Heavy metal pollution and co-selection for antibiotic resistance: A microbial palaeontology approach

This is the final version. Available on open access from Elsevier via the DOI in this recordFrequent and persistent heavy metal pollution has profound effects on the composition and activity of microbial communities. Heavy metals select for metal resistance but can also co-select for resistance to antibiotics, which is a global health concern. We here document metal concentration, metal resistance and antibiotic resistance along a sediment archive from a pond in the North West of the United Kingdom covering over a century of anthropogenic pollution. We specifically focus on zinc, as it is a ubiquitous and toxic metal contaminant known to co-select for antibiotic resistance, to assess the impact of temporal variation in heavy metal pollution on microbial community diversity and to quantify the selection effects of differential heavy metal exposure on antibiotic resistance. Zinc concentration and bioavailability was found to vary over the core, likely reflecting increased industrialisation around the middle of the 20th century. Zinc concentration had a significant effect on bacterial community composition, as revealed by a positive correlation between the level of zinc tolerance in culturable bacteria and zinc concentration. The proportion of zinc resistant isolates was also positively correlated with resistance to three clinically relevant antibiotics (oxacillin, cefotaxime and trimethoprim). The abundance of the class 1 integron-integrase gene, intI1, marker for anthropogenic pollutants correlated with the prevalence of zinc- and cefotaxime resistance but not with oxacillin and trimethoprim resistance. Our microbial palaeontology approach reveals that metal-contaminated sediments from depths that pre-date the use of antibiotics were enriched in antibiotic resistant bacteria, demonstrating the pervasive effects of metal-antibiotic co-selection in the environment.University of Exete

Functional expression of purinergic P2 receptors and transient receptor potential channels by the human urothelium

In addition to its role as a physical barrier, the urothelium is considered to play an active role in mechanosensation. A key mechanism is the release of transient mediators that activate purinergic P2 receptors and transient receptor potential (TRP) channels to effect changes in intracellular Ca 2ϩ . Despite the implied importance of these receptors and channels in urothelial tissue homeostasis and dysfunctional bladder disease, little is known about their functional expression by the human urothelium. To evaluate the expression and function of P2X and P2Y receptors and TRP channels, the human ureter and bladder were used to separate urothelial and stromal tissues for RNA isolation and cell culture. RT-PCR using stringently designed primer sets was used to establish which P2 and TRP species were expressed at the transcript level, and selective agonists/antagonists were used to confirm functional expression by monitoring changes in intracellular Ca 2ϩ and in a scratch repair assay. The results confirmed the functional expression of P2Y4 receptors and excluded nonexpressed receptors/channels (P2X 1, P2X3, P2X6, P2Y6, P2Y11, TRPV5, and TRPM8), while a dearth of specific agonists confounded the functional validation of expressed P2X 2, P2X4, P2Y1, P2Y2, TRPV2, TRPV3, TRPV6 and TRPM7 receptors/channels. Although a conventional response was elicited in control stromal-derived cells, the urothelial cell response to well-characterized TRPV1 and TRPV4 agonists/ antagonists revealed unexpected anomalies. In addition, agonists that invoked an increase in intracellular Ca 2ϩ promoted urothelial scratch repair, presumably through the release of ATP. The study raises important questions about the ligand selectivity of receptor/ channel targets expressed by the urothelium. These pathways are important in urothelial tissue homeostasis, and this opens the possibility of selective drug targeting. calcium; purinergic; transient receptor potential channel; urothelium THERE HAS BEEN a growing appreciation that rather than a simple passive barrier, the urothelium plays a more active role in the urinary tract. After physical or other damage, the urothelium will self-repair by switching from a mitotically quiescent to a highly regenerative state More intriguingly, the urothelium has been reported to possess sensory neuronal-like properties and to respond to mechanical and chemical stimulation through the release of transient mediators (4). Various mediators have been implicated, including ATP, nitric oxide, acetylcholine, and substance P (1, 7, 11). These short-lived mediators are considered to actuate suburothelial afferent neurons involved in the regulation of sensory perception and pain, but the urothelium is itself widely reported to express an array of receptors and channels that may respond in an autocrine/paracrine fashion to released mediators. These include purinergic P2X and P2Y (8, 24, 27), transient receptor potential (TRPV1, TRPV2, TRPV4, and TRPM8), acetylcholine (nicotinic and muscarinic), tachykinin, nerve growth factor, endothelin, sphingosine-1-phosphate, and bradykinin (3, 9, 15, 17) receptors. The outcome of such signaling is incompletely understood as it may play a bidirectional feedback role in modulating the neuronal signal and/or effect changes in urothelial homeostasis, such as barrier repair. It has also been suggested that abnormal expression of receptors and/or mediator release by the urothelium may be involved in dysfunctional diseases of the bladder, including idiopathic detrusor instability and interstitial cystitis Despite the literature reporting expression of these channels and receptors by the urothelium, consensus is confounded by contradictions in experimental approaches, including the species, specificity of reagents, and the nature of the tissue preparation (for a review, see Ref. 30). There has been limited characterization of these receptor/mediator signaling pathways in the human urothelium, where functional TRPV1 (10) and an autocrine-activated P2Y receptor pathway (19, 26) have been reported. Ultimately, this conflict and the lack of consensus are hindrances to the development of selective drugs. To attribute expression and function to specific tissue compartments, the present study was designed to define the functional expression of purinergic and transient receptors in the isolated human urothelium and stromal cells in situ and in vitro. A preliminary investigation revealed a lack of specificity of commercially available antibodies. For this reason, our rationalized experimental approach was to identify candidate receptors based on mRNA expression followed by confirmatory functional experiments to measure changes in intracellular Ca 2ϩ using specific agonists/antagonists. Finally, to examine whether receptor activation plays a role in urothelial homeostasis, we examined the effect of receptor activation on human urothelial scratch wound repair in vitro

