Topological and functional discovery in a gene coexpression meta-network of gastric cancer.
Gastric cancer is a leading cause of global cancer mortality, but comparatively little is known about the cellular pathways regulating different aspects of the gastric cancer phenotype. To achieve a better understanding of gastric cancer at the levels of systems topology, functional modules, and constituent genes, we assembled and systematically analyzed a consensus gene coexpression meta-network of gastric cancer incorporating >300 tissue samples from four independent patient populations (the "gastrome"). We find that the gastrome exhibits a hierarchical scale-free architecture, with an internal structure comprising multiple deeply embedded modules associated with diverse cellular functions. Individual modules display distinct subtopologies, with some (cellular proliferation) being integrated within the primary network, and others (ribosomal biosynthesis) being relatively isolated. One module associated with intestinal differentiation exhibited a remarkably high degree of autonomy, raising the possibility that its specific topological features may contribute towards the frequent occurrence of intestinal metaplasia in gastric cancer. At the single-gene level, we discovered a novel conserved interaction between the PLA2G2A prognostic marker and the EphB2 receptor, and used tissue microarrays to validate the PLA2G2A/EphB2 association. Finally, because EphB2 is a known target of the Wnt signaling pathway, we tested and provide evidence that the Wnt pathway may also similarly regulate PLA2G2A. Many of these findings were not discernible by studying the single patient populations in isolation. Thus, besides enhancing our knowledge of gastric cancer, our results show the broad utility of applying meta-analytic approaches to genome-wide data for the purposes of biological discovery.


No association between the HLA-A2 allele and Alzheimer disease.
The apolipoprotein E (APOE)-4 allele is a major risk factor for late-onset Alzheimer disease (AD), but it does not account for all the genetic variation in late-onset AD; thus, other genetic markers must be examined. Previous studies suggest an HLA-A2 allele association with risk and earlier onset age of AD. Because these effects may be additive to those of APOE-4, we studied HLA-A2 and APOE-4 frequencies in AD patients and cognitively intact controls. A total of 712 unrelated Caucasian subjects included 479 patients with AD (435 sporadic, 44 familial) and 233 controls. Patients (mean+/-SD age 73.9+/-7.9 years, range 42-93 years) had probable AD, according to standard diagnostic criteria; controls (mean+/-SD age 70.4+/-8.5 years, range 37-92 years) were cognitively intact. APOE and HLA-A2 typing used polymerase chain reaction to indicate the number of APOE-4 alleles present as well as the presence (A1/A2, A2/A2 genotypes) or absence (A1/A1 genotype) of HLA-A2. A two-way analysis of variance was used to assess the effect of the HLA-A2 allele on age at onset of dementia. No association between HLA-A2 and APOE-4 was found, and the presence of HLA-A2 allele did not increase AD risk. There was also no evidence for an association between HLA-A2 and earlier onset age of AD. Examination age, sex, family history of AD, and recruitment site had no influence on these results. In conclusion, the HLA-A2 allele did not influence AD risk or onset age in this study population. A2 heterozygosity, and population differences, including stratification sub-structures, and other undetermined factors could contribute to discrepant findings among studies.


Framework for the impact analysis and implementation of Clinical Prediction Rules (CPRs).
Clinical Prediction Rules (CPRs) are tools that quantify the contribution of symptoms, clinical signs and available diagnostic tests, and in doing so stratify patients according to the probability of having a target outcome or need for a specified treatment. Most focus on the derivation stage with only a minority progressing to validation and very few undergoing impact analysis. Impact analysis studies remain the most efficient way of assessing whether incorporating CPRs into a decision making process improves patient care. However there is a lack of clear methodology for the design of high quality impact analysis studies.We have developed a sequential four-phased framework based on the literature and the collective experience of our international working group to help researchers identify and overcome the specific challenges in designing and conducting an impact analysis of a CPR.There is a need to shift emphasis from deriving new CPRs to validating and implementing existing CPRs. The proposed framework provides a structured approach to this topical and complex area of research.


Sutureless re-anastomosis by laparoscopy versus microsurgical re-anastomosis by laparotomy for sterilization reversal: a matched cohort study.
Sutureless re-anastomosis per laparoscopy is an alternative for microsurgical re-anastomosis by laparotomy in the treatment of sterilized women with renewed child wish. Our aim was to compare pregnancy rates after both surgical techniques. We performed a retrospective cohort study in which consecutive women who underwent sutureless re-anastomosis per laparoscopy were compared to women who underwent microsurgical re-anastomosis by laparotomy. Both procedures were performed in neighbouring hospitals in Northern-Brabant, The Netherlands, and women were matched for age. The primary outcome was time to ongoing pregnancy. Overall, we included 41 women who had sutureless re-anastomosis by laparoscopy, and 41 age-matched women who underwent microsurgical re-anastomosis by laparotomy. The number of women who conceived was 20 (15 ongoing pregnancies) in the sutureless laparoscopic group versus 26 (24 ongoing pregnancies) in the laparotomic group, a difference due to a longer follow-up period in the laparotomic group. Time to ongoing pregnancy was comparable in both groups (P=0.46), with 3 year cumulative ongoing pregnancy rates of 45 and 52% respectively. After adjustment for other prognostic factors, the fecundity rate ratio was 0.97 (95% CI 0.26-3.6), indicating a similar performance of the two techniques. The simplified stitchless laparoscopic procedure for reversal of tubal sterilization with the use of a tubal splint, clip fixation of the muscularis and fibrin glue resulted in a promising pregnancy rate, which was similar to the pregnancy rate obtained with the microsurgical re-anastomosis per laparotomy.


Nocturnal awakening caused by asthma in children with mild-to-moderate asthma in the childhood asthma management program.
Nocturnal symptoms of asthma are a cause of significant morbidity and are included as a central feature in the categorization of asthma severity. Data from the Childhood Asthma Management Program were used to estimate the prevalence of nocturnal awakenings in 1041 children with mild-to-moderate asthma and to investigate the relationships between awakenings and peak flows, severity of asthma, and allergen sensitivity and exposure. Daily diary care data were recorded during a 28-day interval in the Childhood Asthma Management Program screening process. The data on morning and evening peak flows, overall symptom codes, albuterol use for symptoms, and nocturnal awakenings for asthma symptoms were analyzed and compared with measures of personal characteristics, pulmonary function, and environmental characteristics of the patients. Three hundred fifty-one (33.7%) children experienced 1 or more night awakenings caused by asthma during the 28-day screening period while not taking any maintenance medications. Greater risk of night awakening was associated with more severe asthma (greater responsiveness to bronchodilator, airway reactivity to methacholine, peak flow variability, and use of albuterol for symptoms, all P <.0001) and atopy (increased IgE and allergy skin test reactivity, both P =.0002). Those with a positive skin test response to dog and a high level of dog allergen in the home had a greater risk of night awakening caused by asthma (P =.01), as did those with a positive skin test response to cat and a high level of cat allergen in the home (P =.04). Mean daily symptom code and use of albuterol for asthma symptoms increased in the 3 days immediately before a single awakening compared with in the 4 to 6 days before the awakening (P =.02 and P =.01, respectively); however, both morning and evening peak flows as a percentage of personal best were similar in both intervals. Mean daily symptom code and daily use of albuterol were greater in the 3 days after an awakening than in the 3 days before (P <.0001 and P =.0002, respectively). Mean evening peak flow percentage of personal best the day after an episode of awakening was lower when a second consecutive awakening occurred than when there was only a single awakening (P =.01). Nocturnal awakening occurred in one third of the children with mild-to-moderate asthma during a month of relative stability and appears to be an indicator of asthma that is becoming increasingly severe.


Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in the treatment of osteoporosis. Alendronate Once-Weekly Study Group.
Dosing convenience is a key element in the effective management of any chronic disease, and is particularly important in the long-term management of osteoporosis. Less frequent dosing with any medication may enhance compliance, thereby maximizing the effectiveness of therapy. Animal data support the rationale that once-weekly dosing with alendronate 70 mg (7 times the daily oral treatment dose) could provide similar efficacy to daily dosing with alendronate 10 mg due to its long duration of effect in bone. In addition, dog studies suggest that the potential for esophageal irritation, observed with daily oral bisphosphonates, may be substantially reduced with once-weekly dosing. This dosing regimen would provide patients with increased convenience and would be likely to enhance patient compliance. We compared the efficacy and safety of treatment with oral once-weekly alendronate 70 mg (N=519), twice-weekly alendronate 35 mg (N=369), and daily alendronate 10 mg (N=370) in a one-year, double-blind, multicenter study of postmenopausal women (ages 42 to 95) with osteoporosis (bone mineral density [BMD] of either lumbar spine or femoral neck at least 2.5 SDs below peak premenopausal mean, or prior vertebral or hip fracture). The primary efficacy endpoint was the comparability of increases in lumbar spine BMD, using strict pre-defined equivalence criteria. Secondary endpoints included changes in BMD at the hip and total body and rate of bone turnover, as assessed by biochemical markers. Both of the new regimens fully satisfied the equivalence criteria relative to daily therapy. Mean increases in lumbar spine BMD at 12 months were: 5.1% (95% CI 4.8, 5.4) in the 70 mg once-weekly group, 5.2% (4.9, 5.6) in the 35 mg twice-weekly group, and 5.4% (5.0, 5.8) in the 10 mg daily treatment group. Increases in BMD at the total hip, femoral neck, trochanter, and total body were similar for the three dosing regimens. All three treatment groups similarly reduced biochemical markers of bone resorption (urinary N-telopeptides of type I collagen) and bone formation (serum bone-specific alkaline phosphatase) into the middle of the premenopausal reference range. All treatment regimens were well tolerated with a similar incidence of upper GI adverse experiences. There were fewer serious upper GI adverse experiences and a trend toward a lower incidence of esophageal events in the once-weekly dosing group compared to the daily dosing group. These data are consistent with preclinical animal models, and suggest that once-weekly dosing has the potential for improved upper GI tolerability. Clinical fractures, captured as adverse experiences, were similar among the groups. We conclude that the alendronate 70 mg once-weekly dosing regimen will provide patients with a more convenient, therapeutically equivalent alternative to daily dosing, and may enhance compliance and long-term persistence with therapy.


