Control of cell mobility by cyclic AMP.
Cyclic AMP concentrations have been measured in a number of different cell types under a variety of culture conditions in an attempt to define the relationship between the endogenous concentration of cyclic AMP and cell mobility. In previous work it was shown that agents that increase the intracellular concentration of cyclic AMP can effectively suppress cell movement. In Balb/c 3T3 cells, which have a very low mobility in cellular aggregates, the intracellular concentration of cyclic AMP was elevated only transiently soon after the formation of the three-dimensional cell masses. In contrast, in the highly mobile virally transformed counterpart of Balb/c 3T3 cells, called SVT-2, the concentration of cyclic AMP was relatively low soon after the cell masses were formed, but later rose to a level that was higher than that in Balb/c 3T3 cells. Using NIL B cells, SV40-transformed NIL B cells, and several lines of tumour cells derived from NIL B cells, it was found that the average intracellular concentration of cyclic AMP did not vary significantly from one population of cells to another. Finally, the intracellular concentration of cyclic AMP was measured in chick embryo ventricle cells. The mobility of these cells had previously been found to decrease as embryonic development progressed; furthermore, it had been shown that dibutyryl cyclic AMP plus theophylline produced nearly complete inhibition of their movement in cell masses. In the series of experiments reported here we found that the endogenous concentration of cyclic AMP in aggregates and fragments of chick embryo ventricle cells decreases as development proceeds; these data are consistent with preliminary experiments reported by other investigators. In a separate set of experiments, the intracellular concentration of cyclic AMP was measured in cells that had been cultured in a medium containing 1.2 mM-dibutyryl cyclic AMP plus 1.0 mM-theophylline. This drug treatment has previously been shown to inhibit the movement of cells both in aggregates and in monolayers; it also produces striking effects on cell shape and ultrastructure. In aggregates of chick embryo ventricle cells, treatment with these drugs resulted in increases in the intracellular concentrations of cyclic AMP from approximately 10 picomol/mg protein to approximately 500 picomol/mg protein. In Balb/c 3T3 and SVT-2 cells this treatment increased cyclic AMP concentrations from 3.7 to 160 and from 6.4 to 470 picomol/mg protein, respectively.


Which anaesthesia should be recommended for prostate biopsy?
Although transrectal ultrasound-guided prostatic biopsies are associated with significant discomfort and pain, most urologists do not use any kind of anaesthesia. We therefore compared the efficacy of two local anaesthetics, namely, the rectal administration of lidocaine gel and lidocaine periprostatic infiltration prior to biopsies. Three hundred and fifty-six randomized patients received either 15 mL of 2% lidocaine gel administered intrarectally ten minutes before prostate biopsies in group 1 (180 patients) or 10 mL of 1% lidocaine given under ultrasound guidance in two periprostatic injections of 5 mL, four minutes before the biopsies in group 2 (176 patients). A visual analogue scale (VAS) was used to assess the pain score during anaesthesia (VAS 1), during the biopsies (VAS 2) and 30 minutes after them (VAS 3). Patients receiving lidocaine gel experienced statistically less pain than the lidocaine injection group for mean VAS 1 (0.1 vs 1.4, p < 0.0001) and mean VAS 3 (0.8 vs 1.4, p < 0. 001) but VAS 2 showed no statistically significant difference (2.0 vs 2.1). No major morbidity was noted with either anaesthetic. Rectal administration of lidocaine gel is both safe, simple and effective and results are more satisfactory than with lidocaine periprostatic infiltration.


The effects of beta-glucan on human immune and cancer cells.
Non-prescriptional use of medicinal herbs among cancer patients is common around the world. The alleged anti-cancer effects of most herbal extracts are mainly based on studies derived from in vitro or in vivo animal experiments. The current information suggests that these herbal extracts exert their biological effect either through cytotoxic or immunomodulatory mechanisms. One of the active compounds responsible for the immune effects of herbal products is in the form of complex polysaccharides known as beta-glucans. beta-glucans are ubiquitously found in both bacterial or fungal cell walls and have been implicated in the initiation of anti-microbial immune response. Based on in vitro studies, beta-glucans act on several immune receptors including Dectin-1, complement receptor (CR3) and TLR-2/6 and trigger a group of immune cells including macrophages, neutrophils, monocytes, natural killer cells and dendritic cells. As a consequence, both innate and adaptive response can be modulated by beta-glucans and they can also enhance opsonic and non-opsonic phagocytosis. In animal studies, after oral administration, the specific backbone 1-->3 linear beta-glycosidic chain of beta-glucans cannot be digested. Most beta-glucans enter the proximal small intestine and some are captured by the macrophages. They are internalized and fragmented within the cells, then transported by the macrophages to the marrow and endothelial reticular system. The small beta-glucans fragments are eventually released by the macrophages and taken up by other immune cells leading to various immune responses. However, beta-glucans of different sizes and branching patterns may have significantly variable immune potency. Careful selection of appropriate beta-glucans is essential if we wish to investigate the effects of beta-glucans clinically. So far, no good quality clinical trial data is available on assessing the effectiveness of purified beta-glucans among cancer patients. Future effort should direct at performing well-designed clinical trials to verify the actual clinical efficacy of beta-glucans or beta-glucans containing compounds.


Optical reconfigurable demultiplexer based on Bragg grating assisted ring resonators.
A polarization independent reconfigurable optical demultiplexer with low crosstalk between adjacent channels and high number of potential allocated channels is designed on silicon on insulator technology. On to off state transitions can be implemented by changing the coupling factor or the ring length. Wavelength selective switch units are cascaded to form the demultiplexer. Crosstalks below -30dB with 50GHz channel spacing and losses below 1.5dB in the off state are obtained from simulations. Designs using carrier dispersion effect and power consumption estimations are included.


Effects of manganese and hypoxia on coelomocyte renewal in the echinoderm, Asterias rubens (L.).
Manganese (Mn) is a naturally abundant metal and particularly so in soft-bottom oceanic sediments where it generally occurs bound in a four-valent colloidal state as MnO2. When hypoxic conditions occur in bottom waters, the metal reduces to the bioavailable ion Mn2+ and can reach concentrations known to have immunotoxic effects in the crustacean Nephrops norvegicus, reducing numbers of circulating haemocytes as a consequence. However, we have previously shown that Mn seems to have a contrasting effect on the echinoderm Asterias rubens in which it triggers the proliferation of haematopoietic cells and increases coelomocyte numbers. Since elevated Mn levels mostly co-occur with hypoxia in nature, here we investigated whether hypoxia has a negative effect on haematopoiesis. Proliferation and differentiation of coelomocytes and cells in the coelomic epithelium of A. rubens were compared after 3 days of exposure to realistic levels of Mn, hypoxia or a combination of these two parameters. We can confirm that Mn elevated numbers of coelomocytes and increased proliferation of epithelial cells, but hypoxia did not affect these levels. However, hypoxia did affect differentiation of these cells as judged by investigating the expression of a Runt domain transcription factor, which was also cloned and sequenced. Through comparative quantification using a real time PCR technique, we found that exposure to hypoxia had a clearly stimulating effect on mRNA expression of Runt gene in both coelomocytes and epithelial cells. These results indicate that during hypoxic conditions the composition of coelomocyte sub-populations changed.


Improving therapeutic use of homework: suggestions from mental health clinicians.
The majority of mental health clinicians report the use of homework to support their case management, but practitioner surveys indicate that homework is not routinely used. To examine barriers that mental health case managers experience in implementing homework and to identify strategies to promote successful homework administration. One hundred thirty-four surveys were completed by mental health case managers. The survey examined their use of homework for individuals diagnosed with a severe mental health problem. It also asked them to identify barriers to regularly implement homework and describe strategies to promote more regular use of homework. On average, homework was used at 50% of clinical contacts. The primary reasons for not using homework included allocating insufficient time at appointments, perceived client resistance for using homework and concerns that the client was too unwell. Strategies used to overcome these difficulties included prioritising the use of homework and ensuring that homework assignments were achievable. Clinicians are able to identify a range of practical strategies to promote the use of homework. Discussion focuses on the application of the suggested strategies to promote regular use of homework. This includes discussion of possible training approaches to enhance systematic homework administration.


