Bile acid binding resin improves metabolic control through the induction of energy expenditure.
Besides well-established roles of bile acids (BA) in dietary lipid absorption and cholesterol homeostasis, it has recently become clear that BA is also a biological signaling molecule. We have shown that strategies aimed at activating TGR5 by increasing the BA pool size with BA administration may constitute a significant therapeutic advance to combat the metabolic syndrome and suggest that such strategies are worth testing in a clinical setting. Bile acid binding resin (BABR) is known not only to reduce serum cholesterol levels but also to improve glucose tolerance and insulin resistance in animal models and humans. However, the mechanisms by which BABR affects glucose homeostasis have not been established. We investigated how BABR affects glycemic control in diet-induced obesity models. We evaluated the metabolic effect of BABR by administrating colestimide to animal models for the metabolic syndrome. Administration of BABR increased energy expenditure, translating into significant weight reduction and insulin sensitization. The metabolic effects of BABR coincide with activation of cholesterol and BA synthesis in liver and thermogenesis in brown adipose tissue. Interestingly, these effects of BABR occur despite normal food intake and triglyceride absorption. Administration of BABR and BA had similar effects on BA composition and thermogenesis, suggesting that they both are mediated via TGR5 activation. Our data hence suggest that BABR could be useful for the management of the impaired glucose tolerance of the metabolic syndrome, since they not only lower cholesterol levels, but also reduce obesity and improve insulin resistance.


Factors associated with the quality of life of family caregivers for leukemia patients in China.
The leukemia affects not only the quality of life (QOL) of patients with the disease but also that of their family caregivers (FCs). The research studies on QOL of FCs for leukemia patients are limited. This study aimed to evaluate the QOL of FCs for leukemia patients in Heilongjiang province, China. A cross-sectional questionnaire survey was undertaken with 309 FCs for leukemia patients recruited from three hospitals in Heilongjiang province. The QOL of the participants was assessed using the Chinese version of WHOQOL-BREF. Multivariate regression models were established to determine the predictors of the QOL of FCs, including the socio-economic characteristics of patients and FCs, and the emotional distress, social support and family functions of FCs. The FCs had low QOL scores in all four domains: 12.7 ± 2.8 for physical, 12.2 ± 2.5 for psychological, 13.2 ± 2.9 for social and 11.3 ± 2.5 for environment. Social support is a major predictor of the QOL of FCs, with a standardized β coefficient of "high support" ranging from 0.41 to 0.58 for the four domains, followed by family function (β = 0.37 ~ 0.44 for psychological, social and environmental domains). The FCs who were older, highly educated, had no religious belief, suffered from a higher level of emotional distress, and provided care to younger patients and the patients without insurance coverage had lower QOL than the others. The study provides some important insights into the QOL of FCs for leukemia patients. The QOL of FCs for leukemia patients is low and low levels of support to FCs are a major predictor of low QOL of FCs.


A scaffold protein that chaperones a cysteine-sulfenic acid in H2O2 signaling.
In Saccharomyces cerevisiae, Yap1 regulates an H2O2-inducible transcriptional response that controls cellular H2O2 homeostasis. H2O2 activates Yap1 by oxidation through the intermediary of the thiol peroxidase Orp1. Upon reacting with H2O2, Orp1 catalytic cysteine oxidizes to a sulfenic acid, which then engages into either an intermolecular disulfide with Yap1, leading to Yap1 activation, or an intramolecular disulfide that commits the enzyme into its peroxidatic cycle. How the first of these two competing reactions, which is kinetically unfavorable, occurs was previously unknown. We show that the Yap1-binding protein Ybp1 brings together Orp1 and Yap1 into a ternary complex that selectively activates condensation of the Orp1 sulfenylated cysteine with one of the six Yap1 cysteines while inhibiting Orp1 intramolecular disulfide formation. We propose that Ybp1 operates as a scaffold protein and as a sulfenic acid chaperone to provide specificity in the transfer of oxidizing equivalents by a reactive sulfenic acid species.


The evolution of XY recombination: sexually antagonistic selection versus deleterious mutation load.
Recombination arrest between X and Y chromosomes, driven by sexually antagonistic genes, is expected to induce their progressive differentiation. However, in contrast to birds and mammals (which display the predicted pattern), most cold-blooded vertebrates have homomorphic sex chromosomes. Two main hypotheses have been proposed to account for this, namely high turnover rates of sex-determining systems and occasional XY recombination. Using individual-based simulations, we formalize the evolution of XY recombination (here mediated by sex reversal; the "fountain-of-youth" model) under the contrasting forces of sexually antagonistic selection and deleterious mutations. The shift between the domains of elimination and accumulation occurs at much lower selection coefficients for the Y than for the X. In the absence of dosage compensation, mildly deleterious mutations accumulating on the Y depress male fitness, thereby providing incentives for XY recombination. Under our settings, this occurs via "demasculinization" of the Y, allowing recombination in XY (sex-reversed) females. As we also show, this generates a conflict with the X, which coevolves to oppose sex reversal. The resulting rare events of XY sex reversal are enough to purge the Y from its load of deleterious mutations. Our results support the "fountain of youth" as a plausible mechanism to account for the maintenance of sex-chromosome homomorphy.


Ice hockey injuries: incidence, nature and causes.
In this prospective study, we have investigated incidence of injuries of different severity, types of injury, and mechanisms of injury during ice hockey games. All twelve Swedish elite hockey teams were observed during the season 1988-1989 when a total number of 664 games were played. There was a total number of 285 injuries, of which the majority were minor (61%) and only 9% were classified as major. Seventy-four per cent of the injuries occurred during games and 26% during practice. The overall incidence of injury was 53.0 per 1000 player-game hours. Eighty-five per cent of injuries were caused by trauma and 15% by over-use. Injuries were most often localized to the head/face (39%) or the lower limb (32%). Most injuries resulted from stick contact or player contact including checking. A reduction of minor and moderate injuries should be possible by stricter enforcement of the hockey rules, and more widespread use of visors.


Assessing equivalence and noninferiority.
For systematic reviews, no guidance exists for what review methods support valid conclusions of equivalence (EQ) and noninferiority (NI). To provide such guidance, we convened a workgroup of 13 experienced systematic reviewers from seven evidence-based practice centers (EPCs) and the Agency for Healthcare Research and Quality (AHRQ). The Lead EPC first performed two methods projects intended to assist the workgroup in clarifying the context, prioritizing the issues, targeting the scope, and summarizing the state of the art. Based on expert opinion, we devised guidance in four areas: 1) Unique risk of bias issues for trials self-identifying as EQ-NI trials; 2) Setting the reviewer's minimum important difference; 3) Analytic foundations for concluding EQ or NI; and 4) Language considerations when concluding EQ or NI. This article summarizes the main recommendations, and the full guidance chapter appears on the AHRQ Web site.


Mutagenicity of low-filtered 30 kVp X-rays, mammography X-rays and conventional X-rays in cultured mammalian cells.
To measure the mutagenic effectiveness of low-filtered 30 kVp X-rays, mammography X-rays and conventional (200 kVp) X-rays in mammalian cells. Two different cell lines and mutation assays were used. Exponentially growing SV40-transformed human fibroblasts were exposed to graded doses of mammography (29 kVp, tungsten anode, 50 microm Rh filter) or conventional X-rays and the frequency of 6-thioguanine-resistent HPRT-deficient mutants was determined. Exponentially growing hamster A(L) cells, which contain a single human chromosome 11 conferring the expression of the human surface protein CD59, were subjected to magnetic cell separation (MACS) in order to remove spontaneous mutants before irradiation with low-filtered 30 kVp (tungsten anode, 0.5 mm Al filter) or conventional X-rays. Fractions of radiation-induced CD59- mutants were quantified by flow-cytometry after immunofluorescence labelling of CD59 proteins. Mammography X-rays were more effective than conventional X-rays at inducing killing of human fibroblasts, whereas 30 kVp X-rays and conventional X-rays were about equally effective at killing Al. cells. Mutant frequencies were linearly related to dose in both mutation assays. An RBE = 2.7 was calculated for the yield of HPRT mutants in human fibroblasts exposed to mammography relative to conventional X-rays and an RBE = 2.4 was obtained for the CD59 mutant frequency in A(L) cells irradiated with low-filtered 30 kVp relative to conventional X-rays. Both low-filtered 30 kVp and mammography X-rays are mutagenic in mammalian cells in vitro. It is unknown if and how the enhanced mutagenicity of mammography X-rays measured in human cells in vitro translates into breast cancer risk for predisposed women with an enhanced inherited risk for breast cancer. Although the ICRP guidelines attribute the same relative biological effectiveness to all radiations of low LET, including X- and gamma-radiations of all energies for radiobiological protection purposes including the assessment of risks in general terms, they also state that 'for the estimation of the likely consequences of an exposure of a known population, it will sometimes be better to use absorbed dose and specific data relating to the relative biological effectiveness of the radiations concerned and the probability coefficients relating to the exposed population' (ICRP 1991: 32). This latter statement may apply for the population of familial predisposed women. We hope that the presented data on the enhanced mutagenicity of mammography X-rays may stimulate a re-evaluation of the risk assessment of mammography for familial predisposed women. In the meantime, one should be cautious and avoid early and frequent mammography exposure of predisposed women. Alternative examination methods should be applied for these women with an inherited increased risk for breast cancer.


Supporting positive dimensions of health, challenges in mental health care.
This paper will explore two contrasting paradigms in mental health care and their relationship to evidence-based practice. The biomedical perspective of pathogenesis and the health perspective of salotogenesis are two major diverse views in mental health care. Positive dimensions of health are traditionally viewed as software not suitable for statistical analysis, while absence of symptoms of disease are regarded as measurable and suitable for statistical analysis and appropriate as a foundation of evidence-based practice. If the main goal of mental health care is to enhance subjectively experienced health among patients, it will not be sufficient to evaluate absence of symptoms of disease as a measure of quality of care. The discussion focuses on the paradox of evidence-based absence of illness and disease versus subjectively experienced health and well-being as criterions of quality of care in mental health care.


