Subtype-selective GABAA receptor mimetics—novel antihyperalgesic agents?

Agonists at the benzodiazepine-binding site of ionotropic γ-aminobutyric acid (GABAA) receptors are in clinical use as hypnotics, anxiolytics, and anticonvulsants since the early 1960. Analgesic effects of classical benzodiazepines have occasionally been reported in certain subgroups of patients suffering from chronic pain or after spinal delivery through intrathecal catheters. However, these drugs are generally not considered as analgesics but should in fact be avoided in patients with chronic pain. Recent evidence from genetically modified mice now indicates that agents targeting only a subset of benzodiazepine (GABAA) receptors should provide pronounced antihyperalgesic activity against inflammatory and neuropathic pain. Several such compounds have been developed recently, which exhibit significant antihyperalgesia in mice and rats and appear to be devoid of the typical side-effects of classical benzodiazepine

Antihyperalgesia by α2-GABAA Receptors Occurs Via a Genuine Spinal Action and Does Not Involve Supraspinal Sites

Drugs that enhance GABAergic inhibition alleviate inflammatory and neuropathic pain after spinal application. This antihyperalgesia occurs mainly through GABAA receptors (GABAARs) containing α2 subunits (α2-GABAARs). Previous work indicates that potentiation of these receptors in the spinal cord evokes profound antihyperalgesia also after systemic administration, but possible synergistic or antagonistic actions of supraspinal α2-GABAARs on spinal antihyperalgesia have not yet been addressed. Here we generated two lines of GABAAR-mutated mice, which either lack α2-GABAARs specifically from the spinal cord, or, which express only benzodiazepine-insensitive α2-GABAARs at this site. We analyzed the consequences of these mutations for antihyperalgesia evoked by systemic treatment with the novel non-sedative benzodiazepine site agonist HZ166 in neuropathic and inflammatory pain. Wild-type mice and both types of mutated mice had similar baseline nociceptive sensitivities and developed similar hyperalgesia. However, antihyperalgesia by systemic HZ166 was reduced in both mutated mouse lines by about 60% and was virtually indistinguishable from that of global point-mutated mice, in which all α2-GABAARs were benzodiazepine insensitive. The major (α2-dependent) component of GABAAR-mediated antihyperalgesia was therefore exclusively of spinal origin, whereas supraspinal α2-GABAARs had neither synergistic nor antagonistic effects on antihyperalgesia. Our results thus indicate that drugs that specifically target α2-GABAARs exert their antihyperalgesic effect through enhanced spinal nociceptive control. Such drugs may therefore be well-suited for the systemic treatment of different chronic pain conditions

A cluster of multidrug-resistant Mycobacterium tuberculosis among patients arriving in Europe from the Horn of Africa: a molecular epidemiological study.

BACKGROUND: The risk of tuberculosis outbreaks among people fleeing hardship for refuge in Europe is heightened. We describe the cross-border European response to an outbreak of multidrug-resistant tuberculosis among patients from the Horn of Africa and Sudan. METHODS: On April 29 and May 30, 2016, the Swiss and German National Mycobacterial Reference Laboratories independently triggered an outbreak investigation after four patients were diagnosed with multidrug-resistant tuberculosis. In this molecular epidemiological study, we prospectively defined outbreak cases with 24-locus mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) profiles; phenotypic resistance to isoniazid, rifampicin, ethambutol, pyrazinamide, and capreomycin; and corresponding drug resistance mutations. We whole-genome sequenced all Mycobacterium tuberculosis isolates and clustered them using a threshold of five single nucleotide polymorphisms (SNPs). We collated epidemiological data from host countries from the European Centre for Disease Prevention and Control. FINDINGS: Between Feb 12, 2016, and April 19, 2017, 29 patients were diagnosed with multidrug-resistant tuberculosis in seven European countries. All originated from the Horn of Africa or Sudan, with all isolates two SNPs or fewer apart. 22 (76%) patients reported their travel routes, with clear spatiotemporal overlap between routes. We identified a further 29 MIRU-VNTR-linked cases from the Horn of Africa that predated the outbreak, but all were more than five SNPs from the outbreak. However all 58 isolates shared a capreomycin resistance-associated tlyA mutation. INTERPRETATION: Our data suggest that source cases are linked to an M tuberculosis clone circulating in northern Somalia or Djibouti and that transmission probably occurred en route before arrival in Europe. We hypothesise that the shared mutation of tlyA is a drug resistance mutation and phylogenetic marker, the first of its kind in M tuberculosis sensu stricto. FUNDING: The Swiss Federal Office of Public Health, the University of Zurich, the Wellcome Trust, National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), the Medical Research Council, BELTA-TBnet, the European Union, the German Center for Infection Research, and Leibniz Science Campus Evolutionary Medicine of the Lung (EvoLUNG)

A cluster of multidrug-resistant Mycobacterium tuberculosis among patients arriving in Europe from the Horn of Africa: a molecular epidemiological study