Epigenetic and pharmacological regulation of 5HT3 receptors controls compulsive ethanol seeking in mice.
Factors underlying individual vulnerability to develop alcoholism are largely unknown. In humans, the risk for alcoholism is associated with elevated cue reactivity. Recent evidence suggests that in animal models, reactivity to reward-paired cues is predictive of addictive behaviors. To model cue reactivity in mice, we used a Pavlovian approach (PA) paradigm in which mice were trained to associate a cue with delivery of a food reinforcer. We then investigated the relationship between PA status with habitual and compulsive-like ethanol seeking. After training mice to respond for 10% ethanol, habitual behavior was investigated using both an outcome devaluation paradigm, in which ethanol was devalued via association with lithium chloride-induced malaise, and a contingency degradation paradigm in which the relationship between action and outcome was disrupted. Compulsive-like behavior was investigated in a modified conditioned place preference paradigm in which footshock was paired with the reward-paired chamber. PA was found to be predictive of habitual and compulsive-like ethanol seeking. Additionally, innate risk status was related to epigenetic changes in the gene encoding the requisite subunit of the 5HT3 receptor, Htr3a, as well as 5HT3A protein expression in the amygdala. We then used pharmacological tools to demonstrate that risk status determines the ability of a 5HT3 antagonist to reduce compulsive ethanol seeking. These data indicate that risk status can be identified prior to any alcohol exposure by assessment of cue reactivity, and further that this endophenotype may be predictive of response to pharmacological treatment for components of alcoholism.


Longitudinal modes along thin piezoelectric waveguides for liquid sensing applications.
The propagation of longitudinally polarized acoustic modes along thin piezoelectric plates (BN, ZnO, InN, AlN and GaN) is theoretically studied, aiming at the design of high frequency electroacoustic devices suitable for work in liquid environments. The investigation of the acoustic field profile across the plate revealed the presence of longitudinally polarized Lamb modes, travelling at velocities close to that of the longitudinal bulk acoustic wave propagating in the same direction. Such waves are suitable for the implementation of high-frequency, low-loss electroacoustic devices operating in liquid environments. The time-averaged power flow density, the phase velocity and the electroacoustic coupling coefficient K2 dispersion curves were studied, for the first (S0) and four higher order (S1, S2, S3, S4) symmetrical modes for different electrical boundary conditions. Two electroacoustic coupling configurations were investigated, based on interdigitated transducers, with or without a metal floating electrode at the opposite plate surface. Enhanced performances, such as a K2 as high as 8.5% and a phase velocity as high as 16,700 m/s, were demostrated for the ZnO- and BN-based waveguides, as an example. The relative velocity changes, and the inertial and viscous sensitivities of the first symmetric and anti-symmetric mode, S0 and A0, propagating along thin plates bordered by a viscous liquid were derived using the perturbation approach. The present study highlights the feasibility of the piezoelectric waveguides to the development of high-frequency, integrated-circuits compatible electroacoustic devices suitable for working in liquid environment.


Initiating community engagement in an ecohealth research project in Southern Africa.
Community Engagement (CE) in health research ensures that research is consistent with the socio-cultural, political and economic contexts where the research is conducted. The greatest challenges for researchers are the practical aspects of CE in multicentre health research. This study describes the CE in an ecohealth community-based research project focusing on two vulnerable and research naive rural communities. A qualitative, longitudinal multiple case study approach was used. Data was collected through Participatory Rural Appraisals, Focus Group Discussions, In-depth Interviews, and observations. The two sites had different cultural values, research literacy levels, and political and administrative structures. The engagement process included 1) introductions to the administrative and political leaders of the area; 2) establishing a community advisory mechanism; 3) community empowerment and 4) initiating sustainable post-study activities. In both sites the study employed community liaison officers to facilitate the community entry and obtaining letters of permission. Both sites opted to form Community Advisory Boards as their main advisory mechanism together with direct advice from community leaders. Empowerment was achieved through the education of ordinary community members at biannual meetings, employment of community research assistants and utilising citizen science. Through the research assistants and the citizen science group, the study has managed to initiate activities that the community will continue to utilise after the study ends. General strategies developed are similar in principle, but implementation and emphasis of various aspects differed in the two communities. We conclude that it is critical that community engagement be consistent with community values and attitudes, and considers community resources and capacity. A CE strategy fully involving the community is constrained by community research literacy levels, time and resources, but creates a conducive research environment.


IFNγ-Dependent Tissue-Immune Homeostasis Is Co-opted in the Tumor Microenvironment.
Homeostatic programs balance immune protection and self-tolerance. Such mechanisms likely impact autoimmunity and tumor formation, respectively. How homeostasis is maintained and impacts tumor surveillance is unknown. Here, we find that different immune mononuclear phagocytes share a conserved steady-state program during differentiation and entry into healthy tissue. IFNγ is necessary and sufficient to induce this program, revealing a key instructive role. Remarkably, homeostatic and IFNγ-dependent programs enrich across primary human tumors, including melanoma, and stratify survival. Single-cell RNA sequencing (RNA-seq) reveals enrichment of homeostatic modules in monocytes and DCs from human metastatic melanoma. Suppressor-of-cytokine-2 (SOCS2) protein, a conserved program transcript, is expressed by mononuclear phagocytes infiltrating primary melanoma and is induced by IFNγ. SOCS2 limits adaptive anti-tumoral immunity and DC-based priming of T cells in vivo, indicating a critical regulatory role. These findings link immune homeostasis to key determinants of anti-tumoral immunity and escape, revealing co-opting of tissue-specific immune development in the tumor microenvironment.


Development and usability testing of a web-based decision support for users and health professionals in psychiatric services.
Shared decision making (SMD) related to treatment and rehabilitation is considered a central component in recovery-oriented practice. Although decision aids are regarded as an essential component for successfully implementing SDM, these aids are often lacking within psychiatric services. The aim of this study was to use a participatory design to facilitate the development of a user-generated, web-based decision aid for individuals receiving psychiatric services. The results of this effort as well as the lessons learned during the development and usability processes are reported. The participatory design included 4 iterative cycles of development. Various qualitative methods for data collection were used with potential end users participating as informants in focus group and individual interviews and as usability and pilot testers. Interviewing and testing identified usability problems that then led to refinements and making the subsequent prototypes increasingly user-friendly and relevant. In each phase of the process, feedback from potential end-users provided guidance in developing the formation of the web-based decision aid that strengthens the position of users by integrating access to information regarding alternative supports, interactivity between staff and users, and user preferences as a continual focus in the tool. This web-based decision aid has the potential to strengthen service users' experience of self-efficacy and control as well as provide staff access to user knowledge and preferences. Studies employing participatory models focusing on usability have potential to significantly contribute to the development and implementation of tools that reflect user perspectives. (PsycINFO Database Record


Etanercept in psoriatic arthritis.
In this update on etanercept (ETN) in psoriatic arthritis (PsA) we analyze this drug's mechanism of action, clinical efficacy/effectiveness, optimal dosage, disease-modifying antirheumatic drugs (DMARD) association, radiological progression, safety, switching aspects, and pharmacoeconomy. The efficacy/effectiveness of ETN in PsA has been demonstrated in randomized placebo-controlled trials as well as in observational studies representing routine clinical practice. At 1 and 2 years, ETN inhibited radiographic disease progression, assessed by the modified total Sharp score. ETN (generally at a dosage of 50 mg/weekly) can be used either in monotherapy or in combination with DMARD such as methotrexate. A systematic search of randomized, placebo-controlled trials of ETN to treat adults with plaque psoriasis or PsA suggests that the short-term risk/benefit ratio is favorable. Longterm studies, such as observational studies, confirmed this safety profile of ETN. A variable percentage of patients withdrew anti-tumor necrosis factor-α (TNF-α) inhibitor treatment owing to inefficacy or poor tolerability. Observational studies showed that in the case of treatment failure with 1 agent, switching to the other agent may also be useful in patients with PsA because of the different molecular structures and targets of available TNF-α blockers. The clinical effect of ETN is associated with favorable pharmacoeconomic considerations.


Microalgae-activated sludge treatment of molasses wastewater in sequencing batch photo-bioreactor.
The aim of this work was the examination of the treatment potential of molasses wastewater, by the utilization of activated sludge and microalgae. The systems used included a sequencing batch bioreactor and a similar photo-bioreactor, favoring microalgae growth. The microalgae treatment of molasses wastewater mixture resulted in a considerable reduction in the total nitrogen content. A reduction in the ammonium and nitrate content was observed in the photo-bioreactor, while the effluent's total nitrogen consisted mainly of 50% organic nitrogen. The transformation of the nitrogen forms in the photo-bioreactor was attributed to microalgae activity, resulting in the production of a better quality effluent. Lower COD removal was observed for the photo-bioreactor than the control, which however increased, by the replacement of the anoxic phase by a long aeration period. The mechanism of nitrogen removal included both the denitrification process during the anoxic stage and the microalgae activities, as the replacement of the anoxic stage resulted in low total nitrogen removal capacities. A decrease in the photobioreactor performance was observed after 35 days of operation due to biofilm formation on the light tube surface, while the operation at higher temperature accelerated microalgae growth, resulting thus in the early failure of the photoreactor.


Reconstitution of an active surface CD2 by DNA transfer in CD2-CD3+ Jurkat cells facilitates CD3-T cell receptor-mediated IL-2 production.
To investigate the requirements for CD2 expression in the activation of T lymphocytes via the CD3-TCR complex, we produced and characterized a series of CD2-variants of the IL-2 producing Jurkat leukemia cell line, J32 (surface phenotype, CD2+, CD3+, CD28+). These mutants were derived by radiation and immunoselection, and were cloned under limiting dilution conditions. A total of 3 out of 30 of these mutants selectively lost the expression of both CD2 surface molecules and CD2 mRNA, and retained the expression of the CD3-TCR complex and the CD28 molecule. A mitogenic combination of anti-CD2 antibodies (9.6 + 9-1) failed to stimulate activation of these variants as measured by mobilization of intracellular Ca2+ and by IL-2 production. The CD2- mutants stimulated with anti-CD3 or anti-TCR mAb revealed an 8- to 32-fold decrease in IL-2 production and IL-2 mRNA accumulation as compared with the parental cells. No alteration of CD3-TCR-induced mobilization of intracellular Ca2+ was observed in the CD2- mutants. Reconstitution of CD2 expression by gene transfer in two J32 CD2- mutants restored IL-2 production and IL-2 mRNA accumulation in responses to both anti-CD2 and anti-CD3-TCR mAb. These results are the first direct demonstration of the requirement for CD2 molecules in optimizing IL-2 response in human T cells stimulated via CD3-TCR complex.


