Hyaluronan Does Not Regulate Human Epidermal Keratinocyte Proliferation and Differentiation.
Hyaluronan (HA) is synthesized by three HA synthases (HAS1, HAS2, and HAS3) and secreted in the extracellular matrix. In human skin, large amounts of HA are found in the dermis. HA is also synthesized by keratinocytes in the epidermis, although its epidermal functions are not clearly identified yet. To investigate HA functions, we studied the effects of HA depletion on human keratinocyte physiology within in vitro reconstructed human epidermis. Inhibition of HA synthesis with 4-methylumbelliferone (4MU) did not modify the expression profile of the epidermal differentiation markers involucrin, keratin 10, and filaggrin during tissue reconstruction. In contrast, when keratinocytes were incubated with 4MU, cell proliferation was decreased. In an attempt to rescue the proliferation function, HA samples of various mean molecular masses were added to keratinocyte cultures treated with 4MU. These samples were unable to rescue the initial proliferation rate. Furthermore, treatments with HA-specific hyaluronidase, although removing almost all HA from keratinocyte cultures, did not alter the differentiation or proliferation processes. The differences between 4MU and hyaluronidase effects did not result from differences in intracellular HA, sulfated glycosaminoglycan concentration, apoptosis, or levels of HA receptors, all of which remained unchanged. Similarly, knockdown of UDP-glucose 6-dehydrogenase (UGDH) using lentiviral shRNA effectively decreased HA production but did not affect proliferation rate. Overall, these data suggest that HA levels in the human epidermis are not directly correlated with keratinocyte proliferation and differentiation and that incubation of cells with 4MU cannot equate with HA removal.


Underlying causes of underutilization of maternal, neonatal and child health (MNCH) services in Africa: A survey from Lagos State, Nigeria.
Lagos State, Nigeria, Africa's largest city with an estimaed 21 million population, continues to face challenges in its attempts to reduce maternal mortality (555 deaths per 100,000 live births) and deaths of children under five (59 per 1,000 live births). These deaths are more common among women and children living in poverty, many of whom rarely utilize health services. This paper describes the trend in the use of maternal, neonatal and child health (MNCH) services in the State in the past decade and shows barriers to the use of the services. Significant improvement in the coverage of the services were not observed. We identified the following five types of barriers to the use of MNCH services: i) financial barriers, ii) physical barriers, iii) cognitive barriers, iv) organizational barriers, and v) psychological and socio-cultural barriers. To address these interrelated barriers, the Lagos State Ministry of Health should prioritize regular outreach health services including health promotion, and realize the current initiative for massive recruitment of health personnel and appropriate deployment of them.


Controversies for Glucose Control Targets in Type 2 Diabetes: Exposing the Common Ground.
Glycated hemoglobin targets have been given in guidelines for the last three decades, mostly without change at around 6.5-7.0% (47-53 mmol/mol). Personalization of such targets has also long been advocated, but often with little and inappropriate guidance. More recently some have suggested higher targets might be indicated, and more specifically lower targets avoided, even in those in whom they are easily attained without seeming burden or risk. Prospective data from randomized and observational studies, in people with type 2 diabetes and indeed those without diabetes, find cardiovascular and mortality risk are uniformly lowest at lower levels including into the normal range. In some studies with large populations, a high proportion of people are found to attain such levels, and the UK Prospective Diabetes Study (UKPDS) and more recent studies appear to confirm the importance of starting low and continuing long. Studies of cardiovascular events and mortality in people with diabetes will already factor in any effect of hypoglycemia, which therefore should not be double-counted in setting targets. Nevertheless, some factors should lead to modification of target levels, and these will include experience of hypoglycemia where therapy change and glucose monitoring cannot ameliorate it and sometimes prospectively in those at social or occupational risk. The fact that clinical experience will modify targets emphasizes that targets will not be stable over time but will change, for example, with occurrence of adverse events or perceptions of increase/decreased burden of therapy. The evidence suggests that glucose control takes 5 years or more to have any impact on vascular outcomes or mortality, so targets may also be higher in those with shorter life expectancy or higher health burden or simply reflect individual preferences. This article discusses the evidence behind these conclusions.


Effect of thyroid status on thin-filament Ca2+ regulation and expression of troponin I in perinatal and adult rat hearts.
There is evidence for the existence of developmental changes in expression of troponin I (TNI) in cardiac thin filaments; however, regulation of TNI expression has not been described. We tested whether thyroid state affects expression of TNI using neonatal and adult rats made hypothyroid by treatment with 6-n-propyl-2-thiouracil. Polyacrylamide gels of myofibrils from hearts of 7-, 14-, 21-, and 28-day-old animals indicated that both euthyroid and hypothyroid rats display a developmental shift toward the adult form of TNI. However, hypothyroid rats displayed a lower percentage of adult TNI at each age studied. When adult rats were made hypothyroid, the proportion of adult TNI decreased slightly. Thin-filament activity was determined from measurements of the effect of acidic pH on calcium activation of myofibrillar ATPase activity. Sensitivity to acidic pH was measured by the magnitude of shift in pCa50 (-log of half-maximally activating molar Ca2+) between pH 7.0 and 6.5. Euthyroid rats displayed developmental increases in pH sensitivity. At 7, 14, and 28 days of development, shifts in pCa50 were 0.11, 0.38, and 0.43 units, respectively. Hypothyroid rats displayed less pH sensitivity with pCa50 shifts of 0.07, 0.21, and 0.15 units at 7, 14, and 28 days of development. Adult hypothyroid rats displayed a 0.38-unit shift in pCa50, whereas euthyroid adults displayed a 0.44-unit shift. Our results indicate that pH sensitivity and expression of cardiac TNI are influenced by developmental stage and hormonal status.


The Scottish national LifeCurve™ survey: costs of functional decline, opportunities to achieve early intervention to support well-being in later life, and meaningfulness of the LifeCurve™.
The aim of the Scottish AHP LifeCurve™ survey was to gather a snapshot of where people are on their LifeCurve™ when receiving allied health professions (AHP) services and to understand the cost consequence of intervening 'late' in the ageing trajectory. The objectives were to promote discussion around preventing functional decline, support innovation in service delivery, and facilitate broader engagement with individuals, communities, and wider environments for improving health and well-being in later life. In addition, subsequent learning could help address the increasing resource gap between the demand and capacity across health and social care. The survey was paper-based in the form of a printed booklet, which contained the 15 activities of daily living (ADL) and instrumental ADL (IADL) which comprise the LifeCurve™ with additional lifestyle questions and information about the member of staff and service the participant was seen in, including their Community Health Index (CHI) number. The survey questions and booklet layout were tested over a five-month period with AHPs and people receiving AHP services. Liaison with national health literacy colleagues and lead speech and language therapists ensured that the survey material was accessible to a wide range of people. In addition, the survey could be made available in alternative formats, on request. Agreement to undertake the national survey was obtained in November 2016 by all AHP directors and associate directors who appointed communication support leads in their area who would support implementation at all stages at a local level. All materials relating to the survey were published on a dedicated area of a community of practice to support awareness and training during the preimplementation phase. AHPs working in adult services were asked to complete a survey with a minimum of two people they would 'typically' see in their service during a two-week period in May 2017, with the exclusion of people who were too unwell to participate, children and young people under 16 years, and adults with incapacity and without a guardianship arrangement in place. Approval was gained from the Public Benefit Privacy Panel to link the survey data to participants' health service usage using their CHI number. Completed forms were returned to the University of Strathclyde for entry into an encrypted electronic database using a double data entry process and were allocated a unique identifier. The unique identifier and CHI numbers were sent to Information Services Division (ISD), and then, the CHI numbers were deleted from the encrypted database. ISD sent the linked health data to the Scottish Government Analytical Services Division, which thus produced a full encrypted and anonymised database. The data explain what stages on the LifeCurve™ AHPs are intervening, and the matched data provide associated healthcare costs at each stage. Due to poor or missing data in the AHP/Service section, only 60% (n = 8261) of the total completed surveys were able to be matched with health service usage records. These data show that whilst AHPs are seeing people at each of the 15 ADL/IADL stages on the LifeCurve™, interventions fell into three groups where 25% of people where seen at the 'precurve' stage, 13% of people at 'mid-curve' (stage number five), and 39% of people at 'late-curve' (stages 10 to 13). The healthcare cost usage of these participants increased the further along the LifeCurve™ a person moves, with an average annual cost of £2700 at 'precurve' rising to £12,330 at 'late-curve' in 2016-2017. The results indicate that different services and professions are represented at each of these three points. So, for example, as might be expected, outpatient (especially musculoskeletal) services were seen more often at the 'precurve' stage, and in-patient and community rehabilitation, services were seen more often at the 'late-curve' stages; diagnostic radiographers and orthoptists saw people at the 'early-curve' stages, dieticians and podiatrists saw people at the 'mid-curve' stage, whilst physiotherapists, speech and language therapists, and occupational therapists saw people at the 'late-curve' stages. Data analysis showed this pattern is different for people receiving mental health services and, so, their data were removed and will be analysed and reported separately. It is clear from the results that healthcare costs increased as participants moved down LifeCurve™ stages, that is, as their levels of functional decline increase. It is also clear that AHPs are intervening late in a person's functional decline with associated limitations on changing their ageing trajectory. The cost consequence of this is significant - moving someone from 'late- to mid-curve' could save £3200 per person per annum. However, those AHPs typically associated with reabling approaches and rehabilitation, which have greatest potential to change ageing trajectories, were not represented at the 'mid-curve' stage (e.g., physiotherapists, occupational therapists). Therefore, we must find places to have conversations with people to inform them that functional decline is malleable and not inevitable purely by virtue of chronological age and provide education and support to prevent or reverse functional decline and collaborate around strategic planning and commissioning to offer different options that support an optimum LifeCurve™.


