Protocol-based medical management of post-ERCP pancreatitis.
Although numerous studies have evaluated outcomes pertaining to endoscopic retrograde cholangio-pancreatography (ERCP) complications, studies evaluating outcomes of management of post-ERCP pancreatitis are scant. This study evaluated the effectiveness of a standard treatment protocol in management of post-ERCP pancreatitis. This is a retrospective study of consecutive patients managed for post-ERCP pancreatitis, using a standard treatment protocol over a 3-year period. By protocol, patients received only intravenous fluids, narcotics, and analgesics for the first 24-72 h after admission. Oral intake was attempted when white cell count was normal or followed a downward trend, abdominal pain was absent or minimal without need for narcotics over a 12-h period, and serum lipase was less than three times normal range. For patients hospitalized beyond 72 h, an abdomen CT was obtained at days 4 and 10 to guide management. Intravenous antibiotics were administered only for patients with pancreatic necrosis. Jejunal feeding and a meperidine pump for pain control were initiated in symptomatic patients at day 4. Data on ERCP complications were collected prospectively and graded per consensus criteria. Effectiveness of the treatment protocol was evaluated by comparing clinical outcomes of patients managed by protocol versus those managed outside protocol. 45 of 1976 patients (2.3%) who underwent ERCP developed post-ERCP pancreatitis. Of the 45 (female 31; mean age 43 years) patients, 32 were managed by protocol and 13 outside protocol. Protocol based management was associated with less severe disease as compared with those managed outside protocol (crude odds ratio (OR) = 11.2; 95% confidence interval (CI) = 1.9-68.7; P = 0.002). One patient managed outside protocol died of severe pancreatitis. When compared with those managed outside protocol, the median duration of hospital stay (7 vs 3 days; P = 0.01), the use of CT (100% vs 15.6%; P < 0.001), and the use of antibiotics (50% vs 3.1%; P = 0.01) were significantly lower in those managed by protocol. By multiple logistic regression, protocol-based management was associated with less severe disease (adjusted OR = 18.7; 95% CI = 2.6-132.1; P = 0.003) when adjusted for age, comorbidity, endotherapy and pancreatic stenting. A protocol-based management strategy was associated with less severe pancreatitis, shorter length of hospital stay, need for fewer imaging studies, and use of antibiotics. Prospective validation of these findings is justified.


Amino-acid selective isotope labeling enables simultaneous overlapping signal decomposition and information extraction from NMR spectra.
Signal overlapping is a major bottleneck for protein NMR analysis. We propose a new method, stable-isotope-assisted parameter extraction (SiPex), to resolve overlapping signals by a combination of amino-acid selective isotope labeling (AASIL) and tensor decomposition. The basic idea of Sipex is that overlapping signals can be decomposed with the help of intensity patterns derived from quantitative fractional AASIL, which also provides amino-acid information. In SiPex, spectra for protein characterization, such as 15N relaxation measurements, are assembled with those for amino-acid information to form a four-order tensor, where the intensity patterns from AASIL contribute to high decomposition performance even if the signals share similar chemical shift values or characterization profiles, such as relaxation curves. The loading vectors of each decomposed component, corresponding to an amide group, represent both the amino-acid and relaxation information. This information link provides an alternative protein analysis method that does not require "assignments" in a general sense; i.e., chemical shift determinations, since the amino-acid information for some of the residues allows unambiguous assignment according to the dual selective labeling. SiPex can also decompose signals in time-domain raw data without Fourier transform, even in non-uniformly sampled data without spectral reconstruction. These features of SiPex should expand biological NMR applications by overcoming their overlapping and assignment problems.


Deficiency in TR4 nuclear receptor abrogates Gadd45a expression and increases cytotoxicity induced by ionizing radiation.
The testicular receptor 4 (TR4) is a member of the nuclear receptor superfamily that controls various biological activities. A protective role of TR4 against oxidative stress has recently been discovered. We here examined the protective role of TR4 against ionizing radiation (IR) and found that small hairpin RNA mediated TR4 knockdown cells were highly sensitive to IR-induced cell death. IR exposure increased the expression of TR4 in scramble control small hairpin RNA expressing cells but not in TR4 knockdown cells. Examination of IR-responsive molecules found that the expression of Gadd45a, the growth arrest and DNA damage response gene, was dramatically decreased in Tr4 deficient (TR4KO) mice tissues and could not respond to IR stimulation in TR4KO mouse embryonic fibroblast cells. This TR4 regulation of GADD45A was at the transcriptional level. Promoter analysis identified four potential TR4 response elements located in intron 3 and exon 4 of the GADD45A gene. Reporter and chromatin immunoprecipitation (ChIP) assays provided evidence indicating that TR4 regulated the GADD45A expression through TR4 response elements located in intron 3 of the GADD45A gene. Together, we find that TR4 is essential in protecting cells from IR stress. Upon IR challenges, TR4 expression is increased, thereafter inducing GADD45A through transcriptional regulation. As GADD45A is directly involved in the DNA repair pathway, this suggests that TR4 senses genotoxic stress and up-regulates GADD45A expression to protect cells from IR-induced genotoxicity.


Global realized niche divergence in the African clawed frog Xenopus laevis.
Although of crucial importance for invasion biology and impact assessments of climate change, it remains widely unknown how species cope with and adapt to environmental conditions beyond their currently realized climatic niches (i.e., those climatic conditions existing populations are exposed to). The African clawed frog Xenopus laevis, native to southern Africa, has established numerous invasive populations on multiple continents making it a pertinent model organism to study environmental niche dynamics. In this study, we assess whether the realized niches of the invasive populations in Europe, South, and North America represent subsets of the species' realized niche in its native distributional range or if niche shifts are traceable. If shifts are traceable, we ask whether the realized niches of invasive populations still contain signatures of the niche of source populations what could indicate local adaptations. Univariate comparisons among bioclimatic conditions at native and invaded ranges revealed the invasive populations to be nested within the variable range of the native population. However, at the same time, invasive populations are well differentiated in multidimensional niche space as quantified via n-dimensional hypervolumes. The most deviant invasive population are those from Europe. Our results suggest varying degrees of realized niche shifts, which are mainly driven by temperature related variables. The crosswise projection of the hypervolumes that were trained in invaded ranges revealed the south-western Cape region as likely area of origin for all invasive populations, which is largely congruent with DNA sequence data and suggests a gradual exploration of novel climate space in invasive populations.


Birefringence measurements in gradient-index rod lenses.
Stress birefringence can be found in gradient-index (GRIN) materials because they contain a variation in composition. GRIN glass fabricated by ion exchange may contain stress from two different processes. These include a size difference between the exchange and the diffusing ions and a variation in the thermal-expansion coefficient across the gradient region. The optical properties of the stressed material are polarization dependent, and therefore image quality is directly affected. We examine birefringence in GRIN rod lenses that have lengths more than ten times greater than their diameters. The effects are more easily observed in long rod lenses because of the large optical path lengths.


The effect of discontinuation of postmilking teat disinfection in low somatic cell count herds. II. Dynamics of intramammary infections.
Results of a 20 month split-udder trial on the effect of discontinuation of postmilking teat disinfection on intramammary infections (IMI) with major and minor pathogens in seven dairy herds with a low somatic cell count are described. The incidence of Escherichia coli IMI was found to be significantly lower, whereas the incidence of IMI with Staphylococcus aureus and minor pathogens was significantly higher in quarters for which postmilking teat disinfection was discontinued than in disinfected quarters. It was concluded that discontinuation of postmilking teat disinfection decreased the incidence of E. coli IMI, accompanied by a, from a practical point of view, acceptable rise in somatic cell count. However, the possible increase in the incidence of S. aureus IMI calls for careful monitoring of the dynamics of IMI with contagious pathogens, when postmilking teat disinfection is discontinued in an attempt to reduce E. coli mastitis.


Mycobacterium bovis in Argentina: isolates from cats typified by spoligotyping.
In the present work, 19 Mycobacterium bovis isolates from different cats were typified by spoligotyping. We detected nine spoligotypes. There was only one cluster, which grouped 11 of the isolates (57.9%), showing the main spoligotype from cattle from Argentina. The rest of the spoligotypes presented only one isolate each. Five of them were not found in cattle, and were unique and exclusive of cats. The isolates studied show that tuberculosis of bovine origin in cats constitutes a potential public health problem in Buenos Aires region. The identification of genotypes from non-natural hosts could contribute to understand the spread of bovine tuberculosis. This is the first report showing genetic profiles of M. bovis isolates in felines from Argentina.


A Systematic Review and Meta-Analysis of Treatment and Outcome of Blister-Like Aneurysms.
Blister-like aneurysms are uncommon but challenging lesions. Their small size and atypical location often make the diagnosis difficult. Microsurgery and endovascular procedures have been used for their treatment, but there is no consensus on the best treatment technique. We conducted a systematic review and meta-analysis of treatments and outcomes of these vascular lesions. We reviewed English-language articles on "blood blister-like aneurysms" published between January 1997 and November 2014. All studies reporting patients with these aneurysms treated with surgery, endovascular procedures, or combined therapy with data on treatment modalities and clinical and/or angiographic outcomes were selected, including case reports and series. We performed a meta-analysis on the 2 largest treatment groups (surgery and endovascular management). Sixty studies with 334 patients met our inclusion criteria. Surgery was performed in 114 patients (34.2%), and endovascular treatment, in 199 patients (59.5%). A combined treatment was used in 19 patients (5.7%). A favorable outcome (mRS 0-2) was reported in 67.4% and 78.9% of patients treated with surgery and with endovascular therapy, respectively (P = .034). Blister-like aneurysms are challenging vascular lesions. The choice of treatment method must be based on the initial clinical presentation and an analysis of the radiologic features of the lesion to select the best technique. Endovascular treatment seems to have lower morbidity and mortality and provides a better outcome compared with surgical approaches. Further prospective studies must be performed to confirm such interesting results.


