblasts (45% drop; p < 0.05). Increased production of a fibronectin isoform containing the oncofetal domain and its release in the circulation in patients with primary biliary cirrhosis is at least partially responsible for the decrease in bone formation seen in these patients. This establishes that a molecule that has thus far been viewed as an extracellular matrix protein exerts hormone‐like actions.