Comparison of compensatory reserve and arterial lactate as markers of shock and resuscitation.
During traumatic hemorrhage, the ability to identify shock and intervene before decompensation is paramount to survival. Lactate is extremely sensitive to shock, and its clearance has been demonstrated a useful gauge of shock and resuscitation status. Though lactate can be measured in the field, logistical constraints render it impractical in certain environments. The compensatory reserve represents a new clinical measurement reflecting the remaining capacity to compensate for hypoperfusion. We hypothesized the compensatory reserve index (CRI) would be an effective surrogate marker of shock and resuscitation compared to lactate. The CRI device was placed on consecutive patients meeting trauma center activation criteria and remained on the patient until discharge, admission, or transport to operating suite. All subjects had a lactate level measured as part of their routine admission metabolic analysis. Time-corresponding CRI and lactate values were matched in regards to initial and subsequent lactate levels. Mean time from lactate sample collection to data availability in the electronic medical record was calculated. Predictive capacity of CRI and lactate in predicting hemorrhage was determined by receiver-operator characteristic curve analysis. Correlation analysis was performed to determine if any association existed between changing CRI and lactate values. Receiver-operator characteristic (ROC) curves were generated and area under the curve was 0.8052 and 0.8246 for CRI and lactate, respectively. There was no significant difference in each parameter's ability to predict hemorrhage (p = 0.8015). The mean duration from lactate sample collection to clinical availability was 44 minutes whereas CRI values were available immediately. Analysis of the concomitant change in serial CRI and lactate levels revealed a Spearman's correlation coefficient of -0.73 (p < 0.01). CRI performed with equivalent predictive capacity to lactate with respect to identifying initial perfusion status associated with hemorrhage and subsequent resuscitation. Diagnostic, Level II.


Switchable friction using contacts of stimulus-responsive and nonresponding swollen polymer brushes.
Stimulus-responsive (SR), solvated polymers can switch between an expanded state and a collapsed state via external stimuli. Using molecular dynamics simulations, I show that such SR polymers can be employed to control the frictional response between two opposing polymer brushes in relative sliding motion. By using a brush composed of SR polymers in contact with a nonresponding solvated polymer brush, the presence of capillaries and the overlap between molecules of the opposing brushes can be switched. When both brushes are solvated, a capillary is formed and polymers of the opposing brushes interdigitate. Interdigitation dominates friction upon shearing flat brush-bearing surfaces, while the breaking and formation of capillaries dominate friction in the low-velocity limit between rough brush-bearing surfaces. Thus, when either rough or flat polymer-bearing surfaces are sheared, friction between two swollen brushes can be high. In contrast, when the SR brush is collapsed, the solvent absorbs only in the brush that does not respond to the external stimulus. The latter circumvents the presence of capillaries and interdigitation of the brushes, which results in a low friction force upon shearing.


Using whole mount in situ hybridization to examine thyroid hormone deiodinase expression in embryonic and larval zebrafish: a tool for examining OH-BDE toxicity to early life stages.
Polybrominated diphenyl ethers (PBDEs) and their oxidative metabolites (hydroxylated PBDEs; OH-BDEs) are known endocrine disrupting contaminants that have been shown to disrupt thyroid hormone regulation both in mammals and in fish. The purpose of this study was to determine the precise organ and tissue locations that express genes critical to thyroid hormone regulation in developing zebrafish (Danio rerio), and to determine the effects of an OH-BDE on their expression. While RT-PCR can provide quantitative data on gene expression, it lacks spatial sensitivity to examine localized gene expression; and, isolation of organs from zebrafish embryos is technically difficult, if not impossible. For this reason, the present study used whole mount in situ hybridization to simultaneously localize and quantify gene expression in vivo. While PBDEs and OH-BDEs have been shown to inhibit the activity and expression of deiodionases, a family of enzymes that regulate thyroid hormone concentrations intracellularly, it is unclear whether or not they can affect regional expression of the different isoforms during early development. In this study we investigated deiodinase 1 (Dio1), deiodinase 2 (Dio2), and deiodinase 3 (Dio3) mRNA expression at the following life stages (2, 8, and 1k-cells; 50%-epiboly, 6 and 18-somites, 22, 24, 48, 72 hpf and/or 10 dpf) in zebrafish and found life stage specific expression of these genes that were highly localized. To demonstrate the use of this technique for investigating potential endocrine disrupting effects, zebrafish embryos were exposed to 1, 10 and 100nM 6-OH-BDE-47. Significant increases in mean intensity of Dio1 and Dio3 expression in the periventricular zone of brain and pronephric duct, respectively (quantified by measuring intensity of coloration using ImageJ analysis software) were observed, suggesting localized response at the HPT axis with the possibility of impacting neurodevelopment. Our results demonstrate effects of OH-BDEs on thyroid regulating gene expression and provide more insight into potential sites of injury during early life stages.


Diffuse ganglioneuromatosis of intestine in a 15-year-old girl.
The authors present the case of a 15-year-old girl with diffuse ganglioneuromatosis, principally involving the caecum. This is a rare condition and usually associated with multiple endocrine neoplasm IIb and neurofibromatosis type I. In our case, the myentric nerve plexus was exclusively involved. The patient presented with episodes of vomiting and weight loss. So far, to our knowledge no other manifestations of the above mentioned genetic conditions have become apparent in this patient.


Glucose transporter 1 expression accompanies hypoxia sensing in the cyclic canine corpus luteum.
The canine corpus luteum (CL) functions as a source of progesterone (P4) and 17β-oestradiol (E2); however, the transport of energy substrates to maintain its high hormonal output has not yet been characterised. This study involved the localisation and temporal distribution of the facilitative glucose transporter 1 and the quantification of the corresponding protein (GLUT1) and gene (SLC2A1) expression. Some GLUT1/SLC2A1 regulatory proteins, such as hypoxia-inducible factor 1α (HIF1A) and fibroblast growth factor 2 (FGF2); mRNAs, such as HIF1A, FGF2 and vascular endothelial growth factor A (VEGFA); and VEGFA receptors 1 and 2 (FLT1 and KDR) were also analysed from days 10 to 70 after ovulation. Additionally, plasma P4 and E2 levels were assessed via chemiluminescence. Moreover, the canine KDR sequence has been cloned, thereby enabling subsequent semi-quantitative PCR analysis. Our results demonstrate time-dependent variations in the expression profile of SLC2A1 during dioestrus, which were accompanied by highly correlated changes (0.84<r<0.98; P<0.03) in the gene expression of HIF1A, VEGF and FLT1 as well as in P4 plasma concentrations. FGF2 mRNA correlated with E2 plasma concentrations (r=0.61; P=0.01). Our data reveal that the glucose transporter is regulated throughout the CL lifespan and suggest that CL depends on the sensing of hypoxia and the status of luteal vascularisation. Moreover, time-dependent expression of GLUT1/SLC2A1 may lie underneath increased metabolic and energetic requirements for sustaining P4 production.


Gender inequalities in health and wellbeing across the first two decades of life: an analysis of 40 low-income and middle-income countries in the Asia-Pacific region.
By adulthood, gender inequalities in health and wellbeing are apparent. Yet, the timing and nature of gender inequalities during childhood and adolescence are less clear. We describe the emergence of gender inequalities in health and wellbeing across the first two decades of life. We focused on the 40 low-income and middle-income countries in Asia and the Pacific. A measurement framework was developed around four key domains of wellbeing across the first two decades: health, education and transition to employment, protection, and a safe environment. Specific measurement constructs were then defined by considering gender indicator frameworks, the Sustainable Development Goals, indicator frameworks for child and adolescent health and wellbeing, and key stakeholder input. Available data were then mapped to define 87 indicators, subsequently populated using databases (UN agencies and the Global Burden of Diseases, Injuries, and Risk Factors Study) and nationally representative surveys. Where possible, estimates in girls were compared with boys to report relative risks. Although son preference is evident in some settings-as shown by higher than expected male-to-female sex ratios at birth in India, Vietnam, and China (all >1·10 compared with an expected ratio of 1·05) and excess mortality of girl children in some South Asian and Pacific nations-it is during early adolescence where marked gender inequalities consistently emerged. Adolescent girls face considerable disadvantage in relation to sexual and reproductive health (notably in South Asia and the Pacific), with high rates of child marriage (≥30% of women aged 20-24 years married before 18 years in Bangladesh, Nepal, and Afghanistan), fertility (≥65 livebirths per 1000 girls in Nauru, Laos, Afghanistan, Nepal, Marshall Islands, Bangladesh, Vanuatu, and Papua New Guinea), and intimate partner violence (>20% in Timor Leste, Afghanistan, Pakistan, and Myanmar). Despite educational parity in many countries, females aged 15-24 years were less likely than males to be in education, employment, or training in 17 of 19 countries for which data were available. Compared with girls, adolescent boys experienced excess all-cause mortality and substantially higher mortality due to unintentional injury, interpersonal violence, alcohol and other drugs, and suicide, and higher prevalence of harmful drinking and tobacco smoking. These findings call for a focus on gender policy and programming in later childhood and early adolescence before gender inequalities become embedded. UNICEF.


Responses of butterflies to twentieth century climate warming: implications for future ranges.
We analyse distribution records for 51 British butterfly species to investigate altitudinal and latitudinal responses to twentieth century climate warming. Species with northern and/or montane distributions have disappeared from low elevation sites and colonized sites at higher elevations during the twentieth century, consistent with a climate explanation. We found no evidence for a systematic shift northwards across all species, even though 11 out of 46 southerly distributed species have expanded in the northern part of their distributions. For a subset of 35 species, we model the role of climate in limiting current European distributions and predict potential future distributions for the period 2070-2099. Most northerly distributed species will have little opportunity to expand northwards and will disappear from areas in the south, resulting in reduced range sizes. Southerly distributed species will have the potential to shift northwards, resulting in similar or increased range sizes. However, 30 out of 35 study species have failed to track recent climate changes because of lack of suitable habitat, so we revised our estimates accordingly for these species and predicted 65% and 24% declines in range sizes for northern and southern species, respectively. These revised estimates are likely to be more realistic predictions of future butterfly range sizes.