Endogenous Opioid-Masked Latent Pain Sensitization: Studies from Mouse to Human.
Following the resolution of a severe inflammatory injury in rodents, administration of mu-opioid receptor inverse agonists leads to reinstatement of pain hypersensitivity. The mechanisms underlying this form of latent pain sensitization (LS) likely contribute to the development of chronic pain, but LS has not yet been demonstrated in humans. Using a C57BL/6 mouse model of cutaneous mild heat injury (MHI) we demonstrated a dose-dependent reinstatement of pain sensitization, assessed as primary (P < 0.001) and secondary hyperalgesia (P < 0.001) by naloxone (0.3–10 mg/kg), 168 hrs after the induction of MHI. Forward-translating the dose data to a human MHI model (n = 12) we could show that LS does indeed occur after naloxone 2 mg/kg, 168 hrs after a MHI. Our previous unsuccessful efforts to demonstrate unmasking of LS in humans are thus likely explained by an insufficient naloxone dose (0.021 mg/kg). However, while LS was consistently demonstrated in 21/24 mice, LS was only seen in 4/12 subjects. This difference is likely due to selection bias since the C57BL/6 mouse strain exhibits markedly enhanced pain sensitivity in assays of acute thermal nociception. Future exploratory studies in humans should prioritize inclusion of "high-sensitizers" prone to develop LS and use post-surgical models to elucidate markers of vulnerability to chronic postsurgical pain. EudraCT 2012-005663-27.


An orally active TRPV4 channel blocker prevents and resolves pulmonary edema induced by heart failure.
Pulmonary edema resulting from high pulmonary venous pressure (PVP) is a major cause of morbidity and mortality in heart failure (HF) patients, but current treatment options demonstrate substantial limitations. Recent evidence from rodent lungs suggests that PVP-induced edema is driven by activation of pulmonary capillary endothelial transient receptor potential vanilloid 4 (TRPV4) channels. To examine the therapeutic potential of this mechanism, we evaluated TRPV4 expression in human congestive HF lungs and developed small-molecule TRPV4 channel blockers for testing in animal models of HF. TRPV4 immunolabeling of human lung sections demonstrated expression of TRPV4 in the pulmonary vasculature that was enhanced in sections from HF patients compared to controls. GSK2193874 was identified as a selective, orally active TRPV4 blocker that inhibits Ca(2+) influx through recombinant TRPV4 channels and native endothelial TRPV4 currents. In isolated rodent and canine lungs, TRPV4 blockade prevented the increased vascular permeability and resultant pulmonary edema associated with elevated PVP. Furthermore, in both acute and chronic HF models, GSK2193874 pretreatment inhibited the formation of pulmonary edema and enhanced arterial oxygenation. Finally, GSK2193874 treatment resolved pulmonary edema already established by myocardial infarction in mice. These findings identify a crucial role for TRPV4 in the formation of HF-induced pulmonary edema and suggest that TRPV4 blockade is a potential therapeutic strategy for HF patients.


Captivation with encapsulation: a dozen years of exploring uranyl peroxide capsules.
Uranyl peroxide clusters containing from 16 to 124 uranyl ions self-assemble in aqueous solution and exhibit tremendous topological complexity. Most of these clusters are cages, with the inside and outside surfaces passivated by oxygen atoms that are triply bonded to U(vi) cations (yl oxygen). It has become increasing apparent that the counter cations associated with these anionic cage clusters impact their assembly, topologies, and behavior in solution, including aggregation and aqueous solubility. Here we review the chemical compositions and topologies of uranyl peroxide clusters. We focus attention on the role of counter cations in cluster assembly, the properties of clusters in solution including supramolecular assembly, thermodynamic studies, and endohedral encapsulation. We also review the most useful solution characterization techniques of the counter cations and counter cation-capsule interactions. Potential applications in nuclear fuel cycles are discussed, including exerting nanoscale control of actinides to revolutionize separation technologies and provide novel pathways to nuclear materials including fuels, and an improved understanding of the transport of uranium in various systems. Finally, we elucidate some future directions.


[Endocarditis caused by Candida parapsilosis after total correction of tetralogy of Fallot. Medico-surgical treatment].
Three children with Candida Parapsilosis endocarditis after total surgical correction for Tetralogy of Fallot, are reported. Blood cultures became negative in one child with amphotericin-B and in the other two with Ketoconazole, before reoperation for septal patch replacement. Oral therapy with Ketoconazole continued for a total of 24 months, and during a mean follow-up of 36 months no side effects or reinfection occurred. Medical and surgical conjoined therapy, with surgical timing decided on clinical and laboratorial grounds, were important for good results and cure.


The Million Women Study: design and characteristics of the study population. The Million Women Study Collaborative Group.
To describe the design of the Million Women Study and the characteristics of the study population. Population-based cohort study of women aged 50-64 in the UK. Women are asked to join the Million Women Study when they are invited to routine screening for breast cancer at 61 of the screening centres of the UK National Health Service Breast Screening Programme (NHSBSP). An estimated 71% of women screened by the NHSBSP return a completed questionnaire. 800 000 women were recruited between May 1996 and June 1999, and it is planned that an additional 200 000 will be recruited by the year 2000. The characteristics of the first 121 000 women recruited into the Million Women Study are described here. At recruitment 33% of the study population were currently using hormone replacement therapy and 47% had used it at some time. Over half (54%) had used oral contraceptives, and 18% were current smokers at the time of recruitment. Before they were screened 1.4% of the women had been diagnosed with breast cancer in the past, 6% had a mother with a history of breast cancer and 3.7% had a sister with a history of breast cancer. It is estimated that 1 million women will have been recruited by early in the year 2000, and that by the end of the year 2002 there will be 5000 screen-detected breast cancers and 23 000 deaths in the cohort, the majority of which will be attributed to cancer (12 600 deaths) and circulatory disease (8000 deaths). By the end of the year 2002, the Million Women Study will have sufficient statistical power to detect relative risks of 0.8 or less, or of 1.2 or more in current users compared with never users of hormone replacement therapy for mortality from breast cancer, colorectal cancer, lung and ovarian cancer, ischaemic heart disease and stroke.


Insights into chemoselectivity principles in metal oxide affinity chromatography using tailored nanocast metal oxide microspheres and mass spectrometry-based phosphoproteomics.
The ability to comprehensively characterize biological samples, including tissues and body fluids, opens up new possibilities to diagnose and treat diseases and to better understand fundamental biological processes. For this purpose, suitable experimental workflows need to be designed. In this context, materials with particular chemoselective properties are used for the enrichment of certain classes of (bio)molecules. Metal oxides such as titanium dioxide have become the materials of choice for the large-scale study of protein phosphorylation in phosphoproteomics. Despite their widespread use, the main factors influencing their performance (for example, affinity and specificity) are not completely understood. This understanding is, however, crucial to develop improved materials and methods. Here, we used the nanocasting method to prepare microspheres of seven metal oxides with comparable textural properties, allowing an objective comparison of the materials and their binding properties. We evaluated these materials with samples of different complexity, ranging from synthetic peptides to whole cell lysates, using liquid chromatography-tandem mass spectrometry as a readout. A set of more than 7000 identified phosphopeptides allowed us to study differences between the metal oxide sorbents in detail. Importantly, the performance of the affinity materials was found to be mainly correlated with the oxides' isoelectric points (IEPs), with the materials that enriched the highest number of phosphopeptides having an IEP of around 6. This included the widely used TiO2 and ZrO2, but also In2O3 that was not previously known to possess affinity to phosphates. This finding supports the conclusion that the IEP has a stronger influence than the particular type of metal oxide and contrasts earlier reports that compared a limited number of materials with often unknown textural properties. Taken together, we introduce new metal oxides suitable for phosphopeptide enrichment, provide deeper insight into the properties that affect their performance, and offer a strategy to optimize enrichment protocols and materials.


Reporting non-adherence in cluster randomised trials: A systematic review.
Treatment non-adherence in randomised trials refers to situations where some participants do not receive their allocated treatment as intended. For cluster randomised trials, where the unit of randomisation is a group of participants, non-adherence may occur at the cluster or individual level. When non-adherence occurs, randomisation no longer guarantees that the relationship between treatment receipt and outcome is unconfounded, and the power to detect the treatment effects in intention-to-treat analysis may be reduced. Thus, recording adherence and estimating the causal treatment effect adequately are of interest for clinical trials. To assess the extent of reporting of non-adherence issues in published cluster trials and to establish which methods are currently being used for addressing non-adherence, if any, and whether clustering is accounted for in these. We systematically reviewed 132 cluster trials published in English in 2011 previously identified through a search in PubMed. One-hundred and twenty three cluster trials were included in this systematic review. Non-adherence was reported in 56 cluster trials. Among these, 19 reported a treatment efficacy estimate: per protocol in 15 and as treated in 4. No study discussed the assumptions made by these methods, their plausibility or the sensitivity of the results to deviations from these assumptions. The year of publication of the cluster trials included in this review (2011) could be considered a limitation of this study; however, no new guidelines regarding the reporting and the handling of non-adherence for cluster trials have been published since. In addition, a single reviewer undertook the data extraction. To mitigate this, a second reviewer conducted a validation of the extraction process on 15 randomly selected reports. Agreement was satisfactory (93%). Despite the recommendations of the Consolidated Standards of Reporting Trials statement extension to cluster randomised trials, treatment adherence is under-reported. Among the trials providing adherence information, there was substantial variation in how adherence was defined, handled and reported. Researchers should discuss the assumptions required for the results to be interpreted causally and whether these are scientifically plausible in their studies. Sensitivity analyses to study the robustness of the results to departures from these assumptions should be performed.


[Multidisciplinary care for victims of sexual assault: the experience at the Federal University in São Paulo, Brazil].
This article discusses the importance of multidisciplinary care for victims of sexual assault in order to mitigate the respective physical, psychological, and social harm. The article begins with a brief description of the activities by various professionals involved in the care of victims treated at the Women's Health Center of the Federal University in São Paulo, and presents the outcome of some cases treated at this institution in its five years of experience. The article provides the socio-demographic profile of female rape victims since the beginning of this women's health service, with the number of women who became pregnant, those who underwent abortion, and the number of court suits filed.


