Postoperative Intensive Care Management of Aortic Repair.
Vascular surgery patients have multiple comorbidities and are at high risk for perioperative complications. Aortic repair surgery has greatly evolved in recent years, with an increasing predominance of endovascular techniques (EVAR). The incidence of cardiac complications is significantly reduced with endovascular repair, but high-risk patients require postoperative ST-segment monitoring. Open aortic repair may portend a prohibitive risk of respiratory complications that could be a contraindication for surgery. This risk is greatly reduced in the case of an endovascular approach, and general anesthesia should be avoided whenever possible in the case of endovascular repair. Preoperative renal function and postoperative kidney injury are powerful determinants of short- and long-term outcome, so that preoperative risk stratification and secondary prevention are critical tasks. Intraoperative renal protection with selective renal and distal aortic perfusion is essential during open repair. EVAR has lower rates of postoperative renal failure compared to open repair, with approximately half the risk for acute kidney injury (AKI) and one-third of the risk of hemodialysis requirement. Spinal cord ischemia used to be the most distinctive and feared complication of aortic repair. The risk has significantly decreased since the beginning of aortic surgery, with advances in surgical technique and spinal protection protocols, and is lower with endovascular repair. Endovascular repair avoids extensive aortic dissection and aortic cross-clamping and is generally associated with reduced blood loss and less coagulopathy. The intensive care physician must be aware that aortic repair surgery has an impact on every organ system, and the importance of early recognition of organ failure cannot be overemphasized.


The lithocholic acid 6 beta-hydroxylase cytochrome P-450, CYP 3A10, is an active catalyst of steroid-hormone 6 beta-hydroxylation.
CYP 3A10 is a hamster liver cytochrome P-450 (P450) that encodes lithocholic acid 6 beta-hydroxylase, an enzyme that plays an important role in the detoxification of the cholestatic secondary bile acid lithocholate. Western-blot analysis revealed that the expression of CYP 3A10 protein is male-specific in hamster liver microsomes, a finding that is consistent with earlier analysis of CYP 3A10 mRNA. Since it has not been established whether the specificities of bile acid hydroxylase P450s, such as CYP 3A10, are restricted to their anionic bile acid substrates, we investigated the role of CYP 3A10 in the metabolism of a series of neutral steroid hormones using cDNA directed-expression in COS cells. The steroid hormones examined, testosterone, androstenedione and progesterone, were each metabolized by the expressed CYP 3A10, with 6 beta-hydroxylation corresponding to a major activity in all three instances. CYP 3A10-dependent steroid hydroxylation was increased substantially when the microsomes were prepared from COS cells co-transfected with NADPH:P450 reductase cDNA. In this case, the expressed P450 actively catalysed the 6 beta-hydroxylation of testosterone (288 +/- 23 pmol of product formed/min per mg of COS-cell microsomal protein), androstenedione (107 +/- 19 pmol/min per mg) and progesterone (150 +/- 7 pmol/min per mg). Other major CYP 3A10-mediated steroid hydroxylase activities included androstenedione 16 alpha-hydroxylation, progesterone 16 alpha- and 21-hydroxylation, and the formation of several unidentified products. CYP 3A10 exhibited similar Vmax. values for the 6 beta-hydroxylation of androstenedione and lithocholic acid (132 and 164 pmol/min per mg respectively), but metabolized the bile acid with a 3-fold lower Km (25 microM, as against 75 microM for androstenedione). Together, these studies establish that the substrate specificity of the bile acid hydroxylase CYP 3A10 is not restricted to bile acids, and further suggest that CYP 3A10 can play a physiologically important role in the metabolism of two classes of endogenous P450 substrates:steroid hormones and bile acids.


Health Care Utilization for Musculoskeletal Issues During the Prediagnosis Period in Psoriatic Arthritis: A Population-Based Study.
Information about the prediagnosis period in psoriatic arthritis (PsA) is limited. The present study was undertaken to compare health care utilization related to musculoskeletal issues during a 5-year period prior to the diagnosis of PsA versus that of subjects with no prior inflammatory arthritis within a primary care setting. We conducted a population-based, matched cohort study using electronic medical records and administrative data in Ontario, Canada. Age- and sex-matched cohorts of PsA patients and comparators from the same family physicians were assembled. Comparators were not allowed to have prior spondyloarthritis, ankylosing spondylitis, or rheumatoid arthritis billing code diagnoses. The study outcomes included health care utilization and costs related to nonspecific musculoskeletal issues during a 5-year period prior to the index date. We studied 462 PsA patients and 2,310 matched comparators. The odds ratio (OR) related to visiting a primary care physician for nonspecific musculoskeletal issues in patients with PsA was 2.14 (95% confidence interval 1.73-2.64) in the year immediately preceding the index date and was similarly elevated up to 5 years prior. The OR related to using other musculoskeletal-related health care services, including musculoskeletal specialists visits, joint injections, joint imaging, and emergency department visits, was higher in PsA as early as 5 years preceding the index date. Total and musculoskeletal-related health care costs prior to the index date were higher for patients with PsA versus comparators. A prodromal PsA phase characterized by nonspecific musculoskeletal symptoms may exist. Further study is needed to determine if this represents a window for earlier diagnosis of PsA.


Sharing data for future research-engaging participants' views about data governance beyond the original project: a DIRECT Study.
Biomedical data governance strategies should ensure that data are collected, stored, and used ethically and lawfully. However, research participants' preferences for how data should be governed is least studied. The Diabetes Research on Patient Stratification (DIRECT) project collected substantial amounts of health and genetic information from patients at risk of, and with type II diabetes. We conducted a survey to understand participants' future data governance preferences. Results will inform the postproject data governance strategy. A survey was distributed in Denmark, Sweden, The Netherlands, and the United Kingdom. In total 855 surveys were returned. Ninety-seven percent were supportive of sharing data postproject, and 90% were happy to share data with universities, and 56% with commercial companies. The top three priorities for data sharing were highly secure database, DIRECT researchers to monitor data used by other researchers, and researchers cannot identify participants. Respondents frequently suggested that a postproject Data Access Committee should involve a DIRECT researcher, diabetes clinician, patient representative, and a DIRECT participant. Preferences of how data should be governed, and what data could be shared and with whom varied between countries. Researchers are considered as key custodians of participant data. Engaging participants aids in designing governance to support their choices.


Hunting for hydrogen: random structure searching and prediction of NMR parameters of hydrous wadsleyite.
The structural chemistry of materials containing low levels of nonstoichiometric hydrogen is difficult to determine, and producing structural models is challenging where hydrogen has no fixed crystallographic site. Here we demonstrate a computational approach employing ab initio random structure searching (AIRSS) to generate a series of candidate structures for hydrous wadsleyite (β-Mg2SiO4 with 1.6 wt% H2O), a high-pressure mineral proposed as a repository for water in the Earth's transition zone. Aligning with previous experimental work, we solely consider models with Mg3 (over Mg1, Mg2 or Si) vacancies. We adapt the AIRSS method by starting with anhydrous wadsleyite, removing a single Mg(2+) and randomly placing two H(+) in a unit cell model, generating 819 candidate structures. 103 geometries were then subjected to more accurate optimisation under periodic DFT. Using this approach, we find the most favourable hydration mechanism involves protonation of two O1 sites around the Mg3 vacancy. The formation of silanol groups on O3 or O4 sites (with loss of stable O1-H hydroxyls) coincides with an increase in total enthalpy. Importantly, the approach we employ allows observables such as NMR parameters to be computed for each structure. We consider hydrous wadsleyite (∼1.6 wt%) to be dominated by protonated O1 sites, with O3/O4-H silanol groups present as defects, a model that maps well onto experimental studies at higher levels of hydration (J. M. Griffin et al., Chem. Sci., 2013, 4, 1523). The AIRSS approach adopted herein provides the crucial link between atomic-scale structure and experimental studies.


Lymphangioma of the spleen in an elderly patient.
Splenic cystic lymphangioma is a very rare condition, and is classified among cystic proliferations of the spleen. It is considered to be the result of a developmental malformation of the lymphatic system and can involve the spleen alone or be a part of multiorgan disease. It is usually seen in children, often found incidentally. We describe a case of cystic lymphangioma of the spleen in an elderly woman putting emphasis on the rarity of the case in old age, and on the problems of differential diagnosis with the other cystic proliferations of the spleen, in particular hydatid disease, in the absence of histologic information.


Room-temperature scavengers for macromolecular crystallography: increased lifetimes and modified dose dependence of the intensity decay.
The advent of highly intense wiggler and undulator beamlines has reintroduced the problem of X-ray radiation damage in protein crystals even at cryogenic temperatures (100 K). Although cryocrystallography can be utilized for the majority of protein crystals, certain macromolecular crystals (e.g. of viruses) suffer large increases in mosaicity upon flash cooling and data are still collected at room temperature (293 K). An alternative mechanism to cryocooling for prolonging crystal lifetime is the use of radioprotectants. These compounds are able to scavenge the free radical species formed upon X-ray irradiation which are thought to be responsible for part of the observed damage. Three putative radioprotectants, ascorbate, 1,4-benzoquinone and 2,2,6,6-tetramethyl-4-piperidone (TEMP), were tested for their ability to prolong lysozyme crystal lifetimes at 293 K. Plots of relative summed intensity against dose were used as a metric to assess radioprotectant ability: ascorbate and 1,4-benzoquinone appear to be effective, whereas studies on TEMP were inconclusive. Ascorbate, which scavenges OH* radicals (k(OH) = 8 x 10(9) M(-1) s(-1)) and electrons with a lower rate constant (k(e-(aq)) = 3.0 x 10(8) M(-1) s(-1)), doubled the crystal dose tolerance, whereas 1,4-benzoquinone, which also scavenges both OH* radicals (k(OH) = 1.2 x 10(9) M(-1) s(-1)) and electrons (k(e-(aq)) = 1.2 x 10(10) M(-1) s(-1)), offered a ninefold increase in dose tolerance at the dose rates used. Pivotally, these preliminary results on a limited number of samples show that the two scavengers also induced a striking change in the dose dependence of the intensity decay from a first-order to a zeroth-order process.


