Diazepam enhances the action but not the binding of the GABA analog, THIP

GABA (4-aminobutyric acid) and its bicyclic analog THIP (4,5,6,7-tetrahydroisoxazolo-[4,5-c]-pyridin-3-ol) produced membrane hyperpolarization and increased chloride ion conductance of mouse spinal cord neurons in cell culture. Above 1 nM diazepam enhanced the actions of both GABA and THIP with similar potency and efficacy. Diazepam has been shown to enhance the binding of [3H]GABA to rat brain membranes over similar concentration ranges, with the EC50 values for enhancement of [3H]GABA binding and increase in membrane conductance being similar. In contrast, binding of [3H]THIP has been shown to be unaltered by diazepam under a variety of conditions. The possible reasons for such a discrepancy between these electrophysiological and neurochemical results with THIP are discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24844/1/0000270.pd

Benzodiazepine Ro 15-1788: Electrophysiological evidence for partial agonist activity

The effects of diazepam and Ro 15-1788 were assessed upon responses of mouse spinal cord (SC) neurons in cell culture to the amino acid neurotransmitters 4-aminobutyric acid (GABA) and S-glutamic acid. Diazepam (100 nM) enhanced GABA responses by 65 +/- 3% (113 cells), while Ro 15-1788 (100 nM) failed to alter GABA responses but reduced their enhancement by diazepam. Higher Ro 15-1788 concentrations (1 [mu]M or 10 [mu]M) enhanced GABA responses to a moderate extent, while blocking further enhancement of GABA by diazepam. Neither diazepam nor Ro 15-1788 affected glutamate responses or resting membrane potential or conductance of spinal cord neurons. These results provide electrophysiological support for partial agonist, rather than pure antagonist, activity of Ro 15-1788.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25039/1/0000466.pd

Diazepam and its Anomalous p-Chloro-derivative Ro 5-4864: Comparative effects on mouse neurons in cell culture

The actions of diazepam and its p-chloro-derivative Ro 5-4864 were compared on mouse spinal cord and dorsal root ganglion neurons in cell culture. Diazepam enhanced but Ro 5-4864 reduced iontophoretic GABA responses in a concentration-dependent manner. Both diazepam and Ro 5-4864 limited sustained, high frequency repetitive firing of spinal cord neurons but diazepam was more potent. Ro 5-4864 was, however, more potent than diazepam in inhibiting spontaneous neuronal activity of spinal cord neurons and reducing the duration of calcium-dependent action potentials of dorsal root ganglion neurons. The differeing actions of diazepam and Ro 5-4864 may account for the contrasting pharmalogical spectra of the two benzodiazepines.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24698/1/0000117.pd

Differential modulation of [gamma]-aminobutyric acid receptors by caprolactam derivatives with central nervous system depressant on convulsant activity

The effects of a series of caprolactam derivatives with central depressant, convulsant or muscle relaxant activity were investigated upon [gamma]-aminobutyric acid (GABA) receptor-ionophore binding to rat brain membranes using [3H]GABA, [3H]muscimol and [35S]-tert.-butylbicyclophophorothionate ([35S]TBPS) as ligands, and GABA resonses in mouse spinal cord neurones in dissociated cell culture. Some caprolactams produced a picrotoxin-like chloride-dependent partial inhibition of muscimol binding and were potent inhibitors of TBPS binding. One compound that was further investigated (4,4,6,6,-tetramethylhexahydro-2H-azepin-2-one), inhibited GABA responses and increased the frequency of paroxysmal depolarizations in cultured neurones. Other caprolactams enhanced muscimol binding and were relatively weak inhibitors of TBPS binding, and one (3,3-diallyl-6,6-dimethylhexahydro-2H-azepin-2,4-dione) was shown to enhance GABA responses and produced quiescence of activity in cultured neurones. There was a direct correaltion between caprolactam effects on muscimol binding in the presence of chloride ions and their effects on TBPS binding suggesting a similar site of action for the caprolactams influencing the binding of these two ligands. For the two classes of caprolactams, with respect to inhibition or enhancement of muscimol binding, there appeared to be a relationship between in vitro effects and their convulsant or depressant activity in mice. Caprolactams may be useful low molecular weight probes for the study of GABA receptor-ionophore complexes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25708/1/0000262.pd

