An evaluation of data-driven motion estimation in comparison to the usage of external-surrogates in cardiac SPECT imaging.
Motion estimation methods in single photon emission computed tomography (SPECT) can be classified into methods which depend on just the emission data (data-driven), or those that use some other source of information such as an external surrogate. The surrogate-based methods estimate the motion exhibited externally which may not correlate exactly with the movement of organs inside the body. The accuracy of data-driven strategies on the other hand is affected by the type and timing of motion occurrence during acquisition, the source distribution, and various degrading factors such as attenuation, scatter, and system spatial resolution. The goal of this paper is to investigate the performance of two data-driven motion estimation schemes based on the rigid-body registration of projections of motion-transformed source distributions to the acquired projection data for cardiac SPECT studies. Comparison is also made of six intensity based registration metrics to an external surrogate-based method. In the data-driven schemes, a partially reconstructed heart is used as the initial source distribution. The partially-reconstructed heart has inaccuracies due to limited angle artifacts resulting from using only a part of the SPECT projections acquired while the patient maintained the same pose. The performance of different cost functions in quantifying consistency with the SPECT projection data in the data-driven schemes was compared for clinically realistic patient motion occurring as discrete pose changes, one or two times during acquisition. The six intensity-based metrics studied were mean-squared difference, mutual information, normalized mutual information (NMI), pattern intensity (PI), normalized cross-correlation and entropy of the difference. Quantitative and qualitative analysis of the performance is reported using Monte-Carlo simulations of a realistic heart phantom including degradation factors such as attenuation, scatter and system spatial resolution. Further the visual appearance of motion-corrected images using data-driven motion estimates was compared to that obtained using the external motion-tracking system in patient studies. Pattern intensity and normalized mutual information cost functions were observed to have the best performance in terms of lowest average position error and stability with degradation of image quality of the partial reconstruction in simulations. In all patients, the visual quality of PI-based estimation was either significantly better or comparable to NMI-based estimation. Best visual quality was obtained with PI-based estimation in one of the five patient studies, and with external-surrogate based correction in three out of five patients. In the remaining patient study there was little motion and all methods yielded similar visual image quality.


Disabled people's organisations and the disability movement: Perspectives from Burkina Faso.
In Burkina Faso, the disability movement is rather weak, both in terms of funding and staffing - its range does not extend far outside the capital city and is largely dependent on international non-governmental organisations (INGOs). Despite the huge number of grassroots disabled people's organisations (DPOs), many of these organisations do not function beyond the occasional meeting and celebration of the International Day of Persons with Disabilities. The reasons for this are various, including dependency on external funding (such as from international organisations), lack of access to resources, being dependent on voluntary members, and lack of organisation. This article looks at the functioning of - and politics governing - DPOs in Burkina Faso, their significance in the lives of people with disabilities and the challenges they encounter. This article is based on research findings obtained through interviews conducted with people with disabilities, as well as INGOs working with people with disabilities and state authorities in Burkina Faso. Evidence suggests that the farther people with disabilities are from the capital, the lesser are their chances of being heard and of being involved in decision-making. However, DPOs offer a haven for many, offering people with disabilities solace in meeting other members and finding a sense of belonging in these associations. Others give importance to the role of DPOs in raising awareness and human rights advocacy. Finally, the article raises the question as to what the future of DPOs in Burkina Faso might entail. Burkina Faso; disability identity; disability movement; disabled people's organisations; income-generating activities; international non-governmental organisations; socialisation; vie associative; voluntary organisations; urban-rural divide.


FoxM1B is overexpressed in human glioblastomas and critically regulates the tumorigenicity of glioma cells.
The transcription factor Forkhead box M1 (FoxM1) is overexpressed in malignant glioma. However, the functional importance of this factor in human glioma is not known. In the present study, we found that FoxM1B was the predominant FoxM1 isoform expressed in human glioma but not in normal brain tissue. The level of FoxM1 protein expression in human glioma tissues was directly correlated with the glioma grade. The level of FoxM1 protein expression in human glioblastoma tissues was inversely correlated with patient survival. Enforced FoxM1B expression caused SW1783 and Hs683 glioma cells, which do not form tumor xenografts, to regain tumorigenicity in nude mouse model systems. Moreover, gliomas that arose from FoxM1B-transfected anaplastic astrocytoma SW1783 cells displayed glioblastoma multiforme phenotypes. Inhibition of FoxM1 expression in glioblastoma U-87MG cells suppressed their anchorage-independent growth in vitro and tumorigenicity in vivo. Furthermore, we found that FoxM1 regulates the expression of Skp2 protein, which is known to promote degradation of the cell cycle regulator p27(Kip1). These results showed that FoxM1 is overexpressed in human glioblastomas and contributes to glioma tumorigenicity. Therefore, FoxM1 might be a new potential target of therapy for human malignant gliomas.


The association between laminin and microglial morphology in vitro.
Microglia are immune cells in the central nervous system (CNS) that contribute to primary innate immune responses. The morphology of microglia is closely associated with their functional activities. The majority of microglial studies have focused on the ramified or amoeboid morphology; however, bipolar/rod-shaped microglia have recently received much attention. Bipolar/rod-shaped microglia form trains with end-to-end alignment in injured brains and retinae, which is proposed as an important mechanism in CNS repair. We previously established a cell culture model system to enrich bipolar/rod-shaped microglia simply by growing primary microglia on scratched poly-D-lysine (PDL)/laminin-coated surfaces. Here, we investigated the role of laminin in morphological changes of microglia. Bipolar/rod-shaped microglia trains were transiently formed on scratched surfaces without PDL/laminin coating, but the microglia alignment disappeared after 3 days in culture. Amoeboid microglia digested the surrounding laminin, and the gene and protein expression of laminin-cleaving genes Adam9 and Ctss was up-regulated. Interestingly, lipopolysaccharide (LPS)-induced transformation from bipolar/rod-shaped into amoeboid microglia increased the expression of Adam9 and Ctss, and the expression of these genes in LPS-treated amoeboid-enriched cultures remained unchanged. These results indicate a strong association between laminin and morphological transformation of microglia, shedding new light on the role of bipolar/rod-shaped microglia in CNS repair.


Routine Microsecond Molecular Dynamics Simulations with AMBER on GPUs. 1. Generalized Born.
We present an implementation of generalized Born implicit solvent all-atom classical molecular dynamics (MD) within the AMBER program package that runs entirely on CUDA enabled NVIDIA graphics processing units (GPUs). We discuss the algorithms that are used to exploit the processing power of the GPUs and show the performance that can be achieved in comparison to simulations on conventional CPU clusters. The implementation supports three different precision models in which the contributions to the forces are calculated in single precision floating point arithmetic but accumulated in double precision (SPDP), or everything is computed in single precision (SPSP) or double precision (DPDP). In addition to performance, we have focused on understanding the implications of the different precision models on the outcome of implicit solvent MD simulations. We show results for a range of tests including the accuracy of single point force evaluations and energy conservation as well as structural properties pertainining to protein dynamics. The numerical noise due to rounding errors within the SPSP precision model is sufficiently large to lead to an accumulation of errors which can result in unphysical trajectories for long time scale simulations. We recommend the use of the mixed-precision SPDP model since the numerical results obtained are comparable with those of the full double precision DPDP model and the reference double precision CPU implementation but at significantly reduced computational cost. Our implementation provides performance for GB simulations on a single desktop that is on par with, and in some cases exceeds, that of traditional supercomputers.


Ultrafast dynamics of the real and imaginary permittivity parts of a photoexcited silver layer revealed by surface plasmon resonance.
Dynamics of the real and imaginary parts of the dielectric permittivity of a photoexcited silver layer has been investigated by means of femtosecond pump-probe spectroscopy in a surface plasmon resonance Kretschmann configuration. Both real and imaginary permittivity parts experience changes in the visible-near-IR regions under silver excitation at 400 nm. The changes are stronger, particularly those of the imaginary part, at longer wavelengths. Three excited states are formed during the relaxation process, which are attributed to the nonequilibrium and equilibrium heated electron distributions and lattice heating. Different time evolutions of the real and imaginary dielectric permittivity parts are explained by different contributions from interband and intraband transitions caused by plasma frequency and electron scattering frequency variations.


Prevalence and predictability of handling effects in field studies: results from field experiments and a meta-analysis.
Various effects on plant growth associated with handling or touching plants are well documented from greenhouse and laboratory studies, but are generally unknown or ignored under field conditions. We examined the prevalence of the effects of handling, at levels typical of many ecological experiments, on aboveground biomass and damage by invertebrate herbivores for a total of 16 common species from three plant communities in western Canada. Significant effects of handling were observed in the alpine meadow and grassland, but not in the boreal forest. Handling reduced aboveground biomass and increased the mean intensity of invertebrate leaf damage for most species. A meta-analysis of the relationship between plant traits and response to handling indicated that woody plants and species without strong chemical or conspicuous morphological defenses were most strongly affected. Overall, our results indicate that potentially confounding effects of routinely sampling plants in the field are widespread and merit further investigation.


Oncogenic KRAS-Driven Metabolic Reprogramming in Pancreatic Cancer Cells Utilizes Cytokines from the Tumor Microenvironment.
A hallmark of pancreatic ductal adenocarcinoma (PDAC) is an exuberant stroma comprised of diverse cell types that enable or suppress tumor progression. Here, we explored the role of oncogenic KRAS in protumorigenic signaling interactions between cancer cells and host cells. We show that KRAS mutation (KRAS*) drives cell-autonomous expression of type I cytokine receptor complexes (IL2rγ-IL4rα and IL2rγ-IL13rα1) in cancer cells that in turn are capable of receiving cytokine growth signals (IL4 or IL13) provided by invading Th2 cells in the microenvironment. Early neoplastic lesions show close proximity of cancer cells harboring KRAS* and Th2 cells producing IL4 and IL13. Activated IL2rγ-IL4rα and IL2rγ-IL13rα1 receptors signal primarily via JAK1-STAT6. Integrated transcriptomic, chromatin occupancy, and metabolomic studies identified MYC as a direct target of activated STAT6 and that MYC drives glycolysis. Thus, paracrine signaling in the tumor microenvironment plays a key role in the KRAS*-driven metabolic reprogramming of PDAC. SIGNIFICANCE: Type II cytokines, secreted by Th2 cells in the tumor microenvironment, can stimulate cancer cell-intrinsic MYC transcriptional upregulation to drive glycolysis. This KRAS*-driven heterotypic signaling circuit in the early and advanced tumor microenvironment enables cooperative protumorigenic interactions, providing candidate therapeutic targets in the KRAS* pathway for this intractable disease.


