Antibiotic sensitization using biphenyl tetrazoles as potent inhibitors of Bacteroides fragilis metallo-beta-lactamase

BACKGROUND: High level resistance to carbapenem antibiotics in gram negative bacteria such as Bacteroides fragilis is caused, in part, by expression of a wide-spectrum metallo-beta-lactamase that hydrolyzes the drug to an inactive form. Co-administration of metallo-beta-lactamase inhibitors to resistant bacteria is expected to restore the antibacterial activity of carbapenems. RESULTS: Biphenyl tetrazoles (BPTs) are a structural class of potent competitive inhibitors of metallo-beta-lactamase identified through screening and predicted using molecular modeling of the enzyme structure. The X-ray crystal structure of the enzyme bound to the BPT L-159,061 shows that the tetrazole moiety of the inhibitor interacts directly with one of the two zinc atoms in the active site, replacing a metal-bound water molecule. Inhibition of metallo-beta-lactamase by BPTs in vitro correlates well with antibiotic sensitization of resistant B. fragilis. CONCLUSIONS: BPT inhibitors can sensitize a resistant B. fragilis clinical isolate expressing metallo-beta-lactamase to the antibiotics imipenem or penicillin G but not to rifampicin.     

Mutagenesis induced by the tumor microenvironment

Genomic instability is a commonly observed feature of tumors. Most investigations addressing the mechanism of tumor progression have focused on the genetic factors that may play a role. Growing evidence now suggests that, in addition to these endogenous factors, the exogenous environment within solid tumors may by itself be mutagenic and constitute a significant source of genetic instability. The tumor microenvironment is characterized by regions of fluctuating hypoxia, low pH, and nutrient deprivation. Each of these microenvironmental factors has been shown to cause severe disturbance in cell metabolism and physiology. Both in vivo and in vitro data demonstrate that exposure of tumor cells to adverse conditions can directly cause mutations, contributing to genetic instability. In this review, we will reexamine the current body of evidence on the role of the tumor microenvironment in inducing mutagenesis and consequent tumor progression.     

Colonic motor activity in women during sleep

Regulators of G-protein signalling (RGS) are recently identified proteins that shorten the lifetime of the activated G protein. We now show that rat cardiac myocytes express mRNA for at least 10 RGS. The mRNA for RGS-r is barely detectable in rat ventricles, but increases more than 20-fold during the 60- to 90-min process of isolating ventricular myocytes, and after 90 min of culture of atrial pieces in medium with Ca2+. Both in myocytes and in atria, the rise in RGS-r is transient. The mRNA for cardiac RGS5, but not RGS-r, is developmentally regulated. These studies suggest that rapid regulation of RGS levels may be a new mechanism that governs how signals are transmitted across the cardiac cell membrane.     

Quantitative determination of oxalate and other organic acids in drinking water at low microgram/1 concentrations

This study investigated the prevalence of snoring and symptoms of sleep breathing-related disorders in the multi-ethnic population of Singapore (3 million people, comprising 75% Chinese, 15% Malay and 7% Indian). A multistaged, area cluster, disproportionate stratified, random sampling of adults aged 20-74 yrs was used to obtain a sample of 2,298 subjects (65% response), with approximately equal numbers of Chinese, Malay and Indian and in each 10 yr age group. An interviewer-administered field questionnaire was used to record symptoms of snoring and breathing disturbances during sleep witnessed by a room-mate and other personal and health-related data. The weighted point estimate (and 95% confidence interval) of the whole population prevalence of snoring was 6.8% (53-83). There were pronounced ethnic differences among Chinese, 6.2% (4.4-8.1); Malay, 8.1% (6.1-10.2) and Indian, 10.9% (85-13.4). The minimum whole population prevalence by the most restricted symptom criteria for defining sleep breathing-related disorder was 0.43% (0.05-0.8%). Similar marked ethnic differences in rates were observed using various symptom criteria. The ethnic differences in sleep breathing symptoms paralleled the differences in body mass index, neck circumference and hypertension, but statistically significant differences remained after adjustment for sex, age and these known associated factors. Marked ethnic differences in snoring and sleep breathing-related disorders were observed in Chinese, Malays and Indians in Singapore, which were only partly explained by known factors of sex, age and body habitus.     

Clinical experience with sodium valproate in children

Good control was achieved with sodium valproate (Epilim) in 44 (71%) of a sample of 62 children with severe recurrent epileptic seizures. The medication was most effective in the control of petit mal; good results, however, were also achieved in some patients with previously poorly controlled grand mal epilepsy and psychomotor and myoclonic seizures. Twenty children required no other anti-convulsant and 28 required only one other. Side-effects were infrequent and mild. Only the high cost of sodium valproate in South Africa precludes its more general use in childhood epilepsy.