Critical role of natural killer cells in lung immunopathology during influenza infection in mice.
Influenza viral infection results in excessive pulmonary inflammation that has been linked to the damage caused by immune responses and viral replication. The multifunctional cytokine interleukin (IL-15), influences the proliferation and maintenance of immune cells such as CD8(+) T cells and natural killer (NK) cells. Here we show that IL-15(-/-) mice are protected from lethal influenza infection. Irrespective of the mouse strains, the protection observed was linked to the lack of NK cells. Increased survival in the IL-15(-/-) or NK1.1(+) cell-depleted wild-type mice was associated with significantly lower lung lesions as well as decreased mononuclear cells and neutrophils in the airway lumen. Levels of interleukin 10 were significantly higher and levels of proinflammatory cytokines, including interleukin 6 and interleukin 12, were significantly lower in the bronchoalveolar lavage fluid from IL-15(-/-) and NK1.1(+) cell-depleted wild-type mice than in that from control mice. Our data suggest that NK cells significantly augment pulmonary inflammation, contributing to the pathogenesis of influenza infection.


Stable and accurate method for modal analysis of multilayer waveguides using a graph approach.
A method for calculating the propagation constants of allowed guided and leaky modes in multilayer planar waveguides is presented. We develop a two-way graph model to describe the tangential fields propagating in the waveguides. According to the special structure of the graph model, it is convenient to employ a topology scheme to derive analytical and closed-form dispersion equations for TE and TM modes. By comparing the dispersion equations formulated by series-expansion methods, approximation methods, and transfer-matrix methods, we find that the use of these equations for finding the eigenmodes has some benefits. First, this method can be easily employed to solve eigenmodes accurately in numerical computation without using series truncation. Second, the dispersion equations are exact. Moreover, all the eigenmodes can be determined according to the formulas without losing roots or causing numerical instability even for a waveguide with thick layers.


[Conduct disorders in autism spectrum disorders].
Autism spectrum disorders (ASD) are neurodevelopmental disorders that affect social communication and present stereotypic behaviours. Comorbidity associated to conduct disorders is frequent, starts in infancy and, in general, continues into adulthood. It is sometimes associated with aggressiveness, negativism, self-harm and breaking social norms. It causes a high degree of dysfunctionality in persons with ASD, their family, professionals and those around them, and is the main cause of pharmacological treatment, hospitalisation and special education. Factors related to the symptoms of ASD, comorbidity and social factors are associated with an increased risk of conduct disorders. In many cases it would be necessary to perform a detailed examination that includes a functional analysis and a combination of psychoeducational, social and pharmacological interventions. To review the precipitating factors, causes, evaluation and treatment of the conduct disorders associated with ASD. The study outlines what is understood by conduct disorders in ASD, the different clinical and cognitive mechanisms associated with it, and the most effective strategies for intervention. Comorbid ASD with conduct disorders is frequent, begins in early infancy and continues throughout life. A detailed evaluation that includes a functional analysis of the behaviour to be eliminated and treatment with different psychological, social educational and pharmacological strategies are essential.


IgM nephropathy; can we still ignore it.
IgM nephropathy (IgMN) is a relatively less recognized clinico-immunopathological entity in the domain of glomerulonephritis , often thought to be a bridge between minimal change disease and focal segmental glomerulosclerosis. Directory of Open Access Journals (DOAJ), Google Scholar, Pubmed (NLM), LISTA (EBSCO) and Web of Science has been searched. IgM nephropathy can present as nephritic syndrome or less commonly with subnephrotic proteinuria or rarely hematuria. About 30% patients respond to steroids whereas others are steroid dependent / resistant. They should be given a trial of Rituximab or stem cell therapy. IgM nephropathy (IgMN) is an important and rather neglected pathology responsible for renal morbidity in children and adults in developing countries as compared to developed nations with incidence of 2-18.5% of native biopsies. Abnormal T-cell function with hyperfunctioning suppressor T-cells are believed to be responsible for this disease entity. Approximately one third of the patients are steroid responders where as the remaining two thirds are steroid resistant or dependent. Therapeutic trials including cell therapies targeting suppressor T-cells are required.


Interrogating trees for isotopic archives of atmospheric sulphur deposition and comparison to speleothem records.
Palaeorecords which depict changes in sulphur dynamics form an invaluable resource for recording atmospheric pollution. Tree rings constitute an archive that are ubiquitously available and can be absolutely dated, providing the potential to explore local- to regional-scale trends in sulphur availability. Rapid isotopic analysis by a novel "on-line" method using elemental analyser isotope ratio mass spectrometry (EA-IRMS) is developed, achieving sample precision of <0.4‰ using sample sizes of 40 mg wood powder. Tree cores from NE Italy show trends in pollution, evidenced through increasing concentrations of sulphur towards the youngest growth, and inverse trends in sulphur isotopes differentiating modern growth with light sulphur isotopes (+0.7‰) from pre-industrial growth (+7.5‰) influenced by bedrock composition. Comparison with speleothem records from the same location demonstrate replication, albeit offset in isotopic value due to groundwater storage. Using EA-IRMS, tree ring archives form a valuable resource for understanding local- to regional-scale sulphur pollution dynamics.


Primary Leiomyosarcoma of the Pancreas-a Case Report and a Comprehensive Review.
Primary mesenchymal tumors of the pancreas are rare, with leiomyosarcomas the most encountered entities among the pancreatic sarcomas. With few exceptions, single case reports published over the last six decades constitute the entire scientific literature on this topic. Thus, evidence regarding clinical decision-making is scant. Based on a case report and an extensive literature search in PubMed, we discuss the clinical aspects and current management of this rare malignancy. We identified only two papers with more than a single case presentation; these institutional patient series were limited to five and nine patients. Additionally, a few papers sought to summarize the individual case reports published in the English and/or Chinese language. The clinical presentation is rather non-specific. Moreover, modern imaging modalities are insufficiently accurate to diagnose leiomyosarcoma of the pancreas. Treatment goals include a complete resection with free margins. Proper morphologic examination using immunohistochemistry and the application of a grading system are clinically important for prognostication. The efficacy of adjuvant treatments has not been established. Primary pancreatic leiomyosarcoma is extremely rare, and the scientific literature is primarily based on single case reports. Conclusions on management and prognosis should be drawn with caution. A multidisciplinary team consultation is warranted to discuss a thorough individual treatment plan based on the available scientific literature, despite its low evidence level.


Role of acid/base homeostasis in the suppression of apoptosis in haemopoietic cells by v-Abl protein tyrosine kinase.
Removal of interleukin-3 from murine IC.DP pre-mast cells results in irreversible commitment to apoptosis within 18 hours. To identify early events necessary for the engagement of apoptosis we examined the regulation of intracellular pH (pH(i)). IC.DP cells acidified 2 hours after removal of interleukin-3 (before discernible signs of apoptosis) and by 18 hours pH(i) had decreased by 0.15 units. The acidification was due to both an increase in an acid-loading process which only occurs when intracellular pH is above 6.8 and a slight reduction in H+ efflux via NA+/H+ exchange. Activation of a temperature sensitive mutant of v-Abl protein tyrosine kinase suppressed apoptosis of IC.DP cells in the absence of interleukin-3 but did not stimulate proliferation, and moreover prevented cellular acidification. Acidification of the cells by 0.2 units to pH 6.86 by complete inhibition of Na+/H+ exchange by 10 microM 5'-(N-methyl-N-isobutyl)-amiloride prevented the suppression of apoptosis by v-abl protein tyrosine kinase following IL 3 withdrawal. However in the presence of interleukin-3, addition of 10 microM 5'-(N-methyl-N-isobutyl)-amiloride only resulted in a fall of pH(i) to 7.17. Apoptosis did not occur and the cells continued to proliferate. Thus, in this model intracellular pH must fall below a critical value for apoptosis to occur. Together these data point to a step in cytokine deprivation induced apoptosis (at least in some haemopoietic cell types) which is either enhanced by or dependent upon an acidic intracellular environment which is the result of an increase in acid loading and inhibition of Na+/H+ exchange activity. One of the mechanisms by which activation of v-Abl protein tyrosine kinase suppresses apoptosis is by prevention of intracellular acidification.


Health consequences of reduced daily cigarette consumption.
To determine the risk of dying from specified smoking-related diseases and from any cause in heavy smoking men and women (> or =15 cigarettes/day), who reduced their daily cigarette consumption by >50%. A prospective cohort study. Three counties in Norway. 24,959 men and 26,251 women, aged 20-49 years, screened for risk factors of cardiovascular disease in the mid-1970s, screened again after 3-13 years, and followed up throughout 2003. Absolute mortality and relative risks adjusted for confounding variables, of dying from all causes, cardiovascular disease, ischaemic heart disease, all smoking-related cancer and lung cancer. With sustained heavy smokers as reference, the smokers of both sexes who reduced their daily consumption (reducers) had the following adjusted relative risks (95% confidence interval (CI)): of dying from any cause, 1.02 (0.84 to 1.22); cardiovascular disease, 1.02 (0.75 to 1.39); ischaemic heart disease, 0.96 (0.65 to 1.41); smoking-related cancer, 0.86 (0.57 to 1.29); and lung cancer, 0.66 (0.36 to 1.21). The difference in cigarette consumption between two examinations was not a significant predictor of death from any of the causes. A follow-up from a third screening of the subgroup who were reducers at both second and third examinations (sustained reducers) did not have a lower risk than those who were heavy smokers at all three examinations. Long-term follow-up provides no evidence that heavy smokers who cut down their daily cigarette consumption by >50% reduce their risk of premature death significantly. In health education and patient counselling, it may give people false expectations to advise that reduction in consumption is associated with reduction in harm.


Selective Tsuji-Trost type C-allylation of hydrazones: a straightforward entry into 4,5-dihydropyrazoles.
The 4,5-dihydropyrazole motif has drawn considerable attention over the years as it was shown to exhibit a plethora of biological and pharmacological properties, including anticancer, antibacterial, antifungal, antiviral, and anti-inflammatory properties. As such, it has been the target of a number of methods and drug discovery programs. We report here a straightforward and highly selective approach featuring a key palladium-catalysed Tsuji-Trost type C-allylation and subsequent intramolecular 1,4-addition of hydrazones.