Defining and managing incidental findings in genetic and genomic practice.
The rapidly declining costs and increasing speeds of whole-genome analysis mean that genetic testing is undergoing a shift from targeted approaches to broader ones that look at the entire genome. As whole-genome technologies gain widespread use, questions about the management of so-called incidental findings-those unrelated to the question being asked-need urgent consideration. In this review, we bring together current understanding and arguments about (1) appropriate terminology, (2) the determination of clinical utility and when to disclose incidental findings, (3) the differences in management and disclosure in clinical, research and commercial contexts and (4) ethical and practical issues about familial implications and recontacting those tested. We recommend that greater international consensus is developed around the disclosure and management of incidental findings, with particular attention to when, and how, less clear-cut results should be communicated. We suggest that there is no single term that captures all the issues around these kinds of findings and that different terms may, therefore, need to be used in different settings. We also encourage the use of clear consent processes, but suggest that the absence of consent should not always preclude disclosure. Finally, we recommend further research to identify ways to implement the use of a genome output as a resource, accessible over time, to facilitate appropriate disclosure and recontact when the significance of a previously unclear incidental finding is clarified.


Venous blood arterialization and parameters from the minimal models of glucose disappearance and post-hepatic insulin delivery.
1. Modelling analysis of intravenous glucose tolerance test glucose and insulin concentrations can provide measures of insulin sensitivity and metabolism from a single straightforward procedure. However, little is known of the effects of blood arterialization on model-derived parameters. 2. Intravenous glucose tolerance tests were carried out on 18 subjects, with measurement of glucose and insulin concentrations in simultaneously sampled non-arterialized and arterialized blood. Blood oxygen saturation, partial pressure of CO2 and pH were measured on both non-arterialized and arterialized blood during the intravenous glucose tolerance test. Using the minimal models of glucose disappearance and post-hepatic insulin delivery, measures of insulin sensitivity, glucose-dependent glucose disposal, first- and second-phase post-hepatic insulin responsiveness to glucose and plasma insulin elimination rate were derived from intravenous glucose tolerance test glucose and insulin concentrations in both arterialized and non-arterialized blood. 3. During the intravenous glucose tolerance test mean blood oxygen saturation was 6.7% higher, partial pressure of CO2 was 0.3 kPa lower and pH was 0.015 higher in arterialized than non-arterialized blood. Mean parameter values did not differ when derived from measurements made on non-arterialized and arterialized blood. Model-derived parameters were not related to the degree of arterialization, although there was some consistent variation with sampling site for parameters of glucose-dependent glucose disposal (Sg), first-phase post-hepatic insulin responsiveness (phi 1) and insulin elimination (ni). 4. Measurements made on non-arterialized blood are suitable for analyses employing the minimal models of glucose disappearance and post-hepatic insulin delivery. Imprecision in some parameters may be diminished by adherence to a single sampling site.


Passage of ions and dextran molecules across the rete mirabile of the eel. The effects of charge.
The countercurrent-perfused rete mirabile of the eel is a preparation in which capillary permeability values can be determined accurately in broadscale fashion. To provide insight into charge effects on transendothelial passage, the permeability values of small inorganic cations (labeled sodium and rubidium, and stable potassium) and anions (labeled chloride, iodide, sulfate, and ferrocyanide) were compared to those expected for neutral solutes with approximately matched diffusion coefficients, and that of a neutral dextran fraction was compared to that of a negatively charged dextran sulfate with a similar diffusion coefficient. In the small ion experiments, the labeled iodide values were unexpectedly high, apparently due to the contamination of the labeled iodide solution with I-3. The permeabilities of the rest of the ions clustered at a level about 0.5 of the values which would have been expected for neutral solutes with similar diffusion coefficients. The decrement was interpreted to reflect the presence of both positive and negative charges along the transendothelial pathway, which effectively decrease the dimensions of the limiting part of the pathway for the charged microions relative to that accessible to comparable nonelectrolytes. The larger negatively charged dextran sulfate was also reduced in its passage, in comparison with its matching neutral dextran; this was taken to indicate the presence of a larger scale average net negative charge along its pathway. The data indicate the presence of a staggering of positive and negative charges along the transendothelial pathway accessible to the microions, and a net negative charge in the more restricted part of the pathway available to the dextrans.


Multiperson visual focus of attention from head pose and meeting contextual cues.
This paper introduces a novel contextual model for the recognition of people's visual focus of attention (VFOA) in meetings from audio-visual perceptual cues. More specifically, instead of independently recognizing the VFOA of each meeting participant from his own head pose, we propose to jointly recognize the participants' visual attention in order to introduce context-dependent interaction models that relate to group activity and the social dynamics of communication. Meeting contextual information is represented by the location of people, conversational events identifying floor holding patterns, and a presentation activity variable. By modeling the interactions between the different contexts and their combined and sometimes contradictory impact on the gazing behavior, our model allows us to handle VFOA recognition in difficult task-based meetings involving artifacts, presentations, and moving people. We validated our model through rigorous evaluation on a publicly available and challenging data set of 12 real meetings (5 hours of data). The results demonstrated that the integration of the presentation and conversation dynamical context using our model can lead to significant performance improvements.


Lattice Boltzmann modeling of heat conduction enhancement by colloidal nanoparticle deposition in microporous structures.
Drying of colloidal suspension towards the exploitation of the resultant nanoparticle deposition has been applied in different research and engineering fields. Recent experimental studies have shown that neck-based thermal structure (NTS) by colloidal nanoparticle deposition between microsize filler particle configuration (FPC) can significantly enhance vertical heat conduction in innovative three-dimensional chip stacks [Brunschwiler et al., J. Electron. Packag. 138, 041009 (2016)10.1115/1.4034927]. However, an in-depth understanding of the mechanisms of colloidal liquid drying, neck formation, and their influence on heat conduction is still lacking. In this paper, using the lattice Boltzmann method, we model neck formation in FPCs and evaluate the thermal performances of resultant NTSs. The colloidal liquid is found drying continuously from the periphery of the microstructure to its center with a decreasing drying rate. With drying, more necks of smaller size are formed between adjacent filler particles, while fewer necks of larger size are formed between filler particle and the top/bottom plate of the FPCs. The necks, forming critical throats between the filler particles, are found to improve the heat flux significantly, leading to an overall heat conduction enhancement of 2.4 times. In addition, the neck count, size, and distribution as well as the thermal performance of NTSs are found to be similar for three different FPCs at a constant filler particle volume fraction. Our simulation results on neck formation and thermal performances of NTSs are in good agreement with experimental results. This demonstrates that the current lattice Boltzmann models are accurate in modeling drying of colloidal suspension and heat conduction in microporous structures, and have high potentials to study other problems such as surface coating, salt transport, salt crystallization, and food preserving.


Examining potential school contextual influences on gambling among high school youth.
Gambling is an increasing concern among adolescence, yet there has been limited investigation into school-level factors that may increase the risk for gambling. The current study examined the relationship between substance use and gambling, and explored the influence of school context on adolescent gambling. Data come from 25,456 students in 58 high schools participating in the Maryland Safe and Supportive Schools Initiative. Youth-reports of socio-demographics, lifetime gambling, and past-month substance use (ie, alcohol, cigarette, marijuana, non-medical prescription drug) were collected. School-level characteristics were student suspension rate, student mobility, percentage of students receiving free/reduce-priced meals, percentage of African American students, urbanicity, gambling prevalence, gambling problem prevalence, and substance use prevalence. Weighted multilevel analyses were conducted. One-third (n = 8,318) reported lifetime gambling, and 10% (n = 2,580) of the full sample, or 31% of the gamblers, experienced gambling problems. Being male and alcohol, marijuana, and non-medical prescription drug use were associated with twice the odds of gambling. Among gamblers, being male, African American, and cigarette, marijuana, and non-medical prescription drug use were associated with higher odds of gambling problems. The school-level factors of suspension rate and percentage of African American had minimal, inverse associations with gambling; however, none were related to gambling problems. Multilevel results indicated that adolescents that are male and use substances are more likely to gamble and have gambling problems. The findings indicate a need for prevention programs targeting risky behaviors to also target gambling as such behaviors often co-occur among adolescents.


Bolus Residue Scale: An Easy-to-Use and Reliable Videofluoroscopic Analysis Tool to Score Bolus Residue in Patients with Dysphagia.
Background. We aimed to validate an easy-to-use videofluoroscopic analysis tool, the bolus residue scale (BRS), for detection and classification of pharyngeal retention in the valleculae, piriform sinuses, and/or the posterior pharyngeal wall. Methods. 50 randomly selected videofluoroscopic images of 10 mL swallows (recorded in 18 dysphagia patients and 8 controls) were analyzed by 4 experts and 6 nonexpert observers. A score from 1 to 6 was assigned according to the number of structures affected by residue. Inter- and intrarater reliabilities were assessed by calculation of intraclass correlation coefficients (ICCs) for expert and nonexpert observers. Sensitivity, specificity, and interrater agreement were analyzed for different BRS levels. Results. Intrarater reproducibility was almost perfect for experts (mean ICC 0.972) and ranged from substantial to almost perfect for nonexperts (mean ICC 0.835). Interjudge agreement of the experts ranged from substantial to almost perfect (mean ICC 0.780), but interrater reliability of nonexperts ranged from substantial to good (mean 0.719). BRS shows for experts a high specificity and sensitivity and for nonexperts a low sensitivity and high specificity. Conclusions. The BRS is a simple, easy-to-carry-out, and accessible rating scale to locate pharyngeal retention on videofluoroscopic images with a good specificity and reproducibility for observers of different expertise levels.