Impact of Applying Palliative Care on Symptoms and Survival of Patients with Advanced Chronic Disease Admitted to the Emergency Department.
In the emergency department, there is a need to provide palliative care; however, they are not usually administered. The present study evaluates the evolution of the intensity of the symptoms when applying palliative care, in adult patients with advanced chronic disease admitted to the emergency room, and compares survival between those who receive this care and those who do not. A clinical intervention study was conducted including patients older than 18 years with advanced chronic disease admitted to the emergency room with an indication of palliative support according to the Supportive and Palliative Care Indicators Tool 2015. Three hundred and seven patients were studied (74 in the intervention group and 233 in the group not intervened). In the intervention group, the intensity of pre- and postintervention symptoms was compared (Wilcoxon test). The survival of both the groups were then compared (logrank test). There was a significant decrease in pain and dyspnea at 24 and 48 h postintervention (P < 0.01), respectively, while drowsiness increased significantly at 24 h (P < 0.01) but did not change at 48 h (P = 0.38). Excluding patients with better functional status, there was less survival at 3 months in the intervention group (P = 0.01). Dyspnea and pain decreased with the application of palliative care but not drowsiness. Survival in the intervention group was lower than in the nonintervention group. However, the reason for providing palliative care is to relieve suffering at the end of life.


Prevalence of doping use in elite sports: a review of numbers and methods.
The prevalence of doping in elite sports is relevant for all those involved in sports, particularly for evaluating anti-doping policy measures. Remarkably, few scientific articles have addressed this subject so far, and the last review dates back to 1997. As a consequence, the true prevalence of doping in elite sports is unknown. Even though it is virtually impossible to uncover the exact prevalence of a prohibited activity such as doping, various methods are available to uncover parts of this particular problem, which enables the circumvention (to a certain degree) of the issues of truthfulness, definition problems and the limits of pharmacological evidence. This review outlines the various methods that exist and presents the scarce data available in this area. It is concluded that a combination of questionnaires using the Randomised Response Technique and models of biological parameters is able to provide the statistical possibilities to reveal accurate estimates of this often undisclosed practice. Data gathered in this way yield an estimation of 14-39% of current adult elite athletes who intentionally used doping. These period prevalences have been found in specific sub-groups of elite athletes, and the available data suggest that the prevalence of doping is considerably different between sub-groups with varying types of sport, levels and nationalities. The above-mentioned figure of 14-39% is likely to be a more accurate reflection of the prevalence of intentional doping in elite sports than that provided by doping control test results (estimate of doping: 1-2% annually) or questionnaire-based research (estimations between 1 and 70% depending on sport, level and exact definitions of intent and doping). In the future, analytical science may play a more important role in this topic if it may become feasible to detect very low concentrations of prohibited substances in sewage systems downstream of major sporting events. However, it is clear that current doping control test results show a distinct underestimation of true doping prevalence. It does not seem feasible to distil better estimates of the prevalence of doping based on performance indicators or ego documents because of the various existing effects that influence athletic performance. Such information can only be used as extra information to augment the accuracy of prevalence rates that have been found by using other techniques. True doping prevalence studies have been scarce in elite sports so far. With the correct application of the available scientific methods, preferably using harmonised definitions of the terms 'doping' and 'elite sports', more information on this topic may be gathered in a relatively short time. This would assist anti-doping professionals in the future in order to evaluate the effects of possible anti-doping measures, and better anti-doping policies would serve athletes who compete without doping. The existing anti-doping measures seriously impact the lives of elite athletes and their immediate entourage, which imposes a moral burden to evaluate these measures in the best possible way.


The societal benefits of reducing six behavioural risk factors: an economic modelling study from Australia.
A large proportion of disease burden is attributed to behavioural risk factors. However, funding for public health programs in Australia remains limited. Government and non-government organisations are interested in the productivity effects on society from reducing chronic diseases. We aimed to estimate the potential health status and economic benefits to society following a feasible reduction in the prevalence of six behavioural risk factors: tobacco smoking; inadequate fruit and vegetable consumption; high risk alcohol consumption; high body mass index; physical inactivity; and intimate partner violence. Simulation models were developed for the 2008 Australian population. A realistic reduction in current risk factor prevalence using best available evidence with expert consensus was determined. Avoidable disease, deaths, Disability Adjusted Life Years (DALYs) and health sector costs were estimated. Productivity gains included workforce (friction cost method), household production and leisure time. Multivariable uncertainty analyses and correction for the joint effects of risk factors on health status were undertaken. Consistent methods and data sources were used. Over the lifetime of the 2008 Australian adult population, total opportunity cost savings of AUD2,334 million (95% Uncertainty Interval AUD1,395 to AUD3,347; 64% in the health sector) were found if feasible reductions in the risk factors were achieved. There would be 95,000 fewer DALYs (a reduction of about 3.6% in total DALYs for Australia); 161,000 less new cases of disease; 6,000 fewer deaths; a reduction of 5 million days in workforce absenteeism; and 529,000 increased days of leisure time. Reductions in common behavioural risk factors may provide substantial benefits to society. For example, the total potential annual cost savings in the health sector represent approximately 2% of total annual health expenditure in Australia. Our findings contribute important new knowledge about productivity effects, including the potential for increased household and leisure activities, associated with chronic disease prevention. The selection of targets for risk factor prevalence reduction is an important policy decision and a useful approach for future analyses. Similar approaches could be applied in other countries if the data are available.


A simple optical encryption based on shape merging technique in periodic diffraction correlation imaging.
In Periodic diffraction correlation imaging (PDCI), the images of several objects located in different spatial positions can be integrated into one image following certain rules, which is named shape merging. In this paper, we proposed and demonstrated this new technique. It can be realized without SLM or beam-splitter. And this effect can find novel application in optical encryption, enabling transmission of object information to a remote place secretly.


An HIV/AIDS knowledge scale for adolescents: item response theory analyses based on data from a study in South Africa and Tanzania.
A 14-item human immunodeficiency virus/acquired immunodeficiency syndrome knowledge scale was used among school students in 80 schools in 3 sites in Sub-Saharan Africa (Cape Town and Mankweng, South Africa, and Dar es Salaam, Tanzania). For each item, an incorrect or don't know response was coded as 0 and correct response as 1. Exploratory factor analyses based on polychoric correlations showed two separate factors for all sites. Two-parameter item response theory (IRT) analysis (bifactorial multiple indicators multiple causes confirmatory factor analysis models) consistently showed a general first factor and a second 'method' factor. One single global latent variable seemed to sufficiently well capture most of the systematic variation in knowledge. Some items did not discriminate well between levels of the underlying knowledge latent variable and information values were highest for low levels of knowledge. The scale might be improved by adding items, in particular items that are more difficult to answer. Some differential item functioning effects related to site and socioeconomic status were identified. Scores on the latent knowledge variable were particularly low among females in Dar es Salaam and Mankweng, and were negatively associated with socioeconomic status. This study illustrates advantages of using IRT analysis instead of more conventional approaches to examining psychometric properties of knowledge scales.


Healthy lifestyle factors in the primary prevention of coronary heart disease among men: benefits among users and nonusers of lipid-lowering and antihypertensive medications.
Healthy lifestyle choices such as eating a prudent diet, exercising regularly, managing weight, and not smoking may substantially reduce coronary heart disease (CHD) risk by improving lipids, blood pressure, and other risk factors. The burden of CHD that could be avoided through adherence to these modifiable lifestyle factors has not been assessed among middle-aged and older US men, specifically men taking medications for hypertension or hypercholesterolemia. We prospectively monitored 42 847 men in the Health Professionals Follow-up Study, 40 to 75 years of age and free of disease in 1986. Lifestyle factors were updated through self-reported questionnaires. Low risk was defined as (1) absence of smoking, (2) body mass index <25 kg/m2, (3) moderate-to-vigorous activity > or = 30 min/d, (4) moderate alcohol consumption (5 to 30 g/d), and (5) the top 40% of the distribution for a healthy diet score. Over 16 years, we documented 2183 incident cases of CHD (nonfatal myocardial infarction and fatal CHD). In multivariate-adjusted Cox proportional hazards models, men who were at low risk for 5 lifestyle factors had a lower risk of CHD (relative risk: 0.13; 95% confidence interval [CI]: 0.09, 0.19) compared with men who were at low risk for no lifestyle factors. Sixty-two percent (95% CI: 49%, 74%) of coronary events in this cohort may have been prevented with better adherence to these 5 healthy lifestyle practices. Among men taking medication for hypertension or hypercholesterolemia, 57% (95% CI: 32%, 79%) of all coronary events may have been prevented with a low-risk lifestyle. Compared with men who did not make lifestyle changes during follow-up, those who adopted > or = 2 additional low-risk lifestyle factors had a 27% (95% CI: 7%, 43%) lower risk of CHD. A majority of CHD events among US men may be preventable through adherence to healthy lifestyle practices, even among those taking medications for hypertension or hypercholesterolemia.


Beliefs and practices about antiretroviral medication: a study of poor urban Kenyans living with HIV/AIDS.
Interest in medication-taking as a social behaviour is growing. Drawing on qualitative data, this study interrogates beliefs and practices related to antiretroviral therapy (ART) use among urban poor Kenyan people living with HIV/AIDS (PLWHA). Responding PLWHA relied on a range of ingenious strategies to remember to take their medications but did not necessarily perceive compliance with medical instructions as key to treatment efficacy. They also believed that compliance can even hurt some patients. PLWHA relied on both compliance and non-compliance to seek social acceptance, maintain a reputation of being healthy, dispel rumours about one's status, and minimise economic vulnerability. Compliance was further used to mark gratitude to supportive caregivers and providers, and non-compliance to appraise the efficacy of other treatments which promise permanent cure. The medication-taking practices of poor Kenyan PLWHA reflect their struggles with deprived livelihoods and stigma.


