Associations of exercise-induced hormone profiles and gains in strength and hypertrophy in a large cohort after weight training.
The purpose of this study was to investigate associations between acute exercise-induced hormone responses and adaptations to high intensity resistance training in a large cohort (n = 56) of young men. Acute post-exercise serum growth hormone (GH), free testosterone (fT), insulin-like growth factor (IGF-1) and cortisol responses were determined following an acute intense leg resistance exercise routine at the midpoint of a 12-week resistance exercise training study. Acute hormonal responses were correlated with gains in lean body mass (LBM), muscle fibre cross-sectional area (CSA) and leg press strength. There were no significant correlations between the exercise-induced elevations (area under the curve-AUC) of GH, fT and IGF-1 and gains in LBM or leg press strength. Significant correlations were found for cortisol, usually assumed to be a hormone indicative of catabolic drive, AUC with change in LBM (r = 0.29, P < 0.05) and type II fibre CSA (r = 0.35, P < 0.01) as well as GH AUC and gain in fibre area (type I: r = 0.36, P = 0.006; type II: r = 0.28, P = 0.04, but not lean mass). No correlations with strength were observed. We report that the acute exercise-induced systemic hormonal responses of cortisol and GH are weakly correlated with resistance training-induced changes in fibre CSA and LBM (cortisol only), but not with changes in strength.


Stressful life events, psychological appraisal and coping style in postmenopausal women.
The study aim was to investigate what life events postmenopausal women attending a menopause clinic, report as stressful and how psychological appraisal of these events, menopausal symptoms and general stress mediate coping style. An observational design was used to recruit 179 postmenopausal women attending a menopause clinic for the first time. Data was collected using self-report questionnaires assessing socio-demographic information, menopausal symptoms, perceived stress, named stressful event, psychological appraisal and coping styles employed. All of the women were postmenopausal, with a mean age of 50.74 years (SD=4.75). Stressful events were categorised into family problems, menopause symptoms, work problems, daily hassles and other health problems. The most commonly reported coping styles were in order, catharsis (68%), direct action (66%), and seeking social support (63%). Logistic regression was used to determine what predicts coping style. Socio-demographic variables, menopausal symptoms and general stress levels were not predictive of coping styles in this study. Specific aspects of psychological appraisal were predictive of distraction, direct action, catharsis and seeking social support. Coping styles most commonly implemented were also the ones predicted by psychological appraisal of the stressful event in this study and tend to be used more so by older women. This information could be used to develop more appropriate interventions for postmenopausal women.


From assessment to improvement of elderly care in general practice using decision support to increase adherence to ACOVE quality indicators: study protocol for randomized control trial.
Previous efforts such as Assessing Care of Vulnerable Elders (ACOVE) provide quality indicators for assessing the care of elderly patients, but thus far little has been done to leverage this knowledge to improve care for these patients. We describe a clinical decision support system to improve general practitioner (GP) adherence to ACOVE quality indicators and a protocol for investigating impact on GPs' adherence to the rules. We propose two randomized controlled trials among a group of Dutch GP teams on adherence to ACOVE quality indicators. In both trials a clinical decision support system provides un-intrusive feedback appearing as a color-coded, dynamically updated, list of items needing attention. The first trial pertains to real-time automatically verifiable rules. The second trial concerns non-automatically verifiable rules (adherence cannot be established by the clinical decision support system itself, but the GPs report whether they will adhere to the rules). In both trials we will randomize teams of GPs caring for the same patients into two groups, A and B. For the automatically verifiable rules, group A GPs receive support only for a specific inter-related subset of rules, and group B GPs receive support only for the remainder of the rules. For non-automatically verifiable rules, group A GPs receive feedback framed as actions with positive consequences, and group B GPs receive feedback framed as inaction with negative consequences. GPs indicate whether they adhere to non-automatically verifiable rules. In both trials, the main outcome measure is mean adherence, automatically derived or self-reported, to the rules. We relied on active end-user involvement in selecting the rules to support, and on a model for providing feedback displayed as color-coded real-time messages concerning the patient visiting the GP at that time, without interrupting the GP's workflow with pop-ups. While these aspects are believed to increase clinical decision support system acceptance and its impact on adherence to the selected clinical rules, systems with these properties have not yet been evaluated. Controlled Trials NTR3566.


DNA damage-sensing kinases mediate the mouse 2-cell embryo's response to genotoxic stress.
A critical function of cells is the maintenance of their genomic integrity. A family of phosphoinositide-3-kinase-related protein kinases, which includes ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3 related (ATR) kinases, play key roles in sensing DNA damage. ATM and ATR were demonstrated in the cleavage stages of mouse embryo development. Genotoxic stress was imposed by exposure to ultraviolet (UV) radiation (causes DNA strand breaks) or cisplatin (causes strand cross-links). UV irradiation or cisplatin treatment of 2-cell embryos in the G(2) phase of the cell cycle caused DNA damage as defined by increased phosphorylation of the H2A histone family, member X (H2AFX; previously H2AX) variant. UV irradiation caused a stable G(2)-M arrest, and cisplatin treatment allowed progression through mitosis followed by activation of a G(1)-S checkpoint. Both checkpoints were transformation-related protein 53-independent. Caffeine (inhibits both ATM and ATR), but not KU55933 (ATM-selective inhibitor), reversed the G(2)-M block induced by UV, inferring a primary role for ATR in sensing this form of DNA damage. Caffeine and KU55933 were equally effective in reversing the cisplatin-induced G(1)-S block, implicating ATM as the primary sensing enzyme. Breaching of either checkpoint by treatment with caffeine or KU55933 allowed embryos to progress through several further cell cycles, yet none developed to blastocysts. The results show, to our knowledge for the first time, that the G(2)-M and G(1)-S cell-cycle checkpoints in the early embryo are differentially regulated by ATM and ATR in response to genotoxic stress and that they act as an initial point for containment of genomic damage. Under conditions of extensive or persistent DNA damage, the demise of the embryo is the ultimate method of protecting genomic integrity.


Barrier to linearity and anharmonic force field of the ketenyl radical.
The troublesome barrier to linearity of the ketenyl radical (HCCO) is precisely determined using state-of-the-art computations within the focal point approach, by combining complete basis set extrapolation, utilizing the aug-cc-pVXZ (X = D, T, Q, 5, 6) family of basis sets, with electron correlation treatments as extensive as coupled cluster theory with single, double, triple, and perturbative quadruple excitations [CCSDT(Q)]. Auxiliary terms such as diagonal Born-Oppenheimer corrections (DBOCs) and relativistic contributions are included. To gain a definitive theoretical treatment and to assess the effect of higher-order correlation on the structure of HCCO, we employ a composite approximation (c approximately ) to all-electron (AE) CCSDT(Q) theory at the complete basis set (CBS) limit for geometry optimizations. A final classical barrier to linearity of 630 +/- 30 cm(-1) is obtained for reaching the (2)Pi Renner-Teller configuration of HCCO from the (2)A'' ground state. Additionally, we compute fundamental vibrational frequencies and other spectroscopic constants by application of second-order vibrational perturbation theory (VPT2) to the full quartic force field at the AE-CCSD(T)/aug-cc-pCVQZ level. The resulting (nu(1), nu(2), nu(5)) fundamental frequencies of (3212, 2025, 483) cm(-1) agree satisfactorily with the experimental values (3232, 2023, 494) cm(-1).


[Screening induced by health services: impact and consequences. Ethical issues].
The main aim of screening is to identify people with an increased probability to benefit from preventive interventions, generally from secondary prevention but also from primary prevention activities. The goal is to facilitate early diagnosis and treatment in order to modify positively the prognosis (the former case), or to recognize people exposed to risk factors which increase the incidence rate of disease, and then to prevent the disease (the latter case). Good intentions are not enough to achieve good results in terms of effectiveness, safety, efficiency or equity. It is necessary to have a systematic assessment of the consequences of screening, particularly on the impact on peoples health and on the health services. Due to the diversity of types of screenings that are done, it is very difficult to estimate the net impact caused by their implementation. Moreover, the changes in the health of a population depend on many factors other than health service interventions. Thus, it is very important to determine the effectiveness and safety of the screening methods that are most frequently applied. Unfortunately, assessment of the benefits and the harm potentially caused by preventive interventions has not been done often. In Spain only a few partial assessments have been published, and they focus on the activities and the processes themselves rather than the final outcomes. Given that screening activities are carried out in health care services, and that the populations screened are mostly healthy people, the ethical issues have great importance when health policies are designed and implemented. Thus, it is recommended that screenings activities be analyzed applying the ethical principles of autonomy, benefit, safety and justice. If any screening program cannot reasonably satisfy these principles then they should be removed from the list of public health activities that are financed by public resources. In the same sense, all screening procedures offered to the population must be subjected to a systematic evaluation of their effectiveness, safety, efficiency and equity in terms of how the procedure would be applied. Lastly, to achieve an effective implementation of the principle of autonomy as well the desired goal of empowering the population to exercise some control over their determinants of health, it is recommended to explore new ways of achieving active citizen participation to establish preventive priorities and to assess the impact of screening interventions.