Discovery and Characterization of Novel Nonsubstrate and Substrate NAMPT Inhibitors.
Cancer cells are highly reliant on NAD+-dependent processes, including glucose metabolism, calcium signaling, DNA repair, and regulation of gene expression. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD+ salvage from nicotinamide, has been investigated as a target for anticancer therapy. Known NAMPT inhibitors with potent cell activity are composed of a nitrogen-containing aromatic group, which is phosphoribosylated by the enzyme. Here, we identified two novel types of NAM-competitive NAMPT inhibitors, only one of which contains a modifiable, aromatic nitrogen that could be a phosphoribosyl acceptor. Both types of compound effectively deplete cellular NAD+, and subsequently ATP, and produce cell death when NAMPT is inhibited in cultured cells for more than 48 hours. Careful characterization of the kinetics of NAMPT inhibition in vivo allowed us to optimize dosing to produce sufficient NAD+ depletion over time that resulted in efficacy in an HCT116 xenograft model. Our data demonstrate that direct phosphoribosylation of competitive inhibitors by the NAMPT enzyme is not required for potent in vitro cellular activity or in vivo antitumor efficacy. Mol Cancer Ther; 16(7); 1236-45. ©2017 AACR.


Reverse concreteness effects are not a typical feature of semantic dementia: evidence for the hub-and-spoke model of conceptual representation.
The role of anterior temporal lobes (ATLs) in semantic processing is controversial. One theory, influenced by semantic dementia (SD) patients, is that this region is a pan-modal hub for all concepts. An alternative view is that atrophy in SD specifically affects knowledge for visual features. This is supported by reports of reverse concreteness effects in a few SD patients, suggesting that abstract word knowledge is spared relative to concrete words. However, it is not clear whether such effects are typical in SD, hence reliably associated with ATL damage, because most reports are of single cases and group studies have produced conflicting results. To address these contradictions, we investigated concreteness effects in 7 SD patients, using multiple tests from earlier studies in addition to new assessments. Comprehension was impaired for both word types but was better for concrete words. However, this pattern was not found uniformly across all tests and was most likely to be observed when: 1) concrete and abstract words were well matched for word frequency and 2) concrete and abstract words were selected with sufficient variation along the imageability scale. These factors account for the variability in previous studies and indicate that reverse concreteness effects are not common in SD.


Treatment and prophylaxis of hematologic malignancy in the central nervous system.
Central nervous system (CNS) involvement is a serious, and frequently fatal, complication of acute leukemias and very aggressive lymphomas. In patients with no evidence of CNS involvement at the time of diagnosis, the decision to include CNS prophylaxis in the treatment regimen should be based on cytologic diagnosis and other risk factors. Patients with a risk of CNS relapse greater than 10% should receive CNS prophylaxis with high-dose systemic chemotherapy, intrathecal therapy, radiation, or a combination thereof. The most commonly used systemic and intrathecal chemotherapies are methotrexate and cytarabine. Liposomal cytarabine, which increases CNS bioavailability and decreases the number of lumbar punctures needed, is our preference for intrathecal therapy. We usually reserve radiation therapy for patients who may not tolerate other forms of CNS prophylaxis. Patients with evidence of CNS involvement, either at diagnosis or relapse, should be treated until CNS disease clearance or dose-limiting toxicity is reached. Recent studies suggest that autologous stem cell transplantation may offer longer survivals for patients with CNS involvement and should be considered for patients who can tolerate the procedure. The use of rituximab in CNS prophylaxis and treatment has not yet been clearly delineated, but initial reports indicate that this agent and others may soon be available as an effective and tolerable CNS-directed therapy for lymphomas.


Patient and Provider Satisfaction with Teledermatology.
There is little research comparing dermatologist and patient satisfaction with in-person, store-and-forward, and live interactive examinations. To compare satisfaction with in-person examinations to store-and-forward and live interactive consultations having two types of video. A controlled study was conducted where patients referred for dermatology consultations were examined in-person, by video, and by store-and-forward methods. Video changed between compressed and uncompressed on alternate clinics. Patients and dermatologists rated encounters after each examination. Dermatologists doing store-and-forward evaluations rated the quality of information provided. After experiencing all methods patients ranked their preferences. Dermatologists ranked their preferences at the end of the study. In-person examinations were preferred by both patients and dermatologists. Overall, satisfaction with teledermatology was still high. Patients were evenly divided in preferring store-and-forward workups or live interactive video. Dermatologists were also divided on store-and-forward and uncompressed video, but tended toward the latter. Compressed video was the least preferred method among dermatologists. Dermatology residents took store-and-forward photos and their quality was likely superior to those normally taken in practice. Patients and dermatologists prefer in-person examinations and diverge on preferring store-and-forward and live interactive when video is not compressed. The amount of video compression that can be applied without noticeable image degradation is a question for future research.


TRAF4-mediated ubiquitination of NGF receptor TrkA regulates prostate cancer metastasis.
Receptor tyrosine kinases (RTKs) are important drivers of cancers. In addition to genomic alterations, aberrant activation of WT RTKs plays an important role in driving cancer progression. However, the mechanisms underlying how RTKs drive prostate cancer remain incompletely characterized. Here we show that non-proteolytic ubiquitination of RTK regulates its kinase activity and contributes to RTK-mediated prostate cancer metastasis. TRAF4, an E3 ubiquitin ligase, is highly expressed in metastatic prostate cancer. We demonstrated here that it is a key player in regulating RTK-mediated prostate cancer metastasis. We further identified TrkA, a neurotrophin RTK, as a TRAF4-targeted ubiquitination substrate that promotes cancer cell invasion and found that inhibition of TrkA activity abolished TRAF4-dependent cell invasion. TRAF4 promoted K27- and K29-linked ubiquitination at the TrkA kinase domain and increased its kinase activity. Mutation of TRAF4-targeted ubiquitination sites abolished TrkA tyrosine autophosphorylation and its interaction with downstream proteins. TRAF4 knockdown also suppressed nerve growth factor (NGF) stimulated TrkA downstream p38 MAPK activation and invasion-associated gene expression. Furthermore, elevated TRAF4 levels significantly correlated with increased NGF-stimulated invasion-associated gene expression in prostate cancer patients, indicating that this signaling axis is significantly activated during oncogenesis. Our results revealed a posttranslational modification mechanism contributing to aberrant non-mutated RTK activation in cancer cells.


Mapping shape to visuomotor mapping: learning and generalisation of sensorimotor behaviour based on contextual information.
Humans can learn and store multiple visuomotor mappings (dual-adaptation) when feedback for each is provided alternately. Moreover, learned context cues associated with each mapping can be used to switch between the stored mappings. However, little is known about the associative learning between cue and required visuomotor mapping, and how learning generalises to novel but similar conditions. To investigate these questions, participants performed a rapid target-pointing task while we manipulated the offset between visual feedback and movement end-points. The visual feedback was presented with horizontal offsets of different amounts, dependent on the targets shape. Participants thus needed to use different visuomotor mappings between target location and required motor response depending on the target shape in order to "hit" it. The target shapes were taken from a continuous set of shapes, morphed between spiky and circular shapes. After training we tested participants performance, without feedback, on different target shapes that had not been learned previously. We compared two hypotheses. First, we hypothesised that participants could (explicitly) extract the linear relationship between target shape and visuomotor mapping and generalise accordingly. Second, using previous findings of visuomotor learning, we developed a (implicit) Bayesian learning model that predicts generalisation that is more consistent with categorisation (i.e. use one mapping or the other). The experimental results show that, although learning the associations requires explicit awareness of the cues' role, participants apply the mapping corresponding to the trained shape that is most similar to the current one, consistent with the Bayesian learning model. Furthermore, the Bayesian learning model predicts that learning should slow down with increased numbers of training pairs, which was confirmed by the present results. In short, we found a good correspondence between the Bayesian learning model and the empirical results indicating that this model poses a possible mechanism for simultaneously learning multiple visuomotor mappings.


Initiatives in South Africa to enhance the prescribing of generic proton pump inhibitors: findings and implications.
There have been multiple reforms in South Africa to conserve resources including policies to enhance generic use, such as compulsory generic substitution and copayments. However, there are concerns with the limited knowledge of their impact. The objective was to determine utilization and expenditure of different proton pump inhibitors (PPIs). A retrospective drug utilization study was conducted on a prescription database of a medical aid administrator in 2010. The limited prescribing of single-sourced PPIs accounted for 21.5% of total prescriptions. The limited use of originators omeprazole and lansoprazole accounted for 1.8 and 1.4% of total prescriptions for the molecule, respectively. Generic prices accounted for 36-68% of the originator in 2010. Patients received on average 2.91 PPI prescriptions during the year. Policies to enhance prescribing of generics appear working. Opportunities exist to further lower generic prices given low prices in some European countries.


Developmental Cascades from Aggression to Internalizing Problems via Peer and Teacher Relationships from Early to Middle Adolescence.
Previous research has provided evidence for developmental cascades between externalizing and internalizing problems via mechanisms such as peer and academic problems; however, there remains a need to illuminate other key mediating processes that could serve as intervention targets. This study, thus, evaluated whether developmental associations between aggression and internalizing are mediated by teacher-as well as peer-relationships. Using data from z-proso, a longitudinal study of Swiss youth (n = 1523; 785 males), an autoregressive latent trajectory model with structured residuals (ALT-SR) was fit over ages 11, 13, and 15 to examine within-person developmental links between aggression, internalizing problems, and the mediating role of peer and teacher relationships, while disaggregating between- and within-person effects. Teacher and peer relationships did not play a role in the progression of externalizing to internalizing problems or vice versa, however, teacher and peer relationships showed a protective effect against developing internalizing problems at ages 13. The results suggest that good quality relationships with teachers in early adolescence can help prevent internalizing problems from developing.


Effects of gamma-irradiation on midgut proteolytic activity of the mediterranean fruit fly, Ceratitis capitata (Diptera: Tephritidae).
The Mediterranean fruit fly (medfly), Ceratitis capitata (Wiedemann), is a key pest of citrus in Spain because of significant yield losses and to quarantine restrictions. Biologically based control methods, such as the Sterile Insect Technique (SIT), which relies on the sterilization by irradiation of large numbers of insects, is gaining an increasing role in the control of medfly in Mediterranean areas. However, gamma-irradiation might damage the midgut epithelium cells, causing a lowering of nutritive assimilation that can negatively affect adult performance. Irradiation effects on digestive physiology are well established for a number of insect pests, but there is no information on medfly. Our aim was to determine the effects of gamma-irradiation on C. capitata digestive protease activity. Both larvae and adults were found to use a similar proteolytic system based on aspartyl-, trypsin-, chymotrypsin-, amino peptidase-, and carboxypeptidase A- and B-like activities. Pupae of the Vienna-7 (tsl) strain were irradiated at 70 or 140 Gy, two days before emergence, and the adults fed during 5 days on sugar-protein (4:1) diets. Protease activity was measured in midgut extracts and compared with males non-irradiated reared in the same conditions. The results showed that the irradiation doses tested had no effect on the digestive proteolytic activities of medfly adults. Moreover, the longevity of irradiated medflies at the highest dose (140 Gy) was similar to that of controls.