Left ventricular hypertrophy by electrocardiogram as a predictor of success in home blood pressure control: HOMED-BP study.
Few studies have focused on the effect of organ damage on achievement of long-term home blood pressure (BP) control. Based on the nationwide home BP-based trial data, we aimed to investigate the factors associated with home BP control, in particular, left ventricular hypertrophy (LVH) using the electrocardiogram in patients who started antihypertensive drug treatment. According to the trial protocol, we defined BP as controlled when systolic home BP reached specified targets (125-134 mm Hg in usual control (UC), n=1261; <125 mm Hg in tight control (TC), n=1288). At baseline, before drug treatment started, the mean Sokolow-Lyon voltage was 2.57±0.87 mV, and the mean Cornell product was 1573±705 mm·ms. The numbers of patients who achieved the target BP level in the UC and TC groups were 892 (70.7%) and 576 (44.7%), respectively. In both the UC and TC groups, systolic home BP at baseline was significantly lower in patients who achieved target levels than in those who did not achieve target levels (P<0.0001). Sokolow-Lyon voltage was significantly lower in patients who achieved target levels than in those who did not (P⩽0.0055). The Cornell product levels in each group were similar (P⩾0.12), although significantly different between patients who did or did not achieve the target level when the UC and TC groups were combined for analysis (P=0.031). Sokolow-Lyon voltage was significantly associated with achievement of home BP control in the multivariable-adjusted model (odds ratio, 1.13; 95% confidence intervals, 1.02-1.26; P=0.015), but Cornell product was not (P=0.13). These results indicate the difficulty of sufficient antihypertensive treatment when untreated patients had target organ damage, that is, LVH diagnosed by Sokolow-Lyon voltage.


Animal anorexias.
Eating very little in the presence of food or failure to serach for food has been documented in various species during the hibernation season, incubation, molting, and defense of the territory or harem. At these times feeding competes with other, more important activities. One way to avoid conflicts between feeding and these other activities to lower the programmed weight or set-point for body fat. Experiments on mammalian hibernators and incubating birds provide evidence that set-points are indeed lowered. Failure to eat in these two examples depends on anorexia, loss of appetite. A review of other examples suggests that conceptualization in terms of lowered set-points provides a unified and testable way of understanding many naturally occurring instances of fasting in the animal kingdom. Finally, spontaneous animal anorexias are contrasted with attempts by people to lose weight.


Meta-Analysis of Studies Comparing Single and Multi-Tablet Fixed Dose Combination HIV Treatment Regimens.
Availability of a single source review of once-daily fixed-dose single tablet regimen (STR) and multiple tablet fixed-dose regimen (MTR) would optimally inform healthcare providers and policy makers involved in the management of population with human immunodeficiency virus (HIV).We conducted a meta-analysis of published literature to compare patient adherence, clinical, and cost outcomes of STR to MTR.Published literature in English between 2005 and 2014 was searched using Embase, PubMed (Medline in-process), and ClinicalTrials.Gov databases. Two-level screening was undertaken by 2 independent researchers to finalize articles for evidence synthesis. Adherence, efficacy, safety, tolerability, healthcare resource use (HRU), and costs were assessed comparing STR to MTR. A random-effects meta-analysis was performed and heterogeneity examined using meta-regression.Thirty-five articles were identified for qualitative evidence synthesis, of which 9 had quantifiable data for meta-analysis (4 randomized controlled trials and 5 observational studies). Patients on STR were significantly more adherent when compared to patients on MTR of any frequency (odds ratio [OR]: 2.37 [95% CI: 1.68, 3.35], P < 0.001; 4 studies), twice-daily MTR (OR: 2.53 [95% CI: 1.13, 5.66], P = 0.02; 2 studies), and once-daily MTR (OR: 1.81 [95% CI: 1.15, 2.84], P = 0.01; 2 studies). The relative risk (RR) for viral load suppression at 48 weeks was higher (RR: 1.09 [95% CI: 1.04, 1.15], P = .0003; 3 studies) while RR of grade 3 to 4 laboratory abnormalities was lower among patients on STR (RR: 0.68 [95% CI: 0.49, 0.94], P = 0.02; 2 studies). Changes in CD4 count at 48 weeks, any severe adverse events (SAEs), grade 3 to 4 AEs, mortality, and tolerability were found comparable between STR and MTR. Several studies reported significant reduction in HRU and costs among STR group versus MTR.Study depicted comparable tolerability, safety (All-SAE and Grade 3-4 AE), and mortality and fewer Grade 3 to 4 lab abnormalities and better viral load suppression and adherence among patients on FDC-containing STR versus MTR; literature depicted favorable HRU and costs for STRs.These findings may help decision makers especially in resource-poor settings to plan for optimal HIV disease management when the choice of both STRs and MTRs are available.


Characteristics and Outcome of Extranodal NK/T-Cell Lymphoma in North America: A Retrospective Multi-Institutional Experience.
Extranodal natural killer/T-cell lymphoma (ENKTL) is rare and clinicaldata from non-Asian countries are lacking. It is unclear whether outcomes and diseasenatural history is similar to reported Asian series. We assessed characteristics and outcomes of patients with ENKTL from major North American centers. We retrospectively identified patients with newly-diagnosedCD56 + ENKTL and studied disease characteristics and clinical outcomes. 121 patients with ENKTL diagnosed between June 1990 and November 2012 were identified. Eighty-three patients (69%) had stage I/II disease and were treatedwith combined modality therapy (CMT) (n=53), chemotherapy alone (CT) (n=14) orradiotherapy alone (RT) (n=16). Thirty-eight patients (31%) had stage III/IV diseaseand were treated with CMT (n=12), CT (n=23), or RT (n=3). The median follow-up forthe entire cohort was 51 months. Patients with stage I/II disease, compared to thosewith stage III/IV disease, had superior 2-year progression free survival (PFS) 43% vs19% (p=0.03) and overall survival (OS) 59% vs 29% (p=0.004). Outcomes were similarfor stage I/II patients who received CMT vs RT alone with 2-year PFS (53% vs 47%;p=0.91) and OS (67% vs 67%; p=0.58). No significant differences in outcomes werenoted based on race/ethnicity. This series represents a large experience of ENKTL treated at several major North American academic centers. 1) majority of patients present with early-stage disease; 2) overall poor outcome regardless of race/ethnicity; 3) CMT likely yields favorable outcomes for suitable candidates with early-stage disease.


Evaluation of compatibility between different types of adhesives and dual-cured resin cement.
The objective of this in vitro study was to evaluate the bonding compatibility between different adhesives and a dual-cured resin cement, using a conventional tensile bond test. The adhesives used were: Prime & Bond (PB) (Dentsply) (PB), Scotchbond Multi Purpose (SB) (3M), and the activator Self Cure (SC) (Dentsply). The dual-curing resin cement used was Enforce (EF) (Dentsply). Six groups with five specimens in each were tested: G1: EF/PB/EF (light cured); G2: EF/SB/EF (light cured); G3: EF/PB+SC/EF (light cured); G4: EF/PB+SC/EF (only chemically cured); G5: EF/EF (light cured); G6: EF/EF (only chemically cured). The resin cement was applied in two stainless steel molds with a cone-shaped perforation measuring 4 mm in diameter and 1 mm in thickness, and the adhesive was applied between them. Ten minutes after specimens were cured, the tensile strength was measured in a universal testing machine at a crosshead speed of 0.5 mm/min. The mean values (MPa) +/- SD obtained in each experimental group were: G1: 1.4 +/- 0.2; G2: 1.3 +/- 0.2; G3: 1.2 +/- 0.4; G4: 0.8 +/- 0.2; G5: 1.2 +/- 0.1; G6: 0.7 +/- 0.1. The results were statistically evaluated using nonparametric Kruskal-Wallis and Dunn tests (p < or = 0.05). Statistically significant differences among groups were found only between G1 and G4, and G1 and G6. There was no incompatibility among the different adhesives used with dual-cured resin cement. The lowest tensile bond strength values occurred in the absence of photoactivation.


[Profitability of a day hospital: analysis of activity, cost and effectiveness].
Day hospitals are an alternative to conventional hospital care. We analyzed the functioning and profitability of the day hospital of Hospital Clínico de Valladolid, Spain, in 2009. Profitability is expressed as the provision of identical health coverage at a lower cost than that generated by conventional hospital care and with adequate quality indicators. We performed a retrospective, observational and descriptive study of the information obtained on each patient attended in the day hospital from January 1 to December 31, 2009. We studied four quality indicators: cancellation of meetings, the rate of transfusion reactions, the out-patient rate and the satisfaction index. The estimated savings for each process was calculated as the difference in the average cost of hospitalization minus the average cost of the process in the day hospital. The most frequent diseases were systemic and connective tissue diseases, accounting for 25.4% of the processes treated; of these, 17.1% corresponded to rheumatoid arthritis. Patient satisfaction was 93%. Meetings cancellations and the rate of transfusion reactions were 0%. The out-patient rate was 26%. Day hospital costs were 8.6% of conventional hospital costs, with savings of 78,390.69 euros. The day hospital is cost effective due to savings compared with conventional hospitalization and has a satisfactory quality index.


A nanoparticle-based combination chemotherapy delivery system for enhanced tumor killing by dynamic rewiring of signaling pathways.
Exposure to the EGFR (epidermal growth factor receptor) inhibitor erlotinib promotes the dynamic rewiring of apoptotic pathways, which sensitizes cells within a specific period to subsequent exposure to the DNA-damaging agent doxorubicin. A critical challenge for translating this therapeutic network rewiring into clinical practice is the design of optimal drug delivery systems. We report the generation of a nanoparticle delivery vehicle that contained more than one therapeutic agent and produced a controlled sequence of drug release. Liposomes, representing the first clinically approved nanomedicine systems, are well-characterized, simple, and versatile platforms for the manufacture of functional and tunable drug carriers. Using the hydrophobic and hydrophilic compartments of liposomes, we effectively incorporated both hydrophobic (erlotinib) and hydrophilic (doxorubicin) small molecules, through which we achieved the desired time sequence of drug release. We also coated the liposomes with folate to facilitate targeting to cancer cells. When compared to the time-staggered application of individual drugs, staggered release from tumor-targeted single liposomal particles enhanced dynamic rewiring of apoptotic signaling pathways, resulting in improved tumor cell killing in culture and tumor shrinkage in animal models.