Radiation-hypersensitive cancer patients do not manifest protein expression abnormalities in components of the nonhomologous end-joining (NHEJ) pathway

Radiation therapy (RT) is utilised for the treatment of around half of all oncology patients during the course of their illness. Despite great clinical progress in the rational deployment of RT, the underlying molecular basis for its efficacy and toxicity are currently imperfectly understood. In this study, we took a biochemical approach to evaluate the potential role of key ionising radiation repair proteins in the treatment outcomes of patients with severe acute or late RT side effects. Lymphoblastoid cell lines were established from blood samples from 36 radiosensitive cases and a number of controls (the latter had had RT but did not develop significant toxicity). The expression level and migration of key proteins from the nonhomologous end-joining (NHEJ) pathway was evaluated by Western blot analysis on cases and controls. We did not observe any abnormalities in expression level or migration pattern of the following NHEJ proteins in radiosensitive cancer cases: Ku70, Ku80, XRCC4, DNA Ligase IV. These important negative results provide evidence that mutations that affect protein expression of these NHEJ components are unlikely to underlie clinical radiation sensitivity

Risk factors for suicide in Bali: a psychological autopsy study

<p>Abstract</p> <p>Background</p> <p>The suicide rate in Bali has significantly increased in recent years. However, to date, there have been no case-control studies investigating risk factors for suicide.</p> <p>Methods</p> <p>A psychological autopsy study was conducted comparing 60 suicide cases and 120 living controls matched in age, sex, and area of residence.</p> <p>Results</p> <p>Multiple logistic regression analysis identified the following risk factors for suicide: at least one diagnosis of axis-I mental disorder (OR: 14.84 CI: 6.12 - 35.94); low level of religious involvement (OR: 7.24 CI: 2.28 - 22.95); and severe interpersonal problems (OR: 3.86 CI: 1.36 - 11.01). Forty-eight (80.0%) of the suicide cases were diagnosed with mental disorders; however, only 16.7% visited a primary care health professional and none received psychiatric treatment during the 1 month prior to death.</p> <p>Conclusion</p> <p>Clinical, religious, and psychosocial factors were associated with suicide. These results highlight the significance of early recognition and treatment of mental disorders, religious activities, and interpersonal problem-solving strategies for suicide prevention in Bali.</p

Sub-ice-shelf sediments record history of twentieth-century retreat of Pine Island Glacier

