Mechanisms underlying age- and performance-related differences in working memory.
This study took advantage of the subsecond temporal resolution of ERPs to investigate mechanisms underlying age- and performance-related differences in working memory. Young and old subjects participated in a verbal n-back task with three levels of difficulty. Each group was divided into high and low performers based on accuracy under the 2-back condition. Both old subjects and low-performing young subjects exhibited impairments in preliminary mismatch/match detection operations (indexed by the anterior N2 component). This may have undermined the quality of information available for the subsequent decision-making process (indexed by the P3 component), necessitating the appropriation of more resources. Additional anterior and right hemisphere activity was recruited by old subjects. Neural efficiency and the capacity to allocate more resources to decision-making differed between high and low performers in both age groups. Under low demand conditions, high performers executed the task utilizing fewer resources than low performers (indexed by the P3 amplitude). As task requirements increased, high-performing young and old subjects were able to appropriate additional resources to decision-making, whereas their low-performing counterparts allocated fewer resources. Higher task demands increased utilization of processing capacity for operations other than decision-making (e.g., sustained attention) that depend upon a shared pool of limited resources. As demands increased, all groups allocated additional resources to the process of sustaining attention (indexed by the posterior slow wave). Demands appeared to have exceeded capacity in low performers, leading to a reduction of resources available to the decision-making process, which likely contributed to a decline in performance.


Ventricular pressure-area loop characteristics in the stage 16 to 24 chick embryo.
The accurate description of embryonic cardiovascular function requires the adaption of standard measurement techniques to the small scale of the developing heart. In the mature heart, the analysis of ventricular pressure and volume accurately defines function. Because in vivo measures of volume are not feasible in the embryonic heart, we tested the hypothesis that ventricular pressure-area loops accurately define ventricular function in the stage 16 to stage 24 white Leghorn chick embryo. We simultaneously measured ventricular pressure with a servo-null pressure system and recorded video images at 60 Hz. The pressure waveform was superimposed onto the video image in real time. Video fields were planimetered for epicardial ventricular cross-sectional area and ventricular pressure. Pressure and area data were smoothed using a fast Fourier transform filter and plotted. Data are reported as mean +/- SEM, n greater than or equal to 4, and were tested by regression analysis and analysis of variance (p less than 0.05). Heart rate increased from 90 +/- 7 beats/min at stage 16 to 130 +/- 13 beats/min at stage 24. All pressure-area loops displayed diastolic filling, isometric contraction, ejection, and isometric relaxation, similar to pressure-volume loops of the mature heart. Isometric contraction time increased from 42 +/- 5 to 62 +/- 4 msec (p less than 0.05), while isometric relaxation time was 124 +/- 12 and 120 +/- 10 msec (p greater than 0.05) between stages 16 and 24, respectively. The maximum ratio of instantaneous ventricular pressure to area identified end systole better than peak ventricular pressure or minimum ventricular area. Thus, pressure-area relations define ventricular function in the embryonic chick heart.


Computational fluid dynamic simulations for determination of ventricular workload in aortic arch obstructions.
The cardiac workload associated with various types of aortic obstruction was determined using computational fluid dynamic simulations. Computed tomography image data were collected from 4 patients with 4 distinct types of aortic arch obstructions and 4 controls. The categorization of arch hypoplasia corresponded to the "A, B, C" nomenclature of arch interruption; a type "D" was added to represent diffuse arch hypoplasia. Measurements of the vessel diameter were compared against the normal measurements to determine the degree of narrowing. Three-dimensional models were created for each patient, and additional models were created for type A and B hypoplasia to represent 25%, 50%, and 75% diameter narrowing. The boundary conditions for the computational simulations were chosen to achieve realistic flow and pressures in the control cases. The simulations were then repeated after changing the boundary conditions to represent a range of cardiac and vascular adaptations. The resulting cardiac workload was compared with the control cases. Of the 4 patients investigated, 1 had aortic coarctation and 3 had aortic hypoplasia. The cardiac workload of the patients with 25% narrowing type A and B hypoplasia was not appreciably different from that of the control. When comparing the different arch obstructions, 75% type A, 50% type B, and 50% type D hypoplasia required a greater workload increase than 75% coarctation. The present study has determined the hemodynamic significance of aortic arch obstruction using computational simulations to calculate the cardiac workload. These results suggest that all types of hypoplasia pose more of a workload challenge than coarctation with an equivalent degree of narrowing.


SNCA Gene, but Not MAPT, Influences Onset Age of Parkinson's Disease in Chinese and Australians.
α-Synuclein (SNCA) and microtubule-associated protein tau (MAPT) are the two major genes independently, but not jointly, associated with susceptibility for Parkinson's disease (PD). The SNCA gene has recently been identified as a major modifier of age of PD onset. Whether MAPT gene synergistically influences age of onset of PD is unknown. Objective. To investigate independent and joint effects of MAPT and SNCA on PD onset age. 412 patients with PD were recruited from the Australian PD Research Network (123) and the Neurology Department, Ruijin Hospital Affiliated to Shanghai Jiaotong University, China (289). MAPT (rs17650901) tagging H1/H2 haplotype and SNCA (Rep1) were genotyped in the Australian cohort, and MAPT (rs242557, rs3744456) and SNCA (rs11931074, rs894278) were genotyped in the Chinese cohort. SPSS regression analysis was used to test genetic effects on age at onset of PD in each cohort. SNCA polymorphisms associated with the onset age of PD in both populations. MAPT polymorphisms did not enhance such association in either entire cohort. This study suggests that, in both ethnic groups, SNCA gene variants influence the age at onset of PD and α-synuclein plays a key role in the disease course of PD.


Quaternary structure of the yeast Arc1p-aminoacyl-tRNA synthetase complex in solution and its compaction upon binding of tRNAs.
In the yeast Saccharomyces cerevisiae, the aminoacyl-tRNA synthetases (aaRS) GluRS and MetRS form a complex with the auxiliary protein cofactor Arc1p. The latter binds the N-terminal domains of both synthetases increasing their affinity for the transfer-RNA (tRNA) substrates tRNA(Met) and tRNA(Glu). Until now, structural information was available only on the enzymatic domains of the individual aaRSs but not on their complexes with associated cofactors. We have analysed the yeast Arc1p-complexes in solution by small-angle X-ray scattering (SAXS). The ternary complex of MetRS and GluRS with Arc1p, displays a peculiar extended star-like shape, implying possible flexibility of the complex. We reconstituted in vitro a pentameric complex and demonstrated by electrophoretic mobility shift assay that the complex is active and contains tRNA(Met) and tRNA(Glu), in addition to the three protein partners. SAXS reveals that binding of the tRNAs leads to a dramatic compaction of the pentameric complex compared to the ternary one. A hybrid low-resolution model of the pentameric complex is constructed rationalizing the compaction effect by the interactions of negatively charged tRNA backbones with the positively charged tRNA-binding domains of the synthetases.


Distinct Size and Distribution Patterns of the Sand-sifting Sea Star, Archaster typicus, in an Urbanised Marine Environment.
Yong Kit Samuel Chan, Tai Chong Toh, and Danwei Huang (2018) Archaster typicus is a microphagous sea star ubiquitous throughout sandy shoals of the Indo-Pacific. Along highly urbanised coasts, loss of sandy habitats through land reclamation and degradation of adjacent mangrove forests and seagrass meadows, which serve as nurseries for A. typicus, could lead to local extinction of this species. To determine the population status of A. typicus in Singapore, we performed belt-transect surveys at three modified shores, then compared size structure, clustering patterns and ontogenetic shifts within the Central Indo-Pacific region. We found that A. typicus individuals were, among other things, larger in Singapore (79.2 ± 14.2 mm) than the rest of the Central Indo-Pacific region with further differences amongst Singapore's sites. Sea stars of this species were also greatly clustered in smaller areas within the transects, with most transects presenting small Nearest Neighbour Index values of < 1. While ontogenetic shifts were noted in previous studies, no juveniles have been recorded in the nursery habitats of mangroves and seagrasses, with limited size and mating seasonalities. Although A. typicus appears to have grown in size considerably on reclaimed beaches in Singapore, the lack of any apparent ontogenetic connectivity here may threaten the sea star populations in the near future, particularly in the context of growing coastal development in Southeast Asia.


The Park is Ruining our Livelihoods. We Support the Park! Unravelling the Paradox of Attitudes to Protected Areas.
Despite considerable field-based innovation and academic scrutiny, the nexus between conservation approaches, local support for parks and park effectiveness remains quite puzzling. Common approaches to understanding notions of environmental justice are to understand distributional and procedural issues, representation in decision making, and recognition of authorities and claims. We took a different approach and analysed environmental justice claims through institutional, ideational and psychological lenses. We sought to understand how the national park could have such broad support from local communities despite their acknowledgement that it severely curtailed their livelihoods. We conducted 100 household interviews in three villages that border Nam Et-Phou Louey National Protected Area. Our study found that villagers 1) hold on to broken promises by the State for agricultural activities and alternative revenues without fully changing forest use behaviours; 2) were influenced heavily by the 'educational' programmes by the State; 3) accepted the authority of the State and lack of participation in decision-making based on historical experiences and values; 4) justified their burdens by over-emphasising the positive aspects of the park. Our findings present a complementary framework to explain environmental justice claims, allowing for a nuanced analysis of how people respond to justices and injustices, and specifically how injustices can be identified through proven social science concepts.


Glucose metabolism dysregulation at the onset of mental illness is not limited to first episode psychosis: A systematic review and meta-analysis.
To compare the differences of glucose metabolism outcomes between treatment-naïve, patients with first episode psychosis (FEP) and mood disorders. We conducted a systematic review and meta-analysis of glucose intolerance in treatment-naïve, first episode patients with severe mental illnesses (SMIs). We identified 31 eligible studies. Compared to healthy controls, FEP group have higher insulin and insulin resistance levels, and both groups have higher glucose tolerance test results. No significant differences were found in glucose metabolism outcomes between FEP and mood disorder groups. Our results highlight impaired glucose metabolism at the onset of SMIs, suggesting both patients with psychosis and mood disorders are high-risk groups for diabetes development.