Detection of rifampin resistance by single-strand conformation polymorphism analysis of cerebrospinal fluid of patients with tuberculosis of the central nervous system.
Mutations in a 69-bp region of the rpoB gene of Mycobacterium tuberculosis are associated with rifampin resistance (Rif[r]). These have been detected with mycobacterial DNA extracted from bacterial suspensions or respiratory specimens that were acid-fast smear positive. We experimented with a strategy for the rapid detection of Rif(r) in cerebrospinal fluid (CSF) samples. The strategy involves the amplification of the 69-bp region of rpoB by means of PCR and the identification of nucleotide mutations by single-strand conformation polymorphism (SSCP) analysis of the amplification products. Sixty-five CSF specimens collected from 29 patients (19 patients were coinfected with human immunodeficiency virus) with culture or autopsy-confirmed (22 patients) or highly probable (7 patients) tuberculosis of the central nervous system (CNS-TB) were processed. Amplified products suitable for evaluation by SSCP analysis were obtained from 37 CSF specimens from 25 subjects (86.2%). PCR-SSCP of CSF correctly identified the rifampin susceptibility phenotype of isolates from all 17 patients for whom the results of susceptibility tests carried out with strains cultured from CSF or respiratory samples were available. Moreover, this assay revealed the rifampin susceptibility genotype of isolates from the eight patients (three patients with culture-confirmed CNS-TB and five patients in whom CNS-TB was highly probable) for whom no susceptibility test results were available; the PCR-SSCP data obtained for these patients were concordant with the outcome after a standard antituberculosis treatment. The evolution of a mutation in the rpoB gene was documented in a patient during the course of treatment. PCR-SSCP analysis of CSF seems to be an efficacious method of predicting Rif(r) and would reduce the time required for susceptibility testing from approximately 4 to 8 weeks to a few days.


Graphene structures at an extreme degree of buckling.
The distinctive properties of graphene sheets may be significantly influenced by the presence of corrugation structures. Our understanding of these graphene structures has been limited to the mesoscopic scale. Here we characterize angstrom-scale periodic buckling structures in free-standing graphene bilayers produced by liquid-phase processing in the absence of specific substrates. Monochromated, aberration-corrected transmission electron microscopy with sub-angstrom resolution revealed that the unit structures in the major buckling direction consist of only two and three unit cells of graphene's honeycomb lattice, resulting in buckling wavelengths of 3.6 ± 0.5 and 6.4 ± 0.8 Å, respectively. The buckling shows a strong preference of chiral direction and spontaneously chooses the orientation of the lowest deformation energy, governed by simple geometry rules agreeing with Euler buckling theory. Unexpectedly, the overall buckled structures demonstrate geometric complexity with cascaded features. First-principles calculations suggest that significant anisotropic changes in the electronic structure of graphene are induced by the buckling.


Lipoprotein lipase activity in skeletal muscle is related to insulin sensitivity.
The relative effects of obesity, alone or in combination with insulin resistance and hyperinsulinemia (with or without diabetes), on lipoprotein concentrations, blood pressure, and other risk factors for cardiovascular disease were investigated in 28 men (mean age, 63 years). Special attention was given to lipoprotein lipase (LPL) activity in tissues and to postheparin plasma LPL activity and hepatic lipase activity and their relation to insulin resistance. The 28 men fulfilled the entrance criteria of the study so that they could be allocated to one of the four groups (seven in each group): 1) normal body weight, normal fasting insulin level, and normal glucose tolerance (controls); 2) the same as in group 1 but with moderate obesity; 3) the same as in group 2 but with fasting hyperinsulinemia; 4) the same as in group 3 but with non-insulin-dependent diabetes mellitus. Glucose infusion rate for the control group was 8.1 +/- 2.1 mg/kg body wt/min (mean +/- SD) at an insulin infusion rate of 56 milliunits/m2/min. The average values in groups 2, 3, and 4 were 6.0 +/- 0.7, 3.2 +/- 0.5, and 1.9 +/- 1.0 mg/kg body wt/min, respectively. Concentrations of very low density lipoproteins as well as blood pressure and urate concentrations were highest and those of high density lipoproteins were lowest in the two hyperinsulinemic groups (groups 3 and 4). Skeletal muscle LPL activity was 46 +/- 23, 41 +/- 25, 23 +/- 6, and 31 +/- 13 milliunits/g wet wt (mean +/- SD) in the four groups, respectively. There was a positive correlation between glucose infusion rate and muscle LPL activity (r = 0.58, p less than 0.0001). The hepatic lipase activity was positively correlated with the insulin area under the curve of the intravenous glucose tolerance test (r = 0.35, p = 0.02). Furthermore, blood pressure, free fatty acid concentration, liver enzymes, and urate concentrations were significantly correlated with glucose infusion rate at the clamp test. These data give further support for insulin resistance as an important factor behind the observed lipoprotein abnormalities and blood pressure elevations as part of the insulin resistance syndrome characteristic for obese and diabetic patients.


Psychological distress in rheumatoid arthritis patients: an evaluation within the conservation of resources theory.
Rheumatoid arthritis (RA) is a chronic disease, which can lead to considerable psychological distress. The present study evaluated anxiety and depression symptoms for this chronic and painful illness within the framework of the conservation of resources (COR) theory. Coping strategies, coping self-efficacy, religiousness and social support are very important personal resources, which have been found to protect individuals from psychological distress. The aim of the present study was to examine the predictive values of socio-demographic and illness-related variables, perceived social support, ways of coping, religiousness, arthritis self-efficacy and resource loss for psychological distress in a sample of 117 RA patients from Turkey, a secular, Islamic, non-western developing country. The results revealed that RA patients experience considerable anxiety and depressive symptoms. The results of the regression analysis showed that gender, helplessness coping and resource loss are significant predictors of anxiety, whereas arthritis self-efficacy and resource loss are significant predictors of depression. Resource loss appeared as an important predictor for both anxiety and depression. This finding was consistent with the COR theory. The clinical implications of these findings are discussed.


Type 2 diabetes in adolescents and young adults.
The prevalence of type 2 diabetes in adolescents and young adults is dramatically increasing. Similar to older-onset type 2 diabetes, the major predisposing risk factors are obesity, family history, and sedentary lifestyle. Onset of diabetes at a younger age (defined here as up to age 40 years) is associated with longer disease exposure and increased risk for chronic complications. Young-onset type 2 diabetes also affects more individuals of working age, accentuating the adverse societal effects of the disease. Furthermore, evidence is accumulating that young-onset type 2 diabetes has a more aggressive disease phenotype, leading to premature development of complications, with adverse effects on quality of life and unfavourable effects on long-term outcomes, raising the possibility of a future public health catastrophe. In this Review, we describe the epidemiology and existing knowledge regarding pathophysiology, risk factors, complications, and management of type 2 diabetes in adolescents and young adults.


Understanding relapse in the broader context of post-treatment functioning.
There exists much interest in developing more sophisticated conceptual and data analytic frameworks for evaluating and understanding the post-treatment functioning of alcoholics. Much of this interest has been fostered by the systematic research endeavors of Moos and his colleagues, whose "systems model" of treatment outcome closely parallels multivariate models of illness and health. This article focuses on an extrapolation of the systems model to the study of relapse, viewing relapse as one outcome of a set of independent variables that include person and environmental factors. The subjects were 142 clients entering either inpatient or outpatient treatment for alcoholism. Preliminary assessments, using path analyses and multiple regression models, are presented on the interrelationships between background characteristics, pretreatment alcohol involvement/ symptomatology, treatment, coping skills/responses, stressors and relapse/outcome following treatment entry. The results overall showed a considerable amount of convergence in the sense that the composite "blocks" representing background characteristics, alcohol involvement/symptomatology and coping skills/responses generally were significant predictors of various relapse and other posttreatment functioning variables. However, the variables contributing to the predictive power of a particular composite varied as a function of the dependent variable being assessed. The conceptual model and associated analytic strategies guiding this research would appear to hold much potential for advancing knowledge in this area.


TH588, an MTH1 inhibitor, enhances phenethyl isothiocyanate-induced growth inhibition in pancreatic cancer cells.
Chemotherapy and radiotherapy are the most common approaches in cancer therapy. They may kill cancer cells through the generation of high levels of reactive oxygen species (ROS), which leads to oxidative DNA damage. However, tumor resistance to ROS is a problem in cancer therapy. MTH1 sanitizes oxidized dNTP pools to prevent the incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, cancer cells require MTH1 activity to avoid the incorporation of oxidized dNTPs, which would result in DNA damage and cell death. By targeting a redox-adaptation mechanism, MTH1 inhibition represents a novel therapeutic strategy against cancer. However, recent reports have indicated that growth inhibition by MTH1 inhibitors may be due to off-target cytotoxic effects. TH588, one of the first-in-class MTH1 inhibitors, kills cancer cells by an off-target effect. However, a low concentration of TH588 may effectively inhibit MTH1 activity without inhibiting cell proliferation. Phenethyl isothiocyanate (PEITC) is a dietary anticarcinogenic compound and an inducer of ROS. In the present study, it has been demonstrated that combined treatment with PEITC and TH588 effectively inhibited the growth of pancreatic cancer MIAPaCa-2 and Panc-1 cells. The antioxidant N-acetylcysteine negated this synergistic growth inhibition. PEITC and TH588 cooperatively induced the formation of 8-oxo-deoxyguanine in nuclei and pH2AX foci, a marker of DNA damage. However, the combined effects are not associated with MTH1 mRNA expression in several cancer cell lines, suggesting that the possibility of an off-target effect of TH588 cannot be eliminated. These results suggest that the combination of PEITC and TH588 has potential as a novel therapeutic strategy against pancreatic cancer.