Glutathione depletion is associated with decreased Bcl-2 expression and increased apoptosis in cholangiocytes.
Cholangiocytes are the target of a group of liver diseases termed the cholangiopathies that include conditions characterized by periductal inflammation and cholangiocyte apoptosis. Because inflammation is associated with oxidative stress, we developed the hypothesis that cholangiocytes exposed to oxidative stress will be depleted of endogenous cytoprotective molecules, leading to cholangiocyte apoptosis. To begin to test this hypothesis, we explored the relationships among glutathione (GSH) depletion, expression of Bcl-2 (a protooncogene that inhibits apoptosis), and apoptosis in a nonmalignant human cholangiocyte cell line. Monolayers of human bile duct epithelial cells, derived from normal liver and immortalized by SV40 transformation, were depleted of GSH using buthionine sulfoximine (BSO). Bcl-2 expression was assessed by quantitative immunoblot analysis, and apoptosis quantified by fluorescence microscopy using the DNA binding dye 4', 6'-diamidino-2-phenylindole. Bcl-2 message was assessed by RNase protection assay, and Bcl-2 protein synthesis and half-life by pulse-chase analysis. Exposure of human cholangiocytes in culture to BSO reduced GSH levels by 93 +/- 3% (P < 0.01). In addition, treatment of cholangiocytes with BSO reduced Bcl-2 levels by 87 +/- 2% (P < 0.01) and was associated with a time-dependent increase in the number of cells undergoing apoptosis; approximately 11 +/- 1% of cultured cells demonstrated morphological changes of apoptosis by 72 h compared with 1.5 +/- 0.1% in untreated cholangiocytes (P < 0. 01). Maintenance of GSH levels by addition of glutathione ethyl ester in the presence of BSO blocked the BSO-associated increase in apoptosis in BSO-treated cholangiocytes and also prevented the decrease in Bcl-2 protein. BSO treatment of cholangiocytes did not change steady-state levels of bcl-2 mRNA or Bcl-2 protein synthesis. However, Bcl-2 protein half-life decreased 57% in BSO-treated vs. untreated cells. Our results using a human cholangiocyte cell line demonstrate that reduction in the cellular levels of an antioxidant such as GSH results in increased degradation of Bcl-2 protein and an increase in apoptosis. These data provide a mechanistic link between the consequences of oxidative stress and cholangiocyte apoptosis, an observation that may be important in the pathogenesis of the inflammatory cholangiopathies.


Multi-taxa trait and functional responses to physical disturbance.
Examining assemblage trait responses to environmental stressors extends our understanding beyond patterns of taxonomic diversity and composition, with results potentially transferable among bioregions. But the degree to which trait responses may be generalized across taxonomic groups remains incompletely understood. We compared trait responses among carabids, spiders and plants to an experimentally manipulated gradient of physical disturbance, replicated in open habitats within a forested landscape. Recolonization of recently disturbed habitats is expected to favour species with traits that promote greater dispersal ability, independent of taxa. We specifically predicted that physical disturbance would increase the representation of carabids with smaller body size, wings or wing dimorphism, spiders able to disperse aerially, and plants with therophyte life-history and wind-dispersed seed. We sampled 197 arthropod species (14,738 individuals) and 164 species of plant. The strength of association between each trait and the disturbance intensity was quantified by correlating matrices of species by traits, species abundance by sites and sites by environment, with significance assessed by comparison with a null model. Responses of biological traits varied among taxa but could be consistently interpreted in terms of dispersal ability. Trait shifts for carabid and plant assemblages were as predicted and correspond to those observed in other disturbance regimes. Assemblages after disturbance comprised smaller and winged carabids, and smaller plants with wind-dispersed seed, consistent with selection for species with better dispersal ability. In contrast, aerial dispersal did not appear important in spider recolonization, instead terrestrial dispersal ability was suggested by the increased abundance of larger-bodied and cursorial species. However, larger spider body size was also associated with an active-hunting strategy, also favoured in the post-disturbance environment. Trait-function linkage differed among taxa and was sometimes diffuse, with covariance among biological traits and the mapping of individual traits to multiple ecological functions. In particular, body size responses reflected correlations with life history, susceptibility to perturbation and dispersal ability that were inconsistent between the two arthropod groups. Selection of traits for assessment should therefore be taxa specific. Generalizations of trait responses across taxa should only be conducted where functional or ecological significance of assembly-level changes can be understood.


Clinical implications of subclinical hypothyroidism in continuous ambulatory peritoneal dialysis patients.
Despite the high prevalence of subclinical hypothyroidism in patients with chronic kidney disease, little is known about the clinical features and implications of this disorder in end-stage renal disease patients. This study aimed to investigate the clinical implications of subclinical hypothyroidism in continuous ambulatory peritoneal dialysis (CAPD) patients. This is a cross-sectional study with 51 stable patients who were maintained on CAPD for more than 3 months. A thyroid function test with blood sampling and echocardiography were conducted. Subclinical hypothyroidism was defined as a thyrotropin (TSH) level over 5 mIU/l and normal free T(4). Of the 51 patients, subclinical hypothyroidism was detected in 14 (27.5%). Among those with subclinical hypothyroidism, only 4 (28.6%) patients had autoimmune thyroiditis. Patients with subclinical hypothyroidism had lower left ventricular ejection fractions (LVEF; 61.5 vs. 70.0%, p = 0.002) and lower fractional shortening at endocardial levels (endoFS; 33.9 vs. 40.0%, p = 0.009) compared to those with normal TSH levels. In addition, logTSH was inversely associated with LVEF (r = -0.361, p = 0.009) and endoFS (r = -0.320, p = 0.022). In a multivariate linear regression, adjusted for age, diabetes, previous coronary artery disease and logCRP (C-reactive protein), logTSH was an independent correlate with LVEF (beta = -0.388, p < 0.001). This study suggests that subclinical hypothyroidism is common and might be implicated in cardiac dysfunction in CAPD patients.


A G protein-coupled receptor is essential for Schwann cells to initiate myelination.
The myelin sheath allows axons to conduct action potentials rapidly in the vertebrate nervous system. Axonal signals activate expression of specific transcription factors, including Oct6 and Krox20, that initiate myelination in Schwann cells. Elevation of cyclic adenosine monophosphate (cAMP) can mimic axonal contact in vitro, but the mechanisms that regulate cAMP levels in vivo are unknown. Using mutational analysis in zebrafish, we found that the G protein-coupled receptor Gpr126 is required autonomously in Schwann cells for myelination. In gpr126 mutants, Schwann cells failed to express oct6 and krox20 and were arrested at the promyelinating stage. Elevation of cAMP in gpr126 mutants, but not krox20 mutants, could restore myelination. We propose that Gpr126 drives the differentiation of promyelinating Schwann cells by elevating cAMP levels, thereby triggering Oct6 expression and myelination.


Investigation on using high-energy proton beam for total body irradiation (TBI).
This work investigated the possibility of using proton beam for total body irradia-tion (TBI). We hypothesized the broad-slow-rising entrance dose from a monoen-ergetic proton beam can deliver a uniform dose to patient with varied thickness. Comparing to photon-based TBI, it would not require any patient-specific com-pensator or beam spoiler. The hypothesis was first tested by simulating 250 MeV, 275 MeV, and 300 MeV protons irradiating a wedge-shaped water phantom in a paired opposing arrangement using Monte Carlo (MC) method. To allow ± 7.5% dose variation, the maximum water equivalent thickness (WET) of a treatable patient separation was 29 cm for 250 MeV proton, and > 40 cm for 275 MeV and 300 MeV proton. The compared 6 MV photon can only treat patients with up to 15.5 cm water-equivalent separation. In the second step, we simulated the dose deposition from the same beams on a patient's whole-body CT scan. The maximum patient separation in WET was 23 cm. The calculated whole-body dose variations were ± 8.9%, ± 9.0%, ± 9.6%, and ± 14% for 250 MeV proton, 275 MeV proton, 300 MeV proton, and 6 MV photon. At last, we tested the current machine capability to deliver a monoenergetic proton beam with a large uniform field. Experiments were performed on a compact double scattering single-gantry proton system. With its C-shaped gantry design, the source-to-surface distance (SSD) reached 7 m. The measured dose deposition curve had 22 cm relatively flat entrance region. The full width half maximum field size was measured 105 cm. The current scatter filter had to be redesigned to produce a uniform intensity at such treatment distance. In con-clusion, this work demonstrated the possibility of using proton beam for TBI. The current commercially available proton machines would soon be ready for such task.


An insight into the molecular and surface state photoluminescence of carbon dots revealed through solvent-induced modulations in their excitation wavelength dependent emission properties.
This study explores the intriguing modulations in the excitation wavelength dependence of carbon dot photoluminescence (PL), induced by the solvent medium. Our results indicate that different emissive states of carbon dots are stabilized to different extents by the surrounding solvent environment. Consequently, in some solvents, such as ethyl acetate and acetonitrile, the PL of the carbon dots is strongly dependent on the excitation wavelength, while in other solvents, like water, the PL of the same carbon dot becomes independent of the excitation wavelength. These observations contribute to the enhancement of our understanding of the photophysics and PL mechanisms of this important class of luminescent materials, especially to discriminate between the PL arising from the "molecular state" and the "surface state".


Differences in functional impairment across subtypes of dementia.
Dementia is a cause of disability in later life. Despite the importance of functional status to the diagnosis of dementia, limited information exists on differences in functional limitations by dementia subtype. We conducted a cross-sectional analysis using the Aging, Demographics, and Memory Study (ADAMS) to determine the extent of functional impairment among older adults with dementia due to different etiologies. The ADAMS sample consisted of 856 individuals aged 71 years and older originally surveyed as part of the Health and Retirement Study. Based on a comprehensive in-person cognitive evaluation, respondents were assigned to diagnostic categories of normal cognition, cognitive impairment not demented, and demented. Dementia subtypes were grouped into three categories: vascular dementia (VaD), Alzheimer's dementia (AD), and dementia due to other etiologies. For 744 of the 856 respondents, a proxy informant completed a questionnaire asking whether the respondent had difficulty completing instrumental activities of daily living and activities of daily living (ADLs). Of 744 ADAMS participants, 263 had dementia: 199 (70.5%) with AD, 42 (16.9%) with VaD, and 22 (12.6%) were demented due to other etiologies. After adjustment for demographics, chronic illnesses, and dementia severity, participants with VaD (odds ratio [OR] 5.74; 95% confidence interval [CI] 2.60-12.69) and other etiologies of dementia (OR 21.23; 95% CI 7.25-62.16) were more likely to have greater than or equal to four ADL limitations compared with those with AD. VaD is associated with significantly more ADL limitations than AD. These physical limitations should be considered when designing adult day care programs, which adequately accommodate the needs of non-AD patients.