Relationship between sociodemographic factors and selection into UK postgraduate medical training programmes: a national cohort study.
Knowledge about allocation of doctors into postgraduate training programmes is essential in terms of workforce planning, transparency and equity issues. However, this is a rarely examined topic. To address this gap in the literature, the current study examines the relationships between applicants' sociodemographic characteristics and outcomes on the UK Foundation Training selection process. A longitudinal, cohort study of trainees who applied for the first stage of UK postgraduate medical training in 2013-2014. We used UK Medical Education Database (UKMED) to access linked data from different sources, including medical school admissions, assessments and postgraduate training. Multivariable ordinal regression analyses were used to predict the odds of applicants being allocated to their preferred foundation schools. Applicants allocated to their first-choice foundation school scored on average a quarter of an SD above the average of all applicants in the sample. After adjusting for Foundation Training application score, no statistically significant effects were observed for gender, socioeconomic status (as determined by income support) or whether applicants entered medical school as graduates or not. Ethnicity and place of medical qualification were strong predictors of allocation to preferred foundation school. Applicants who graduated from medical schools in Wales, Scotland and Northern Ireland were 1.17 times, 3.33 times and 12.64 times (respectively), the odds of applicants who graduated from a medical school in England to be allocated to a foundation school of their choice. The data provide supportive evidence for the fairness of the allocation process but highlight some interesting findings relating to 'push-pull' factors in medical careers decision-making. These findings should be considered when designing postgraduate training policy.


Defining the Functional Role of NaV1.7 in Human Nociception.
Loss-of-function mutations in NaV1.7 cause congenital insensitivity to pain (CIP); this voltage-gated sodium channel is therefore a key target for analgesic drug development. Utilizing a multi-modal approach, we investigated how NaV1.7 mutations lead to human pain insensitivity. Skin biopsy and microneurography revealed an absence of C-fiber nociceptors in CIP patients, reflected in a reduced cortical response to capsaicin on fMRI. Epitope tagging of endogenous NaV1.7 revealed the channel to be localized at the soma membrane, axon, axon terminals, and the nodes of Ranvier of induced pluripotent stem cell (iPSC) nociceptors. CIP patient-derived iPSC nociceptors exhibited an inability to properly respond to depolarizing stimuli, demonstrating that NaV1.7 is a key regulator of excitability. Using this iPSC nociceptor platform, we found that some NaV1.7 blockers undergoing clinical trials lack specificity. CIP, therefore, arises due to a profound loss of functional nociceptors, which is more pronounced than that reported in rodent models, or likely achievable following acute pharmacological blockade. VIDEO ABSTRACT.


Cdk5 interacts with Hif-1α in neurons: a new hypoxic signalling mechanism?
The cyclin dependent kinase 5 (Cdk5)/p35 complex is essential for regulation of cell survival during development and in models of neuronal excitotoxicity. Dysregulation of Cdk5, by cleavage of its neuronal specific activators p35 and p39, has been implicated in various neurodegenerative disorders such as Alzheimer's disease, however targets of the complex that regulate neuronal survival physiologically and/or during pathogenesis are largely unknown. Since hypoxia is a key feature in the pathogenesis of several neuronal disorders we investigated a role for Cdk5/p35 in the neuronal hypoxic response. Our data show that hypoxia modulates the p35/Cdk5 complex in primary cortical neurons at the transcriptional and protein level. Furthermore hypoxic induction of Cdk5 activity correlates with Hif-1α stabilisation, and direct interaction between these proteins can occur. Importantly, we demonstrate that Cdk5-mediated signaling is involved in Hif-1α stabilisation since inhibition of Cdk5 by roscovitine abrogates Hif-1α accumulation and induces cell death. Taken together our results show that the Cdk5/p35 complex may significantly contribute to modulation of Hif-1α stabilisation and impact neuronal survival during oxygen deprivation. Thus this study highlights a new hypoxia-mediated signaling pathway and implicates the cytoskeleton as a potential regulator of Hif-1α.


Timing of liver transplantation in biliary atresia-results in 71 children managed by a multidisciplinary team.
Kasai portoenterostomy (KP) remains the initial surgical therapy for biliary atresia (BA). Liver transplantation (LTx) is offered after a failed KP or if KP is not feasible. The timing of LTx in these children is not well established. We attempted to define factors that may help choose the optimal timing for LTx in children with BA managed by a multidisciplinary team including a pediatric surgeon, hepatologist, and liver transplant surgeon. Records of children who underwent LTx for BA at our institution between January 1998 and December 2006 were reviewed. Clinical data such as pre-LTx pediatric end-stage liver disease (PELD) score, location of KP, and outcome were evaluated. Seventy one children underwent 77 liver transplants for BA at an average age of 25 months (range, 3-216 months). Sixty-one had a previous KP, 30 at our institution. Ten had LTx without KP. The overall patient survival was 94.4% and overall graft survival was 87% at median follow-up of 58 months (range, 6-111 months). Four patients died, 1 because of vascular thrombosis despite repeat LTx, 1 because of fungal infection after LTx, and 2 because of causes unrelated to LTx. Six children required retransplantation. Living donor liver transplantation was performed in 32 of these children with 91% patient and graft survival. Fifty-three children had a PELD score of 10 or higher with patient and graft survivals of 92% and 86%, respectively. Eighteen children had a PELD score of less than 10 with patient and graft survivals of 100%. For the 30 children who underwent KP at our institution, the median age at LTx was 9 months (range, 3-168 months), and patient and graft survival were both 93%. Outcome of LTx for BA is excellent. Children with higher PELD scores (>/=10) at LTx may have worse outcome. Children with a PELD score of less than 10 survived with their original grafts. In children with BA, the PELD score should be monitored and may help stratify patients for eventual LTx. When a child with BA is deemed a candidate for LTx, the PELD score should be determined. A PELD score that approaches 10 should trigger discussion of LTx and living donor liver transplantation with the family.


Study on transition from photonic-crystal laser to random laser.
The dependence of the lasing threshold on the amount of positional disorder in photonic crystal structures is newly studied by means of the finite element method, not of the finite difference time domain method usually used. A two-dimensional model of a photonic crystal consisting of dielectric cylinders arranged on a triangular lattice within a circular region is considered. The cylinders are assumed to be homogeneous and infinitely long. Positional disorder of the cylinders is introduced to the photonic crystals. Optically active medium is introduced to the interspace among the cylinders. The population inversion density of the optically active medium is modeled by the negative imaginary part of dielectric constant. The ratio between radiative power of electromagnetic field without amplification and that with amplification is computed as a function of the frequency and the imaginary part of the dielectric constant, and the threshold of the imaginary part, namely population inversion density for laser action is obtained. These analyses are carried out for various amounts of disorder. The variation of the lasing threshold from photonic-crystal laser to random laser is revealed by systematic computations with numerical method of reliable accuracy for the first time. Moreover, a novel phenomenon, that the lasing threshold have a minimum against the amount of disorder, is found. In order to investigate the properties of the lasing states within the circular system, the distributions of the electric field amplitudes of the states are also calculated.


A genome-wide study shows a limited contribution of rare copy number variants to Alzheimer's disease risk.
We assessed the role of rare copy number variants (CNVs) in Alzheimer's disease (AD) using intensity data from 3260 AD cases and 1290 age-matched controls from the genome-wide association study (GWAS) conducted by the Genetic and Environmental Risk for Alzheimer's disease Consortium (GERAD). We did not observe a significant excess of rare CNVs in cases, although we did identify duplications overlapping APP and CR1 which may be pathogenic. We looked for an excess of CNVs in loci which have been highlighted in previous AD CNV studies, but did not replicate previous findings. Through pathway analyses, we observed suggestive evidence for biological overlap between single nucleotide polymorphisms and CNVs in AD susceptibility. We also identified that our sample of elderly controls harbours significantly fewer deletions >1 Mb than younger control sets in previous CNV studies on schizophrenia and bipolar disorder (P = 8.9 × 10(-4) and 0.024, respectively), raising the possibility that healthy elderly individuals have a reduced rate of large deletions. Thus, in contrast to diseases such as schizophrenia, autism and attention deficit/hyperactivity disorder, CNVs do not appear to make a significant contribution to the development of AD.


Characterization and comparison of lidocaine-tetracaine and lidocaine-camphor eutectic mixtures based on their crystallization and hydrogen-bonding abilities.
Eutectic mixtures formed between active pharmaceutical ingredients and/or excipients provide vast scope for pharmaceutical applications. This study aimed at the exploration of the crystallization abilities of two eutectic mixtures (EM) i.e., lidocaine-tetracaine and lidocaine-camphor (1:1 w/w). Thermogravimetric analysis (TGA) for degradation behavior whereas modulated temperature differential scanning calorimetry (MTDSC) set in first heating, cooling, and second heating cycles, was used to qualitatively analyze the complex exothermic and endothermic thermal transitions. Raman microspectroscopy characterized vibrational information specific to chemical bonds. Prepared EMs were left at room temperature for 24 h to visually examine their crystallization potentials. The degradation of lidocaine, tetracaine, camphor, lidocaine-tetracaine EM, and lidocaine-camphor EM began at 196.56, 163.82, 76.86, 146.01, and 42.72°C, respectively, which indicated that eutectic mixtures are less thermostable compared to their individual components. The MTDSC showed crystallization peaks for lidocaine, tetracaine, and camphor at 31.86, 29.36, and 174.02°C, respectively (n = 3). When studying the eutectic mixture, no crystallization peak was observed in the lidocaine-tetracaine EM, but a lidocaine-camphor EM crystallization peak was present at 18.81°C. Crystallization occurred in lidocaine-camphor EM after being kept at room temperature for 24 h, but not in lidocaine-tetracaine EM. Certain peak shifts were observed in Raman spectra which indicated possible interactions of eutectic mixture components, when a eutectic mixture was formed. We found that if the components forming a eutectic mixture have crystallization peaks close to each other and have sufficient hydrogen-bonding capability, then their eutectic mixture is least likely to crystallize out (as seen in lidocaine-tetracaine EM) or vice versa (lidocaine-camphor EM).