Effects of crystallization and dopant concentration on the emission behavior of TiO2:Eu nanophosphors.
Uniform, spherical-shaped TiO2:Eu nanoparticles with different doping concentrations have been synthesized through controlled hydrolysis of titanium tetrabutoxide under appropriate pH and temperature in the presence of EuCl3·6H2O. Through air annealing at 500°C for 2 h, the amorphous, as-grown nanoparticles could be converted to a pure anatase phase. The morphology, structural, and optical properties of the annealed nanostructures were studied using X-ray diffraction, scanning electron microscopy, energy-dispersive X-ray spectroscopy [EDS], and UV-Visible diffuse reflectance spectroscopy techniques. Optoelectronic behaviors of the nanostructures were studied using micro-Raman and photoluminescence [PL] spectroscopies at room temperature. EDS results confirmed a systematic increase of Eu content in the as-prepared samples with the increase of nominal europium content in the reaction solution. With the increasing dopant concentration, crystallinity and crystallite size of the titania particles decreased gradually. Incorporation of europium in the titania particles induced a structural deformation and a blueshift of their absorption edge. While the room-temperature PL emission of the as-grown samples is dominated by the 5D0 - 7Fj transition of Eu+3 ions, the emission intensity reduced drastically after thermal annealing due to outwards segregation of dopant ions.


Effects of ocean acidification on primary production in a coastal North Sea phytoplankton community.
We studied the effect of ocean acidification (OA) on a coastal North Sea plankton community in a long-term mesocosm CO2-enrichment experiment (BIOACID II long-term mesocosm study). From March to July 2013, 10 mesocosms of 19 m length with a volume of 47.5 to 55.9 m3 were deployed in the Gullmar Fjord, Sweden. CO2 concentrations were enriched in five mesocosms to reach average CO2 partial pressures (pCO2) of 760 μatm. The remaining five mesocosms were used as control at ambient pCO2 of 380 μatm. Our paper is part of a PLOS collection on this long-term mesocosm experiment. Here, we here tested the effect of OA on total primary production (PPT) by performing 14C-based bottle incubations for 24 h. Furthermore, photoacclimation was assessed by conducting 14C-based photosynthesis-irradiance response (P/I) curves. Changes in chlorophyll a concentrations over time were reflected in the development of PPT, and showed higher phytoplankton biomass build-up under OA. We observed two subsequent phytoplankton blooms in all mesocosms, with peaks in PPT around day 33 and day 56. OA had no significant effect on PPT, except for a marginal increase during the second phytoplankton bloom when inorganic nutrients were already depleted. Maximum light use efficiencies and light saturation indices calculated from the P/I curves changed simultaneously in all mesocosms, and suggest that OA did not alter phytoplankton photoacclimation. Despite large variability in time-integrated productivity estimates among replicates, our overall results indicate that coastal phytoplankton communities can be affected by OA at certain times of the seasonal succession with potential consequences for ecosystem functioning.


H++ 3.0: automating pK prediction and the preparation of biomolecular structures for atomistic molecular modeling and simulations.
The accuracy of atomistic biomolecular modeling and simulation studies depend on the accuracy of the input structures. Preparing these structures for an atomistic modeling task, such as molecular dynamics (MD) simulation, can involve the use of a variety of different tools for: correcting errors, adding missing atoms, filling valences with hydrogens, predicting pK values for titratable amino acids, assigning predefined partial charges and radii to all atoms, and generating force field parameter/topology files for MD. Identifying, installing and effectively using the appropriate tools for each of these tasks can be difficult for novice and time-consuming for experienced users. H++ (http://biophysics.cs.vt.edu/) is a free open-source web server that automates the above key steps in the preparation of biomolecular structures for molecular modeling and simulations. H++ also performs extensive error and consistency checking, providing error/warning messages together with the suggested corrections. In addition to numerous minor improvements, the latest version of H++ includes several new capabilities and options: fix erroneous (flipped) side chain conformations for HIS, GLN and ASN, include a ligand in the input structure, process nucleic acid structures and generate a solvent box with specified number of common ions for explicit solvent MD.


Cryosurgery Versus Primary Androgen Deprivation Therapy for Locally Recurrent Prostate Cancer After Primary Radiotherapy: A Propensity-Matched Survival Analysis.
Background Optimal management of isolated local recurrence of prostate cancer after primary radiotherapy remains to be defined. Up-front androgen deprivation therapy (ADT) is widely used but may adversely affect the quality of life and is essentially a palliative treatment. Local salvage carries a different side-effect profile and is potentially curative, but it has not been compared to ADT. Materials and methods We conducted a propensity-matched analysis of cohorts of men treated with either whole gland cryotherapy (CRYO) or primary ADT following the diagnosis of locally recurrent prostate cancer. Our specific objectives were to compare overall survival (OS) and prostate cancer-specific mortality (PCSM) between CRYO vs. ADT. Results After a one-to-one matching, 169 patients from each cohort were included in comparisons. Median follow-up time was 6.7 years (ADT) vs. 18 years (CRYO). The 10-year PCSM was 18.5% (ADT) vs. 16.2% (CRYO), which was not statistically different [hazard ratioo (HR): 0.69, 95% CI: 0.36-1.34, p=0.27]. The median OS was 12.3 years (CRYO) versus 10.2 years (ADT) (HR: 0.63, 95% CI: 0.42-0.95, p=0.03). Conclusions While PCSM was similar between the two strategies, CRYO was associated with a longer OS compared to primary ADT. Given the retrospective nature of the trial, these results should be considered hypothesis-generating, and phase III trials comparing these two options are required to further explore these findings.


Molecular medicine in ophthalmic care.
Lipofuscin is the most consistent and phylogenically constant morphologic marker of cellular aging. Autofluorescence of the A2E fluorophore within retinal pigment epithelial (RPE) lipofuscin affords the opportunity for noninvasive evaluation of age- and disease-related pathophysiological changes in the human retina. It is being used in National Eye Institute/Age-Related Eye Disease Study II to evaluate age-related macular degeneration (AMD) geographic atrophy expansion. Experiments show lipofuscin can be reversed in cell culture and animal models in heart, brain, spinal cord, and retinal tissues, using an array of antioxidants and iron chelators. An 80-year-old man with a gastric resection presented with complaints of unremitting night driving difficulty despite treatment with lutein and omega III fatty acids. Notable parafoveal deposition of retinal lipofuscin by 50 degrees fundus auto-fluorescence (580 nm excitation/660 barrier filters) and concurrent abnormalities in non-Snellen measures of visual function-Contrast Sensitivity Function, 6.5 degrees large field tritan threshold, 10 degrees threshold visual fields, and deficits in the National Institutes of Health/National Eye Institute Visual Function Questionnaire (VFQ) 25 subjective night driving/mental health subscale questionnaire were obtained. The patient was placed on an over-the-counter daily oral polyphenolic mixture containing resveratrol and re-evaluated 5 months later. The data reveal improvements in all measures of visual function, subjective improvement in vision and mental functioning on the VFQ 25, and visible clearing of RPE lipofuscin. To our knowledge, we believe this to be the first reported human clinical case of lipofuscin reversal in the human eye correlated with measured clinical and subjective improvement in visual and mental function after nutraceutical intervention.


[Bilateral stress fractures of the pelvic rami in a woman with anorexia nervosa].
This is a case report of a 51-year-old woman with bilateral stress fractures of the pelvic rami and a history of anorexia nervosa (AN). AN is a psychiatric condition of low weight caused by restricted food intake, impaired body image and an exaggerated fear of gaining weight in addition to compensating behaviour such as excessive physical activity. Among patients with AN, reduced bone density is common, and a higher risk of fractures is present. Stress fractures should be suspected in patients, who have AN and experience pain from the musculoskeletal system without a history of trauma.


A multicenter prospective study of neonatal outcomes at less than 32 weeks associated with indications for maternal admission and delivery.
Counseling for patients with impending premature delivery traditionally has been based primarily on the projected gestational age at delivery. There are limited data regarding how the indications for the preterm birth affect the neonatal outcome and whether this issue should be taken into account in decisions regarding management and patient counseling. We performed a prospective study of pregnancies resulting in premature delivery at less than 32 weeks to determine the influence of both the indications for admission and their associated indications for delivery on neonatal mortality and complications of prematurity. This is a multicenter, prospective study in 10 hospitals where all data from the neonatal intensive care unit routinely was imported to a deidentified data warehouse. Maternal data were collected prospectively at or near the time of delivery. Eligible subjects included singleton deliveries in these hospitals between 23 0/7 and 31 6/7 weeks. The primary hypothesis of the study was to determine whether there was a difference in the primary outcome, which was defined as neonatal composite morbidity, between those neonates delivered after admission for premature labor vs premature rupture of membranes, because these were expected to be the 2 most frequent diagnoses leading to premature birth. The sample size was calculated based on a 10% difference in outcomes for these 2 entities. We based this hypothesis on the knowledge that premature rupture of membranes has a greater incidence of intra-amniotic infection and inflammation than premature labor and that outcomes for premature neonates are worse when delivery is associated with intra-amniotic infection. Additional outcomes were analyzed for all other indications for admission and delivery. Composite morbidity was defined as ≥1 of the following: respiratory distress syndrome (oxygen requirement, clinical diagnosis, and consistent chest radiograph), bronchopulmonary dysplasia (requirement for oxygen support at 28 days of life), severe intraventricular hemorrhage (grades 3 or 4), periventricular leukomalacia, blood culture-proven sepsis present within 72 hours of birth, necrotizing enterocolitis, or neonatal death before discharge from the hospital. A secondary composite of serious neonatal morbidity also was defined prospectively. The study included 1089 mother/baby pairs. Composite morbidity between those with premature labor (77.2%) and premature rupture of membranes (73.2%) was not significantly different (P = .29). A few neonatal complications were associated with indications for admission and delivery, but on logistic regression adjusting for gestational age and other confounders, suspected intrauterine growth restriction was the only indication for admission or delivery associated with an increase in serious morbidity (odds ratio 4.5, [2.1 to 9.8], P < .003). Other factors not related to the indications for admission including cesarean delivery, and low 5-minute Apgar were associated with an increase in morbidity. Studies of many single factors related to the indications for preterm delivery have been shown to be associated with adverse neonatal outcome. In this study evaluating all of the most frequent indications, however, we found only suspected intrauterine growth restriction as an indication for admission and delivery was found to be so. Thus, it seems that in almost all situations counseling patients can be based primarily on gestational age along with other factors including estimated fetal weight, sex, race, plurality, and completion of a course of antenatal corticosteroids.