Pre-amyloid oligomers of the proteotoxic RepA-WH1 prionoid assemble at the bacterial nucleoid.
Upon binding to short specific dsDNA sequences in vitro, the N-terminal WH1 domain of the plasmid DNA replication initiator RepA assembles as amyloid fibres. These are bundles of single or double twisted tubular filaments in which distorted RepA-WH1 monomers are the building blocks. When expressed in Escherichia coli, RepA-WH1 triggers the first synthetic amyloid proteinopathy in bacteria, recapitulating some of the features of mammalian prion diseases: it is vertically transmissible, albeit non-infectious, showing up in at least two phenotypically distinct and interconvertible strains. Here we report B3h7, a monoclonal antibody specific for oligomers of RepA-WH1, but which does not recognize the mature amyloid fibres. Unlike a control polyclonal antibody generated against the soluble protein, B3h7 interferes in vitro with DNA-promoted or amyloid-seeded assembly of RepA-WH1 fibres, thus the targeted oligomers are on-pathway amyloidogenic intermediates. Immuno-electron microscopy with B3h7 on thin sections of E. coli cells expressing RepA-WH1 consistently labels the bacterial nucleoid, but not the large cytoplasmic aggregates of the protein. This observation points to the nucleoid as the place where oligomeric amyloid precursors of RepA-WH1 are generated, and suggests that, once nucleated by DNA, further growth must continue in the cytoplasm due to entropic exclusion.


Assessing protective factors for sexually violent offending with the SAPROF.
The Structured Assessment of Protective Factors for violence risk (SAPROF) has recently been developed as a risk assessment tool to focus solely on protective factors for (sexual) violence risk. Research on protective factors for sexual offending is very limited and most risk assessment tools for adult sexual offenders do not incorporate protective factors. The current study investigates the applicability and predictive validity of the SAPROF for forensic psychiatric patients who have sexually offended. For a sample of 83 hands-on sexual offenders, risk assessments were carried out retrospectively with the SAPROF, the Historical Clinical Risk Management-20 (HCR-20) and the Sexual Violence Risk-20 (SVR-20). Results show good interrater reliability and negative correlations between the SAPROF and both risk tools. Predictive validities of the SAPROF protective factors for reconvictions of general and sexual violence were good for short-term (1-3 year) as well as for long-term follow-up (15 year). Moreover, the SAPROF remained a statistically significant predictor of future violence and sexual violence even after controlling for the HCR-20 and the SVR-20. Implications of these findings and recommendations for future research are discussed.


A global inventory of photovoltaic solar energy generating units.
Photovoltaic (PV) solar energy generating capacity has grown by 41 per cent per year since 20091. Energy system projections that mitigate climate change and aid universal energy access show a nearly ten-fold increase in PV solar energy generating capacity by 20402,3. Geospatial data describing the energy system are required to manage generation intermittency, mitigate climate change risks, and identify trade-offs with biodiversity, conservation and land protection priorities caused by the land-use and land-cover change necessary for PV deployment. Currently available inventories of solar generating capacity cannot fully address these needs1-9. Here we provide a global inventory of commercial-, industrial- and utility-scale PV installations (that is, PV generating stations in excess of 10 kilowatts nameplate capacity) by using a longitudinal corpus of remote sensing imagery, machine learning and a large cloud computation infrastructure. We locate and verify 68,661 facilities, an increase of 432 per cent (in number of facilities) on previously available asset-level data. With the help of a hand-labelled test set, we estimate global installed generating capacity to be 423 gigawatts (-75/+77 gigawatts) at the end of 2018. Enrichment of our dataset with estimates of facility installation date, historic land-cover classification and proximity to vulnerable areas allows us to show that most of the PV solar energy facilities are sited on cropland, followed by aridlands and grassland. Our inventory could aid PV delivery aligned with the Sustainable Development Goals.


Myosin Light Chain Kinase (MLCK) Gene Influences Exercise Induced Muscle Damage during a Competitive Marathon.
Myosin light chain kinase (MLCK) phosphorylates the regulatory light chain (RLC) of myosin producing increases in force development during skeletal muscle contraction. It has been suggested that MLCK gene polymorphisms might alter RLC phosphorylation thereby decreasing the ability to produce force and to resist strain during voluntary muscle contractions. Thus, the genetic variations in the MLCK gene might predispose some individuals to higher values of muscle damage during exercise, especially during endurance competitions. The aim of this investigation was to determine the influence of MLCK genetic variants on exercise-induced muscle damage produced during a marathon. Sixty-seven experienced runners competed in a marathon race. The MLCK genotype (C37885A) of these marathoners was determined. Before and after the race, a sample of venous blood was obtained to assess changes in serum myoglobin concentrations and leg muscle power changes were measured during a countermovement jump. Self-reported leg muscle pain and fatigue were determined by questionnaires. A total of 59 marathoners (88.1%) were CC homozygotes and 8 marathoners (11.9%) were CA heterozygotes. The two groups of participants completed the race with a similar time (228 ± 33 vs 234 ± 39 min; P = 0.30) and similar self-reported values for fatigue (15 ± 2 vs 16 ± 2 A.U.; P = 0.21) and lower-limb muscle pain (6.2 ± 1.7 vs 6.6 ± 1.8 cm; P = 0.29). However, CC marathoners presented higher serum myoglobin concentrations (739 ± 792 vs 348 ± 144 μg·mL-1; P = 0.03) and greater pre-to-post- race leg muscle power reduction (-32.7 ± 15.7 vs -21.2 ± 21.6%; P = 0.05) than CA marathoners. CA heterozygotes for MLCK C37885A might present higher exercise-induced muscle damage after a marathon competition than CC counterparts.


Migratory herbivorous waterfowl track satellite-derived green wave index.
Many migrating herbivores rely on plant biomass to fuel their life cycles and have adapted to following changes in plant quality through time. The green wave hypothesis predicts that herbivorous waterfowl will follow the wave of food availability and quality during their spring migration. However, testing this hypothesis is hampered by the large geographical range these birds cover. The satellite-derived normalized difference vegetation index (NDVI) time series is an ideal proxy indicator for the development of plant biomass and quality across a broad spatial area. A derived index, the green wave index (GWI), has been successfully used to link altitudinal and latitudinal migration of mammals to spatio-temporal variations in food quality and quantity. To date, this index has not been used to test the green wave hypothesis for individual avian herbivores. Here, we use the satellite-derived GWI to examine the green wave hypothesis with respect to GPS-tracked individual barnacle geese from three flyway populations (Russian n = 12, Svalbard n = 8, and Greenland n = 7). Data were collected over three years (2008-2010). Our results showed that the Russian and Svalbard barnacle geese followed the middle stage of the green wave (GWI 40-60%), while the Greenland geese followed an earlier stage (GWI 20-40%). Despite these differences among geese populations, the phase of vegetation greenness encountered by the GPS-tracked geese was close to the 50% GWI (i.e. the assumed date of peak nitrogen concentration), thereby implying that barnacle geese track high quality food during their spring migration. To our knowledge, this is the first time that the migration of individual avian herbivores has been successfully studied with respect to vegetation phenology using the satellite-derived GWI. Our results offer further support for the green wave hypothesis applying to long-distance migrants on a larger scale.


Smoking and Parkinson disease: Evidence for gene-by-smoking interactions.
To investigate whether cigarette smoking interacts with genes involved in individual susceptibility to xenobiotics for the risk of Parkinson disease (PD). Two French population-based case-control studies (513 patients, 1,147 controls) were included as a discovery sample to examine gene-smoking interactions based on 3,179 single nucleotide polymorphisms (SNPs) in 289 genes involved in individual susceptibility to xenobiotics. SNP-by-cigarette smoking interactions were tested in the discovery sample through an empirical Bayes (EB) approach. Nine SNPs were selected for replication in a population-based case-control study from California (410 patients, 845 controls) with standard logistic regression and the EB approach. For SNPs that replicated, we performed pooled analyses including the discovery and replication datasets and computed pooled odds ratios and confidence intervals (CIs) using random-effects meta-analysis. Nine SNPs interacted with smoking in the discovery dataset and were selected for replication. Interactions of smoking with rs4240705 in the RXRA gene and rs1900586 in the SLC17A6 gene were replicated. In pooled analyses (logistic regression), the interactions between smoking and rs4240705-G and rs1900586-G were 1.66 (95% CI 1.28-2.14, p = 1.1 × 10-4, p for heterogeneity = 0.366) and 1.61 (95% CI 1.17-2.21, p = 0.003, p for heterogeneity = 0.616), respectively. For both SNPs, while smoking was significantly less frequent in patients than controls in AA homozygotes, this inverse association disappeared in G allele carriers. We identified and replicated suggestive gene-by-smoking interactions in PD. The inverse association of smoking with PD was less pronounced in carriers of minor alleles of both RXRA-rs4240705 and SLC17A6-rs1900586. These findings may help identify biological pathways involved in the inverse association between smoking and PD.