Study design for a comprehensive assessment of biologic safety using multiple healthcare data systems.
Although biologic treatments have excellent efficacy for many autoimmune diseases, safety concerns persist. Understanding the absolute and comparative risks of adverse events in patient and disease subpopulations is critical for optimal prescribing of biologics. The Safety Assessment of Biologic Therapy collaborative was federally funded to provide robust estimates of rates and relative risks of adverse events among biologics users using data from national Medicaid and Medicare plus Medicaid dual-eligible programs, Tennessee Medicaid, Kaiser Permanente, and state pharmaceutical assistance programs supplementing New Jersey and Pennsylvania Medicare programs. This report describes the organizational structure of the collaborative and the study population and methods. This retrospective cohort study (1998-2007) examined risks of seven classes of adverse events in relation to biologic treatments prescribed for seven autoimmune diseases. Propensity scores were used to control for confounding and enabled pooling of individual-level data across data systems while concealing personal health information. Cox proportional hazard modeling was used to analyze study hypotheses. The cohort was composed of 159,000 subjects with rheumatic diseases, 33,000 with psoriasis, and 46,000 with inflammatory bowel disease. This report summarizes demographic characteristics and drug exposures. Separate reports will provide outcome definitions and estimated hazard ratios for adverse events. This comprehensive research will improve understanding of the safety of these treatments. The methods described may be useful to others planning similar evaluations.


Post-ritual Circumcision Bleeding-Characteristics and Treatment Outcome.
To report the characteristics, treatment, and short-term outcome of neonatal post-circumcision bleeding, and to identify predictors of surgical treatment. The medical records of 90 consecutive neonates who presented to the emergency room with post-circumcision bleeding between 2009 and 2014 were reviewed. Circumcisions were performed using the traditional Mogen shield device. The study end point was surgical intervention for hemostasis. Predictors of surgical treatment were evaluated. An estimated total of 28,383 circumcisions were performed during the study period; thus, the post-circumcision bleeding rate was 0.32%. Initial treatment included compressive dressing in 15 infants (17%) and hemostatic dressing in 47 infants (52%); 28 infants (31%) did not require treatment upon arrival to the emergency room. Two infants (2%) received blood transfusion. Surgical treatment was required in 11 infants (12%); 10 of 43 infants (23%) with active bleeding on arrival to the emergency room required surgery compared to 1 of 47 infants (2%) without active bleeding (P = .003). Similarly, 3 of 7 infants (43%) referred from other hospitals required surgery compared to 8 of 83 infants (10%) referred from the community (P = .037). Abnormal blood tests at presentation were not associated with surgical treatment. At 1 month of follow-up, 2 infants were admitted for recurrent bleeding. Coagulation abnormalities were found in 4 infants. Surgical treatment was required in 12% of infants presenting to the emergency room with post-circumcision bleeding. The rate of surgical intervention was significantly higher in infants with active bleeding at presentation and in those referred from other hospitals. Physicians should consider admitting infants presenting with active post-circumcision bleeding, whereas infants without active bleeding may be observed and discharged.


Matrix stiffness regulation of integrin-mediated mechanotransduction during osteogenic differentiation of human mesenchymal stem cells.
Mesenchymal stem cells (MSCs) cultured on extracellular matrices with different stiffness have been shown to possess diverse lineage commitment owing to the extracellular mechanical stimuli sensed by the cells. The aim of this study was to further delineate how matrix stiffness affects intracellular signaling through the mechanotransducers Rho kinase (ROCK) and focal adhesion kinase (FAK) and subsequently regulates the osteogenic phenotype of MSCs. MSCs were cultured in osteogenic medium on tunable polyacrylamide hydrogels coated with type I collagen with elasticities corresponding to Young's modulus of 7.0 ± 1.2 and 42.1 ± 3.2 kPa. Osteogenic differentiation was increased on stiffer matrices, as evident by type I collagen, osteocalcin, and Runx2 gene expressions and alizarin red S staining for mineralization. Western blot analysis demonstrated an increase in kinase activities of ROCK, FAK, and ERK1/2 on stiffer matrices. Inhibition of FAK, an important mediator of osteogenic differentiation, and inhibition of ROCK, a known mechanotransducer of matrix stiffness during osteogenesis, resulted in decreased expression of osteogenic markers during osteogenic induction. In addition, FAK affects osteogenic differentiation through ERK1/2, whereas ROCK regulates both FAK and ERK1/2. Furthermore, α(2)-integrin was upregulated on stiffer matrices during osteogenic induction, and its knockdown by siRNA downregulated the osteogenic phenotype through ROCK, FAK, and ERK1/2. Taken together, our results provide evidence that the matrix rigidity affects the osteogenic outcome of MSCs through mechanotransduction events that are mediated by α(2)-integrin.


Life events and borderline personality features: the influence of gene-environment interaction and gene-environment correlation.
Traumatic life events are generally more common in patients with borderline personality disorder (BPD) than in non-patients or patients with other personality disorders. This study investigates whether exposure to life events moderates the genetic architecture of BPD features. As the presence of genotype-environment correlation (rGE) can lead to spurious findings of genotype-environment interaction (G × E), we also test whether BPD features increase the likelihood of exposure to life events. The extent to which an individual is at risk to develop BPD was assessed with the Personality Assessment Inventory - Borderline features scale (PAI-BOR). Life events under study were a divorce/break-up, traffic accident, violent assault, sexual assault, robbery and job loss. Data were available for 5083 twins and 1285 non-twin siblings. Gene-environment interaction and correlation were assessed by using structural equation modelling (SEM) and the co-twin control design. There was evidence for both gene-environment interaction and correlation. Additive genetic influences on BPD features interacted with the exposure to sexual assault, with genetic variance being lower in exposed individuals. In individuals who had experienced a divorce/break-up, violent assault, sexual assault or job loss, environmental variance for BPD features was higher, leading to a lower heritability of BPD features in exposed individuals. Gene-environment correlation was present for some life events. The genes that influence BPD features thus also increased the likelihood of being exposed to certain life events. To our knowledge, this study is the first to test the joint effect of genetic and environmental influences and the exposure to life events on BPD features in the general population. Our results indicate the importance of both genetic vulnerability and life events.


Scanning ultrasound removes amyloid-β and restores memory in an Alzheimer's disease mouse model.
Amyloid-β (Aβ) peptide has been implicated in the pathogenesis of Alzheimer's disease (AD). We present a nonpharmacological approach for removing Aβ and restoring memory function in a mouse model of AD in which Aβ is deposited in the brain. We used repeated scanning ultrasound (SUS) treatments of the mouse brain to remove Aβ, without the need for any additional therapeutic agent such as anti-Aβ antibody. Spinning disk confocal microscopy and high-resolution three-dimensional reconstruction revealed extensive internalization of Aβ into the lysosomes of activated microglia in mouse brains subjected to SUS, with no concomitant increase observed in the number of microglia. Plaque burden was reduced in SUS-treated AD mice compared to sham-treated animals, and cleared plaques were observed in 75% of SUS-treated mice. Treated AD mice also displayed improved performance on three memory tasks: the Y-maze, the novel object recognition test, and the active place avoidance task. Our findings suggest that repeated SUS is useful for removing Aβ in the mouse brain without causing overt damage, and should be explored further as a noninvasive method with therapeutic potential in AD.


The Seattle children's bicycle helmet campaign: changes in helmet use and head injury admissions.
To describe the impact of a community bicycle helmet campaign on helmet use and the incidence of bicycle-related head injuries. Metropolitan community and a large health maintenance organization. Communitywide bicycle helmet campaign. Rate of observed bicycle helmet use in the community and incidence of bicycle-related injuries in an health maintenance organization population. Helmet use among school-aged children increased from 5.5% in 1987 to 40.2% in 1992. Bicycle-related head injuries decreased by 66.6% in 5- to 9-year-old and 67.6% in 10- to 14-year-old members of an health maintenance organization. Educational campaigns can increase helmet use and decrease the incidence of bicycle-related head injury.


Channeling vorticity: modeling the filter-feeding mechanism in silver carp using μCT and 3D PIV.
Invasive silver carp are thriving within eutrophic environments in the United States, in part because of their highly efficient filter-feeding mechanism. Silver carp utilize modified gill rakers to capture a specific range of food; however, their greatly modified filtering morphology allows them to feed on phytoplankton and zooplankton ranging in size from 4 to 85 µm. The filtering apparatus of silver carp comprises rigid filtering plates where the outer anatomy of these plates is characterized by long parallel channels that change in orientation along the length of the plate. Here, we investigate the underlying morphology and concomitant hydrodynamics that support the filtration mechanisms of silver and bighead carp. Bighead carp are also invasive filter feeders, but their filtering apparatus is morphologically distinct from that of silver carp. Using 3D particle image velocimetry, we determined how particles and fluid interact with the surface of the gill rakers/plates. Filtering plates in silver carp induce strong directed vortical flow, whereas the filtering apparatus of bighead carp resulted in a type of haphazard cross-flow filtration. The organized vortical flow established by silver carp likely increased the number of interactions that the particle-filled water had with the filtering membrane. This strong vortical organization is maintained only at 0.75 body lengths s-1, and vortical flow is poorly developed and maintained at slower and faster speeds. Moreover, we found that absolute vorticity magnitude in silver carp is an order of magnitude greater than in bighead carp.


Identification of a functional hotspot on ubiquitin required for stimulation of methyltransferase activity on chromatin.
Ubiquitylation of histone H2B at lysine 120 (H2B-Ub) plays a critical role in transcriptional elongation, chromatin conformation, as well as the regulation of specific histone H3 methylations. Herein, we report a strategy for the site-specific chemical attachment of ubiquitin to preassembled nucleosomes. This allowed expedited structure-activity studies into how H2B-Ub regulates H3K79 methylation by the methyltransferase human Dot1. Through an alanine scan of the ubiquitin surface, we identified a functional hotspot on ubiquitin that is required for the stimulation of human Dot1 in vitro. Importantly, this result was validated in chromatin from isolated nuclei by using a synthetic biology strategy that allowed selective incorporation of the hotspot-deficient ubiquitin mutant into H2B. The ubiquitin hotspot additionally impacted the regulation of ySet1-mediated H3K4 methylation but was not required for H2B-Ub-induced impairment of chromatin fiber compaction. These data demonstrate the utility of applying chemical ligation technologies to preassembled chromatin and delineate the multifunctionality of ubiquitin as a histone posttranslational modification.