Costs of childhood asthma due to traffic-related pollution in two California communities.
Recent research suggests the burden of childhood asthma that is attributable to air pollution has been underestimated in traditional risk assessments, and there are no estimates of these associated costs. We aimed to estimate the yearly childhood asthma-related costs attributable to air pollution for Riverside and Long Beach, CA, USA, including: 1) the indirect and direct costs of healthcare utilisation due to asthma exacerbations linked with traffic-related pollution (TRP); and 2) the costs of health care for asthma cases attributable to local TRP exposure. We calculated costs using estimates from peer-reviewed literature and the authors' analysis of surveys (Medical Expenditure Panel Survey, California Health Interview Survey, National Household Travel Survey, and Health Care Utilization Project). A lower-bound estimate of the asthma burden attributable to air pollution was US$18 million yearly. Asthma cases attributable to TRP exposure accounted for almost half of this cost. The cost of bronchitic episodes was a major proportion of both the annual cost of asthma cases attributable to TRP and of pollution-linked exacerbations. Traditional risk assessment methods underestimate both the burden of disease and cost of asthma associated with air pollution, and these costs are borne disproportionately by communities with higher than average TRP.


In situ hybridization of CoOX nanoparticles on N-doped graphene through one step mineralization of co-responsive hydrogels.
The in situ hydrothermal mineralization for a mixture of graphene oxide (GO) and Co-responsive supramolecular hydrogels led to a hybrid graphene aerogel, doped with Co and N elements. The as-prepared aerogels exhibited a competitive half-wave potential (0.840 V, versus RHE) and peak current density (2.35 mA cm-2) to that of Pt/C (0.836 V, 2.23 mA cm-2, respectively). Furthermore, they demonstrated a significantly perfect catalytic efficiency (nearly 100% of 4e- ORR) toward the oxygen reduction reaction (ORR). Insight into the structural details of the hybrid aerogels indicates that the CoOX active sites anchored on the graphene matrix play a central role in the upgrading of the catalytic performance of graphene aerogels.


Cloning, nucleotide sequence, and expression of a gene encoding an adhesin subunit protein of Helicobacter pylori.
Gene hpaA, which codes for the receptor-binding subunit of the N-acetylneuraminyllactose-binding fibrillar hemagglutinin (NLBH) of Helicobacter pylori, was cloned and sequenced. The protein expressed by hpaA, designated HpaA, was identified as the adhesin subunit on the basis of its fetuin-binding activity and its reactivity with a polyclonal, monospecific rabbit serum prepared against NLBH purified from H. pylori. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis and Western blots (immunoblots) showed that the cloned adhesin has the same molecular weight (20,000) as that found on H. pylori. Also, HpaA contains a short sequence of amino acids (KRTIQK) which are all either identical or functionally similar to those which compose the sialic acid-binding motif of Escherichia coli SfaS, K99, and CFA/I. Affinity-purified antibody specific for a 12-residue synthetic peptide that included this sequence blocked the hemagglutinating activity of H. pylori and was shown by immuno-gold electron microscopy to react with almost transparent material on unstained H. pylori cells, which is consistent with previous observations concerning the location and morphology of the NLBH.


Prospective randomized controlled trial of simulator-based versus traditional in-surgery laparoscopic camera navigation training.
Surgical residents often use a laparoscopic camera in minimally invasive surgery for the first time in the operating room (OR) with no previous education or experience. Computer-based simulator training is increasingly used in residency programs. However, no randomized controlled study has compared the effect of simulator-based versus the traditional OR-based training of camera navigation skills. This prospective randomized controlled study included 24 pregraduation medical students without any experience in camera navigation or simulators. After a baseline camera navigation test in the OR, participants were randomized to six structured simulator-based training sessions in the skills lab (SL group) or to the traditional training in the OR navigating the camera during six laparoscopic interventions (OR group). After training, the camera test was repeated. Videos of all tests (including of 14 experts) were rated by five blinded, independent experts according to a structured protocol. The groups were well randomized and comparable. Both training groups significantly improved their camera navigational skills in regard to time to completion of the camera test (SL P = 0.049; OR P = 0.02) and correct organ visualization (P = 0.04; P = 0.03). Horizon alignment improved without reaching statistical significance (P = 0.20; P = 0.09). Although both groups spent an equal amount of actual time on camera navigation training (217 vs. 272 min, P = 0.20), the SL group spent significantly less overall time in the skill lab than the OR group spent in the operating room (302 vs. 1002 min, P < 0.01). This is the first prospective randomized controlled study indicating that simulator-based training of camera navigation can be transferred to the OR using the traditional hands-on training as controls. In addition, simulator camera navigation training for laparoscopic surgery is as effective but more time efficient than traditional teaching.


The limits of molecular signatures for pancreatic ductal adenocarcinoma subtyping.
Molecular signatures have been suggested as biomarkers to classify pancreatic ductal adenocarcinoma (PDAC) into two, three, four or five subtypes. Since the robustness of existing signatures is controversial, we performed a systematic evaluation of four established signatures for PDAC stratification across nine publicly available datasets. Clustering revealed inconsistency of subtypes across independent datasets and in some cases a different number of PDAC subgroups than in the original study, casting doubt on the actual number of existing subtypes. Next, we built sixteen classification models to investigate the ability of the signatures for tumor subtype prediction. The overall classification performance ranged from ∼35% to ∼90% accuracy, suggesting instability of the signatures. Notably, permuted subtypes and random gene sets achieved very similar performance. Cellular decomposition and functional pathway enrichment analysis revealed strong tissue-specificity of the predicted classes. Our study highlights severe limitations and inconsistencies that can be attributed to technical biases in sample preparation and tumor purity, suggesting that PDAC molecular signatures do not generalize across datasets. How stromal heterogeneity and immune compartment interplay in the diverging development of PDAC is still unclear. Therefore, a more mechanistic or a cross-platform multi-omic approach seems necessary to extract more robust and clinically exploitable insights.


[In Memory of a Master: Professor Ernesto L. Medina, M.D. (1925-2013)].
Seldom, in the history of Chilean medicine, there has been such a unique parallelism between the professional development of a person and that of a discipline as it has been the case of Professor Ernesto L. Medina and Public Health in Chile. Dr. Medina's undergraduate (University of Chile) and postgraduate (Harvard School of Public Health) studies coincided with the foundation of the University of Chile School of Public Health by an agreement among the University and two governmental health care providers, and also with the foundation of the Chilean National Health Service. His research covered the epidemiology of non- infectious diseases in the adult, such as cancer, their socio economic impact, the importance of early detection, treatment and surveillance, as well as the epidemiology of other chronic diseases, accidents and new epidemics. As Director of the School of Public Health for 25 years, he promoted the development of disciplines and courses addressed to health and other care-providers in order to improve their knowledge and expertise as statisticians, epidemiologists, administrators, budget officers. An example of his innovative look at medical education was the creation of post graduate training in the basic clinical specialties combined with public health, in order to have specialists able to undertake both the clinical and administrative duties at the primary care clinics. These programs ran in parallel with the rural internships financed by the Kellogg Foundation at the School of Medicine. Enumerating the distinctions and prizes awarded to Professor Medina would be too long for the purpose of this tribute, and selecting just a few would run the risk of being unfair. Still, there is one: the "Orden de la Cruz del Sur" that deserves the exception given its long existence and the fact that it was awarded to a physician "for distinguished achievements in Public Health".


Amplification-free detection of Cryptosporidium parvum nucleic acids with the use of DNA/RNA-directed gold nanoparticle assemblies.
This study describes the development and evaluation of an amplification-free molecular assay for detection of Cryptosporidium parvum oocysts. The assay employed a pair of oligonucleotide-functionalized gold nanoparticle (AuNP) probes that were complementary to adjacent sequences on C. parvum 18s rRNA. Hybridization of the probes to the target RNA resulted in the assembly of AuNPs into target-linked networks, which were detected both visibly and spectroscopically, by a redshift in the wavelength of light scattered by the gold nanoparticles. The limit of detection was between 4 × 10(5) and 4 × 10(6) copies of RNA per microliter reaction mix, when a short synthetic target or full-length in vitro transcribed target was employed. With total nucleic acids purified from C. parvum oocysts spiked into 100-mg stool, as few as 670 oocysts/μl reaction mix were detected. The ability to detect the nucleic acids of C. parvum oocysts in stool, without the need for complex amplification, offers unique advantages for such AuNP aggregation assays to be extended toward use in resource-limited settings where protozoan detection is needed most.


Development and validation of a novel pre-operative comprehensive prognostic score in esophageal squamous cell carcinoma.
We herein propose a novel integrative score based on inflammatory and nutritional score, coagulation indicator and tumor marker, named comprehensive prognostic score (CPS), to predict postoperative survival in resectable esophageal squamous cell carcinoma (ESCC). We also aimed to establish and validate a nomogram based on CPS and other clinical features for individual survival prediction. A total of 490 resectable ESCC patients were randomly divided into either a training or validation cohort at a ratio of 7:3 for retrospective analysis. The CPS, based on squamous cell carcinoma antigen (SCCA), C-reactive protein to albumin ratio (CAR), neutrophil to lymphocyte ratio (NLR), and fibrinogen (FIB), was divided into two models to verify its prognostic value. The predictive model of CPS-based nomogram was established and validated in two cohorts. Patients with CPS low group in model 1 had better 5-year cancer-specific survival (CSS) than those in CPS high group (50.7% vs. 17.8%, P<0.001). For model 2, the 5-year CSS for CPS 0, 1 and 2 were 75.0%, 38.9% and 13.3%, respectively (P<0.001). CPS was confirmed as an independent prognostic score in both models. The CPS-based nomogram can accurately and effectively predict survival in resected ESCC. The CPS is a novel, simple, and effective predictor in resectable ESCC. Moreover, CPS has a potential independent prognostic value in predicting postoperative survival, which can accurately and effectively predict individual survival in resectable ESCC.