Microbiological Spectrum and Outcomes of Acute Pyelonephritis in North Indian Population.
A wide range of causative organisms can cause acute pyelonephritis (APN). However, in recent times, these pathogens have increasingly become resistant to most of the antibiotics making treatment difficult. This was a prospective observational single-center study with a aim to study the microbiological spectrum, resistance patterns, and clinical outcome of patients with APN conducted in a private tertiary care hospital in India. All adult patients hospitalized in the department of nephrology at our institute with a diagnosis of APN from February 2016 to May 2017 were included. Patients <18 years of age, kidney-transplant recipients, and pregnant patients were excluded. Demographic details, clinical symptoms, signs, and radiological and laboratory data including urine and blood cultures of all patients were recorded. The details of treatment received and outcomes in hospital and after discharge were noted. Patients were followed up three months post discharge. Decision of antibiotic and duration of antibiotics was documented by treating nephrologists. Quantitative data were presented in terms of means and standard deviation. Student's "t" test was used for comparison of quantitative outcome parameters. P <0.05 is considered statistically significant. SPSS software version 23.0 was used for statistical analysis. A total of 89 patients with a mean age of 50.33 ± 13.9 years, of which 61.8% were males and were studied; 82/89 had complicated pyelonephritis. The most common risk factor for APN was diabetes mellitus in 64 (72%). Most common symptom was fever in 80 (90%). A triad of fever, flank pain, and dysuria was present only in 27 (30.33%). Overall, 15 patients (16.8%) had severe pyelonephritis requiring intensive care unit admission. The most common organism isolated was Escherichia coli in 26/49 (53%), followed by Klebsiella pneumoniae in 12 (24.40%). Twenty-two (58%) isolates were extended-spectrum beta lactamase producers. Six (12.20%) were resistant to carbapenems and two (4%) were pan-resistant. All 89 were treated with intravenous antibiotics. Older patients, those with diabetes, with poor glycemic control, and with emphysematous pyelonephritis and patients in whom ESBL organisms were grown had poor outcome. Piperacillin tazobactam, aminopenicillins, cefoperazone sulbactam, and carbapenems (in severe pyelonephritis) can be considered as the empirical antibiotic of choice.


Stable ultra-fast broad-bandwidth photodetectors based on α-CsPbI3 perovskite and NaYF4:Yb,Er quantum dots.
Photodetectors (PDs), especially those that respond in the infrared region, are highly desirable and have a wide range of applications ranging from cell phones, cameras, and home electronics to airplanes and satellites. Herein, we designed and fabricated PDs based on air-stable α-CsPbI3 QDs and an up-conversion material (NaYF4:Yb,Er QDs) using a facial low temperature spin-coating method. When the α-CsPbI3 QDs are surface-modified using NaYF4:Yb,Er QDs, their optical response is extended to the NIR region to allow broadband application from the UV to visible to NIR region (260 nm-1100 nm). The optoelectronic properties and compositional stability of the devices were also studied in detail. From the results, the PDs are capable of broad-bandwidth photodetection from the deep UV to NIR region (260 nm-1100 nm) with good photoresponsivity (R, 1.5 A W-1), high on/off ratio (up to 104) and very short rise/decay time (less than 5 ms/5 ms). It was found that the photoresponsivity performance of the PDs in this work is better than that of all the other previously reported perovskite QD-based PDs with a lateral device structure. Furthermore, the device performance shows very little degradation over the course of 60 days of storage under ambient conditions. The combination of remarkable stability, high performance broad-bandwidth photodetection, and easy fabrication suggest that these QDs are a very promising semiconducting candidate for optoelectronic applications.


Usability of eHealth and Mobile Health Interventions by Young People Living With Juvenile Idiopathic Arthritis: Systematic Review.
Considering the changing landscape of internet use and rising ownership of digital technology by young people, new methods could be considered to improve the current model of juvenile idiopathic arthritis (JIA) management. This systematic review aims to evaluate the usability of eHealth and mobile health (mHealth) interventions currently available for young people living with JIA. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were used to oversee this review. We systematically searched 15 databases for 252 potential studies; 2 authors independently screened all quantitative studies reporting the use of eHealth and mHealth interventions for young people (aged 1-18 years) diagnosed with JIA. Studies were excluded if they did not report outcome measures or were reviews, commentaries, or qualitative studies. Study methodological quality was scored using the Down and Black (modified) checklist. A narrative descriptive methodology was used to quantify the data because of heterogeneity across the studies. A total of 11 studies were included in this review, reporting 7 eHealth and mHealth interventions for young people (aged 4-18 years) living with JIA, targeting health issues such as pain, health-related quality of life, physical activity, and chronic disease self-management. The usability of the interventions was facilitated through training and ongoing support. The engagement was promoted by a combination of persuasive influences, and barriers preventing adherence were removed through personal reminders and flexible program schedules to cater to JIA and non-JIA illnesses or other commonly seen activities in childhood. The feedback obtained was that most young people and their parents liked the interventions. The results of this review need to be considered cautiously because of the lack of rigorous testing and heterogeneity, which limits the detailed descriptions of data synthesis. Further research is needed to consider gender differences, associated costs, and the effectiveness of the interventions on health outcomes to better support young people living with JIA.


End-of-life preferences for atheists.
Atheists represent an understudied population in palliative care medicine. Although professional and regulatory organizations require an individualized plan of care for each patient and family, little is known about atheist preferences for end-of-life (EOL) care. The aims of this pilot study were twofold: (1) to explore the EOL preferences for atheists, and (2) to apply a threefold model of spiritual care (intrapersonal, interpersonal, and natural interconnectedness) to assess the appropriateness of potential interventions for a group of atheists. Eighty-eight participants completed either an online or paper survey. Analyses of open-ended and closed questions were consistent with prior studies on EOL preferences, including components of a ;;good death.'' The results related to the first aim of the study, to explore EOL preferences, suggests that participants view of a good death was expanded to include respect for nonbelief and the withholding of prayer or other references to God. Strong preference for physician-assisted suicide and evidence-based medical interventions were central themes from participants. The second aim of the study, to apply a threefold definition of spirituality--which includes intrapersonal, interpersonal, and natural focus--appears appropriate in planning interventions for atheists at EOL. Participants expressed a deep desire to find meaning in their own lives (intrapersonal), to maintain connection with family and friends (interpersonal), and to continue to experience and appreciate the natural world (natural interconnectedness) through the dying experience. Additional research is necessary to explore the preferences for this understudied group. Further clarification of the use of the term "atheist'' is also necessary to ensure that the inclusion of all individuals with nontheist beliefs are represented in future research efforts.


Damage control surgery and casualty evacuation: techniques for surgeons, lessons for military medical planners.
Damage Control Surgery (DCS) is a three-phase team-based approach to maximal injury penetrating abdominal trauma. In Phase I, the hypothermic, coagulopathic, acidotic, hypotensive casualty undergoes a proactively planned one-hour time limited laparotomy by an appropriately trained surgical trauma team. In phase II physiological stabilization takes place in the Intensive Care Unit. In phase III--definitive repair occurs. DCS is extremely resource intensive but will save lives on the battlefield. A military DCS patient will perioperatively require fourteen units of blood and seven units of fresh frozen plasma--half the blood stock of a light-scaled FST. Two DCS patients will in one day, exhaust this FSTs oxygen supply. We know that hypothermic patients with an iliac vascular injury (initial core temp < 34 degrees C) suffer four-fold increases in their mortality, yet we cannot heat our tents above 20 degrees C during a mild British winter. Our primary casualty retrieval is excessively slow. A simple casevac request has to go to too much 'middle-management' before a flight decision is made. In Vietnam, wounded soldiers arrived in hospital within twenty-five minutes of injury. In Iraq in 2005, that figure is over one hundred and ten minutes. We use support or anti-tank helicopters that are re-roled on an adhoc basis for the critical care and transport of our sickest patients. We still do not have a dedicated all-weather military helicopter evacuation fleet despite significant evidence that intensive care unit level military evacuation is safe and eminently achievable in both in the primary and secondary care setting. Should we not be asking why?


Elastic strains in antler trabecular bone determined by synchrotron X-ray diffraction.
The microstructure and associated mechanical properties of antler trabecular bone have been studied using a variety of techniques. The local trabeculae properties, as well as the three-dimensional architecture were characterized using nanoindentation and X-ray microtomography, respectively. An elastic modulus of 10.9+/-1.1 GPa is reported for dry bone, compared with 5.4+/-0.9 GPa for fully hydrated bone. Trabeculae thickness and separation were found to be comparable to those of bovine trabecular bone. Uniaxial compression conducted in situ during X-ray microtomography showed that antler can undergo significant architectural rearrangement, dominated by trabeculae bending and buckling, due to its low mineral content. High-energy synchrotron X-ray diffraction was used to measure elastic strains in the apatite crystals of the trabeculae, also under in situ uniaxial compression. During elastic loading, strain was found to be accommodated largely by trabeculae aligned parallel to the loading direction. Prior to the macroscopic yield point, internal strains increased as trabeculae deformed by bending, and load was also found to be redistributed to trabeculae aligned non-parallel to the loading direction. Significant bending of trabecular walls resulted in tensile strains developing in trabeculae aligned along the loading direction.


The risk factor for urethral recurrence after radical cystectomy in patients with transitional cell carcinoma of the bladder.
We evaluated the incidence and risk factors for urethral recurrence following radical cystectomy and urinary diversion in transitional cell carcinoma. A retrospective review was performed of the 412 consecutive patients who underwent radical cystectomy and urinary diversion for transitional cell carcinoma of the bladder between 1986 and 2004. A total of 294 patients were enrolled in this study. We investigated the impact of various clinical and pathological features on urethral recurrence by univariate and multivariate analysis. Urethral recurrence developed in 13 patients (4.4%) and the 5-year urethral recurrence-free probability was 94.9%. On univariate analysis, positive urethral margin, prostatic stromal invasion, and prostatic urethral involvement had a significant influence on urethral recurrence (p < 0.05). The other clinical and pathological features were not significantly associated with urethral recurrence (p > 0.05). A multivariate Cox proportional hazard model revealed that a positive urethral margin (hazards ratio (HR) = 18.33, p < 0.001), prostatic urethral involvement (HR = 7.95, p < 0.001), and prostatic stromal invasion (HR = 5.80, p = 0.018) were independent risk factors for urethral recurrence. A positive urethral margin is considered an absolute indication for prophylactic urethrectomy. In addition, more careful patient selection is necessary for orthotopic urinary diversion in patients with prostatic urethral involvement and prostatic stromal invasion.


Meeting report: a workshop on Best Practices in Genome Annotation.
Efforts to annotate the genomes of a wide variety of model organisms are currently carried out by sequencing centers, model organism databases and academic/institutional laboratories around the world. Different annotation methods and tools have been developed over time to meet the needs of biologists faced with the task of annotating biological data. While standardized methods are essential for consistent curation within each annotation group, methods and tools can differ between groups, especially when the groups are curating different organisms. Biocurators from several institutes met at the Third International Biocuration Conference in Berlin, Germany, April 2009 and hosted the 'Best Practices in Genome Annotation: Inference from Evidence' workshop to share their strategies, pipelines, standards and tools. This article documents the material presented in the workshop.