Tolerability of dipeptidyl peptidase-4 inhibitors: a review.
Oral glucose-lowering agents are used to treat patients with type 2 diabetes mellitus (T2DM). Most patients require multiple agents to maintain glycemic targets. Dipeptidyl peptidase-4 (DPP-4) inhibitors are administered as monotherapy and in combination therapy for the treatment of T2DM. The aim of this article was to provide a thorough review of published tolerability data on 5 DPP-4 inhibitors. PubMed and Web of Science were searched for English-language clinical trials published from January 2000 to June 2001, using the following key words: dipeptidyl peptidase-4 inhibitor, vildagliptin, alogliptin, sitagliptin, saxagliptin, linagliptin, safety, tolerability, efficacy, effect, AE, and adverse effect. Studies were considered for inclusion if they were randomized, double-blind trials performed in patients ≥18 years of age with T2DM and with a hemoglobin A(1c) of ≥6.5%; included ≥1 arm that received monotherapy with DPP-4; and reported adverse events (AEs). Studies in patients with a history of type 1 or secondary forms of diabetes, significant diabetic complications or cardiovascular disease within the 6 months before the start of the study, hepatic disease or abnormalities, and/or renal abnormalities were excluded. A total of 45 clinical trials, 5 pharmacokinetic studies, and 28 meta-analyses or reviews were included. The duration of studies ranged from 7 days to 104 weeks. The most commonly reported AEs were nasopharyngitis, upper respiratory infections, all-cause infections, headache, gastrointestinal symptoms, and musculoskeletal pain. Based on the findings from the studies, the DPP-4 inhibitors had minimal impact on weight and were not associated with an increased risk for hypoglycemia relative to placebo. Rates of nasopharyngitis were higher with the DDP-4 inhibitors than with placebo. Pancreatitis was reported at lower rates with the DPP-4 inhibitors compared with other oral antihyperglycemic agents. Cardiovascular events were limited, and postmarketing studies are ongoing. The tolerability of DPP-4 inhibitors is supported by published clinical trials. The rates of weight gain, gastrointestinal AEs, and hypoglycemia were minimal with the DPP-4 inhibitors studied.


Characterization of insertions affecting the expression of the bacterio-opsin gene in Halobacterium halobium.
We have determined the sequence of the inverted repeats and duplicated target DNA of the halobacterial insertion elements ISH2 (520 bp), ISH23 (900 bp) and ISH24 (3000 bp) associated with bacterio-opsin (bop) mutants. ISH2 has a perfect 19 bp inverted repeat (3,5), while both ISH23 and ISH24 have imperfect inverted repeats of 29 bp and 14 bp respectively. ISH23 was shown to be highly homologous to ISH50 (6). Variable lengths of duplicated target DNA are found when ISH2 and ISH23 (ISH50) transpose into different sites. A 550 bp DNA insert ("ISH25") reverts the Bop mutation caused by ISH24. "ISH25" lacks typical structural features of a transposable element. "ISH25" and ISH24 are found adjacent to each other upstream of the bop gene. An identical arrangement of "ISH25" and ISH24 is found in the cccDNA of H. halobium NRC817. Comparative sequence analysis of both areas suggests that the translocation of "ISH25" to the bop gene region occurred by a recombination event.


Association of Surgeon Age and Experience With Congenital Heart Surgery Outcomes.
Surgeon experience concerns both families of children with congenital heart disease and medical providers. Relationships between surgeon seniority and patient outcomes are often assumed, yet there are little data. This national study used linked data from the American Medical Association Physician Masterfile and the Society of Thoracic Surgeons-Congenital Heart Surgery Database to examine associations between surgeon years since medical school and major morbidity/mortality for children undergoing cardiac surgery. Sensitivity analyses explored the effects of patient characteristics, institutional/surgeon volumes, and various measures of institutional surgeon team experience. In secondary analyses, major morbidity and mortality were examined as separate end points. We identified 206 congenital heart surgeons from 91 centers performing 62 851 index operations (2010-2014). Median time from school was 25 years (range 9-55 years). A major morbidity/mortality occurred in 11.5% of cases. In multivariable analyses, the odds of major morbidity/mortality were similar for early-career (<15 years from medical school, ≈<40 years old), midcareer (15-24 years, ≈40-50 years old), and senior surgeons (25-35 years, ≈50-60 years old). The odds of major morbidity/mortality were ≈25% higher for operations performed by very senior surgeons (35-55 years from school, ≈60-80 years old; n=9044 cases). Results were driven by differences in morbidity. In extensive sensitivity analyses, these effects remained constant. In this study of >200 congenital heart surgeons, we found patient outcomes for surgeons with the fewest years of experience to be comparable to those of their midcareer and senior colleagues, within the context of existing referral and support practices. Very senior surgeons had higher risk-adjusted odds of major morbidity/mortality. Contemporary approaches to training, referral, mentoring, surgical planning, and other support practices might contribute to the observed outcomes of junior congenital heart surgeons being comparable to those of more experienced colleagues. Understanding and disseminating these practices might benefit the medical community at large.


Psychological resilience after Hurricane Sandy: the influence of individual- and community-level factors on mental health after a large-scale natural disaster.
Several individual-level factors are known to promote psychological resilience in the aftermath of disasters. Far less is known about the role of community-level factors in shaping postdisaster mental health. The purpose of this study was to explore the influence of both individual- and community-level factors on resilience after Hurricane Sandy. A representative sample of household residents (N = 418) from 293 New York City census tracts that were most heavily affected by the storm completed telephone interviews approximately 13-16 months postdisaster. Multilevel multivariable models explored the independent and interactive contributions of individual- and community-level factors to posttraumatic stress and depression symptoms. At the individual-level, having experienced or witnessed any lifetime traumatic event was significantly associated with higher depression and posttraumatic stress, whereas demographic characteristics (e.g., older age, non-Hispanic Black race) and more disaster-related stressors were significantly associated with higher posttraumatic stress only. At the community-level, living in an area with higher social capital was significantly associated with higher posttraumatic stress. Additionally, higher community economic development was associated with lower risk of depression only among participants who did not experience any disaster-related stressors. These results provide evidence that individual- and community-level resources and exposure operate in tandem to shape postdisaster resilience.


One-to-one embedding between honeycomb mesh and Petersen-Torus networks.
As wireless mobile telecommunication bases organize their structure using a honeycomb-mesh algorithm, there are many studies about parallel processing algorithms like the honeycomb mesh in Wireless Sensor Networks. This paper aims to study the Peterson-Torus graph algorithm in regard to the continuity with honeycomb-mesh algorithm in order to apply the algorithm to sensor networks. Once a new interconnection network is designed, parallel algorithms are developed with huge research costs to use such networks. If the old network is embedded in a newly designed network, a developed algorithm in the old network is reusable in a newly designed network. Petersen-Torus has been designed recently, and the honeycomb mesh has already been designed as a well-known interconnection network. In this paper, we propose a one-to-one embedding algorithm for the honeycomb mesh (HMn) in the Petersen-Torus PT(n,n), and prove that dilation of the algorithm is 5, congestion is 2, and expansion is 5/3. The proposed one-to-one embedding is applied so that processor throughput can be minimized when the honeycomb mesh algorithm runs in the Petersen-Torus.


Is exercise effective for the management of subacromial impingement syndrome and other soft tissue injuries of the shoulder? A systematic review by the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration.
Exercise is a key component of rehabilitation for soft tissue injuries of the shoulder; however its effectiveness remains unclear. Determine the effectiveness of exercise for shoulder pain. We searched seven databases from 1990 to 2015 for randomized controlled trials (RCTs), cohort and case control studies comparing exercise to other interventions for shoulder pain. We critically appraised eligible studies using the Scottish Intercollegiate Guidelines Network (SIGN) criteria. We synthesized findings from scientifically admissible studies using best-evidence synthesis methodology. We retrieved 4853 articles. Eleven RCTs were appraised and five had a low risk of bias. Four studies addressed subacromial impingement syndrome. One study addressed nonspecific shoulder pain. For variable duration subacromial impingement syndrome: 1) supervised strengthening leads to greater short-term improvement in pain and disability over wait listing; and 2) supervised and home-based strengthening and stretching leads to greater short-term improvement in pain and disability compared to no treatment. For persistent subacromial impingement syndrome: 1) supervised and home-based strengthening leads to similar outcomes as surgery; and 2) home-based heavy load eccentric training does not add benefits to home-based rotator cuff strengthening and physiotherapy. For variable duration low-grade nonspecific shoulder pain, supervised strengthening and stretching leads to similar short-term outcomes as corticosteroid injections or multimodal care. The evidence suggests that supervised and home-based progressive shoulder strengthening and stretching are effective for the management of subacromial impingement syndrome. For low-grade nonspecific shoulder pain, supervised strengthening and stretching are equally effective to corticosteroid injections or multimodal care. CRD42013003928.


Terahertz photoconductive antenna with metal nanoislands.
This work presents a nanoplasmonic photoconductive antenna (PCA) with metal nanoislands for enhancing terahertz (THz) pulse emission. The whole photoconductive area was fully covered with metal nanoislands by using thermal dewetting of thin metal film at relatively low temperature. The metal nanoislands serve as plasmonic nanoantennas to locally enhance the electric field of an ultrashort pulsed pump beam for higher photocarrier generation. The plasmon resonance of metal nanoislands was achieved at an excitation laser wavelength by changing the initial thickness of metal film. This nanoplasmonic PCA shows two times higher enhancement for THz pulse emission power than a conventional PCA. This work opens up a new opportunity for plasmon enhanced large-aperture THz photoconductive antennas.


Optimization of probe-laser focal offsets for single-particle tracking.
In optical tweezers applications, tracking a trapped particle is essential for force measurement. One of the most popular techniques for single-particle tracking is achieved by analyzing the forward and backward light pattern, scattered by the target particle trapped by a trap laser beam, of an additional probe-laser beam with different wavelength whose focus is slightly apart from the trapping center. However, the optimized focal offset has never been discussed. In this paper, we investigate the tracking range and sensitivity as a function of the focal offset between the trapping and the probe-laser beams. As a result, the optimized focal offsets are a 3.3-fold radius ahead and a 2.0-fold radius behind the trapping laser focus in the forward tracking and the backward tracking, respectively. The experimental result agrees well with a theoretical prediction using the Mie scattering theory.


Increased sensitivity of the neuronal nicotinic receptor alpha 2 subunit causes familial epilepsy with nocturnal wandering and ictal fear.
Sleep has traditionally been recognized as a precipitating factor for some forms of epilepsy, although differential diagnosis between some seizure types and parasomnias may be difficult. Autosomal dominant frontal lobe epilepsy is characterized by nocturnal seizures with hyperkinetic automatisms and poorly organized stereotyped movements and has been associated with mutations of the alpha 4 and beta 2 subunits of the neuronal nicotinic acetylcholine receptor. We performed a clinical and molecular genetic study of a large pedigree segregating sleep-related epilepsy in which seizures are associated with fear sensation, tongue movements, and nocturnal wandering, closely resembling nightmares and sleep walking. We identified a new genetic locus for familial sleep-related focal epilepsy on chromosome 8p12.3-8q12.3. By sequencing the positional candidate neuronal cholinergic receptor alpha 2 subunit gene (CHRNA2), we detected a heterozygous missense mutation, I279N, in the first transmembrane domain that is crucial for receptor function. Whole-cell recordings of transiently transfected HEK293 cells expressing either the mutant or the wild-type receptor showed that the new CHRNA2 mutation markedly increases the receptor sensitivity to acetylcholine, therefore indicating that the nicotinic alpha 2 subunit alteration is the underlying cause. CHRNA2 is the third neuronal cholinergic receptor gene to be associated with familial sleep-related epilepsies. Compared with the CHRNA4 and CHRNB2 mutations reported elsewhere, CHRNA2 mutations cause a more complex and finalized ictal behavior.