Disease-causing mutations improving the branch site and polypyrimidine tract: pseudoexon activation of LINE-2 and antisense Alu lacking the poly(T)-tail.
Cryptic exons or pseudoexons are typically activated by point mutations that create GT or AG dinucleotides of new 5' or 3' splice sites in introns, often in repetitive elements. Here we describe two cases of tetrahydrobiopterin deficiency caused by mutations improving the branch point sequence and polypyrimidine tracts of repeat-containing pseudoexons in the PTS gene. In the first case, we demonstrate a novel pathway of antisense Alu exonization, resulting from an intronic deletion that removed the poly(T)-tail of antisense AluSq. The deletion brought a favorable branch point sequence within proximity of the pseudoexon 3' splice site and removed an upstream AG dinucleotide required for the 3' splice site repression on normal alleles. New Alu exons can thus arise in the absence of poly(T)-tails that facilitated inclusion of most transposed elements in mRNAs by serving as polypyrimidine tracts, highlighting extraordinary flexibility of Alu repeats in shaping intron-exon structure. In the other case, a PTS pseudoexon was activated by an A>T substitution 9 nt upstream of its 3' splice site in a LINE-2 sequence, providing the first example of a disease-causing exonization of the most ancient interspersed repeat. These observations expand the spectrum of mutational mechanisms that introduce repetitive sequences in mature transcripts and illustrate the importance of intronic mutations in alternative splicing and phenotypic variability of hereditary disorders.


Multispecies in situ monitoring of a static internal combustion engine by near-infrared diode laser sensors.
A multispecies near-infrared diode laser spectrometer has been constructed for measurements of carbon monoxide, carbon dioxide, and methane directly in the exhaust of a static internal combustion engine. A wavelength modulation-division multiplexing scheme was implemented for the two distributed feedback diode lasers. Gas concentration variations were observed for changes in operating conditions such as increasing and decreasing the throttle, adjusting the air-fuel ratio, and engine start-up.


Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11;17).
Analysis of a variant translocation t(11;17) in a case of acute promyelocytic leukemia (APL) led to discovery of a novel zinc finger gene, PLZF, fused to the retinoic acid receptor-alpha (RAR alpha) gene. We reviewed the clinical and molecular features of five additional patients with t(11;17)-associated APL. The clinical course of three patients was characterized by early death and three experienced disseminated intravascular coagulation. Morphologically all of the patients fell in a unusual morphologic spectrum of APL, with features intermediate between M2 and M3 AML. All six patients had PLZF-RAR alpha gene fusion as detected by reverse transcription/polymerase chain reaction assay, Southern blotting, or pulsed-field gel electrophoresis. Five of the six patients failed to achieve complete remission after initial chemotherapy or differentiation therapy with all-trans retinoic acid (ATRA). A sixth patient responded to initial chemotherapy, but on relapse failed to respond to ATRA. When tested in vitro, cultured cells from three of the patients failed to differentiate in response to ATRA. APL associated with t(11;17) and fusion of the PLZF and RAR alpha genes is a discrete clinico-pathologic syndrome with a distinctly worse prognosis than t(15;17) APL.


Provider Knowledge, Attitudes, and Practices Regarding Bronchiolitis and Pneumonia Guidelines.
Practice guidelines have been published for bronchiolitis and community-acquired pneumonia (CAP), but little is known about pediatricians' knowledge of and attitudes toward these guidelines since their publication. We surveyed pediatric providers at 6 children's hospitals in the New York City area. Two vignettes, an infant with bronchiolitis and a child with CAP, were provided, and respondents were asked about management. Associations between respondent characteristics and their reported practices were examined using χ2 and Fisher's exact tests. Associations between questions probing knowledge and attitude barriers relevant to guideline adherence and reported practices were examined using Cochran-Mantel-Haenszel relative risk estimates. Of 283 respondents, 58% were trainees; 57% of attending physician respondents had finished training within 10 years. Overall, 76% and 45% of respondents reported they had read the bronchiolitis and CAP guidelines, respectively. For the bronchiolitis vignette, 40% reported ordering a chest radiograph (CXR), and 38% prescribed bronchodilators (neither recommended). For the CAP vignette, 38% prescribed ceftriaxone (not recommended). Study site, level of training, and practice locations were associated with nonrecommended practices. Site-adjusted knowledge and attitude barriers were used to identify that those who agreed CXRs were useful in managing bronchiolitis were more likely to order CXRs, and those who felt bronchodilators shortened length of stay were more likely to prescribe them. Concerns about ampicillin resistance and lack of confidence using local susceptibility patterns to guide prescribing were associated with ordering ceftriaxone. Provider-level factors and knowledge gaps were associated with ordering nonrecommended treatments for bronchiolitis and CAP.


Pesticide/environmental exposures and Parkinson's disease in East Texas.
Epidemiological evidence suggests that pesticides and other environmental exposures may have a role in the etiology of idiopathic Parkinson's disease (PD). However, there is little human data on risk associated with specific pesticide products, including organic pesticides such as rotenone with PD. Using a case-control design, this study examined self-reports of exposure to pesticide products, organic pesticides such as rotenone, and other occupational and environmental exposures on the risk of PD in an East Texas population. The findings demonstrated significantly increased risk of PD with use of organic pesticides such as rotenone in the past year in gardening (OR = 10.9; 95% CI = 2.5-48.0) and any rotenone use in the past (OR = 10.0; 95% CI = 2.9-34.3). Use of chlorpyrifos products (OR = 2.0; 95% CI = 1.02-3.8), past work in an electronics plant (OR = 5.1; 95% CI = 1.1-23.6), and exposure to fluorides (OR = 3.3; 95% CI = 1.03-10.3) were also associated with significantly increased risk. A trend of increased PD risk was observed with work history in paper/lumber mill (OR = 6.35; 95% CI = 0.7-51.8), exposure to cadmium (OR = 5.3; 95% CI = 0.6-44.9), exposure to paraquat (OR = 3.5; 95% CI = 0.4-31.6), and insecticide applications to farm animals/animal areas and agricultural processes (OR = 4.4; 95% CI = 0.5-38.1). Cigarette smoking, alcohol use, and fish intake were associated with reduced risk. In summary, this study demonstrates an increased risk of PD associated with organic pesticides such as rotenone and certain other pesticides and environmental exposures in this population.


Novel fluorescent anthracene-bodipy dyads displaying sensitivity to pH and turn-on behaviour towards Cu(ii) ions.
Three bichromophoric compounds containing anthracene and bodipy moieties connected by different spacers have been synthesized and fully characterized. The set of spacers comprises a variety of bridges (short and flexible 1,2-diaminoethane in compound 1a, long and flexible 1,8-diaminooctane in compound 1b and short and rigid piperazine in compound 1c). The new compounds show interchromophoric communication via Electronic Energy Transfer (EET). When anthracene is excited, the energy is efficiently transferred to the bodipy moiety. The emission of the acceptor is partially quenched in dyad 1a but remarkably not in 1b and 1c. In an aqueous environment, the fluorescence of the new compounds display sensitivity to pH (emissive at acidic values and non-emissive at neutral ones), a typical behaviour of photoinduced electron-transfer (PET) probes, but with remarkable differences in the pKa of each compound, attributable to the nature of the linker. Additionally, the behaviour in the presence of several metallic cations (Cu2+, Ni2+, Cd2+, Zn2+) has been studied, and a turn-on response towards Cu2+ in water at neutral pH has been found.


Topoisomerase II-mediated DNA cleavage activity and irreversibility of cleavable complex formation induced by DNA intercalator with alkylating capability.
A group of chrysophanol and emodin derivatives with DNA-intercalating capability and with or without alkylating potential have been synthesized and shown to have antitumor activity in vitro. The topoisomerase II (Topo II)-mediated DNA cleavage activities induced by representative compounds 3-(2-chloroethylamino) methyl-1,8-dihydroxy-9,10-anthraquinone (SK-31690), 3-bis [(2-chloroethyl)amino]methyl-1,8-dihydroxy-9,10-anthraquinone (SK-31662), and 3-(2-hydroxyethylamino)methy-1,8-dihydroxy-9,10-anthraquinon e (SK-31694), and their cytotoxicities, have been investigated. All three compounds inhibited the kinetoplast DNA decatenation catalyzed by DNA Topo II. These compounds inhibited leukemia cell growth and stimulated, in a dose-dependent manner from 0.5 to 60 microM, the formation of Topo II-DNA cleavable complexes, when 3'-32P-labeled DNA was used. The mapping of Topo II-mediated DNA cleavage sites using HindIII-digested 3'-32P-labeled DNA showed that, at 10 microM, these compounds induced protein-linked DNA breaks that correlated with cytotoxicity, with respect to their maximal efficacy or the reciprocal concentration for the half-maximal effect. The reversibility study showed that the amounts of protein-linked DNA cleavage induced by 4'-(9-acridinylamino)methanesulfon-m-anisidide and VP-16 as well as SK-31694, which lacks alkylating potential, were markedly decreased during 30-sec exposure to 65 degrees or 0.5 M NaCl. In contrast, protein-linked DNA cleavages induced by SK-31662, which has two alkylating functionalities, and by SK-31690, which has one alkylating functionality in its structure, cannot be reversed during the 15-min exposure to 65 degrees or 0.5 M NaCl. These data suggest that Topo II is a major cellular target for cytotoxicity of these compounds. Furthermore, DNA intercalators with alkylating potential interact with Topo II-DNA cleavable complexes in an irreversible manner, with enhanced toxicity.