Evolutionary dominance of holin lysis systems derives from superior genetic malleability.
For the microviruses and the leviviruses, bacteriophages with small single-stranded genomes, host lysis is accomplished by expression of a single gene that encodes an inhibitor of cell wall synthesis. In contrast, phages with double-stranded DNA genomes use a more complex system involving, at minimum, an endolysin, which degrades peptidoglycan, and a holin, which permeabilizes the membrane in a temporally programmed manner. To explore the basis of this difference, a chimera was created in which lysis gene E of the microvirus phiX174 replaced the entire lysis cassette of phage lambda, which includes the holin gene S and the endolysin gene R. The chimeric phage was viable but more variability was observed both in the distribution of plaque sizes and in the burst sizes of single cells, compared to the isogenic S(+) parent. Using different alleles of E, it was found the average burst size increased with the duration of the latent period, just as observed with S alleles with different lysis times. Moreover, within a set of missense E alleles, it was found that variability in lysis timing was limited and almost exclusively derived from changes in the level of E accumulation. By contrast, missense mutations in S resulted in a wide variation in lysis times that was not correlated with levels of accumulation. We suggest that the properties of greater phenotypic plasticity and lesser phenotypic variation make the function of holin proteins more genetically malleable, facilitating rapid adaptation towards a lysis time that would be optimal for changed host and environmental conditions. The inferior malleability of single-gene systems like E would restrict their occurrence to phages in which coding capacity is the overriding evolutionary constraint.


Continuous flow immobilized enzyme reactor-tandem mass spectrometry for screening of AChE inhibitors in complex mixtures.
A method is described for identifying bioactive compounds in complex mixtures based on the use of capillary-scale monolithic enzyme-reactor columns for rapid screening of enzyme activity. A two-channel nanoLC system was used to continuously infuse substrate coupled with automated injections of substrate/small molecule mixtures, optionally containing the chromogenic Ellman reagent, through sol-gel derived acetylcholinesterase (AChE) doped monolithic columns. This is the first report of AChE encapsulated in monolithic silica for use as an immobilized enzyme reactor (IMER), and the first use of such IMERs for mixture screening. AChE IMER columns were optimized to allow rapid functional screening of compound mixtures based on changes in the product absorbance or the ratio of mass spectrometric peaks for product and substrate ions in the eluent. The assay had robust performance and produced a Z' factor of 0.77 in the presence of 2% (v/v) DMSO. A series of 52 mixtures consisting of 1040 compounds from the Canadian Compound Collection of bioactives was screened and two known inhibitors, physostigmine and 9-aminoacridine, were identified from active mixtures by manual deconvolution. The activity of the compounds was confirmed using the enzyme reactor format, which allowed determination of both IC(50) and K(I) values. Screening results were found to correlate well with a recently published fluorescence-based microarray screening assay for AChE inhibitors.


Kinetic Modeling and Constrained Reconstruction of Hyperpolarized [1-13C]-Pyruvate Offers Improved Metabolic Imaging of Tumors.
Hyperpolarized [1-(13)C]-pyruvate has shown tremendous promise as an agent for imaging tumor metabolism with unprecedented sensitivity and specificity. Imaging hyperpolarized substrates by magnetic resonance is unlike traditional MRI because signals are highly transient and their spatial distribution varies continuously over their observable lifetime. Therefore, new imaging approaches are needed to ensure optimal measurement under these circumstances. Constrained reconstruction algorithms can integrate prior information, including biophysical models of the substrate/target interaction, to reduce the amount of data that is required for image analysis and reconstruction. In this study, we show that metabolic MRI with hyperpolarized pyruvate is biased by tumor perfusion and present a new pharmacokinetic model for hyperpolarized substrates that accounts for these effects. The suitability of this model is confirmed by statistical comparison with alternates using data from 55 dynamic spectroscopic measurements in normal animals and murine models of anaplastic thyroid cancer, glioblastoma, and triple-negative breast cancer. The kinetic model was then integrated into a constrained reconstruction algorithm and feasibility was tested using significantly undersampled imaging data from tumor-bearing animals. Compared with naïve image reconstruction, this approach requires far fewer signal-depleting excitations and focuses analysis and reconstruction on new information that is uniquely available from hyperpolarized pyruvate and its metabolites, thus improving the reproducibility and accuracy of metabolic imaging measurements.


Statistical analysis plan for the Erythropoietin in Traumatic Brain Injury trial: a randomised controlled trial of erythropoietin versus placebo in moderate and severe traumatic brain injury.
The Erythropoietin in Traumatic Brain Injury (EPO-TBI) trial aims to determine whether the administration of erythropoietin to patients with moderate or severe traumatic brain injury improves patient-centred outcomes. EPO-TBI is a multicentre, blinded, randomised, parallel groups, placebo-controlled, phase III superiority trial of erythropoietin in ICU patients with traumatic brain injury conducted in Australia and New Zealand, Saudi Arabia and Europe; 606 critically ill patients aged 15 to 65 years with moderate or severe acute traumatic brain injury will be enrolled. Trial patients will receive either 40,000 IU erythropoietin or placebo by subcutaneous injection administered weekly for up to three doses during their ICU admission. The primary outcome measure is the proportion of unfavourable neurological outcomes, comprising death or severe disability, observed at 6 months following randomisation utilizing the Extended Glasgow Outcome Scale. Secondary outcomes, also assessed at 6 months following randomisation, include the probability of an equal or greater Extended Glasgow Outcome Scale level, mortality, the proportions of patients with proximal deep venous thrombosis or with composite thrombotic vascular events, as well as assessment of quality of life and cost-effectiveness. The planned sample size will allow 90% power to detect a reduction from 50% to 36% in unfavourable neurological outcomes at a two-sided alpha of 0.05. A detailed analysis plan has been developed for EPO-TBI that is consistent with international guidelines. This plan specifies the statistical models for evaluation of primary and secondary outcomes, as well as defining covariates for adjusted analyses. Application of this statistical analysis plan to the forthcoming EPO-TBI trial will facilitate unbiased analyses of these important clinical data. Australian New Zealand Clinical Trials Registry: ACTRN12609000827235 (22 September 2009). ClinicalTrials.gov: NCT00987454 (29 September 2009). European Drug Regulatory Authorities Clinical Trials: 2011-005235-22 (18 January 2012).


Successful lateral transfer requires codon usage compatibility between foreign genes and recipient genomes.
We present evidence supporting the notion that codon usage (CU) compatibility between foreign genes and recipient genomes is an important prerequisite to assess the selective advantage of imported functions, and therefore to increase the fixation probability of horizontal gene transfer (HGT) events. This contrasts with the current tendency in research to predict recent HGTs in prokaryotes by assuming that acquired genes generally display poor CU. By looking at the CU level (poor, typical, or rich) exhibited by putative xenologs still resembling their original CU, we found that most alien genes predominantly present typical CU immediately upon introgression, thereby suggesting that the role of CU amelioration in HGT has been overemphasized. In our strategy, we first scanned a representative set of 103 complete prokaryotic genomes for all pairs of candidate xenologs (exported/imported genes) displaying similar CU. We applied additional filtering criteria, including phylogenetic validations, to enhance the reliability of our predictions. Our approach makes no assumptions about the CU of foreign genes being typical or atypical within the recipient genome, thus providing a novel unbiased framework to study the evolutionary dynamics of HGT.


Why are some STEM fields more gender balanced than others?
Women obtain more than half of U.S. undergraduate degrees in biology, chemistry, and mathematics, yet they earn less than 20% of computer science, engineering, and physics undergraduate degrees (National Science Foundation, 2014a). Gender differences in interest in computer science, engineering, and physics appear even before college. Why are women represented in some science, technology, engineering, and mathematics (STEM) fields more than others? We conduct a critical review of the most commonly cited factors explaining gender disparities in STEM participation and investigate whether these factors explain differential gender participation across STEM fields. Math performance and discrimination influence who enters STEM, but there is little evidence to date that these factors explain why women's underrepresentation is relatively worse in some STEM fields. We introduce a model with three overarching factors to explain the larger gender gaps in participation in computer science, engineering, and physics than in biology, chemistry, and mathematics: (a) masculine cultures that signal a lower sense of belonging to women than men, (b) a lack of sufficient early experience with computer science, engineering, and physics, and (c) gender gaps in self-efficacy. Efforts to increase women's participation in computer science, engineering, and physics may benefit from changing masculine cultures and providing students with early experiences that signal equally to both girls and boys that they belong and can succeed in these fields. (PsycINFO Database Record


Structural and functional studies on the N-terminal domain of the Shigella type III secretion protein MxiG.
MxiG is a single-pass membrane protein that oligomerizes within the inner membrane ring of the Shigella flexneri type III secretion system (T3SS). The MxiG N-terminal domain (MxiG-N) is the predominant cytoplasmic structure; however, its role in T3SS assembly and secretion is largely uncharacterized. We have determined the solution structure of MxiG-N residues 6-112 (MxiG-N(6-112)), representing the first published structure of this T3SS domain. The structure shows strong structural homology to forkhead-associated (FHA) domains. Canonically, these cell-signaling modules bind phosphothreonine (Thr(P)) via highly conserved residues. However, the putative phosphate-binding pocket of MxiG-N(6-112) does not align with other FHA domain structures or interact with Thr(P). Furthermore, mutagenesis of potential phosphate-binding residues has no effect on S. flexneri T3SS assembly and function. Therefore, MxiG-N has a novel function for an FHA domain. Positioning of MxiG-N(6-112) within the EM density of the S. flexneri needle complex gives insight into the ambiguous stoichiometry of the T3SS, supporting models with 24 MxiG subunits in the inner membrane ring.


Using a Group-Centered Approach to Observe Interactions in Early Childhood Education.
This study examined the value of using a group-centered approach to evaluate process quality of early childhood education and care (ECEC). Is observed support of group processes a different aspect of classroom quality, and does it predict children's collaborative play in ECEC in the Netherlands? In two play situations, 37 teachers and 120 two- to four-year-old children were observed with the Classroom Assessment Scoring System (CLASS) Toddler and two new measures. In a two-level structural equation model, teachers' support of group processes was positively related to the CLASS domains and to children's collaborative play, over and above the effect of children's cognitive ability and social competence. These findings suggest that ECEC quality evaluation could be enriched by adding group-centered indicators of classroom quality.