A study on N2O measurement characteristics using photoacoustic spectroscopy (PAS).
N2O, which is emitted mainly from nitrogen decomposition via bacteria, livestock manure, agricultural fertilizer use, fossil fuel combustion and waste incineration, is classified as a substance that causes significant destruction of the ozone layer. The N2O measurement methods for these emission sources may be divided into chromatography, optical, and electrical current measurements. Chromatography has been widely utilized for analyzing N2O. However, up until now, few studies have been conducted on N2O using photoacoustic spectroscopy. Therefore, this study aimed to evaluate performance of photoacoustic spectroscopy in this regard based on laboratory and field test results. The repeatability of photoacoustic spectroscopy was measured at 1.12%, which is lower than the repeatability of 3.0% suggested by the ISO 1564 standard, so, it has shown an excellent repeatability. The detection limit was determined to be 0.025 ppm, and the response time was confirmed to be 3 min and 26 s. The results of comparison between these measurements and GC show that the latter has superior accuracy, but mobility and convenience are superior for PAS. On the contrary, GC has a continuous measurement limitation, but PAS makes it possible to conduct continuous measurements. Therefore, PAS can be extremely useful to confirm the characteristics of N2O emissions and to quantify their amount.


Aortoiliac elongation after endovascular aortic aneurysm repair.
Aortoiliac elongation after endovascular aortic aneurysm repair (EVAR) is not well studied. We sought to assess the long-term morphologic changes after EVAR and identify potentially modifiable factors associated with such a change. An institutional review board-approved retrospective review was conducted for 88 consecutive patients who underwent EVAR at a single academic center from 2003 to 2007 and who also had at least 2 follow-up computed tomography angiograms (CTAs) available for review up to 5 years after surgery. Standardized centerline aortic lengths and diameters were obtained on Aquarius iNtuition 3D workstation (TeraRecon Inc., San Mateo, CA) on postoperative and all-available follow-up CTAs. Relationships to aortic elongation were determined using Wilcoxon rank-sum test or linear regression (Stata version 12.1, College Station, TX). Changes in length over time were determined by mixed-effects analysis (SAS version 9.3, Cary, NC). The study cohort was composed of mostly men (88%), with a mean age of (76 ± 8) and a mean follow-up of 3.2 years (range, 0.4-7.5 years). Fifty-seven percent of patients (n = 50) had devices with suprarenal fixation and 43% (n = 38) had no suprarenal fixation. Significant lengthening was observed over the study period in the aortoiliac segments, but not in the iliofemoral segments. Aortoiliac elongation over time was not associated with sex (P = 0.3), hypertension (P = 0.7), coronary artery disease (P = 0.3), diabetes (P = 0.3), or tobacco use (P = 0.4), but was associated with the use of statins (P = 0.03) and the presence of chronic obstructive pulmonary disease (P = 0.02). Significant aortic lengthening was associated with increased type I endoleaks (P = 0.03) and reinterventions (P = 0.03). Over the study period, 4 different devices were used; Zenith (Cook Medical Inc., Bloomington, IN), Talent (Medtronic, Minneapolis, MN), Aneuryx (Medtronic), and Excluder (W. L. Gore and Associates Inc., Flagstaff, AZ). After adjusting for differences in proximal landing zone, significant differences in aortic lengthening over time were observed by device type (P = 0.02). Significant aortoiliac elongation was observed after EVAR. Such morphologic changes may impact long-term durability of EVAR, warranting further investigation into factors associated with these morphologic changes.


Detection and staging of esophageal cancers.
Technology for detection and staging of esophageal cancer has made significant strides advances in the past 2 years. These advances have led to the enhanced selection of appropriate treatments for esophageal cancer. Cancers that are discovered at an early stage can be treated with endoscopic therapy, whereas advanced cancers are primarily treated with chemotherapy and radiation. Detection of esophageal cancer can be enhanced by two major mechanisms: one is by enhancing the lesion, which has typically been done using vital dyes and the other is by changing the method of imaging of the lesion, which has been accomplished by the use of several technologies including fluorescence and optical coherence tomography. Neither of these techniques has been proven, but some investigators have been able to use them to enhance cancer detection. Similar technologies have been applied to staging esophageal cancer. The optical imaging devices also have the potential to stage mucosa-based malignancy. The use of positron emission tomography has been the most recent development that may have application for advanced cancer. Endoscopic ultrasonography has also been improved in resolution and ability to perform fine needle aspiration. The most significant development for staging early cancers is mucosal resection. Finally, by using mucosal resection techniques, the depth of tumor invasion can be established by histology, which allows gastroenterologists to treat early cancers with greater confidence regarding rates of metastatic disease. Early detection of esophageal cancer can be enhanced by the use of vital dyes for mucosal staining, but the advancement of novel optical diagnostic strategies may be more suitable for clinical use. The primary advantage of these new staging methods is to clearly identify early stage cancer that potentially can be treated without traditional surgical resection techniques. More advanced cancers can be staged with positron emission tomography, but definitive studies demonstrating its role are still lacking.


Carbapenem susceptibility among Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae isolates obtained from patients in intensive care units in Taiwan in 2005, 2007, and 2009.
To investigate the evolutionary trends in non-susceptibility of carbapenems against the isolates of Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae from patients hospitalized in intensive care units (ICUs) of major teaching hospitals throughout Taiwan during 2005-2009, we applied the breakpoints of MICs recommended by Clinical and Laboratory Standards Institute and European Committee on Antimicrobial Susceptibility Testing in 2013. Escalations in imipenem MIC levels for overall E. coli and E. cloacae isolates and extended-spectrum β-lactamase (ESBL)-producing K. pneumoniae isolates were noted during this period. The overall MIC levels against imipenem and meropenem for subgroups of ESBL producers of 3 Enterobacteriaceae species were significantly higher than those of respective overall groups in 2007 and 2009. Compared with meropenem, we found that significant evidence of imipenem MIC creep and evidence of extraordinarily high rates of non-susceptibility to ertapenem among isolates of 3 species in 2009 existed. The prominent rises in rates of ertapenem non-susceptibility for ESBL-producing E. coli and K. pneumoniae during 2005-2009 and rate of ESBL positivity for E. cloacae between 4 years were notably found. Based on our findings, ertapenem should be used cautiously in management of the ICU infections caused by these potentially ESBL-producing Enterobacteriaceae isolates in Taiwan.


Hyperexcitability and reduced low threshold potassium currents in auditory neurons of mice lacking the channel subunit Kv1.1.
A low voltage-activated potassium current, IKL, is found in auditory neuron types that have low excitability and precisely preserve the temporal pattern of activity present in their presynaptic inputs. The gene Kcna1 codes for Kv1.1 potassium channel subunits, which combine in expression systems to produce channel tetramers with properties similar to those of IKL, including sensitivity to dendrotoxin (DTX). Kv1.1 is strongly expressed in neurons with IKL, including auditory neurons of the medial nucleus of the trapezoid body (MNTB). We therefore decided to investigate how the absence of Kv1.1 affected channel properties and function in MNTB neurons from mice lacking Kcna1. We used the whole cell version of the patch clamp technique to record from MNTB neurons in brainstem slices from Kcna1-null (-/-) mice and their wild-type (+/+) and heterozygous (+/-) littermates. There was an IKL in voltage-clamped -/- MNTB neurons, but it was about half the amplitude of the IKL in +/+ neurons, with otherwise similar properties. Consistent with this, -/- MNTB neurons were more excitable than their +/+ counterparts; they fired more than twice as many action potentials (APs) during current steps, and the threshold current amplitude required to generate an AP was roughly halved. +/- MNTB neurons had excitability and IKL amplitudes identical to the +/+ neurons. The IKL remaining in -/- neurons was blocked by DTX, suggesting the underlying channels contained subunits Kv1.2 and/or Kv1.6 (also DTX-sensitive). DTX increased excitability further in the already hyperexcitable -/- MNTB neurons, suggesting that -/- IKL limited excitability despite its reduced amplitude in the absence of Kv1.1 subunits.


