Over the 75‐year lifetime of the British Pharmacological Society there has been an enormous expansion in our understanding of how opioid drugs act on the nervous system, with much of this effort ...aimed at developing powerful analgesic drugs devoid of the side effects associated with morphine – the Holy Grail of opioid research. At the molecular and cellular level multiple opioid receptors have been cloned and characterised, their potential for oligomerisation determined, a large family of endogenous opioid agonists has been discovered, multiple second messengers identified and our understanding of the adaptive changes to prolonged exposure to opioid drugs (tolerance and physical dependence) enhanced. In addition, we now have greater understanding of the processes by which opioids produce the euphoria that gives rise to the intense craving for these drugs in opioid addicts. In this article, we review the historical pathway of opioid research that has led to our current state of knowledge.
British Journal of Pharmacology (2006) 147, S153–S162. doi:10.1038/sj.bjp.0706435
The reproductive microbiome is becoming increasingly recognised for its influence on fertility. While there has been much work to investigate the treatment of bacterial vaginosis and disordered ...microbiomes in optimizing outcomes in Assisted Reproductive Technology (ART), the role of routinely prescribed probiotics is yet to be established. The therapeutic potential of probiotic therapy remains an exciting opportunity in ART and this review endeavours to summarise its evidence to date.
A systematic review of MEDLINE (Pubmed), Allied Health Literature (CINAHL), EMBASE, Web of Science and the Cochrane database was performed on 7th May 2019, and repeated on 26th August 2019. The search was built using the terms ‘subfertility;’ ‘probiotic therapy;’ ‘clinical pregnancy rate’ and ‘assisted reproductive outcomes.’ The primary outcome was change in clinical pregnancy rate. Secondary outcomes included improvements in male and female fertility parameters and microbial assessment.
The initial search found 882 articles, of which 26 full manuscripts were reviewed. Four articles were eligible for inclusion. Of the two studies that reported the primary outcome, only one study found probiotics increased the clinical pregnancy rate non-significantly (48.0%–58.8%, p = 0.47). It also found higher miscarriage rate (30 % vs 16.6 %, p = 0.47) in the group treated with probiotics. Both studies on males with oral probiotic found significantly improved sperm motility.
While benefit in sperm motility has been observed with male probiotic therapy, there is conflicting evidence on the efficacy of probiotic therapy for women undergoing assisted reproduction. High quality randomized studies are needed to definitively examine probiotic therapy and establish its benefit for couples undergoing assisted reproduction.
Summary Objective To compare the effectiveness of acupuncture with other relevant physical treatments for alleviating pain due to knee osteoarthritis. Design Systematic review with network ...meta-analysis, to allow comparison of treatments within a coherent framework. Comprehensive searches were undertaken up to January 2013 to identify randomised controlled trials in patients with osteoarthritis of the knee, which reported pain. Results Of 156 eligible studies, 114 trials (covering 22 treatments and 9,709 patients) provided data suitable for analysis. Most trials studied short-term effects and many were classed as being of poor quality with high risk of bias, commonly associated with lack of blinding (which was sometimes impossible to achieve). End of treatment results showed that eight interventions: interferential therapy, acupuncture, TENS, pulsed electrical stimulation, balneotherapy, aerobic exercise, sham acupuncture, and muscle-strengthening exercise produced a statistically significant reduction in pain when compared with standard care. In a sensitivity analysis of satisfactory and good quality studies, most studies were of acupuncture (11 trials) or muscle-strengthening exercise (9 trials); both interventions were statistically significantly better than standard care, with acupuncture being statistically significantly better than muscle-strengthening exercise (standardised mean difference: 0.49, 95% credible interval 0.00–0.98). Conclusions As a summary of the current available research, the network meta-analysis results indicate that acupuncture can be considered as one of the more effective physical treatments for alleviating osteoarthritis knee pain in the short-term. However, much of the evidence in this area of research is of poor quality, meaning there is uncertainty about the efficacy of many physical treatments.
The use of radiofrequency ablation (RFA) for complete eradication of Barrett's esophagus has shown promise in trials conducted at predominantly tertiary academic centers; however less is known ...regarding outcomes in the community. We evaluated the safety and efficacy of RFA for Barrett's esophagus delivered in a community practice setting.