Timing manipulations reveal the lack of a causal link across timing of annual-cycle stages in a long-distance migrant.
Organisms need to time their annual-cycle stages, like breeding and migration, to occur at the right time of the year. Climate change has shifted the timing of annual-cycle stages at different rates, thereby tightening or lifting time constraints of these annual-cycle stages, a rarely studied consequence of climate change. The degree to which these constraints are affected by climate change depends on whether consecutive stages are causally linked (scenario I) or whether the timing of each stage is independent of other stages (scenario II). Under scenario I, a change in timing in one stage has knock-on timing effects on subsequent stages, whereas under scenario II, a shift in the timing of one stage affects the degree of overlap with previous and subsequent stages. To test this, we combined field manipulations, captivity measurements and geolocation data. We advanced and delayed hatching dates in pied flycatchers (Ficedula hypoleuca) and measured how the timing of subsequent stages (male moult and migration) were affected. There was no causal effect of manipulated hatching dates on the onset of moult and departure to Africa. Thus, advancing hatching dates reduced the male moult-breeding overlap with no effect on the moult-migration interval. Interestingly, the wintering location of delayed males was more westwards, suggesting that delaying the termination of breeding carries over to winter location. Because we found no causal linkage of the timing of annual-cycle stages, climate change could shift these stages at different rates, with the risk that the time available for some becomes so short that this will have major fitness consequences.


Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase.
Mycobacterium tuberculosis claims more human lives each year than any other bacterial pathogen. Infection is maintained in spite of acquired immunity and resists eradication by antimicrobials. Despite an urgent need for new therapies targeting persistent bacteria, our knowledge of bacterial metabolism throughout the course of infection remains rudimentary. Here we report that persistence of M. tuberculosis in mice is facilitated by isocitrate lyase (ICL), an enzyme essential for the metabolism of fatty acids. Disruption of the icl gene attenuated bacterial persistence and virulence in immune-competent mice without affecting bacterial growth during the acute phase of infection. A link between the requirement for ICL and the immune status of the host was established by the restored virulence of delta icl bacteria in interferon-gamma knockout mice. This link was apparent at the level of the infected macrophage: Activation of infected macrophages increased expression of ICL, and the delta icl mutant was markedly attenuated for survival in activated but not resting macrophages. These data suggest that the metabolism of M. tuberculosis in vivo is profoundly influenced by the host response to infection, an observation with important implications for the treatment of chronic tuberculosis.


Internet-based recruitment to a depression prevention intervention: lessons from the Mood Memos study.
Recruiting participants to randomized controlled trials of health interventions can be very difficult. Internet-based recruitment is becoming an increasingly important mode of recruitment, yet there are few detailed accounts of experiences recruiting participants to mental health interventions. To report on our experience with Internet-based recruitment to an online depression prevention intervention and pass on lessons we learned. Participants were recruited to the Mood Memos study, an online preventive depression intervention, purely through Internet-based sources. The study was targeted to adults with subthreshold depression symptoms from several English-speaking countries. A variety of online recruitment sources were trialed, including search engine advertising (Google, Yahoo!, Bing), Facebook advertising, posts in forums and online noticeboards, and promotion through relevant websites and email newsletters of mental health organizations. The study website received visits from 94,808 individuals over the 14-month recruitment period. The recruitment target was reached with 1699 individuals signing up to the randomized controlled trial and 1326 fully enrolling. Most visitors arrived via Google advertising, which promoted a depression-screening questionnaire. Google advertising accounted for nearly half of the total participants who signed up to the study, at an average cost of AUD $12 per participant. Promoting the study through trustworthy organizations and websites known to participants was also effective. Recruitment techniques that were less effective were contacting forums, email groups, and community noticeboards. Several techniques, including Google advertising, were successful in recruiting participants to a trial evaluating an online depression intervention. Results suggest that Internet-based recruitment to mental health interventions is feasible and can be relatively affordable. ACTRN12609000925246.


Stressors, allostatic load, and health outcomes among women hotel housekeepers: A pilot study.
Hotel housekeepers are exposed to stressors at work and outside of work. A minimal amount is known about these workers' pathophysiological responses to those stressors. Allostatic load is a concept increasingly used to understand pathophysiologic manifestations of individuals' bodily response to stress. The purpose of this study was to examine the associations between work and nonwork stressors, allostatic load, and health outcomes among hotel housekeepers. Work and nonwork stressors (e.g., the number of traumatic events, everyday discrimination, and job strain) and health outcomes (e.g., general health status, physical and mental health, and chronic diseases) were measured. Biometric and anthropometric measures and fasting blood specimens were collected. Blood biomarkers included CRP, HbA1c, HDL, and cortisol. Descriptive analyses, correlations, regressions, and t-tests were conducted. Forty-nine women hotel housekeepers participated, with a mean age of 40 years. One-fifth reported high job strain and more than 40% had at least one traumatic event. Chronic conditions were commonly reported, with about 78%, 55%, and 35% reporting one, two, and three chronic conditions, respectively. Correlation analyses showed that reports of high job strain and everyday discrimination were significantly associated with high ALI quartile score (r = 0.39, p = 0.011; r = 0.41, p = 0.004). Job strain and everyday discrimination had medium to large effect sizes on ALI quartile scores. High ALI quartile score was significantly associated with having at least one chronic disease (r = 0.40, p = 0.005), and it had a large effect size on chronic diseases. To our knowledge, this is the first study to explore allostatic load among hotel housekeepers. Hotel housekeepers have high exposure to stressors within and outside of their work and experience poor chronic conditions. Allostatic load had strong associations with both stressors and health outcomes. Despite this worker group being a hard-to-reach worker group to participate in research studies, this study demonstrates the feasibility of accessing, recruiting and collecting survey data and blood samples among them to determine health risks and guide future targeted interventions.


Medical informatics: an essential tool for health sciences research in acute care.
Medical Informatics has become an important tool in modern health care practice and research. In the present article we outline the challenges and opportunities associated with the implementation of electronic medical records (EMR) in complex environments such as intensive care units (ICU). We share our initial experience in the design, maintenance and application of a customized critical care, Microsoft SQL based, research warehouse, ICU DataMart. ICU DataMart integrates clinical and administrative data from heterogeneous sources within the EMR to support research and practice improvement in the ICUs. Examples of intelligent alarms -- "sniffers", administrative reports, decision support and clinical research applications are presented.


The Eczema Priority Setting Partnership: a collaboration between patients, carers, clinicians and researchers to identify and prioritize important research questions for the treatment of eczema.
Eczema is a common condition, yet there are uncertainties regarding many frequently used treatments. Knowing which of these uncertainties matter to patients and clinicians is important, because they are likely to have different priorities from those of researchers and funders. To identify the uncertainties in eczema treatment that are important to patients who have eczema, their carers and the healthcare professionals (HCPs) who treat them. An eczema Priority Setting Partnership was established, including patients, HCPs and researchers. Eczema treatment uncertainties were gathered from patients and clinicians, and then prioritized in a transparent process, using a methodology advocated by the James Lind Alliance. In the consultation stage 493 participants (including 341 patients/carers) made 1070 submissions, of which 718 were uncertainties relating to the treatment of eczema. Treatment uncertainties with more than one submission were grouped into 52 'indicative uncertainties', which were then ranked by 514 participants (including 399 patients/carers). The top 14 treatment uncertainties were prioritized for research. The first four were common to patients/carers and HCPs (shared uncertainties): (i) the best and safest way of using topical steroids (including frequency of application, potency, length of time, alternation with other topical treatments and age limits); (ii) the long-term safety of topical steroids; (iii) the role of food allergy tests; and (iv) the most effective and safe emollients in treating eczema. The remaining 10 of the top 14 uncertainties comprised the next five highest ranked uncertainties for patients and the next five highest ranked uncertainties for HCPs. At a workshop involving 40 participants (patients, HCPs and researchers), shared uncertainties were formulated into possible research questions. The top 14 treatment uncertainties around the treatment of eczema provide guidance for researchers and funding bodies to ensure that future research answers questions that are important to both clinicians and patients.


faint sausage encodes a novel extracellular protein of the immunoglobulin superfamily required for cell migration and the establishment of normal axonal pathways in the Drosophila nervous system.
We examined the structure of the nervous system in Drosophila embryos homozygous for a null mutation in the faint sausage (fas) gene. In the peripheral nervous system (PNS) of fas mutants, neurons fail to delaminate from the ectodermal epithelium; in the central nervous system (CNS), the positions of neuronal cell bodies and glial cells are abnormal and normal axonal pathways do not form. Sequence analysis of fas cDNAs revealed that the fas protein product has characteristics of an extracellular protein and that it is a novel member of the immunoglobulin (Ig) superfamily. In situ hybridization demonstrated that fas transcripts are expressed throughout the embryo but they are in relatively high concentrations in the lateral ectoderm, from which the peripheral nervous system delaminates and in the CNS. Antiserum directed against Fas protein was found to stain neurons but not glia in the CNS. We conclude that fas encodes a protein that, in the developing nervous system, is present on the surface of neurons and is essential for nerve cell migration and the establishment of axonal pathways.


The increase of firearm-related violence in Sweden.
Firearm-related violence is common in our contemporary world and causes serious harm to humans as well as to the society. One of the countries in which firearm-related violence is increasing is Sweden and its most southern region, Skane, in which Malmo, Sweden's third largest city, is highly affected. If not contained and limited, Sweden risks becoming more and more violent.