Clinical utility of cancer family history collection in primary care.
This systematic review aimed to evaluate, within unselected populations: the (1) performance of family history (FHx)-based models in predicting cancer risk; (2) overall benefits and harms associated with established cancer prevention interventions; (3) impact of FHx-based risk information on the uptake of preventive interventions; and (4) potential for harms associated with collecting cancer FHx. MEDLINE, EMBASE, CINAHL, Cochrane Central, Cochrane Database of Systematic Reviews, and PsycINFO were searched from 1990 to June 2008 inclusive. Cancer guidelines and recommendations were searched from 2002 forward and systematic reviews from 2003 to June 2008. Standard systematic review methodology was employed. Eligibility criteria included English studies evaluating breast, colorectal, ovarian, or prostate cancers. Study designs were restricted to systematic review, experimental and diagnostic types. Populations were limited to those unselected for cancer risk. Interventions were limited to collection of cancer FHx; primary and/or secondary prevention interventions for breast, colorectal, ovarian, and prostate cancers. Accuracy of models. Seven eligible studies evaluated systems based on the Gail model, and on the Harvard Cancer Risk Index. No evaluations demonstrated more than modest discriminatory accuracy at an individual level. No evaluations were identified relevant to ovarian or prostate cancer risk. Efficacy of preventive interventions. From 29 eligible systematic reviews, seven found no experimental studies evaluating interventions of interest. Of the remaining 22, none addressed ovarian cancer prevention. The reviews were generally based on limited numbers of randomized or controlled clinical trials. There was no evidence either to support or refute the use of selected chemoprevention interventions, there was some evidence of effectiveness for mammography and fecal occult blood testing. Uptake of intervention. Three studies evaluated the impact of FHx-based risk information on uptake of clinical preventive interventions for breast cancer. The evidence is insufficient to draw conclusions on the effect of FHx-based risk information on change in preventive behavior. Potential harms of FHx taking. One uncontrolled trial evaluated the impact of FHx-based breast cancer risk information on psychological outcomes and found no evidence of significant harm. Our review indicates a very limited evidence base with which to address all four of the research questions: 1) the few evaluations of cancer risk prediction models do not suggest useful individual predictive accuracy; 2) the experimental evidence base for primary and secondary cancer prevention is very limited; 3) there is insufficient evidence to assess the effect of FHx-based risk assessment on preventive behaviors; 4) there is insufficient evidence to assess whether FHx-based personalized risk assessment directly causes adverse outcomes.


Organocatalytic controlled/living ring-opening polymerization of cyclotrisiloxanes initiated by water with strong organic base catalysts.
Organocatalytic controlled/living ring-opening polymerization of cyclotrisiloxanes, such as hexamethylcyclotrisiloxane, 1,3,5-trimethyl-1,3,5-triphenylcyclotrisiloxane, 1,3,5-trimethyl-1,3,5-trivinylcyclotrisiloxane, and 1,3,5-trimethyl-1,3,5-tris(3,3,3-trifluoropropyl)cyclotrisiloxane, using water as an initiator and strong organic bases, such as amidines, guanidines, phosphazene bases, and proazaphosphatrane, as catalysts produced a variety of polysiloxanes with controlled number-average molecular weights (M n = 2.64-102.3 kg mol-1), narrow polydispersity (Đ = 1.03-1.16), and well-defined symmetric structures. Controlled syntheses of statistical copolymers and triblock copolymers were achieved by copolymerizations of two cyclotrisiloxanes. Various terminal functionalities were successfully introduced by the end-capping reaction of propagating polysiloxanes using functional chlorosilanes. Kinetic investigations demonstrated that the polymerization proceeded through the initiator/chain-end activation mechanism, namely activations of water in the initiation reaction and of terminal silanols in propagating polysiloxanes in the propagation reaction. Catalytic activities of strong organic bases were revealed to depend on their Brønsted basicity and efficiency of the proton transfer in the initiation and propagation reactions. Guanidines possessing an R-N[double bond, length as m-dash]C(N)-NH-R' unit, in particular 1,3-trimethylene-2-propylguanidine, showed excellent performance as a catalyst. In this system, even non-dehydrated solvents are usable for the polymerization.


Tackle-related injury rates and nature of injuries in South African Youth Week tournament rugby union players (under-13 to under-18): an observational cohort study.
The tackle situation is most often associated with the high injury rates in rugby union. Tackle injury epidemiology in rugby union has previously been focused on senior cohorts but less is known about younger cohorts. The aim of this study was to report on the nature and rates of tackle-related injuries in South African youth rugby union players representing their provinces at national tournaments. Observational cohort study. Four South African Youth Week tournaments (under-13 Craven Week, under-16 Grant Khomo Week, under-18 Academy Week, under-18 Craven Week). Injury data were collected from 3652 youth rugby union players (population at risk) in 2011 and 2012. Tackle-related injury severity ('time-loss' and 'medical attention'), type and location, injury rate per 1000 h (including 95% CIs). Injury rate ratios (IRR) were calculated and modelled using a Poisson regression. A χ(2) analysis was used to detect linear trends between injuries and increasing match quarters. The 2012 under-13 Craven Week had a significantly greater 'time-loss' injury rate when compared with the 2012 under-18 Academy Week (IRR=4.43; 95% CI 2.13 to 9.21, p<0.05) and under-18 Craven Week (IRR=3.52; 95% CI 1.54 to 8.00, p<0.05). The Poisson regression also revealed a higher probability of 'overall' ('time-loss' and 'medical attention' combined) and 'time-loss' tackle-related injuries occurring at the under-13 Craven Week. The proportion of 'overall' and 'time-loss' injuries increased significantly with each quarter of the match when all four tournaments were combined (p<0.05). There was a difference in the tackle-related injury rate between the under-13 tournament and the two under-18 tournaments, and the tackle-related injury rate was higher in the final quarter of matches. Ongoing injury surveillance is required to better interpret these findings. Injury prevention strategies targeting the tackle may only be effective once the rate and nature of injuries have been accurately determined.


Single-cell census of mechanosensitive channels in living bacteria.
Bacteria are subjected to a host of different environmental stresses. One such insult occurs when cells encounter changes in the osmolarity of the surrounding media resulting in an osmotic shock. In recent years, a great deal has been learned about mechanosensitive (MS) channels which are thought to provide osmoprotection in these circumstances by opening emergency release valves in response to membrane tension. However, even the most elementary physiological parameters such as the number of MS channels per cell, how MS channel expression levels influence the physiological response of the cells, and how this mean number of channels varies from cell to cell remain unanswered. In this paper, we make a detailed quantitative study of the expression of the mechanosensitive channel of large conductance (MscL) in different media and at various stages in the growth history of bacterial cultures. Using both quantitative fluorescence microscopy and quantitative Western blots our study complements earlier electrophysiology-based estimates and results in the following key insights: i) the mean number of channels per cell is much higher than previously estimated, ii) measurement of the single-cell distributions of such channels reveals marked variability from cell to cell and iii) the mean number of channels varies under different environmental conditions. The regulation of MscL expression displays rich behaviors that depend strongly on culturing conditions and stress factors, which may give clues to the physiological role of MscL. The number of stress-induced MscL channels and the associated variability have far reaching implications for the in vivo response of the channels and for modeling of this response. As shown by numerous biophysical models, both the number of such channels and their variability can impact many physiological processes including osmoprotection, channel gating probability, and channel clustering.


Modelling digestive constraints in non-ruminant and ruminant foregut-fermenting mammals.
It has been suggested that large foregut-fermenting marsupial herbivores, the kangaroos and their relatives, may be less constrained by food intake limitations as compared with ruminants, due mainly to differences in their digestive morphology and management of ingesta particles through the gut. In particular, as the quality of forage declines with increasing contents of plant fibre (cellulose, hemicelluloses and lignin; measured as neutral-detergent fibre, NDF), the tubiform foregut of kangaroos may allow these animals to maintain food intakes more so than ruminants like sheep, which appear to be limited by fibrous bulk filling the foregut and truncating further ingestion. Using available data on dry matter intake (DMI, g kg(-0.75) d(-1)), ingesta mean retention time (MRT, h), and apparent digestibility, we modelled digestible dry matter intake (DDMI) and digestible energy intake (DEI) by ruminant sheep (Ovis aries) and by the largest marsupial herbivore, the red kangaroo (Macropus rufus). Sheep achieved higher MRTs on similar DMIs, and hence sheep achieved higher DDMIs for any given level of DMI as compared with kangaroos. Interestingly, MRT declined in response to increasing DMI in a similar pattern for both species, and the association between DMI and plant NDF contents did not support the hypothesis that kangaroos are less affected by increasing fibre relative to sheep. However, when DEI was modelled according to DDMIs and dietary energy contents, we show that the kangaroos could meet their daily maintenance energy requirements (MER) at lower levels of DMI and on diets with higher fibre contents compared with sheep, due largely to the kangaroos' lower absolute maintenance and basal energy metabolisms compared with eutherians. These results suggest that differences in the metabolic set-point of different species can have profound effects on their nutritional niche, even when their digestive constraints are similar, as was the case for these ruminant and non-ruminant foregut fermenters.


Direct lineage conversion of terminally differentiated hepatocytes to functional neurons.
Several recent studies have showed that mouse and human fibroblasts can be directly reprogrammed into induced neuronal (iN) cells, bypassing a pluripotent intermediate state. However, fibroblasts represent heterogeneous mesenchymal progenitor cells that potentially contain neural crest lineages, and the cell of origin remained undefined. This raises the fundamental question of whether lineage reprogramming is possible between cell types derived from different germ layers. Here, we demonstrate that terminally differentiated hepatocytes can be directly converted into functional iN cells. Importantly, single-cell and genome-wide expression analyses showed that fibroblast- and hepatocyte-derived iN cells not only induced a neuronal transcriptional program, but also silenced their donor transcriptome. The remaining donor signature decreased over time and could not support functional hepatocyte properties. Thus, the reprogramming factors lead to a binary lineage switch decision rather than an induction of hybrid phenotypes, but iN cells retain a small but detectable epigenetic memory of their donor cells.