Effect of incubation temperature on the diagnostic sensitivity of the glanders complement fixation test.
The complement fixation test (CFT) is the only serological test prescribed by the World Organisation for Animal Health (OIE) for the diagnosis of glanders in international trading of equids. However, false-positive reactions have caused financial losses to the animal owners in the past, and false-negative tests have resulted in the introduction of glanders into healthy equine populations in previously glanders-free areas. Both warm (incubation at 37°C for 1 h) and cold (overnight incubation at 4°C) procedures are recommended by the OIE for serodiagnosis of glanders. In a comparison of the sensitivity and specificity of the two techniques, using the United States Department of Agriculture antigen, warm CFT was found to be significantly less sensitive (56.8%; p < 0.0005) than the cold CFT (83.6%). Cold CFT thus increases the detection rate of glanders but a lower diagnostic specificity has to be accepted. The immunoblot was used as the gold standard.


Advances in the Biofabrication of 3D Skin in vitro: Healthy and Pathological Models.
The relevance for in vitro three-dimensional (3D) tissue culture of skin has been present for almost a century. From using skin biopsies in organ culture, to vascularized organotypic full-thickness reconstructed human skin equivalents, in vitro tissue regeneration of 3D skin has reached a golden era. However, the reconstruction of 3D skin still has room to grow and develop. The need for reproducible methodology, physiological structures and tissue architecture, and perfusable vasculature are only recently becoming a reality, though the addition of more complex structures such as glands and tactile corpuscles require advanced technologies. In this review, we will discuss the current methodology for biofabrication of 3D skin models and highlight the advantages and disadvantages of the existing systems as well as emphasize how new techniques can aid in the production of a truly physiologically relevant skin construct for preclinical innovation.


Impact of end-user search training on pharmacy students: a four-year follow-up study.
The Alfred Taubman Medical Library at the University of Michigan has offered instruction in online literature searching to third-year pharmacy students as a component of the course "Drug Information and Scientific Literature Evaluation" since 1983. In the spring of 1989, a follow-up study was conducted to assess the impact of instruction on four classes of graduates. Of a pool of 151 graduates, 90 (60%) responded to a mailed questionnaire on their use of information and computerized literature searching. The respondents were divided into four subgroups: end-user searchers, users of intermediaries, end users who used intermediaries, and those who did not use computerized literature search systems. Seventy-two percent of the respondents used some type of computerized literature searching, and 42% performed their own searches. The four subgroups differed in general computer use, familiarity with MEDLINE search terminology, information use, reasons for using or not using literature searching, and characteristics of searches (i.e., type, time frame, amount, and frequency). Training in end-user search systems appears to have had an impact on the continued use of computerized literature searching several years after the formal educational program.


Role of PTEN in Oxidative Stress and DNA Damage in the Liver of Whole-Body Pten Haplodeficient Mice.
Type 2 diabetes (T2DM) and obesity are frequently associated with non-alcoholic fatty liver disease (NAFLD) and with an elevated cancer incidence. The molecular mechanisms of carcinogenesis in this context are only partially understood. High blood insulin levels are typical in early T2DM and excessive insulin can cause elevated reactive oxygen species (ROS) production and genomic instability. ROS are important for various cellular functions in signaling and host defense. However, elevated ROS formation is thought to be involved in cancer induction. In the molecular events from insulin receptor binding to genomic damage, some signaling steps have been identified, pointing at the PI3K/AKT pathway. For further elucidation Phosphatase and Tensin homolog (Pten), a tumour suppressor phosphatase that plays a role in insulin signaling by negative regulation of PI3K/AKT and its downstream targets, was investigated here. Dihydroethidium (DHE) staining was used to detect ROS formation in immortalized human hepatocytes. Comet assay and micronucleus test were performed to investigate genomic damage in vitro. In liver samples, DHE staining and western blot detection of HSP70 and HO-1 were performed to evaluate oxidative stress response. DNA double strand breaks (DSBs) were detected by immunohistostaining. Inhibition of PTEN with the pharmacologic inhibitor VO-OHpic resulted in increased ROS production and genomic damage in a liver cell line. Knockdown of Pten in a mouse model yielded increased oxidative stress levels, detected by ROS levels and expression of the two stress-proteins HSP70 and HO-1 and elevated genomic damage in the liver, which was significant in mice fed with a high fat diet. We conclude that PTEN is involved in oxidative stress and genomic damage induction in vitro and that this may also explain the in vivo observations. This further supports the hypothesis that the PI3K/AKT pathway is responsible for damaging effects of high levels of insulin.


The relationship between anxiety, coping strategies and characteristics of patients with diabetes.
This study provided essential information, about Turkish patients with type I and type II diabetes, concerning: levels of anxiety, coping strategies used, and relationships that exist among anxiety, coping strategies, sociodemographic and medical characteristics. A sample comprising 161 Turkish adults with both types of diabetes participated in the study. The trait anxiety scale, the brief COPE, sociodemographic and medical questionnaire were administered to patients with diabetes. The mean age was 49.01 (SD = 9.74), with a range from 20 to 60 years. The majority of the participants were female (60.9%) and type II diabetes (75.8%). 79% of the participants experienced anxiety. A clear majority of the participants reported to integrate their diabetes. Acceptance, religion, planning, positive reframing, instrumental support, emotional support, self-distraction and venting were the most frequently used coping strategies. The most frequently used problem-focused and the emotion-focused coping strategies were found to be similar in both type I and type II diabetes. However, participants with type II diabetes had relatively higher scores on the problem-focused strategies than those with type I. Participants with type I diabetes used humour, venting and self-blame more than those with type II diabetes. Other findings indicated that only a small minority responded to diabetes-related problems by denial, behavioural disengagement and substance use. Significant correlations were found among anxiety, coping strategies and sociodemographic characteristics of the participants. Moreover, Self-blame was found to be correlated significantly with both the problem-focused and emotion-focused coping strategies. Self-blame was also significantly correlated with both instrumental support and emotional support indicated that higher self-blame caused more frequent use of instrumental and emotional support by patients with diabetes. The findings of this study indicate that care for patients with diabetes should address their physical, psychological, social and economic wellbeing and the findings point to the importance of taking individual coping strategies into account when evaluating the impact of diabetes on psychosocial wellbeing. Because of the mean of anxiety were not in normal range, for this study, health professionals need to pay attention to patient's psychological state. This is especially true for patients who are likely to use self-blame and behavioural disengagement as a coping strategy. Through psychosocial interventions, professionals need to assist patients in establishing positive self evaluations. Delineation of coping strategies might be useful for identifying patients in need of particular counselling and support.


A multilevel analysis of tobacco use and tobacco consumption levels in France: are there any combination risk groups?
Both the predictors for tobacco use and the determinants of the amounts of tobacco consumed by smokers should be taken into account when designing prevention programmes. Using a sample of 12,948 individuals representative of the French population in 1999, multilevel models were used to carry out a comparative investigation for the predictors of tobacco use and the determinants of the amount of tobacco consumed by smokers. At the individual level, a combination of risks (higher risk of smoking and larger amounts of tobacco consumed by smokers) was found for males, for individuals with a low level of education and for divorcees. At the level of the area of residence, both the risk of smoking (odds ratio 1.07, 95% confidence interval: 1.01-1.12 for an increase by one standard deviation) and the amount of tobacco consumed among smokers (percentage variation +4%, 95% confidence interval: 0% - +8%) increased with the gross domestic product per capita. This study justifies the combined use, in such analyses, of consumption levels for smokers in addition to the risk of smoking, in order to identify the profiles with the highest risk. It was possible to identify various groups with both a high risk of tobacco use and a high level of consumption among smokers, on the basis of individual (male, divorced or less educated) and environmental (living in a high GDP area) factors. The prevention efforts should thus be focused on such groups.


Fulminant myocarditis: Characteristics, treatment, and outcomes.
Myocarditis is an inflammatory disease of the myocardium with a broad spectrum of clinical presentations, ranging from mild symptoms to severe heart failure. The course of patients with myocarditis is heterogeneous, varying from partial or full clinical recovery in few days to advanced low cardiac output syndrome requiring mechanical circulatory support or heart transplantation. Fulminant myocarditis (FM) is a peculiar clinical condition and is an acute form of myocarditis, whose main characteristic is a rapidly progressive clinical course with the need for hemodynamic support. Despite the common medical belief of the past decades, recent comprehensive data, including a recent registry that compared FM with acute non-FM, highlighted that FM has a poor inhospital outcome, often requires advanced hemodynamic support, and may result in residual left ventricular dysfunction in survivors. This review aimed to provide an updated practical definition of FM, including essentials in the diagnosis and management of the disease. Finally, the outcome of FM was critically revised according to the current published registries focusing on the topic.


Do Oral Health Services in Medical Offices Replace Pediatric Dental Visits?
In the United States, state Medicaid programs pay for medical and dental care for children from low-income families and support nondental primary care providers delivering preventive oral health services (POHS) to young children in medical offices ("medical POHS"). Despite the potential of these policies to expand access to care, there is concern that they may replace dental visits with medical POHS. Using Medicaid claims from 38 states from 2006 to 2014, we conducted a repeated cross-sectional study and used linear probability regression to estimate the association between the annual proportion of children in a county receiving medical POHS and the probability that a child received 1) dental POHS and 2) a dental visit in a given year. Models included county and year fixed effects and controlled for child- and county-level factors, and standard errors were clustered at the state level. In a weighted population of 45.1 million child-years (age, 6 mo to <6 y), we found no significant nor substantively important association between the proportion of children in a county receiving medical POHS and the probability that a child received dental POHS or a dental visit. Additionally, we found an almost zero probability (<0.001) that the reduction in dental POHS was at least as large as the expansion in medical POHS (full substitution) and a 0.50 probability that increased medical POHS was associated with an increase in dental POHS of at least 6.6% of the expansion of medical POHS. Results were similar when receipt of dental visits was examined. This study failed to find evidence that medical POHS replaced dental visits for young children enrolled in Medicaid and, in fact, offers evidence that increased medical POHS was associated with increased utilization of dental care. Given lower-than-desired rates of dental visits for this population, delivery of medical POHS should be expanded.