Mitochondrial Hyperacetylation in the Failing Hearts of Obese Patients Mediated Partly by a Reduction in SIRT3: The Involvement of the Mitochondrial Permeability Transition Pore.
Cyclophilin D (CypD) mediates the mitochondrial permeability transition pore (mPTP) opening that contributes to mitochondrial dysfunction. CypD is regulated by its acetylation/deacetylation state that depends on Sirtuin-3 (SIRT3) mitochondrial deacetylase. Since obesity and metabolic syndrome decrease SIRT3 activity and expression, we tested the hypothesis that CypD hyperacetylation promotes mitochondrial dysfunction under this pathophysiological state, which is associated with ventricular dysfunction and heart failure. Myocardial tissue samples from patients with left ventricular heart failure, with either obesity or normal weight, were processed for the expression of SIRT3 and acetylation profile by Western Blot (WB). In addition, a rat model of obesity and metabolic syndrome induced by 30% (w/v) of sucrose was conducted. The WB analysis was used to determine the levels of mitochondrial expression of SIRT3, Adenine Nucleotide Translocator (ANT), CypD and the acetylation profile, as well as immunoprecipitation to establish the acetylation levels of CypD. Mitochondrial function was assessed by oxygen consumption analysis and maximum Ca2+ retention capacity. Oxidative stress was assessed by aconitase activity, protein carbonyl and thiol groups content. SIRT3 expression in the biopsies of the failing human hearts showed a 46% decrease in the expression levels of obese patients in comparison to the non-obese patients (p=0.0219). Remarkably, body mass index was associated with protein acetylation (0.627; p = 0.035), suggesting that the acetylation profiles of the failing hearts of obese patients are partly mediated by a reduction in SIRT3, which is also associated with higher BNP levels, indicating a more severe ventricular dysfunction (-0.636; p = 0.043). Accordingly, obese rats demonstrated a SIRT3 mitochondrial expression decrease of 22% concomitantly with a hyperacetylated mitochondrial profile, including CypD. Cardiac mitochondria from obese animals were 2.5-fold more prone to mPTP opening than the controls. Our results indicate that obesity reduces SIRT3 expression and that CypD hyperacetylation increases mPTP opening, suggesting that the activation of SIRT3 might be a potential target to decrease ventricular dysfunction and slow the progression of heart failure.


MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism.
Angiocentric gliomas are pediatric low-grade gliomas (PLGGs) without known recurrent genetic drivers. We performed genomic analysis of new and published data from 249 PLGGs, including 19 angiocentric gliomas. We identified MYB-QKI fusions as a specific and single candidate driver event in angiocentric gliomas. In vitro and in vivo functional studies show that MYB-QKI rearrangements promote tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression and hemizygous loss of the tumor suppressor QKI. To our knowledge, this represents the first example of a single driver rearrangement simultaneously transforming cells via three genetic and epigenetic mechanisms in a tumor.


Perceptions of complete dentures by prospective implant patients.
The purpose of this study was to facilitate the recognition of denture patients who are unable to adapt to conventional dentures and who are likely to benefit from treatment using implant-supported prostheses. Sixty-nine patients who where referred for postgraduate prosthetic treatment at Wits Dental School completed a self-report inventory of items related to their dentures in current use. Conventional dentures were fabricated for all subjects. Those patients who could not adapt to conventional complete denture treatment were referred for treatment with implant-supported prostheses provided that they conformed with the recommended criteria for this treatment modality. Analysis of the inventory of pretreatment denture complaints yielded variables that differentiated between the group who remained with conventional dentures and the group that was referred for implants. Significant variables were the period that a mandibular denture was used before new dentures were requested (P = 0.025); the period that a maxillary denture was used before further treatment was sought (P = 0.03); the discarding of a mandibular denture (P = 0.035); and pain complaints related to maxillary dentures (P = 0.045). A logistic regression model was used to compare the clinical division of the sample with that determined by the mathematic model. Sixty-six percent of the subjects who accepted conventional treatment and 69% of implant patients corresponded for both classifications. The authors conclude that pretreatment denture complaints can be used diagnostic aids for evaluating patients who are likely to benefit from implant-supported prostheses.


Not all brains are created equal: the relevance of individual differences in responsiveness to transcranial electrical stimulation.
A current issue in the research of augmentation of brain functions using transcranial electrical stimulation (tES) is the diversity and inconsistency in outcome results. Similar studies often report different results, depending on the parameters and tasks used. Such inconsistencies have led to significant doubts about the efficacy of the method in the broader scientific community, despite its promising potential for patient recovery and treatment. Evidence on the large variability in individual cortical excitability and response to tES suggests that stimulation may affect individuals differently, depending on the subject's age, gender, brain state, hormonal levels, and pre-existing regional excitability. Certain factors might even lead to the reversal of polarity-dependent effects, and therefore have crucial implications for neurorehabilitation and cognitive enhancement. Research paradigms may have to be refined in the future to avoid the confounding effects of such factors.


Taxonomy-Based Approaches to Quality Assurance of Ontologies.
Ontologies are important components of health information management systems. As such, the quality of their content is of paramount importance. It has been proven to be practical to develop quality assurance (QA) methodologies based on automated identification of sets of concepts expected to have higher likelihood of errors. Four kinds of such sets (called QA-sets) organized around the themes of complex and uncommonly modeled concepts are introduced. A survey of different methodologies based on these QA-sets and the results of applying them to various ontologies are presented. Overall, following these approaches leads to higher QA yields and better utilization of QA personnel. The formulation of additional QA-set methodologies will further enhance the suite of available ontology QA tools.


Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX.
Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease in which the risk of disease is influenced by complex genetic and environmental contributions. Alleles of HLA-DRB1, IRF5, and STAT4 are established susceptibility genes; there is strong evidence for the existence of additional risk loci. We genotyped more than 500,000 single-nucleotide polymorphisms (SNPs) in DNA samples from 1311 case subjects with SLE and 1783 control subjects; all subjects were North Americans of European descent. Genotypes from 1557 additional control subjects were obtained from public data repositories. We measured the association between the SNPs and SLE after applying strict quality-control filters to reduce technical artifacts and to correct for the presence of population stratification. Replication of the top loci was performed in 793 case subjects and 857 control subjects from Sweden. Genetic variation in the region upstream from the transcription initiation site of the gene encoding B lymphoid tyrosine kinase (BLK) and C8orf13 (chromosome 8p23.1) was associated with disease risk in both the U.S. and Swedish case-control series (rs13277113; odds ratio, 1.39; P=1x10(-10)) and also with altered levels of messenger RNA in B-cell lines. In addition, variants on chromosome 16p11.22, near the genes encoding integrin alpha M (ITGAM, or CD11b) and integrin alpha X (ITGAX), were associated with SLE in the combined sample (rs11574637; odds ratio, 1.33; P=3x10(-11)). We identified and then confirmed through replication two new genetic loci for SLE: a promoter-region allele associated with reduced expression of BLK and increased expression of C8orf13 and variants in the ITGAM-ITGAX region.


Phase II trial of alternating weekly chemohormonal therapy for patients with androgen-independent prostate cancer.
Two distinct regimens of weekly chemotherapy for hormone-refractory prostate cancer were combined in an alternating schedule and tested in a Phase II trial to determine efficacy and toxic effects. Forty-six patients with hormone-refractory prostate cancer and rising prostate-specific antigen (PSA) levels entered the trial. Therapy consisted of doxorubicin (20 mg/m2/week) plus oral ketoconazole (400 mg three times a day) given at weeks 1, 3, and 5 and vinblastine (5 mg/m2/week) plus oral estramustine (140 mg three times a day) given at weeks 2, 4, and 6. No therapy was given at weeks 7 and 8. Replacement doses of hydrocortisone were administered throughout treatment to counteract potential adrenal insufficiency secondary to the ketoconazole. In 67% of patients (31 of 46), the PSA declined by 50% or greater for a minimum duration of 8 weeks (95% confidence interval, 52-80%). Among the 16 patients with measurable soft tissue disease, there were 12 responses (75%; 95% confidence interval, 47-92%). The median duration of response was 8. 4 months (1.8-14.9). The median survival for the entire group was 19 months. The median survival of PSA responders has not been reached, whereas that of nonresponders was 13 months (P = 0.010). Seventy-six percent of symptomatic patients noted improvement. Hematological toxicity was modest and was managed without growth factors. Peripheral edema (49%) and deep venous thrombosis (18%) were the most common nonhematological toxicities. The alternating weekly regimen of chemohormonal therapy is active for hormone-refractory prostate cancer, providing a high rate of symptom control, soft tissue response, and PSA decline.


Modeling the detachment and transport of bubbles from nucleation sites in small vessels.
Decompression sickness is known to be due to the formation of bubbles in the body as a result of decompression. It is likely that these bubbles form from pre-existing nuclei, which, for bubbles in the bloodstream, are thought to be housed within blood vessel walls. Gas pockets emerging from these sites will be subject to forces due to blood flow, a portion of the gas eventually being swept away to form a free bubble in the bloodstream. These continue to grow and may grow to similar dimensions to the vessel, developing into elongated "gas plugs," potentially occluding the flow. In this correspondence, we derive a simple model to investigate whether this vessel occlusion is a serious concern.


Direct visualization of membrane architecture of myelinating cells in transgenic mice expressing membrane-anchored EGFP.
Myelinogenesis is a complex process that involves substantial and dynamic changes in plasma membrane architecture and myelin interaction with axons. Highly ramified processes of oligodendrocytes in the central nervous system (CNS) make axonal contact and then extrapolate to wrap around axons and form multilayer compact myelin sheathes. Currently, the mechanisms governing myelin sheath assembly and axon selection by myelinating cells are not fully understood. Here, we generated a transgenic mouse line expressing the membrane-anchored green fluorescent protein (mEGFP) in myelinating cells, which allow live imaging of details of myelinogenesis and cellular behaviors in the nervous systems. mEGFP expression is driven by the promoter of 2'-3'-cyclic nucleotide 3'-phosphodiesterase (CNP) that is expressed in the myelinating cell lineage. Robust mEGFP signals appear in the membrane processes of oligodendrocytes in the CNS and Schwann cells in the peripheral nervous system (PNS), wherein mEGFP expression defines the inner layers of myelin sheaths and Schmidt-Lanterman incisures in adult sciatic nerves. In addition, mEGFP expression can be used to track the extent of remyelination after demyelinating injury in a toxin-induced demyelination animal model. Taken together, the membrane-anchored mEGFP expression in the new transgenic line would facilitate direct visualization of dynamic myelin membrane formation and assembly during development and process remodeling during remyelination after various demyelinating injuries.