On-chip electrical impedance tomography for imaging biological cells.
Electrical impedance tomography is an imaging technology that spatially characterizes the electrical properties of an object. We present a miniaturized electrical impedance tomography system that can image the electrical conductivity distribution within a two-dimensional cell culture. A chip containing a circular 16-electrode array was fabricated using printed circuit board developing technology and used to inject current and to measure spatial voltage across the object. The signal stimulation and voltage data acquisition were performed using an impedance analyzer, operating in four-electrode mode. An open source software, EIDORS was used for image reconstruction. Finite element modelling was used to simulate the image reconstruction process by imaging two ellipsoidal phantoms in the circular 16-electrode array. The effect of the regularization parameter in the reconstruction algorithm and the influence from noise on the fidelity of the images has been numerically analyzed. Experimentally, we show reconstructed images of a multi-nuclear single cellular organism, Physarum Polycephalum, demonstrating the first step towards impedance imaging of single cells in culture. Our system provides a non-invasive lab-on-a-chip technology for spatially mapping the electrical properties of single cells, which would be significant and useful for diagnostic and clinical applications.


Association of Proton Pump Inhibitors With Risk of Dementia: A Pharmacoepidemiological Claims Data Analysis.
Medications that influence the risk of dementia in the elderly can be relevant for dementia prevention. Proton pump inhibitors (PPIs) are widely used for the treatment of gastrointestinal diseases but have also been shown to be potentially involved in cognitive decline. To examine the association between the use of PPIs and the risk of incident dementia in the elderly. We conducted a prospective cohort study using observational data from 2004 to 2011, derived from the largest German statutory health insurer, Allgemeine Ortskrankenkassen (AOK). Data on inpatient and outpatient diagnoses (coded by the German modification of the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision) and drug prescriptions (categorized according to the Anatomical Therapeutic Chemical Classification System) were available on a quarterly basis. Data analysis was performed from August to November 2015. Prescription of omeprazole, pantoprazole, lansoprazole, esomeprazole, or rabeprazole. The main outcome was a diagnosis of incident dementia coded by the German modification of the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. The association between PPI use and dementia was analyzed using time-dependent Cox regression. The model was adjusted for potential confounding factors, including age, sex, comorbidities, and polypharmacy. A total of 73,679 participants 75 years of age or older and free of dementia at baseline were analyzed. The patients receiving regular PPI medication (n = 2950; mean [SD] age, 83.8 [5.4] years; 77.9% female) had a significantly increased risk of incident dementia compared with the patients not receiving PPI medication (n = 70,729; mean [SD] age, 83.0 [5.6] years; 73.6% female) (hazard ratio, 1.44 [95% CI, 1.36-1.52]; P < .001). The avoidance of PPI medication may prevent the development of dementia. This finding is supported by recent pharmacoepidemiological analyses on primary data and is in line with mouse models in which the use of PPIs increased the levels of β-amyloid in the brains of mice. Randomized, prospective clinical trials are needed to examine this connection in more detail.


Hypnosis: practical applications and theoretical considerations in normal labour.
To assess the effects of hypnotherapy on the first and second stages of labour in a large group of pregnant women. A semi-prospective case control study in which women attending antenatal clinics were invited to undergo hypnotherapy. One hundred twenty-six primigravid women with 300 age matched controls, and 136 parous women having their second baby with 300 age matched controls. Only women who had spontaneous deliveries were included. Aberdare District Maternity Unit, Mid Glamorgan, Wales. Six sessions of hypnotherapy given by a trained medical hypnotherapist during pregnancy. Analgesic requirements, duration of first and second stages of labour. The mean lengths of the first stage of labour in the primigravid women was 6.4 h after hypnosis and 9.3 h in the control group (P < 0.0001); the mean lengths of the second stage were 37 min and 50 min, respectively (P < 0.001). In the parous women the corresponding values were 5.3 h and 6.2 h (P < 0.01); and 24 and 22 min (ns). The use of analgesic agents was significantly reduced (P < 0.001) in both hypnotised groups compared with their controls. In addition to demonstrating the benefits of hypnotherapy, the study gives some insight into the relative proportions of mechanical and psychological components involved in the longer duration of labour in primigravid women.


Human type II receptor for bone morphogenic proteins (BMPs): extension of the two-kinase receptor model to the BMPs.
Bone morphogenic proteins (BMPs) are universal regulators of animal development. We report the identification and cloning of the BMP type II receptor (BMPR-II), a missing component of this receptor system in vertebrates. BMPR-II is a transmembrane serine/threonine kinase that binds BMP-2 and BMP-7 in association with multiple type I receptors, including BMPR-IA/Brk1, BMPR-IB, and ActR-I, which is also an activin type I receptor. Cloning of BMPR-II resulted from a strong interaction of its cytoplasmic domain with diverse transforming growth factor beta family type I receptor cytoplasmic domains in a yeast two-hybrid system. In mammalian cells, however, the interaction of BMPR-II is restricted to BMP type I receptors and is ligand dependent. BMPR-II binds BMP-2 and -7 on its own, but binding is enhanced by coexpression of type I BMP receptors. BMP-2 and BMP-7 can induce a transcriptional response when added to cells coexpressing ActR-I and BMPR-II but not to cells expressing either receptor alone. The kinase activity of both receptors is essential for signaling. Thus, despite their ability to bind to type I and II receptors receptors separately, BMPs appear to require the cooperation of these two receptors for optimal binding and for signal transduction. The combinatorial nature of these receptors and their capacity to crosstalk with the activin receptor system may underlie the multifunctional nature of their ligands.


A Phase II, Prospective, Randomized, Multicenter, Open-Label Study of GX-188E, an HPV DNA Vaccine, in Patients with Cervical Intraepithelial Neoplasia 3.
To determine the efficacy of the therapeutic DNA vaccine GX-188E for inducing regression of cervical intraepithelial neoplasia (CIN) 3. We conducted a prospective, randomized, multicenter, open-label, phase II clinical trial of GX-188E in CIN3 patients positive for human papillomavirus (HPV) type 16/18. The primary endpoint was to determine the histopathologic regression to ≤CIN1 at visit seven (V7; 20 weeks after the first GX-188E injection), and an extension study was pursued until visit 8 (V8; 36 weeks after the first GX-188E injection). HPV-sequencing analysis and an ex vivo IFNγ ELISpot assay were performed using the collected cervical biopsy and blood samples from patients. In total, 72 patients were enrolled and underwent randomization. Of them, 64 patients were included in per-protocol analysis (V7) and 52 in extension analysis (V8). Our data showed 52% (33/64) of patients at V7 and 67% (35/52) of patients at V8 presented histopathologic regression after receiving the GX-188E injection. We found that 73% (V7) and 77% (V8) of the patients with histologic regression showed HPV clearance. HPV clearance and histopathologic regression were significantly associated at V7 and at V8. Compared with the measurements at V1 (baseline), the patients at V8 with HPV clearance showed significantly higher fold changes in their IFNγ ELISpot responses compared with those without HPV clearance. The HPV sequence analysis revealed that the HPV type 16 E6/E7 variants D25E, V83L, and N29S were inversely associated with histopathologic regression at V8. GX-188E is an effective therapeutic vaccine against a cohort containing only CIN3 patients.


Problem-Solving Exercise for Undergraduate Students Involving the Japanese Fermented Food Natto.
Natto is a traditional Japanese food made from soybeans fermented by Bacillus subtilis natto. Because natto is high in protein and contains healthful bacteria, dieticians and producers have campaigned for higher consumption of natto in areas such as Kansai, where our university is located. One of the reasons for the low consumption of natto is its distinctive flavor. As a problem-solving exercise, undergraduate students attempted to make natto more marketable. Students set a goal of modifying natto flavor by adding spices to achieve flavors deemed palatable by organoleptic tests. During the exercise, they noticed that lemongrass, Cymbopogon citratus, had a flavor-masking ability that reduced the intensity of natto flavor, and they finally determined that it was a useful food additive to make natto marketable. The exercise was an active learning process that effectively induced voluntary student effort of to solve problems originating from microorganisms.


PSD-95 is associated with the postsynaptic density and not with the presynaptic membrane at forebrain synapses.
PSD-95, a prominent protein component of the postsynaptic density (PSD) fraction from rat forebrain, has been localized by light microscopy to dendrites of hippocampal neurons (Cho et al., 1992) and to the presynaptic plexus of cerebellar basket cells (Kistner et al., 1993). Here we extend these studies to show that an affinity-purified antibody to PSD-95 labels the dendrites of most neurons in the forebrain and of a subset of neurons in the cerebellum. To confirm that PSD-95 is associated with the PSD at forebrain synapses and to clarify whether it is also associated with the presynaptic membrane, we employed immunogold electron microscopy of forebrain synaptosomes. Gold-labeled antibodies to PSD-95 labeled postsynaptic densities in both intact and lysed forebrain synaptosomes but did not label presynaptic terminals or the presynaptic membrane. The asymmetric distribution of PSD-95 at synapses contrasts with that of its homologs, disks-large and ZO-1, which are arranged symmetrically at septate and tight junctions, respectively.


Gap junction protein Cx37 interacts with endothelial nitric oxide synthase in endothelial cells.
The gap junction protein connexin37 (Cx37) plays an important role in cell-cell communication in the vasculature. A C1019T Cx37 gene polymorphism, encoding a P319S substitution in the regulatory C terminus of Cx37 (Cx37CT), correlates with arterial stenosis and myocardial infarction in humans. This study was designed to identify potential binding partners for Cx37CT and to determine whether the polymorphism modified this interaction. Using a high-throughput phage display, we retrieved 2 binding motifs for Cx37CT: WHK ... [K,R]XP ... and FHK ... [K,R]XXP ... , the first being more common for Cx37CT-319P and the second more common for Cx37CT-319S. One of the peptides (WHRTPRLPPPVP) showed 77.7% homology with residues 843 to 854 of endothelial nitric oxide synthase (eNOS). In vitro binding of this peptide or of the homologous eNOS sequence to both Cx37CT isoforms was confirmed by cross-linking and surface plasmon resonance. Electrophysiological analysis of Cx37 single channel activity in transfected N2a cells showed that eNOS-like and eNOS(843-854) increased the frequency of events with conductances higher than 300 pS. We demonstrated that eNOS coimmunoprecipitated with Cx37 in a mouse endothelial cell (EC) line (bEnd.3), human primary ECs, and a human EC line transfected with Cx37-319P or Cx37-319S. Cx37 and eNOS colocalized at EC membranes. Moreover, a dose-dependent increase in nitric oxide production was observed in ECs treated with Cx37 antisense. Overall, our data show for the first time a functional and specific interaction between eNOS and Cx37. This interaction may be relevant for the control of vascular physiology both in health and in disease.


