Chemokines and peripheral nerve demyelination

It has been speculated that beta-chemokines play a pivotal role in the development of peripheral nervous system (PNS) disorders characterized by mononuclear cell infiltration. In experimental allergic neuritis (EAN), an animal model for human Guillain-Barré syndrome (GBS) with mononuclear cell infiltration, we found by quantitative PCR that beta-chemokine messages were upregulated during the active stage. Moreover, an increase in the monocyte chemoattractant protein-1 (MCP-1) message was found in the preclinical stage of EAN, suggesting the critical role of MCP-1 for inducing mononuclear cell infiltrations in this model. Since many cell lineages other than immune cells can produce chemokines, this early upregulation of MCP-1 may be mediated by non-immune cells, probably endothelia or Schwann cells. To date, apart from MCP-1, only RANTES (Regulated on activation, normal T cell expressed and secreted) and macrophage inflammatory protein (MIP)-1alpha have been examined in EAN and found to have similar kinetics of induction. Therefore, understanding the regulation of production of these chemokines as well as mechanisms of inhibiting chemokine/receptor interactions in the PNS may ultimately lead to disease-specific therapy for GBS and related demyelinating disorders.     

POSSIBLE INVOLVEMENT OF INOSITOL-LIPID METABOLISM IN MALIGNANT HYPERTHERMIA

-Adrenoceptor stimulation may induce malignant hyperthermia(MH) in vivo. Consequently, we have investigated the effectsof the -adrenoceptor agonist phenylephrine and, for comparison,the effects of the ß-adrenoceptor agonist isoproterenolon inositol-lipid metabolism of malignant hyperthermia susceptible(MHS) and healthy control (MHN) swine. The experiments wereperformed on electrically stimulated (frequency 0.2 Hz) trabeculaeisolated from the right ventricles of the hearts of MHS andMHN animals. After labelling with [³H] inositol for 6 h, differentinositol phosphates were measured by high pressure liquid chromatography,including inositol 1 - phosphate, inositol 1,4-bisphosphate,inositol 1,3,4-trisphosphate, inositol 1,4,5-trisphosphate (1,4,5-IP₃)and inositol 1,3,4,5 - tetrakisphosphate. After stimulationwith isoproterenol, the inositol phosphate content did not increaseor vary between muscle from MHS and MHN animals. In contrast,all inositol phosphates increased after stimulation with phenylephrinein both muscle types, the effects being greater in MHS thanin MHN, especially as regards 1,4,5-IP₃ content. As 1,4,5-IP₃,a presumed second messenger, has been shown to mobilize intracellularcalcium, it is concluded that an enhanced -adrenergic responseis involved in the development of MH. ^*Address for correspondence: Abteilung für Anästhesiologie,Universitäts-Krankenhaus Eppendorf, Martinistrasse52, D-2000Hamburg 20, Germany. Presented in part at the 1989 Meeting of the European Academyof Anaesthesiology in Bonn.     

Randomised controlled trial of zinc supplementation in malnourished Bangladeshi children with acute diarrhoea

OBJECTIVE: To evaluate the impact of zinc supplementation on the clinical course, stool weight, duration of diarrhoea, changes in serum zinc, and body weight gain of children with acute diarrhoea. DESIGN: Randomised double blind controlled trial. Children were assigned to receive zinc (20 mg elemental zinc per day) containing multivitamins or control group (zinc-free multivitamins) daily in three divided doses for two weeks. SETTING: A diarrhoeal disease hospital in Dhaka, Bangladesh. PATIENTS: 111 children, 3 to 24 months old, below 76% median weight for age of the National Center for Health Statistics standard with acute diarrhoea. Children with severe infection and/or oedema were excluded. MAIN OUTCOME MEASURES: Total diarrhoeal stool output, duration of diarrhoea, rate of weight gain, and changes in serum zinc levels after supplementation. RESULTS: Stool output was 28% less and duration 14% shorter in the zinc supplemented group than placebo (p = 0.06). There were reductions in median total diarrhoeal stool output among zinc supplemented subjects who were shorter (less than 95% height for age), 239 v 326 g/kg (p < 0.04), and who had a lower initial serum zinc (< 14 mmol/l), 279 v 329 g/kg (p < 0.05); a shortening of mean time to recovery occurred (4.7 v 6.2 days, p < 0.04) in those with lower serum zinc. There was an increase in mean serum zinc in the zinc supplemented group (+2.4 v -0.3 mumol/l, p < 0.001) during two weeks of supplementation, and better mean weight gain (120 v 30 g, p < 0.03) at the time of discharge from hospital. CONCLUSIONS: Zinc supplementation is a simple, acceptable, and affordable strategy which should be considered in the management of acute diarrhoea and in prevention of growth faltering in children specially those who are malnourished.     

Growth of Pakistani children in relation to the 1990 growth standards

This study was designed to compare the growth of Pakistani schoolchildren in the UK with the 1990 UK growth standards. Measurements of height, weight, and sitting height were performed on 785 Pakistani schoolchildren aged 5-14 years with the mean values for each age and sex being plotted on the UK growth standards. The results were expressed as SD scores relative to the 1990 reference data. The mean height for the boys was only 0.2 SD scores below the mean for the new growth standards with the mean height for the girls being 0.4 SD scores below the mean. The mean values for weight and body mass index were 0.3 and 0.5 SD scores less than the mean for boys and girls respectively. This study demonstrates that the growth of Pakistani schoolchildren in the UK is comparable to the 1990 UK growth standards with only minor differences. It is not safe to assume that short stature or low body weight in a Pakistani child is due to his or her ethnic background.     