Reduction of urinary catheter use and prescription of antibiotics for asymptomatic bacteriuria in hospitalised patients in internal medicine: before-and-after intervention study.
Unnecessary treatment of asymptomatic bacteriuria and overuse of urinary catheters in hospitals are of concern regarding antimicrobial resistance and patient safety, respectively. We investigated the effectiveness of a multifaceted intervention in reducing urinary catheter use and unnecessary prescription of antibiotics for asymptomatic bacteriuria in hospitalised patients in a clinic for internal medicine. Data were collected retrospectively from all inpatients during a 3-month period both before and after a multifaceted intervention from the Clinic for Internal Medicine of our secondary care hospital. The intervention consisted of implementation of guidelines, establishment of a standard for urinary catheter management, introduction of restricted orders and a reminder of indwelling catheters, as well as lectures and internet-based learning focusing on asymptomatic bacteriuria. The incidence rate of urinary catheter days decreased significantly from 27 to 17 catheter days per 100 patient days (incidence rate ratio 0.61, 95% confidence interval 0.57-0.67). The incidence rate of unnecessary antibiotic treatment days for asymptomatic bacteriuria dropped significantly from 22 to 10 treatment days per 1,000 patient days (incidence rate ratio 0.46, 95% confidence interval 0.33-0.63). A multifaceted intervention was effective in reducing both urinary catheter days and inappropriate antibiotic use for asymptomatic bacteriuria.


Secrecy, ostentation, and the illustration of exotic animals in sixteenth-century Portugal.
During the first decades of the sixteenth century, several animals described and viewed as exotic by the Europeans were regularly shipped from India to Lisbon. This paper addresses the relevance of these 'new' animals to knowledge and visual representations of the natural world. It discusses their cultural and scientific meaning in Portuguese travel literature of the period as well as printed illustrations, charts and tapestries. This paper suggests that Portugal did not make the most of its unique position in bringing news and animals from Asia. This was either because secrecy associated with trade and military interests hindered the diffusion of illustrations presented in Portuguese travel literature or because the illustrations commissioned by the nobility were represented on expensive media such as parchments and tapestries and remained treasured possessions. However, the essay also proposes that the Portuguese contributed to a new sense of the experience and meaning of nature and that they were crucial mediators in access to new knowledge and new ways of representing the natural world during this period.


The Future of Basic Science in Academic Surgery: Identifying Barriers to Success for Surgeon-scientists.
The aim of this study was to examine the challenges confronting surgeons performing basic science research in today's academic surgery environment. Multiple studies have identified challenges confronting surgeon-scientists and impacting their ability to be successful. Although these threats have been known for decades, the downward trend in the number of successful surgeon-scientists continues. Clinical demands, funding challenges, and other factors play important roles, but a rigorous analysis of academic surgeons and their experiences regarding these issues has not previously been performed. An online survey was distributed to 2504 members of the Association for Academic Surgery and Society of University Surgeons to determine factors impacting success. Survey results were subjected to statistical analyses. We also reviewed publicly available data regarding funding from the National Institutes of Health (NIH). NIH data revealed a 27% decline in the proportion of NIH funding to surgical departments relative to total NIH funding from 2007 to 2014. A total of 1033 (41%) members responded to our survey, making this the largest survey of academic surgeons to date. Surgeons most often cited the following factors as major impediments to pursuing basic investigation: pressure to be clinically productive, excessive administrative responsibilities, difficulty obtaining extramural funding, and desire for work-life balance. Surprisingly, a majority (68%) did not believe surgeons can be successful basic scientists in today's environment, including departmental leadership. We have identified important barriers that confront academic surgeons pursuing basic research and a perception that success in basic science may no longer be achievable. These barriers need to be addressed to ensure the continued development of future surgeon-scientists.


Acid shock of Listeria monocytogenes at low environmental temperatures induces prfA, epithelial cell invasion, and lethality towards Caenorhabditis elegans.
The saprophytic pathogen Listeria monocytogenes has to cope with a variety of acidic habitats during its life cycle. The impact of low-temperature coupled with pH decrease for global gene expression and subsequent virulence properties, however, has not been elucidated. qRT-PCR revealed for the first time a transient, acid triggered prfA induction of approximately 4-fold, 5.7-fold, 7-fold and 9.3-fold 60 to 90 min after acid shock of L. monocytogenes at 37°C, 25°C, 18°C, and 10°C, respectively. Comparable data were obtained for seven different L. monocytogenes strains, demonstrating that prfA induction under these conditions is a general response of L. monocytogenes. Transcriptome analysis revealed that the in vivo-relevant genes bsh, clpP, glpD, hfq, inlA, inlB, inlE, lisR, and lplA1 as well as many other genes with a putative role during infection are transiently induced upon acid shock conducted at 25°C and 37°C. Twenty-five genes repressed upon acid shock are known to be down regulated during intracellular growth or by virulence regulators. These data were confirmed by qRT-PCR of twelve differentially regulated genes and by the identification of acid shock-induced genes influenced by σB. To test if up regulation of virulence genes at temperatures below 37°C correlates with pathogenicity, the capacity of L. monocytogenes to invade epithelial cells after acid shock at 25°C was measured. A 12-fold increased number of intracellular bacteria was observed (acid shock, t = 60 min) that was reduced after adaptation to the level of the unshocked control. This increased invasiveness was shown to be in line with the induction of inlAB. Using a nematode infection assay, we demonstrated that Caenorhabditis elegans fed with acid-shocked L. monocytogenes exhibits a shorter time to death of 50% (TD50) of the worms (6.4 days) compared to infection with unshocked bacteria (TD50 = 10.2 days). PrfA and other listerial virulence genes are induced by an inorganic acid in a temperature-dependent manner. The data presented here suggest that low pH serves as a trigger for listerial pathogenicity at environmental temperatures.


Climate change not to blame for late Quaternary megafauna extinctions in Australia.
Late Quaternary megafauna extinctions impoverished mammalian diversity worldwide. The causes of these extinctions in Australia are most controversial but essential to resolve, because this continent-wide event presaged similar losses that occurred thousands of years later on other continents. Here we apply a rigorous metadata analysis and new ensemble-hindcasting approach to 659 Australian megafauna fossil ages. When coupled with analysis of several high-resolution climate records, we show that megafaunal extinctions were broadly synchronous among genera and independent of climate aridity and variability in Australia over the last 120,000 years. Our results reject climate change as the primary driver of megafauna extinctions in the world's most controversial context, and instead estimate that the megafauna disappeared Australia-wide ∼13,500 years after human arrival, with shorter periods of coexistence in some regions. This is the first comprehensive approach to incorporate uncertainty in fossil ages, extinction timing and climatology, to quantify mechanisms of prehistorical extinctions.


Knowledge and risk perception of oral cavity and oropharyngeal cancer among non-medical university students.
To assess non-medical university students' knowledge and perceived risk of developing oral cavity and oropharyngeal cancer. A cross-sectional survey was conducted among non-medical students of a private Midwestern university in the United States in May 2012. Questionnaire assessed demographic information and contained 21 previously validated questions regarding knowledge and perceived risk of developing oral cavity and oropharyngeal cancer. Knowledge scale was categorized into low and high. Risk level was estimated based on smoking, drinking, and sexual habits. Bivariate associations between continuous and categorical variables were assessed using Pearson correlation and Chi-square tests, respectively. The response rate was 87% (100 out of 115 students approached). Eighty-one percent (81%) had low oral cavity and oropharyngeal cancer knowledge; and only 2% perceived that their oral cavity and oropharyngeal cancer risk was high. Risk perception was negatively correlated with age at sexual debut, r (64) = -0.26, p = 0.037; one-way ANOVA showed a marginally significant association between risk perception and number of sexual partners, F(4, 60) = 2.48, p = 0.05. There was no significant association between knowledge and perception of risk; however, oral cavity and oropharyngeal cancer knowledge was significantly associated with frequency of prevention of STDs (p < 0.05). Although 86% had heard about oral cavity and oropharyngeal cancer, only 18% had heard of oral mouth examination, and 7% of these reported ever having an oral cavity and oropharyngeal cancer exam. Oral cavity and oropharyngeal cancer knowledge and risk perception is low among this student population. Since oral cavity and oropharyngeal cancer incidence is increasingly shifting towards younger adults, interventions must be tailored to this group in order to improve prevention and control.


Cultural dissimilarities in general practice: development and validation of a patient's cultural background scale.
Due to increased migration physicians encounter more communication difficulties due to poor language proficiency and different culturally defined views about illness. This study aimed to develop and validate a 'patient's cultural background scale' in order to classify patients based on culturally conditioned norms instead of on ethnicity. A total of 986 patients from 38 multi-ethnic general practices were included. From a list of 36 questions, non-contributing and non-consistent questions were deleted and from the remaining questions the scale was constructed by principal component analysis. Comparing the scale with two other methods of construction assessed internal validity. Comparing the found dimensions with known dimensions from literature assessed the construct validity. Criterion validity was determined by comparing the patient's score with criteria assumed or known to have relationship with cultural background. Criterion validity was reasonably good but poor for income. A valid patient's cultural background scale was developed, for use in large-scale quantitative studies.


Household Food Insecurity and Mental Health Problems Among Adolescents: What Do Parents Report?
To investigate whether adolescents living in households with food insecurity have poorer parent-reported mental health (MH) than peers. We analyzed cross-sectional data from ∼8600 adolescents who participated in the 2007 (8th grade) wave of the Early Childhood Longitudinal Study-Kindergarten. Household food insecurity (HFI) was assessed by parental report on the 18-item US Household Food Security Scale. Total Difficulties score >13 on the parent-reported Strengths and Difficulties Questionnaire (SDQ) indicated problems with adolescent MH. SDQ subscale scores (Emotional, Conduct, Hyperactivity, Peer Problems) were also calculated. Associations between HFI and MH were explored in bivariate and multivariable analyses. Interactions of HFI and gender and HFI and receipt of free/reduced-price school lunch were analyzed with regard to problems with MH. A total of 10.2% of adolescents lived with HFI; 11.2% had SDQ >13. Adolescents with HFI had higher rates of overall MH problems (28.7% vs 9.2%), emotional problems (21.6% vs 6.6%), conduct problems (26.5% vs 11.6%), hyperactivity (22.4% vs 11.3%), and peer problems (19.8% vs 8.6%) (all P < .01). After adjustment for confounders, the association between HFI and overall MH problems (odds ratio 2.3; 95% confidence interval 1.6-3.3) remained. Interactions of HFI and gender and HFI and free/reduced-price school lunch were not significant. HFI was associated with increased risk of parent-reported MH problems among both male and female adolescents. Free/reduced-price school lunch did not significantly alter this relationship. Effective interventions to promote MH and reduce HFI among adolescents are necessary.