Means restriction for the prevention of suicide on roads.
Road traffic suicides are common. However, due to the difficulty in distinguishing between motor vehicle crash fatalities and actual suicides, no official figures exist for this method of suicide. Restricting access to means is an important universal or population-based approach to suicide prevention with clear evidence of its effectiveness. However, the evidence with respect to means restriction for the prevention of suicide on roads is not well established. We conducted a systematic review to assess the impact of restrictions on the availability of, or access to, means of suicide on roads. To evaluate the effectiveness of interventions to restrict the availability of, or access to, means of suicide on roads. We searched the Cochrane Library, MEDLINE, Embase, PsycINFO, and the Transport Research International Documentation (TRID) Database from the date of database inception to March 2020. We conducted searches of the World Health Organization International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov to identify unpublished and ongoing studies. We applied no date, language, or publication status restrictions to these searches. Eligible studies were randomised or quasi-randomised controlled trials, controlled intervention studies without randomisation, before-after studies, or studies using interrupted time series designs, which evaluated interventions to restrict the availability of, or access to, means of suicide on roads. Two review authors screened abstracts and full-text publications against the inclusion criteria. Two review authors planned to independently extract data and assess risk of bias of included studies. However, we identified no studies eligible for inclusion. We identified no studies that met the inclusion criteria for this review. This systematic review highlights the paucity of research around road traffic suicides and the need for future robust studies that aim to investigate the effectiveness of interventions to prevent suicide on roads. Suicide ascertainment is a key issue; therefore, clear objective criteria are necessary in order to scale up and study this method more accurately. In the absence of any substantial evidence, we advocate for more awareness on road traffic suicides and its inclusion in future government suicide prevention policies. Further research exploring effective measures, particularly those that do not require driver compliance, are also needed.


Palliative Integration Into Ambulatory Oncology: An Advance Care Planning Quality Improvement Project.
Advance care planning (ACP) is essential to ensuring that patient-centered end-of-life goals are respected if a health crisis occurs. Advanced practitioner barriers to ACP include insufficient time and limited confidence in discussions. The purpose of this quality improvement project was to increase advanced cancer patients' electronic health record (EHR) documented surrogate decision maker and ACP documentation by 25% over 8 weeks. A secondary aim was to decrease patients' decisional conflict scores (DCS) related to life-sustaining treatment preferences after a clinical nurse specialist (CNS)-led ACP session. Using the define, measure, analyze, improve, and control (DMAIC) process of quality improvement methodology, an interprofessional team led by a palliative CNS fostered practice change by (a) incorporating a patient self-administered Supportive Care and Communication Questionnaire (SCCQ) to standardize the ACP assessment, (b) creating an EHR nursing and provider documentation template, (c) offering advanced cancer patients a palliative CNS consultation for ACP review and advance directive completion, and (d) evaluating patients' DCS through the four-item SURE tool. Of 126 participants provided with the SCCQ, 90 completed the document, resulting in a 71% return rate. Among the completed SCCQs, 37% (n = 33) requested a CNS consultation, with 76% (n = 25) returning for the ACP session. The CNS intervention yielded an average reduction of 1.4 points in SURE tool findings, a statistically significant decrease determined by a paired sample t-test. The project's interprofessional collaboration promoted a system-wide standardized ACP process throughout ambulatory, acute, and post-hospital settings.


How Common is Men's Self-Reported Sexual Interest in Prepubescent Children?
Consistent evidence exists for sexual interest in children in nonclinical/nonforensic male populations. However, prevalences for community men's self-reported sexual interest in children have been based on indiscriminate definitions including postpubescent individuals, age-restricted samples, and/or small convenience samples. The present research assessed men's self-reported sexual interest in children (including child prostitution and child sex tourism) on the community level and examined the link between strictly defined sexual fantasies and behaviors involving prepubescent children. In an online survey of 8,718 German men, 4.1% reported sexual fantasies involving prepubescent children, 3.2% reported sexual offending against prepubescent children, and 0.1% reported a pedophilic sexual preference. Sexual fantasies involving prepubescent children were positively related to sexual offending against prepubescent children. Sexual interest in children was associated with subjectively perceived need for therapeutic help. In contrast to findings from forensic samples, men who reported child pornography use exclusively were identified as a subgroup differing from contact sexual offenders against prepubescent children and men who reported both child pornography use and contact sexual offenses against prepubescent children. The empirical link between child-related sexual fantasies and sexual victimization of prepubescent children and high levels of subjective distress from this inclination underscore the importance of evidence-based child sexual abuse prevention approaches in the community. Findings are discussed in terms of their relation to pedophilic disorder.


The hidden land use cost of upscaling cover crops.
Cover cropping is considered a cornerstone practice in sustainable agriculture; however, little attention has been paid to the cover crop production supply chain. In this Perspective, we estimate land use requirements to supply the United States maize production area with cover crop seed, finding that across 18 cover crops, on average 3.8% (median 2.0%) of current production area would be required, with the popular cover crops rye and hairy vetch requiring as much as 4.5% and 11.9%, respectively. The latter land requirement is comparable to the annual amount of maize grain lost to disease in the U.S. We highlight avenues for reducing these high land use costs.


An outbreak of rubella in British troops in Bosnia.
An outbreak of rubella in April 1996 involved four male British soldiers deployed to Bosnia-Herzegovina. All were helicopter ground crew who were members of the same unit and who periodically travelled to and worked at forward air refuelling stations in Bosnia. There was a potential for spread of the infection to adjacent British units, to troops of other nations in the peacekeeping force, and also to the local civilian population. The British force included 620 female personnel, some of whom may have been non-immune to rubella. One pregnant British servicewoman was repatriated to UK for her own protection. There was a potential health risk, including the possibility of congenital rubella syndrome, in the non-immune wives and partners of deployed male personnel, as a result of contact during the mid-tour home leave of the husbands or partners. The outbreak was monitored through a medical surveillance system known as ARRC 97, and was contained by prompt and rigorous control measures. This outbreak shows the importance of effective surveillance and of good microbiology laboratory support during military operations. The role of immunization against rubella during future military deployments is discussed.


An examination of the relationships among gender, health status, social support, and HIV-related stigma.
This secondary analysis used E. Goffman's (1963) model of stigma to examine how social support and health status are related to HIV stigma, after controlling for specific sociodemographic factors, and how these relationships differed between men and women living with HIV. Baseline data from 183 subjects in a behavioral randomized clinical trial were analyzed using multigroup structural equation modeling. Women reported significantly higher levels of stigma than men after controlling for race, history of injection drug use, and exposure category. HIV-related stigma was negatively predicted by social support regardless of gender. The theorized model explained a significant amount of the variance in stigma for men and women (24.4% and 44%, respectively) and may provide novel and individualized intervention points for health care providers to effect positive change in perceived stigma for the person living with HIV. The study offers insight into understanding the relationships among gender, health status, social support, and HIV-related stigma.


Leucine supplementation protects from insulin resistance by regulating adiposity levels.
Leucine supplementation might have therapeutic potential in preventing diet-induced obesity and improving insulin sensitivity. However, the underlying mechanisms are at present unclear. Additionally, it is unclear whether leucine supplementation might be equally efficacious once obesity has developed. Male C57BL/6J mice were fed chow or a high-fat diet (HFD), supplemented or not with leucine for 17 weeks. Another group of HFD-fed mice (HFD-pairfat group) was food restricted in order to reach an adiposity level comparable to that of HFD-Leu mice. Finally, a third group of mice was exposed to HFD for 12 weeks before being chronically supplemented with leucine. Leucine supplementation in HFD-fed mice decreased body weight and fat mass by increasing energy expenditure, fatty acid oxidation and locomotor activity in vivo. The decreased adiposity in HFD-Leu mice was associated with increased expression of uncoupling protein 3 (UCP-3) in the brown adipose tissue, better insulin sensitivity, increased intestinal gluconeogenesis and preservation of islets of Langerhans histomorphology and function. HFD-pairfat mice had a comparable improvement in insulin sensitivity, without changes in islets physiology or intestinal gluconeogenesis. Remarkably, both HFD-Leu and HFD-pairfat mice had decreased hepatic lipid content, which likely helped improve insulin sensitivity. In contrast, when leucine was supplemented to already obese animals, no changes in body weight, body composition or glucose metabolism were observed. These findings suggest that leucine improves insulin sensitivity in HFD-fed mice by primarily decreasing adiposity, rather than directly acting on peripheral target organs. However, beneficial effects of leucine on intestinal gluconeogenesis and islets of Langerhans's physiology might help prevent type 2 diabetes development. Differently, metabolic benefit of leucine supplementation is lacking in already obese animals, a phenomenon possibly related to the extent of the obesity before starting the supplementation.


Carbonylative enantioselective meso-desymmetrization of cis-epoxides to trans-β-lactones: effect of salen-ligand electronic variation on enantioselectivity.
Carbonylation catalysts for the desymmetrization of meso-epoxides yielding enantioenriched trans-β-lactones are reported. Fine-tuning the electronic properties of the ligand further improved enantioselectivity. The sterics of the substrate dictated whether a given electronic variation decreased or increased enantioenrichment, revealing an unexpected relationship between the substrate's steric environment and the electronic nature of the optimal catalyst.


Water-selective spectral-spatial contrast-enhanced breast MRI for cancer detection in patients with extracapsular and injected free silicone.
This study investigates the use of contrast-enhanced, T1-weighted, water-selective spectral-spatial 3D gradient echo magnetic resonance imaging (MRI) with magnetization transfer (3DSSMT) for detecting breast cancer in patients with intraparenchymal silicone. Water-selective 3DSSMT provides superior fat and silicone suppression in patients with free silicone as compared with conventional fat saturation. It enables direct, high-quality, high-spatial-resolution, T1-weighted breast MRI of contrast enhancement without the need for subtraction processing and aids diagnosis of cancer in the breast with free silicone.