Conservation successes and challenges for wide-ranging sharks and rays

Overfishing is the most significant threat facing sharks and rays. Given the growth in consumption of seafood, combined with the compounding effects of habitat loss, climate change, and pollution, there is a need to identify recovery paths, particularly in poorly managed and poorly monitored fisheries. Here, we document conservation through fisheries management success for 11 coastal sharks in US waters by comparing population trends through a Bayesian state-space model before and after the implementation of the 1993 Fisheries Management Plan for Sharks. We took advantage of the spatial and temporal gradients in fishing exposure and fisheries management in the Western Atlantic to analyze the effect on the Red List status of all 26 wide-ranging coastal sharks and rays. We show that extinction risk was greater where fishing pressure was higher, but this was offset by the strength of management engagement (indicated by strength of National and Regional Plan of Action for sharks and rays). The regional Red List Index (which tracks changes in extinction risk through time) declined in all regions until the 1980s but then improved in the North and Central Atlantic such that the average extinction risk is currently half that in the Southwest. Many sharks and rays are wide ranging, and successful fisheries management in one country can be undone by poorly regulated or unregulated fishing elsewhere. Our study underscores that well-enforced, science-based management of carefully monitored fisheries can achieve conservation success, even for slow-growing species

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Benzodiazepine receptor ligand actions on GABA responses. Benzodiazepines, CL 218872, zopiclone

The effects on GABA (4-aminobutyric acid) responses of several benzodiazepine and nonbenzodiazepine benzodiazepine receptor ligands were examined using mouse spinal cord neurons in dissociated cell culture. Diazepam, clonazepam and nitrazepam enhanced GABA responses potently at low nanomolar concentrations. Diazepam and clonazepam were most potent with significant enhancement at 1nM and peak enhancement of 80.7 and 50.2% at 10 nM respectively. Nitrazepam was least potent with no significant enhancement at 1 nM and enhancement of only 20.7% at 10 nM. The benzodiazepine antagonist, Ro 15-1788, blocked enhancement by diazepam but also weakly enhanced GABA responses at low micromolar concentrations, suggesting partial agonist activity. The convulsant benzodiazepine, Ro 5-4864, did not enhance GABA responses at any concentration tested but antagonized GABA responses at 1 [mu]M and above. Diazepam shifted GABA dose-response curves to the left by decreasing the apparent KD but without altering the apparent Vmax (Lineweaver-Burk analysis). Two nonbenzodiazepine anxiolytic/anticonvulsants, CL 218872 and zopiclone, were weak enhancers of GABA responses at high nanomolar concentrations. These results with benzodiazepines, CL 218872 and zoplicone are consistent with their anxiolytic and anticonvulsant profile in vivo and with studies of their effects upon low affinity GABA binding in vitro.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24816/1/0000242.pd

Benzodiazepine receptor ligand actions on GABA responses. [beta]-carbolines, purines

The effects of several [beta]-carboline and purine ligands for benzodiazepine receptors were studied upon GABA (4-aminobutyric acid) responses and upon diazepan enhancement of GABA responses, using mouse spinal cord neurons in dissociated cell culture. While the potent convulsant [beta]-carboline DMCM (methyl-6,7-dimethyoxy-4-ethyl-carboline-3-carboxylate), reduced GABA responses, methyl-carboline-3-carboxylate ([beta]CCMe) and the corresponding ethyl ester ([beta]CCEt) did not alter GABA responses. The propyl ester ([beta]CCPr) enhanced GABA responses in a concentration-dependent fashion, while both [beta]CCMe and [beta]CCPr blocked diazepam enhancement of GABA responses. [beta]CCPr may thus have partial agonist activity. Two purines with moderate benzodiazepine receptor affinity, 1-methylisoguanosine (MeIG) and 6-dimethylaminopurine (DMAP), weakly enhanced GABA responses. MeIG also significantly antagonized diazepam enhancement of GABA responses. Inosine and hypoxanthine had no apparent actions upon GABA responses or upon diazepam enhancement of such responses. The results with [beta]-carbolines are consistent with their behavioural profile in vivo and with neurochemical studies of their effects upon GABA-benzodiazepine receptor complexes. Furthermore, certain purines are also able to interact with these complexes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24817/1/0000243.pd