Deep brain stimulation of the medial septum or nucleus accumbens alleviates psychosis-relevant behavior in ketamine-treated rats.
Deep brain stimulation (DBS) has been shown to be effective for relief of Parkinson's disease, depression and obsessive-compulsive disorder in humans, but the effect of DBS on psychosis is largely unknown. In previous studies, we showed that inactivation of the medial septum or nucleus accumbens normalized the hyperactive and psychosis-related behaviors induced by psychoactive drugs. We hypothesized that DBS of the medial septum or nucleus accumbens normalizes the ketamine-induced abnormal behaviors and brain activity in freely moving rats. Male Long-Evans rats were subcutaneously injected with ketamine (3 mg/kg) alone, or given ketamine and DBS, or injected with saline alone. Subcutaneous injection of ketamine resulted in loss of gating of hippocampal auditory evoked potentials (AEPs), deficit in prepulse inhibition (PPI) and hyperlocomotion, accompanied by increased hippocampal gamma oscillations of 70-100 Hz. Continuous 130-Hz stimulation of the nucleus accumbens, or 100-Hz burst stimulation of the medial septum (1s on and 5s off) significantly attenuated ketamine-induced PPI deficit and hyperlocomotion. Medial septal stimulation also prevented the loss of gating of hippocampal AEPs and the increase in hippocampal gamma waves induced by ketamine. Neither septal or accumbens DBS alone without ketamine injection affected spontaneous locomotion or PPI. The results suggest that DBS of the medial septum or nucleus accumbens may be an effective method to alleviate psychiatric symptoms of schizophrenia. The effect of medial septal DBS in suppressing both hippocampal gamma oscillations and abnormal behaviors induced by ketamine suggests that hippocampal gamma oscillations are a correlate of disrupted behaviors.


Short-lived intermediates in aspartate aminotransferase systems.
The kinetics of the reaction of aspartate aminotransferase with erythro-beta-hydroxy-aspartate, in which rapid mixing is followed (upon reaching a suitable stationary state) by a very fast temperature jump, is numerically simulated. Values for rate constants are used to the extent known, otherwise estimated. It is shown that reaction steps not resolvable by rapid mixing can be resolved by subsequent chemical relaxation. Since several absorption spectra of enzyme complexes overlap, use of a pH-indicator is investigated. When the pH-indicator is coupled to the protonic dissociation of free enzyme, the fast steps are easily detected in the chemical relaxation portion of the simulation. When the pH-indicator is coupled to the protonic dissociation of the (short-lived) quinoid intermediate, protonic dissociation is easily detectable in the stopped flow phase and in the chemical relaxation phase. Such transient protonic dissociation has not been detected experimentally, but is predicted by the simulation. When natural substrates are used, the magnitude of the rate constants makes it unlikely that transient proton dissociation can be detected by stopped flow alone, but a combination of stopped flow with very fast temperature perturbation allows detection of the transient proton through use of a suitable nonbinding pH-indicator. This is demonstrated by simulation for a specific case. Finally, an alternate mechanism is introduced and distinction of its kinetics from that of the original mechanism is demonstrated.


Localized complement activation in the development of protective immunity against Ostertagia ostertagi infections in cattle.
The abomasal nematode Ostertagia ostertagi is a major causal agent contributing to production inefficiencies in the cattle industry in temperate regions of the world. Protective immunity to infections develops very slowly and resistance to reinfection manifests only after prolonged exposure. Mechanisms underlying the development of protective immunity remain largely unexplored. Immune animals, which have significantly reduced worm burdens, were developed after multiple drug-attenuated experimental infections and were compared to a primary infected group and their respective uninfected controls. In this study, transcriptomic analysis identified three signaling pathways significantly impacted during both primary and repeat infections, the complement system, leukocyte extravasation and acute phase responses. Increased mRNA levels of complement components C3, factor B (CFB) and factor I (CFI) in the abomasal mucosa of the infected cattle were confirmed using quantitative PCR while Western blot analysis established the presence of elevated levels of activated C3 proteins in the mucosa. One of the initiators of local complement activation could be related to secretory IgA and IgM because infections significantly up-regulated expression of J chain (IGJ), as well as polymeric Ig receptor (PIGR) and an IgM-specific receptor (FAIM3), suggesting sustained increases in both synthesis and transepithelial transport of IgA and IgM during the infection. The elevated levels of pro-inflammatory cytokines, such as IL-4 and IL-1β, during infection may be involved in gene regulation of complement components. Our results suggest enhanced tissue repair and mucin secretion in immune animals may also contribute to protective immunity. These results are the first evidence that local complement activation may be involved in the development of long-term protective immunity and provide a novel mechanistic insight into resistance against O. ostertagi in cattle.


Factors influencing the fate of antibiotic resistance genes during thermochemical pretreatment and anaerobic digestion of pharmaceutical waste sludge.
The prevalence of antibiotic resistance genes (ARGs) in waste sludge, especially for the pharmaceutical waste sludge, presents great potential risks to human health. Although ARGs and factors affecting their spreading are of major importance for human health, the factors influencing the fate of ARGs during sludge treatment, especially for pharmaceutical sludge treatment are not yet well understood. In order to be able to minimize ARGs spreading, it is important to find what is influencing their spreading. Therefore, certain factors, such as the sludge characteristics, bacterial diversity and community composition, and mobile genetic elements (MGEs) during the advanced AD of pharmaceutical sludge with different pretreatments were studied, and their affinity with ARGs was elucidated by Spearman correlation analysis. Furthermore, multiple linear regression was introduced to evaluate the importance of the various factors. Results showed that 59.7%-88.3% of the variations in individual ARGs and total ARGs can be explained by the corresponding factors. Bacterial diversity rather than specific bacterial community composition affected the fate of ARGs, whereas alkalinity was the most important factor on ARGs among all sludge characteristics investigated in this study. Besides, 66.4% of variation of total ARGs was driven by the changes of MGEs. Multiple linear regression models also reveal the collective effect of these factors on ARGs, and the contributions of each factor impact on ARGs. This study provides more comprehension about the factors impact on the fate of ARGs during pharmaceutical sludge treatment, and offers an approach to evaluate the importance of each factor, which method could be introduced for evaluation of factors influencing ARGs during other types of sludge or wastewater treatment.


Coping response and survival in breast cancer patients: a new analysis.
The purpose of this study was to analyse the impact of coping response on survival of breast cancer by using a new method of assessing coping. Adjustment to cancer was assessed using a revised measure in a large cohort of breast cancer patients (N = 578) followed up over a period of 10 years. Impact of coping response measured early in the disease process (<4 months from primary diagnosis of early-stage breast cancer) was assessed, and survival analyses were undertaken including known clinical staging data and cancer treatment details. After 5 years of follow-up from primary diagnosis, the effect of prior 'negative adjustment' was statistically significantly linked to increased risk of death and relapse of breast cancer, and for the 10-year analysis, this result remained for both risk of death and relapse. There was no statistically significant effect on survival of the novel 'positive adjustment' response. Coping with cancer was assessed using a new methodology and is linked to an adverse impact of negative adjustment on overall survival. Positive adjustment was unrelated to survival. The current study strengthens previous evidence that there is a link between survival and coping response. The question remains of how coping response might affect physical outcome. It is considered that coping response likely impacts survival through the mediating effects on lifestyle and health behaviour that may contribute to an adverse prognosis.


Rock climbing injury rates and associated risk factors in a general climbing population.
The objective was to examine injury rates and associated risk factors in a representative sample of climbers. A random sample (n=606) of the Swedish Climbing Association members was sent a postal survey, with an effective response rate of 63%. Self-reported data regarding climbing history, safety practices and retrospective accounts of injury events (recall period 1.5 years) were obtained. Descriptive statistical methods were used to calculate injury incidences, and a two-step method including zero-inflated Poisson's regression analysis of re-injuries was used to determine the combination of risk factors that best explained individual injury rates. Overall, 4.2 injuries per 1000 climbing hours were reported, overuse injuries accounting for 93% of all injuries. Inflammatory tissue damages to fingers and wrists were the most common injury types. The multivariate analysis showed that overweight and practicing bouldering generally implied an increased primary injury risk, while there was a higher re-injury risk among male climbers and a lower risk among the older climbers. The high percentage of overuse injuries implies that climbing hours and loads should be gradually and systematically increased, and climbers regularly controlled for signs and symptoms of overuse. Further study of the association between body mass index and climbing injury is warranted.


primerJinn - a tool for rationally designing multiplex PCR primer sets and in silico PCR.
Multiplex PCR amplifies numerous targets in a single tube reaction and is essential in molecular biology and clinical diagnostics. One of its most important applications is in the targeted sequencing of pathogens. Despite this importance, few tools are available for designing multiplex primers. We developed primerJinn, a tool that designs a set of multiplex primers and allows for the in silico PCR evaluation of primer sets against numerous input genomes. We used primerJinn to create a multiplex PCR for the sequencing of drug resistance-conferring gene regions from Mycobacterium tuberculosis, which were then successfully sequenced. primerJinn provides a user-friendly, efficient, and accurate method for designing multiplex PCR primers and performing in silico PCR. It can be used for various applications in molecular biology and bioinformatics research, including the design of assays for amplifying and sequencing drug-resistance-conferring regions in important pathogens.