Cost-effectiveness of oral appliances in the treatment of obstructive sleep apnoea-hypopnoea.
Oral appliances (OA) are commonly prescribed for the treatment of obstructive sleep apnoea-hypopnoea (OSAH), but there is limited evidence on their cost-effectiveness. A model was designed to simulate the costs and benefits of treatment of OSAH with OA or continuous positive airway pressure (CPAP) based on their effects on quality of life, motor vehicle crashes, and cardiovascular effects. The primary outcome was the incremental cost-effectiveness ratio (ICER) in terms of costs per one quality-adjusted life year (QALY) gained 5 years after treatment. Compared with no treatment, OA results in $268 higher costs and an incremental QALY of 0.0899 per patient (ICER = $2,984/QALY). Compared with OA, CPAP resulted in $1,917 more costs and 0.0696 additional QALYs (ICER = $27,540/QALY). For the most part in the sensitivity analyses, CPAP remained cost-effective compared to OA, and OA remained cost-effective with respect to no treatment in almost all scenarios. OAs are less economically attractive than CPAP but remain a cost-effective treatment for patients who are unwilling or unable to adhere to CPAP therapy.


Changes in amniotic fluid prostaglandins with oxytocin-induced labor.
Amniotic fluid prostaglandin levels were measured serially in 15 patients who underwent successful induction of labor and compared with those of patients presenting in spontaneous labor. At comparable cervical dilation the induced group demonstrated significantly lower prostaglandin levels. Four of these patients delivered without any increment in prostaglandins while in the remaining patients increases in prostaglandins followed the attainment of efficient uterine contractions by several hours. These data support the hypothesis that oxytocin acts directly on myometrial cells and not primarily by prior generation of prostaglandin synthesis in the membranes.


Identifying a distinctive familial frequency band in reaction time fluctuations in ADHD.
Patients with ADHD are typically more variable in their reaction times (RT) than control children. Signal processing analyses have shown that time series RT data of children with ADHD have a distinctive low frequency periodic structure suggestive of a pattern of occasional spontaneous performance lapses. Here we use a fine-grained analysis of spectral power across a broader frequency range to differentiate the periodic qualities of ADHD time series RT data from (a) 1/frequency noise, and (b) control performance. We also assess the familiality of these frequencies by using a proband-sibling design. Seventy-one children with ADHD, one of their siblings, and 50 control participants completed a simple RT task. Power across the RT frequency spectrum was calculated. The frequencies significantly differentiating the two groups were identified. Familiality was assessed in two ways: first, by comparing probands with their unaffected siblings and controls, and, second, by investigating the siblings of neuropsychologically impaired and unimpaired children with ADHD. Analyses converged to highlight the potential importance of the .20-.26 Hz band in differentiating the periodic structure of ADHD RT time series data from both 1/frequency noise and control performance. This frequency band also showed the strongest evidence of familiality. RT performance of children with ADHD had a distinctive periodic structure. The band identified as most differentiating and familial was at a higher frequency than in most previous reports. This highlights the importance of employing tasks with faster interstimulus intervals that will allow a larger portion of the frequency spectrum to be examined.


Challenges in microarray class discovery: a comprehensive examination of normalization, gene selection and clustering.
Cluster analysis, and in particular hierarchical clustering, is widely used to extract information from gene expression data. The aim is to discover new classes, or sub-classes, of either individuals or genes. Performing a cluster analysis commonly involve decisions on how to; handle missing values, standardize the data and select genes. In addition, pre-processing, involving various types of filtration and normalization procedures, can have an effect on the ability to discover biologically relevant classes. Here we consider cluster analysis in a broad sense and perform a comprehensive evaluation that covers several aspects of cluster analyses, including normalization. We evaluated 2780 cluster analysis methods on seven publicly available 2-channel microarray data sets with common reference designs. Each cluster analysis method differed in data normalization (5 normalizations were considered), missing value imputation (2), standardization of data (2), gene selection (19) or clustering method (11). The cluster analyses are evaluated using known classes, such as cancer types, and the adjusted Rand index. The performances of the different analyses vary between the data sets and it is difficult to give general recommendations. However, normalization, gene selection and clustering method are all variables that have a significant impact on the performance. In particular, gene selection is important and it is generally necessary to include a relatively large number of genes in order to get good performance. Selecting genes with high standard deviation or using principal component analysis are shown to be the preferred gene selection methods. Hierarchical clustering using Ward's method, k-means clustering and Mclust are the clustering methods considered in this paper that achieves the highest adjusted Rand. Normalization can have a significant positive impact on the ability to cluster individuals, and there are indications that background correction is preferable, in particular if the gene selection is successful. However, this is an area that needs to be studied further in order to draw any general conclusions. The choice of cluster analysis, and in particular gene selection, has a large impact on the ability to cluster individuals correctly based on expression profiles. Normalization has a positive effect, but the relative performance of different normalizations is an area that needs more research. In summary, although clustering, gene selection and normalization are considered standard methods in bioinformatics, our comprehensive analysis shows that selecting the right methods, and the right combinations of methods, is far from trivial and that much is still unexplored in what is considered to be the most basic analysis of genomic data.


Terahertz radiation from an InAs surface due to lateral photocurrent transients.
We report on terahertz (THz) emission from a (111)-cut InAs crystal in the reflection and transmission directions, excited by femtosecond optical pulses in the direction of its surface normal. THz pulse amplitudes emitted from the crystal surface in this case were only ~20% smaller than for optimal photoexcitation at a 45° angle. This observation evidences that THz emission from InAs is caused by lateral photocurrent transients appearing due to a crystal anisotropy rather than directly by the photo-Dember effect, which creates fast changing electric polarization perpendicular to the surface. Such a simple geometry of the photoexcitation could greatly enhance the fields of surface THz emitter applications.


Preclinical evaluation on the tumor suppression efficiency and combination drug effects of fermented wheat germ extract in human ovarian carcinoma cells.
Fermented wheat germ extract (FWGE) is a nutrient supplement and a potential antitumor ingredient for developing an integrated chemotherapy with standard chemotherapeutic drugs for treating ovarian cancer patients. In this study, we evaluated the tumor suppression efficiency of FWGE in human ovarian carcinoma cells, SKOV-3 and ES-2, and found the half-maximal inhibitory concentrations (IC50s) to be 643.76 μg/mL and 246.11 μg/mL after 48 h of FWGE treatment. FWGE treatment also induced programmed cell death by activating the caspase-7 cleavage in both SKOV-3 and ES-2 cells, but only caspase-3 and poly(adenosine diphosphate-ribose) polymerase cleavages were activated in SKOV-3 cells. Moreover, FWGE exhibited combination drug effects with cisplatin and docetaxel in SKOV-3 and ES-2 cells by enhancing the cytotoxicity of both drugs. In conclusion, we found that FWGE not only suppressed cell growth but also induced caspase-3-related and caspase-7-related cell death in human ovarian carcinoma cells. FWGE treatment further enhanced the cytotoxicity of cisplatin and docetaxel, suggesting that FWGE is a potential ingredient in the development of adjuvant chemotherapy with cisplatin or docetaxel for treating ovarian cancer patients.


Mortality from Parkinson disease.
Levodopa therapy for Parkinson disease (PD) has improved quality of life, but mortality rates remain high. Although the presence of dementia and severity of extrapyramidal signs (EPSs) influence morbidity in PD, it is not known whether these manifestations contribute to mortality. Patients with PD were compared with nondemented and demented elderly subjects. Each underwent annual neurological and neuropsychological examinations. Dementia was diagnosed by Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised criteria, and EPSs were rated with the Unified Parkinson's Disease Rating Scale. Survival rates were compared using Kaplan-Meier analysis and Cox proportional hazards models. The risk of mortality, when compared with nondemented elderly subjects, was highest among those with both PD and dementia (rate ratio, 4.9; 95% confidence interval, 3.4-7.1), but also was elevated in patients with PD only (rate ratio, 2.7; 95% confidence interval, 1.7-4.4). Dementia in the absence of PD also was associated with an increased risk of mortality (rate ratio, 1.6; 95% confidence interval, 1.1-2.3). A high baseline total EPS score was associated with significantly earlier mortality. Compared with nondemented elderly people in the same community, patients with PD have a 2- to 5-fold increased risk of mortality. The risk is strongly related to the presence of severe EPSs, especially bradykinesia. Despite the introduction of levodopa and other advances in the treatment of PD, these factors greatly increase mortality.


Bolstering geometric morphometrics sample sizes with damaged and pathologic specimens: Is near enough good enough?
Obtaining coordinate data for geometric morphometric studies often involves the sampling of dry skeletal specimens from museum collections. But many specimens exhibit damage and/or pathologic conditions. Such specimens can be considered inadequate for the analyses of shape and are excluded from study. However, the influences that damaged specimens may have on the assessment of normal shape variation have only been explored in two-dimensional coordinate data and no studies have addressed the inclusion of pathological specimens to date. We collected three-dimensional coordinate data from the cranium and mandible of 100 crab-eating macaques (Macaca fascicularis). Tests typically employed to analyze shape variation were performed on five datasets that included specimens with varying degrees of damage/pathology. We hypothesized that the inclusion of these specimens into larger datasets would strengthen statistical support for dominant biological predictors of shape, such as sex and size. However, we also anticipated that the analysis of only the most questionable specimens may confound statistical outputs. We then analyzed a small sample of good quality specimens bolstered by specimens that would generally be excluded due to damage or pathologic morphology and compared the results with previous analyses. The inclusion of damaged/pathologic specimens in a larger dataset resulted in increased variation linked to allometry, sexual dimorphism, and covariation, supporting our initial hypothesis. We found that analyzing the most questionable specimens alone gave consistent results for the most dominant aspects of shape but could affect outputs for less influential principal components and predictors. The small dataset bolstered with damaged/pathologic specimens provided an adequate assessment of the major components of shape, but finer scale differences were also identified. We suggest that normal and repeatable variation contributed by specimens exhibiting damage and/or pathology emphasize the dominant components and shape predictors in larger datasets, however, the various unique conditions may be more influential for limited sample sizes. Furthermore, we find that exclusion of damaged/pathologic specimens can, in some cases, omit important demographic-specific shape variation of groups of individuals more likely to exhibit these conditions. These findings provide a strong case for inclusion of these specimens into studies that focus on the dominant aspects of intraspecific shape variation. However, they may present issues when testing hypotheses relating to more fine-scale aspects of morphology.