A single-nucleotide polymorphism causes smaller grain size and loss of seed shattering during African rice domestication.
Grain size is one of the most important components of grain yield and selecting large seeds has been a main target during plant domestication. Surprisingly, the grain of African cultivated rice (Oryza glaberrima Steud.) typically is smaller than that of its progenitor, Oryza barthii. Here we report the cloning and characterization of a quantitative trait locus, GL4, controlling the grain length on chromosome 4 in African rice, which regulates longitudinal cell elongation of the outer and inner glumes. Interestingly, GL4 also controls the seed shattering phenotype like its orthologue SH4 gene in Asian rice. Our data show that a single-nucleotide polymorphism (SNP) mutation in the GL4 gene resulted in a premature stop codon and led to small seeds and loss of seed shattering during African rice domestication. These results provide new insights into diverse domestication practices in African rice, and also pave the way for enhancing crop yield to meeting the challenge of cereal demand in West Africa.


Prospective biomarker study in newly diagnosed glioblastoma: Cyto-C clinical trial.
Glioblastoma (GBM) has a 5-year survival rate of 3%-5%. GBM treatment includes maximal resection followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ). Cytochrome C oxidase (CcO) is a mitochondrial enzyme involved in the mechanism of resistance to TMZ. In a prior retrospective trial, CcO activity in GBMs inversely correlated with clinical outcome. The current Cyto-C study was designed to prospectively evaluate and validate the prognostic value of tumor CcO activity in patients with newly diagnosed primary GBM, and compared to the known prognostic value of MGMT promoter methylation status. This multi-institutional, blinded, prospective biomarker study enrolled 152 patients with newly diagnosed GBM who were to undergo surgical resection and would be candidates for standard of care. The primary end point was overall survival (OS) time, and the secondary end point was progression-free survival (PFS) time. Tumor CcO activity and MGMT promoter methylation status were assayed in a centralized laboratory. OS and PFS did not differ by high or low tumor CcO activity, and the prognostic validity of MGMT promoter methylation was confirmed. Notably, a planned exploratory analysis suggested that the combination of low CcO activity and MGMT promoter methylation in tumors may be predictive of long-term survival. Tumor CcO activity alone was not confirmed as a prognostic marker in GBM patients. However, the combination of low CcO activity and methylated MGMT promoter may reveal a subgroup of GBM patients with improved long-term survival that warrants further evaluation. Our work also demonstrates the importance of performing large, multi-institutional, prospective studies to validate biomarkers. We also discuss lessons learned in assembling such studies.


Role of protein kinase C in modulation of excitability of CA1 pyramidal neurons in the rat.
Biochemical and in situ hybridization studies demonstrated that the levels of protein kinase C variants were significantly increased in the hippocampus of the experimental models of epilepsy in rats. In addition it has been demonstrated that protein kinase C plays an important role in modulating synaptic transmission in the hippocampus. We examined the effects of activating of protein kinase C on the excitability of CA1 pyramidal neurons and synaptic transmission, using whole-cell current-clamp and extracellular field potential recording techniques. Indolactam V (1 microM) a novel protein kinase C activator, increased the excitability of CA1 neurons acting at both pre- and post-synaptic sites. Indolactam V, acting postsynaptically, significantly reduced the threshold for initiation of action potential from -42+/-3.8 mV to -51+/-3.1 mV and selectively inhibited the slow afterhyperpolarizing potential. Indolactam V also altered the neuronal firing properties in response to prolonged depolarizing pulse by eliminating the spike frequency accommodation. Our data indicate that indolactam V potentiated both amplitudes of Shaffer-collateral stimulation evoked excitatory postsynaptic currents and disynaptically evoked inhibitory evoked postsynaptic currents. However, the potentiation of inhibitory evoked postsynaptic currents amplitudes was not observed after blockade of NMDA and AMPA/kainate currents suggesting it was due to excitatory activity driving inhibitory neurons. The results indicate that the potentiation of pharmacologically isolated excitatory postsynaptic currents (215% of control) and amplitudes of population spikes (290% of control) was due to action of indolactam V presynaptically since the agonist reduced the paired-pulse ratio and the potentiating effect was not blocked by dialyzing the postsynaptic neuron through the recording electrode with a specific protein kinase C inactivator calphostin C. These findings suggest that protein kinase C increases the amplitude of epileptiform activity by causing potentiation of excitatory synaptic transmission, increasing the excitability of postsynaptic neurons and reducing negative feed back provided by slow afterhyperpolarizing potential.


FPGA-based fused smart-sensor for tool-wear area quantitative estimation in CNC machine inserts.
Manufacturing processes are of great relevance nowadays, when there is a constant claim for better productivity with high quality at low cost. The contribution of this work is the development of a fused smart-sensor, based on FPGA to improve the online quantitative estimation of flank-wear area in CNC machine inserts from the information provided by two primary sensors: the monitoring current output of a servoamplifier, and a 3-axis accelerometer. Results from experimentation show that the fusion of both parameters makes it possible to obtain three times better accuracy when compared with the accuracy obtained from current and vibration signals, individually used.


Association of estrogen receptor alpha polymorphisms with symptoms of autism among Chinese Han children.
Autism has a significant sex difference. This implies that the sex hormones might have effect on autism. Estrogens play an important role in early nervous system development and sex differentiation through estrogen receptors in brain. Thus, we tested the hypothesis that estrogen receptor alpha (ESR1) gene affects the pathogenesis of autism and related symptoms. Genotypes of rs11155819 and rs2234693 were determined in boys with autism and normal boys from Chinese Han population. A case-control study was performed to explore the association between polymorphisms in ESR1 gene and autism susceptibility. Assessment tool was used to evaluate the neuropsychological developmental level of autistic children. Finally, we analyzed the association of these single nucleotide polymorphisms (SNPs) with specific symptoms. The results showed no significant differences between cases and controls in the distribution of genotypes and allele frequencies of the two SNPs. However, rs11155819 TT genotype showed a lower neuropsychological development level among autistic children, especially in the aspects of fine motor and adaptation ability (p=0.028; p=0.042). Polymorphisms of ESR1 are relevant to autism symptoms in Chinese Han children.


A new system for determining the causes of stillbirth.
To describe the methods for assigning the cause of death for stillbirths enrolled in the Stillbirth Collaborative Research Network (SCRN). A complete evaluation, including postmortem examination, placental pathology, medical record abstraction, and maternal interview was available on 512 stillbirths among 500 women. These 512 stillbirths were evaluated for cause of death using the definitions outlined in this report. Using the best available evidence, SCRN investigators developed a new methodology to assign the cause of death of stillbirths using clinical, postmortem, and placental pathology data. This new tool, designated the Initial Causes of Fetal Death, incorporates known causes of death and assigns them as possible or probable based on strict diagnostic criteria, derived from published references and pathophysiologic sequences that lead to stillbirth. Six broad categories of causes of death are accounted for, including maternal medical conditions; obstetric complications; maternal or fetal hematologic conditions; fetal genetic, structural, and karyotypic abnormalities; placental infection, fetal infection, or both; and placental pathologic findings. Isolated histologic chorioamnionitis and small for gestational age were not considered causes of death. A new system, Initial Causes of Fetal Death, to assign cause of death in stillbirths was developed by the SCRN investigators for use in this study but has broader applicability. Initial Causes of Fetal Death is a standardized method to assign probable and possible causes of death of stillbirths based on information routinely collected during prenatal care and the clinical evaluation of fetal death.


Spatially and polarization resolved electroluminescence of 1.3-microm InGaAsP semiconductor diode lasers.
A technique for obtaining spatially and polarization resolved maps of the electroluminescence along the length of 1.3-microm InGaAsP semiconductor diode lasers is described. The technique yields valuable information on the mechanical strain and uniformity of material in the active region. Measurements on thirty lasers of two different types-planar buried heterostructure (PBH) and gain guided-are summarized. This technique provides a means of correlating operating characteristics of the lasers with the physical properties of the laser material. Large differences between PBH and gain guided lasers are found. PBH exhibit typically a larger average value of strain and more scattering centers than gain guided lasers. A laser with a bent active region exhibited spectral bistability with respect to temperature. The strain distribution in the active region was observed to change during the first few hours of high temperature aging.


Oxygen consumption and cellular ion transport: evidence for adenosine triphosphate to O2 ratio near 6 in intact cell.
Oxygen (O2) consumption and net K+ uptake were measured simultaneously upon reintroduction of K+ into a K+-depleted suspension of renal tubules. The K+/O2 stoichiometries of 11.8 +/- 0.2 and 8.4 +/- 0.6 were obtained for reduced nicotinamide adenine dinucleotide- and flavoprotein-linked substrates, respectively. These values complement classical K+ to adenosine triphosphate (ATP) and ATP/O2 stoichiometries, thereby demonstrating a remarkably efficient coupling between the processes of Na+- and K+-dependent adenosinetriphosphatase-mediated ion transport and oxidative phosphorylation within the intact cell.