Propensity for obtaining alcohol through shoulder tapping.
Underage youth often obtain alcohol from adults who illegally provide the alcohol. One method for obtaining alcohol from adults is shoulder tapping, where youth approach an adult outside an alcohol establishment and ask the adult to purchase alcohol for them. The goal of this study was to assess what percentage of the general and youth-targeted adult population approached outside of a convenience/liquor store will agree to purchase and then provide alcohol to individuals who appear under age 21. We conducted 2 waves of pseudo-underage shoulder tap request attempts, using requesters who were age 21 or older but appeared 18 to 20 years old. In both waves, requests were conducted at randomly selected liquor and convenience stores, requesters explained that the reason they were asking the adult was because they did not have their identification with them, and requesters asked the adults to purchase a 6-pack of beer. During wave 1, we conducted 102 attempts, with the requester approaching the first adult entering the store alone. During wave 2, we conducted 102 attempts where the requester approached the first casually dressed male entering the store alone who appeared to be 21 to 30 years old. During wave 1, 8% of the general sample of approached adults provided alcohol to the pseudo-underage requesters. The odds of adults providing alcohol in urban areas were 9.4 times greater than in suburban areas. During wave 2, 19% of the approached young men provided alcohol to the requesters. No requester, request attempt, establishment, or community characteristics were associated with request attempt outcomes during wave 2. A small percentage of the general population of adults will agree to provide alcohol to underage youth when approached outside an alcohol establishment. The likelihood of underage youth obtaining alcohol through shoulder tapping increases substantially if the youth approach young men.


Shifts in the Oral Microbiota During a Four-Week Commercial Saturation Dive to 200 Meters.
During commercial saturation diving, divers live and work under hyperbaric and hyperoxic conditions. The myriads of bacteria that live in and on the human body must adjust to the resultant hyperbaric stress. In this study, we examined the shifts in bacterial content in the oral cavity of saturation divers, using a metagenomic approach to determine the diversity in the composition of bacterial phyla and genera in saliva from 23 male divers before, during, and immediately after 4 weeks of commercial heliox saturation diving to a working depth of circa 200 m. We found that the bacterial diversity fell during saturation, and there was a change in bacterial composition; with a decrease at the phylum level of obligate anaerobe Fusobacteria, and an increase of the relative abundance of Actinobacteria and Proteobacteria. At the genus level, Fusobacterium, Leptotrichia, Oribacterium, and Veillonella decreased, whereas Neisseria and Rothia increased. However, at the end of the decompression, both the diversity and composition of the microbiota returned to pre-dive values. The results indicate that the hyperoxic conditions during saturation may suppress the activity of anaerobes, leaving a niche for other bacteria to fill. The transient nature of the change could imply that hyperbaric heliox saturation has no lasting effect on the oral microbiota, but it is unknown whether or how a shift in oral bacterial diversity and abundance during saturation might impact the divers' health or well-being.


Serum CA19-9 is significantly upregulated up to 2 years before diagnosis with pancreatic cancer: implications for early disease detection.
Biomarkers for the early detection of pancreatic cancer are urgently needed. The primary objective of this study was to evaluate whether increased levels of serum CA19-9, CA125, CEACAM1, and REG3A are present before clinical presentation of pancreatic cancer and to assess the performance of combined markers for early detection and prognosis. This nested case-control study within the UKCTOCS included 118 single and 143 serial serum samples from 154 postmenopausal women who were subsequently diagnosed with pancreatic cancer and 304 matched noncancer controls. Samples were split randomly into independent training and test sets. CA19-9, CA125, CEACAM1, and REG3A were measured using ELISA and/or CLIA. Performance of markers to detect cancers at different times before diagnosis and for prognosis was evaluated. At 95% specificity, CA19-9 (>37 U/mL) had a sensitivity of 68% up to 1 year, and 53% up to 2 years before diagnosis. Combining CA19-9 and CA125 improved sensitivity as CA125 was elevated (>30 U/mL) in approximately 20% of CA19-9-negative cases. CEACAM1 and REG3A were late markers adding little in combined models. Average lead times of 20 to 23 months were estimated for test-positive cases. Prediagnostic levels of CA19-9 and CA125 were associated with poor overall survival (HR, 2.69 and 3.15, respectively). CA19-9 and CA125 have encouraging sensitivity for detecting preclinical pancreatic cancer, and both markers can be used as prognostic tools. This work challenges the prevailing view that CA19-9 is upregulated late in the course of pancreatic cancer development.


Body shrinkage due to Arctic warming reduces red knot fitness in tropical wintering range.
Reductions in body size are increasingly being identified as a response to climate warming. Here we present evidence for a case of such body shrinkage, potentially due to malnutrition in early life. We show that an avian long-distance migrant (red knot, Calidris canutus canutus), which is experiencing globally unrivaled warming rates at its high-Arctic breeding grounds, produces smaller offspring with shorter bills during summers with early snowmelt. This has consequences half a world away at their tropical wintering grounds, where shorter-billed individuals have reduced survival rates. This is associated with these molluscivores eating fewer deeply buried bivalve prey and more shallowly buried seagrass rhizomes. We suggest that seasonal migrants can experience reduced fitness at one end of their range as a result of a changing climate at the other end.


Distinguishing the Clinical Nurse Specialist From Other Graduate Nursing Roles.
Today's healthcare environment poses diverse and complex patient care challenges and requires a highly qualified and experienced nursing workforce. To mitigate these challenges are graduate nursing roles, each with a different set of competencies and expertise. With the availability of many different graduate nursing roles, both patients and healthcare professionals can be confused in understanding the benefit of each role. To gain the maximum benefit from each role, it is important that healthcare providers and administrators are able to distinguish the uniqueness of each role to best use the role and develop strategies for effective collaboration and interprofessional interaction. The purpose of this article was to define the role, educational preparation, role differences, and practice competencies for the clinical nurse specialist (CNS), nurse practitioner, clinical nurse leader, and nurse educator/staff development educator roles. A second purpose was to provide role clarity and demonstrate the unique value the CNS brings to the healthcare environment. Using evidence and reviewing role competencies established by varying organizations, each role is presented with similarities and differences among the roles discussed. In addition, collaboration among the identified roles was reviewed, and recommendations were provided for the new and practicing CNSs. Although there are some similarities among the graduate nursing roles such as in educational, licensing, and certification requirements, each role must be understood to gain the full role scope and benefit and glean the anticipated outcomes. Healthcare providers must be aware of the differences in graduate nursing roles, especially in comparing the CNS with other roles to avoid confusion that may lead to roles being underused with a limited job scope. The CNS provides a unique set of services at all system outcome levels and is an essential part of the healthcare team especially in the acute care setting.


Weight-loss strategies used by baby boomer men: a mixed methods approach.
Baby Boomer men (those born in 1946-1964) are becoming obese at an earlier age compared to previous generations. The present study aimed to identify weight-loss strategies used by Baby Boomer men, to determine whether those strategies varied by weight status and to explore their dieting experiences. The study used a cross-sectional survey of 211 men and 20 in-depth interviews. Men had a mean (SD) body mass index (BMI) of 29.35 (5.07) kg m(-2), with 82% being overweight or obese. Fifty-six percent were currently trying to lose weight. Healthy weight-loss strategies included reducing portions, increasing physical activity, cutting back on fried foods, cutting back on sweets, cutting back on alcohol, using meal replacement drinks/bars and joining a weight-loss programme. Unhealthy strategies included skipping meals and using over-the-counter 'diet pills'. Men who reduced portions, skipped meals, cut back on sweets, joined a weight-loss programme and used diet pills had significantly higher BMIs than men who said they did not (P < 0.05 for all). Interviews revealed that older men struggle to lose weight, 'I've been struggling for the last 2-3 years'. 'The last time I really tried to lose weight I stayed on the diet for just a day or two'. Wives were considered essential to their weight management success. Men used a do-it-yourself weight-loss approach using both healthy and unhealthy strategies. Obese men were more likely to use unhealthy practices than overweight men.


Second language acquisition effects of a primary physical education intervention: A pilot study with young refugees.
A physical education (PE) intervention for young refugees was designed combining physical activity within the context of primary PE games with second language learning activities in German. The intervention was based on theoretical implications from the field of second language acquisition and evidence for positive effects of physical activity on cognitive outcomes (e.g. language acquisition). The aim of this study was to analyze short term effects on second language acquisition. Sixty-one young refugees were included in the study (age: 8.5 ± 1.4 years). The intervention group participated in language-enriched PE lessons based on an elaborated approach to second language learning acquisition. The control group did not receive any treatment. Both groups were pre-and post-tested in domain specific vocabulary, listening comprehension and use of local prepositions within the context of primary PE games. Results from linear mixed-effect modelling suggest that the intervention group significantly improved domain specific vocabulary and listening comprehension in comparison to the control group. The intervention was successful since the PE lessons contributed to the second language acquisition of young refugees. Therefore, this learning approach might also be useful for physical activity based second language learning activities in other PE contexts for early second language learners in primary school.


Age related effects of transitional floor surfaces and obstruction of view on gait characteristics related to slips and falls.
A laboratory study was conducted to examine gait changes between younger and older subjects as they walked across different floor surfaces. Twenty subjects participated in the experiment (five each of older and younger males and females). For half of the trials, subjects carried light loads that blocked their view of the floor surface immediately in front of them. Subjects walked on slippery (soapy water on vinyl) and stable (outdoor carpet) floor surfaces, as well as transitioning from one surface to another. Responses studied included: required coefficient of friction (RCOF), stride length (SL), and minimum toe clearance (MTC). Significant effects were found for the floor surface, load versus no load condition, and some interactions involving age (older versus younger subjects). Not all expected differences due to age were found in this experiment. The lack of significant differences between younger and older subjects could be due to the older subjects that participated in the experiment. They were volunteers at a local medical center, were in good physical shape, and were probably not typical of the population of people over 65 years of age. RELEVANCE TO INDUSTRY: Slips and falls in industry are costly safety issues in terms of human suffering as well as financial compensation. In many facilities and at home, people make transitions from one floor surface to another many times each day, while carrying loads or just walking. A better understanding of characteristics of people as they walk on slippery floor surfaces and the changes that might occur with age, will allow engineers to design better floor surfaces to reduce the incidence of slips and falls.