SummaryBackground The risk of tuberculosis outbreaks among people fleeing hardship for refuge in Europe is heightened. We describe the cross-border European response to an outbreak of multidrug-resistant tuberculosis among patients from the Horn of Africa and Sudan. Methods On April 29 and May 30, 2016, the Swiss and German National Mycobacterial Reference Laboratories independently triggered an outbreak investigation after four patients were diagnosed with multidrug-resistant tuberculosis. In this molecular epidemiological study, we prospectively defined outbreak cases with 24-locus mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) profiles; phenotypic resistance to isoniazid, rifampicin, ethambutol, pyrazinamide, and capreomycin; and corresponding drug resistance mutations. We whole-genome sequenced all Mycobacterium tuberculosis isolates and clustered them using a threshold of five single nucleotide polymorphisms (SNPs). We collated epidemiological data from host countries from the European Centre for Disease Prevention and Control. Findings Between Feb 12, 2016, and April 19, 2017, 29 patients were diagnosed with multidrug-resistant tuberculosis in seven European countries. All originated from the Horn of Africa or Sudan, with all isolates two SNPs or fewer apart. 22 (76%) patients reported their travel routes, with clear spatiotemporal overlap between routes. We identified a further 29 MIRU-VNTR-linked cases from the Horn of Africa that predated the outbreak, but all were more than five SNPs from the outbreak. However all 58 isolates shared a capreomycin resistance-associated tlyA mutation. Interpretation Our data suggest that source cases are linked to an M tuberculosis clone circulating in northern Somalia or Djibouti and that transmission probably occurred en route before arrival in Europe. We hypothesise that the shared mutation of tlyA is a drug resistance mutation and phylogenetic marker, the first of its kind in M tuberculosis sensu stricto. Funding The Swiss Federal Office of Public Health, the University of Zurich, the Wellcome Trust, National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), the Medical Research Council, BELTA-TBnet, the European Union, the German Center for Infection Research, and Leibniz Science Campus Evolutionary Medicine of the Lung (EvoLUNG)

The SIB Swiss Institute of Bioinformatics' resources: focus on curated databases

The SIB Swiss Institute of Bioinformatics (www.isb-sib.ch) provides world-class bioinformatics databases, software tools, services and training to the international life science community in academia and industry. These solutions allow life scientists to turn the exponentially growing amount of data into knowledge. Here, we provide an overview of SIB's resources and competence areas, with a strong focus on curated databases and SIB's most popular and widely used resources. In particular, SIB's Bioinformatics resource portal ExPASy features over 150 resources, including UniProtKB/Swiss-Prot, ENZYME, PROSITE, neXtProt, STRING, UniCarbKB, SugarBindDB, SwissRegulon, EPD, arrayMap, Bgee, SWISS-MODEL Repository, OMA, OrthoDB and other databases, which are briefly described in this article

Use of fat-modified food products to change dietary fat intake of young people

Food purchasing and preparation practices were modified in two boarding high schools to increase the polyunsaturated-to-saturated fat ratio (P/S) of the diet of students by changing food products rather than attempting to change eating behaviors. During years when fat-modified products were served, the P/S of males increased by 75 percent, versus a decrease of 6 percent during control years. For females, P/S increased by 53 percent during intervention years, versus an increase of 6 percent during control years

Effects of alterations in fatty acid intake on the blood pressure of adolescents: the Exeter-Andover Project

To judge the effect on blood pressure, the ratio of polyunsaturated to saturated fatty acids (P:S) of foods served to students at two boarding high schools was modified alternately at each school for one school year. The average P:S of the diet of males increased from 0.53 to 0.93 during the intervention whereas among females it increased from 0.64 to 0.98. Comparison of repeated systolic and diastolic blood pressure measurements near the end of the school year did not demonstrate a beneficial effect of the dietary fat changes on the blood pressure of these normotensive adolescents. Compared with the blood pressure patterns during control years, the dietary intervention resulted in slightly higher systolic (+0.88 mm Hg; 95% CI -0.66, +2.42) and diastolic (+1.23 mm Hg; 95% CI = +0.04, +2.42) blood pressure readings among males. Among females the intervention resulted in slightly lower systolic (-0.54 mm Hg; 95% CI = -1.95, +0.88) and diastolic (-0.80 mm Hg (95% CI -2.18, +0.58) blood pressure readings

Effects of alterations in fatty acid intake on the blood pressure of adolescents: the Exeter-Andover Project

To judge the effect on blood pressure, the ratio of polyunsaturated to saturated fatty acids (P:S) of foods served to students at two boarding high schools was modified alternately at each school for one school year. The average P:S of the diet of males increased from 0.53 to 0.93 during the intervention whereas among females it increased from 0.64 to 0.98. Comparison of repeated systolic and diastolic blood pressure measurements near the end of the school year did not demonstrate a beneficial effect of the dietary fat changes on the blood pressure of these normotensive adolescents. Compared with the blood pressure patterns during control years, the dietary intervention resulted in slightly higher systolic (+0.88 mm Hg; 95% CI -0.66, +2.42) and diastolic (+1.23 mm Hg; 95% CI = +0.04, +2.42) blood pressure readings among males. Among females the intervention resulted in slightly lower systolic (-0.54 mm Hg; 95% CI = -1.95, +0.88) and diastolic (-0.80 mm Hg (95% CI -2.18, +0.58) blood pressure readings