The article of record as published may be found at http://dx.doi.org/10.1038/nature20136The West Antarctic Ice Sheet is one of the largest potential sources of rising sea levels. Over the past 40 years, glaciers flowing into the Amundsen Sea sector of the ice sheet have thinned at an accelerating rate, and several numerical models suggest that unstable and irreversible retreat of the grounding line—which marks the boundary between grounded ice and floating ice shelf—is underway. Understanding this recent retreat requires a detailed knowledge of grounding-line history, but the locations of the grounding line before the advent of satellite monitoring in the 1990s are poorly dated. In particular, a history of grounding-line retreat is required to understand the relative roles of contemporaneous ocean-forced change and of ongoing glacier response to an earlier perturbation in driving ice-sheet loss. Here we show that the present thinning and retreat of Pine Island Glacier in West Antarctica is part of a climatically forced trend that was triggered in the 1940s. Our conclusions arise from analysis of sediment cores recovered beneath the floating Pine Island Glacier ice shelf, and constrain the date at which the grounding line retreated from a prominent seafloor ridge. We find that incursion of marine water beyond the crest of this ridge, forming an ocean cavity beneath the ice shelf, occurred in 1945 (±12 years); final ungrounding of the ice shelf from the ridge occurred in 1970 (±4 years). The initial opening of this ocean cavity followed a period of strong warming of West Antarctica, associated with El Niño activity. Furthermore our results suggest that, even when climate forcing weakened, ice-sheet retreat continued.USDO

Search for CP violation in D+→ϕπ+ and D+s→K0Sπ+ decays

A search for CP violation in D + → ϕπ + decays is performed using data collected in 2011 by the LHCb experiment corresponding to an integrated luminosity of 1.0 fb−1 at a centre of mass energy of 7 TeV. The CP -violating asymmetry is measured to be (−0.04 ± 0.14 ± 0.14)% for candidates with K − K + mass within 20 MeV/c 2 of the ϕ meson mass. A search for a CP -violating asymmetry that varies across the ϕ mass region of the D + → K − K + π + Dalitz plot is also performed, and no evidence for CP violation is found. In addition, the CP asymmetry in the D+s→K0Sπ+ decay is measured to be (0.61 ± 0.83 ± 0.14)%

Trajectories of dementia-related cognitive decline in a large mental health records derived patient cohort

Background: Modeling trajectories of decline can help describe the variability in progression of cognitive impairment in dementia. Better characterisation of these trajectories has significant implications for understanding disease progression, trial design and care planning. Methods: Patients with at least three Mini-mental State Examination (MMSE) scores recorded in the South London and Maudsley NHS Foundation Trust Electronic Health Records, UK were selected (N = 3441) to form a retrospective cohort. Trajectories of cognitive decline were identified through latent class growth analysis of longitudinal MMSE scores. Demographics, Health of Nation Outcome Scales and medications were compared across trajectories identified. Results: Four of the six trajectories showed increased rate of decline with lower baseline MMSE. Two trajectories had similar initial MMSE scores but different rates of decline. In the faster declining trajectory of the two, a higher incidence of both behavioral problems and sertraline prescription were present. Conclusions: We find suggestive evidence for association of behavioral problems and sertraline prescription with rate of decline. Further work is needed to determine whether trajectories replicate in other datasets

Free abdominal fluid without obvious solid organ injury upon CT imaging: an actual problem or simply over-diagnosing?

Whereas a non-operative approach for hemodynamically stable patients with free intraabdominal fluid in the presence of solid organ injury is generally accepted, the presence of free fluid in the abdomen without evidence of solid organ injury not only presents a challenge for the treating emergency physician but also for the surgeon in charge. Despite recent advances in imaging modalities, with multi-detector computed tomography (CT) (with or without contrast agent) usually the imaging method of choice, diagnosis and interpretation of the results remains difficult. While some studies conclude that CT is highly accurate and relatively specific at diagnosing mesenteric and hollow viscus injury, others studies deem CT to be unreliable. These differences may in part be due to the experience and the interpretation of the radiologist and/or the treating physician or surgeon