Adaptive response of human melanoma cells to methylglyoxal injury

The effects of methylglyoxal on the growth of a line of human melanoma cells are investigated. Methylglyoxal inhibits cell growth in a dose- dependent manner and causes an increase in glyceraldehyde 3-phosphate dehydrogenase, and glyoxalase 1 and glyoxalase 2 specific activities. The cellular response to increasing concentrations of methylglyoxal in the culture medium is also studied by measuring L-lactate production, reduced-oxidized glutathione levels and apoptotic cell death. Methylglyoxal seems to promote a change of cell population phenotypic repertoire toward a more monomorphic phenotype. In conclusion, methylglyoxal seems to induce an enzymatic cellular response that lowers methylglyoxal levels and selects the most resistant cells.      

The effect of non-genotoxic carcinogens, phenobarbital and clofibrate, on the relationship between reactive oxygen species, antioxidant enzyme expression and apoptosis

Phenobarbital and clofibrate, two non-genotoxic carcinogens, have been investigated regarding the relationship between reactive oxygen species, antioxidant enzyme expression and apoptosis in primary cultures of rat hepatocytes. Low toxicity concentrations, 200 and 100 microg/ml for phenobarbital and clofibrate respectively, were used to examine their effect on spontaneous or transforming growth factor beta1 (TGFbeta1)-induced apoptosis and on the expression of antioxidant defence enzymes (superoxide dismutases and catalase). The increased incidence of apoptotic nuclei was visualized in TGFbeta1-treated cultures with the fluorescent dye Hoechst 33258 and was quantified under all experimental conditions by measurement of the hypodiploid peak in DNA histograms obtained by flow cytometry. Both substances, when added separately to hepatocyte cultures and incubated for 24 and 48 h, significantly diminished spontaneous apoptosis and exhibited a slight suppression of TGFbeta1-induced apoptosis. Endogenous peroxide production by hepatocytes increased with TGFbeta1, phenobarbital or clofibrate and the increase was greater with phenobarbital and in the presence of TGFbeta1 with both drugs. Gene expression of catalase and Mn- and Cu,Zn superoxide dismutases (SOD) was evaluated by northern blot analysis of hepatocytes incubated in the presence of phenobarbital or clofibrate with or without TGFbeta1 and the following differences were detected: phenobarbital induced a significant decrease in both dismutases (to 56%, P < 0.05, and 55%, P < 0.05, for Mn- and Cu,Zn-SOD respectively) and a 2-fold increase (P < 0.01) in catalase; clofibrate induced a slight decrease in both SODs and a 4-fold increase (P < 0.05) in catalase; TGFbeta1 significantly decreased to 37% (P < 0.05) expression of catalase while not significantly affecting expression of both SODs. We conclude that inhibition of spontaneous apoptosis induced by either phenobarbital or clofibrate is accompanied by increases in the endogenous levels of peroxides and by significant induction of catalase gene expression. Furthermore, the lack of effect of both compounds on TGFbeta1-induced apoptosis could be a consequence of the inability of these two compounds to counteract the depressing effect of TGFbeta1 on expression of catalase.      

Rendu–Osler–Weber syndrome presenting with pulmonary arteriovenous fistula

A pulmonary arteriovenous fistula is an abnormal connection between pulmonary arteries and veins. Patients with Rendu–Osler–Weber syndrome may present with this vascular malformation, which is a typical finding of the disease. Approximately 5–15% of Rendu–Osler–Weber syndrome patients have pulmonary arteriovenous malformations (AVM) and there is usually a family history of AVM in these patients. The malformations are usually located in the lower lobes. In this paper, I describe a 49‐year‐old male patient with dyspnoea, cough, haemoptysis and epistaxis. Physical examination showed nasal telangiectasias, cyanosis of the lips and nails, and a systolic bruit over the left lung. Chest X‐ray revealed a 5‐cm mass in the left lower lobe and after magnetic resonance examination, together with 3‐D magnetic resonance angiography, it was demonstrated to be a pulmonary arteriovenous fistula. The history of a niece with a similiar history of suspected pulmonary arteriovenous fistula led me to consider the possibility of Rendu–Osler–Weber syndrome presenting with a pulmonary arteriovenous fistula.     

中枢神经系统炎性脱髓鞘损伤髓鞘再生的细胞学治疗

多发性硬化（MS）损伤的病理特征是髓鞘脱失。髓鞘再生近年来被认为是自身免疫性脱髓鞘疾病，尤其是MS治疗中非常有前景的方向。髓鞘再生治疗可分为内源性和外源性，所以大量的临床和实验研究都集中于通过外源性移植细胞或通过促进内源性再生机制来获得中枢神经系统脱髓鞘区域的髓鞘再生，并均取得一定的成功。本文对近年来MS髓鞘再生的细胞学治疗的现状和神经科学背景及再生髓鞘治疗的将来可能发展方向进行了评述。