Efficacy of a web-based, tailored, alcohol prevention/intervention program for college students: initial findings.
Reduce college student at-risk drinking (ARD) using a Web-based brief motivational alcohol prevention/intervention called Michigan Prevention and Alcohol Safety for Students (M-PASS). Participants included 1,137 randomly sampled first-year college students, including 59% female, 80% white, and averaged age 18.1 years. Intervention group participants (n = 616) attended 4 online M-PASS sessions, receiving feedback tailored to individual drinking patterns and concepts from 4 behavior change theories. Control group participants (n = 521) completed a mid-phase survey, and both groups were surveyed at baseline and posttest. Evidence of M-PASS's efficacy was found. The intervention was associated with advanced stage of change, lower tolerance of drinking and drink/driving, fewer reasons to drink, and use of more strategies to avoid ARD. Preliminary evidence of behavioral change was also found. Efficacy was greater for women than men. Web-based programs may be useful in reducing alcohol-related risk among college students. Further evaluation is needed.


Discovery and reconstitution of the cycloclavine biosynthetic pathway--enzymatic formation of a cyclopropyl group.
The ergot alkaloids, a class of fungal-derived natural products with important biological activities, are derived from a common intermediate, chanoclavine-I, which is elaborated into a set of diverse structures. Herein we report the discovery of the biosynthetic pathway of cycloclavine, a complex ergot alkaloid containing a cyclopropyl moiety. We used a yeast-based expression platform along with in vitro biochemical experiments to identify the enzyme that catalyzes a rearrangement of the chanoclavine-I intermediate to form a cyclopropyl moiety. The resulting compound, cycloclavine, was produced in yeast at titers of >500 mg L(-1) , thus demonstrating the feasibility of the heterologous expression of these complex alkaloids.


Inhibition of mitochondrial respiration by nitric oxide rapidly stimulates cytoprotective GLUT3-mediated glucose uptake through 5'-AMP-activated protein kinase.
Recently, we have reported that the inhibition of mitochondrial respiration by nitric oxide (NO) leads to an up-regulation of glycolysis and affords cytoprotection against energy failure through the stimulation of AMPK (5'-AMP-activated protein kinase) [Almeida, Moncada and Bolanos (2004) Nat. Cell Biol. 6, 45-51]. To determine whether glucose transport contributes specifically to this effect, we have now investigated the possible role of NO in modulating glucose uptake through GLUT3, a facilitative high-affinity glucose carrier that has been suggested to afford cytoprotection against hypoglycaemic episodes. To do so, GLUT3-lacking HEK-293T cells (human embryonic kidney 293T cells) were transformed to express a plasmid construction encoding green fluorescent protein-tagged GLUT3 cDNA. This carrier was preferentially localized to the plasma membrane, was seen to be functionally active and afforded cytoprotection against low glucose-induced apoptotic death. Inhibition of mitochondrial respiration by NO triggered a rapid, cGMP-independent enhancement of GLUT3-mediated glucose uptake through a mechanism that did not involve transporter translocation. Furthermore, the functional disruption of AMPK by the RNA interference strategy rendered cells unable to respond to NO by activating GLUT3-mediated glucose uptake. These results suggest that the inhibition of mitochondrial respiration by NO activates AMPK to stimulate glucose uptake, thereby representing a novel survival pathway during pathophysiological conditions involving transient reductions in the supply of cellular glucose.


Utilization of a population health survey in policy and practice: a case study.
There is growing interest by funding bodies and researchers in assessing the impact of research on real world policy and practice. Population health monitoring surveys provide an important source of data on the prevalence and patterns of health problems, but few empirical studies have explored if and how such data is used to influence policy or practice decisions. Here we provide a case study analysis of how the findings from an Australian population monitoring survey series of children's weight and weight-related behaviors (Schools Physical Activity and Nutrition Survey (SPANS)) have been used, and the key facilitators and barriers to their utilization. Data collection included semi-structured interviews with the chief investigators (n = 3) and end-users (n = 9) of SPANS data to explore if, how and under what circumstances the survey findings had been used, bibliometric analysis and verification using documentary evidence. Data analysis involved thematic coding of interview data and triangulation with other data sources to produce case summaries of policy and practice impacts for each of the three survey years (1997, 2004, 2010). Case summaries were then reviewed and discussed by the authors to distil key themes on if, how and why the SPANS findings had been used to guide policy and practice. We found that the survey findings were used for agenda setting (raising awareness of issues), identifying areas and target groups for interventions, informing new policies, and supporting and justifying existing policies and programs across a range of sectors. Reported factors influencing use of the findings were: i) the perceived credibility of survey findings; ii) dissemination strategies used; and, iii) a range of contextual factors. Using a novel approach, our case study provides important new insights into how and under what circumstances population health monitoring data can be used to influence real world policy and practice. The findings highlight the importance of population monitoring programs being conducted by independent credible agencies, researchers engaging end-users from the inception of survey programs and utilizing existing policy networks and structures, and using a range of strategies to disseminate the findings that go beyond traditional peer review publications.


Rotary manipulation for cervical radiculopathy: observations on the importance of the direction of the thrust.
To describe the clinical presentation of eight patients with cervical spine radiculopathy, the manipulation technique used for each patient and the outcomes of treatment. The cause of radiculopathy in four patients was disc herniation. The other four patients had a combination of spondylosis, disc herniation and sprain injury. Six of eight patients had a good outcome associated with receiving manipulation performed by contacting the cervical spine at the level of the radiculopathy, laterally flexing toward the side of radiculopathy, rotating the neck away from the side of the radiculopathy and applying a gentle high-velocity, low-amplitude thrust. Two patients had an exacerbation of arm pain and increased neurological deficit associated with manipulation performed with the neck rotated toward the side of radiculopathy. There is little compelling evidence supporting or disputing the use of manipulation for patients with cervical spine radiculopathy. In our patients, rotary manipulation was associated with a different outcome depending on the direction of neck rotation. Prospective time-series studies and randomized, blind trials are needed to identify the efficacy and effectiveness of different manipulation techniques for this condition.


An echocardiographic predictor of contrast-induced nephropathy following percutaneous coronary intervention in acute coronary syndrome: aortic valve sclerosis.
Objective. Aortic valve sclerosis (AVS) is closely related to endothelial dysfunction. The association of AVS with contrast-induced nephropathy (CIN) is unknown. We planned to investigate the relationship of AVS besides known parameters with CIN. Design. Baseline characteristics, biochemical values, and AVS of 292 consecutive patients with acute coronary syndrome (ACS) that underwent percutaneous coronary intervention (PCI) were analyzed. Results. Fifty-three patients (18.2%) had CIN. Patients with CIN were older, less likely to be smokers, and had more prevalent prior bypass surgery, higher Mehran score, creatinine, and uric acid concentrations than those without CIN. AVS was more prevalent in patients with CIN. Logistic regression analysis including all related parameters identified Mehran score (OR = 1.036, p = .033), uric acid concentration (OR = 1.244, p = .023), and AVS (OR: 2.223, p = .027) as independent predictors of CIN. Conclusion. AVS is independently associated with CIN in patients with acute coronary syndrome undergoing percutaneous coronary intervention. AVS may help to identify high-risk patients for CIN, who would benefit from preventive measures.


Obesity is underestimated using body mass index and waist-hip ratio in long-term adult survivors of childhood cancer.
Obesity, represented by high body mass index (BMI), is a major complication after treatment for childhood cancer. However, it has been shown that high total fat percentage and low lean body mass are more reliable predictors of cardiovascular morbidity. In this study longitudinal changes of BMI and body composition, as well as the value of BMI and waist-hip ratio representing obesity, were evaluated in adult childhood cancer survivors. Data from 410 survivors who had visited the late effects clinic twice were analyzed. Median follow-up time was 16 years (interquartile range 11-21) and time between visits was 3.2 years (2.9-3.6). BMI was measured and body composition was assessed by dual X-ray absorptiometry (DXA, Lunar Prodigy; available twice in 182 survivors). Data were compared with healthy Dutch references and calculated as standard deviation scores (SDS). BMI, waist-hip ratio and total fat percentage were evaluated cross-sectionally in 422 survivors, in who at least one DXA scan was assessed. BMI was significantly higher in women, without significant change over time. In men BMI changed significantly with time (ΔSDS = 0.19, P<0.001). Percentage fat was significantly higher than references in all survivors, with the highest SDS after cranial radiotherapy (CRT) (mean SDS 1.73 in men, 1.48 in women, P<0.001). Only in men, increase in total fat percentage was significantly higher than references (ΔSDS = 0.22, P<0.001). Using total fat percentage as the gold standard, 65% of female and 42% of male survivors were misclassified as non-obese using BMI. Misclassification of obesity using waist-hip ratio was 40% in women and 24% in men. Sixteen years after treatment for childhood cancer, the increase in BMI and total fat percentage was significantly greater than expected, especially after CRT. This is important as we could show that obesity was grossly underestimated using BMI and waist-hip ratio.