Voltage-gated currents in identified rat olfactory receptor neurons.
Whole-cell recording techniques were used to characterize voltage-gated membrane currents in neonatal rat olfactory receptor neurons (ORNs) in cell culture. Mature ORNs were identified in culture by their characteristic bipolar morphology, by retrograde labeling techniques, and by olfactory marker protein (OMP) immunoreactivity. ORNs did not have spontaneous activity, but fired action potentials to depolarizing current pulses. Action potentials were blocked by tetrodotoxin (TTX), which contrasts with the TTX-resistant action potentials in salamander olfactory receptor cells (e.g., Firestein and Werblin, 1987). Prolonged, suprathreshold current pulses evoked only a single action potential; however, repetitive firing up to 35 Hz could be elicited by a series of brief depolarizing pulses. Under voltage clamp, the TTX-sensitive sodium current had activation and inactivation properties similar to other excitable cells. In TTX and 20 mM barium, sustained inward current were evoked by voltage steps positive to -30 mV. This current was blocked by Cd (100 microM) and by nifedipine (IC50 = 368 nM) consistent with L-type calcium channels in other neurons. No T-type calcium current was observed. Voltage steps positive to -20 mV also evoked an outward current that did not inactivate during 100-msec depolarizations. Tail current analysis of this current was consistent with a selective potassium conductance. The outward current was blocked by external tetraethylammonium but was unaffected by Cd or 4-aminopyridine (4-AP) or by removal of external calcium. A transient outward current was not observed. The 3 voltage-dependent conductances in cultured rat ORNs appear to be sufficient for 2 essential functions: action potential generation and transmitter release. As a single odorant-activated channel can trigger an action potential (e.g., Lynch and Barry, 1989), the repetitive firing seen with brief depolarizing pulses suggests that ORNs do not integrate sensory input, but rather act as high-fidelity relays such that each opening of an odorant-activated channel reaches the olfactory bulb glomeruli as an action potential.


The conceptual basis of ethnic group terminology and classifications.
"Ethnic group" is a problematic variable in health-related research. While self-identification is now widely accepted as the appropriate mode of assignment, the impracticalities of a free response in the collection of ethnic group data mean that categorisation into a limited set of choices must take place. The substantial and increasing number of persons in minority ethnic groups who identify through non-standard responses emphasises the need to develop classifications that accommodate salient vernacular terminology. The use of informants in cognitive settings and the monitoring of open-ended responses appear to offer the best way of determining which group labels to employ. The recommended approach addresses the research priorities for accurate, consistent, and high quality data and is also responsive to the dynamic nature of ethnic group and the growing ethnic diversity of the population.


Retractions in the research literature: misconduct or mistakes?
To determine how commonly articles are retracted on the basis of unintentional mistakes, and whether these articles differ from those retracted for scientific misconduct in authorship, funding, type of study, publication, and time to retraction. All retractions of English language publications indexed in MEDLINE between 1982 and 2002 were extracted. Two reviewers categorised the reasons for retraction of each article as misconduct (falsification, fabrication, or plagiarism) or unintentional error (mistakes in sampling, procedures, or data analysis; failure to reproduce findings; accidental omission of information about methods or data analysis). Of the 395 articles retracted between 1982 and 2002, 107 (27.1%) were retracted because of scientific misconduct, 244 (61.8%) because of unintentional errors, and 44 (11.1%) could not be categorised. Compared with articles retracted because of misconduct, articles with unintentional mistakes were more likely to have multiple authors, no reported funding source, and to be published in frequently cited journals. They were more likely to be retracted by the author(s) of the article, and the retraction was more likely to occur more promptly (mean, 2.0 years; 95% CI, 1.8-2.2) than articles withdrawn because of misconduct (mean, 3.3 years; 95% CI, 2.7-3.9) (P < 0.05 for all comparisons). Retractions in the biomedical literature were more than twice as likely to result from unintentional mistakes than from scientific misconduct. The different characteristics of articles retracted for misconduct and for mistakes reflect distinct causes and, potentially, distinct solutions.


Spinal Control of Locomotion: Individual Neurons, Their Circuits and Functions.
Systematic research on the physiological and anatomical characteristics of spinal cord interneurons along with their functional output has evolved for more than one century. Despite significant progress in our understanding of these networks and their role in generating and modulating movement, it has remained a challenge to elucidate the properties of the locomotor rhythm across species. Neurophysiological experimental evidence indicates similarities in the function of interneurons mediating afferent information regarding muscle stretch and loading, being affected by motor axon collaterals and those mediating presynaptic inhibition in animals and humans when their function is assessed at rest. However, significantly different muscle activation profiles are observed during locomotion across species. This difference may potentially be driven by a modified distribution of muscle afferents at multiple segmental levels in humans, resulting in an altered interaction between different classes of spinal interneurons. Further, different classes of spinal interneurons are likely activated or silent to some extent simultaneously in all species. Regardless of these limitations, continuous efforts on the function of spinal interneuronal circuits during mammalian locomotion will assist in delineating the neural mechanisms underlying locomotor control, and help develop novel targeted rehabilitation strategies in cases of impaired bipedal gait in humans. These rehabilitation strategies will include activity-based therapies and targeted neuromodulation of spinal interneuronal circuits via repetitive stimulation delivered to the brain and/or spinal cord.


Argininosuccinate lyase is a potential therapeutic target in breast cancer.
Arginine is a non-essential amino acid that modulates nitric oxide production and cancer homeostasis. In our previous study, we observed that blocking argininosuccinate lyase (ASL) attenuates tumor progression in liver cancer. However, the role of ASL in human breast cancer has been studied to a lesser degree. In the present study, we investigated the effect of targeting ASL in breast cancer. We found that ASL was induced by ER stress and was significantly upregulated in breast cancer tissues compared to that in the corresponding normal tissues. Downregulation of ASL inhibited the growth of breast cancer in vitro and in vivo. The level of cell cycle-related gene, cyclin A2, was reduced and was accompanied by a delay in G2/M transition. ASL shRNA-induced cell inhibition was rescued by exogenous cyclin A2. Furthermore, autophagy was observed in the cells expressing ASL shRNA, and inhibition of autophagy reduced cell growth, indicating that autophagy played a cell survival role in the ASL knockdown cells. Moreover, inhibition of ASL reduced NO content. Introduction of the NO donor partially restored the growth inhibition by ASL shRNA. Thus, the mechanism induced by ASL shRNA which occurred in human breast cancer may be attributed to a decrease in cyclin A2 and NO.


CCP1/Nna1 functions in protein turnover in mouse brain: Implications for cell death in Purkinje cell degeneration mice.
Purkinje cell degeneration (pcd) mice have a mutation within the gene encoding cytosolic carboxypeptidase 1 (CCP1/Nna1), which has homology to metallocarboxypeptidases. To assess the function of CCP1/Nna1, quantitative proteomics and peptidomics approaches were used to compare proteins and peptides in mutant and wild-type mice. Hundreds of peptides derived from cytosolic and mitochondrial proteins are greatly elevated in pcd mouse hypothalamus, amygdala, cortex, prefrontal cortex, and striatum. However, the major proteins detected on 2-D gel electrophoresis were present in mutant and wild-type mouse cortex and hypothalamus at comparable levels, and proteasome activity is normal in these brain regions of pcd mice, suggesting that the increase in cellular peptide levels in the pcd mice is due to reduced degradation of the peptides downstream of the proteasome. Both nondegenerating and degenerating regions of pcd mouse brain, but not wild-type mouse brain, show elevated autophagy, which can be triggered by a decrease in amino acid levels. Taken together with previous studies on CCP1/Nna1, these data suggest that CCP1/Nna1 plays a role in protein turnover by cleaving proteasome-generated peptides into amino acids and that decreased peptide turnover in the pcd mice leads to cell death.


Transcriptional profiling and network analysis of the murine angiotensin II-induced abdominal aortic aneurysm.
We sought to characterize temporal gene expression changes in the murine angiotensin II (ANG II)-ApoE-/- model of abdominal aortic aneurysm (AAA). Aortic ultrasound measurements were obtained over the 28-day time-course. Harvested suprarenal aortic segments were evaluated with whole genome expression profiling at 7, 14, and 28 days using the Agilent Whole Mouse Genome microarray platform and Statistical Analysis of Microarrays at a false discovery rate of <1%. A group of angiotensin-treated mice experienced contained rupture (CR) within 7 days and were analyzed separately. Progressive aortic dilatation occurred throughout the treatment period. However, the numerous early expression differences between ANG II-treated and control were not sustained over time. Ontologic analysis revealed widespread upregulation of inflammatory, immune, and matrix remodeling genes with ANG II treatment, among other pathways such as apoptosis, cell cycling, angiogenesis, and p53 signaling. CR aneurysms displayed significant decreases in TGF-β/BMP-pathway signaling, MAPK signaling, and ErbB signaling genes vs. non-CR/ANG II-treated samples. We also performed literature-based network analysis, extracting numerous highly interconnected genes associated with aneurysm development such as Spp1, Myd88, Adam17 and Lox. 1) ANG II treatment induces extensive early differential expression changes involving abundant signaling pathways in the suprarenal abdominal aorta, particularly wide-ranging increases in inflammatory genes with aneurysm development. 2) These gene expression changes appear to dissipate with time despite continued growth, suggesting that early changes in gene expression influence disease progression in this AAA model, and that the aortic tissue adapts to prolonged ANG II infusion. 3) Network analysis identified nexus genes that may constitute aneurysm biomarkers or therapeutic targets.