This was a multicenter registry conducted in community-based gastroenterology practices. Patients had confirmed intestinal metaplasia with or without dysplasia on biopsy of a Barrett's esophagus. Intervention was step-wise RFA with follow-up esophageal biopsies. Endpoints were histology-based; complete response was defined as all biopsies at most recent endoscopy negative for intestinal metaplasia (CR-IM) or dysplasia (CR-D). Three cohorts were reported: 1) safety cohort, all patients; 2) efficacy cohort A, patients with at least one biopsy session after initial treatment; 3) efficacy cohort B, patients with at least one biopsy session > or = 1 year after initial treatment.
The safety cohort included 429 patients (71 % men, median age 59 years, median Barrett's segment 3.0 cm). There were no serious adverse events (bleeding, perforation, death), and a stricture occurred after 1.1 % of cases (2.1 % of patients). In efficacy cohort A (n = 338), CR-IM and CR-D were achieved in 72 % and 89 % of patients, respectively (median follow-up 9 months). In efficacy cohort B (n = 137), CR-IM and CR-D were achieved in 77 % and 100 % of patients, respectively (median follow-up 20 months).
In this multicenter registry conducted at four community-based practices, the observed safety and efficacy outcomes associated with RFA for Barrett's esophagus are comparable to those previously reported in multicenter trials from predominantly tertiary academic centers.
South African gold mines.
To determine the prevalence of latent tuberculosis infection (LTBI) and risk factors for a positive tuberculin skin test (TST) among gold miners.
Cross-sectional survey. ...Human immunodeficiency virus (HIV) status was determined by self-report and medical records. TST positivity was defined by the mirror method to estimate the prevalence of LTBI, and by the US Centers for Disease Control and Prevention definitions to explore risk factors at the individual level.
Among 429 participants (105/130 subjects aged <30 years, 324/390 > or = 30 years), the estimated prevalence of LTBI was 89%; 45.5% of HIV-positive participants had a zero TST response compared to respectively 13% and 13.5% in the HIV-negative and status unknown participants. In participants with TST > 0, there was no significant difference between size of response by HIV status: the mean (standard deviation) widths for HIV-positive, HIV-negative and HIV status unknown were respectively 11.84 (2.75), 12.03 (2.75) and 12.52 mm (3.04) (analysis of variance P = 0.28). Factors independently associated with a TST < 10 mm were positive HIV status (aOR 0.41, 95%CI 0.17-0.96) and not working underground (aOR 0.25, 95%CI 0.09-0.71).
The prevalence of LTBI is very high in gold miners in South Africa. HIV-infected individuals are more likely to have a negative TST, but HIV infection does not affect the size of TST response.
The estuaries of Tampa Bay, Sarasota Bay, Lemon Bay, and Upper Charlotte Harbor are contiguous waterbodies located within the subtropical environment of Southwest Florida. Based on an examination of ...rainfall data over the period of record (1916–2001) within the watersheds of these estuaries, there is no evidence for spatial differences (at the watershed level) or monotonic trends in annual rainfall. During the 1980s, nitrogen loads into Tampa Bay and Sarasota Bay (generated primarily by domestic wastewater treatment facilities) were reduced by 57% and 46%, respectively. In response, both Tampa Bay and Sarasota Bay have lower phytoplankton concentrations, greater water clarity and more extensive seagrass coverage in 2002 than in the early 1980s. As there is no evidence of a concurrent trend in rainfall during the period of 1982–2001, it is unlikely that variation in rainfall can account for the observed increase in seagrass coverage in these two bays. In contrast, seagrass coverage has remained relatively constant since the mid 1980s in Lemon Bay and Charlotte Harbor. Domestic wastewater treatment facilities are minor sources of nitrogen to Lemon Bay, and water clarity in Charlotte Harbor varies mostly as a function of dissolved organic matter and non-chlorophyll associated turbidity, not phytoplankton levels. Even in estuaries that share boundaries and are within 100
km of each other, varied responses to anthropogenic changes and natural phenomena were observed in water quality and associated seagrass extent. Resource management strategies must take into account system-specific factors—not all strategies will result in similar results in different systems.