Semi-supervised clustering methods.
Cluster analysis methods seek to partition a data set into homogeneous subgroups. It is useful in a wide variety of applications, including document processing and modern genetics. Conventional clustering methods are unsupervised, meaning that there is no outcome variable nor is anything known about the relationship between the observations in the data set. In many situations, however, information about the clusters is available in addition to the values of the features. For example, the cluster labels of some observations may be known, or certain observations may be known to belong to the same cluster. In other cases, one may wish to identify clusters that are associated with a particular outcome variable. This review describes several clustering algorithms (known as "semi-supervised clustering" methods) that can be applied in these situations. The majority of these methods are modifications of the popular k-means clustering method, and several of them will be described in detail. A brief description of some other semi-supervised clustering algorithms is also provided.


Physician awareness of domestic violence: does continuing medical education have an impact?
One hundred currently practicing physicians were surveyed regarding screening and management of domestic violence to determine whether mandatory continuing medical education (CME) is likely to increase awareness of and response to domestic violence. The authors surveyed 25 family physicians and 25 obstetrician/gynecologists in each of two states, Florida and New Jersey. In addition, they polled 26 family practice residents in the University of Medicine and Dentistry of New Jersey-School of Osteopathic Medicine program. Practices with a female physician were four times more likely to screen for domestic violence than practices with all male physicians. No difference existed in screening between family physicians and obstetrician/gynecologists; physicians in Florida and those in New Jersey; or attending physicians and family practice residents. Findings indicate that Florida's mandatory CME law does not appear to have made an impact on the management of domestic violence. Practices with a female physician were more likely to screen for domestic violence.


Current and Future Pharmacologic Therapies for Diabetic Retinopathy.
Currently, diabetic retinopathy is the leading cause of permanent visual loss in workingage adults in industrialized nations. The chronic microangiopathic changes associated with diabetic retinopathy lead to the most common causes of severe permanent visual loss: diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR). Multiple studies have evaluated different pharmacotherapies for different levels of retinopathy. A review of the pathophysiology of diabetic retinopathy and current and emerging pharmacotherapies for diabetic retinopathy. Historically, DME has been the primary focus of treatment in patients with nonproliferative diabetic retinopathy (NPDR). Due to the rapidly increasing number of agents and treatment options, management algorithms for DME have become increasingly complex. Furthermore, spectral domain optical coherence tomography (OCT) has allowed unparalleled sensitivity and specificity for detecting macular edema. All available intravitreal vascular endothelial growth factor (VEGF) inhibitors have demonstrated efficacy in the treatment of patients with DME and PDR. Intravitreal triamcinolone acetonide has also proven beneficial in diabetic retinopathy. Most recently, various corticosteroids have been designed as sustained-release intraocular implants in order to reduce the burden and risks associated with retreatment. Current research is focused on providing new agents that target alternate pathways and signaling molecules to provide patients with additional therapeutic tools, especially in patients who have an incomplete response to the current medications. Anti-VEGF therapy has revolutionized the medical management of diabetic retinopathy. The most important existing challenges in the treatment of diabetic retinopathy are improving visual outcomes and decreasing the treatment burden associated with repeated intravitreal injections. Combination therapy with anti-VEGF and corticosteroids with other previously available treatments, such as panretinal photocoagulation, may be a reasonable clinical strategy to reduce the intravitreal injections burden. Many exciting novel drugs that target newly discovered pathways hold clinical promise. The results of ongoing randomized clinical trials will answer the important concerns surrounding new drugs and delivery devices: safety and visual outcomes.


Weather and children's physical activity; how and why do relationships vary between countries?
Globally most children do not engage in enough physical activity. Day length and weather conditions have been identified as determinants of physical activity, although how they may be overcome as barriers is not clear. We aim to examine if and how relationships between children's physical activity and weather and day length vary between countries and identify settings in which children were better able to maintain activity levels given the weather conditions they experienced. In this repeated measures study, we used data from 23,451 participants in the International Children's Accelerometry Database (ICAD). Daily accelerometer-measured physical activity (counts per minute; cpm) was matched to local weather conditions and the relationships assessed using multilevel regression models. Multilevel models accounted for clustering of days within occasions within children within study-cities, and allowed us to explore if and how the relationships between weather variables and physical activity differ by setting. Increased precipitation and wind speed were associated with decreased cpm while better visibility and more hours of daylight were associated with increased cpm. Models indicated that increases in these variables resulted in average changes in mean cpm of 7.6/h of day length, -13.2/cm precipitation, 10.3/10 km visibility and -10.3/10kph wind speed (all p < 0.01). Temperature showed a cubic relationship with cpm, although between 0 and 20 degrees C the relationship was broadly linear. Age showed interactions with temperature and precipitation, with the associations larger among younger children. In terms of geographic trends, participants from Northern European countries and Melbourne, Australia were the most active, and also better maintained their activity levels given the weather conditions they experienced compared to those in the US and Western Europe. We found variation in the relationship between weather conditions and physical activity between ICAD studies and settings. Children in Northern Europe and Melbourne, Australia were not only more active on average, but also more active given the weather conditions they experienced. Future work should consider strategies to mitigate the impacts of weather conditions, especially among young children, and interventions involving changes to the physical environment should consider how they will operate in different weather conditions.


Accelerated loss of telomeric repeats may not explain accelerated replicative decline of Werner syndrome cells.
The Werner syndrome (WS) is characterized by the premature onset and accelerated rate of development of major geriatric disorders, including atherosclerosis, diabetes mellitus, osteoporosis, ocular cataracts, and various neoplasms. Cultures of WS skin-fibroblastlike cells have been previously shown to undergo accelerated rates of decline of the replicative potentials and to exhibit variegated chromosomal translocations and deletions. Since the replicative decline of normal somatic cells is associated with a loss of telomeric repeats, we investigated the kinetics of telomeric repeat loss in WS cells. The mean length of telomere restriction fragments (TRF) from the earliest passages of WS cells studied was not shorter than those of controls, possibly reflecting selective pressure for subsets of cells with relatively high residual replicative capacity. Statistical evidence indicated an accelerated shortening of TRF length in serially passaged WS cultures, but the mean TRF lengths of WS cultures that had ceased replicating were significantly longer than those of senescent controls. Thus, while accelerated loss of telomeric repeats could potentially explain the rapid decline in proliferation of WS cells, it is possible that WS cells exit the cell cycle via mechanisms that differ from those of replicatively senescent cells from control subjects.


Digital image enhancement and noise filtering by use of local statistics.
Computational techniques involving contrast enhancement and noise filtering on two-dimensional image arrays are developed based on their local mean and variance. These algorithms are nonrecursive and do not require the use of any kind of transform. They share the same characteristics in that each pixel is processed independently. Consequently, this approach has an obvious advantage when used in real-time digital image processing applications and where a parallel processor can be used. For both the additive and multiplicative cases, the a priori mean and variance of each pixel is derived from its local mean and variance. Then, the minimum mean-square error estimator in its simplest form is applied to obtain the noise filtering algorithms. For multiplicative noise a statistical optimal linear approximation is made. Experimental results show that such an assumption yields a very effective filtering algorithm. Examples on images containing 256 × 256 pixels are given. Results show that in most cases the techniques developed in this paper are readily adaptable to real-time image processing.


Can CT scanning be used to select patients with unilateral primary spontaneous pneumothorax for bilateral surgery?
Despite advances in the surgical treatment of spontaneous pneumothorax, the timing of surgical intervention continues to be a subject of controversy. We test the hypothesis that CT scanning can help to predict the probability of the occurrence of primary spontaneous pneumothorax (PSP) by detecting lung bullae. Prospective, longitudinal cohort study. Between May 1994 to March 1995, 28 consecutive patients (23 men; age range, 18 to 47 years; mean, 29 years) with unilateral PSP who were to undergo video-assisted thoracic surgery (VATS) received preoperative CT of the thorax. CT scans were interpreted by one radiologist blinded to the clinical data for the presence of bullae in both lungs. All patients were followed-up in our outpatient clinic for an average of 59.0 months (range, 54 to 64 months). Eighty-eight percent of the blebs or bullae identified intraoperatively were demonstrated on preoperative CT scans. CT scans also showed the presence of lung blebs or bullae in the contralateral lung in 15 patients (53.6%). During the follow-up period, 4 of these 15 patients (26.7%) with contralateral blebs developed PSP in the untreated lung; none of the patients who did not have contralateral blebs (n = 13) developed PSP (p = 0.04 [chi(2) analysis]). The detection of lung bullae by CT scanning in the contralateral lung following unilateral PSP is associated with a higher rate of subsequent occurrence of pneumothorax in that lung. Thus, CT scanning can be used to predict the risk of occurrence of this condition, allowing preemptive surgical intervention in selected patients.


Dlk1 dosage regulates hippocampal neurogenesis and cognition.
Neurogenesis in the adult brain gives rise to functional neurons, which integrate into neuronal circuits and modulate neural plasticity. Sustained neurogenesis throughout life occurs in the subgranular zone (SGZ) of the dentate gyrus in the hippocampus and is hypothesized to be involved in behavioral/cognitive processes such as memory and in diseases. Genomic imprinting is of critical importance to brain development and normal behavior, and exemplifies how epigenetic states regulate genome function and gene dosage. While most genes are expressed from both alleles, imprinted genes are usually expressed from either the maternally or the paternally inherited chromosome. Here, we show that in contrast to its canonical imprinting in nonneurogenic regions, Delta-like homolog 1 (Dlk1) is expressed biallelically in the SGZ, and both parental alleles are required for stem cell behavior and normal adult neurogenesis in the hippocampus. To evaluate the effects of maternally, paternally, and biallelically inherited mutations within the Dlk1 gene in specific behavioral domains, we subjected Dlk1-mutant mice to a battery of tests that dissociate and evaluate the effects of Dlk1 dosage on spatial learning ability and on anxiety traits. Importantly, reduction in Dlk1 levels triggers specific cognitive abnormalities that affect aspects of discriminating differences in environmental stimuli, emphasizing the importance of selective absence of imprinting in this neurogenic niche.