The Brain of the Archerfish Toxotes chatareus: A Nissl-Based Neuroanatomical Atlas and Catecholaminergic/Cholinergic Systems.
Over recent years, the seven-spot archerfish (Toxotes chatareus) has emerged as a new model for studies in visual and behavioral neuroscience thanks to its unique hunting strategy. Its natural ability to spit at insects outside of water can be used in the laboratory for well controlled behavioral experiments where the fish is trained to aim at targets on a screen. The need for a documentation of the neuroanatomy of this animal became critical as more research groups use it as a model. Here we present an atlas of adult T. chatareus specimens caught in the wild in South East Asia. The atlas shows representative sections of the brain and specific structures revealed by a classic Nissl staining as well as corresponding schematic drawings. Additional immunostainings for catecholaminergic and cholinergic systems were conducted to corroborate the identification of certain nuclei and the data of a whole brain scanner is available online. We describe the general features of the archerfish brain as well as its specificities, especially for the visual system and compare the neuroanatomy of the archerfish with other teleosts. This atlas of the archerfish brain shows all levels of the neuraxis and intends to provide a solid basis for further neuroscientific research on T. chatareus, in particular electrophysiological studies.


Hospital volume and other risk factors for in-hospital mortality among diverticulitis patients: A nationwide analysis.
Previous studies have found that a higher volume of colorectal surgery was associated with lower mortality rates. While diverticulitis is an increasingly common condition, the effect of hospital volume on outcomes among diverticulitis patients is unknown. To evaluate the relationship between hospital volume and other factors on in-hospital mortality among patients admitted for diverticulitis. Data from the Nationwide Inpatient Sample (years 1993 to 2008) were analyzed to identify 822,865 patients representing 4,108,726 admissions for diverticulitis. Hospitals were divided into quartiles based on the volume of diverticulitis cases admitted over the study period, adjusted for years contributed to the dataset. Mortality according to hospital volume was modelled using logistic regression adjusting for age, sex, race, comorbidities, health care insurance, admission type, calendar year, colectomy, disease severity and clustering. Risk estimates were expressed as adjusted ORs with 95% CIs. Patients at high-volume hospitals were more likely to be admitted emergently, undergo surgical treatment and have more severe disease. In-hospital mortality was higher among the lowest quartile of hospital volume compared with the highest volume (OR 1.13 [95% CI 1.05 to 1.21]). In-hospital mortality was increased among patients admitted emergently (OR 2.58 [95% CI 2.40 to 2.78]) as well as those receiving surgical treatment (OR 3.60 [95% CI 3.42 to 3.78]). Diverticulitis patients admitted to hospitals with a low volume of diverticulitis cases had an increased risk for death compared with those admitted to high-volume centres.


The giraffe (Giraffa camelopardalis) rumen microbiome.
Recent studies have shown that wild ruminants are sources of previously undescribed microorganisms, knowledge of which can improve our understanding of the complex microbial interactions in the foregut. Here, we investigated the microbial community of seven wild-caught giraffes (Giraffa camelopardalis), three of which were fed natural browse and four were fed Boskos pellets, leafy alfalfa hay, and cut savanna browse, by characterizing the 16S rRNA gene diversity using 454 FLX high-throughput sequencing. The microbial community composition varied according to diet, but differed little between the ruminal fluid and solid fraction. The giraffe rumen contained large levels of the phyla of Firmicutes and Bacteroidetes independent of diet, while Prevotella, Succinclasticium, and Methanobrevibacter accounted for the largest abundant taxonomic assigned genera. However, up to 21% of the generated sequences could not been assigned to any known bacterial phyla, and c. 70% not to genus, revealing that the giraffe rumen hosts a variety of previously undescribed bacteria.


Sialic Acid-Imprinted Fluorescent Core-Shell Particles for Selective Labeling of Cell Surface Glycans.
The expression of cell surface glycans terminating with sialic acid (SA) residues has been found to correlate with various disease states there among cancer. We here report a novel strategy for specific fluorescence labeling of such motifs. This is based on sialic acid-imprinted core-shell nanoparticles equipped with nitrobenzoxadiazole (NBD) fluorescent reporter groups allowing environmentally sensitive fluorescence detection at convenient excitation and emission wavelengths. Imprinting was achieved exploiting a hybrid approach combining reversible boronate ester formation between p-vinylphenylboronic acid and SA, the introduction of cationic amine functionalities, and the use of an NBD-appended urea-monomer as a binary hydrogen-bond donor targeting the SA carboxylic acid and OH functionalities. The monomers were grafted from 200 nm RAFT-modified silica core particles using ethylene glycol dimethacrylate (EGDMA) as cross-linker resulting in a shell thickness of ca. 10 nm. The particles displayed strong affinity for SA in methanol/water mixtures (K = 6.6 × 10(5) M(-1) in 2% water, 5.9 × 10(3) M(-1) in 98% water, B(max) ≈ 10 μmol g(-1)), whereas binding of the competitor glucuronic acid (GA) and other monosaccharides was considerably weaker (K (GA) = 1.8 × 10(3) M(-1) in 98% water). In cell imaging experiments, the particles selectively stained different cell lines in correlation with the SA expression level. This was further verified by enzymatic cleavage of SA and by staining using a FITC labeled SA selective lectin.


Continuous infusion of glucose with model assessment: measurement of insulin resistance and beta-cell function in man.
Continuous infusion of glucose with model assessment (CIGMA) is a new method of assessing glucose tolerance, insulin resistance and beta-cell function. It consists of a continuous glucose infusion 5 mg glucose/kg ideal body weight per min for 60 min, with measurement of plasma glucose and insulin concentrations. These are similar to postprandial levels, change slowly, and depend on the dynamic interaction between the insulin produced and its effect on glucose turnover. The concentrations can be interpreted using a mathematical model of glucose and insulin homeostasis to assess insulin resistance and beta-cell function. In 23 subjects (12 normal and 11 with Type 2 (non-insulin-dependent diabetes) the insulin resistance measured by CIGMA correlated with that measured independently by euglycaemic clamp (Rs = 0.87, p less than 0.0001). With normal insulin resistance defined as 1, the median resistance in normal subjects was 1.35 by CIGMA and 1.39 by clamp, and in diabetic patients 4.0 by CIGMA and 3.96 by clamp. In 21 subjects (10 normal and 11 Type 2 diabetic) the beta-cell function measured by CIGMA correlated with steady-state plasma insulin levels during hyperglycaemic clamp at 10 mmol/l (Rs = 0.64, p less than 0.002). The CIGMA coefficient of variability was 21% for resistance and 19% for beta-cell function. CIGMA is a simple, non-labour-intensive method for assessing insulin resistance and beta-cell function in normal and Type 2 diabetic subjects who do not have glycosuria during the test.


Bioactive lipids lysophosphatidic acid and sphingosine 1-phosphate mediate breast cancer cell biological functions through distinct mechanisms.
Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are structurally related bioactive lipids with growth factor-like activities. LPA and S1P are naturally produced in vivo by blood platelets upon platelet aggregation and at least in vitro by fibroblasts, adipocytes, and multiple types of tumor cells. Breast cancer cells respond to LPA and S1P. However, their specific actions on breast cancer cell biological functions remain unclear. We therefore conducted an in vitro side-by-side study of these two lipids on breast cancer cells. LPA mediates human breast cancer MDA-BO2 cell proliferation, migration, and invasion through activation of a G(alpha i)/ERK1/2-dependent signaling pathway, whereas activation of G(alpha i)/PI3K predominates upon S1P stimulation. In MDA-BO2 cells, LPA but not S1P activities were dependent on active type 1 insulin-like growth factor and epithelial growth factor receptors. LPA and S1P act directly on endothelial cells to induce angiogenesis. We demonstrate that LPA and S1P have indirect angiogenic properties as judged by induced secretion of angiogenic factors by breast cancer cells primed with these lysophospholipids. S1P, but not LPA, controlled the expression of VEGF-A by breast cancer cells, while LPA, but not S1P, controlled the expression of GM-CSF, Gro-alpha, MCP-1, and IL-6. According to the secretion of these paracrine osteoclastic factors, LPA, but not S1P, stimulates breast cancer cell-induced osteoclastogenesis. These findings suggest that, in vivo, LPA and S1P can coordinate their action on tumor and surrounding cells to induce breast cancer progression both at primary and bone metastatic sites.


Comparison of transmucosal midazolam with inhalation sedation for dental extractions in children. A randomized, cross-over, clinical trial.
The transmucosal route for conscious sedation in children has been reported widely in the field of medicine, but less so in dental patients. The aim of this study was to evaluate the efficacy and safety profile of midazolam (0.2 mg/kg) administered by the buccal transmucosal route, in comparison with nitrous oxide/oxygen inhalation sedation, for orthodontic extractions in 10-16-year-old dental patients. Each patient attended for two visits and was randomly allocated to receive buccal midazolam (0.2 mg/kg) or nitrous oxide/oxygen titrated to 30%/70% at the first visit, the alternative being used at the second visit. The patients' vital signs, sedation levels and behavioural scores were recorded throughout. Post-operatively, side-effects, recall of the visit and satisfaction levels were recorded via questionnaire. Thirty-six patients, with a mean age of 12.9 years, completed both arms of the trial. The maximum level of sedation was achieved with buccal midazolam in a mean time of 14.42 min, compared with 7.05 min with inhalation sedation. The vital signs with both types of sedation remained within acceptable limits and the reported side-effects were of no clinical significance. Buccal midazolam was found to be acceptable by 65.7%. Only 28.6% of cases preferred this technique, the main disadvantage being the taste of the solution. Buccal midazolam sedation (0.2 mg/kg) seems to be equally as safe and effective as nitrous oxide/oxygen for the extraction of premolar teeth in anxious children. However, further research is required to refine the midazolam vehicle to improve acceptability.