The Use of Ropivacaine in Therapeutic Treatment of Oral Aphthosis.
The use of anaesthetic drugs in the treatment of oral aphthosis is one of the pharmaceutical possibilities that a doctor can use for the most painful forms. Normally, Lidocaine or Diclofenac is used to treat this disease, but they can be used for a very limited time and so they are of little practical use. In this study, the authors have used Ropivacaine whose pharmaceutical kinetics allows the analgesic effect to be active for 60 to 90 minutes. In our research, we compared 8 groups of patients who have been given 3 principal pharmaceutical products: one group was given an anaesthetic drug, one had a topical medication administered which is often used for the treatment of aphthous lesions, and the last group was given a multivitamin. These pharmaceutical products were used alone and in various possible combinations in the 8 groups. The results of this study are very interesting and show that in all the groups that used anaesthetics there was more satisfaction on the patients' part because their pain level became more manageable right after the first application of the drug and the patients could carry on with their normal lives.


Are some teat disinfectant formulations more effective against specific bacteria isolated on teat skin than others?
The use of pre- and post-milking teat disinfectants can reduce teat bacterial load and aid in the collection of high-quality milk. The objective of this study was to compare the reduction in bacteria populations on teat skin after the application of different commercial teat disinfectant products. Ten teat disinfectant products were applied to the teats of 10 Holstein-Friesian cows. One cow received one teat disinfectant product at each sampling point before cluster application for milking. A composite swab sample was taken of the 4 teats of each cow before and after teat disinfectant application. Swab samples were placed on three different selective agars to enumerate bacterial counts of staphylococcal, streptococcal and coliforms isolates on teat skin. Staphylococcal isolates were the most prominent bacterial group recovered on teat swabs (49%), followed by streptococcal (36%) and coliform (15%) isolates before the application of disinfectant. The average bacterial reductions on teat skin were shown to be 76%, 73% and 60% for staphylococcal, streptococcal and coliform isolates, respectively. All of the teat disinfectant products tested reduced teat bacterial load for all three bacterial groups. Product 4 containing 0.6% w/w diamine was the most effective against bacterial populations of staphylococcal and streptococcal isolates on teat skin with a reduction of 90% and 94%, respectively. Whereas product 10, which contained 0.5% w/w iodine, resulted in the highest reduction in coliforms on teat skin with a reduction of 91%. Results from this study suggest that specific bacterial population loads on teats can be reduced using different teat disinfectant formulations.


Organic Food Consumption during Pregnancy and Hypospadias and Cryptorchidism at Birth: The Norwegian Mother and Child Cohort Study (MoBa).
The etiologies of the male urogenital anomalies hypospadias and cryptorchidism remain unclear. It has been suggested that maternal diet and environmental contaminants may affect the risk of these anomalies via placental or hormonal disturbances. We examined associations between organic food consumption during pregnancy and prevalence of hypospadias and cryptorchidism at birth. Our study includes 35,107 women participating in the Norwegian Mother and Child Cohort Study (MoBa) who delivered a singleton male infant. Information about use of six groups of organically produced food (vegetables, fruit, bread/cereal, milk/dairy products, eggs, and meat) during pregnancy was collected by a food frequency questionnaire. Women who indicated that they sometimes, often, or mostly consumed organic foods in at least one of the six food groups were classified as organic food consumers in analyses. Hypospadias and cryptorchidism diagnoses were retrieved from the Medical Birth Registry of Norway. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using multiple logistic regression. Seventy-four male newborns were diagnosed with hypospadias (0.2%), and 151 with cryptorchidism (0.4%). Women who consumed any organic food during pregnancy were less likely to give birth to a boy with hypospadias (OR = 0.42; 95% CI: 0.25, 0.70, based on 21 exposed cases) than women who reported they never or seldom consumed organic food. Associations with specific organic foods were strongest for vegetable (OR = 0.36; 95% CI: 0.15, 0.85; 10 exposed cases) and milk/dairy (OR = 0.43; 95% CI: 0.17, 1.07; 7 exposed cases) consumption. No substantial association was observed for consumption of organic food and cryptorchidism. Consumption of organically produced foods during pregnancy was associated with a lower prevalence of hypospadias in our study population. These findings were based on small numbers of cases and require replication in other study populations.


Thiamine Deficiency-Mediated Brain Mitochondrial Pathology in Alaskan Huskies with Mutation in SLC19A3.1.
Alaskan Husky encephalopathy (AHE(1) ) is a fatal brain disease associated with a mutation in SLC19A3.1 (c.624insTTGC, c.625C>A). This gene encodes for a thiamine transporter 2 with a predominately (CNS) central nervous system distribution. Considering that brain is particularly vulnerable to thiamine deficiency because of its reliance on thiamine pyrophosphate (TPP)-dependent metabolic pathways involved in energy metabolism and neurotransmitter synthesis, we characterized the impact of this mutation on thiamine status, brain bioenergetics and the contribution of oxidative stress to this phenotype. In silico modeling of the mutated transporter indicated a significant loss of alpha-helices resulting in a more open protein structure suggesting an impaired thiamine transport ability. The cerebral cortex and thalamus of affected dogs were severely deficient in TPP-dependent enzymes accompanied by decreases in mitochondrial mass and oxidative phosphorylation (OXPHOS) capacity, and increases in oxidative stress. These results along with the behavioral and pathological findings indicate that the phenotype associated with AHE is consistent with a brain-specific thiamine deficiency, leading to brain mitochondrial dysfunction and increased oxidative stress. While some of the biochemical deficits, neurobehavior and affected brain areas in AHE were shared by Wernicke's and Korsakoff's syndromes, several differences were noted likely arising from a tissue-specific vs. that from a whole-body thiamine deficiency.


Severe Hypoglycemia and Cognitive Function in Older Adults With Type 1 Diabetes: The Study of Longevity in Diabetes (SOLID).
In children with type 1 diabetes (T1D), severe hypoglycemia (SH) is associated with poorer cognition, but the association of SH with cognitive function in late life is unknown. Given the increasing life expectancy in people with T1D, understanding the role of SH in brain health is crucial. We examined the association between SH and cognitive function in 718 older adults with T1D from the Study of Longevity in Diabetes (SOLID). Subjects self-reported recent SH (previous 12 months) and lifetime history of SH resulting in inpatient/emergency department utilization. Global and domain-specific cognition (language, executive function, episodic memory, and simple attention) were assessed. The associations of SH with cognitive function and impaired cognition were evaluated via linear and logistic regression models, respectively. Thirty-two percent of participants (mean age 67.2 years) reported recent SH and 50% reported lifetime SH. Compared with those with no SH, subjects with a recent SH history had significantly lower global cognition scores. Domain-specific analyses revealed significantly lower scores on language, executive function, and episodic memory with recent SH exposure and significantly lower executive function with lifetime SH exposure. Recent SH was associated with impaired global cognition (odds ratio [OR] 3.22, 95% CI 1.30, 7.94) and cognitive impairment on the language domain (OR 3.15, 95% CI 1.19, 8.29). Among older adults with T1D, recent SH and lifetime SH were associated with worse cognition. Recent SH was associated with impaired global cognition. These findings suggest a deleterious role of SH on the brain health of older patients with T1D and highlight the importance of SH prevention.


Characterization of sugar uptake in wild-type Streptomyces clavuligerus, which is impaired in glucose uptake, and in a glucose-utilizing mutant.
Wild-type Streptomyces clavuligerus NRRL 3585 is unable to utilize glucose. A glucose-utilizing (gut-1) mutant of S. clavuligerus NRRL 3585 has been obtained by N-methyl-N'-nitro-N-nitrosoguanidine mutagenesis. The gut-1 mutant is able to grow on glucose or galactose, while the wild type is unable to catabolize these hexoses. Similar binding affinities of glucose by cells of the wild type and the gut-1 mutant were found, but the wild type was unable to complete glucose transport. A soluble intracellular ATP-dependent (but not phosphoenolpyruvate-dependent) glucokinase activity was found both in the wild type and the gut-1 mutant. The gut-1 mutant has acquired a functional transport system that allows transport of glucose, 2-deoxyglucose, and galactose, as shown by hexose competition experiments. The gut-1 transport system concentrates glucose inside the cell at least 10- to 20-fold and is strongly inhibited by respiratory inhibitors, which prevent the establishment of a proton motive force, and by proton-conducting ionophores, suggesting that it is energized by a proton motive force. The new transport system is not completely sugar specific (transporting galactose and glucose through the same system), as opposed to the hexose-specific system reported in wild-type Streptomyces griseus.


Advancing the long view of ecological change in tundra systems. Introduction.
Despite uncertainties related to sustained funding, ideological rivalries and the turnover of research personnel, long-term studies and studies espousing a long-term perspective in ecology have a history of contributing landmark insights into fundamental topics, such as population- and community dynamics, species interactions and ecosystem function. They also have the potential to reveal surprises related to unforeseen events and non-stationary dynamics that unfold over the course of ongoing observation and experimentation. The unprecedented rate and magnitude of current and expected abiotic changes in tundra environments calls for a synthetic overview of the scope of ecological responses these changes have elicited. In this special issue, we present a series of contributions that advance the long view of ecological change in tundra systems, either through sustained long-term research, or through retrospective or prospective modelling. Beyond highlighting the value of long-term research in tundra systems, the insights derived herein should also find application to the study of ecological responses to environmental change in other biomes as well.


Temporal lobe volume measurement from MR images: accuracy and left-right asymmetry in normal persons.
The effect of several magnetic resonance (MR) variables on the accuracy of volume measurements in phantom objects was investigated by use of an off-line automatic border-outlining and internal area pixel-counting computer program, and an optimal set of imaging variables was identified. Measurements were made of the temporal lobe volumes of a gross fixed brain specimen from MR image data. The range in accuracy was from -2 to +7%, and the standard deviation of the difference in right minus left lobe volume measurements obtained from the MR images and those obtained by use of Archimedes' principle was 1 cm3. This volumetric technique was applied to 25 normal persons, most of whom were right-handed. The median ratio of right to left temporal lobe volume was 1.16 (range 0.99-1.23). The nondominant temporal lobe was significantly larger than the dominant. The mean difference (95% confidence interval) between right and left volumes was 7 cm3 (6-9 cm3). This confidence interval was similar to that obtained when the variability within a subject (estimated from the gross fixed brain specimen) was taken into account. Unilateral temporal lobe atrophy, particularly in patients with temporal lobe epilepsy, should be interpreted from MR images with this range of discrepancy in normal left-right size in mind.