Impact of oxidative stress on male fertility - a review.
Oxidative stress is a state related to increased cellular damage caused by oxygen and oxygen-derived free radicals known as reactive oxygen species (ROS). It is a serious condition, as ROS and their metabolites attack DNA, lipids and proteins, alter enzymatic systems and cell signalling pathways, producing irreparable alterations, cell death and necrosis. While small amounts of ROS have been shown to be required for several functions of spermatozoa, their excessive levels can negatively impact the quality of spermatozoa and impair their overall fertilising capacity. These questions have recently attracted the attention of the scientific community; however, research aimed at exploring the role of oxidative stress and antioxidants associated with male fertility is still at its initial stages. This review summarises the current facts available in this field and intends to stimulate interest in basic and clinical research, especially in the development of effective methods for the diagnosis and therapy of semen damage caused by oxidative stress.


Understanding the role α7 nicotinic receptors play in dopamine efflux in nucleus accumbens.
Neuronal nicotinic acetylcholine receptors (NNRs) of the α7 subtype have been shown to contribute to the release of dopamine in the nucleus accumbens. The site of action and the underlying mechanism, however, are unclear. Here we applied a circuit modeling approach, supported by electrochemical in vivo recordings, to clarify this issue. Modeling revealed two potential mechanisms for the drop in accumbal dopamine efflux evoked by the selective α7 partial agonist TC-7020. TC-7020 could desensitize α7 NNRs located predominantly on dopamine neurons or glutamatergic afferents to them or, alternatively, activate α7 NNRs located on the glutamatergic afferents to GABAergic interneurons in the ventral tegmental area. Only the model based on desensitization, however, was able to explain the neutralizing effect of coapplied PNU-120596, a positive allosteric modulator. According to our results, the most likely sites of action are the preterminal α7 NNRs controlling glutamate release from cortical afferents to the nucleus accumbens. These findings offer a rationale for the further investigation of α7 NNR agonists as therapy for diseases associated with enhanced mesolimbic dopaminergic tone, such as schizophrenia and addiction.


Cost-effectiveness of febuxostat in chronic gout.
Our objective was to evaluate data on the cost-effectiveness of febuxostat compared with standard clinical practice with allopurinol in patients with gout that was presented to the Scottish Medicines Consortium (SMC) in 2010. A Markov health-state model estimated the direct health-related costs and clinical benefits expressed as quality-adjusted life-years (QALYs). Adults with chronic gout and established hyperuricaemia received treatment sequences of daily doses of allopurinol 300 mg alone or allopurinol 300 mg followed by febuxostat 80 mg/120 mg. The proportion of patients achieving the target serum uric acid (sUA) level of less than 6 mg/dl (0.36 mmol/l) was linked to the utility per sUA level to generate an incremental cost-effectiveness ratio (ICER). Second-line therapy with febuxostat 80 mg/120 mg versus with allopurinol alone resulted in an ICER of £3,578 per QALY over a 5-year time horizon. Additional univariate analyses showed that ICER values were robust and ranged from £2,550 to £7,165 per QALY when different parameters (e.g., low- and high-dose allopurinol titrations and variations in treatment-induced flare rates) were varied. Febuxostat reduces sUA below the European League Against Rheumatism target of 0.36 mmol/l (6 mg/dl) in significantly more patients with gout than allopurinol in its most frequently prescribed dose of 300 mg per day. The SMC accepted febuxostat as cost-effective as a suitable second-line option for urate-lowering therapy for the treatment of patients with chronic hyperuricaemia in conditions where urate deposition has already occurred (including a history or presence of tophus and/or gouty arthritis) when treatment with allopurinol was inadequate, not tolerated, or contraindicated.


Chronic pulmonary aspergillosis.
Chronic pulmonary aspergillosis (CPA) is a group of consuming diseases usually presenting with prolonged and relapsing cough, dyspnoea and weight loss. Acute symptoms such as haemoptysis and bronchial or pulmonary haemorrhage may occasionally occur. CPA affects patients with underlying pulmonary conditions, for example, chronic obstructive pulmonary disease or mycobacteriosis or common immunosuppressive conditions such as diabetes. Precise epidemiology is unknown, and while prevalence is considered low the chronic and relapsing nature of the disease challenges the treating physician. Diagnostics largely rely on serologic Aspergillus precipitins and findings on thoracic computed tomography. The latter are manifold comprising cavity formation, pleural involvement and sometimes aspergilloma. Other markers for aspergillosis are less helpful, in part due to the non- or semi-invasive nature of these forms of Aspergillus infection. Various antifungals were shown to be effective in CPA treatment. Azoles are the most frequently applied antifungals in the outpatient setting, but are now compromised by findings of Aspergillus resistance. Long-term prognosis is not fully elucidated and may be driven by the underlying morbidities. Prospective registry-type studies may be suitable to systematically broaden our CPA knowledge base. This article gives an overview of the available literature and proposes a clinical working algorithm for CPA management.


Stress and visual function in infantile nystagmus syndrome.
Infantile nystagmus syndrome (INS) is an involuntary oscillation of the eyes that has been reported to impair vision and worsen under stress. This investigation aimed to measure visual function in terms of visual acuity (VA) and response time (RT), when INS subjects are placed under stress. A total of 23 subjects with INS and 20 control subjects performed a 2-alternative forced choice (2AFC) staircase procedure identifying the gap in a Landolt C, under 4 experimental conditions: initial acclimatization (A); task demand (TD), during which subjects received a small electrical shock for every incorrect answer; anticipatory anxiety (AA), during which subjects received a small shock at random intervals; and relaxed (R). Arousal was monitored with galvanic skin conductance (SkC). In addition to VA and eye movements, RTs were recorded. The SkC was higher in the TD and AA periods and lower during A and R. Shock significantly increased nystagmus amplitude (P < 0.01) and intensity (P < 0.007), and reduced foveation periods (FPs, P < 0.022). In both groups, VA was not reduced, but showed a slight improvement. However, shock increased RT (P < 0.009), and INS subjects were slower than controls (P < 0.0005). Increased arousal ("stress") provoked more intense nystagmus eye movements. As seen in other studies, stress did not reduce VA despite the shorter FPs. Although VA and FP can correlate across subjects, there would appear to be little correlation, if any, within a subject. However, RTs did increase with stress and shorter FPs, which may have an adverse impact on the visual performance of those with INS.


A systematic review of environmental factors and obesogenic dietary intakes among adults: are we getting closer to understanding obesogenic environments?
This study examined whether physical, social, cultural and economical environmental factors are associated with obesogenic dietary behaviours and overweight/obesity among adults. Literature searches of databases (i.e. PubMed, CSA Illumina, Web of Science, PsychInfo) identified studies examining environmental factors and the consumption of energy, fat, fibre, fruit, vegetables, sugar-sweetened drinks, meal patterns and weight status. Twenty-eight studies were in-scope, the majority (n= 16) were conducted in the USA. Weight status was consistently associated with the food environment; greater accessibility to supermarkets or less access to takeaway outlets were associated with a lower BMI or prevalence of overweight/obesity. However, obesogenic dietary behaviours did not mirror these associations; mixed associations were found between the environment and obesogenic dietary behaviours. Living in a socioeconomically-deprived area was the only environmental factor consistently associated with a number of obesogenic dietary behaviours. Associations between the environment and weight status are more consistent than that seen between the environment and dietary behaviours. The environment may play an important role in the development of overweight/obesity, however the dietary mechanisms that contribute to this remain unclear and the physical activity environment may also play an important role in weight gain, overweight and obesity.


How the Respiratory Epithelium Senses and Reacts to Influenza Virus.
The human lung is constantly exposed to the environment and potential pathogens. As the interface between host and environment, the respiratory epithelium has evolved sophisticated sensing mechanisms as part of its defense against pathogens. In this review, we examine how the respiratory epithelium senses and responds to influenza A virus, the biggest cause of respiratory viral deaths worldwide.


Towards a Novel Patch Material for Cardiac Applications: Tissue-Specific Extracellular Matrix Introduces Essential Key Features to Decellularized Amniotic Membrane.
There is a growing need for scaffold material with tissue-specific bioactivity for use in regenerative medicine, tissue engineering, and for surgical repair of structural defects. We developed a novel composite biomaterial by processing human cardiac extracellular matrix (ECM) into a hydrogel and combining it with cell-free amniotic membrane via a dry-coating procedure. Cardiac biocompatibility and immunogenicity were tested in vitro using human cardiac fibroblasts, epicardial progenitor cells, murine HL-1 cells, and human immune cells derived from buffy coat. Processing of the ECM preserved important matrix proteins as demonstrated by mass spectrometry. ECM coating did not alter the mechanical characteristics of decellularized amniotic membrane but did cause a clear increase in adhesion capacity, cell proliferation and viability. Activated monocytes secreted less pro-inflammatory cytokines, and both macrophage polarization towards the pro-inflammatory M1 type and T cell proliferation were prevented. We conclude that the incorporation of human cardiac ECM hydrogel shifts and enhances the bioactivity of decellularized amniotic membrane, facilitating its use in future cardiac applications.


Clean subglacial access: prospects for future deep hot-water drilling.
Accessing and sampling subglacial environments deep beneath the Antarctic Ice Sheet presents several challenges to existing drilling technologies. With over half of the ice sheet believed to be resting on a wet bed, drilling down to this environment must conform to international agreements on environmental stewardship and protection, making clean hot-water drilling the most viable option. Such a drill, and its water recovery system, must be capable of accessing significantly greater ice depths than previous hot-water drills, and remain fully operational after connecting with the basal hydrological system. The Subglacial Lake Ellsworth (SLE) project developed a comprehensive plan for deep (greater than 3000 m) subglacial lake research, involving the design and development of a clean deep-ice hot-water drill. However, during fieldwork in December 2012 drilling was halted after a succession of equipment issues culminated in a failure to link with a subsurface cavity and abandonment of the access holes. The lessons learned from this experience are presented here. Combining knowledge gained from these lessons with experience from other hot-water drilling programmes, and recent field testing, we describe the most viable technical options and operational procedures for future clean entry into SLE and other deep subglacial access targets.