Stabilization of Thylakoid Membranes by Spermine during Stress-induced Senescence of Barley Leaf Discs.
The effect of spermine on photochemical activity and polypeptide composition of chloroplasts from barley leaf discs during senescence in the dark was studied. Chloroplast membranes did not show photosystem II activity after spermine treatment when water was the electron donor, but in the presence of diphenylcarbazide, this activity was observed. The diphenylcarbazide-stimulated photoreduction of dichloroindophenol was 3-fold greater in leaf discs incubated for 72 hours in spermine than in water. Photosystem I activity was reduced by about 90% within the first 24 hours in the spermine-treated samples. This reduction, however, was not due to a decrease in the photosynthetic unit size. A preferential loss of polypeptides other than those associated with photosystem II was observed during senescence of the leaf discs in water, but this loss was reduced by spermine. Spermine treatment also prevented the appearance of several additional chlorophyll proteins found in the controls during senescence. The results have been interpreted on the basis of the interaction of spermine with thylakoid membranes resulting in stabilization of membrane function during senescence.


The sedentary office: an expert statement on the growing case for change towards better health and productivity.
An international group of experts convened to provide guidance for employers to promote the avoidance of prolonged periods of sedentary work. The set of recommendations was developed from the totality of the current evidence, including long-term epidemiological studies and interventional studies of getting workers to stand and/or move more frequently. The evidence was ranked in quality using the four levels of the American College of Sports Medicine. The derived guidance is as follows: for those occupations which are predominantly desk based, workers should aim to initially progress towards accumulating 2 h/day of standing and light activity (light walking) during working hours, eventually progressing to a total accumulation of 4 h/day (prorated to part-time hours). To achieve this, seated-based work should be regularly broken up with standing-based work, the use of sit-stand desks, or the taking of short active standing breaks. Along with other health promotion goals (improved nutrition, reducing alcohol, smoking and stress), companies should also promote among their staff that prolonged sitting, aggregated from work and in leisure time, may significantly and independently increase the risk of cardiometabolic diseases and premature mortality. It is appreciated that these recommendations should be interpreted in relation to the evidence from which they were derived, largely observational and retrospective studies, or short-term interventional studies showing acute cardiometabolic changes. While longer term intervention studies are required, the level of consistent evidence accumulated to date, and the public health context of rising chronic diseases, suggest initial guidelines are justified. We hope these guidelines stimulate future research, and that greater precision will be possible within future iterations.


Effect of 7 vs 14 Days of Antibiotic Therapy on Resolution of Symptoms Among Afebrile Men With Urinary Tract Infection: A Randomized Clinical Trial.
Determination of optimal treatment durations for common infectious diseases is an important strategy to preserve antibiotic effectiveness. To determine whether 7 days of treatment is noninferior to 14 days when using ciprofloxacin or trimethoprim/sulfamethoxazole to treat urinary tract infection (UTI) in afebrile men. Randomized, double-blind, placebo-controlled noninferiority trial of afebrile men with presumed symptomatic UTI treated with ciprofloxacin or trimethoprim/sulfamethoxazole at 2 US Veterans Affairs medical centers (enrollment, April 2014 through December 2019; final follow-up, January 28, 2020). Of 1058 eligible men, 272 were randomized. Participants continued the antibiotic prescribed by their treating clinician for 7 days of treatment and were randomized to receive continued antibiotic therapy (n = 136) or placebo (n = 136) for days 8 to 14 of treatment. The prespecified primary outcome was resolution of UTI symptoms by 14 days after completion of active antibiotic treatment. A noninferiority margin of 10% was selected. The as-treated population (participants who took ≥26 of 28 doses and missed no more than 2 consecutive doses) was used for the primary analysis, and a secondary analysis included all patients as randomized, regardless of treatment adherence. Secondary outcomes included recurrence of UTI symptoms and/or adverse events within 28 days of stopping study medication. Among 272 patients (median [interquartile range] age, 69 [62-73] years) who were randomized, 100% completed the trial and 254 (93.4%) were included in the primary as-treated analysis. Symptom resolution occurred in 122/131 (93.1%) participants in the 7-day group vs 111/123 (90.2%) in the 14-day group (difference, 2.9% [1-sided 97.5% CI, -5.2% to ∞]), meeting the noninferiority criterion. In the secondary as-randomized analysis, symptom resolution occurred in 125/136 (91.9%) participants in the 7-day group vs 123/136 (90.4%) in the 14-day group (difference, 1.5% [1-sided 97.5% CI, -5.8% to ∞]) Recurrence of UTI symptoms occurred in 13/131 (9.9%) participants in the 7-day group vs 15/123 (12.9%) in the 14-day group (difference, -3.0% [95% CI, -10.8% to 6.2%]; P = .70). Adverse events occurred in 28/136 (20.6%) participants in the 7-day group vs 33/136 (24.3%) in the 14-day group. Among afebrile men with suspected UTI, treatment with ciprofloxacin or trimethoprim/sulfamethoxazole for 7 days was noninferior to 14 days of treatment with regard to resolution of UTI symptoms by 14 days after antibiotic therapy. The findings support the use of a 7-day course of ciprofloxacin or trimethoprim/sulfamethoxazole as an alternative to a 14-day course for treatment of afebrile men with UTI. ClinicalTrials.gov identifier: NCT01994538.


Increased alpha-adrenergic receptor affinity in resistance vessels from hypertensive rats.
alpha-Adrenergic receptor-related properties, specifically, norepinephrine affinity, occupancy and reserve during contraction, were determined in segments of rat resistance arteries. These were obtained from the superior mesenteric bed of spontaneously hypertensive rats and Wistar-Kyoto strain controls. Receptor affinity for norepinephrine in the spontaneously hypertensive rats was significantly greater than that for the Wistar-Kyoto controls. There were no differences in the estimates of receptor occupancy and reserve. This finding taken together with other studies is consistent with the conclusion that increased alpha-adrenergic receptor-mediated sensitivity of vascular smooth muscle of the spontaneously hypertensive rat reflects differences in the agonist site on the alpha-adrenergic receptor.


Effects of hydroxymetabolites of bupropion on nicotine dependence behavior in mice.
Bupropion is an atypical antidepressant that also has utility as a smoking cessation aid. Hydroxybupropions are major metabolites of bupropion and are believed to contribute to antidepressant and perhaps smoking cessation activities. Because bupropion metabolism is more similar in humans and mice than in humans and rats, the present study investigated effects of hydroxybupropion enantiomers in mouse behavioral models measuring various aspects of nicotine dependence. Bupropion and (2S,3S)-hydroxybupropion, but not (2R,3R)-hydroxybupropion, significantly decreased the development of nicotine reward as measured in the conditioned place preference and withdrawal paradigm in mice. Bupropion and both of its metabolites reversed affective and somatic withdrawal signs in nicotine-dependent mice, but the (2S,3S)-hydroxymetabolite had higher potency. Bupropion and (2S,3S)-, but not (2R,3R)-hydroxybupropion, produced partial substitution for nicotine in drug discrimination tests. Our findings support the hypothesis that the effects of bupropion on measures of nicotine dependence reflect actions of bupropion itself, its hydroxymetabolites, or a combination and suggest that the (2S,3S)-hydroxy isomer is the most active principle, making it a potentially better drug candidate for smoking cessation than bupropion.


A prior feature SVM-MRF based method for mouse brain segmentation.
We introduce an automated method, called prior feature Support Vector Machine-Markov Random Field (pSVMRF), to segment three-dimensional mouse brain Magnetic Resonance Microscopy (MRM) images. Our earlier work, extended MRF (eMRF) integrated Support Vector Machine (SVM) and Markov Random Field (MRF) approaches, leading to improved segmentation accuracy; however, the computation of eMRF is very expensive, which may limit its performance on segmentation and robustness. In this study pSVMRF reduces training and testing time for SVM, while boosting segmentation performance. Unlike the eMRF approach, where MR intensity information and location priors are linearly combined, pSVMRF combines this information in a nonlinear fashion, and enhances the discriminative ability of the algorithm. We validate the proposed method using MR imaging of unstained and actively stained mouse brain specimens, and compare segmentation accuracy with two existing methods: eMRF and MRF. C57BL/6 mice are used for training and testing, using cross validation. For formalin fixed C57BL/6 specimens, pSVMRF outperforms both eMRF and MRF. The segmentation accuracy for C57BL/6 brains, stained or not, was similar for larger structures like hippocampus and caudate putamen, (~87%), but increased substantially for smaller regions like susbtantia nigra (from 78.36% to 91.55%), and anterior commissure (from ~50% to ~80%). To test segmentation robustness against increased anatomical variability we add two strains, BXD29 and a transgenic mouse model of Alzheimer's disease. Segmentation accuracy for new strains is 80% for hippocampus, and caudate putamen, indicating that pSVMRF is a promising approach for phenotyping mouse models of human brain disorders.


Intrarater reliability of measuring the patella position by ultrasonography in weight-bearing condition.
[Purpose] The aim of this study was to determine the intrarater reliability of using ultrasonography as a measurement tool to assess the patella position in a weight-bearing condition. [Subjects and Methods] Ten healthy adults participated in this study. Ultrasonography was used to assess the patella position during step down with the loading knee in flexion (0° and 20°). The distance between the patella and lateral condyle was measured to represent the patella position on the condylar groove. Two measurements were obtained on the first day and the day after 1 week by the same investigator. [Results] Excellent intrarater reliability, ranging from 0.83 to 0.93, was shown in both conditions. Standard errors of the measurements were 0.5 mm in the straight knee and 0.7 mm in the knee flexion at 20°. Minimal differences in knee flexion at 0° and knee flexion at 20° were 1.5 mm and 1.9 mm, respectively. [Conclusion] Ultrasonography is a reliable assessment tool for evaluating the positional changes of the patella in weight-bearing activities, and it can be easily used by practitioners in the clinical setting.