Denoising and 4D visualization of OCT images.
We are using Optical Coherence Tomography (OCT) to image structure and function of the developing embryonic heart in avian models. Fast OCT imaging produces very large 3D (2D + time) and 4D (3D volumes + time) data sets, which greatly challenge ones ability to visualize results. Noise in OCT images poses additional challenges. We created an algorithm with a quick, data set specific optimization for reduction of both shot and speckle noise and applied it to 3D visualization and image segmentation in OCT. When compared to baseline algorithms (median, Wiener, orthogonal wavelet, basic non-orthogonal wavelet), a panel of experts judged the new algorithm to give much improved volume renderings concerning both noise and 3D visualization. Specifically, the algorithm provided a better visualization of the myocardial and endocardial surfaces, and the interaction of the embryonic heart tube with surrounding tissue. Quantitative evaluation using an image quality figure of merit also indicated superiority of th new algorithm. Noise reduction aided semi-automatic 2D image segmentation, as quantitatively evaluated using a contour distance measure with respect to an expert segmented contour. In conclusion, the noise reduction algorithm should be quite useful for visualization and quantitative measurements (e.g., heart volume, stroke volume, contraction velocity, etc.) in OCT embryo images. With its semi-automatic, data set specific optimization, we believe that the algorithm can be applied to OCT images from other applications.


Living without eosinophils: evidence from mouse and man.
The enduring view of eosinophils, as immune effector cells whose primary function is host defence against infection by helminths and other microbial pathogens, sets the stage for a fundamental question regarding the safety of therapeutic eosinophil depletion. If eosinophils are significantly reduced or altogether depleted in an effort to alleviate the negative effects of tissue eosinophilia and eosinophilic inflammation in conditions such as asthma, COPD, chronic rhinosinusitis with nasal polyps, eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome, would these patients become susceptible to infection or another illness? Development of mouse models in which the eosinophil lineage has been ablated, observations in patients naturally lacking eosinophils and data from studies of eosinophil-depleting medical therapies indicate that the absence of eosinophils is not detrimental to health. The evidence available to date, as presented in this review, supports the conclusion that even if certain homeostatic roles for the eosinophil may be demonstrable in controlled animal models and human in vitro settings, the evolution of the human species appears to have provided sufficient immune redundancy such that one may be hale and hearty without eosinophils.


A retrospective study investigating the rate of HER2 discordance between primary breast carcinoma and locoregional or metastatic disease.
Overall survival of HER2 positive metastatic breast cancer patients has been significantly improved with inclusion of trastuzumab to chemotherapy. Several studies have demonstrated discordant HER2 status in the primary and metastatic tumour. However, rates of discordance vary considerably in published reports. Information collected prospectively was analysed for all patients seen from 1999 to 2009 with primary breast cancer and who had biopsy of a local or distant recurrence. Patients were included if adequate tissue was available from both paired samples. Recurrent samples included fine needle aspirations, core and excisional biopsies. HER2 status in all paired samples was assessed by in-situ hybridisation by a single pathologist in a national reference laboratory. This was compared with HER2 immunohistochemistry results provided in the course of routine diagnosis at regional laboratories. In total, 157 patients with recurrent (n = 137; 87.3%) or synchronous primary and metastatic (n = 20; 12.7%) breast cancer had biopsy of the metastatic site. The study population comprised of 116 patients with adequate tissue in both primary and metastasis. The concordance between HER2 status of the paired samples by local immunohistochemistry testing and central in-situ hybridization were 78% and 99%, respectively. Only one patient demonstrated HER2 discordance--primary lesion was positive whilst a metastatic site was negative. This single institution study demonstrated a low rate of HER2 discordance between primary and recurrent breast cancer as assessed by in-situ hybridisation. This contrasts to results reported by others, which may be explained by differences in study methodology, definition of recurrent disease samples and generally small numbers of patients assessed. Despite the current findings, the decision to obtain metastatic tissue for evaluation is influenced by other factors. These include disease-free interval, which may raise the possibility of a new malignancy and the accuracy of initial HER2 assessment of the primary tumour.


Hatha yoga for depression: critical review of the evidence for efficacy, plausible mechanisms of action, and directions for future research.
The purpose of this article is to review the evidence for the efficacy of hatha yoga for depression and possible mechanisms by which yoga may have an impact on depression, and to outline directions for future research. Literature review and synthesis. A literature search for clinical trials examining yoga for depression uncovered eight trials: 5 including individuals with clinical depression, and 3 for individuals with elevated depression symptoms. Although results from these trials are encouraging, they should be viewed as very preliminary because the trials, as a group, suffered from substantial methodological limitations. We would argue, however, that there are several reasons to consider constructing careful research on yoga for depression. First, current strategies for treating depression are not sufficient for many individuals, and patients have several concerns about existing treatments. Yoga may be an attractive alternative to or a good way to augment current depression treatment strategies. Second, aspects of yoga-including mindfulness promotion and exercise-are thought to be "active ingredients" of other successful treatments for depression. Third, there are plausible biological, psychological, and behavioral mechanisms by which yoga may have an impact on depression. We provide suggestions for the next steps in the study of yoga as a treatment for depression.


XAS studies of Ni and Zn sorbed to hydrous manganese oxide.
Adsorption mechanisms of Zn2+ and Ni2+ on hydrous manganese oxide (HMO) were investigated using XAS. Analyses reveal that both metal ions retain their primary hydration shell when sorbed to HMO, which is consistent with physical sorption. These local structures are invariant of pH (3.0-7.0) and adsorbate loading (10(-4) - 10(-2) mol (g of HMO)-1), suggesting one average type of adsorption mechanism. In addition to the first shell, a second shell was observed with 6-8 O atoms at 3.34 A for Ni and 8-10 O atoms at 3.49 A for Zn. The lack of Ni or Zn contributions in the second shell eliminates the possibility of surface precipitation or polymerization. Likewise, the absence of Mn atoms in the second shell suggests outer-sphere adsorption. Interestingly, the local structure of Ni and Zn sorbed to HMO did not change with reaction time when as much as 90% of the sorbed contribution was due to the slow sorption process, thus supporting intraparticle diffusion as the rate-limiting mechanism. This result demonstrates that adsorption sites located along the micropore walls of HMO are similar to ones located on the external surface. Overall, metals from the same group in the Periodic Table appear to form similar adsorption complexes with HMO.


Development of self-adhesive pulp-capping agents containing a novel hydrophilic and highly polymerizable acrylamide monomer.
Several studies have shown the clinical success of hydraulic calcium-silicate cements (hCSCs) for direct and indirect pulp capping and root repair. However, hCSCs have various drawbacks, including long setting time, poor mechanical properties, low bond strength to dentin, and relatively poor handling characteristics. To overcome these limitations, a light-curable, resin-based hCSC (Theracal LC, Bisco) was commercially introduced; however, it did not exhibit much improvement in bond strength. We developed a light-curable self-adhesive pulp-capping material that contains the novel acrylamide monomer N,N'-{[(2-acrylamido-2-[(3-acrylamidopropoxy)methyl]propane-1,3-diyl)bis(oxy)]bis(propane-1,3-diyl)}diacrylamide (FAM-401) and the functional monomer 4-methacryloxyethyl trimellitate anhydride (4-MET). Two experimental resin-based hCSCs containing different calcium sources (portlandite: Exp_Pl; tricalcium silicate cement: Exp_TCS) were prepared, and the commercial hCSCs Theracal LC and resin-free hCSC Biodentine served as controls. The performance of each cement was evaluated based on parameters relevant for vital pulp therapy, such as curing degree on a wet surface, mechanical strength, as determined using a three-point bending test, shear bond strength to dentin, cytotoxicity, as determined using an MTT assay, and the amount of calcium released, as determined using inductively coupled plasma atomic emission spectrometry. Both experimental cements cured on wet surfaces and showed relatively low cytotoxicity. Furthermore, their flexural and shear bond strength to dentin were significantly higher than those of the commercial references. High calcium release was observed for both Exp_Pl and Biodentine. Thus, Exp_Pl as a new self-adhesive pulp-capping agent performed better than the commercial resin-based pulp-capping agent in terms of mechanical strength, bond strength, and calcium release.


Trigeminal neuralgia associated with Chiari 1 malformation: symptom resolution following craniocervical decompression and duroplasty: Case report and review of the literature.
Trigeminal neuralgia (TN) may rarely be the presenting or only symptom of Chiari 1 malformation (CM). Isolated case reports have described resolution of TN following craniocervical decompression where TN is present in association with CM. This report discusses an unusual case of pure TN associated with CM that was successfully treated with craniocervical decompression and duroplasty and reviews the limited literature on the subject. TN may be the sole presenting symptom of CM and can be successfully managed with craniocervical decompression. Clinicians should be aware of the association of TN with CM and consider surgical management.


Surgical Management of a Persistent Stapedial Artery: A Review.
To evaluate the outcome and per- and postoperative complications of the surgical management of patients with a persistent stapedial artery (PSA). A systemic literature search for reports on patients treated for pulsatile tinnitus and/or conductive hearing loss caused by a PSA was conducted of the PubMed and Embase databases using the terms "stapedial" and "artery." Inclusion criteria were adequate description of the intervention and pre- and postoperative signs and symptoms. In addition, one case of a PSA, treated at VU University Medical Center Amsterdam, The Netherlands, was included in this series. Middle ear surgery consisting of stapedotomy or stapedectomy, and/or transection of the PSA. Pre- and postoperative hearing levels, pre- and postoperative pulsatile tinnitus, and per- and postoperative complications. Seventeen patients and 18 operated ears were evaluated (16 patients described in 14 articles and our case). Twelve out of 14 ears in which a stapedotomy or stapedectomy was initiated experienced improvement in hearing. In four cases pulsatile tinnitus was described pre- and postoperatively. In all four, pulsatile tinnitus subsided after transection of the PSA. Peroperative bleeding from the PSA was described in four patients, which could be controlled during the procedure. No significant postoperative sequelae were reported. In case of a PSA, improvement of conductive hearing loss is best achieved by stapes surgery, while pulsatile tinnitus is effectively treated with transection of the PSA. To date no long-term postoperative complications have been reported.