The Influence of Normalization Technique on Between-Muscle Activation during a Back-Squat.
Currently, no gold standard electromyography (EMG) normalizing technique exists when conducting between-muscle comparisons of muscle activity during isotonic resistance training exercises. The aim of this study was to assess if between-muscle activation during the back-squat differed among electromyography (EMG) normalization techniques when normalizing to: (1) 1 repetition maximum (1RM), (2) maximal voluntary isometric contraction (MVIC), and (3) the first of a set of three repetitions (Rep1%) in trained female lifters. Thirteen participants completed a back-squat 1RM, MVIC of the rectus-femoris (RF) and gluteus-maximus (GM), and three repetitions of the back-squat at 80% 1RM. For the 1RM and MVIC normalization techniques, the average of the peak RMS signal of both muscles during the three submaximal reps were normalized to the peak 1RM and MVIC signals. The Rep1% averaged the peak RMS signals of both muscles during the 2nd and 3rd submaximal repetitions normalized to the peak signal during the 1st repetition. The RF-GM between-muscle EMG (ΔEMG) differed among normalization techniques (p < 0.001, ηp 2 = 0.48). Post-hoc pairwise comparisons indicated MVIC normalization elicited different ΔEMG with large effects compared to both 1RM (p = 0.037; d = 1.2) and Rep1% (p = 0.004; d = 1.9) techniques, but the 1RM and Rep1% did not produce different ΔEMG (p = 0.27; d = 0.8). Our findings suggest EMG normalization technique influences the magnitude and direction of between-muscle activation during common lifting exercises, and we recommend normalizing isotonic movements to dynamic normalization methods such as a 1RM or Rep1%.


Surgical management of intractable epilepsy.
Cortical resective surgery (including amygdalohippocampectomy) and corpus callosotomy are the most widely accepted modes of surgical treatment for intractable epilepsy. Between July 1989 and May 1996, 146 surgeries for epilepsy were done at Severance Hospital, Yonsei University. Resective surgery was performed in 126 patients and corpus callosotomy in 20 patients. Of the 126 patients who underwent resective surgery, surgery for the removal of the epileptic lesion (lesionectomy) was performed in 21 patients (16.7%) while 105 patients (83.3%) underwent surgery without a structural lesion. Current surgical therapy for intractable epilepsy requires the precise localization of a resectable zone of epileptogenesis. Unfortunately, finding a localized focus in an extratemporal region is far more difficult than in the temporal lobe. Surgeries for extratemporal lobe epilepsy without lesions have been less successful than surgeries for temporal lobe epilepsy. Although surgery for intractable epilepsy has been increasingly successful, we still need to refine our techniques to further improve the success rate and to reduce complications of surgery such as language and memory impairment.


Levosimendan and mortality after coronary revascularisation: a meta-analysis of randomised controlled trials.
Patients undergoing coronary revascularization often require inotropic support that has been associated with an increased risk for death and morbidity. The purpose of this study was to evaluate the effect of levosimendan versus control on survival after coronary revascularization. A systemic review and meta-analysis of the literature was carried out on published randomized controlled clinical trials that investigated the efficacy of levosimendan compared to other therapy in patients having coronary revascularisaion. The databases searched were Pubmed, EMBASE, the Cochrane Registry of Clinical Trials and the metaRegister of Controlled Trials. Studies that compared levosimendan to any other therapy for coronary revascularisation in adult humans and reported at least one outcome of interest were considered for inclusion. Both percutaneous coronary intervention and cardiac surgery were included. Data extraction was performed independently by two reviewers using predefined criteria. Relevant outcomes included mortality, cardiac index, cardiac enzymes, length of stay and post-procedural atrial fibrillation. The meta-analysis included 729 patients from 17 studies. Levosimendan was associated with a mortality reduction after coronary revascularization, (19/386 in the levosimendan group vs 39/343 in the control arm) odds ratio (OR) 0.40 (95% confidence interval (CI) 0.21 to 0.76, P for overall effect 0.005, P for heterogeneity = 0.33, I2 = 12% with a total of 729 patients. Levosimendan also had a favourable effect on cardiac index (standardised mean difference 1.63, 95% CI 1.43 to 1.83, P for overall effect < 0.00001), length of intensive care stay (random effects model, mean difference - 26.18 hours 95% CI 46.20 to 6.16, P for heterogeneity < 0.00001, I2 = 95%, P for overall effect P = 0.01), reductions in the rate of atrial fibrillation (OR 0.54, 95% CI 0.36 to 0.82, P for effect = 0.004, P for heterogeneity 0.84, I2 = 0% for 465 patients) and troponin I levels group (mean difference -1.59, 95% CI 1.78 to 1.40, P for overall effect < 0.00001, P for heterogeneity < 0.00001, I2 = 95%). Limitations of this analysis are discussed. Levosimendan is associated with a significant improvement in mortality after coronary revascularization. There are also improvements in several secondary endpoints. A suitably powered randomised controlled trial is required to confirm these findings and to address the unresolved questions about the timing and dosing of levosimendan.


Physical Activities of U.S. High School Students--2010 National Youth Physical Activity and Nutrition Survey.
The 2008 Physical Activity Guidelines recommend youth participate in a variety of physical activities; however, few nationally representative studies describe the types and variety of youth activity. This study assessed the most frequently reported types and variety of activities among U.S. high school students, and examined the association between variety and meeting the 2008 Guidelines for aerobic activity (aerobic guideline). We analyzed data on 8628 U.S. high school students in grades 9-12 from the 2010 National Youth Physical Activity and Nutrition Survey. Types of physical activity were assessed by identifying which activities each student reported in the past 7 days. Variety was assessed by the total number of different activities each student reported. Percentage (95% CI) of students who reported engaging in each activity was assessed. Logistic regression was used to examine the association between variety and meeting the aerobic guideline. Walking was the most frequently reported activity among U.S. high school students. On average, students reported participating in 6 different activities. Variety was positively associated with meeting the aerobic guideline. These findings support encouraging youth to participate in many physical activities and may be useful for developing interventions that focus on the most prevalent activities.


An RNA-centric global view of Clostridioides difficile reveals broad activity of Hfq in a clinically important gram-positive bacterium.
The gram-positive human pathogen Clostridioides difficile has emerged as the leading cause of antibiotic-associated diarrhea. However, little is known about the bacterium's transcriptome architecture and mechanisms of posttranscriptional control. Here, we have applied transcription start site and termination mapping to generate a single-nucleotide-resolution RNA map of C. difficile 5' and 3' untranslated regions, operon structures, and noncoding regulators, including 42 sRNAs. Our results indicate functionality of many conserved riboswitches and predict cis-regulatory RNA elements upstream of multidrug resistance (MDR)-type ATP-binding cassette (ABC) transporters and transcriptional regulators. Despite growing evidence for a role of Hfq in RNA-based gene regulation in C. difficile, the functions of Hfq-based posttranscriptional regulatory networks in gram-positive pathogens remain controversial. Using Hfq immunoprecipitation followed by sequencing of bound RNA species (RIP-seq), we identify a large cohort of transcripts bound by Hfq and show that absence of Hfq affects transcript stabilities and steady-state levels. We demonstrate sRNA expression during intestinal colonization by C. difficile and identify infection-related signals impacting its expression. As a proof of concept, we show that the utilization of the abundant intestinal metabolite ethanolamine is regulated by the Hfq-dependent sRNA CDIF630nc_085. Overall, our study lays the foundation for understanding clostridial riboregulation with implications for the infection process and provides evidence for a global role of Hfq in posttranscriptional regulation in a gram-positive bacterium.