Genetic relatedness between influenza A (H1N1) viruses isolated from humans and pigs.
Complete nucleotide sequences were obtained from the nucleoprotein genes of three influenza A viruses and partial nucleotide sequences were obtained from the polymerase, neuraminidase, matrix, and non-structural protein genes of four influenza A viruses that had been isolated between 1931 and 1939 from clinically sick pigs in the United States or Europe. A phylogenetic analysis of the open reading frames of nine nucleoprotein genes showed that the U.S. swine influenza virus isolates from 1931 and 1937 originated from the classic swine viral nucleoprotein lineage, whereas the European swine strains fro 1938 and 1939 were placed among the early human influenza virus nucleoprotein lineage. All the partial gene sequences obtained from the two European swine strains fro 1938 and 1939 were also more closely related to early human H1N1 reference strains than to the U.S. swine isolates from 1931 and 1937, indicating that none of the four viruses isolated from swine had acquired genes from a heterologous lineage through reassortment.


Macromolecular crowding and membrane binding proteins: The case of phospholipase A1.
Cells contain high levels of macromolecular crowding; understanding how macromolecular crowding impacts the behaviour of biological systems can give new insights into biological phenomena and disease pathologies. In this study, we assess the effect of macromolecular crowding on the catalytic activity of the biomembrane binding protein phospholipase A1 (PLA1). Using 3D-printed equilibrium dialysis chambers we show that macromolecular crowding increases the binding of PLA1 to lipid vesicles. However, using a mass spectrometry assay of the hydrolysis of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) by PLA1 we surprisingly find that macromolecular crowding decreases the reaction rate and causes early cessation of the catalytic activity of PLA1. Using kinetic equilibrium modelling, we are able to estimate the effect of macromolecular crowding on the association and dissociation rate constants for PLA1 binding to the lipid vesicles. These data, coupled with particle sizing measurements enable us to construct a model to explain the early cessation of catalytic activity of PLA1 with increasing levels of macromolecular crowding. This model suggests that compositional changes in the membrane, due to PLA1 action, lead to the formation of larger vesicles, which deactivate the protein. This process is more rapid in the presence of macromolecular crowding agents, suggesting that a more detailed understanding of the effects of macromolecular crowding on membrane dynamics is required to understand membrane interacting proteins in macromolecularly crowded environments. The implications of this discovery are significant given the wide range of roles of membrane fusion and fission in neurocognitive processes and the failure of these processes in neurodegenerative diseases.


Reactor design for minimizing product inhibition during enzymatic lignocellulose hydrolysis: I. Significance and mechanism of cellobiose and glucose inhibition on cellulolytic enzymes.
Achievement of efficient enzymatic degradation of cellulose to glucose is one of the main prerequisites and one of the main challenges in the biological conversion of lignocellulosic biomass to liquid fuels and other valuable products. The specific inhibitory interferences by cellobiose and glucose on enzyme-catalyzed cellulose hydrolysis reactions impose significant limitations on the efficiency of lignocellulose conversion - especially at high-biomass dry matter conditions. To provide the base for selecting the optimal reactor conditions, this paper reviews the reaction kinetics, mechanisms, and significance of this product inhibition, notably the cellobiose and glucose inhibition, on enzymatic cellulose hydrolysis. Particular emphasis is put on the distinct complexity of cellulose as a substrate, the multi-enzymatic nature of the cellulolytic degradation, and the particular features of cellulase inhibition mechanisms and kinetics. The data show that new strategies that place the bioreactor design at the center stage are required to alleviate the product inhibition and in turn to enhance the efficiency of enzymatic cellulose hydrolysis. Accomplishment of the enzymatic hydrolysis at medium substrate concentration in separate hydrolysis reactors that allow continuous glucose removal is proposed to be the way forward for obtaining feasible enzymatic degradation in lignocellulose processing.


Uncertainty during the transition from cancer patient to survivor.
This prospective study evaluated the impact that uncertainty has on quality of life as cancer patients end the active phase of their treatment. The transition from patient status to survivor may be a particularly important point in recovery because it may affect how much stress cancer survivors experience. Guided by a within-subjects design framework, 53 cancer patients (predominantly breast cancer) participated in the present study as they approached the end of adjuvant treatment and were followed for 4 months. Distress levels increased the further patients moved away from the end-of-active treatment; however, preceding these ascending scores of distress was a period characterized by little unrest-best described as a "honeymoon" phase. Using hierarchical linear modeling, greater uncertainty 1 month after treatment ended predicted more functional and physical impairment 4 months after the completion of adjuvant treatment. In both cases, uncertainty accounted for nearly 70% of the variance of these changes over time. A period of rest may emerge as active treatment ends, but that it is short-lived, particularly if uncertainty regarding health emerges. Furthermore, uncertainty may a represent a key mechanism (and target for intervention) during the transition from cancer patient to survivor.


Assessment of Outcomes of a Metatarsal Bone Ostectomy for Chronic Plantar Ulcers: A Preliminary Study.
Clinical management of chronic plantar ulcers is a difficult issue in medical practice. Pressure overloading is a problem that needs to be resolved. Herein, we report a surgical method to reduce plantar pressure: a dorsal approach to a metatarsal ostectomy. From March 2011 to October 2016, 16 patients suffering from chronic plantar ulcers underwent ostectomy procedures at Taipei Wan-Fang Municipal Hospital (Taipei Medical University). A bone segment about 0.5 to 1 cm long was removed via a dorsal foot approach. The plantar wound was treated with debridement only or was simultaneously covered with a skin graft. In total, 16 patients with an average age of 57.81 (SD, 11.6) years (12 males and 4 females) were included; 15 patients (93.75%) had a diagnosis of type 2 diabetes for a mean of 20.66 years (range, 5-30 years). The mean glycated hemoglobin was 9.14 g/dL (range, 5.2-13.2 g/dL). The mean plantar wound size was 5.72 cm. Four patients (25%) needed to receive a skin graft with a mean skin graft size of 8.13 cm. The mean follow-up time was 15.2 months. The plantar wounds completely healed in 14 patients (87.5%) in an average of 2.14 months. No plantar ulcer was complicated with recurrence, but transfer ulcers developed in 2 patients (12.5%) at an average of 7.5 months postoperatively. Metatarsal ostectomy surgery via a dorsal foot approach is an efficient way to reduce pressure overloading of chronic plantar wounds. Our study provides an alternative method to treat this difficult problem with a high wound healing rate and less recurrence.


Model of Ischemic Heart Disease and Video-Based Comparison of Cardiomyocyte Contraction Using hiPSC-Derived Cardiomyocytes.
Ischemic heart disease is a significant cause of death worldwide. It has therefore been the subject of a tremendous amount of research, often with small-animal models such as rodents. However, the physiology of the human heart differs significantly from that of the rodent heart, underscoring the need for clinically relevant models to study heart disease. Here, we present a protocol to model ischemic heart disease using cardiomyocytes differentiated from human induced pluripotent stem cells (hiPS-CMs) and to quantify the damage and functional impairment of the ischemic cardiomyocytes. Exposure to 2% oxygen without glucose and serum increases the percentage of injured cells, which is indicated by staining of the nucleus with propidium iodide, and decreases cellular viability. These conditions also decrease the contractility of hiPS-CMs as confirmed by displacement vector field analysis of microscopic video images. This protocol may furthermore provide a convenient method for personalized drug screening by facilitating the use of hiPS cells from individual patients. Therefore, this model of ischemic heart disease, based on iPS-CMs of human origin, can provide a useful platform for drug screening and further research on ischemic heart disease.


Orientation-independent charge transport in single spherulites from solution-processed organic semiconductors.
Due to the rapidity of morphological development during deposition, solution-processed organic semiconductor thin films exist in semicrystalline or polycrystalline states, incorporating a high degree of local variations in molecular orientation compared to their single-crystal counterparts. Spherulites, a common crystalline superstructure found in these systems, for example, incorporate a large distribution of molecular orientations about the radial axis to maintain their space-filling growth habit. Here, we aim to determine how this distribution of molecular orientations influences charge transport by fabricating arrays of devices on single spherulites. Given that the orientation distribution that is present about the radial axis mandates the presence of low-angle grain boundaries within single spherulites, we find intraspherulitic charge transport to be independent of the general direction of π-stacking; organic field-effect transistors exhibit comparable mobilities regardless of how their channels are oriented with respect to the general π-stacking direction.


Marginal zone SIGN-R1+ macrophages are essential for the maturation of germinal center B cells in the spleen.
The mechanisms that regulate germinal center (GC) B cell responses in the spleen are not fully understood. Here we use a combination of pharmacologic and genetic approaches to delete SIGN-R1+ marginal zone (MZ) macrophages and reveal their specific contribution to the regulation of humoral immunity in the spleen. We find that while SIGN-R1+ macrophages were not essential for initial activation of B cells, they were required for maturation of the response and development of GC B cells. These defects could be corrected when follicular helper T (Tfh) cells were induced before macrophage ablation or when Tfh responses were enhanced. Moreover, we show that in the absence of SIGN-R1+ macrophages, DCIR2+ dendritic cells (DCs), which play a key role in priming Tfh responses, were unable to cluster to the interfollicular regions of the spleen and were instead displaced to the MZ. Restoring SIGN-R1+ macrophages to the spleen corrected positioning of DCIR2+ DCs and rescued the GC B cell response. Our study reveals a previously unappreciated role for SIGN-R1+ macrophages in regulation of the GC reaction and highlights the functional specification of macrophage subsets in the MZ compartment.


A genetic link between epigenetic repressor AS1-AS2 and DNA replication factors in establishment of adaxial-abaxial leaf polarity of Arabidopsis.
Balanced development of adaxial and abaxial domains in leaf primordia is critical for the formation of flat symmetric leaf lamina. Arabidopsis ASYMMETRIC LEAVES1 (AS1) and AS2 proteins form a complex (AS1-AS2), which acts as key regulators for the adaxial development by the direct repression of expression of the abaxial gene ETTIN/AUXIN RESPONSE FACTOR3 (ETT/ARF3). Many modifier mutations have been identified, which enhance the defect of as1 and as2 mutations to generate abaxialized filamentous leaves without adaxial traits, suggesting that the development of the adaxial domain is achieved by cooperative repression by AS1-AS2 and the wild-type proteins corresponding to the modifiers. Mutations of several genes for DNA replication-related chromatin remodeling factors such as Chromatin Assembly Factor-1 (CAF-1) have been also identified as modifiers. It is still unknown, however, whether mutations in genes involved in DNA replication themselves might act as modifiers. Here we report that as1 and as2 mutants grown in the presence of hydroxyurea, a known inhibitor of DNA replication, form abaxialized filamentous leaves in a concentration-dependent manner. We further show that a mutation of the INCURVATA2 (ICU2) gene, which encodes the putative catalytic subunit of DNA polymerase α, and a mutation of the Replication Factor C Subunit3 (RFC3) gene, which encodes a protein used in replication as a clamp loader, act as modifiers. In addition, as2-1 icu2-1 double mutants showed increased mRNA levels of the genes for leaf abaxialization. These results suggest a tight link between DNA replication and the function of AS1-AS2 in the development of flat leaves.