Evaluation of the effect of topical chamomile (Matricaria chamomilla L.) oleogel as pain relief in migraine without aura: a randomized, double-blind, placebo-controlled, crossover study.
Phytotherapy is a source of finding new remedies for migraine. Traditional chamomile oil (chamomile extraction in sesame oil) is a formulation in Persian medicine (PM) for pain relief in migraine. An oleogel preparation of reformulated traditional chamomile oil was prepared and then standardized based on chamazulene (as a marker in essential oil) and apigenin via gas chromatography (GC) and high-performance liquid chromatography (HPLC) methods, respectively. A crossover double-blind clinical trial was performed with 100 patients. Each patient took two tubes of drug and two tubes of placebo during the study. Visual analog scale (VAS) questionnaires were filled in by the patients and scores were given, ranging from 0 to 10 (based on the severity of pain) during 24 h. Other complications like nausea, vomiting, photophobia, and phonophobia were also monitored. There was 4.48 ± 0.01 μl/ml of chamazulene and 0.233 mg/g of apigenin in the preparation (by correcting the amount with extraction ratio). Thirty-eight patients in the drug-placebo and 34 patients in the placebo-drug groups (a total number of 72 patients as per protocol) completed the process in the randomized controlled trial (RCT). Adapted results from the questionnaires showed that pain, nausea, vomiting, photophobia, and phonophobia significantly (p < 0.001) decreased by using chamomile oleogel on the patients after 30 min. Results supported the efficacy of chamomile oleogel as a pain relief in migraine without aura.


Molecular phylogeny, pathogenicity and toxigenicity of Fusarium oxysporum f. sp. lycopersici.
The present study aimed at the molecular characterization of pathogenic and non pathogenic F. oxysporum f. sp. lycopersici strains isolated from tomato. The causal agent isolated from symptomatic plants and soil samples was identified based on morphological and molecular analyses. Pathogenicity testing of 69 strains on five susceptible tomato varieties showed 45% of the strains were highly virulent and 30% were moderately virulent. Molecular analysis based on the fingerprints obtained through ISSR indicated the presence of wide genetic diversity among the strains. Phylogenetic analysis based on ITS sequences showed the presence of at least four evolutionary lineages of the pathogen. The clustering of F. oxysporum with non pathogenic isolates and with the members of other formae speciales indicated polyphyletic origin of F. oxysporum f. sp. lycopersici. Further analysis revealed intraspecies variability and nucleotide insertions or deletions in the ITS region among the strains in the study and the observed variations were found to be clade specific. The high genetic diversity in the pathogen population demands for development of effective resistance breeding programs in tomato. Among the pathogenic strains tested, toxigenic strains harbored the Fum1 gene clearly indicating that the strains infecting tomato crops have the potential to produce Fumonisin.


Chronic hepatitis C treatment outcomes in low- and middle-income countries: a systematic review and meta-analysis.
To assess the effectiveness of treatment for hepatitis C virus (HCV) infection in low- and middle-income countries and identify factors associated with successful outcomes. We performed a systematic review and meta-analysis of studies of HCV treatment programmes in low- and middle-income countries. The primary outcome was a sustained virological response (SVR). Factors associated with treatment outcomes were identified by random-effects meta-regression analysis. The analysis involved data on 12 213 patients included in 93 studies from 17 countries. The overall SVR rate was 52% (95% confidence interval, CI: 48-56). For studies in which patients were predominantly infected with genotype 1 or 4 HCV, the pooled SVR rate was 49% (95% CI: 43-55). This was significantly lower than the rate of 59% (95% CI: 54-64) found in studies in which patients were predominantly infected with other genotypes (P = 0.012). Factors associated with successful outcomes included treatment with pegylated interferon and ribavirin, infection with an HCV genotype other than genotype 1 or 4 and the absence of liver damage or human immunodeficiency virus infection at baseline. No significant difference in the SVR rate was observed between weight-adjusted and fixed-dose ribavirin treatment. Overall, 17% (95% CI: 13-23) of adverse events resulted in treatment interruption or dose modification, but only 4% (95% CI: 3-5) resulted in treatment discontinuation. The outcomes of treatment for HCV infection in low- and middle-income countries were similar to those reported in high-income countries.


Rare-earth-doped fluoride nanoparticles with engineered long luminescence lifetime for time-gated in vivo optical imaging in the second biological window.
Biomedicine is continuously demanding new luminescent materials to be used as optical probes for the acquisition of high resolution, high contrast and high penetration in vivo images. These materials, in combination with advanced techniques, could constitute the first step towards new diagnosis and therapy tools. In this work, we report on the synthesis of long lifetime rare-earth-doped fluoride nanoparticles by adopting different strategies: core/shell and dopant engineering. The here developed nanoparticles show intense infrared emission in the second biological window with a long luminescence lifetime close to 1 millisecond. These two properties make the here presented nanoparticles excellent candidates for time-gated infrared optical bioimaging. Indeed, their potential application as optical imaging contrast agents for autofluorescence-free in vivo small animal imaging has been demonstrated, allowing high contrast real-time tracking of gastrointestinal absorption of nanoparticles and transcranial imaging of intracerebrally injected nanoparticles in the murine brain.


Influence of bending on power distribution in step-index plastic optical fibers and the calculation of bending loss.
A means of calculating optical power distribution in bent multimode optical fibers is proposed. It employs the power-flow equation approximated by the Fokker-Planck equation that is solved by the explicit finite-difference method. Conceptually important steps of this procedure include (i) dividing the full length of the bent optical fiber into a finite number of short, straight segments; (ii) solving the power equation for each segment sequentially to find its output distribution; and (iii) expressing that output distribution in rotated coordinates of the subsequent segment along the curved fiber to determine the input distribution for that subsequent segment and thus enable the calculation of the power flow and output distribution for it. The segment length and bend-induced perturbation of output angles are determined by geometric optics. The resulting power distributions are given at different cross sections along the curved fiber axis. They vary with the radius of fiber curvature and launch conditions. Results are compared to those for straight fiber. Bending loss is calculated as well.


Inhibition of SRC family kinases and receptor tyrosine kinases by dasatinib: possible combinations in solid tumors.
Dasatinib is a small molecule tyrosine kinase inhibitor that targets a wide variety of tyrosine kinases implicated in the pathophysiology of several neoplasias. Among the most sensitive dasatinib targets are ABL, the SRC family kinases (SRC, LCK, HCK, FYN, YES, FGR, BLK, LYN, and FRK), and the receptor tyrosine kinases c-KIT, platelet-derived growth factor receptor (PDGFR) α and β, discoidin domain receptor 1 (DDR1), c-FMS, and ephrin receptors. Dasatinib inhibits cell duplication, migration, and invasion, and it triggers apoptosis of tumoral cells. As a consequence, dasatinib reduces tumoral mass and decreases the metastatic dissemination of tumoral cells. Dasatinib also acts on the tumoral microenvironment, which is particularly important in the bone, where dasatinib inhibits osteoclastic activity and favors osteogenesis, exerting a bone-protecting effect. Several preclinical studies have shown that dasatinib potentiates the antitumoral action of various drugs used in the oncology clinic, paving the way for the initiation of clinical trials of dasatinib in combination with standard-of-care treatments for the therapy of various neoplasias. Trials using combinations of dasatinib with ErbB/HER receptor antagonists are being explored in breast, head and neck, and colorectal cancers. In hormone receptor-positive breast cancer, trials using combinations of dasatinib with antihormonal therapies are ongoing. Dasatinib combinations with chemotherapeutic agents are also under development in prostate cancer (dasatinib plus docetaxel), melanoma (dasatinib plus dacarbazine), and colorectal cancer (dasatinib plus oxaliplatin plus capecitabine). Here, we review the preclinical evidence that supports the use of dasatinib in combination for the treatment of solid tumors and describe various clinical trials developed following a preclinical rationale.


Prognostic value of pacing-induced mechanical alternans in patients with mild-to-moderate idiopathic dilated cardiomyopathy in sinus rhythm.
The relation between the occurrence of pacing-induced mechanical alternans and prognosis in patients with mild-to-moderate idiopathic dilated cardiomyopathy (IDCM) in sinus rhythm was investigated prospectively. The myocardial expression of genes for Ca2+-handling proteins in such patients was also examined. Mechanical alternans occurs in some patients with severe heart failure, but the relation between the occurrence of mechanical alternans and prognosis in patients with IDCM has remained unknown. Left ventricular (LV) pressure was measured during atrial pacing, and LV endomyocardial biopsy specimens were collected in 36 IDCM patients and 8 controls. Idiopathic dilated cardiomyopathy patients were divided into two groups consisting of 22 individuals who did not develop mechanical alternans at heart rates up to 140 beats/min (group A) and of 14 individuals who did (group B). The patients were followed up for a mean of 3.7 years. There was no significant difference in LV ejection fraction or the plasma concentration of brain natriuretic peptide between groups A and B. The myocardial abundance of ryanodine receptor 2 messenger ribonucleic acid (mRNA) was significantly lower in groups A and B than in controls, whereas that of sarcoplasmic reticulum Ca2+-ATPase mRNA was significantly lower in group B than in group A or controls. Stepwise multivariate analysis identified pacing-induced mechanical alternans as the strongest predictor of cardiac events. Event-free survival in group A was significantly greater than that in group B. The occurrence of pacing-induced mechanical alternans is a potentially useful indicator of poor prognosis in patients with mild-to-moderate IDCM in sinus rhythm.