Personal health promotion at US medical schools: a quantitative study and qualitative description of deans' and students' perceptions.
Prior literature has shown that physicians with healthy personal habits are more likely to encourage patients to adopt similar habits. However, despite the possibility that promoting medical student health might therefore efficiently improve patient outcomes, no one has studied whether such promotion happens in medical school. We therefore wished to describe both typical and outstanding personal health promotion environments experienced by students in U.S. medical schools. We collected information through four different modalities: a literature review, written surveys of medical school deans and students, student and dean focus groups, and site visits at and interviews with medical schools with reportedly outstanding student health promotion programs. We found strong correlations between deans' and students' perceptions of their schools' health promotion environments, including consistent support of the idea of schools' encouraging healthy student behaviors, with less consistent follow-through by schools on this concept. Though students seemed to have thought little about the relationships between their own personal and clinical health promotion practices, deans felt strongly that faculty members should model healthy behaviors. Deans' support of the relationship between physicians' personal and clinical health practices, and concern about their institutions' acting on this relationship augurs well for the role of student health promotion in the future of medical education. Deans seem to understand their students' health environment, and believe it could and should be improved; if this is acted on, it could create important positive changes in medical education and in disease prevention.


A combined machine-learning and graph-based framework for the segmentation of retinal surfaces in SD-OCT volumes.
Optical coherence tomography is routinely used clinically for the detection and management of ocular diseases as well as in research where the studies may involve animals. This routine use requires that the developed automated segmentation methods not only be accurate and reliable, but also be adaptable to meet new requirements. We have previously proposed the use of a graph-theoretic approach for the automated 3-D segmentation of multiple retinal surfaces in volumetric human SD-OCT scans. The method ensures the global optimality of the set of surfaces with respect to a cost function. Cost functions have thus far been typically designed by hand by domain experts. This difficult and time-consuming task significantly impacts the adaptability of these methods to new models. Here, we describe a framework for the automated machine-learning based design of the cost function utilized by this graph-theoretic method. The impact of the learned components on the final segmentation accuracy are statistically assessed in order to tailor the method to specific applications. This adaptability is demonstrated by utilizing the method to segment seven, ten and five retinal surfaces from SD-OCT scans obtained from humans, mice and canines, respectively. The overall unsigned border position errors observed when using the recommended configuration of the graph-theoretic method was 6.45 ± 1.87 μm, 3.35 ± 0.62 μm and 9.75 ± 3.18 μm for the human, mouse and canine set of images, respectively.


Dielectric study of equimolar acetaminophen-aspirin, acetaminophen-quinidine, and benzoic acid-progesterone molecular alloys in the glass and ultraviscous states and their relevance to solubility and stability.
Equimolar mixtures of acetaminophen-aspirin, acetaminophen-quinidine, and benzoic acid-progesterone have been vitrified and dielectric properties of their glassy and ultraviscous alloys have been studied. For 20 K/min heating rate, their T(g)s are 266, 330, and 263 K, respectively. The relaxation has an asymmetric distribution of times, and the distribution parameter increases with increase in temperature. The dielectric relaxation time varies with T according to the Vogel-Fulcher-Tammann equation, log(10)(tau(0)) = A(VFT) + [B(VFT)/(T - T(0))], where A(VFT), B(VFT), and T(0) are empirical constants. The equilibrium permittivity is highest for the aspirin-acetaminophen and lowest for the benzoic acid-progesterone alloy, indicating a substantial interpharmaceutical hydrogen bonding that makes the alloy more stable against crystallization than the pure components. The benzoic acid-progesterone alloy is thermodynamically the most nonideal. It showed cold crystallization on heating, which is attributed to its relatively greater magnitude of the JG relaxation in relation to its alpha-relaxation. It is argued that the difference between the free energy of an alloy and the pure components would have an effect on the solubility. Studies of solution thermodynamics of a glassy molecular alloy may be useful for optimizing choice of components and composition to form molecular alloys and to impact drug delivery.


Radiographic sensitivity and negative predictive value for acute canine spinal trauma.
The objectives of this study were to establish the sensitivity and negative predictive value of radiography for acute spinal osseous lesions in the canine trauma patient, and to evaluate the interobserver variability in radiographic assessment of the spine in traumatized dogs. This was a retrospective multiple observer blinded study. The study population included 30 canine patients that presented following acute trauma, with clinical signs attributable to the spinal column. Radiography and computed tomography (CT) were performed in all cases. Radiographic interpretation was performed independently by four observers with different experience levels who were blinded to clinical information (other than trauma) and the CT results. CT studies were interpreted by a further three radiologists who formed a consensus opinion on the presence of specific osseous lesions. Using the CT results as a gold standard, the sensitivities and negative predictive values of radiography for specific osseous lesions were calculated. Interobserver agreement was also evaluated. Radiography was found to have only a moderate sensitivity for fractures (72%) and subluxations (77.5%). Low negative predictive values were found for the presence of vertebral canal narrowing (58%) and fracture fragments within the vertebral canal (51%). Interobserver agreement was only moderate to fair for most lesion types. In conclusion, radiography cannot be used to reliably rule out potentially unstable acute vertebral lesions in the canine trauma patient, and further imaging is therefore often indicated in the patient with a high risk of such injuries.


Identification of meningococcal serosubtypes by polymerase chain reaction.
The polymerase chain reaction was used as the basis of a novel typing method for Neisseria meningitidis. Southern hybridization experiments demonstrated that it was possible to identify genes encoding different serological variants of the meningococcal class 1 outer membrane protein by probing with polymerase chain reaction products corresponding to known epitopes. A set of 14 defined variable regions was prepared in bacteriophage M13mp19 by the cloning of polymerase chain reaction products. The phage were dot blotted onto membrane filters, which were used as targets for hybridization of radiolabeled amplified class 1 outer membrane protein genes. Thus, the presence of many different subtype-specific epitopes could be investigated in one experiment. This technique was evaluated with a set of serological reference strains, mainly of serogroup B organisms, and provided an alternative, rapid, and comprehensive typing system that was capable of distinguishing known serosubtypes and also of defining currently untypeable strains independently of sodium dodecyl sulfate-polyacrylamide gel electrophoresis or serological analysis. An additional advantage of this technique was that in the case of an unknown serosubtype (i.e., one that did not hybridize with any of the known samples), the DNA amplified from the original sample could be used to determine the nucleotide sequence of the novel serosubtype and to clone the corresponding variable region into bacteriophage M13. It may be possible to develop this procedure for the diagnostic detection and typing of meningococci directly from clinical samples even when culture is not possible because of antibiotic treatment of an acute case.


Meteorologically Driven Simulations of Dengue Epidemics in San Juan, PR.
Meteorological factors influence dengue virus ecology by modulating vector mosquito population dynamics, viral replication, and transmission. Dynamic modeling techniques can be used to examine how interactions among meteorological variables, vectors and the dengue virus influence transmission. We developed a dengue fever simulation model by coupling a dynamic simulation model for Aedes aegypti, the primary mosquito vector for dengue, with a basic epidemiological Susceptible-Exposed-Infectious-Recovered (SEIR) model. Employing a Monte Carlo approach, we simulated dengue transmission during the period of 2010-2013 in San Juan, PR, where dengue fever is endemic. The results of 9600 simulations using varied model parameters were evaluated by statistical comparison (r2) with surveillance data of dengue cases reported to the Centers for Disease Control and Prevention. To identify the most influential parameters associated with dengue virus transmission for each period the top 1% of best-fit model simulations were retained and compared. Using the top simulations, dengue cases were simulated well for 2010 (r2 = 0.90, p = 0.03), 2011 (r2 = 0.83, p = 0.05), and 2012 (r2 = 0.94, p = 0.01); however, simulations were weaker for 2013 (r2 = 0.25, p = 0.25) and the entire four-year period (r2 = 0.44, p = 0.002). Analysis of parameter values from retained simulations revealed that rain dependent container habitats were more prevalent in best-fitting simulations during the wetter 2010 and 2011 years, while human managed (i.e. manually filled) container habitats were more prevalent in best-fitting simulations during the drier 2012 and 2013 years. The simulations further indicate that rainfall strongly modulates the timing of dengue (e.g., epidemics occurred earlier during rainy years) while temperature modulates the annual number of dengue fever cases. Our results suggest that meteorological factors have a time-variable influence on dengue transmission relative to other important environmental and human factors.