Patellofemoral kinematics during weight-bearing and non-weight-bearing knee extension in persons with lateral subluxation of the patella: a preliminary study.
Single-group, repeated-measures design. To compare patellofemoral joint kinematics during weight-bearing and non-weight-bearing knee extension in persons with lateral subluxation of the patella. The only previous study to quantify differences in patellofemoral joint kinematics during weight-bearing and non-weight-bearing tasks was limited in that static loading conditions were utilized. Differences in patellofemoral joint kinematics between weight-bearing and non-weight-bearing conditions have not been quantified during dynamic movement. Six females with a diagnosis of patellofemoral pain and lateral subluxation of the patella participated. Using kinematic magnetic resonance imaging, axial images of the patellofemoral joint were obtained as subjects extended their knee from 45 degrees to 0 degrees during non-weight-bearing (5% body weight resistance) and weight-bearing (unilateral squat) conditions. Measurements of patellofemoral joint relationships (medial/lateral patellar displacement and patellar tilt), as well as femur and patella rotations relative to an external reference system (ie, the image field of view), were obtained at 3 degrees increments during knee extension. During non-weight-bearing knee extension, lateral patellar displacement was more pronounced than during the weight-bearing condition between 30 degrees and 12 degrees of knee extension, with statistical significance being reached at 27 degrees, 24 degrees, and 21 degrees. No differences in lateral patellar tilt were observed between conditions (P = .065). During the weight-bearing condition, internal femoral rotation was significantly greater than during the non-weight-bearing condition as the knee extended from 18 degrees to 0 degrees. During the non-weight-bearing condition, the amount of lateral patellar rotation was significantly greater than during the weight-bearing condition throughout the range of motion tested. The results of this study demonstrated that lateral patellar displacement was more pronounced during non-weight-bearing knee extension compared to weight-bearing knee extension in persons with lateral patellar subluxation. In addition, the results of this investigation suggest that the patellofemoral joint kinematics during non-weight-bearing could be characterized as the patella rotating on the femur, while the patellofemoral joint kinematics during the weight-bearing condition could be characterized as the femur rotating underneath the patella.


Evaluation of azithromycin, trovafloxacin and grepafloxacin as prophylaxis against experimental murine Brucella melitensis infection.
The prophylactic potential of the azalide azithromycin as well as the fluoroquinolones trovafloxacin and grepafloxacin was assessed for the control of infection with Brucella melitensis in an experimental mouse model, determined by reduction in splenic bacterial burden. Trovafloxacin showed limited protective efficacy when administered 2h following a low-dose B. melitensis challenge, whereas grepafloxacin was ineffective. In comparison, azithromycin provided significant control of infection both following low- and high-dose challenges. Overall, the data confirm the potential utility of azithromycin in the prophylaxis of brucellosis and suggest that neither trovafloxacin nor grepafloxacin would likely be valuable for post-exposure prophylaxis of Brucella infection.


Review of purchases of unapproved medications by the Veterans Health Administration.
Many medications that were marketed prior to 1962 but lack Food and Drug Administration (FDA) approval are prescribed in the United States. Usage patterns of these "unapproved medications" are poorly elucidated, which is concerning due to potential lack of data on safety and efficacy. The purpose of this project was to characterize purchases of unapproved medications within the Veterans Health Administration (VHA) by type, frequency, and cost. VHA purchasing databases were used to create a list of all products with National Drug Codes (NDCs) purchased nationwide in fiscal year 2016 (FY16). This list was compared to FDA databases to identify unapproved prescription medications. For each identified combination of active pharmaceutical ingredient (API) and route of administration ("API/route combination"), numbers of packages purchased and associated costs were added. VHA pharmacy purchasing records contained 3,299 unapproved products with NDCs in FY16. After excluding equipment, nutrition products, compounding ingredients, nonmedication products, and duplicate NDCs, there were 600 unique NDCs associated with 130 distinct API/route combinations. The most commonly acquired product was prescription sodium fluoride dental paste (350,775 packages). The greatest pharmaceutical expenditure was for sodium hyaluronate injection ($24.5 million). Unapproved products accounted for less than 1% of overall VHA pharmacy purchasing in FY16. VHA purchased many unapproved prescription products in FY16 but is taking action to address use of such products in consideration of safety and efficacy data and available alternatives.


Effect of traditional and integrative regimens on quality of life and early renal impairment in elderly patients with isolated systolic hypertension.
To observe the effect of Chinese medical regimen and integrative medical regimen on quality of life and early renal impairment in elderly patients with isolated systolic hypertension (EISH). A multi-center, randomized, double-blinded controlled trail was adopted. A total of 270 cases of EISH were randomly divided into 3 groups: Chinese medicine group (CM), combination group and Western medicine group (WM). The course of treatment was 4 weeks. The clinical blood pressure, integral of quality of life (SF-36 scale), immunoglubin G (IgG), microalbumin (mALB), beta(2)-microglobulin (beta(2)-MG), transferrin (TRF) and N-acetyl-beta'-D-glucosa-minidase (NAG) in urine were determined before and after the treatment. After treatment, systolic blood pressure depressed significantly in each group (P<0.05), and the combination group was superior to CM or WM group in depressing SBP (P<0.05); in each group, integral of quality of life improved in different degree, and combination group was superior to WM group in all 8 dimensions (P<0.05). The level of mALB and beta(2)-MG in urine decreased in all groups (P<0.05), and the combination group was superior to CM group or WM group in decreasing mALB (P<0.05). Chinese medical regimen has affirmative effect in treating EISH patients, and could lower the systolic blood pressure, improve quality of life and early renal impairment of the patients, and integrative medical regimen has superiority on account of cooperation, and deserves further study.


Prominence of slow acetylator phenotype among patients with sulfonamide hypersensitivity reactions.
Delayed hypersensitivity reactions are among the most severe adverse effects of the sulfonamides in current clinical use. These reactions appear to occur because of differences in the metabolism and detoxification of reactive metabolites of the sulfonamides. N-Acetylation is a major metabolic pathway for the sulfonamides. Slow acetylation phenotype might be a risk factor for the development of these reactions. We determined the acetylation phenotype of 21 patients who had suffered hypersensitivity reactions to the sulfonamides. There were 11 females and 10 males in the group, with a mean age of 15 years (age range, 1.8 to 50 years). Their acetylator phenotype was determined by determining the ratio of urinary caffeine metabolites (1-methylxanthine to 5-amino-6-formylmethyluracil after an oral dose of 50 mg caffeine). Nineteen (90%) of the patients were slow acetylators compared to a 55% incidence of slow acetylators in a race-matched control population (p less than 0.008). This suggests that a slow acetylator phenotype is a risk factor for the development of sulfonamide hypersensitivity reactions and provides further support for the role of imbalances in genetically determined pathways of metabolism and detoxification of the sulfonamides in the pathogenesis of these reactions.


Evaluating Digital Health Interventions: Key Questions and Approaches.
Digital health interventions have enormous potential as scalable tools to improve health and healthcare delivery by improving effectiveness, efficiency, accessibility, safety, and personalization. Achieving these improvements requires a cumulative knowledge base to inform development and deployment of digital health interventions. However, evaluations of digital health interventions present special challenges. This paper aims to examine these challenges and outline an evaluation strategy in terms of the research questions needed to appraise such interventions. As they are at the intersection of biomedical, behavioral, computing, and engineering research, methods drawn from all of these disciplines are required. Relevant research questions include defining the problem and the likely benefit of the digital health intervention, which in turn requires establishing the likely reach and uptake of the intervention, the causal model describing how the intervention will achieve its intended benefit, key components, and how they interact with one another, and estimating overall benefit in terms of effectiveness, cost effectiveness, and harms. Although RCTs are important for evaluation of effectiveness and cost effectiveness, they are best undertaken only when: (1) the intervention and its delivery package are stable; (2) these can be implemented with high fidelity; and (3) there is a reasonable likelihood that the overall benefits will be clinically meaningful (improved outcomes or equivalent outcomes at lower cost). Broadening the portfolio of research questions and evaluation methods will help with developing the necessary knowledge base to inform decisions on policy, practice, and research.


Antimalarial mass drug administration in large populations and the evolution of drug resistance.
Mass drug administration (MDA) with antimalarials has been shown to reduce prevalence and interrupt transmission in small populations, in populations with reliable access to antimalarial drugs, and in populations where sustained improvements in diagnosis and treatment are possible. In addition, when MDA is effective it eliminates both drug-resistant parasites and drug-sensitive parasites, which has the long-term benefit of extending the useful therapeutic life of first-line therapies for all populations, not just the focal population where MDA was carried out. However, in order to plan elimination measures effectively, it is necessary to characterize the conditions under which failed MDA could exacerbate resistance. We use an individual-based stochastic model of Plasmodium falciparum transmission to evaluate this risk for MDA using dihydroartemisinin-piperaquine (DHA-PPQ), in populations where access to antimalarial treatments may not be uniformly high and where re-importation of drug-resistant parasites may be common. We find that artemisinin-resistance evolution at the kelch13 locus can be accelerated by MDA when all three of the following conditions are met: (1) strong genetic bottlenecking that falls short of elimination, (2) re-importation of artemisinin-resistant genotypes, and (3) continued selection pressure during routine case management post-MDA. Accelerated resistance levels are not immediate but follow the rebound of malaria cases post-MDA, if this is allowed to occur. Crucially, resistance is driven by the selection pressure during routine case management post-MDA and not the selection pressure exerted during the MDA itself. Second, we find that increasing treatment coverage post-MDA increases the probability of local elimination in low-transmission regions (prevalence < 2%) in scenarios with both low and high levels of drug-resistance importation. This emphasizes the importance of planning for and supporting high coverage of diagnosis and treatment post-MDA.