A pilot study of an anti-endotoxin Ig-enriched bovine colostrum to prevent experimental sepsis.
Despite the dramatic increase in antimicrobial resistance, there is a dearth of antibiotics in development and few pharmaceutical companies working in the field. Further, any new antibiotics are likely to have a short shelf life. Ab-based interventions offer alternatives that are not likely to be circumvented by the widely prevalent antibiotic resistance genes. Bovine colostrum (BC)-the first milk after parturition, rich in nutrients and immune components-promotes gut integrity and modulates the gut microbiome. We developed a hyperimmune BC (HBC) enriched in Abs to a highly conserved LOS core region of Gram-negative bacteria by immunizing pregnant cows with a vaccine comprised of detoxified LOS from Escherichia coli O111 Rc (J5) mutant non-covalently complexed to group B meningococcal outer membrane protein (J5dLOS/OMP). This vaccine generated robust levels of anti-J5 LOS Ab in the colostrum. When given orally to neutropenic rats challenged orally with Pseudomonas aeruginosa, administration of HBC improved survival compared to non-immune rats, while both BC preparations improved survival compared to PBS controls. Elevated circulating endotoxin levels correlated with mortality. HBC and to a lesser extent non-immune BC reduced bacterial burden from the liver, lung, and spleen. We conclude that HBC and to a lesser extent BC may be effective supplements that improve outcome from lethal gut-derived disseminated infection and may reduce transmission of Gram-negative bacilli from the gastrointestinal tract.


OUTCOMES AND PROGNOSTIC FACTORS ASSOCIATED WITH CANINE SINONASAL TUMORS TREATED WITH CURATIVE INTENT CONE-BASED STEREOTACTIC RADIOSURGERY (1999-2013).
Stereotactic radiosurgery (SRS) is a relatively new therapeutic option in veterinary oncology. The role of this modality has not been extensively evaluated for the use in canine nasal tumors. The objective of this retrospective, observational study was to describe the clinical outcome and prognostic factors associated with survival times in a sample of canine patients treated with SRS for sinonasal tumors. Fifty-seven dogs with sinonasal tumors met inclusion criteria. Histologic diagnoses included sarcoma (SA) (n = 9), carcinoma (CA) (n = 40), osteosarcoma (OSA) (n = 7), and round cell (n = 1). Four of 57 cases were treated twice with SRS. For these, the median and mean doses delivered were 30Gy and 33Gy, respectively (range 18.75Gy-56Gy). Late effects occurred in 23 cases and ranged from grades I-III. The median overall survival time was 8.5 months. The median overall survival times in dogs with tumor type of CA, SA, and OSA were 10.4, 10.7, and 3.1 months, respectively. Dogs with the tumor type of OSA had shorter overall survival time than that in dogs with tumor type of CA and SA. Findings from this retrospective study indicated that SRS may be beneficial for canine patients with sinonasal tumors, however a controlled clinical trial would be needed to confirm this. Prospective studies are also needed to better define the role of SRS as palliative or curative, and to further investigate the risk of clinically significant toxicity.


Lack of correlation between cyclic GMP elevation and relaxation of nonvascular smooth muscle by nitroglycerin, nitroprusside, hydroxylamine and sodium azide.
Recent reports have suggested that the smooth muscle relaxant effects of drugs such as nitroprusside and nitroglycerin are mediated by increases in tissue levels of cyclic GMP. This hypothesis was examined by comparing the effects of nitroprusside, nitroglycerin, hydroxylamine and sodium azide on tension and cyclic GMP levels in rat vas deferens, rat myometrium and guinea-pig taenia coli. All four of the agents were capable of increasing cyclic GMP levels in these tissues but there did not appear to be a good correlation between cyclic GMP elevation and muscle relaxation in any of the tissues studied. For example, nitroprusside markedly elevated cyclic GMP levels in rat vas deferens and myometrium but had no relaxant effect on either tissue. Nitroglycerin was less effective than nitroprusside in elevating cyclic GMP levels, but was an effective relaxant in both tissues. Significant increases in myometrial cyclic GMP were seen with 0.1, 1 and 5 mM concentrations of hydroxylamine but only the highest concentration had a definite relaxant effect on the muscles. A similar concentration of nitroprusside produced a greater elevation of cyclic GMP than did hydroxylamine, but had no relaxant effect in this preparation. In guinea-pig taenia coli, significant increases in cyclic GMP levels were obtained with concentrations of sodium azide and hydroxylamine which had no effect on the contractile activity of the preparations. These results, together with previous results from this laboratory, suggest that the relaxant effects of this group of drugs in rat vas deferens, rat myometrium and guinea-pig taenia coli are not mediated by increases in tissue levels of cyclic GMP. Further experiments are necessary to determine whether a causal relationship exists between cyclic GMP elevation and relaxation in other types of smooth muscle.


Technologies and approaches to elucidate and model the virulence program of salmonella.
Salmonella is a primary cause of enteric diseases in a variety of animals. During its evolution into a pathogenic bacterium, Salmonella acquired an elaborate regulatory network that responds to multiple environmental stimuli within host animals and integrates them resulting in fine regulation of the virulence program. The coordinated action by this regulatory network involves numerous virulence regulators, necessitating genome-wide profiling analysis to assess and combine efforts from multiple regulons. In this review we discuss recent high-throughput analytic approaches used to understand the regulatory network of Salmonella that controls virulence processes. Application of high-throughput analyses have generated large amounts of data and necessitated the development of computational approaches for data integration. Therefore, we also cover computer-aided network analyses to infer regulatory networks, and demonstrate how genome-scale data can be used to construct regulatory and metabolic systems models of Salmonella pathogenesis. Genes that are coordinately controlled by multiple virulence regulators under infectious conditions are more likely to be important for pathogenesis. Thus, reconstructing the global regulatory network during infection or, at the very least, under conditions that mimic the host cellular environment not only provides a bird's eye view of Salmonella survival strategy in response to hostile host environments but also serves as an efficient means to identify novel virulence factors that are essential for Salmonella to accomplish systemic infection in the host.


Synthetic glycoconjugates characterize the fine specificity of Brucella A and M monoclonal antibodies.
The dominant cell wall antigen of Brucella bacteria is the O-polysaccharide component of the smooth lipopolysaccharide. Infection by various Brucella biovars causes abortions and infertility in a wide range of domestic and wild animals and debilitating disease in humans. Diagnosis relies on the detection of antibodies to the A and M antigens expressed in the O-polysaccharide. This molecule is a homopolymer of the rare monosaccharide, 4-formamido-4,6-dideoxy-d-mannopyranose (Rha4NFo). The A epitope is created by a uniform α1,2 linked internal polymeric sequence capped by a distinct tetrasaccharide sequence defining the M antigen. Unique oligosaccharides only available by chemical synthesis and conjugated via reducing and non-reducing residues to bovine serum albumin have revealed the structural basis of the fine specificity that allows the discrimination of these closely related A and M epitopes. All three M specific monoclonal antibodies (mAbs) are inferred to possess groove type binding sites open at each end, and recognize an α1,3 linked Rha4NFo disaccharide as a part of a trisaccharide epitope, which in two mAbs includes the terminal Rha4NFo residue. The binding site of one of these antibodies is sufficiently large to engage up to six Rha4NFo residues and involves weak recognition of α1,2 linked Rha4NFo residues. The third mAb binds an internal trisaccharide epitope of the M tetrasaccharide. Two A specific mAbs also possess groove type binding sites that accommodate six and four α1,2 linked Rha4NFo residues.


Women-Only Cardiac Rehabilitation Delivery Around the World.
Women utilise cardiac rehabilitation (CR) significantly less than men. Gender-tailored CR improves adherence and mental health outcomes when compared to traditional programs. This study ascertained the availability of women-only (W-O) CR classes globally. In this cross-sectional study, an online survey was administered to CR programs globally, assessing delivery of W-O classes, among other program characteristics. Univariate tests were performed to compare provision of W-O CR by program characteristics. Data were collected in 93/111 countries with CR (83.8% country response rate); 1,082 surveys (32.1% program response rate) were initiated. Globally, 38 (40.9%; range 1.2-100% of programs/country) countries and 110 (11.8%) programs offered W-O CR. Women-Only CR was offered in 55 (7.4%) programs in high-income countries, versus 55 (16.4%) programs in low- and middle-income countries (p<0.001); it was offered most commonly in the Eastern Mediterranean region (n=5, 55.6%; p=0.22). Programs that offered W-O CR were more often located in an academic or tertiary facility, served more patients/year, offered more components, treated more patients/session, offered alternative forms of exercise, had more staff (including cardiologists, dietitians, and administrative assistants, but not mental health care professionals), and perceived space and human resources to be less of a barrier to delivery than programs not offering W-O CR (all p<0.05). Women-Only CR was not commonly offered. Only larger, well-resourced programs seem to have the capacity to offer it, so expanding delivery may require exploiting low-cost, less human resource-intensive approaches such as online peer support.


Prevention of depression and anxiety in later life: design of a randomized controlled trial for the clinical and economic evaluation of a life-review intervention.
Depressive and anxiety symptoms in older adults could develop into significant health problems with detrimental effects on quality of life and a possibly poor prognosis. Therefore, there is a need for preventive interventions which are at once effective, acceptable and economic affordable. This paper describes the design of a study evaluating "The stories we live by", a preventive life-review group intervention, which was recently developed for adults of 55 years and over with depressive and anxiety symptoms. Both clinical and economic effectiveness will be evaluated in a pragmatic randomized controlled trial. The participants in the intervention condition will receive the 8-session preventive intervention. The participants in the control condition will have access to usual care. Clinical end-terms are depressive and anxiety symptoms, current major depressive episode, quality of life and positive mental health post-treatment (3 months after baseline) and at follow-ups (6 and 12 months after baseline). Additional goals of this study are to identify groups for whom the intervention is particularly effective and to identify the therapeutic pathways that are vital in inducing clinical change. This will be done by analyzing if treatment response is moderated by demographics, personality, past major depressive episodes, important life events and chronically disease, and mediated by reminiscence functions, perceived control, automatic positive thoughts and meaning in life. Finally the cost-effectiveness of the intervention relative to care as usual will be assessed by computing incremental costs per case of depression and anxiety avoided (cost-effectiveness) and per quality adjusted life year (QALY) (cost utility). It is expected that both the life-review intervention and its evaluation will contribute to the existing body of knowledge in several ways. First, the intervention is unique in linking life-review with narrative therapy and in its focus on specific, positive memories. Second, the evaluation is likely to answer questions regarding the acceptability and cost-effectiveness of life-review that have not been addressed thoroughly until now. Positive results of this study will make available a new evidence-based intervention to improve public health among people of 55 years and over. Nederlands Trial Register TC = 1860.