Maternal morbidity and perinatal outcomes among women in rural versus urban areas.
Most studies examining geographic barriers to maternity care in industrialized countries have focused solely on fetal and neonatal outcomes. We examined the association between rural residence and severe maternal morbidity, in addition to perinatal mortality and morbidity. We conducted a retrospective population-based cohort study of all women who gave birth in British Columbia, Canada, between Jan. 1, 2005, and Dec. 31, 2010. We compared maternal mortality and severe morbidity (e.g., eclampsia) and adverse perinatal outcomes (e.g., perinatal death) between women residing in areas with moderate to no metropolitan influence (rural) and those living in metropolitan areas or areas with a strong metropolitan influence (urban). We used logistic regression analysis to obtain adjusted odds ratios (ORs) and 95% confidence intervals (CIs). We found a significant association between death or severe maternal morbidity and rural residence (adjusted OR 1.15, 95% CI 1.03-1.28). In particular, women in rural areas had significantly higher rates of eclampsia (adjusted OR 2.70, 95% CI 1.79-4.08), obstetric embolism (adjusted OR 2.16, 95% CI 1.14-4.07) and uterine rupture or dehiscence (adjusted OR 1.96, 95% CI 1.42-2.72) than women in urban areas. Perinatal mortality did not differ significantly between the study groups. Infants in rural areas were more likely than those in urban areas to have a severe neonatal morbidity (adjusted OR 1.14, 95% CI 1.02-1.29), to be born preterm (adjusted OR 1.06, 95% CI 1.01-1.11), to have an Apgar score of less than 7 at 5 minutes (adjusted OR 1.24, 95% CI 1.13-1.31) and to be large for gestational age (adjusted OR 1.14, 95% CI 1.10-1.19). They were less likely to be small for gestational age (adjusted OR 0.90, 95% CI 0.85-0.95) and to be admitted to an neonatal intensive care unit (NICU) (adjusted OR 0.36, 95% CI 0.33-0.38) compared with infants in urban areas. Compared with women in urban areas, those in rural areas had higher rates of severe maternal morbidity and severe neonatal morbidity, and a lower rate of NICU admission. Maternity care providers in rural regions need to be aware of potentially life-threatening maternal and perinatal complications requiring advanced obstetric and neonatal care.


Prognostic significance of Notch ligands in patients with non-small cell lung cancer.
The Notch signaling pathway is deregulated in numerous solid types of cancer including non-small cell lung cancer (NSCLC). However, the profile of Notch ligand expression remains unclear. Therefore, the present study aimed to determine the profile of Notch ligands in NSCLC patients and to investigate whether quantitative assessment of Notch ligand expression may have prognostic significance in NSCLC patients. The study was performed in 61 pairs of tumor and matched unaffected lung tissue specimens obtained from patients with various stages of NSCLC, which were analyzed by reverse transcription-polymerase chain reaction. The marked expression levels of certain analyzed genes were detected in NSCLC samples and in noncancerous lung samples. Of the five Notch ligands, jagged 1 (Jag1), jagged 2, delta-like protein 1 and delta-like protein 4 were expressed in the majority of tissues, but their expression levels were reduced in NSCLC when compared with noncancerous lung tissue (P<0.001). Delta-like protein 3 expression was consistently low and was observed only in 21/61 tumor tissue samples. Taken together, Notch ligands are expressed in NSCLC. However, the expression level is reduced when compared to noncancerous tissue. Furthermore, the present study revealed that quantitative assessment of Jag1 expression in NSCLC may improve prognostication of patient survival.


Prediction of regulatory modules comprising microRNAs and target genes.
MicroRNAs (miRNAs) are small endogenous RNAs that can play important regulatory roles via the RNA-interference pathway by targeting mRNAs for cleavage or translational repression. We propose a computational method to predict miRNA regulatory modules (MRMs) or groups of miRNAs and target genes that are believed to participate cooperatively in post-transcriptional gene regulation. We tested our method with the human genes and miRNAs, predicting 431 MRMs. We analyze a module with genes: BTG2, WT1, PPM1D, PAK7 and RAB9B, and miRNAs: miR-15a and miR-16. Review of the literature and annotation with Gene Ontology terms reveal that the roles of these genes can indeed be closely related in specific biological processes, such as gene regulation involved in breast, renal and prostate cancers. Furthermore, it has been reported that miR-15a and miR-16 are deleted together in certain types of cancer, suggesting a possible connection between these miRNAs and cancers. Given that most known functionalities of miRNAs are related to negative gene regulation, extending our approach and exploiting the insight thus obtained may provide clues to achieving practical accuracy in the reverse-engineering of gene regulatory networks. A list of predicted modules is available from the authors upon request.


Relationships between Religion and Two Forms of Homonegativity in Europe--A Multilevel Analysis of Effects of Believing, Belonging and Religious Practice.
This paper examines relationships between religion and two forms of homonegativity across 43 European countries using a bivariate response binary logistic multilevel model. The model analyzes effects of religious believing, belonging and practice on two response variables: a) a moral rejection of homosexuality as a practice and b) intolerance toward homosexuals as a group. The findings indicate that both forms of homonegativity are prevalent in Europe. Traditional doctrinal religious believing (belief in a personal God) is positively related to a moral rejection of homosexuality but to a much lesser extent associated with intolerance toward homosexuals as a group. Members of religious denominations are more likely than non-members to reject homosexuality as morally wrong and to reject homosexuals as neighbors. The analysis found significant differences between denominations that are likely context-dependent. Attendance at religious services is positively related to homonegativity in a majority of countries. The findings vary considerably across countries: Religion is more strongly related to homonegativity in Western than in Eastern Europe. In the post-soviet countries homonegativity appears to be largely a secular phenomenon. National contexts of high religiosity, high perceived government corruption, high income inequality and shortcomings in the implementation of gay rights in the countries' legislations are statistically related to higher levels of both moralistic homonegativity and intolerance toward homosexuals as a group.


Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial.
Randomised placebo-controlled trials have shown that daily oral pre-exposure prophylaxis (PrEP) with tenofovir-emtricitabine reduces the risk of HIV infection. However, this benefit could be counteracted by risk compensation in users of PrEP. We did the PROUD study to assess this effect. PROUD is an open-label randomised trial done at 13 sexual health clinics in England. We enrolled HIV-negative gay and other men who have sex with men who had had anal intercourse without a condom in the previous 90 days. Participants were randomly assigned (1:1) to receive daily combined tenofovir disoproxil fumarate (245 mg) and emtricitabine (200 mg) either immediately or after a deferral period of 1 year. Randomisation was done via web-based access to a central computer-generated list with variable block sizes (stratified by clinical site). Follow-up was quarterly. The primary outcomes for the pilot phase were time to accrue 500 participants and retention; secondary outcomes included incident HIV infection during the deferral period, safety, adherence, and risk compensation. The trial is registered with ISRCTN (number ISRCTN94465371) and ClinicalTrials.gov (NCT02065986). We enrolled 544 participants (275 in the immediate group, 269 in the deferred group) between Nov 29, 2012, and April 30, 2014. Based on early evidence of effectiveness, the trial steering committee recommended on Oct 13, 2014, that all deferred participants be offered PrEP. Follow-up for HIV incidence was complete for 243 (94%) of 259 patient-years in the immediate group versus 222 (90%) of 245 patient-years in the deferred group. Three HIV infections occurred in the immediate group (1·2/100 person-years) versus 20 in the deferred group (9·0/100 person-years) despite 174 prescriptions of post-exposure prophylaxis in the deferred group (relative reduction 86%, 90% CI 64-96, p=0·0001; absolute difference 7·8/100 person-years, 90% CI 4·3-11·3). 13 men (90% CI 9-23) in a similar population would need access to 1 year of PrEP to avert one HIV infection. We recorded no serious adverse drug reactions; 28 adverse events, most commonly nausea, headache, and arthralgia, resulted in interruption of PrEp. We detected no difference in the occurrence of sexually transmitted infections, including rectal gonorrhoea and chlamydia, between groups, despite a suggestion of risk compensation among some PrEP recipients. In this high incidence population, daily tenofovir-emtricitabine conferred even higher protection against HIV than in placebo-controlled trials, refuting concerns that effectiveness would be less in a real-world setting. There was no evidence of an increase in other sexually transmitted infections. Our findings strongly support the addition of PrEP to the standard of prevention for men who have sex with men at risk of HIV infection. MRC Clinical Trials Unit at UCL, Public Health England, and Gilead Sciences.