Activation of tyrosine kinase c-Abl contributes to α-synuclein-induced neurodegeneration.
Aggregation of α-synuclein contributes to the formation of Lewy bodies and neurites, the pathologic hallmarks of Parkinson disease (PD) and α-synucleinopathies. Although a number of human mutations have been identified in familial PD, the mechanisms that promote α-synuclein accumulation and toxicity are poorly understood. Here, we report that hyperactivity of the nonreceptor tyrosine kinase c-Abl critically regulates α-synuclein-induced neuropathology. In mice expressing a human α-synucleinopathy-associated mutation (hA53Tα-syn mice), deletion of the gene encoding c-Abl reduced α-synuclein aggregation, neuropathology, and neurobehavioral deficits. Conversely, overexpression of constitutively active c-Abl in hA53Tα-syn mice accelerated α-synuclein aggregation, neuropathology, and neurobehavioral deficits. Moreover, c-Abl activation led to an age-dependent increase in phosphotyrosine 39 α-synuclein. In human postmortem samples, there was an accumulation of phosphotyrosine 39 α-synuclein in brain tissues and Lewy bodies of PD patients compared with age-matched controls. Furthermore, in vitro studies show that c-Abl phosphorylation of α-synuclein at tyrosine 39 enhances α-synuclein aggregation. Taken together, this work establishes a critical role for c-Abl in α-synuclein-induced neurodegeneration and demonstrates that selective inhibition of c-Abl may be neuroprotective. This study further indicates that phosphotyrosine 39 α-synuclein is a potential disease indicator for PD and related α-synucleinopathies.


Neonatal Bisphenol A Exposure Affects the IgM Humoral Immune Response to 4T1 Breast Carcinoma Cells in Mice.
Bisphenol A (BPA) is an endocrine disruptor of estrogenic nature. During the early stages of development, any exposure to BPA can have long-term effects. In this work, we study the potential alterations to the humoral antitumor immune (IgM) response in adult life after a single neonatal exposure to BPA. Female syngeneic BALB/c mice were exposed to a single dose of BPA of 250 μg/kg. Once sexual maturity was reached, a breast tumor was induced. After 25 days, the serum was obtained, and the populations of B cells in the spleen and lymph nodes were analyzed by flow cytometry. The reactivity of IgM was evaluated by 2D immunoblots. No significant changes were found in the B cell populations in the peripheral lymph nodes and the spleen. The level of ERα expression was not significantly different. However, the IgM reactivity was affected. In individuals treated with BPA, a decrease in the number of IgMs that recognize tumor antigens was observed. The possibility that these antibodies are the high affinity products of the adaptive response is discussed. The recognition of IgG was also evaluated but a null recognition was found in the controls as in the individuals treated with the 4T1 cells.


A positive genetic selection for disrupting protein-protein interactions: identification of CREB mutations that prevent association with the coactivator CBP.
The Escherichia coli tet-repressor (TetR) operator system was used to develop a variation of the yeast two-hybrid assay in which disruptions of protein-protein interactions can be identified by a positive selection. This assay, designated the "split-hybrid system," contains a two-component reporter. The first component contains LexA binding sites upstream of the TetR gene and the second contains TetR operator binding sites upstream of HIS3. Interaction of one protein fused to the LexA DNA binding domain with a second protein fused to the VP16 activation domain results in TetR expression. TetR subsequently binds to the tet operators, blocking the expression of HIS3 and preventing yeast growth in media lacking histidine. The utility of the split-hybrid system was analyzed by examining the phosphorylation-dependent interaction of CREB and its coactivator CREB binding protein (CBP). CREB and CBP associate through an interaction that depends upon CREB phosphorylation at Ser-133. Mutation of this phosphorylation site prevents yeast growth in the standard two-hybrid assay but allows growth in the split-hybrid strains. The split-hybrid system was used to identify other CREB mutations that disrupt its association with CBP. These mutations localized around the site of CREB phosphorylation, indicating that only a small portion of the CREB activation domain is required for CBP interaction. The yeast split-hybrid system should be useful in identifying mutations, proteins, peptides, and drugs that disrupt protein-protein interactions.


The Global Landscape of Nursing and Genomics.
Nurses have a pivotal role in bringing the benefits of genomics and precision medicine to everyday health care, but a concerted global effort is needed to transform nursing policy and practice to address widely acknowledged deficits in nurses' genomic literacy. The purpose was to conduct a global country and organization review of nursing engagement with genomics, informing a landscape analysis to assess readiness for integration of genomics into nursing. Global nursing leaders and nursing organizations were recruited using a purposive sampling strategy to complete an online survey that assessed the scope of genomic integration in practice and education, challenges and barriers, and priorities for action. The survey was administered online following an orientation webinar. Given the small numbers of nurse leaders globally, results were analyzed and presented descriptively. Delegates consisted of 23 nurse leaders from across the world. Genomic services were offered predominantly in specialty centers consisting mostly of newborn screening (15/18) and prenatal screening (11/18). Genomic literacy and infrastructure deficits were identified in both practice and education settings, with only one country reporting a genetic/genomic knowledge and skill requirement to practice as a general nurse. These data provide insights into the commitment to and capacity for nursing to integrate genomics, revealing common themes and challenges associated with adoption of genomic health services and integration into practice, education, and policy. Such insights offer valuable context and baseline information to guide the activities of a new Global Genomics Nursing Alliance (G2NA). The G2NA will use the landscaping exercise as a springboard to explore how to accelerate the integration of genomics into nursing healthcare. Genomics is relevant to all healthcare providers across the healthcare continuum. It provides an underpinning for understanding health, risks for and manifestations of disease, therapeutic decisions, development of new therapies, and responses to interventions. Harnessing the benefits of genomics to improve health and care outcomes and reduce costs is a global nursing challenge.


Substitution of nevirapine or efavirenz for protease inhibitor versus lipid-lowering therapy for the management of dyslipidaemia.
To evaluate simplified protease inhibitor (PI)-sparing antiretroviral treatment versus lipid-lowering therapy for the management of highly active antiretroviral therapy (HAART)-induced hyperlipidaemia. Randomized, open-label clinical trial assessing the efficacy on hyperlipidaemia of a switching therapy from PI to non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine or efavirenz versus a hypolipidaemic treatment (with pravastatin or bezafibrate) added to current, unchanged antiretroviral combination. All HIV-infected patients on their first HAART regimen, with stable immuno-virological features, naive to all NNRTIs, and with mixed hyperlipidaemia, were randomized to replace PI with nevirapine (arm A) or efavirenz (arm B), or to receive pravastatin (arm C) or bezafibrate (arm D) with unchanged HAART regimen, and were followed-up for 12 months. One hundred and thirty patients were evaluated: 29 patients were randomized to arm A, 34 to arm B, 36 to arm C, and 31 to arm D. At the end of the 12-month follow-up, a reduction of 25.2, 9.4, 41.2 and 46.6% in mean triglyceridaemia versus respective baseline values was reported in groups A, B, C and D, respectively, with statistically significant difference between arms A-B and C-D (P < 0.01). Similar results were reported for total and low-density lipoprotein cholesterol levels. Viro-immunological efficacy and tolerability profile were comparable in all considered arms. Pravastatin and bezafibrate proved significantly more effective in the management of HAART-related hyperlipidaemia than the switching therapy from PI to nevirapine or efavirenz.


Analysis of the autolysins of Bacillus subtilis 168 during vegetative growth and differentiation by using renaturing polyacrylamide gel electrophoresis.
The autolysins of Bacillus subtilis 168 were analyzed by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis with substrate-containing gels. Four bands of vegetative autolytic activity of 90, 50, 34, and 30 kDa (bands A1 to A4) were detected in SDS and LiCl extracts and in native cell walls by using B. subtilis 168 vegetative cell walls as the substrate incorporated in the gel. The four enzyme activities showed different substrate specificities and sensitivities to various chemical treatments. The autolysin profile was not medium dependent and remained constant during vegetative growth. During sporulation, band A4 greatly increased in activity just prior to mother-cell lysis. No germination-associated changes in the profile were observed, although a soluble 41-kDa endospore-associated cortex-lytic enzyme was found. By using insertionally inactivated mutants, bands A1 and A2 were positively identified as the previously characterized 90-kDa glucosaminidase and 50-kDa amidase, respectively. The common filamentous phenotype of various regulatory mutants could not be correlated to specific changes in the autolysin profile.


Insurance Approval for Proton Beam Therapy and its Impact on Delays in Treatment.
Prior authorization (PA) has been widely implemented for proton beam therapy (PBT). We sought to determine the association between PA determination and patient characteristics, practice guidelines, and potential treatment delays. A single-institution retrospective analysis was performed of all patients considered for PBT between 2015 and 2018 at a National Cancer Institute-designated Comprehensive Cancer Center. Differences in treatment start times and denial rates over time were compared, and multivariable logistic regression was used to identify predictors of initial denial. A total of 444 patients were considered for PBT, including 396 adult and 48 pediatric patients. The American Society for Radiation Oncology model policy supported PBT coverage for 77% of the cohort. Of adult patients requiring PA, 64% were initially denied and 32% remained denied after appeal. In patients considered for reirradiation or randomized phase 3 trial enrollment, initial denial rates were 57% and 64%, respectively. Insurance coverage was not related to diagnosis, reirradiation, trial enrollment, or the American Society for Radiation Oncology model policy guidelines, but it was related to insurance category on multivariable analysis (P < .001). Over a 3-year timespan, initial denial rates increased from 55% to 74% (P = .034). PA delayed treatment start by an average of 3 weeks (and up to 4 months) for those requiring appeal (P < .001) and resulted in 19% of denied patients abandoning radiation treatment altogether. Of pediatric patients, 9% were initially denied, all of whom were approved after appeal, and PA requirement did not delay treatment start (P = .47). PA requirements in adults represent a significant burden in initiating PBT and cause significant delays in patient care. Insurance approval is arbitrary and has become more restrictive over time, discordant with national clinical practice guidelines. Payors and providers should seek to streamline coverage policies in alignment with established guidelines to ensure appropriate and timely patient care.