Curcumin inhibits tumor growth and angiogenesis in an orthotopic mouse model of human pancreatic cancer.
Pancreatic cancer is a malignant neoplasm originating from transformed cells arising in tissues forming the pancreas. The best chemotherapeutic agent used to treat pancreatic cancer is the gemcitabine. However, gemcitabine treatment is associated with many side effects. Thus novel strategies involving less toxic agents for treatment of pancreatic cancer are necessary. Curcumin is one such agent that inhibits the proliferation and angiogenesis of a wide variety of tumor cells, through the modulation of many cell signalling pathways. In this study, we investigated whether curcumin plays antitumor effects in MIA PaCa-2 cells. In vitro studies showed that curcumin inhibits the proliferation and enhances apoptosis of MIA PaCa-2 cells. To test whether the antitumor activity of curcumin is also observed in vivo, we generated an orthotopic mouse model of pancreatic cancer by injection of MIA PaCa-2 cells in nude mice. We placed mice on diet containing curcumin at 0.6% for 6 weeks. In these treated mice tumors were smaller with respect to controls and showed a downregulation of the transcription nuclear factor NF-κB and NF-κB-regulated gene products. Overall, our data indicate that curcumin has a great potential in treatment of human pancreatic cancer through the modulation of NF-κB pathway.


Using food insecurity in health prevention to promote consumer's embodied self-regulation.
Health messages designed to address obesity are typically focused on the long-term benefits of eating healthy food. However, according to the insurance hypothesis, obese people are food insecure, and this causes them to be overly concerned about short-term consumption. As such, it is necessary to rethink public health messaging and consider how to reduce short-term insecurity by eating healthy food.


Screening for Prostate Cancer Starting at Age 50-54 Years. A Population-based Cohort Study.
Current prostate cancer screening guidelines conflict with respect to the age at which to initiate screening. To evaluate the effect of prostate-specific antigen (PSA) screening versus zero screening, starting at age 50-54 yr, on prostate cancer mortality. This is a population-based cohort study comparing 3479 men aged 50 yr through 54 yr randomized to PSA-screening in the Göteborg population-based prostate cancer screening trial, initiated in 1995, versus 4060 unscreened men aged 51-55 yr providing cryopreserved blood in the population-based Malmö Preventive Project in the pre-PSA era, during 1982-1985. Cumulative incidence and incidence rate ratios of prostate cancer diagnosis, metastasis, and prostate cancer death. At 17 yr, regular PSA-screening in Göteborg of men in their early 50s carried a more than two-fold higher risk of prostate cancer diagnosis compared with the unscreened men in Malmö (incidence rate ratio [IRR] 2.56, 95% confidence interval [CI] 2.18, 3.02), but resulted in a substantial decrease in the risk of metastases (IRR 0.43, 95% CI 0.22, 0.79) and prostate cancer death (IRR 0.29, 95% CI 0.11, 0.67). There were 57 fewer prostate cancer deaths per 10000 men (95% CI 22, 92) in the screened group. At 17 yr, the number needed to invite to PSA-screening and the number needed to diagnose to prevent one prostate cancer death was 176 and 16, respectively. The study is limited by lack of treatment information and the comparison of the two different birth cohorts. PSA screening for prostate cancer can decrease prostate cancer mortality among men aged 50-54 yr, with the number needed to invite and number needed to detect to prevent one prostate cancer death comparable to those previously reported from the European Randomized Study of Screening for Prostate Cancer for men aged 55-69 yr, at a similar follow-up. Guideline groups could consider whether guidelines for PSA screening should recommend starting no later than at ages 50-54 yr. Guideline recommendations about the age to start prostate-specific antigen screening could be discussed.


Next Generation Sequencing of Actinobacteria for the Discovery of Novel Natural Products.
Like many fields of the biosciences, actinomycete natural products research has been revolutionised by next-generation DNA sequencing (NGS). Hundreds of new genome sequences from actinobacteria are made public every year, many of them as a result of projects aimed at identifying new natural products and their biosynthetic pathways through genome mining. Advances in these technologies in the last five years have meant not only a reduction in the cost of whole genome sequencing, but also a substantial increase in the quality of the data, having moved from obtaining a draft genome sequence comprised of several hundred short contigs, sometimes of doubtful reliability, to the possibility of obtaining an almost complete and accurate chromosome sequence in a single contig, allowing a detailed study of gene clusters and the design of strategies for refactoring and full gene cluster synthesis. The impact that these technologies are having in the discovery and study of natural products from actinobacteria, including those from the marine environment, is only starting to be realised. In this review we provide a historical perspective of the field, analyse the strengths and limitations of the most relevant technologies, and share the insights acquired during our genome mining projects.


Salt-inducible kinase 1 regulates bone anabolism via the CRTC1-CREB-Id1 axis.
New bone anabolic agents for the effective treatment of bone metabolic diseases like osteoporosis are of high clinical demand. In the present study, we reveal the function of salt-inducible kinase 1 (SIK1) in regulating osteoblast differentiation. Gene knockdown of SIK1 but not of SIK2 or SIK3 expression in primary preosteoblasts increased osteoblast differentiation and bone matrix mineralization. SIK1 also regulated the proliferation of osteoblastic precursor cells in osteogenesis. This negative control of osteoblasts required the catalytic activity of SIK1. SIK1 phosphorylated CREB regulated transcription coactivator 1 (CRTC1), preventing CRTC1 from enhancing CREB transcriptional activity for the expression of osteogenic genes like Id1. Furthermore, SIK1 knockout (KO) mice had higher bone mass, osteoblast number, and bone formation rate versus littermate wild-type (WT) mice. Preosteoblasts from SIK1 KO mice showed more osteoblastogenic potential than did WT cells, whereas osteoclast generation among KO and WT precursors was indifferent. In addition, bone morphogenic protein 2 (BMP2) suppressed both SIK1 expression as well as SIK1 activity by protein kinase A (PKA)-dependent mechanisms to stimulate osteogenesis. Taken together, our results indicate that SIK1 is a key negative regulator of preosteoblast proliferation and osteoblast differentiation and that the repression of SIK1 is crucial for BMP2 signaling for osteogenesis. Therefore, we propose SIK1 to be a useful therapeutic target for the development of bone anabolic strategies.


Women's knowledge and attitudes regarding alcohol consumption in pregnancy: a national survey.
Alcohol exposure in pregnancy is a common and modifiable risk factor for poor pregnancy and child outcomes. Alcohol exposure in pregnancy can cause a range of physical and neurodevelopmental problems in the child including the Fetal Alcohol Spectrum Disorders (FASD). In order to improve prevention strategies, we sought to describe the knowledge and attitudes of women of childbearing age regarding alcohol consumption during pregnancy and its effects on the fetus. We conducted a national cross-sectional survey via computer assisted telephone interview of 1103 Australian women aged 18 to 45 years. Participants were randomly selected from the Electronic White Pages. Pregnant women were not eligible to participate. Quotas were set for age groups and a minimum of 100 participants per state to ensure a national sample reflecting the population. The questionnaire was based on a Health Canada survey with additional questions constructed by the investigators. Descriptive statistics were calculated and logistic regression analyses were used to assess associations with participants' knowledge and attitudes. Of women surveyed, 61.5% had heard about effects of alcohol on the fetus and 55.3% had heard of Fetal Alcohol Syndrome. Although 92.7% agreed alcohol can affect the unborn child, 16.2% did not agree that the disabilities could be lifelong. Most women agreed that pregnant women should not drink alcohol (80.2%) and 79.2% reported having negative feelings towards pregnant women drinking alcohol. Women with higher education levels were more likely to know the effects of alcohol consumption in pregnancy (adjusted OR 5.62; 95% CI 3.20 to 9.87) but education level and knowledge were not associated with attitude. There was a disjunction between knowledge and attitudes towards alcohol consumption in pregnancy. These findings will assist in developing effective health promotion campaigns to reduce fetal alcohol exposure and subsequent fetal damage.


Glycoprotein, elastin, and collagen secretion by rat smooth muscle cells.
Smooth muscle cells from rat heart secreted extracellular matrix components at high rates for many generations in culture. The matrix proteins remained anchored to the culture dish and were characterized after removal of cellular material with sodium dodecyl sulfate. Sequential enzyme digestion demonstrated the presence of at least three components, including glycoprotein(s), elastin, and collagen. Prolonged extraction of the matrix with detergent under reducing conditions solubilized a fucosylated glycoprotein having an apparent molecular weight of 250,000 and two other proteins with molecular weights of 72,000 and 45,000, respectively. Sublines derived from discrete colonies of smooth muscle cells synthesized all of the matrix components, and the proportion of collagen secreted by some sublines increased with time in culture. The biosynthesis of a mixed extracellular matrix and the relationships among the component proteins were therefore studied in one system producing milligram quantities of material.


Tokamak equilibria with reversed current density.
Observations of nearly zero toroidal current in the central region of tokamaks (the "current hole") raises the question of the existence of toroidal equilibria with very low or reversed current in the core. The solutions of the Grad-Shafranov equilibrium equation with hollow toroidal current density profile including negative current density in the plasma center are investigated. Solutions of the corresponding eigenvalue problem provide simple examples of such equilibrium configurations. More realistic equilibria with toroidal current density reversal are computed using a new equilibrium problem formulation and computational algorithm which do not assume nested magnetic surfaces.