Development of polymerase chain reaction assays for detection of Listeria monocytogenes in clinical cerebrospinal fluid samples.
In order to improve the diagnosis of Listeria meningitis or meningoencephalitis, especially in patients who have received antibiotics before their cerebrospinal fluid (CSF) has been examined, two assays for the detection of Listeria monocytogenes based on the polymerase chain reaction (PCR) were evaluated. After a standard PCR, the amplified DNA was detected either by a second round of PCR with internal primers followed by gel electrophoresis and ethidium bromide staining (nested PCR) or by dot blot hybridization to an internal digoxigenin-labeled probe (PCR-dot blot). For PCR, two sets of primers within the invasion-associated protein gene (iap gene) were chosen. They allowed for the highly specific detection of all L. monocytogenes reference strains tested (serotypes 1/2a, 1/2b, 1/2c, 3a, 3b, 3c, 4a, 4b, 4c, 4d, and 7). These primers did not detect amplification products from various other gram-positive or gram-negative bacterial DNAs or human DNA. The sensitivities of both assays were assessed on sterile CSF samples that were artificially seeded with serial dilutions of L. monocytogenes serotype 4b cells. By both methods the limit of detection was less than 10 cells in the initial reaction. Since the nested PCR is more prone to contamination because of manipulation of the amplified products, a standard PCR assay followed by dot blot hybridization was applied to 52 CSF samples in a retrospective study. Of 28 CSF samples which were sterile or positive for bacteria other than Listeria species, 24 were PCR negative. In contrast, from 17 patients with culture-proven Listeria meningitis, 14 of 17 initial CSF samples were PCR positive, as were 3 of 7 culture-negative followup CSF samples taken after patients received antibiotics. These results support the usefulness of this approach in the diagnosis of Listeria meningitis, in particular, when antibiotic administration precedes culture of CSF.


Efficient learning mechanisms hold in the social domain and are implemented in the medial prefrontal cortex.
When we are learning to associate novel cues with outcomes, learning is more efficient if we take advantage of previously learned associations and thereby avoid redundant learning. The blocking effect represents this sort of efficiency mechanism and refers to the phenomenon in which a novel stimulus is blocked from learning when it is associated with a fully predicted outcome. Although there is sufficient evidence that this effect manifests itself when individuals learn about their own rewards, it remains unclear whether it also does when they learn about others' rewards. We employed behavioral and neuroimaging methods to address this question. We demonstrate that blocking does indeed occur in the social domain and it does so to a similar degree as observed in the individual domain. On the neural level, activations in the medial prefrontal cortex (mPFC) show a specific contribution to blocking and learning-related prediction errors in the social domain. These findings suggest that the efficiency principle that applies to reward learning in the individual domain also applies to that in the social domain, with the mPFC playing a central role in implementing it.


Debye series of normally incident plane-wave scattering by an infinite multilayered cylinder.
We derive the formula of the Debye-series decomposition for normally incident plane-wave scattering by an infinite multilayered cylinder. A comparison of the scattering diagrams calculated by the Debye series and Mie theory for a graded-index polymer optical fiber is given and the agreement is found to be satisfied. This approach permits us to simulate the rainbow intensity distribution of any single order and the interference of several orders, which is of good use to the study of the scattering characteristics of an inhomogeneous cylinder and to the measurement of the refractive index profile of an inhomogeneous cylinder.


Global motion detection and censoring in high-density diffuse optical tomography.
Motion-induced artifacts can significantly corrupt optical neuroimaging, as in most neuroimaging modalities. For high-density diffuse optical tomography (HD-DOT) with hundreds to thousands of source-detector pair measurements, motion detection methods are underdeveloped relative to both functional magnetic resonance imaging (fMRI) and standard functional near-infrared spectroscopy (fNIRS). This limitation restricts the application of HD-DOT in many challenging imaging situations and subject populations (e.g., bedside monitoring and children). Here, we evaluated a new motion detection method for multi-channel optical imaging systems that leverages spatial patterns across measurement channels. Specifically, we introduced a global variance of temporal derivatives (GVTD) metric as a motion detection index. We showed that GVTD strongly correlates with external measures of motion and has high sensitivity and specificity to instructed motion-with an area under the receiver operator characteristic curve of 0.88, calculated based on five different types of instructed motion. Additionally, we showed that applying GVTD-based motion censoring on both hearing words task and resting state HD-DOT data with natural head motion results in an improved spatial similarity to fMRI mapping. We then compared the GVTD similarity scores with several commonly used motion correction methods described in the fNIRS literature, including correlation-based signal improvement (CBSI), temporal derivative distribution repair (TDDR), wavelet filtering, and targeted principal component analysis (tPCA). We find that GVTD motion censoring on HD-DOT data outperforms other methods and results in spatial maps more similar to those of matched fMRI data.


The Prevalence of High Antiretroviral Coverage and Viral Suppression in Japan: an Excellent Profile for a Downstream Human Immunodeficiency Virus Care Spectrum.
We investigated the effectiveness of the Japanese health care system for human immunodeficiency virus/acquired immunodeficiency virus (HIV/AIDS), in terms of prevention, diagnosis, access to antiretroviral treatment, and treatment outcomes. Clinical information on HIV/AIDS cases was collected via questionnaires sent to 377 registered HIV/AIDS clinics in Japan. Data on 9,040 and 14,569 cases were collected in 2009 and 2014, respectively. The percentages of cases undergoing treatment were 69.6% and 87.8% in 2009 and 2014, respectively, demonstrating an improvement in treatment coverage over the 5 years between the 2 surveys. The proportion of cases with undetectable HIV RNA in the 2014 survey was 87.7%. Thus, our survey revealed that the 2 of the United Nations AIDS Fast-Track targets, 90% treated and 90% virally suppressed, are close to being achieved. However, Japan appears to have fallen short of the upstream target of 90% diagnosed. Japan needs to radically reform its strategies for encouraging people to undergo HIV testing and to develop a system for estimating the number of people living with HIV.


Patellofemoral contact pressures. The influence of q-angle and tendofemoral contact.
Controlled bending moments were applied to twelve human cadaver knee joints using a special loading fixture that allowed variation of both the Q-angle and the flexion angle. The joints were tested at three different Q-angles (physiological, increased 10 degrees, and decreased 10 degrees) and five different angles of flexion (ranging from 20 to 120 degrees). Based on one-third of values in the literature for maximum voluntary isometric quadriceps moments, we applied resultant knee moments of 23.6, 30.7, 47.2, and 35.0 newton-meters at 20, 30, 60, and 90 degrees of flexion, respectively. Based on two-thirds of reported maximum moments, we applied 47.2 newton-meters at 120 degrees of flexion. Normal patellofemoral-contact pressures, measured with a pressure-sensitive film, were remarkably uniformly distributed (+/- 0.25 megapascal ), with approximately the same pressure on the lateral and medial patellar facets. The maximum contact force occurred at 90 degrees of flexion. Extrapolating our measurements to full in vivo moments, we estimated maximum contact forces of 4600 newtons , or approximately 6.5 times body weight. Tendofemoral contact at 120 degrees of knee flexion supported one-third of the total contact force on the patella. A 10-degree increase in the Q-angle resulted in increased peak pressures (an increase of 45 per cent at 20 degrees of flexion). A decrease in the Q-angle resulted in unloading of the vertical crest and, in some knees, of parts of the lateral facet. However, these decreases were always associated with increased peak pressures (50 per cent more at 20 degrees of flexion) at other locations.


Association between dedicated rural training year and the likelihood of becoming a general surgeon in a small town.
Although projections of surgical workforce predict an increased need for general surgeons, especially in rural areas, graduates of residency programs increasingly enter urban or metropolitan specialty practice. To determine whether fourth-year residents at a hospital in a rural setting were more likely to enter general surgery practice than a specialty. In 2002, we initiated a year-long program for fourth-year residents. The records of all surgical residents (n = 70) who completed our general surgical residency and entered practice since the rural rotation began were divided into those completing the rural surgery program (rural) and those who did not (other). Demographic characteristics of the 2 groups and initial intent to practice rural general surgery were compared. Critical end points included completion of a fellowship, general surgery practice, and practice setting population of less than 50,000. As an additional control group, we compared these residents with those who completed residency just before our rural program began (1993-2002) with regard to fellowship and practice characteristics. Age, sex, and initial practice plans. Age, sex, and initial practice plans of the 2 groups did not differ. Residents who completed the rural year were more likely to enter general surgery practice (10 of 11 [91%]) than those who did not (28 of 59 [47%]; P = .009). They were also more likely to practice in a site of population less than 50,000 (4 of 11 [36%] vs 4 of 59 [7%]; P = .02). The practice type and fellowship completion rate of the residents who finished all training years at Oregon Health and Science University during 1993-2002 and 2003-2012 did not differ. Most residents who completed the rural year (6 of 11 [55%]) entered residency with a desire to practice general surgery. All of them are practicing general surgery. Of the residents who entered training with a specialty career in mind, 4 of 5 (80%) who completed the rural year are practicing general surgery, while only 13 of 45 (29%) who stayed at our university program for the entire 5 years are in general surgery practice (P = .04). Providing residents a dedicated and significant experience in a rural setting increases the likelihood that they will practice general surgery in a similar setting despite initial specialty plans. Implementing such programs might help alleviate the increasing gap in workforce needs of small towns and rural hospitals.