Control of annual reproductive cycle in the subtropical house sparrow (Passer domesticus): evidence for conservation of photoperiodic control mechanisms in birds.
In many birds, day length (= photoperiod) regulates reproductive cycle. The photoperiodic environment varies between different seasons and latitudes. As a consequence, species at different latitudes may have evolved separate photoperiodic strategies or modified them as per their adaptive need. We studied this using house sparrow as a model since it is found worldwide and is widely investigated. In particular, we examined whether photoperiodism in house sparrows (Passer domesticus) at 27 degrees N, 81 degrees E shared features with those exhibited by its conspecifics at high latitudes. Initial experiment described in the wild and captive conditions the gonad development and molt (only in captives) cycles over a 12-month period. Both male and female sparrows had similar seasonal cycles, linked with annual variations in day length; this suggested that seasonal reproduction in house sparrows was under the photoperiodic control. However, a slower testis and attenuated follicular growth among captives indicated that other (supplementary) factors are also involved in controlling the reproductive cycle. Next experiment examined if sparrows underwent seasonal variations in their response to stimulatory effects of long day lengths. When birds were transferred every month over a period of 1 year to 16 hours light:8 hours darkness (16L:8D) for 17-26 weeks, there was indeed a time-of-year effect on the growth-regression cycle of gonads. The final experiment investigated response of house sparrows to a variety of light-dark (LD) cycles. In the first set, sparrows were exposed for 31 weeks to photoperiods that were close to what they receive in between the period from sunrise to sunset at this latitude: 9L:15D (close to shortest day length in December), 12L:12D (equinox, in March and September) 15L:9D (close to longest day length in June). They underwent testicular growth and regression and molt in 12L and 15L photoperiods, but not in 9L photoperiod. In the second set, sparrows were exposed for 17 weeks to photoperiods with light periods extending to different duration of the daily photosensitivity rhythm (e.g. 2L:22D, 6L:18D, 10L:14D, 14L:10D, 18L:6D and 22L:2D). Interestingly, a slow and small testicular response occurred under 2L and 10L photoperiods; 6L:18D was non-inductive. On the other hand, 14L, 18L and 22L photoperiods produced testicular growth and subsequent regression response as is typical of a long day photostimulation. Subtropical house sparrows exhibit photoperiodic responses similar to that is reported for its population living at high latitudes. This may suggest the conservation of the photoperiodic control mechanisms in birds evolved over a long period of time, as a physiological strategy in a temporally changing environment ensuring reproduction at the best suited time of the year.


Paired-pulse transcranial magnetic stimulation reveals probability-dependent changes in functional connectivity between right inferior frontal cortex and primary motor cortex during go/no-go performance.
The functional role of the right inferior frontal cortex (rIFC) in mediating human behavior is the subject of ongoing debate. Activation of the rIFC has been associated with both response inhibition and with signaling action adaptation demands resulting from unpredicted events. The goal of this study is to investigate the role of rIFC by combining a go/no-go paradigm with paired-pulse transcranial magnetic stimulation (ppTMS) over rIFC and the primary motor cortex (M1) to probe the functional connectivity between these brain areas. Participants performed a go/no-go task with 20% or 80% of the trials requiring response inhibition (no-go trials) in a classic and a reversed version of the task, respectively. Responses were slower to infrequent compared to frequent go trials, while commission errors were more prevalent to infrequent compared to frequent no-go trials. We hypothesized that if rIFC is involved primarily in response inhibition, then rIFC should exert an inhibitory influence over M1 on no-go (inhibition) trials regardless of no-go probability. If, by contrast, rIFC has a role on unexpected trials other than just response inhibition then rIFC should influence M1 on infrequent trials regardless of response demands. We observed that rIFC suppressed M1 excitability during frequent no-go trials, but not during infrequent no-go trials, suggesting that the role of rIFC in response inhibition is context dependent rather than generic. Importantly, rIFC was found to facilitate M1 excitability on all low frequent trials, irrespective of whether the infrequent event involved response inhibition, a finding more in line with a predictive coding framework of cognitive control.


Modeling salt-dependent proton binding by organic soils with the NICA-Donnan and Stockholm humic models.
Models are available for simulations of proton dissociation and cation binding by natural organic matter; two examples are the NICA-Donnan and Stockholm Humic (SHM) models. To model proton and metal binding, it is necessary to properly account for the ionic strength dependence of proton dissociation. In previous applications of the models for soils itwas assumed that the electrostatic interactions for solid-phase humic substances were the same as in solution; this assumption was recently challenged. Therefore, we reanalyzed previously published acid-base titrations of acid-washed Sphagnum peat, and we produced additional data sets for two Sphagnum peats and two Spodosol Oe horizons. For the soil suspensions, the original NICA-Donnan and SHM models, which were developed for dissolved humic substances, underestimated the observed salt dependence considerably. When a fixed Donnan volume of 1 L kg(-1) for humic substances in the solid phase was used, the NICA-Donnan model fits were much improved. Also for SHM, slight changes produced improved model fits. The models also produced acceptable simulations of the dissolved Ca, Mg, and Cd concentrations, provided that cation selectivitywas introduced. In conclusion, the proposed extensions to the NICA-Donnan and SHM models were shown to predict the salt dependence of solid-phase humic substances more satisfactorily than earlier model versions.


Structural Determinants and Children's Oral Health: A Cross-National Study.
Much research on children's oral health has focused on proximal determinants at the expense of distal (upstream) factors. Yet, such upstream factors-the so-called structural determinants of health-play a crucial role. Children's lives, and in turn their health, are shaped by politics, economic forces, and social and public policies. The aim of this study was to examine the relationship between children's clinical (number of decayed, missing, and filled teeth) and self-reported oral health (oral health-related quality of life) and 4 key structural determinants (governance, macroeconomic policy, public policy, and social policy) as outlined in the World Health Organization's Commission for Social Determinants of Health framework. Secondary data analyses were carried out using subnational epidemiological samples of 8- to 15-y-olds in 11 countries ( N = 6,648): Australia (372), New Zealand (three samples; 352, 202, 429), Brunei (423), Cambodia (423), Hong Kong (542), Malaysia (439), Thailand (261, 506), United Kingdom (88, 374), Germany (1498), Mexico (335), and Brazil (404). The results indicated that the type of political regime, amount of governance (e.g., rule of law, accountability), gross domestic product per capita, employment ratio, income inequality, type of welfare regime, human development index, government expenditure on health, and out-of-pocket (private) health expenditure by citizens were all associated with children's oral health. The structural determinants accounted for between 5% and 21% of the variance in children's oral health quality-of-life scores. These findings bring attention to the upstream or structural determinants as an understudied area but one that could reap huge rewards for public health dentistry research and the oral health inequalities policy agenda.


Promoting public health research in BRICS through a multinational public health prize fund.
This article proposes the establishment of a prize fund to incentivise public health research within the BRICS association, which comprises the five major emerging world economies: Brazil, Russia, India, China and South Africa. This would stimulate cooperative healthcare research within the group and, on the proviso that the benefits of the research are made freely available within the association, would be rewarding for researchers. The results of the research stimulated by the prize would provide beneficial new healthcare technologies, targeting the most vulnerable and needy groups. The proposed fund is consistent with current international patent law and would not only avoid some of the problems associated with the "Health Impact Fund", but also create a new model for healthcare research.


Sarcoidosis vs. Sarcoid-like reactions: The Two Sides of the same Coin?
Differentiating between sarcoidosis as an autonomous disease and sarcoid-like reactions requires considerable efforts. The epithelioid cell granuloma is not equivalent to sarcoidosis because it may be identified in a number of infectious and noninfectious disorders, including neoplastic diseases. At the current state of knowledge, accurate distinction between different causes of epithelioid cell granulomas is in many cases not possible. Despite being characteristic of sarcoidosis and sarcoid-like reactions, the epithelioid cell granuloma is not their synonym, as numerous other causes can give rise to such a type of granulomatous infiltrate. Its etiology should be sought through careful additional investigations, including the genetic signature of both conditions.Sarcoid-like reactions may be grouped generally into several subtypes. The differentiation between each one of them requires a certain combination of diagnostic tests. The major objective of these tests is to exclude or to prove the presence of an infectious, tumoral, or immunogenic antigen on the one hand, and to characterize the genetic profile of the affected patients (for example, sarcoidosis-specific genes) on the other. Only thus may one accurately differentiate between the two pathologic conditions described earlier in the abstract.The clear differentiation between sarcoidosis as a separate disease and sarcoid-like pathologies leads to the more precise clarification of the final diagnosis, which may in turn allow for a more appropriate therapy and improvement in the quality of life of the patients. Equating sarcoid granulomas with sarcoidosis can lead to serious consequences in a number of patients. Sadly enough, after scrutinizing the current available data in the world literature, one cannot find criteria to allow such distinction in a high percentage of the investigated cases.This critical review provides a completely new pathogenetic and diagnostic algorithm, helping in the differentiation between the disease sarcoidosis and the sarcoid-like pathologies with different etiology. An update on the inclusion criteria from the ATS/ERS/WASOG (American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders) statement (which at the current state of knowledge seems to be ineffective) for the diagnosis of sarcoidosis is also suggested.In conclusion, molecular mimicry may be seen as the main pathogenic generator not only of sarcoidosis but also of sarcoid-like reactions. A completely new and exact definition of the notion of or the sarcoidosis disease itself will be possible only after 1. defining the genetic risk for the development of sarcoidosis as an autonomous disease and supplementing the sarcoidosis consensus of ATS/ERS/WASOG from 1999 with this important information, and 2. defining the notion of a sarcoid-like reaction and its subforms.


