Antibacterial effect of four phenothiazines

Various types of phenothiazines were examined for antibacterial effect on 61 Gram-positive and Gram-negative bacterial strains in vitro. The investigated phenothiazines were two neuroleptic drugs, fluphenazine and chlorpromazine, and two antihistaminic drugs, alimemazine and promethazine. All four drugs have antibacterial effects in vitro, the phenothiazines being more potent against the Gram-positive microorganisms. The antibacterial potency of the drugs was measured as IC50: Fluphenazine 29 microM (15 micrograms/ml), alimemzaine 49 microM (37 micrograms/ml), promethazine 88 microM (28 micrograms/ml) and chlorpromazine 92 microM (29 micrograms/ml). The antibacterial potency of the drugs was linked neither to the neuroleptic nor the antihistaminic potency of the drugs, which is in agreement with results of earlier stereoisomeric investigations. Thus, the known phenothiazines may represent a pool of potentially new antimicrobial drugs. A therapeutic application of these results, however, requires additional in vitro an in vivo testing in an animal model. The bacterial model might be of value as a model system in the study of the interaction of neuropharmacological agents and other membrane active compounds on biological membranes.     

Are general practitioner hospitals cost-saving? Evidence from a rural area of Norway

OBJECTIVE: We aimed to determine whether general practitioner GP hospitals, compared with alternative modes of health care, are cost- saving. METHODS: Based on a study of admissions (n = 415) to fifteen GP hospitals in the Finnmark county of Norway during 8 weeks in 1992, a full 1-year patient throughput in GP hospitals was estimated. The alternative modes of care (general hospital, nursing home or home care) were based on assessments by the GPs handling the individual patients. The funds transferred to finance GP hospitals were taken as the cost of GP hospitals, while the cost of alternative care was based on municipality and hospital accounts, and standard charges for patient transport. RESULTS: The estimated total annual operating cost of GP hospitals was 32.2 million NOK (10 NOK = 1 Pound) while the cost of alternative care was in total 35.9 million NOK. Sensitivity analyses, under a range of assumptions, indicate that GP care in hospitals incurs the lowest costs to society. CONCLUSION: GP hospitals are likely to provide health care at lower costs than alternative modes of care.      

Exercise-induced metallothionein expression in human skeletal muscle fibres

Exercise induces free oxygen radicals that cause oxidative stress, and metallothioneins (MTs) are increased in states of oxidative stress and possess anti-apoptotic effects. We therefore studied expression of the antioxidant factors metallothionein I and II (MT-I + II) in muscle biopsies obtained in response to 3 h of bicycle exercise performed by healthy men and in resting controls. Both MT-I + II proteins and MT-II mRNA expression increased significantly in both type I and II muscle fibres after exercise. Moreover, 24 h after exercise the levels of MT-II mRNA and MT-I + II proteins were still highly increased and the MT-II mRNA expression reached a 15-fold increase. As expected, immunohistochemical detection of malondialdehyde (MDA) and nitrotyrosine (NITT) showed that formation of free radicals and oxidative stress were clearly increased in exercising muscle peaking shortly after the end of exercise in both type I and II muscle fibres. This is the first report demonstrating that MT-I + II are significantly induced in human skeletal muscle fibres following exercise. As MT-I + II are antioxidant factors that protect various tissues during pathological conditions, the MT-I + II increases post exercise may represent a mechanism whereby contracting muscle fibres are protected against cellular stress and injury.     

Identification of a type 1 diabetes-associated CD4 promoter haplotype with high constitutive activity

CD4 is a candidate gene in autoimmune diseases, including Type 1 diabetes mellitus (T1DM), because the CD4 receptor is crucial for appropriate antigen responses of CD4(+) T cells. We previously found linkage between a CD4-1188(TTTTC)(5-14) promoter polymorphism and T1DM. In the present study, we screened the human CD4 promoter for mutations and identified three frequent single nucleotide polymorphisms (SNPs): CD4-181C/G, CD4-521C/G and CD4-1050T/C. The SNPs are in strong linkage disequilibrium (LD) and association with the CD4-1188(TTTTC)(5-14) alleles, and we observed nine CD4 promoter haplotypes, of which four are frequent. We genotyped the SNPs in 253 Danish T1DM families (1129 individuals) and found evidence for linkage and association of a CD4 (A4(-1188)T(-1050)G(-521)C(-181)) haplotype to T1DM. In reporter studies, we show that (1) the T1DM-associated CD4 haplotype encodes high constitutive promoter activity and (2) the CD4-181G variant encodes higher stimulated promoter activity than the CD4-181C variant. This difference is in part neutralized in the frequently occurring CD4 promoter haplotypes by the more upstream genetic variants. Thus, we report functional impact of a novel CD4-181C/G SNP on stimulated CD4 promoter activity and the identification of a novel CD4 haplotype with high constitutive promoter activity that is linked and associated with T1DM.     