Health-Related Quality of Life in an Inception Cohort of Children With Juvenile Idiopathic Arthritis: A Longitudinal Analysis.
To describe changes in health-related quality of life (HRQoL) over time in children with juvenile idiopathic arthritis (JIA), relative to other outcomes, and to identify predictors of unfavorable HRQoL trajectories. Children with JIA in the Research in Arthritis in Canadian Children emphasizing Outcomes (ReACCh-Out) cohort were included. The Juvenile Arthritis Quality of Life Questionnaire (JAQQ, a standardized instrument), health-related Quality of My Life (HRQoML, an instrument based on personal valuations), and JIA core variables were completed serially. Analyses included median values, Kaplan-Meier survival curves, and latent trajectory analysis. A total of 1,249 patients enrolled at a median of 0.5 months after diagnosis were followed for a median of 34.2 months. The degree of initial HRQoL impairment and probabilities of reaching the best possible HRQoL scores varied across JIA categories (best for oligoarthritis, worst for rheumatoid factor-positive polyarthritis). Median times to attain best possible HRQoL scores (JAQQ 59.3 months, HRQoML 34.5 months), lagged behind those for disease activity, pain, and disability measures. Most patients followed trajectories with minimal or mild impairment; however, 7.6% and 13.8% of patients, respectively, followed JAQQ and HRQoML trajectories with persistent major impairment in HRQoL. JIA category, aboriginal ethnicity, and baseline disease activity measures distinguished between membership in trajectories with major and minimal impairments. Improvement in HRQoL is slower than for disease activity, pain, and disability. Improvement of a measure based on respondents' preferences (HRQoML) is more rapid than that of a standardized measure (JAQQ). Higher disease activity at diagnosis heralds an unfavorable HRQoL trajectory.


Aryl hydrocarbon receptor ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin enhances liver damage in bile duct-ligated mice.
The environmental pollutant 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD) is known to cause a wide variety of toxic effects, including hepatotoxicity, by way of the aryl hydrocarbon receptor (AHR). Although inducible expression of cytochrome P450 (CYP) 1A1 and CYP1A2 is associated with liver injury caused by high-dose TCDD, the specific role of the AHR-CYP1 cascade in hepatotoxicity remains unclear. We investigated the effects of AHR activation under conditions of cholestasis. We administered oral TCDD to mice at a dose that can effectively induce Cyp1 gene expression without overt liver toxicity and then ligated their bile ducts. TCDD pretreatment enhanced bile duct ligation (BDL)-induced increases in liver and plasma bile acids, bilirubin, and aminotransferases. Histology of TCDD-pretreated BDL mice revealed massive hepatic necrosis without any increase in number of apoptotic cells. Whereas induction of AHR-target genes by TCDD was observed similarly in sham-operated as well as in BDL mice, TCDD pretreatment of BDL mice altered the expression of hepatic genes involved in bile acid synthesis and transport. Increased plasma proinflammatory cytokines, tumor necrosis factor and interleukin-1β, in BDL mice were further elevated by TCDD pretreatment. Liver injury by TCDD plus BDL, such as increased plasma bile acids, bilirubin and aminotransferases, liver necrosis, and increased tumor necrosis factor production, was exaggerated in Cyp1a1/1a2(-/-) double knockout mice. These findings indicate that TCDD aggravates cholestatic liver damage and that the presence of CYP1A1 and CYP1A2 plays a protective role in liver damage caused by TCDD and BDL.


Generation and characterization of the PKC gamma-Cre mouse line.
PKCgamma is a protein kinase C (PKC) isoform that is expressed in the central nervous system (CNS). We generated a PKCgamma-Cre mouse line and characterized the expression and activity of the Cre protein. Our studies show that Cre expression largely recapitulates the endogenous expression of PKCgamma. Several major sites of Cre expression are the cerebral cortex, hippocampus, thalamus, amygdala, and spinal cord. Examination of PKCgamma-Cre/ROSA26 mice reveals a similar X-gal staining pattern in the CNS, indicating that Cre recombinase is capable of removing LoxP sites in vivo. These data indicate that the PKCgamma-Cre mouse line could be a useful reagent for generating Cre-mediated tissue-specific knockouts in the CNS.


An unusual cause of falls in a young woman.
Nitrous oxide is commonly used as an analgesic and anaesthetic agent. Nitrous oxide is also in use in industry as an aerosol propellant and is now recognised as a recreational drug whose use is growing, especially among the young. Nitrous oxide from whipped cream canisters is inhaled to produce a dissociative, intoxicated state. Nitrous oxide is known to inactivate vitamin B12 via oxidation, which can precipitate a demyelinating myelopathy akin to the classical B12 deficiency syndrome, subacute combined degeneration of the spinal cord. This case describes a young woman with chronic pain and a poor nutritional state who took regular nitrous oxide as an opiate-sparing agent. She developed a progressive subacute myelopathy with a sensory level, profoundly impaired joint position sense, extensor plantars and required a wheelchair. Once diagnosed, she responded well to a regime of nitrous oxide withdrawal, high-dose B12 replacement and physiotherapy. The case illustrates the need for clinical teams to be able to dentify a nitrous oxide-precipitated myelopathy as its use as a drug of abuse increases; particularly in the case of malnourished patients who receive nitrous oxide surgically or obstetrically.


Association of Low Fasting Glucose and HbA1c With Cardiovascular Disease and Mortality: The MESA Study.
Trials of intensive glucose control have not improved cardiovascular disease (CVD) risk in populations with type 2 diabetes; however, in the general population, reports are inconsistent about the effects of maintaining lower glucose levels. Some speculate that low glycemic values are associated with increased glycemic variability, which is in turn associated with higher CVD risk. It has also been suggested that fasting glucose and hemoglobin A1c (HbA1c) in the lower ranges have a different relationship with CVD and mortality. In 4990 participants from the Multi-Ethnic Study of Atherosclerosis, we used logistic regression to investigate associations of low fasting glucose (<80 mg/dL) and HbA1c (<5.0%) from baseline and averaged across follow-up with incident CVD and mortality over 13 years. We used normal glycemic ranges (80 to <100 mg/dL and 5.0 to <5.7%) as references and analyzed glycemic levels with visit-matched covariates. We adjusted for potential confounding by age, sex, race/ethnicity, education, income, smoking status, body mass index, total cholesterol level, cholesterol medications, high-density lipoprotein cholesterol, and hypertension. Low baseline glucose and HbA1c were positively, but not significantly, associated with mortality, whereas low average fasting glucose and HbA1c were strongly and significantly associated with incident CVD [glucose OR, 2.04 (95% CI, 1.38-3.00); HbA1c OR, 2.01 (95% CI, 1.58-2.55)] and mortality [glucose OR, 1.93 (95% CI, 1.33-2.79); HbA1c OR, 2.51 (95% CI, 2.00-3.15)]. These results were not due to type 2 diabetes or medication use. Glucose variability did not explain CVD risk beyond average glucose levels. Chronic low fasting glucose and HbA1c may be better indicators of risk than a single low measurement.


Two Opsin 3-Related Proteins in the Chicken Retina and Brain: A TMT-Type Opsin 3 Is a Blue-Light Sensor in Retinal Horizontal Cells, Hypothalamus, and Cerebellum.
Opsin family genes encode G protein-coupled seven-transmembrane proteins that bind a retinaldehyde chromophore in photoreception. Here, we sought potential as yet undescribed avian retinal photoreceptors, focusing on Opsin 3 homologs in the chicken. We found two Opsin 3-related genes in the chicken genome: one corresponding to encephalopsin/panopsin (Opn3) in mammals, and the other belonging to the teleost multiple tissue opsin (TMT) 2 group. Bioluminescence imaging and G protein activation assays demonstrated that the chicken TMT opsin (cTMT) functions as a blue light sensor when forced-expressed in mammalian cultured cells. We did not detect evidence of light sensitivity for the chicken Opn3 (cOpn3). In situ hybridization demonstrated expression of cTMT in subsets of differentiating cells in the inner retina and, as development progressed, predominant localization to retinal horizontal cells (HCs). Immunohistochemistry (IHC) revealed cTMT in HCs as well as in small numbers of cells in the ganglion and inner nuclear layers of the post-hatch chicken retina. In contrast, cOpn3-IR cells were found in distinct subsets of cells in the inner nuclear layer. cTMT-IR cells were also found in subsets of cells in the hypothalamus. Finally, we found differential distribution of cOpn3 and cTMT proteins in specific cells of the cerebellum. The present results suggest that a novel TMT-type opsin 3 may function as a photoreceptor in the chicken retina and brain.


Single-element laser beam shaper for uniform flat-top profiles.
A novel design method is presented for a simple laser beam shaper. Unlike earlier reports and designs based on the 2-element model, we prove it is possible to convert a laser beam from a non-uniform profile to a uniform flat-top distribution with one single aspherical lens.


Abnormal proinsulin levels in thyroid dysfunction measured by a sensitive proinsulin immunochemiluminoassay.
Abnormalities of carbohydrate metabolism in hyperthyroid patients have been long noted. Elevated proinsulin level is considered as an early marker of B-cell impairment. Proinsulin levels in hyperthyroid patients decreased after antithyroid drug therapy. However, proinsulin in hypothyroid patients was only rarely reported, and the difference was only demonstrated after glucose stimulation-there was a greater response of proinsulin secretion after thyroxine therapy-and the basal fasting proinsulin level was not different after therapy. One of the reasons might be that the assay was not sensitive enough to detect the change of basal proinsulin levels in patients with hypothyroidism after therapy. A newly developed immunochemiluminometric assay of proinsulin was used to demonstrate that the suppressed proinsulin level increased after thyroxine therapy in hypothyroid patients (4.2 +/- 2.4 vs. 10.0 +/- 5.6 pmol/L, p < 0.05; n = 7). On the other hand, our study also confirmed that the proinsulin levels decreased in hyperthyroid patients after antithyroid therapy by methimazole (27.8 +/- 26.0 vs. 15.8 +/- 15.7 pmol/L, p < 0.05; n = 12). In conclusion, proinsulin increased in hypothyroid patients after thyroxine therapy and decreased in hyperthyroid patients after methimazole therapy. The results demonstrated there is a high correlation between thyroid function and B-cell function in hypothyroid as well as hyperthyroid patients.