Human aggression.
Research on human aggression has progressed to a point at which a unifying framework is needed. Major domain-limited theories of aggression include cognitive neoassociation, social learning, social interaction, script, and excitation transfer theories. Using the general aggression model (GAM), this review posits cognition, affect, and arousal to mediate the effects of situational and personological variables on aggression. The review also organizes recent theories of the development and persistence of aggressive personality. Personality is conceptualized as a set of stable knowledge structures that individuals use to interpret events in their social world and to guide their behavior. In addition to organizing what is already known about human aggression, this review, using the GAM framework, also serves the heuristic function of suggesting what research is needed to fill in theoretical gaps and can be used to create and test interventions for reducing aggression.


Trial of labor or repeat cesarean delivery in women with morbid obesity and previous cesarean delivery.
Assess effects of body mass index (BMI) on trial of labor after previous cesarean delivery and determine whether morbidly obese women have greater maternal and perinatal morbidity with trial of labor compared with elective repeat cesarean delivery. Secondary analysis from a prospective observational study included all term singletons undergoing trial of labor after previous cesarean delivery. Body mass index groups were as follows: normal 18.5-24.9, overweight 25.0-29.9, obese 30.0-39.9, morbidly obese 40.0 kg/m2 or greater, and were compared for failure and maternal and neonatal morbidities. The morbidly obese trial of labor and elective repeat cesarean delivery were compared for maternal and neonatal morbidities. Multivariable logistic regression analysis controlled for confounding variables. There were 14,142 trial of labor participants and 14,304 elective repeat cesarean delivery participants. Increasing BMI was directly associated with failed trial of labor after previous cesarean delivery: from 15.2% in normal weight (1,344) to 39.3% in morbidly obese (1,638), with combined risk of rupture/dehiscence increasing from 0.9% to 2.1% in morbidly obese women. Among morbidly obese women, trial of labor carried greater than five-fold risk of uterine rupture/dehiscence (2.1% versus 0.4%), almost a two-fold increase in composite maternal morbidity (7.2% versus 3.8%) and five-fold risk of neonatal injury (1.1% versus 0.2%) (fractures, brachial plexus injuries, and lacerations), but no neonatal encephalopathy. Morbidly obese women failing a trial of labor had six-fold greater composite maternal morbidity than those undergoing a successful trial of labor (14.2% versus 2.6%). Body mass index correlates with outcomes in trial of labor after previous cesarean delivery. Morbidly obese women undergoing a trial of labor were at increased risk for failure. Increased BMI was associated with greater composite morbidity and neonatal injury compared with elective repeat cesarean delivery, but absolute morbidities were small. Increased risks should be considered before trial of labor after previous cesarean delivery. II-2.


The Removal of a Fractured Guidewire During Mechanical Thrombectomy. a Case Report.
Recent randomized controlled trials have transformed the treatment of acute ischemic stroke. Mechanical or aspiration thrombectomy is the main treatment option for occlusions of large intracranial vessels. Despite its high technical success rate, endovascular thrombectomy can sometimes be complicated by anatomical peculiarities or device failures. The most frequent complications are related to vessel dissection or vessel perforation by devices while navigating intricate anatomy. Rarer still are technical device failures, like spontaneous stent-retriever detachment, which occurred with older generation retrievers. This case reports a rare device failure, which, to the best of our knowledge, has not been reported in the literature so far, namely a microwire fracture in the middle cerebral artery. This was successfully removed with an Eric stent-retriever. The potential causes and possible management strategies are discussed.


Total knee arthroplasty: the future.
Few areas in orthopaedics have evolved so dramatically over the past few decades as our knowledge of knee physiology, knee kinematics, and knee replacement surgery. This article addresses major breakthroughs in knee replacement surgery, the thought process behind these concepts, and their impact on clinical practice. It focuses on compartmental arthroplasty, use of minimally invasive surgery, advances in biomaterials, and biological solutions for treating arthritis. Compartmental knee replacements are gaining popularity, especially for medial compartment arthritis. Minimally invasive surgery (i.e., quadriceps sparing arthroplasty) has become very popular in the last few years and is being used routinely for unicompartmental knee replacement and increasingly used for total knee replacement. Computer-assisted surgery has the ability to help the surgeon place the components in the desired position, thereby avoiding component malpositioning, which can cause pain, instability, limited range of movement, excessive polyethylene wear, and subsequent implant loosening. Recent advances in the metallurgy have led to the introduction of tantalum trabecular metal which offers several advantages over other current conventional materials used for implants. Expanding knowledge regarding cartilage biochemistry and the pathogenesis of osteoarthritis has focused the research on slowing the progression of osteoarthritis and promoting cartilage matrix synthesis. Perichondrial transplantation as well as periosteal transplantation have been tried by a few investigators but they have limited and temporary success. Autologous chondrocyte implantation is another technique that is gaining popularity. The chondrocytes harvested from the patient are cultured and reimplanted after 3-4 weeks of culturing. In the future, we are likely to see advances in diagnosis as well as management of osteoarthritis. The treatment modalities will probably evolve at the cellular level and it will not be long before a patient-specific medication can be given to a asymptomatic patient in order to prevent development of osteoarthritis. Patients with end-stage osteoarthritis will be offered a combination of treatments (e.g., partial replacement of one compartment or localized cartilage repair if there is localized cartilage defect in the other compartment).


Tumor phenotype and breast density in distinct categories of interval cancer: results of population-based mammography screening in Spain.
Interval cancers are tumors arising after a negative screening episode and before the next screening invitation. They can be classified into true interval cancers, false-negatives, minimal-sign cancers, and occult tumors based on mammographic findings in screening and diagnostic mammograms. This study aimed to describe tumor-related characteristics and the association of breast density and tumor phenotype within four interval cancer categories. We included 2,245 invasive tumors (1,297 screening-detected and 948 interval cancers) diagnosed from 2000 to 2009 among 645,764 women aged 45 to 69 who underwent biennial screening in Spain. Interval cancers were classified by a semi-informed retrospective review into true interval cancers (n = 455), false-negatives (n = 224), minimal-sign (n = 166), and occult tumors (n = 103). Breast density was evaluated using Boyd's scale and was conflated into: <25%; 25 to 50%; 50 to 75%; >75%. Tumor-related information was obtained from cancer registries and clinical records. Tumor phenotype was defined as follows: luminal A: ER+/HER2- or PR+/HER2-; luminal B: ER+/HER2+ or PR+/HER2+; HER2: ER-/PR-/HER2+; triple-negative: ER-/PR-/HER2-. The association of tumor phenotype and breast density was assessed using a multinomial logistic regression model. Adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were calculated. All statistical tests were two-sided. Forty-eight percent of interval cancers were true interval cancers and 23.6% false-negatives. True interval cancers were associated with HER2 and triple-negative phenotypes (OR = 1.91 (95% CI:1.22-2.96), OR = 2.07 (95% CI:1.42-3.01), respectively) and extremely dense breasts (>75%) (OR = 1.67 (95% CI:1.08-2.56)). However, among true interval cancers a higher proportion of triple-negative tumors was observed in predominantly fatty breasts (<25%) than in denser breasts (28.7%, 21.4%, 11.3% and 14.3%, respectively; <0.001). False-negatives and occult tumors had similar phenotypic characteristics to screening-detected cancers, extreme breast density being strongly associated with occult tumors (OR = 6.23 (95% CI:2.65-14.66)). Minimal-sign cancers were biologically close to true interval cancers but showed no association with breast density. Our findings revealed that both the distribution of tumor phenotype and breast density play specific and independent roles in each category of interval cancer. Further research is needed to understand the biological basis of the overrepresentation of triple-negative phenotype among predominantly fatty breasts in true interval cancers.


Development of a robust DNA damage model including persistent telomere-associated damage with application to secondary cancer risk assessment.
Mathematical modelling has been instrumental to understand kinetics of radiation-induced DNA damage repair and associated secondary cancer risk. The widely accepted two-lesion kinetic (TLK) model assumes two kinds of double strand breaks, simple and complex ones, with different repair rates. Recently, persistent DNA damage associated with telomeres was reported as a new kind of DNA damage. We therefore extended existing versions of the TLK model by new categories of DNA damage and re-evaluated those models using extensive data. We subjected different versions of the TLK model to a rigorous model discrimination approach. This enabled us to robustly select a best approximating parsimonious model that can both recapitulate and predict transient and persistent DNA damage after ionizing radiation. Models and data argue for i) nonlinear dose-damage relationships, and ii) negligible saturation of repair kinetics even for high doses. Additionally, we show that simulated radiation-induced persistent telomere-associated DNA damage foci (TAF) can be used to predict excess relative risk (ERR) of developing secondary leukemia after fractionated radiotherapy. We suggest that TAF may serve as an additional measure to predict cancer risk after radiotherapy using high dose rates. This may improve predicting risk-dose dependency of ionizing radiation especially for long-term therapies.


NAD hydrolysis by the tuberculosis necrotizing toxin induces lethal oxidative stress in macrophages.
Mycobacterium tuberculosis (Mtb) kills infected macrophages through necroptosis, a programmed cell death that enhances mycobacterial replication and dissemination. The tuberculosis necrotizing toxin (TNT) is the major cytotoxicity factor of Mtb in macrophages and induces necroptosis by NAD+ hydrolysis. Here, we show that the catalytic activity of TNT triggers the production of reactive oxygen species (ROS) in Mtb-infected macrophages causing cell death and promoting mycobacterial replication. TNT induces ROS formation both by activating necroptosis and by a necroptosis-independent mechanism. Most of the detected ROS originate in mitochondria as a consequence of opening the mitochondrial permeability transition pore. However, a significant part of ROS is produced by mechanisms independent of TNT and necroptosis. Expressing only the tnt gene in Jurkat T-cells also induces lethal ROS formation indicating that these molecular mechanisms are not restricted to macrophages. Both the antioxidant N-acetyl-cysteine and replenishment of NAD+ by providing nicotinamide reduce ROS levels in Mtb-infected macrophages, protect them from cell death, and restrict mycobacterial replication. Our results indicate that a host-directed therapy combining replenishment of NAD+ with inhibition of necroptosis and/or antioxidants might improve the health status of TB patients and augment antibacterial TB chemotherapy.