MRI simulation-based evaluation of image-processing and classification methods.
With the increased interest in computer-aided image analysis methods, there is a greater need for objective methods of algorithm evaluation. Validation of in vivo MRI studies is complicated by a lack of reference data and the difficulty of constructing anatomically realistic physical phantoms. We present here an extensible MRI simulator that efficiently generates realistic three-dimensional (3-D) brain images using a hybrid Bloch equation and tissue template simulation that accounts for image contrast, partial volume, and noise. This allows image analysis methods to be evaluated with controlled degradations of image data.


H3.3K27M mutant proteins reprogram epigenome by sequestering the PRC2 complex to poised enhancers.
Expression of histone H3.3K27M mutant proteins in human diffuse intrinsic pontine glioma (DIPG) results in a global reduction of tri-methylation of H3K27 (H3K27me3), and paradoxically, H3K27me3 peaks remain at hundreds of genomic loci, a dichotomous change that lacks mechanistic insights. Here, we show that the PRC2 complex is sequestered at poised enhancers, but not at active promoters with high levels of H3.3K27M proteins, thereby contributing to the global reduction of H3K27me3. Moreover, the levels of H3.3K27M proteins are low at the retained H3K27me3 peaks and consequently having minimal effects on the PRC2 activity at these loci. H3K27me3-mediated silencing at specific tumor suppressor genes, including Wilms Tumor 1, promotes proliferation of DIPG cells. These results support a model in which the PRC2 complex is redistributed to poised enhancers in H3.3K27M mutant cells and contributes to tumorigenesis in part by locally enhancing H3K27me3, and hence silencing of tumor suppressor genes.


Clinical Efficacy and Safety of Nivolumab: Results of a Multicenter, Open-label, Single-arm, Japanese Phase II study in Malignant Pleural Mesothelioma (MERIT).
Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy with poor prognosis. Patients with MPM who do not respond to standard first-line chemotherapy have limited treatment options. We evaluated the efficacy and safety of nivolumab, an immune checkpoint inhibitor, for the treatment of advanced or metastatic MPM. Japanese patients with unresectable, advanced, or metastatic MPM resistant or intolerant to ≤2 regimens of chemotherapy and ≥1 measurable lesion(s) were enrolled. Patients received nivolumab 240 mg intravenously every 2 weeks until progressive disease or unacceptable toxicity. The primary endpoint was objective response rate by central assessment according to the Modified Response Evaluation Criteria in Solid Tumors. Adverse events (AEs) and treatment-related AEs (TRAEs) were evaluated. Thirty-four patients were enrolled between July 2016 and October 2016. Median follow-up was 16.8 (range: 1.8-20.2) months. Ten (29%, 95% confidence interval, 16.8-46.2) patients showed a centrally assessed objective response. The objective response rates were 26% (7/27), 67% (2/3), and 25% (1/4) patients for epithelioid, sarcomatoid, and biphasic histologic subtypes, respectively. Median duration of response was 11.1 months with a 68% disease control rate. Median overall survival and progression-free survival were 17.3 and 6.1 months, respectively. The objective response rate was 40% with programmed death-ligand 1 expression ≥1% and 8% with <1%. Thirty-two patients (94%) experienced AEs and 26 (76%) experienced TRAEs. Nivolumab met the primary endpoint as second- or third-line treatment for patients with MPM and showed promising efficacy with manageable toxicity.See related commentary by Mansfield and Zauderer, p. 5438.


Modulation of the asymmetry of sea urchin sperm flagellar bending by calmodulin.
Sea urchin spermatozoa demembranated with Triton X-100 in the presence of EGTA, termed potentially asymmetric, generate asymmetric bending waves in reactivation solutions containing EGTA. After they are converted to the potentially symmetric condition by extraction with Triton and millimolar Ca++, they generate symmetric bending waves in reactivation solutions containing EGTA. In the presence of EGTA, their asymmetry can be restored by addition of brain calmodulin or the concentrated supernatant obtained from extraction with Triton and millimolar Ca++. These extracts contain calmodulin, as assayed by gel electrophoresis, radioimmunoassay, activation of brain phosphodiesterase, and Ca++-dependent binding of asymmetry-restoring activity to a trifluorophenothiazine-affinity resin. Conversion to the potentially symmetric condition can also be achieved with trifluoperazine substituted for Triton during the exposure to millimolar Ca++, which suggests that the calmodulin-binding activity of Triton is important for this conversion. These observations suggest that the conversion to the potentially symmetric condition is the result of removal of some of the axonemal calmodulin and provide additional evidence for axonemal calmodulin as a mediator of the effect of Ca++ on the asymmetry of flagellar bending.


Evaluation of the intrinsic catalytic activity of nanoparticles without prior knowledge of the mass loading.
The quantitative characterisation of electrocatalytic properties of nanoparticle catalyst materials is so far only performed for layers typically comprising additionally conducting additives and binders. We propose a method enabling the evaluation of intrinsic catalytic activity of nanoparticles based on the diffusion-limited steady-state current. In a step-after-step process, the influence of coverage on kinetic and diffusion limited current is evaluated to highlight the challenges of sub-monolayer electroanalysis. Conclusions are used to point out strategies and their limitations for qualitative and quantitative comparison of intrinsic catalytic properties. Particularly, the impact of coverage, electrode geometry, altered diffusion profile for nanoparticles and the catalyst activity and selectivity are discussed. Fundamental information about electrochemical sub-monolayer nanoparticle analysis is provided.


Neuropathology of AIDS dementia. A review after 205 post mortem examinations.
109 brains were selected after the exclusion of those affected by space occupying lesions or opportunistic infections. All brains with HIV specificity (nodules with multinucleated cells and, at times, two peculiar kinds of myelin involvement) were atrophic (62%); nevertheless dementia had been mentioned only in the 55% of the corresponding autopsy requests. In agreement with previous studies we conclude that HIV encephalopathy does not always give rise to neurological signs.


Isolation of a variant of subtilosin A with hemolytic activity.
Bacillus subtilis produces an anionic bacteriocin called subtilosin A that possesses antibacterial activity against certain gram-positive bacteria. In this study, we uncovered a hemolytic mutant of B. subtilis that produces an altered form of subtilosin A. The mutant bacteriocin, named subtilosin A1, has a replacement of threonine at position 6 with isoleucine. In addition to the hemolytic activity, subtilosin A1 was found to exhibit enhanced antimicrobial activity against specific bacterial strains. The B. subtilis albB mutant that does not produce a putative immunity peptide was more sensitive to both subtilosin A and subtilosin A1. A spontaneous suppressor mutation of albB that restored resistance to subtilosin A and subtilosin A1 was obtained. The sbr (subtilosin resistance) mutation conferring the resistance is not linked to the sboA-alb locus. The sbr mutation does not increase the resistance of B. subtilis to other cell envelope-targeted antimicrobial agents, indicating that the mutation specifically confers the resistance to subtilosins. The findings suggest possible bioengineering approaches for obtaining anionic bacteriocins with enhanced and/or altered bactericidal activity. Furthermore, future identification of the subtilosin-resistant mutation could provide insights into the mechanism of subtilosin A activity.


Evaluation of several ultrasonography scoring systems for synovitis and comparison to clinical examination: results from a prospective multicentre study of rheumatoid arthritis.
To evaluate different global ultrasonographic (US) synovitis scoring systems as potential outcome measures of rheumatoid arthritis (RA) according to the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) filter. To study selected global scoring systems, for the clinical, B mode and power Doppler techniques, the following joints were evaluated: 28 joints (28-joint Disease Activity Score (DAS28)), 20 joints (metacarpophalangeals (MCPs) + metatarsophalangeals (MTPs)) and 38 joints (28 joints + MTPs) using either a binary (yes/no) or a 0-3 grade. The study was a prospective, 4-month duration follow-up of 76 patients with RA requiring anti-tumour necrosis factor (TNF) therapy (complete follow-up data: 66 patients). Intraobserver reliability was evaluated using the intraclass correlation coefficient (ICC), construct validity was evaluated using the Cronbach alpha test and external validity was evaluated using level of correlation between scoring system and C reactive protein (CRP). Sensitivity to change was evaluated using the standardised response mean. Discriminating capacity was evaluated using the standardised mean differences in patients considered by the doctor as significantly improved or not at the end of the study. Different clinimetric properties of various US scoring systems were at least as good as the clinical scores with, for example, intraobserver reliability ranging from 0.61 to 0.97 versus from 0.53 to 0.82, construct validity ranging from 0.76 to 0.89 versus from 0.76 to 0.88, correlation with CRP ranging from 0.28 to 0.34 versus from 0.28 to 0.35 and sensitivity to change ranging from 0.60 to 1.21 versus from 0.96 to 1.36 for US versus clinical scoring systems, respectively. This study suggests that US evaluation of synovitis is an outcome measure at least as relevant as physical examination. Further studies are required in order to achieve optimal US scoring systems for monitoring patients with RA in clinical trials and in clinical practice.