Hypoglycemia After Gastric Bypass Surgery: Current Concepts and Controversies.
Hypoglycemia, occurring after bariatric and other forms of upper gastrointestinal surgery, is increasingly encountered by clinical endocrinologists. The true frequency of this condition remains uncertain, due, in part, to differences in the diagnostic criteria and in the affected populations, as well as relative lack of patient and physician awareness and understanding of this condition. Postbariatric hypoglycemia can be severe and disabling for some patients, with neuroglycopenia (altered cognition, seizures, and loss of consciousness) leading to falls, motor vehicle accidents, and job and income loss. Moreover, repeated episodes of hypoglycemia can result in hypoglycemia unawareness, further impairing safety and requiring the assistance of others to treat hypoglycemia. In this review, we summarize and integrate data from studies of patients affected by hypoglycemia after Roux-en-Y gastric bypass (RYGB) surgery, obtained from PubMed searches (1990 to 2017) and reference searches of relevant retrieved articles. Whereas hypoglycemia can also be observed after sleeve gastrectomy and fundoplication, this review is focused on post-RYGB, given the greater body of published clinical studies at present. Data addressing specific aspects of diagnosis, pathophysiology, and treatment were reviewed by the authors; when not available, the authors have provided opinions based on clinical experience with this challenging condition. Hypoglycemia, occurring after gastric bypass surgery, is challenging for patients and physicians alike. This review provides a systematic approach to diagnosis and treatment based on the underlying pathophysiology.


Clinical efficacy of 1,444nm Nd:YAG laser for xanthelasma palpebrarum.
Xanthelasma palpebrarum (XP) does not regress spontaneously and most patients complain of cosmetic discomfort. This study presents the results of treatment of XP using 1,444 nm Nd:YAG laser. We aim to evaluate the clinical efficacy of a 1,444 nm Nd:YAG laser in XP. Twenty-eight patients with XP treated with 1,444 nm Nd:YAG laser were analyzed retrospectively. A physician scored the results based on the reduction of the initial lesion area under six categories. The results were scored as follows: no effect (0% clearing of xanthelasma area), some response (1-24% clearing), moderate response (25-49% clearing), marked response (50-74% clearing), satisfactory result (75-99% clearing), and excellent result (100% clearing). Twelve patients (42.8%) showed excellent clearance and 10 patients (35.7%) had clearance greater than 75%. Overall, 24 patients (85.7%) showed improvement higher than 50%. Half of the patients (14 patients) ended the treatment with satisfactory results with one treatment session. Including seven patients who ended the treatment after two laser sessions, 21 patients (75%) reported satisfactory results and ended the treatment after 1 to 2 laser sessions. XP treatment with 1,444 nm Nd:YAG laser showed promising results. We believe it can be an effective and safe treatment modality for XP.


Sorption of hydrophobic organic compounds to a diverse suite of carbonaceous materials with emphasis on biochar.
Carbonaceous materials like biochars are increasingly recognized as effective sorbent materials for sequestering organic pollutants. Here, we study sorption behavior of two common hydrophobic organic contaminants 2,2',5,5'-tetrachlorobiphenyl (CB52) and phenanthrene (PHE), on biochars and other carbonaceous materials (CM) produced at a wide range of conditions and temperatures from various feedstocks. The primary aim was to establish structure-reactivity relationships responsible for the observed variation in CM and biochar sorption characteristics. CM were characterized for their elemental composition, surface area, pore size distribution, aromaticity and thermal stability. Freundlich sorption coefficients for CB52 and PHE (i.e. LogK(F,CB52) and K(F,PHE), respectively) to CM showed a variation of two to three orders of magnitude, with LogK(F,CB52) ranging from 5.12 ± 0.38 to 8.01 ± 0.18 and LogK(F,PHE) from 5.18 ± 0.09 to 7.42 ± 1.09. The highest LogK(F) values were observed for the activated CM, however, non-activated biochars produced at high temperatures (>700 °C) sorbed almost as strongly (within 0.2-0.5 Log units) as the activated ones. Sorption coefficients significantly increased with pyrolysis temperature, CM surface area and pore volume, aromaticity, and thermal stability, and decreased with H/C, O/C, (O + N)/C content. The results of our study contribute to the understanding of processes underlying HOC sorption to CM and explore the potential of CM as engineered sorbents for environmental applications.


Different functional properties of troponin T mutants that cause dilated cardiomyopathy.
The effects of Troponin T (TnT) mutants R141W and DeltaK210, the only two currently known mutations in TnT that cause dilated cardiomyopathy(DCM) independent of familial hypertrophic cardiomyopathy (FHC), and TnT-K273E, a mutation that leads to a progression from FHC to DCM, were investigated. Studies on the Ca2+ sensitivity of force development in porcine cardiac fibers demonstrated that TnT-DeltaK210 caused a significant decrease in Ca2+ sensitivity, whereas the TnT-R141W did not result in any change in Ca2+ sensitivity when compared with human cardiac wild-type TnT (HCWTnT). TnT-DeltaK210 also caused a decrease in maximal force when compared with HCWTnT and TnT-R141W. In addition, the TnT-DeltaK210 mutant decreased maximal ATPase activity in the presence of Ca2+. However, the TnT-K273E mutation caused a significant increase in Ca2+ sensitivity but behaved similarly to HCWTnT in actomyosin activation assays. Inhibition of ATPase activity in reconstituted actin-activated myosin ATPase assays was similar for all three TnT mutants and HCWTnT. Additionally, circular dichroism studies suggest that the secondary structure of all three TnT mutants was similar to that of the HCWTnT. These results suggest that a rightward shift in Ca2+ sensitivity is not the only determinant for the phenotype of DCM.


Improving participation by Aboriginal children in blood lead screening services in Broken Hill, NSW.
Lead poses a health risk to young children with detrimental effects on their intellectual development. Attendance rates for Aboriginal children at routine blood lead screening and at follow-up appointments in Broken Hill, NSW, have declined in recent years. This study sought to identify strategies to improve the participation of Aboriginal children aged 1-4 years in blood lead screening services in Broken Hill. Attendance rates during the period 2000-2010 were determined using the Broken Hill Lead Management database. From June to August 2011, Aboriginal community members, service providers and public health staff were invited to interviews and focus groups to explore barriers, enablers and suggestions for improving participation. In 2009, 27% of Aboriginal children aged 1-4 years attended blood lead screening and 29% of these children with blood lead levels over 15 µg/dL attended follow-up appointments. Barriers to participation in lead screening services included community perceptions, reduced service capacity, socio-economic and interorganisational factors. Enablers included using a culturally acceptable model, linking lead screening with routine health checks and using the finger-prick method of testing. The final report for the study included recommendations to improve participation rates of Aboriginal children including using social marketing, formalising collaboration between health services, supporting disadvantaged families and employing an Aboriginal Health Worker.


Role of detection limits in drinking water regulation.
Some commentators on environmental science and policy have claimed that advances in analytical chemistry, reflected by an ability to detect contaminants at ever-decreasing concentrations, lead to regulations stricter than justified by available toxicological data. We evaluate this claim in the context of drinking water regulation, with respect to contaminants regulated under the Safe Drinking Water Act (SDWA). We examine the relationships between historical and present maximum contaminant levels and goals in the greater context of detection capability and evaluate the extent to which different aspects of the regulatory apparatus (i.e., analytical capability, cost-benefit analysis, analysis of competing risks, and available toxicological data) influence the regulatory process. Our findings do not support the claim that decreases in detection limit lead to more stringent regulation in the context of drinking water regulation in the United States. Further, based on our analysis of the National Primary Drinking Water Regulation and existing United States Environmental Protection Agency approaches to establishing the practical quantifiable level, we conclude that in the absence of changes to the underlying toxicological model, regulatory revision is unlikely.


Anatomy of the joints of the thumb.
The three joints of the thumb differ markedly with respect to anatomy and function. Each contributes its own anatomic personality, and when functioning together, they allow the thumb to move with remarkable versatility and grace yet with the stability necessary to perform a wide variety of tasks. The carpometacarpal and interphalangeal joints allow for thumb mobility while the metacarpophalangeal joint provides stability. Thumb rotation primarily takes place at the CMC joint, although the MP and IP joints each contribute a small amount of pronation with flexion. Although much is known about the static structural anatomy of the thumb, its dynamic anatomy requires further investigation. The fluid, elegant and powerful movements of the thumb are complex, and defining the contributions of the various individual structures is difficult. Hopefully, future investigators using newer techniques will unravel the complexities of the functional anatomy of this remarkable digit.


Evidence for the role of heterotrimeric guanine nucleotide-binding regulatory proteins in the regulation of the mouse sperm adenylyl cyclase by the egg's zona pellucida.
Sperm acrosomal exocytosis is the result of a complex set of signal transduction pathways activated physiologically by the egg's extracellular matrix, the zona pellucida. In the mouse, the zona pellucida has been demonstrated to induce an increase in sperm intracellular pH, Ca2+, and cyclic adenosine monophosphate (cAMP) concentrations as well as to activate proteins of the Gi class (G; guanine nucleotide-binding regulatory proteins). We recently reported that the mouse zona pellucida could activate the adenylyl cyclase of mouse sperm. It is not known, however, whether zona pellucida stimulation of adenylyl cyclase activity is mediated through G proteins. In the present study, we demonstrate that the sperm membrane-bound adenylyl cyclase activity is stimulated by the G protein activators guanosine-5'-O-thiotriphosphate (GTPgammaS) and mastoparan in a concentration-dependent manner. The maximal adenylyl cyclase activity measured with these two G protein activators is similar to the stimulation observed with the zona pellucida, but the effect of GTPgammaS is not additive or synergistic with the effects of mastoparan or the zona pellucida. Pertussis toxin treatment of sperm membranes inhibits the zona pellucida stimulation of adenylyl cyclase activity, while the basal or forskolin-induced activation of the enzyme is not affected. Partial inhibition of the stimulatory effect of the zona pellucida on the adenylyl cyclase activity is observed with guanosine-5'-O-thiodiphosphate (GDPbetaS), another G protein antagonist. To a reconstitution system containing Lubrol-PX, where zona pellucida or GTPgammaS stimulation of the sperm enzyme is not observed, addition of G protein betagamma subunits restores the activation of the sperm adenylyl cyclase by the zona pellucida and GTPgammaS without affecting the enzyme activity under basal or forskolin-stimulated conditions. These results support our hypothesis that mouse sperm adenylyl cyclase is stimulated by the zona pellucida through a pertussis toxin-sensitive pathway involving G proteins of the Gi class.