The influence of alcohol consumption on the risk of vertebral deformity. European Vertebral Osteoporosis Study Group.
The influence of alcohol consumption on the risk of osteoporosis is not well established. The aim of this study was to determine the relationship between frequency of alcohol consumption and the risk of vertebral deformity across different European populations. A population survey method was used. Men and women aged 50 years and over were recruited from population-based sampling frames in 36 centres from 19 European countries. Subjects were invited to attend by letter of invitation for an interviewer-administered questionnaire and lateral spinal radiographs. Vertebral deformity was defined morphometrically using the McCloskey-Kanis method. Data from 14237 individuals were available for this analysis. Alcohol consumption was compared between the 809 men and 884 women with vertebral deformity and the 5905 men and 6639 women without vertebral deformity. The frequency of alcohol intake was greater in men than women. Overall, there was no detectable association between frequency of alcohol intake and vertebral deformity in either men or women. Stratification by age showed that women 65 years and over who took alcohol on more than 5 days per week had a reduced risk of vertebral deformity compared with those taking alcohol less than once per week. This protection was most obvious after adjusting for age, centre, body mass index, smoking, current level of physical activity and previous fractures (odds ratio [OR] = 0.65; 95% confidence intervals [CI] = 0.43, 0.99). There was a smaller and non-significant protective effect amongst men aged 65 years and over and this was most apparent amongst moderately frequent drinkers (1-4 days per week) (OR = 0.81; 95% CI = 0.62, 1.08). There was no association between the occurrence of vertebral deformity and frequency of alcohol consumption in younger men and women. Overall, the effects of the frequency of alcohol consumption on vertebral deformity were modest. In older women, regular consumption on more than 5 days per week is associated with a reduced risk. Further, prospective data are required to confirm these findings. It is also necessary to investigate, in terms of amount of alcohol consumed, at what level the benefits of regular intake are obviated by the increased risks from alcohol excess.


Globalising health informatics: the role of GIScience.
Health systems globally are undergoing significant changes. New systems are emerging in developing countries where there were previously limited healthcare options, existing systems in emerging and developed economies are under significant resource pressures and population dynamics are creating significant pressures for change. As health systems expand and intensify, information quality and timeliness will be central to their sustainability and continuity. Information collection and transfer across diverse systems and international borders already presents a significant challenge for health system operations and logistics. Geographic information science (giscience) has the potential to support and enhance health informatics in the coming decades as health information transfers become increasingly important. In this article we propose a spatially enabled approach to support and increasingly globalised health informatics environment. In a world where populations are ageing and urbanising and health systems are linked to economic and social policy shifts, knowing where patients, diseases, health care workers and facilities are located becomes central to those systems operational capacities. In this globalising environment, health informatics needs to be spatially enabled informatics.


Who are gynandromorphophilic men? Characterizing men with sexual interest in transgender women.
Gynandromorphophilia (GAMP) is sexual interest in gynandromorphs (GAMs; colloquially, shemales). GAMs possess a combination of male and female physical characteristics. Thus, GAMP presents a challenge to conventional understandings of sexual orientation as sexual attraction to the male v. female form. Speculation about GAMP men has included the ideas that they are homosexual, heterosexual, or especially, bisexual. We compared genital and subjective sexual arousal patterns of GAMP men with those of heterosexual and homosexual men. We also compared these groups on their self-ratings of sexual orientation and sexual interests. GAMP men had arousal patterns similar to those of heterosexual men and different from those of homosexual men. However, compared to heterosexual men, GAMP men were relatively more aroused by GAM erotic stimuli than by female erotic stimuli. GAMP men also scored higher than both heterosexual and homosexual men on a measure of autogynephilia. Results provide clear evidence that GAMP men are not homosexual. They also indicate that GAMP men are especially likely to eroticize the idea of being a woman.


[Weight gain rate in early childhood and overweight in children 5-11 years old in Salvador, Bahia State, Brazil].
Overweight children are more prone to become overweight or obese adults. The most effective prevention is intervention in early childhood. We analyzed the association between early weight gain and overweight/obesity in 1,056 children under 11 years of age. Data were collected on lifestyle, sanitation, socioeconomic status, birth weight, and breastfeeding. Weight gain from birth until different age brackets (< 12, > 12 to 18, > 18 to 24, and > 24 to 60 months) was considered a continuous variable in z-scores. Overweight was defined as body mass index (BMI) > +1 z-score, based on 2006 and 2007 World Health Organization (WHO) guidelines. Poisson regression and linear regression were used in the multivariate statistical analysis. Weight gain rate was associated with BMI, and overweight or obesity in the 5-11-year age bracket increased twofold for each unit increase in the weight gain standard deviation between 24 and 60 months of age (RR = 2.08; 95%CI: 1.87-2.32). For all early childhood age brackets, there was an association between rapid weight gain and subsequent overweight or obesity.


'Life does not make it easy to breast-feed': using the socio-ecological framework to determine social breast-feeding obstacles in a low-income population in Tijuana, Mexico.
Breast-feeding rates reflect sociodemographic discrepancies. In Mexico, exclusive breast-feeding under 6 months of age has deteriorated among the poor, rural and indigenous populations from 1999 to 2012. Our objective of the present study was to identify the main social obstacles to breast-feeding in a low-income population in Tijuana, Mexico. Qualitative study using a socio-ecological framework for data collection. Low-income communities in Tijuana, Mexico. Mothers (n 66), fathers (n 11), grandparents (n 27) and key informants (n 25). One hundred and twenty-nine individuals participated in the study: six focus groups (n 53) and fifty-one interviews among mothers, fathers and grandparents; and twenty-five interviews among key informants. Seven social themes were identified: (i) embarrassment to breast-feed in public; (ii) migrant experience; (iii) women's role in society; (iv) association of formula with higher social status; (v) marketing by the infant food industry; (vi) perception of a non-breast-feeding culture; and (vii) lack of breast-feeding social programmes. Socio-structural factors influence infant feeding practices in low-income communities in Tijuana. We hypothesize that messages emphasizing Mexican traditions along with modern healthy practices could help to re-establish and normalize a breast-feeding culture in this population. The target audience for these messages should not be limited to mothers but also include family, health-care providers, the work environment and society as a whole.


Behçet's syndrome: a critical digest of the 2012-2013 literature.
Recent work on the epidemiology of Behçet's syndrome confirm the previous contention that the prevalence increases from North to South and that the disease follows a more severe course in patients with an early age of onset, also when specifically studied in patients with eye and gastrointestinal involvement. Imputation analyses of genome wide association studies revealed new associations such as ERAP-1, CCR1-CCR3, KLRC4 and STAT4. Further work suggested that the BS associated variant of STAT4 is not related to the previously reported one associated with autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. The prognosis of eye involvement seems to have improved over the last decade with better visual acuity and less frequent severe complications in patients reported in the 2000s compared to the 1990s. Immunosuppresssives and corticosteroids were observed to improve the outcome of cardiac involvement in BS. Recurrence and complications were common in these patients when surgery was performed without immunosuppressives. The cognitive dysfunction in BS patients with neurological involvement seemed to be severely impaired and worse than that of multiple sclerosis patients, suggesting a more severe 'frontal'-executive dysfunction. Gastrointestinal involvement seemed to be brought to a remission in the majority of BS within 5 years, with about one fourth of the patients following a relapsing or chronic disease course. TNF-α inhibitors have become standard treatment for patients resistant to conventional immunosuppressives. Switching to another biologic can be effective when the first or even the second biologic agent fails or is stopped due to adverse events.


Fungal factors involved in host immune evasion, modulation and exploitation during infection.
Human and plant pathogenic fungi have a major impact on public health and agriculture. Although these fungi infect very diverse hosts and are often highly adapted to specific host niches, they share surprisingly similar mechanisms that mediate immune evasion, modulation of distinct host targets and exploitation of host nutrients, highlighting that successful strategies have evolved independently among diverse fungal pathogens. These attributes are facilitated by an arsenal of fungal factors. However, not a single molecule, but rather the combined effects of several factors enable these pathogens to establish infection. In this review, we discuss the principles of human and plant fungal pathogenicity mechanisms and discuss recent discoveries made in this field.


Effect of Resourcefulness Training on Symptoms Distress of Patients with Nasopharyngeal Carcinoma.
BACKGROUND Symptom distress is very common in patients with nasopharyngeal carcinoma (NPC) during radiotherapy, seriously affecting their quality of life and impeding the process of rehabilitation. Resourcefulness training can enhance the level of resourcefulness and benefit-finding, palliate symptom distress, and promote disease rehabilitation. However, the effects of resourcefulness training on local complications and benefit-finding in NPC patients during radiotherapy remains poorly understood. MATERIAL AND METHODS Questionnaires and resourcefulness training intervention were used in this study. The relationships among resourcefulness, benefit-finding, and symptom distress of 304 NPC patients were analyzed and the effects of resourcefulness training on NPC patients (N=80) were evaluated during radiotherapy. RESULTS Among the 304 NPC patients, age, educational level, occupation, family monthly income, method of payment of medical expenses, and histological types were significant factors influencing resourcefulness and benefit-finding. The patients' resourcefulness was positively correlated to their benefit-finding; and their distress was negatively correlated to their resourcefulness. After resourcefulness training for 2 months, average scores of the resourcefulness and benefit-finding were significantly increased in the intervention group (N=40) compared to those in the control group (N=40). Average scores of symptom distress were significantly reduced in the 2 groups, but they were reduced more significantly in the intervention group than in the control group. CONCLUSIONS The patients' benefit-finding and symptom distress were correlated with their resourcefulness. Resourcefulness training could enhance the level of resourcefulness and benefit-finding, palliate symptom distress, and promote disease rehabilitation in NPC patients during radiotherapy.


Measuring information-transfer delays.
In complex networks such as gene networks, traffic systems or brain circuits it is important to understand how long it takes for the different parts of the network to effectively influence one another. In the brain, for example, axonal delays between brain areas can amount to several tens of milliseconds, adding an intrinsic component to any timing-based processing of information. Inferring neural interaction delays is thus needed to interpret the information transfer revealed by any analysis of directed interactions across brain structures. However, a robust estimation of interaction delays from neural activity faces several challenges if modeling assumptions on interaction mechanisms are wrong or cannot be made. Here, we propose a robust estimator for neuronal interaction delays rooted in an information-theoretic framework, which allows a model-free exploration of interactions. In particular, we extend transfer entropy to account for delayed source-target interactions, while crucially retaining the conditioning on the embedded target state at the immediately previous time step. We prove that this particular extension is indeed guaranteed to identify interaction delays between two coupled systems and is the only relevant option in keeping with Wiener's principle of causality. We demonstrate the performance of our approach in detecting interaction delays on finite data by numerical simulations of stochastic and deterministic processes, as well as on local field potential recordings. We also show the ability of the extended transfer entropy to detect the presence of multiple delays, as well as feedback loops. While evaluated on neuroscience data, we expect the estimator to be useful in other fields dealing with network dynamics.