Is MED13L-related intellectual disability a recognizable syndrome?

Introduction

MED13L-related intellectual disability is characterized by moderate intellectual disability (ID), speech impairment, and dysmorphic facial features. We present 8 patients with MED13L-related intellectual disability and review the literature for phenotypical and genetic aspects of previously described patients.

Severe acute respiratory syndrome--a new coronavirus from the Chinese dragon's lair

The recent identification of a novel clinical entity, the severe acute respiratory syndrome (SARS), the rapid subsequent spread and case fatality rates of 14-15% have prompted a massive international collaborative investigation facilitated by a network of laboratories established by the World Health Organization (WHO). As SARS has the potential of becoming the first pandemic of the new millennium, a global warning by the WHO was issued on 12 March 2003. The disease, which is believed to have its origin in the Chinese Guangdong province, spread from Hong Kong via international airports to its current worldwide distribution. The concerted efforts of a globally united scientific community have led to the independent isolation and identification of a novel coronavirus from SARS patients by several groups. The extraordinarily rapid isolation of a causative agent of this newly emerged infectious disease constitutes an unprecedented scientific achievement. The main scope of the article is to provide the clinician with an overview of the natural history, epidemiology and clinical characteristics of SARS. On the basis of the recently published viral genome and structural features common to the members of the coronavirus family, a model for host cell-virus interaction and possible targets for antiviral drugs are presented. The epidemiological consequences of introducing a novel pathogen in a previously unexposed population and the origin and evolution of a new and more pathogenic strain of coronavirus are discussed.     

Susceptibility testing of Danish isolates of Capnocytophaga and CDC group DF-2 bacteria

Twelve Capnocytophaga and seven DF-2 strains were tested for their susceptibility to 14 antimicrobial agents using an agar dilution and an agar diffusion method. Twenty-three other antibiotics were evaluated using the diffusion test only. All strains were fully susceptible to penicillin, ampicillin, cefuroxime, cefotaxime, erythromycin, clindamycin, chloramphenicol, doxycycline, rifamycin and ofloxacin using both methods. Clindamycin, rifamycin and cefotaxime were most active. Using agar dilution some strains were susceptible to gentamicin, but agar diffusion showed total resistance. One Capnocytophaga strain was susceptible and another moderately susceptible to metronidazole, other strains were resistant. The agar diffusion test showed that both Capnocytophaga and DF-2 were resistant to most other aminoglycosides, to fosfomycin, polymyxin and trimethoprim. All strains of both taxa were fully susceptible to piperacillin, cefoxitin, imipenem and fusidic acid and showed different susceptibilities to the other agents. Susceptibility testing by means of agar diffusion using an enriched chocolate agar and 5% CO2 atmosphere could be used to test Capnocytophaga and DF-2 strains and gives sufficient accuracy for routine use, when revised inhibition zone breakpoints are employed.     

Manganese exposure in foundry furnacemen and scrap recycling workers

Objectives: Cast iron products are alloyed with small quantities of manganese, and foundry furnacemen are potentially exposed to manganese during tapping and handling of smelts. Manganese is a neurotoxic substance that accumulates in the central nervous system, where it may cause a neurological disorder that bears many similarities to Parkinson's disease. The aim of the study was to investigate the sources and levels of manganese exposure in foundry furnacemen by a combined measuring of blood-manganese (B-Mn) and manganese in ambient air (air-Mn). Methods: During a period of 16 months, Air-Mn and B-Mn (denoted `exposure values') were measured involving 24 furnacemen employed in three small size foundries and 21 scrap recycling workers from one plant. In the study period, 18 furnacemen had B-Mn measured 3–4 weeks after decreasing or stopping exposure (denoted `post-exposure values'). The reference group for the B-Mn measurements consisted of 90 Danish male subjects. Results: Furnacemen who work in insufficiently ventilated smelting departments inhale, absorb, and retain significant amounts of manganese in their blood (approx. 2.5–5 μg/l above reference values) despite a generally low measured airborne level of manganese fumes (0.002–0.064 mg/m³). The `exposure values' compared with `post-exposure values' revealed a significant decrease in the B-Mn (on average 3.7 μg/l) level of the most exposed furnacemen. Two persons in our study were suspected of suffering clinically subacute manganese intoxication as both had B-Mn levels beyond the normal limit (25 and 29 μg/l, respectively). The potential problem disappeared completely after cessation of exposure, and the B-Mn levels decreased to 9.4 and 14.1 μg/l, respectively. Conclusions: Risk assessment based on combined measurements of B-Mn and air-Mn seems to be valid in the interpretation of workers' hazard. Our study indicates that B-Mn may be a valuable parameter for estimating recent exposure (within 1–2 weeks). However, more knowledge is needed about the B-Mn level and its relation to neurological symptoms. Received: 20 January 1999 / Accepted: 14 June 1999