Elective repeat caesarean section versus induction of labour for women with a previous caesarean birth.
When a woman has had a previous caesarean birth and requires induction of labour for a subsequent pregnancy, two options are available for her care: an elective repeat caesarean and planned induction of labour. Although risks and benefits are associated with both elective repeat caesarean birth and planned induction of labour, current sources of information are limited to non-randomised cohort studies, and studies designed in this way have significant potential for bias. Consequently, any conclusions based on results of these studies are limited in their reliability and should be interpreted with caution. To assess, using the best available evidence, the benefits and harms of a policy of planned elective repeat caesarean section versus a policy of induction of labour for women with a previous caesarean birth who require induction of labour for a subsequent pregnancy. Primary outcomes include success of induction of labour, need for caesarean section, maternal and neonatal mortality, and maternal and neonatal morbidity. We searched the Cochrane Pregnancy and Childbirth Trials Register (31 May 2017) and planned to search reference lists of retrieved studies. Randomised controlled trials with reported data on comparison of outcomes in mothers and babies between women who planned an elective repeat caesarean section and women who planned induction of labour when a previous birth was performed by caesarean. Cluster trials and quasi-randomised trials were also eligible for inclusion. We would consider trials published only as abstracts if they provided enough information to meet review inclusion criteria. We performed no data extraction. For future updates, if randomised controlled trials are identified, two review authors will independently assess trials for inclusion and risk of bias, and will extract data and check extracted data for accuracy. Review authors will assess the quality of the evidence using the GRADE approach. Review authors identified no randomised controlled trials. Both planned elective repeat caesarean section and planned induction of labour for women with a prior caesarean birth are associated with benefits and harms. Evidence for these care practices has been drawn from non-randomised studies, which are associated with potential bias. Therefore, any results and conclusions presented must be interpreted with caution. Randomised controlled trials are required to provide the most reliable evidence regarding the benefits and harms of both planned elective repeat caesarean section and planned induction of labour for women with a previous caesarean birth.


Coulombic interactions and crystal packing effects in the folding of donor-acceptor oligorotaxanes.
The folding of a series of donor-acceptor oligorotaxanes is studied by means of molecular dynamics simulations. The oligorotaxanes consist of tetracationic cyclobis(paraquat-p-phenylene) rings threaded onto oligomers of 1,5-dioxynaphthalene linked by polyethers. Minimum energy structures are isolated using simulated annealing from which insights into the interactions responsible for the folding are extracted. The folding in vacuum is primarily driven by Coulombic interactions between the ionic species. In turn, in a high dielectric medium, the folding is the result of a series of conflicting interactions primarily orchestrated by the rings. In both cases, folded globular structures result. The observed secondary structures extend a previously proposed pleated π-stacked model for the folding that has been, in fact, observed in crystal samples of a [3]Rotaxane, the smallest of the oligorotaxanes considered. Simulations using two different force fields in the crystal environment, in vacuum, and in explicit solvent indicate that the π-stacked conformation adopted by the [3]Rotaxane is stable due to crystal packing effects rather than intracomplex interactions. The π-stacked conformation is also shown to be thermodynamically improbable in longer oligomers.


Gradual adaptation of bone structure to aquatic lifestyle in extinct sloths from Peru.
Non-pathological densification (osteosclerosis) and swelling (pachyostosis) of bones are the main modifications affecting the skeleton of land vertebrates (tetrapods) that returned to water. However, a precise temporal calibration of the acquisition of such adaptations is still wanting. Here, we assess the timing of such acquisition using the aquatic sloth Thalassocnus, from the Neogene of the Pisco Formation, Peru. This genus is represented by five species occurring in successive vertebrate-bearing horizons of distinct ages. It yields the most detailed data about the gradual acquisition of aquatic adaptations among tetrapods, in displaying increasing osteosclerosis and pachyostosis through time. Such modifications, reflecting a shift in the habitat from terrestrial to aquatic, occurred over a short geological time span (ca 4 Myr). Otherwise, the bones of terrestrial pilosans (sloths and anteaters) are much more compact than the mean mammalian condition, which suggests that the osteosclerosis of Thalassocnus may represent an exaptation.


Formation and disruption of tonotopy in a large-scale model of the auditory cortex.
There is ample experimental evidence describing changes of tonotopic organisation in the auditory cortex due to environmental factors. In order to uncover the underlying mechanisms, we designed a large-scale computational model of the auditory cortex. The model has up to 100 000 Izhikevich's spiking neurons of 17 different types, almost 21 million synapses, which are evolved according to Spike-Timing-Dependent Plasticity (STDP) and have an architecture akin to existing observations. Validation of the model revealed alternating synchronised/desynchronised states and different modes of oscillatory activity. We provide insight into these phenomena via analysing the activity of neuronal subtypes and testing different causal interventions into the simulation. Our model is able to produce experimental predictions on a cell type basis. To study the influence of environmental factors on the tonotopy, different types of auditory stimulations during the evolution of the network were modelled and compared. We found that strong white noise resulted in completely disrupted tonotopy, which is consistent with in vivo experimental observations. Stimulation with pure tones or spontaneous activity led to a similar degree of tonotopy as in the initial state of the network. Interestingly, weak white noise led to a substantial increase in tonotopy. As the STDP was the only mechanism of plasticity in our model, our results suggest that STDP is a sufficient condition for the emergence and disruption of tonotopy under various types of stimuli. The presented large-scale model of the auditory cortex and the core simulator, SUSNOIMAC, have been made publicly available.


The bantam gene regulates Drosophila growth.
We report here the consequences of mutations of a novel locus, named bantam, whose product is involved in the regulation of growth in Drosophila. bantam mutant animals are smaller than wild type, due to a reduction in cell number but not cell size, and do not have significant disruptions in patterning. Conversely, overexpression of the bantam product using the EP element EP(3)3622 causes overgrowth of wing and eye tissue. Overexpression in clones of cells results in an increased rate of cell proliferation and a matched increase in cellular growth rate, such that the resulting tissue is composed of more cells of a size comparable to wild type. These effects are strikingly similar to those associated with alterations in the activity of the cyclinD-cdk4 complex. However, epistasis and genetic interaction analyses indicate that bantam and cyclinD-cdk4 operate independently. Thus, the bantam locus represents a novel regulator of tissue growth.


Conditions for gatekeeping when GPs consider patient requests unreasonable: a focus group study.
Requests from patients that are regarded by GPs as unreasonable are a source of conflict between GPs and patients. This makes gatekeeping challenging, as GPs negotiate a struggle between maintaining the doctor-patient relationship, protecting patients from the harms of medical overuse and acting as stewards of limited health care resources. More knowledge of how GPs can succeed in these difficult consultations is needed. To explore Norwegian GPs' perceptions of conditions that can promote their ability to act as gatekeepers when facing patient requests which they consider 'unreasonable'. A qualitative study based on three focus groups with Norwegian GPs conducted in 2019, exploring consultations in which the patient made a seemingly unreasonable request, but the GP was able to navigate the consultation in a clinically appropriate manner. Thematic cross-case analysis of verbatim transcripts from the focus groups was carried out using Systematic Text Condensation. The analysis revealed three major themes among the conditions that the GPs considered helpful when faced with an 'unreasonable' patient request: (i) professional communication skills; (ii) a long-term perspective; (iii) acknowledgement and support of GPs' gatekeeping role among peers and from authorities. Professional communication skills and relational continuity need to be prioritized for GPs to maintain their role as gatekeepers. However, support for the gatekeeping role within the profession as well as from society is also required.


dackel acts in the ectoderm of the zebrafish pectoral fin bud to maintain AER signaling.
Classical embryological studies have implied the existence of an apical ectodermal maintenance factor (AEMF) that sustains signaling from the apical ectodermal ridge (AER) during vertebrate limb development. Recent evidence suggests that AEMF activity is composed of different signals involving both a sonic hedgehog (Shh) signal and a fibroblast growth factor 10 (Fgf10) signal from the mesenchyme. In this study we show that the product of the dackel (dak) gene is one of the components that acts in the epidermis of the zebrafish pectoral fin bud to maintain signaling from the apical fold, which is homologous to the AER of tetrapods. dak acts synergistically with Shh to induce fgf4 and fgf8 expression but independently of Shh in promoting apical fold morphogenesis. The failure of dak mutant fin buds to progress from the initial fin induction phase to the autonomous outgrowth phase causes loss of both AER and Shh activity, and subsequently results in a proximodistal truncation of the fin, similar to the result obtained by ridge ablation experiments in the chicken. Further analysis of the dak mutant phenotype indicates that the activity of the transcription factor engrailed 1 (En1) in the ventral non-ridge ectoderm also depends on a maintenance signal probably provided by the ridge. This result uncovers a new interaction between the AER and the dorsoventral organizer in the zebrafish pectoral fin bud.


Modelling the dispersion of flashing jets using CFD.
Risk assessments related to industrial environments where gas is kept in liquid form under high pressure rely on the results from predictive tools. Computational Fluid Dynamics (CFD) is one such predictive tool and it is currently used for a range of applications. One of the most challenging application areas is the simulation of multiphase flows resulting from a breach or leakage in a pressurised pipeline or a vessel containing liquefied gas. The present paper deals with the modelling of the post-flashing scenario of a jet emanating from a circular orifice. In addition to being based on the equations governing fluid flow, the models used are those related to turbulence, droplet transport, evaporation, break-up and coalescence. Some of these models are semi-empirical and based on the data from applications other than flashing. However, these are the only models that are currently available in commercial codes and that would be used by consulting engineers for the type of modelling discussed above, namely the dispersion of a flashing release. A method for calculating inlet boundary conditions after flashing is also presented and issues related to such calculations are discussed. The results from a number of CFD based studies are compared with available experimental results. The results show that whilst a number of features of the experimental results can be reproduced by the CFD model, there are also a number of important shortcomings. The shortcomings are highlighted and discussed. Finally, an optimum approach to modelling of this type is suggested and methods to overcome modelling difficulties are proposed.