Characterization of the vertical evolution of the three-dimensional turbulence for fatigue design of tidal turbines.
A system of two coupled four-beam acoustic Doppler current profilers was used to collect turbulence measurements over a 36-h period at a highly energetic tidal energy site in Alderney Race. This system enables the evaluation of the six components of the Reynolds stress tensor throughout a large proportion of the water column. The present study provides mean vertical profiles of the velocity, the turbulence intensity and the integral lengthscale along the streamwise, spanwise and vertical direction of the tidal current. Based on our results and considering a tidal-stream energy convertor (TEC) aligned with the current main direction, the main elements of turbulence prone to affect the structure (material fatigue) and to alter power generation would likely be: (i) the streamwise turbulence intensity (Ix), (ii) the shear stress, [Formula: see text], (iii) the normal stress, [Formula: see text] and (iv) the vertical integral lengthscale (Lz). The streamwise turbulence intensity, (Ix), was found to be higher than that estimated at other tidal energy sites across the world for similar height above bottom. Along the vertical direction, the length (Lz) of the large-scale turbulence eddies was found to be equivalent to the rotor diameter of the TEC Sabella D10. It is considered that the turbulence metrics presented in this paper will be valuable for TECs designers, helping them optimize their designs as well as improve loading prediction through the lifetime of the machines. This article is part of the theme issue 'New insights on tidal dynamics and tidal energy harvesting in the Alderney Race'.


NY-BR-1 protein expression in breast carcinoma: a mammary gland differentiation antigen as target for cancer immunotherapy.
NY-BR-1 is a recently identified differentiation antigen of the mammary gland. To use NY-BR-1 for T-cell-based immunotherapy, analysis of its co-expression with HLA class I antigens is required. In the present tissue microarray study, primary breast cancers (n = 1,444), recurrences (n = 88), lymph node (n = 525) and distant metastases (n = 91) were studied for NY-BR-1 expression using a novel monoclonal antibody. NY-BR-1 expression was compared with prognosis, estrogen receptor, HER2-status, EGFR and HLA class I antigen expression. NY-BR-1 was more frequently expressed in grade 1 (82%) than in grade 2 (69%) and grade 3 (46%) carcinomas (P < 0.0001). Moreover, NY-BR-1 expression correlated directly with estrogen receptor expression (P < 0.0001) and inversely correlated with HER2-status and EGFR expression (P < 0.0001 for both). Considering high expression level of co-expression, 198/1,321 (15%) primary breast carcinomas and 4/65 (6%) distant metastases expressed NY-BR-1 and HLA class I, suggesting that active immunotherapy can be applied to about 10% of breast cancer patients. Survival analysis showed an association of NY-BR-1 expression with better patient outcome (P = 0.015). No difference between NY-BR-1 expression of primary tumors and metastases could be found, indicating that the presence of NY-BR-1 in metastases can be deduced from their corresponding primary. Forty-three paired biopsies taken from patients before and after chemotherapy suggest that NY-BR-1 expression is not influenced by preceding chemotherapy (kappa = 0.89, P < 0.0001). In summary, the co-expression of NY-BR-1 with HLA class I antigens and its expression in metastases without modification by chemotherapy suggest that NY-BR-1 targeted immunotherapy represents a viable strategy in addition to other targeted cancer drug therapies of breast cancer.


Efficient Rasterization for Outdoor Radio Wave Propagation.
Conventional beam tracing can be used for solving global illumination problems. It is an efficient algorithm and performs very well when implemented on the GPU. This allows us to apply the algorithm in a novel way to the problem of radio wave propagation. The simulation of radio waves is conceptually analogous to the problem of light transport. We use a custom, parallel rasterization pipeline for creation and evaluation of the beams. We implement a subset of a standard 3D rasterization pipeline entirely on the GPU, supporting 2D and 3D frame buffers for output. Our algorithm can provide a detailed description of complex radio channel characteristics like propagation losses and the spread of arriving signals over time (delay spread). Those are essential for the planning of communication systems required by mobile network operators. For validation, we compare our simulation results with measurements from a real-world network. Furthermore, we account for characteristics of different propagation environments and estimate the influence of unknown components like traffic or vegetation by adapting model parameters to measurements.


Iron deficiency in early pregnancy using serum ferritin and soluble transferrin receptor concentrations are associated with pregnancy and birth outcomes.
There are several biomarkers for measuring iron deficiency (ID) in pregnancy, but the prevalence of ID and its association with inflammation and adverse pregnancy outcomes is inconclusive. The aim of this work was to describe the prevalence and determinants of first trimester ID and associations with pregnancy and birth outcomes. A record-linkage cohort study of archived serum samples of women attending first trimester screening and birth and hospital data to ascertain maternal characteristics and pregnancy outcomes. Sera were analysed for iron stores (ferritin; μg/l), lack of iron in the tissues (soluble transferrin receptor (sTfR); nmol/l) and inflammatory (C-reactive protein (CRP); mg/dl) biomarkers. Total body iron (TBI) was calculated from serum ferritin (SF) and sTfR concentrations. Multivariate logistic regression analysed risk factors and pregnancy outcomes associated with ID using the definitions: SF<12 μg/l, TfR ⩾ 21.0 nmol/l, and TBI<0 mg/kg. Of the 4420 women, the prevalence of ID based on ferritin, sTfR and TBI was 19.6, 15.3 and 15.7%, respectively. Risk factors of ID varied depending on which iron parameter was used and included maternal age <25 years, multiparity, socioeconomic disadvantage, high maternal body weight and inflammation. ID, defined by SF and TBI but not TfR, was associated with reduced risk of gestational diabetes mellitus (GDM). ID defined using TBI only was associated with increased risk of large-for-gestation-age (LGA) infants. Nearly one in five Australian women begin pregnancy with ID. Further investigation of excess maternal weight and inflammation in the relationships between ID and GDM and LGA infants is needed.


Indications, complications, and mortality rate following craniotomy or craniectomy in dogs and cats: 165 cases (1995-2016).
To determine the most common indications for cranial surgery and identify risk factors associated with the occurrence of complications and death in the perioperative period following cranial surgery. 150 dogs and 15 cats. For this multi-institutional retrospective case series, medical records of dogs and cats that underwent cranial surgery at any of the 4 participating institutions between 1995 and 2016 were reviewed. Variables were evaluated included species, sex, age, neurolocalization, history of preoperative seizures, surgical approach, histological results, perioperative complications, and outcome. Logistic regression analysis was performed to assess for risk factors for complications. The most common neurolocalization was the forebrain (110/165 [66.7%]), with 94 (57.0%) animals having had seizures preoperatively. The rostrotentorial (116/165 [70.3%]) and caudotentorial (32/165 [19.4%]) surgical approaches were most commonly reported. The most common indication was the treatment of meningioma (75/142 [52.8%]). Complications arose in 58 of the 165 (35.2%) cases within 24 hours and in 86 (52.1%) cases 1 to 10 days postoperatively. Perioperative complications included hypotension (38/165 [23.0%]) and anemia (27/165 [16.4%]). During the postoperative period, the most common complications were neurologic deficits, seizures, postoperative anemia, and aspiration pneumonia. The mortality rate with death or euthanasia perioperatively or ≤ 10 days postoperatively was 14.5% (24/165). Long-term complications occurred in 65 of the 165 (39.4%) animals, with seizures and neurologic deficits being the most common. Cranial surgery was performed most commonly for the removal of neoplastic lesions in dogs and cats, and most complications were not life-threatening.


Assessment of occupational exposures in a general population: comparison of different methods.
To evaluate the relative merits of job specific questionnaires and various alternative assessment methods of occupational exposures often used in general population studies. Subjects were participants in a hospital based case-control study of risk factors for male infertility. Estimates of exposure to organic solvents and chromium, based on job specific questionnaires, generic questionnaires, self reports of exposure, an external job exposure matrix (JEM), and a population specific JEM were compared with passive diffuse dosimeter results and measurements in urine. Urine samples from the end of the shift were analysed for metabolites of toluene, xylene, several glycol ethers, trichloroethylene, and chromium. Passive dosimeter date, metabolites of specific solvents, and urinary chromium concentrations were available for 89, 267, and 156 subjects, respectively. The alternative methods and measurements in urine were compared by means of the Cohen's kappa statistic and by computing the positive predictive value, sensitivity, and specificity of the alternative methods against measurements in urine. Passive dosimeter results indicated that exposure classifications with job specific questionnaire information could discriminate between high and low exposures. The kappa coefficients were < 0.4, so agreement between the various methods and measurements in urine was poor. Sensitivity of the methods ranged from 0.21 to 0.85, whereas specificity ranged from 0.34 to 0.94. Positive predictive values ranged from 0.19 to 0.58, with the highest values for job specific questionnaires. The results indicate that the implementation of job specific questionnaires in a general population study might be worth the extra expense it entails, bearing in mind the paramount importance of avoiding false positive exposure estimates when exposure prevalence is low.


Resistance to mammary tumorigenesis in Copenhagen rats is associated with the loss of preneoplastic lesions.
The resistance of Copenhagen (Cop) rats to mammary tumor development has recently been linked to three loci, but the genes have yet to be cloned and the mechanism of resistance is still largely unknown. In order to determine the cellular events associated with resistance, we prepared mammary whole mounts from Cop and susceptible Wistar Furth (WF) rats 0, 15, 30, 45 and 60 days after treatment with 50 mg/kg N-methyl-N-nitrosourea (MNU). At 15 days, treated rats of both strains had significantly more undifferentiated structures [terminal end buds (TEBs)] and significantly fewer differentiated structures [alveolar buds (ABs)] than untreated rats. Treated Cop rats, however, had significantly more TEBs and fewer ABs than age-matched, treated WF rats. Histological analysis of preneoplastic lesions tentatively identified from the whole mounts showed that like WF rats, Cop rats developed early preneoplastic lesions [intraductal proliferations (IDPs)] by 15 days post-MNU treatment. Unlike IDPs from WF rats, however, the IDPs in Cop rats then decreased in number until they were absent 60 days post-MNU treatment. Furthermore, they failed to progress into more advanced lesions such as ductal carcinomas in situ (DCIS). Finally, we found G-->A activating mutations in codon 12 of the Ha-ras gene in 60% of IDPs from Cop rats and 75% of IDPs from WF rats. Our results show that resistance in Cop rats is not due to a target cell population for the carcinogen that is smaller than in susceptible rats or to the failure of the carcinogen to inhibit mammary gland differentiation. Furthermore, we have shown that Cop rats develop preneoplastic IDPs that harbor Ha-ras mutations but, unlike IDPs in susceptible strains, they fail to progress and ultimately disappear.