A neural network controller for systems with unmodeled dynamics with applications to wastewater treatment.
This paper considers the use of neural networks (NN's) in controlling a nonlinear, stochastic system with unknown process equations. The approach here is based on using the output error of the system to train the NN controller without the need to assume or construct a separate model (NN or other type) for the unknown process dynamics. To implement such a direct adaptive control approach, it is required that connection weights in the NN be estimated while the system is being controlled. As a result of the feedback of the unknown process dynamics, however, it is not possible to determine the gradient of the loss function for use in standard (backpropagation-type) weight estimation algorithms. In principle, stochastic approximation algorithms in the standard (Kiefer-Wolfowitz) finite-difference form can be used for this weight estimation since they are based on gradient approximations from available system output errors. However, these algorithms will generally require a prohibitive number of observed system outputs. Therefore, this paper considers the use of a new stochastic approximation algorithm for this weight estimation, which is based on a "simultaneous perturbation" gradient approximation. It is shown that this algorithm can greatly enhance the efficiency over more standard stochastic approximation algorithms based on finite-difference gradient approximations. The approach is illustrated on a simulated wastewater treatment system with stochastic effects and nonstationary dynamics.


Management competencies required of administrative and clinical practitioners in the new millennium.
Changes in the health care environment necessitate revisiting management-related competencies for both clinical and administrative practitioners. Major changes include the shift from recruitment to reengineering, direct service to multiple service models, department to program management, professional standards to market-driven standards, and single-system to multisystem management. Important competencies include the ability to identify and implement flexible staffing, to use communication technologies to support staff members across multiple sites, to understand of the business of health care, and to create innovative service delivery models consistent with the core values of the profession.


Analysis of Canis mitochondrial DNA demonstrates high concordance between the control region and ATPase genes.
Phylogenetic studies of wild Canis species have relied heavily on the mitochondrial DNA control region (mtDNA CR) to infer species relationships and evolutionary lineages. Previous analyses of the CR provided evidence for a North American evolved eastern wolf (C. lycaon), that is more closely related to red wolves (C. rufus) and coyotes (C. latrans) than grey wolves (C. lupus). Eastern wolf origins, however, continue to be questioned. Therefore, we analyzed mtDNA from 89 wolves and coyotes across North America and Eurasia at 347 base pairs (bp) of the CR and 1067 bp that included the ATPase6 and ATPase8 genes. Phylogenies and divergence estimates were used to clarify the evolutionary history of eastern wolves, and regional comparisons of nonsynonomous to synonomous substitutions (dN/dS) at the ATPase6 and ATPase8 genes were used to elucidate the potential role of selection in shaping mtDNA geographic distribution. We found high concordance across analyses between the mtDNA regions studied. Both had a high percentage of variable sites (CR = 14.6%; ATP = 9.7%) and both phylogenies clustered eastern wolf haplotypes monophyletically within a North American evolved lineage apart from coyotes. Divergence estimates suggest the putative red wolf sequence is more closely related to coyotes (DxyCR = 0.01982 +/- 0.00494 SD; DxyATP = 0.00332 +/- 0.00097 SD) than the eastern wolf sequences (DxyCR = 0.03047 +/- 0.00664 SD; DxyATP = 0.00931 +/- 0.00205 SD). Neutrality tests on both genes were indicative of the population expansion of coyotes across eastern North America, and dN/dS ratios suggest a possible role for purifying selection in the evolution of North American lineages. dN/dS ratios were higher in European evolved lineages from northern climates compared to North American evolved lineages from temperate regions, but these differences were not statistically significant. These results demonstrate high concordance between coding and non-coding regions of mtDNA, and provide further evidence that the eastern wolf possessed distinct mtDNA lineages prior to recent coyote introgression. Purifying selection may have influenced North American evolved Canis lineages, but detection of adaptive selection in response to climate is limited by the power of current statistical tests. Increased sampling and development of alternative analytical tools will be necessary to disentangle demographic history from processes of natural selection.


Derivative weighted active insulin control modelling and clinical trials for ICU patients.
Close control of blood glucose levels significantly reduces vascular complications in Type 1 and Type 2 diabetic individuals. Heavy derivative controllers using the data density available from emerging biosensors are developed to provide tight, optimal control of elevated blood glucose levels, while robustly handling variation in patient response. A two-compartment glucose regulatory system model is developed for intravenous infusion from physiologically verified subcutaneous infusion models enabling a proof-of-concept clinical trial at the Christchurch Hospital Department of Intensive Care Medicine. This clinical trial is the first of its kind to test a high sample rate feedback control algorithm for tight glucose regulation. The clinical trial results show tight control with reductions of 79-89% in blood glucose excursions for an oral glucose tolerance test. Experimental performance is very similar to modelled behaviour. Results include a clear need for an additional accumulator dynamic for insulin behaviour in transport to the blood and strong correlation of 10% or less between modelled insulin infused and the amounts used in clinical trials. Finally, the heavy derivative PD control approach is seen to be able to bring blood glucose levels below the (elevated) basal level, showing the potential for truly tight control.


PCDH10 Interacts With hTERT and Negatively Regulates Telomerase Activity.
Telomerase catalyzes telomeric DNA synthesis, an essential process to maintain the length of telomere for continuous cell proliferation and genomic stability. Telomerase is activated in gametes, stem cells, and most tumor cells, and its activity is tightly controlled by a catalytic human telomerase reverse transcriptase (hTERT) subunit and a collection of associated proteins. In the present work, normal human testis tissue was used for the first time to identify proteins involved in the telomerase regulation under normal physiological conditions. Immunoprecipitation was performed using total protein lysates from the normal testis tissue and the proteins of interest were identified by microfluidic high-performance liquid chromatography and tandem mass spectrometry (HPLC-Chip-MS/MS). The regulatory role of PCDH10 in telomerase activity was confirmed by a telomeric repeat amplification protocol (TRAP) assay, and the biological functions of it were characterized by in vitro proliferation, migration, and invasion assays. A new in vivo hTERT interacting protein, protocadherin 10 (PCDH10), was identified. Overexpression of PCDH10 in pancreatic cancer cells impaired telomere elongation by inhibiting telomerase activity while having no obvious effect on hTERT expression at mRNA and protein levels. As a result of this critical function in telomerase regulation, PCDH10 was found to inhibit cell proliferation, migration, and invasion, suggesting a tumor suppressive role of this protein. Our data suggested that PCDH10 played a critical role in cancer cell growth, by negatively regulating telomerase activity, implicating a potential value in future therapeutic development against cancer.


Site-specific probabilistic ecological risk assessment of a volatile chlorinated hydrocarbon-contaminated tidal estuary.
Groundwater contaminated with volatile chlorinated hydrocarbons (VCHs) was identified as discharging to Penrhyn Estuary, an intertidal embayment of Botany Bay, New South Wales, Australia. A screening-level hazard assessment of surface water in Penrhyn Estuary identified an unacceptable hazard to marine organisms posed by VCHs. Given the limitations of hazard assessments, the present study conducted a higher-tier, quantitative probabilistic risk assessment using the joint probability curve (JPC) method that accounted for variability in exposure and toxicity profiles to quantify risk (delta). Risk was assessed for 24 scenarios, including four areas of the estuary based on three exposure scenarios (low tide, high tide, and both low and high tides) and two toxicity scenarios (chronic no-observed-effect concentrations [NOEC] and 50% effect concentrations [EC50]). Risk (delta) was greater at low tide than at high tide and varied throughout the tidal cycle. Spatial distributions of risk in the estuary were similar using both NOEC and EC50 data. The exposure scenario including data combined from both tides was considered the most accurate representation of the ecological risk in the estuary. When assessing risk using data across both tides, the greatest risk was identified in the Springvale tributary (delta=25%)-closest to the source area-followed by the inner estuary (delta=4%) and the Floodvale tributary (delta=2%), with the lowest risk in the outer estuary (delta=0.1%), farthest from the source area. Going from the screening level ecological risk assessment (ERA) to the probabilistic ERA changed the risk from unacceptable to acceptable in 50% of exposure scenarios in two of the four areas within the estuary. The probabilistic ERA provided a more realistic assessment of risk than the screening-level hazard assessment.


A holistic approach to education programs in thalassemia for a multi-ethnic population: consideration of perspectives, attitudes, and perceived needs.
Hemoglobin disorders which include thalassemias are the most common heritable disorders. Effective treatment is available, and these disorders can be avoided as identification of carriers is achievable using simple hematological tests. An in-depth understanding of the awareness, attitudes, perceptions, and screening reservations towards thalassemia is necessary, as Malaysia has a multi-ethnic population with different religious beliefs. A total of 13 focus group discussions (70 participants) with members of the general lay public were conducted between November 2008 and January 2009. Lack of knowledge and understanding about thalassemia leads to general confusions over differences between thalassemia carriers and thalassemia major, inheritance patterns, and the physical and psychologically impact of the disorder in affected individuals and their families. Although most of the participants have not been tested for thalassemia, a large majority expressed willingness to be screened. Views on prenatal diagnosis and termination of fetuses with thalassemia major received mixed opinions from participants with different religions and practices. Perceived stigma and discrimination attached to being a carrier emerged as a vital topic in some group discussions where disparity in the answers exhibited differences in levels of participants' literacy and ethnic origins. The two most common needs identified from the discussion were information and screening facilities. Participants' interest in knowing the severity of the disease and assessing their risk of getting the disorder may imply the health belief model as a possible means of predicting thalassemia public screening services. Findings provide valuable insights for the development of more effective educational, screening, and prenatal diagnostic services in the multi-ethnic Asian society.