Occurrence of antibiotic resistance genes in reclaimed water and river water in the Werribee Basin, Australia.
The purpose of this study was to investigate the occurrence of antibiotic resistance genes (ARGs) in water used for irrigation in the Werribee River Basin, Australia, including river water and reclaimed effluent water (reclaimed water). Samples of reclaimed water, collected over a one-year period, were screened for the occurrence of ARGs using PCR detection assays. The presence of ARGs in the reclaimed water samples were contrasted with that of water samples taken from the Werribee River Basin, collected over the same time period, from five points selected for varying levels of urban and agricultural impact. Of the 54 river water samples collected, 2 (4%), 2 (4%), 0 and 0 were positive for methicillin, sulfonamide, gentamicin and vancomycin-resistant genes, respectively, while 6 of 11 reclaimed water samples were positive for methicillin (9%) and sulfonamide (45%). The presence/absence of ARGs did not appear to correlate with other measured water quality parameters. The low detection of ARGs in river water indicates that, regardless of its poor quality, the river has not yet been severely contaminated with ARGs. The greater prevalence of ARGs in reclaimed water indicates that this important agricultural water source will need to be monitored into the future.


ERP correlates of error monitoring in 10-year olds are related to socialization.
Research suggests that the anterior cingulate cortex (ACC) generates the error-related negativity (ERN or Ne), an event-related potential component that reflects response monitoring and is influenced by individual differences in personality. The present study examined the relation between personality as indexed by the Junior Eysenck Personality Questionnaire (Extraversion, Neuroticism, Psychoticism, and Lie scale) and the ERN in 10-year-old children. High scores on the Psychoticism and low scores on the Lie scale, which are taken to reflect low socialization in children, were associated with smaller ERNs. Results lend support to previous studies finding this association in adults. We argue that the ERN may be an indirect measure of ACC activity and is affected by one's concern with task performance. The results of the present study extend findings previously reported in adults to a population of normally developing children and show that similar mechanisms of performance monitoring may underlie individual differences in personality across development.


mRNA expression in rabbit experimental aneurysms: a study using gene chip microarrays.
The molecular characteristics of intracranial aneurysms are still poorly documented. A rabbit elastase aneurysm model has been helpful in the evaluation of devices and strategies involved in endovascular treatment of aneurysms. The goal of this project was to document the molecular changes, assessed by gene chip microarrays, associated with the creation of aneurysms in this model compared with the contralateral carotid artery. A microarray of rabbit genes of interest was constructed using rabbit nucleotide sequences from GenBank. Elastase-induced saccular aneurysms were created at the origin of the right common carotid artery in 4 rabbits. Twelve weeks after aneurysm creation, RNA was isolated from the aneurysm as well as the contralateral common carotid artery and used for microarray experiments. Reverse transcription-polymerase chain reaction (RT-PCR) was performed on 1 animal as a confirmatory test. Ninety-six (46%) of 209 genes in the microarray were differentially expressed in the rabbit aneurysm compared with the contralateral common carotid artery. In general, differential gene expression followed specific molecular pathways. Similarities were found between rabbit aneurysms and human intracranial aneurysms, including increased metalloproteinase activity and decreased production of the extracellular matrix. RT-PCR results confirmed the differential expression found by the gene chip microarray. The molecular characteristics of the rabbit elastase-induced saccular aneurysm are described. The rabbit aneurysm model shares some molecular features with human intracranial aneurysms. Future studies can use the rabbit model and the new rabbit gene chip microarray to study the molecular aspects of saccular aneurysms.


Sex-stratified analysis of national trends and outcomes in isolated tricuspid valve surgery.
Female sex is a known risk factor for cardiac surgery, and tricuspid valve (TV) disease is more common in women. There are few data on sex-stratified surgical outcomes for isolated TV surgery. An administrative database was used to compare acute in-hospital outcomes between men and women undergoing isolated TV surgery. Patients aged >18 who underwent TV repair or replacement from 2004 to 2013 were identified using the National Inpatient Sample. Patients were excluded if they had congenital heart disease, endocarditis, or were undergoing concomitant cardiac surgeries except coronary bypass. Results were weighted to represent national averages. Sex-stratified analysis was performed using propensity score matching to compare in-hospital mortality, postoperative complications and hospital costs. Over 10 years, women represented 58% of the 5005 TV surgeries performed. With propensity matching, hospital mortality (7.9% vs 7.7%; P=0.99) and median length of stay (11 vs 11 days; P=0.99) were similar between men and women. However, median hospital charges were higher for men ($166 000 vs $155 000; P=0.04). Isolated TV surgery is rare, but women more commonly undergo the procedure. In-hospital mortality was similar between men and women after propensity matching, but remains markedly high for both men and women in comparison to that reported for left-sided isolated valve surgery.


Battling regional (stage III) lung cancer: bumpy road of a cancer survivor in the immunotherapy age.
A 58-year-old woman, a heavy smoker, was diagnosed with stage III squamous cell lung cancer. She was treated with concurrent chemotherapy and radiotherapy, with partial response. 2 months later, she had haemoptysis caused by brisk bleeding from the radiated right upper lobe. Fortunately, her bleed was self-limited. 4 months later, a rapidly enlarging renal mass was discovered and turned out to be metastatic from the lung primary. Second-line chemotherapy with docetaxel and ramucirumab did not have effects on the renal mass after 2 cycles. Despite not being eligible for a durvalumab trial because of lack of PD-L1 expression, she had a meaningful response to nivolumab. Once every 2 weeks, infusion of nivolumab resulted in rapid tumour shrinkage in multiple areas. In the next few months, she experienced a variety of side effects, some of which were potentially life-threatening. She had disease progression 9 months into treatment.


Microbiological aspects of thermophile pretreatment of activated sludge inhibiting electricity generation of microbial fuel cell.
Thermophile pretreatment of activated sludge greatly improves the biodegradability of sludge, but whether the pretreated products are suitable for the electricity generation of microbial fuel cells (MFCs) is still little known. In this study, municipal activated sludge pretreated by a thermophilic bacterium and heating, respectively, was separately fed into the MFCs. The performance of MFCs was examined and changes of anodic microbial communities were investigated with scanning electron microscopy and 16S rRNA gene high-throughput sequencing on the Illumina Miseq platform. The results showed that MFCs fed with heating-pretreated sludge performed preferably and the power density reached 0.91-2.86 W/m3. MFC anodes were covered with considerable Geobacter spp. However, the bioaugmentation of sludge with the thermophile was not able to support a high potential output although the pretreatment significantly increased the soluble chemical oxygen demand. The maximum power density approached 0.20 W/m3 even when the anolyte was regularly changed. It was observed that amending pH did not improve the performance of MFC. Investigation on this anodic microbial community found that the relative abundance of Lactobacillus spp. exceeded 91%. Consequently, the thermophile-pretreated products stimulated the growth of non-exoelectrogens and finally the niches of anodic biofilm were completely occupied by Lactobacillus spp.


Ambrosia: a new impending disaster for the israeli allergic population.
The pollen of Ambrosia (ragweed) is one of the major causes of pollen-induced allergy worldwide. This genus of plants has apparently evolved in North America but later spread into Europe and Asia. Flowering of the Ambrosias starts in mid-July and continues throughout the autumn and is a cause of major morbidity to allergic sensitized patients. The invasion of new species of Ambrosia into Israel is still in progress. Plants of Ambrosia artemisiifolia (American short ragweed), Ambrosia trifida (American giant ragweed), Ambrosia confertifolia, Ambrosia grayi and Ambrosia tenuifolia are increasingly found in Israel, mainly in the Hula valley in the eastern Galilee and near the Alexander River in the Sharon plain. From experience it is known that the time it takes to eradicate a new invasive species is limited. Action should be taken immediately or this new invasion will spread and cause a significantly increased burden of morbidity and increased health costs in Israel.


Antibiotic prescribing for acute respiratory tract infections in primary care: a systematic review and meta-ethnography.
Numerous interventions have been developed to promote prudent antibiotic use for acute respiratory tract infections (ARTIs). While reviews have assessed which interventions may be most effective, none has examined why some interventions may be more effective than others. Knowing what general practitioners (GPs) feel is acceptable and feasible to implement may help to answer this question. A systematic review was undertaken of 12 studies of GPs' views and experiences of antibiotic prescribing and/or interventions promoting the prudent use of antibiotics. A meta-ethnographic approach was followed to synthesize the findings. Thirteen themes were identified from the synthesis. The first discussed GPs' satisfaction with their prescribing decisions. Seven themes highlighted factors that influence GPs' prescribing decisions; these included perceptions of external pressure to reduce prescribing, uncertainty about ARTI management and previous experience of ARTI management. Five themes highlighted the benefits of interventions that had helped GPs to prescribe more prudently in practice. The last two sets of themes were linked to indicate that interventions may only be beneficial for GPs when they address one or more of the factors that influence their prescribing decisions. The findings suggest that interventions should incorporate five aspects to promote prudent use whilst remaining attractive to GPs and feasible in practice. In order to maximize acceptability, interventions should: allow GPs to reflect on their own prescribing; help decrease uncertainty about appropriate ARTI management; educate GPs about appropriate prescribing; facilitate more patient-centred care; and be beneficial to implement in practice.


A signal-processing pipeline for magnetoencephalography resting-state networks.
To study functional connectivity using magnetoencephalographic (MEG) data, the high-quality source-level reconstruction of brain activity constitutes a critical element. MEG resting-state networks (RSNs) have been documented by means of a dedicated processing pipeline: MEG recordings are decomposed by independent component analysis (ICA) into artifact and brain components (ICs); next, the channel maps associated with the latter ones are projected into the source space and the resulting voxel-wise weights are used to linearly combine the IC time courses. An extensive description of the proposed pipeline is provided here, along with an assessment of its performances with respect to alternative approaches. The following investigations were carried out: (1) ICA decomposition algorithm. Synthetic data are used to assess the sensitivity of the ICA results to the decomposition algorithm, by testing FastICA, INFOMAX, and SOBI. FastICA with deflation approach, a standard solution, provides the best decomposition. (2) Recombination of brain ICs versus subtraction of artifactual ICs (at the channel level). Both the recombination of the brain ICs in the sensor space and the classical procedure of subtracting the artifactual ICs from the recordings provide a suitable reconstruction, with a lower distortion using the latter approach. (3) Recombination of brain ICs after localization versus localization of artifact-corrected recordings. The brain IC recombination after source localization, as implemented in the proposed pipeline, provides a lower source-level signal distortion. (4) Detection of RSNs. The accuracy in source-level reconstruction by the proposed pipeline is confirmed by an improved specificity in the retrieval of RSNs from experimental data.