The association between medication for attention-deficit/hyperactivity disorder and cancer.
A study on chromosomal abnormalities has raised concerns that medication with methylphenidate (MPH) for attention-deficit/hyperactivity disorders (ADHD) might increase the risk of cancer. We performed a rigorous test of the association between cancer and MPH and other drugs used for ADHD, based on data from nationwide Danish registers. Data were linked from five registers containing information on a total of 21,186 patients with ADHD, their drug prescription rates, and associated cancer diagnoses between 1994 and 2010. The cohort included subgroups treated with MPH only, amphetamines only, other ADHD-specific drugs only, antidepressants only, antipsychotics only, mixed medication, and a control group of patients with ADHD who had never taken medication. Frequencies of cancer diagnoses in these groups were compared. In addition, hazard risk (HR) ratios for developing cancer, and survival rates in these subgroups, were analyzed. The mean observation time varied between 1.3 and 10.8 years for the various drugs. Cancer rates in the total group amounted to 1.27 per 10 000 person-years before and to 4.33 per 10 000 person-years after onset of treatment. The frequency of cancer was significantly higher (p = 0.05) after than before medication only in the antipsychotics subgroup. Furthermore, for mixed medication, the cancer frequency in a small subgroup was significantly higher (p < 0.05) after onset of medication than in the unmedicated subgroup. The Cox regression analysis indicated that none of the drugs represented risk factors, whereas higher dose (p < 0.001) and older age (p < 0.05) were risk factors for developing cancer. The concern that children taking MPH and other drugs over long periods of time could be at a significant risk of developing cancer is not substantiated by these findings in a large and representative sample, which had been diagnosed and treated over a period of 17 years.


The Costs and Benefits of Employing an Adult with Autism Spectrum Disorder: A Systematic Review.
Despite an ambition from adults with Autism Spectrum Disorder (ASD) to be employed, there are limited opportunities for competitive employment for this group. Employment is not only an entitlement enjoyed by others in society, but employing adults with ASD also has economic benefits by decreasing lost productivity and resource costs for this group. Few studies have explored the cost-benefit ratio for employing adults with ASD and even fewer have taken the viewpoint of the employer, particularly applying this situation to ASD. Until such study occurs, employers may continue to be reluctant to employ adults from this group. This review aimed to examine the costs, benefits and the cost-benefit ratio of employing adults with ASD, from a societal perspective and from the perspective of employers. Eight databases were searched for scientific studies within defined inclusion criteria. These databases included CINAHL Plus, Cochrane Library, Emerald, Ovid Medline, ProQuest, PsycINFO, Scopus and Web of Science. Enhancing the opportunities for adults with ASD to join the workforce is beneficial from a societal perspective, not only from an inclusiveness viewpoint, but also from a strict economic standpoint. Providing supported employment services for adults with ASD does not only cut the cost compared with providing standard care, it also results in better outcomes for adults with ASD. Despite the fact that ASD was the most expensive group to provide vocational rehabilitation services for, adults with ASD have a strong chance of becoming employed once appropriate measures are in place. Hence, rehabilitation services could be considered as a worthwhile investment. The current systematic review uncovered the fact that very few studies have examined the benefits, the costs and the cost-benefit ratio of employing an adult with ASD from the perspective of employers indicating a need for this topic to be further explored.


Real and implied motion at the center of gaze.
Even though the dynamicity of our environment is a given, much of what we know on fixation selection comes from studies of static scene viewing. We performed a direct comparison of fixation selection on static and dynamic visual stimuli and investigated how far identical mechanisms drive these. We recorded eye movements while participants viewed movie clips of natural scenery and static frames taken from the same movies. Both were presented in the same high spatial resolution (1080 × 1920 pixels). The static condition allowed us to check whether local movement features computed from movies are salient even when presented as single frames. We observed that during the first second of viewing, movement and static features are equally salient in both conditions. Furthermore, predictability of fixations based on movement features decreased faster when viewing static frames as compared with viewing movie clips. Yet even during the later portion of static-frame viewing, the predictive value of movement features was still high above chance. Moreover, we demonstrated that, whereas the sets of movement and static features were statistically dependent within these sets, respectively, no dependence was observed between the two sets. Based on these results, we argue that implied motion is predictive of fixation similarly to real movement and that the onset of motion in natural stimuli is more salient than ongoing movement is. The present results allow us to address to what extent and when static image viewing is similar to the perception of a dynamic environment.


Prevalence & susceptibility to fluconazole of Candida species causing vulvovaginitis.
Vulvovaginal candidiasis is an important cause of morbidity in women of reproductive age. This study was carried out to determine the species prevalence and susceptibility pattern to fluconazole of yeasts isolated from the vagina of symptomatic women. This prospective study was conducted in a rural primary health care center of north India from May 2003 to April 2004 and included 601 married, sexually active women (18-49 yr) with the self reported symptoms of vaginal discharge and/or genital itching and/or genital burning. Specific aetiology of the genitourinary symptoms including candidal infection were determined. Specimens from the lateral wall of vagina were subjected to direct wet mount microscopy and fungal culture on Sabouraud's dextrose agar. Susceptibility testing to fluconazole was carried out using broth microdilution method. Yeasts were isolated in 111 (18.5%) women and these consisted of Candida glabrata (56, 50.4%), C. albicans (39, 35.1%), C. tropicalis (12, 10.8%), C. krusei (3, 2.7%) and C. parapsilosis (1, 0.9%). Susceptibility testing carried out on 30 representative isolates (15 C. glabrata, 10 C. albicans, 4 C. tropicalis and 1 C. parapsilosis) revealed that 21 isolates (70%) were susceptible (MIC, < or = 8 microg/ml) to fluconazole while 9 (30%) were susceptible-dose dependent (S-DD, MIC 16-32 microg/ml). Our findings suggest a low prevalence of fluconazole resistance in vaginal candida isolates in our population. However, a high prevalence of non-albicans candida species and increased dose-dependent resistance in these isolates necessitates vigilance since this may warrant a change in the optimal therapy of non-albicans candida vaginitis.


Targeted ablation of p38α MAPK suppresses denervation-induced muscle atrophy.
The loss of skeletal muscle mass is a major cause of falls and fractures in the elderly, leading to compromised independence and a decrease in the quality of life. However, only a few therapeutic interventions leading to marginal clinical benefits in patients with this condition are currently available. Therefore, the demand to further understand the pathology of muscle atrophy and establish a treatment modality for patients with muscle atrophy is significant. p38α mitogen-activated protein kinase (p38α MAPK) is a ubiquitous signaling molecule that is implicated in various cellular functions, including cell proliferation, differentiation, and senescence. In the present study, we generated a mutant line in which p38α MAPK is specifically abrogated in muscle tissues. Compared with the control mice, these mutant mice are significantly resistant to denervation-induced muscle atrophy, suggesting that p38α MAPK positively regulates muscle atrophy. We also identified CAMK2B as a potential downstream target of p38α MAPK and found that the pharmacological inhibition of CAMK2B activity suppresses denervation-induced muscle atrophy. Altogether, our findings identify p38α MAPK as a novel regulator of muscle atrophy and suggest that the suppression of intracellular signaling mediated by p38α MAPK serves as a potential target for the treatment of muscle atrophy.


The role of PEEP in patients with chronic obstructive pulmonary disease during assisted ventilation.
In patients with acute respiratory failure (ARF) due to acute exacerbation of chronic obstructive pulmonary disease (COPD), the intrinsic positive end-expiratory pressure (PEEPi) can significantly increase workload for ventilation. It has been suggested that, in the presence of expiratory flow limitation, application of low levels of PEEP by the ventilator can be used to reduce PEEPi and therefore the magnitude of the inspiratory effort during assisted mechanical ventilation (or pressure support) and weaning. Clearly, pulmonary hyperinflation should not be further enhanced in order not to counteract the beneficial effect of removing PEEPi by decreasing respiratory muscle length and force. This use of PEEP in COPD patients is supported not only by theory, but also by recent experimental work, although sufficient clinical information is not yet available to provide a guideline for titration of the PEEP level. Therefore, application of PEEP in COPD patients requires close monitoring of the end-expiratory lung volume. This can be accomplished, among other noninvasive ways (e.g. the inductive plethysmography), by inspection of flow/volume curves during application of increasing levels of PEEP. The shape of the expiratory limb of the flow/volume curve can also suggest the presence of dynamic hyperinflation and expiratory flow limitation.