We present limits on spin-independent dark matter-nucleon interactions using a 10.6 g Si athermal phonon detector with a baseline energy resolution of σE = 3.86 ± 0.04 ( stat ) +0.19 −0.00 ( syst ) ...eV . This exclusion analysis sets the most stringent dark matter-nucleon scattering cross-section limits achieved by a cryogenic detector for dark matter particle masses from 93 to 140 MeV / c2 , with a raw exposure of 9.9 g d acquired at an above-ground facility. This work illustrates the scientific potential of detectors with athermal phonon sensors with eV-scale energy resolution for future dark matter searches.
Microbial attachment and biofilm formation is a ubiquitous behaviour of microorganisms and is the most crucial prerequisite of contact bioleaching. Monazite and xenotime are two commercially ...exploitable minerals containing rare earth elements (REEs). Bioleaching using phosphate solubilizing microorganisms is a green biotechnological approach for the extraction of REEs. In this study, microbial attachment and biofilm formation of Klebsiella aerogenes ATCC 13048 on the surface of these minerals were investigated using confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM). In a batch culture system, K. aerogenes was able to attach and form biofilms on the surface of three phosphate minerals. The microscopy records showed three distinctive stages of biofilm development for K. aerogenes commencing with initial attachment to the surface occurring in the first minutes of microbial inoculation. This was followed by colonization of the surface and formation of a mature biofilm as the second distinguishable stage, with progression to dispersion as the final stage. The biofilm had a thin‐layer structure. The colonization and biofilm formation were localized toward physical surface imperfections such as cracks, pits, grooves and dents. In comparison to monazite and xenotime crystals, a higher proportion of the surface of the high‐grade monazite ore was covered by biofilm which could be due to its higher surface roughness. No selective attachment or colonization toward specific mineralogy or chemical composition of the minerals was detected. Finally, in contrast to abiotic leaching of control samples, microbial activity resulted in extensive microbial erosion on the high‐grade monazite ore.
Klebsiella aerogenes form thin‐layer biofilm on monazite and xenotime. The colonization and biofilm formation were localized toward physical surface imperfections such as cracks, pits, grooves and dents. No selective attachment or colonization toward specific mineralogy or chemical composition of the minerals was detected. Finally, in contrast to abiotic leaching of control samples, microbial activity resulted in extensive microbial erosion on the high‐grade monazite ore.
This article presents an analysis and the resulting limits on light dark matter inelastically scattering off of electrons, and on dark photon and axionlike particle absorption, using a ...second-generation SuperCDMS high-voltage eV-resolution detector. The 0.93 g Si detector achieved a 3 eV phonon energy resolution; for a detector bias of 100 V, this corresponds to a charge resolution of 3% of a single electron-hole pair. The energy spectrum is reported from a blind analysis with 1.2 g-days of exposure acquired in an above-ground laboratory. With charge carrier trapping and impact ionization effects incorporated into the dark matter signal models, the dark matter-electron cross section σe is constrained for dark matter masses from 0.5 to 104 MeV / c2; in the mass range from 1.2 to 50 eV / c2 the dark photon kinetic mixing parameter ϵ and the axioelectric coupling constant gae are constrained. The minimum 90% confidence-level upper limits within the above-mentioned mass ranges are σe = 8.7 × 10−34 cm2, ϵ = 3.3 × 10−14, and gae = 1.0 × 10−9.
Identification of agents that target human leukemia stem cells is an important consideration for the development of new therapies. The present study demonstrates that rocaglamide and silvestrol, ...closely related natural products from the flavagline class of compounds, are able to preferentially kill functionally defined leukemia stem cells, while sparing normal stem and progenitor cells. In addition to efficacy as single agents, flavaglines sensitize leukemia cells to several anticancer compounds, including front-line chemotherapeutic drugs used to treat leukemia patients. Mechanistic studies indicate that flavaglines strongly inhibit protein synthesis, leading to the reduction of short-lived antiapoptotic proteins. Notably though, treatment with flavaglines, alone or in combination with other drugs, yields a much stronger cytotoxic activity toward leukemia cells than the translational inhibitor temsirolimus. These results indicate that the underlying cell death mechanism of flavaglines is more complex than simply inhibiting general protein translation. Global gene expression profiling and cell biological assays identified Myc inhibition and the disruption of mitochondrial integrity to be features of flavaglines, which we propose contribute to their efficacy in targeting leukemia cells. Taken together, these findings indicate that rocaglamide and silvestrol are distinct from clinically available translational inhibitors and represent promising candidates for the treatment of leukemia.
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