Site-specific mutagenesis of AIDS virus reverse transcriptase.
Human immunodeficiency virus (HIV) is the causative agent of AIDS (acquired immune deficiency syndrome) a disease which poses a serious challenge to modern medicine. If we are to conquer this disease we will need a protective vaccine or effective drugs able to block the life cycle of the virus. An early stage in the invasion of the host cell is the conversion of the RNA genome of the virus to a double-stranded DNA intermediate which subsequently becomes integrated into the host cell chromosome. The enzyme reverse transcriptase is crucial in this process and is thus an obvious chemotherapeutic target. In this study we have used site-directed mutagenesis of this enzyme expressed in Escherichia coli to reveal several important functional regions of the protein including putative components of the triphosphate binding site and pyrophosphate exchange sites.


Non-canonical NFκB activation promotes chemokine expression in podocytes.
TNF-like weak inducer of apoptosis (TWEAK) receptor Fn14 is expressed by podocytes and Fn14 deficiency protects from experimental proteinuric kidney disease. However, the downstream effectors of TWEAK/Fn14 in podocytes are poorly characterized. We have explored TWEAK activation of non-canonical NFκB signaling in cultured podocytes. In cultured podocytes, TWEAK increased the expression of the chemokines CCL21, CCL19 and RANTES in a time-dependent manner. The inhibitor of canonical NFκB activation parthenolide inhibited the CCL19 and the early RANTES responses, but not the CCL21 or late RANTES responses. In this regard, TWEAK induced non-canonical NFκB activation in podocytes, characterized by NFκB2/p100 processing to NFκB2/p52 and nuclear migration of RelB/p52. Silencing by a specific siRNA of NIK, the upstream kinase of the non-canonical NFκB pathway, prevented CCL21 upregulation but did not modulate CCL19 or RANTES expression in response to TWEAK, thus establishing CCL21 as a non-canonical NFκB target in podocytes. Increased kidney Fn14 and CCL21 expression was also observed in rat proteinuric kidney disease induced by puromycin, and was localized to podocytes. In conclusion, TWEAK activates the non-canonical NFκB pathway in podocytes, leading to upregulation of CCL21 expression. The non-canonical NFκB pathway should be explored as a potential therapeutic target in proteinuric kidney disease.


Mandatory seatbelt law support and opposition in New England--a survey.
Less than one-fifth of the U.S. population consistently wears automobile seatbelts. Automatic seatbelts or air bags will be required in all new cars, unless States whose total population equals two-thirds of the nation's adopt mandatory seatbelt use laws by 1989, according to the U.S. Department of Transportation. In July 1984, New York State passed the first mandatory seatbelt law in the nation, followed by New Jersey, Illinois, Missouri, Michigan, and New Mexico. A telephone survey of 2,982 randomly selected drivers examined belt use and support for mandatory belt use laws in the six New England States. Drivers with little education and low income, younger drivers, and drivers who drove after heavy drinking or marijuana use, or both, were least likely to wear seatbelts. Beliefs that seatbelts are not effective in reducing injury risk and are uncomfortable were more common among those not wearing belts. Sixty percent of drivers favored a mandatory seatbelt use law. The most important predictors of opposition to a belt use law were beliefs that seatbelts are ineffective, inconvenient, and uncomfortable. Opposition was also more likely among persons who reported that they drove after marijuana use, or heavy drinking, or both, drove more miles per year, exhibited a low frequency of seatbelt use, and perceived a low probability of personal crash involvement.


Effects of amino acid substitutions at position 115 on the fidelity of human immunodeficiency virus type 1 reverse transcriptase.
We compared the fidelity of wild-type human immunodeficiency virus type-1 (HIV-1) reverse transcriptase (RT) and two RT mutants, Y115F and Y115V. Although neither mutation had a large effect on the overall fidelity of the enzyme, both mutations altered the spectrum of mutations and the precise nature of the mutational hot spots. The effects of Y115V were greater than those of Y115F. When we compared the behavior of the wild-type enzyme with published data, we found that, in contrast to what has been published, misalignment/slippage could account for only a small fraction of the mutations we observed. We also found that a preponderance of the mutations (both transitions and transversions) resulted in the insertion of an A. Because we were measuring DNA-dependent DNA synthesis (plus-strand synthesis), this bias could contribute to the A-rich nature of the HIV-1 genome.


Regional changes in charcoal-burning suicide rates in East/Southeast Asia from 1995 to 2011: a time trend analysis.
Suicides by carbon monoxide poisoning resulting from burning barbecue charcoal reached epidemic levels in Hong Kong and Taiwan within 5 y of the first reported cases in the early 2000s. The objectives of this analysis were to investigate (i) time trends and regional patterns of charcoal-burning suicide throughout East/Southeast Asia during the time period 1995-2011 and (ii) whether any rises in use of this method were associated with increases in overall suicide rates. Sex- and age-specific trends over time were also examined to identify the demographic groups showing the greatest increases in charcoal-burning suicide rates across different countries. We used data on suicides by gases other than domestic gas for Hong Kong, Japan, the Republic of Korea, Taiwan, and Singapore in the years 1995/1996-2011. Similar data for Malaysia, the Philippines, and Thailand were also extracted but were incomplete. Graphical and joinpoint regression analyses were used to examine time trends in suicide, and negative binomial regression analysis to study sex- and age-specific patterns. In 1995/1996, charcoal-burning suicides accounted for <1% of all suicides in all study countries, except in Japan (5%), but they increased to account for 13%, 24%, 10%, 7%, and 5% of all suicides in Hong Kong, Taiwan, Japan, the Republic of Korea, and Singapore, respectively, in 2011. Rises were first seen in Hong Kong after 1998 (95% CI 1997-1999), followed by Singapore in 1999 (95% CI 1998-2001), Taiwan in 2000 (95% CI 1999-2001), Japan in 2002 (95% CI 1999-2003), and the Republic of Korea in 2007 (95% CI 2006-2008). No marked increases were seen in Malaysia, the Philippines, or Thailand. There was some evidence that charcoal-burning suicides were associated with an increase in overall suicide rates in Hong Kong, Taiwan, and Japan (for females), but not in Japan (for males), the Republic of Korea, and Singapore. Rates of change in charcoal-burning suicide rate did not differ by sex/age group in Taiwan and Hong Kong but appeared to be greatest in people aged 15-24 y in Japan and people aged 25-64 y in the Republic of Korea. The lack of specific codes for charcoal-burning suicide in the International Classification of Diseases and variations in coding practice in different countries are potential limitations of this study. Charcoal-burning suicides increased markedly in some East/Southeast Asian countries (Hong Kong, Taiwan, Japan, the Republic of Korea, and Singapore) in the first decade of the 21st century, but such rises were not experienced by all countries in the region. In countries with a rise in charcoal-burning suicide rates, the timing, scale, and sex/age pattern of increases varied by country. Factors underlying these variations require further investigation, but may include differences in culture or in media portrayals of the method. Please see later in the article for the Editors' Summary.


Age-period-cohort models in cancer surveillance research: ready for prime time?
Standard descriptive methods for the analysis of cancer surveillance data include canonical plots based on the lexis diagram, directly age-standardized rates (ASR), estimated annual percentage change (EAPC), and joinpoint regression. The age-period-cohort (APC) model has been used less often. Here, we argue that it merits much broader use. First, we describe close connections between estimable functions of the model parameters and standard quantities such as the ASR, EAPC, and joinpoints. Estimable functions have the added value of being fully adjusted for period and cohort effects, and generally more precise. Second, the APC model provides the descriptive epidemiologist with powerful new tools, including rigorous statistical methods for comparative analyses, and the ability to project the future burden of cancer. We illustrate these principles by using invasive female breast cancer incidence in the United States, but these concepts apply equally well to other cancer sites for incidence or mortality.


Socio-Demographic Indicators, Intelligence, and Locus of Control as Predictors of Adult Financial Well-Being.
The current study investigated a longitudinal data set of 4790 adults examining a set of socio-demographic and psychological factors that influence adult financial well-being. Parental social status (at birth), childhood intelligence and self-esteem (at age 10), locus of control (at age 16), psychological distress (age 30), educational qualifications (age 34), current occupation, weekly net income, house ownership status, and number of rooms (all measured at age 38 years) were examined. Structural Equation Modelling showed that childhood intelligence, locus of control, education and occupation were all independent predictors of adult financial well-being for both men and women. Parental social status and psychological distress were also significant predictors of the outcome variable for men, but not for women. Whereas for women, in comparison to men, the effects of current occupation and childhood intelligence on the outcome variable appeared to be stronger. The strongest predictor of adult financial well-being was current occupational prestige, followed by educational achievement. The gender deferential of financial well-being indicators and its implications are discussed.


Inhibitory effects of brain chondroitin sulfate proteoglycans on neurite outgrowth from PC12D cells.
Soluble chondroitin sulfate proteoglycans (CSPGs), prepared from 10-d-old rat brain, were added to the culture medium of PC12D cells containing NGF to examine the effects on NGF-induced neurite outgrowth from the cells. PC12D cells, a flat-shaped variant of PC12 pheochromocytoma cells, are characteristic of prompt neurite formation in response not only to NGF, but also to cAMP-enhancing reagents such as forskolin. Brain CSPGs inhibited the neurite elongation irreversibly in a dose-dependent manner; complete inhibition was observed at a concentration of 50 nmol uronic acid/ml. Closely similar dose-dependent inhibition was observed in the forskolin-induced neurite outgrowth from PC12D cells. NGF-induced neurite outgrowth from conventional PC12 cells was also inhibited completely by 50 nmol uronic acid/ml CSPGs. Some brain CSPGs seemed to be inhibitory, but the cartilage-unique CSPG did not show any inhibitory effect. Chondroitin sulfate, a polysaccharide moiety of CSPGs, did not show any inhibitory effect even at a concentration of 250 nmol uronic acid/ml, while core proteins prepared from brain CSPGs by digestion with chondroitinase ABC exhibited inhibitory activity similar to that of intact CSPGs. This indicates that the site of the inhibitory activity exists in the core protein moiety of brain CSPGs. From these observations, it is conceivable that brain CSPGs are involved in the regulation of neuronal differentiation.