Gas production, composition and emission at a modern disposal site receiving waste with a low-organic content.
AV Miljø is a modern waste disposal site receiving non-combustible waste with a low-organic content. The objective of the current project was to determine the gas generation, composition, emission, and oxidation in top covers on selected waste cells as well as the total methane (CH(4)) emission from the disposal site. The investigations focused particularly on three waste disposal cells containing shredder waste (cell 1.5.1), mixed industrial waste (cell 2.2.2), and mixed combustible waste (cell 1.3). Laboratory waste incubation experiments as well as gas modeling showed that significant gas generation was occurring in all three cells. Field analysis showed that the gas generated in the cell with mixed combustible waste consisted of mainly CH(4) (70%) and carbon dioxide (CO(2)) (29%) whereas the gas generated within the shredder waste, primarily consisted of CH(4) (27%) and nitrogen (N(2)) (71%), containing no CO(2). The results indicated that the gas composition in the shredder waste was governed by chemical reactions as well as microbial reactions. CH(4) mass balances from three individual waste cells showed that a significant part (between 15% and 67%) of the CH(4) generated in cell 1.3 and 2.2.2 was emitted through leachate collection wells, as a result of the relatively impermeable covers in place at these two cells preventing vertical migration of the gas. At cell 1.5.1, which is un-covered, the CH(4) emission through the leachate system was low due to the high gas permeability of the shredder waste. Instead the gas was emitted through the waste resulting in some hotspot observations on the shredder surface with higher emission rates. The remaining gas that was not emitted through surfaces or the leachate collection system could potentially be oxidized as the measured oxidation capacity exceeded the potential emission rate. The whole CH(4) emission from the disposal site was found to be 820 ± 202 kg CH(4)d(-1). The total emission rate through the leachate collection system at AV Miljø was found to be 211 kg CH(4)d(-1). This showed that approximately ¼ of the emitted gas was emitted through the leachate collections system making the leachate collection system an important source controlling the overall gas migration from the site. The emission pathway for the remaining part of the gas was more uncertain, but emission from open cells where waste is being disposed of or being excavated for incineration, or from horizontal leachate drainage pipes placed in permeable gravel layers in the bottom of empty cells was likely.


The Human Oral Microbiome Database: a web accessible resource for investigating oral microbe taxonomic and genomic information.
The human oral microbiome is the most studied human microflora, but 53% of the species have not yet been validly named and 35% remain uncultivated. The uncultivated taxa are known primarily from 16S rRNA sequence information. Sequence information tied solely to obscure isolate or clone numbers, and usually lacking accurate phylogenetic placement, is a major impediment to working with human oral microbiome data. The goal of creating the Human Oral Microbiome Database (HOMD) is to provide the scientific community with a body site-specific comprehensive database for the more than 600 prokaryote species that are present in the human oral cavity based on a curated 16S rRNA gene-based provisional naming scheme. Currently, two primary types of information are provided in HOMD--taxonomic and genomic. Named oral species and taxa identified from 16S rRNA gene sequence analysis of oral isolates and cloning studies were placed into defined 16S rRNA phylotypes and each given unique Human Oral Taxon (HOT) number. The HOT interlinks phenotypic, phylogenetic, genomic, clinical and bibliographic information for each taxon. A BLAST search tool is provided to match user 16S rRNA gene sequences to a curated, full length, 16S rRNA gene reference data set. For genomic analysis, HOMD provides comprehensive set of analysis tools and maintains frequently updated annotations for all the human oral microbial genomes that have been sequenced and publicly released. Oral bacterial genome sequences, determined as part of the Human Microbiome Project, are being added to the HOMD as they become available. We provide HOMD as a conceptual model for the presentation of microbiome data for other human body sites. Database URL: http://www.homd.org.


Antioxidant Effect of Extracts from the Coffee Residue in Raw and Cooked Meat.
The residue of ground coffee obtained after the brewing process (spent coffee) still contains various functional components with high antioxidant capacity and health benefits, but no attempts have been made to use it as a resource to produce value-added food ingredients. This study evaluates the antioxidant activity of ethanol or hot water extracts from the residues of coffee after brewing. An extraction experiment was carried out using the conventional solid-liquid methods, including ethanol and water as the extraction media at different temperatures and liquid/solid ratios. The antioxidant activity of extracts was tested for total phenolic compound (TPC), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and 2-thiobarbituric acid reactive substances (TBARS) using oil emulsion and raw/cooked meat systems. The DPPH radical scavenging activity of the ethanol extracts with heating (HEE) and without heating (CEE) were higher than that of the hot water extracts (WE). The highest DPPH value of HEE and CEE at 1000 ppm was 91.22% and 90.21%, respectively. In oil emulsion and raw/cooked systems, both the water and ethanol extracts had similar antioxidant effects to the positive control (BHA), but HEE and CEE extracts showed stronger antioxidant activities than WE extract. These results indicated that the ethanol extracts of coffee residue have a strong antioxidant activity and have the potential to be used as a natural antioxidant in meat.


Genotype-specific responses in Atlantic salmon (Salmo salar) subject to dietary fish oil replacement by vegetable oil: a liver transcriptomic analysis.
Expansion of aquaculture is seriously limited by reductions in fish oil (FO) supply for aquafeeds. Terrestrial alternatives such as vegetable oils (VO) have been investigated and recently a strategy combining genetic selection with changes in diet formulations has been proposed to meet growing demands for aquaculture products. This study investigates the influence of genotype on transcriptomic responses to sustainable feeds in Atlantic salmon. A microarray analysis was performed to investigate the liver transcriptome of two family groups selected according to their estimated breeding values (EBVs) for flesh lipid content, 'Lean' or 'Fat', fed diets containing either FO or a VO blend. Diet principally affected metabolism genes, mainly of lipid and carbohydrate, followed by immune response genes. Genotype had a much lower impact on metabolism-related genes and affected mostly signalling pathways. Replacement of dietary FO by VO caused an up-regulation of long-chain polyunsaturated fatty acid biosynthesis, but there was a clear genotype effect as fatty acyl elongase (elovl2) was only up-regulated and desaturases (Δ5 fad and Δ6 fad) showed a higher magnitude of response in Lean fish, which was reflected in liver fatty acid composition. Fatty acid synthase (FAS) was also up-regulated by VO and the effect was independent of genotype. Genetic background of the fish clearly affected regulation of lipid metabolism, as PPARα and PPARβ were down-regulated by the VO diet only in Lean fish, while in Fat salmon SREBP-1 expression was up-regulated by VO. In addition, all three genes had a lower expression in the Lean family group than in the Fat, when fed VO. Differences in muscle adiposity between family groups may have been caused by higher levels of hepatic fatty acid and glycerophospholipid synthesis in the Fat fish, as indicated by the expression of FAS, 1-acyl-sn-glycerol-3-phosphate acyltransferase and lipid phosphate phosphohydrolase 2. This study has identified metabolic pathways and key regulators that may respond differently to alternative plant-based feeds depending on genotype. Further studies are required but data suggest that it will be possible to identify families better adapted to alternative diet formulations that might be appropriate for future genetic selection programmes.


Risk factors for Salmonella and hygiene indicators in the 10 largest Belgian pig slaughterhouses.
A survey was conducted to collect data on Salmonella prevalence, Escherichia coli counts (ECCs), and aerobic bacteria colony counts (ACCs) on pig carcasses after chilling at the 10 largest Belgian pig slaughterhouses during 2000 through 2004. Potential risk factors of contamination associated with production parameters, technical descriptions of the installations, and cleaning and disinfection methods were assessed during investigations in the slaughterhouses. These variables were used first in a univariate analysis and then were extended to a multivariate analysis with a logistic mixed regression model for Salmonella and a linear mixed model for ECCs and ACCs with slaughterhouses as the random effect. The results indicated high variability concerning Salmonella contamination among the 10 slaughterhouses, with prevalence ranging from 2.6 to 34.3% according to the area of origin. The median ECC and median ACC ranged from -0.43 to 1.11 log CFU/cm2 and from 2.37 to 3.65 log CFU/cm2, respectively. The results of the logistic and linear regressions revealed that some working practices such as scalding with steam, second flaming after polishing, and complete cleaning and disinfection of the splitting machine several times a day were beneficial for reducing Salmonella prevalence, ECCs, and ACCs. Changing the carcass hooks just before chilling, using water as the cleaning method, and a higher frequency of disinfection of the lairage seemed to be protective against E. coli in the multivariate mixed linear model. The monitoring of critical points, slaughterhouse equipment, good slaughtering practices, and effective washing and disinfection are the keys to obtaining good microbiological results.


Heart failure - what's new and what's changed?
Physicians responsible for the care of patients with heart failure due to left ventricular systolic dysfunction have access to a broad range of evidence-based treatments that prolong life and reduce symptoms. In spite of the significant progress made over the last four decades, there is an ongoing need for novel therapies to treat a condition that is associated with stubbornly high morbidity and mortality. In this article, we discuss the findings of SERVE-HF, a randomised controlled trial of adaptive servo-ventilation in patients with left ventricular systolic dysfunction, as well as EMPA-REG, a study of the effects of a novel diabetic agent that may be of greater interest to heart failure specialists than diabetologists. We also examine further analyses of the groundbreaking PARADIGM-HF trial, which attempt to answer some of the unresolved questions from the original study of the first combined angiotensin-receptor blocker and neprilysin inhibitor, sacubitril valsartan. The recently published National Institute for Health and Care Excellence guidelines for the management of acute heart failure and plans to introduce best practice tariffs bring into focus the need for well-organised, multidisciplinary care. We discuss the challenges involved in developing and delivering a specialist service that meets the needs of a growing population of patients living with heart failure.


Forelimb movements evoked by optogenetic stimulation of the macaque motor cortex.
Optogenetics has become an indispensable tool for investigating brain functions. Although non-human primates are particularly useful models for understanding the functions and dysfunctions of the human brain, application of optogenetics to non-human primates is still limited. In the present study, we generate an effective adeno-associated viral vector serotype DJ to express channelrhodopsin-2 (ChR2) under the control of a strong ubiquitous CAG promoter and inject into the somatotopically identified forelimb region of the primary motor cortex in macaque monkeys. ChR2 is strongly expressed around the injection sites, and optogenetic intracortical microstimulation (oICMS) through a homemade optrode induces prominent cortical activity: Even single-pulse, short-duration oICMS evokes long-lasting repetitive firings of cortical neurons. In addition, oICMS elicits distinct forelimb movements and muscle activity, which are comparable to those elicited by conventional electrical ICMS. The present study removes obstacles to optogenetic manipulation of neuronal activity and behaviors in non-human primates.