Complete genome sequence of Vibrio parahaemolyticus FORC_023 isolated from raw fish storage water.
Vibrio parahaemolyticusis a Gram-negative halophilic bacterium that causes food-borne gastroenteritis in humans who consumeV. parahaemolyticus-contaminated seafood.The FORC_023 strain was isolated from raw fish storage water, containing live fish at a sashimi restaurant. Here, we aimed to sequence and characterize the genome of the FORC_023 strain. The genome of the FORC_023 strain showed two circular chromosomes, which contained 4227 open reading frames (ORFs), 131 tRNA genes and 37 rRNA genes. Although the genome of FORC_023 did not include major virulence genes, such as genes encoding thermostable direct hemolysin (TDH) and TDH-related hemolysin (TRH), it contained genes encoding other hemolysins, secretion systems, iron uptake-related proteins and severalV. parahaemolyticusislands. The highest average nucleotide identity value was obtained between the FORC_023 strain and UCM-V493 (CP007004-6). Comparative genomic analysis of FORC_023 with UCM-V493 revealed that FORC_023 carried an additional genomic region encoding virulence factors, such as repeats-in-toxin and type II secretion factors. Furthermore,in vitrocytotoxicity testing showed that FORC_023 exhibited a high level of cytotoxicity toward INT-407 human epithelial cells. These results suggested that the FORC_023 strain may be a food-borne pathogen.


Neural coding in barrel cortex during whisker-guided locomotion.
Animals seek out relevant information by moving through a dynamic world, but sensory systems are usually studied under highly constrained and passive conditions that may not probe important dimensions of the neural code. Here, we explored neural coding in the barrel cortex of head-fixed mice that tracked walls with their whiskers in tactile virtual reality. Optogenetic manipulations revealed that barrel cortex plays a role in wall-tracking. Closed-loop optogenetic control of layer 4 neurons can substitute for whisker-object contact to guide behavior resembling wall tracking. We measured neural activity using two-photon calcium imaging and extracellular recordings. Neurons were tuned to the distance between the animal snout and the contralateral wall, with monotonic, unimodal, and multimodal tuning curves. This rich representation of object location in the barrel cortex could not be predicted based on simple stimulus-response relationships involving individual whiskers and likely emerges within cortical circuits.


The impact of the 2009/2010 enhancement of cigarette health warning labels in Uruguay: longitudinal findings from the International Tobacco Control (ITC) Uruguay Survey.
Framework Convention on Tobacco Control (FCTC) Article 11 Guidelines recommend that health warning labels (HWLs) should occupy at least 50% of the package, but the tobacco industry claims that increasing the size would not lead to further benefits. This article reports the first population study to examine the impact of increasing HWL size above 50%. We tested the hypothesis that the 2009/2010 enhancement of the HWLs in Uruguay would be associated with higher levels of effectiveness. Data were drawn from a cohort of adult smokers (≥18 years) participating in the International Tobacco Control (ITC) Uruguay Survey. The probability sample cohort was representative of adult smokers in five cities. The surveys included key indicators of HWL effectiveness. Data were collected in 2008/09 (prepolicy: wave 2) and 2010/11 (postpolicy: wave 3). Overall, 1746 smokers participated in the study at wave 2 (n=1379) and wave 3 (n=1411). Following the 2009/2010 HWL changes in Uruguay (from 50% to 80% in size), all indicators of HWL effectiveness increased significantly (noticing HWLs: OR=1.44, p=0.015; reading HWLs: OR=1.42, p=0.002; impact of HWLs on thinking about risks of smoking: OR=1.66, p<0.001; HWLs increasing thinking about quitting: OR=1.76, p<0.001; avoiding looking at the HWLs: OR=2.35, p<0.001; and reports that HWLs stopped smokers from having a cigarette 'many times': OR=3.42, p<0.001). The 2009/2010 changes to HWLs in Uruguay, including a substantial increment in size, led to increases of key HWL indicators, thus supporting the conclusion that enhancing HWLs beyond minimum guideline recommendations can lead to even higher levels of effectiveness.


Resource allocation in NHS dentistry: recognition of societal preferences (RAINDROP): study protocol.
Resources in any healthcare systems are scarce relative to need and therefore choices need to be made which often involve difficult decisions about the best allocation of these resources. One pragmatic and robust tool to aid resource allocation is Programme Budgeting and Marginal Analysis (PBMA), but there is mixed evidence on its uptake and effectiveness. Furthermore, there is also no evidence on the incorporation of the preferences of a large and representative sample of the general public into such a process. The study therefore aims to undertake, evaluate and refine a PBMA process within the exemplar of NHS dentistry in England whilst also using an established methodology (Willingness to Pay (WTP)) to systematically gather views from a representative sample of the public. Stakeholders including service buyers (commissioners), dentists, dental public health representatives and patient representatives will be recruited to participate in a PBMA process involving defining current spend, agreeing criteria to judge services/interventions, defining areas for investment and disinvestment, rating these areas against the criteria and making final recommendations. The process will be refined based on participatory action research principles and evaluated through semi-structured interviews, focus groups and observation of the process by the research team. In parallel a representative sample of English adults will be recruited to complete a series of four surveys including WTP valuations of programmes being considered by the PBMA panel. In addition a methodological experiment comparing two ways of eliciting WTP will be undertaken. The project will allow the PBMA process and particularly the use of WTP within it to be investigated and developed. There will be challenges around engagement with the task by the panel undertaking it and with the outputs by stakeholders but careful relationship building will help to mitigate this. The large volume of data will be managed through careful segmenting of the analysis and the use of the well-established Framework approach to qualitative data analysis. WTP has various potential biases but the elicitation will be carefully designed to minimise these and some methodological investigation will take place.


Selective imaging of positively charged polar and nonpolar lipids by optimizing matrix solution composition.
Previous studies have shown that matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS) is useful for studying the distribution of various small metabolites, particularly lipids. However, in this technique, selective ionization of the target molecules is imperative, particularly when analyzing small molecules. Since the sample clean-up procedures available for the MALDI-IMS of small metabolites are limited, the tissue sample will contain numerous molecular species other than the target molecules. These molecules will compete for ionization resulting in severe ion suppression. Hence, it is necessary to develop and optimize a sample preparation protocol for the target molecules. In this study, through model experiments using reference compounds, we optimized the composition of the matrix solution used for positively charged lipids in terms of the concentration of the organic solvent and presence/absence of alkali metal salts. We demonstrated that a high concentration of organic solvent in the matrix solution favors the preferential detection of lipids over peptides. The presence of alkali metal salts in the matrix solution was favorable for the detection of polar lipids, while a salt-free matrix solution was suitable for the detection of nonpolar lipids. Furthermore, potassium salts added to the matrix solution caused merging of various lipid adducts (adducts with proton, sodium, and potassium) into one single potassiated species. Using the optimized protocols, we selectively analyzed phosphatidylcholine (PC) and triacylglycerol (TG) with different fatty acid compositions in a rat kidney section.


Tool for the Meaningful Consideration of Language Barriers in Qualitative Health Research.
Individuals who experience language barriers are largely excluded as participants from health research, resulting in gaps in knowledge that have implications for the development of equitable policies, tools, and strategies. Drawing on the existing literature and on their collective experience conducting occupational health research in contexts of language barriers, the authors propose a tool to assist qualitative researchers and representatives from funding agencies and ethics review boards with the meaningful consideration of language barriers in research. There remain gaps and debates with respect to the relevant ethical and methodological guidance set forth by funding agencies and institutions and proposed in the scientific literature. This article adds to knowledge in this area by contributing our experiences, observations, and recommendations, including around the issue of conducting research in contexts of more or less linguistic diversity.


Transcranial random-noise stimulation of visual cortex potentiates value-driven attentional capture.
Reward feedback following visual search causes the visual characteristics of targets to become salient and attention-drawing, but little is known about the mechanisms underlying this value-driven capture effect. Here, we use transcranial random noise stimulation (tRNS) to demonstrate that such reward potentiation involves induced plasticity in visual cortex. Human participants completed a feature-search reward-learning task involving the selection of a red or green colored target presented among distractors of various color. Each correct trial garnered reward and the magnitude of reward was determined by the color of the target. Three groups completed this task: two groups received tRNS over either occipital or frontal cortex, and the third group received sham stimulation as a control. In a subsequent test phase of the experiment participants searched for a unique shape presented among colored distractors. During the test phase, no tRNS was applied and no reward was available. However, in some trials a single distractor had color matching that associated with reward during training. Search for the target was impacted by the presence of such reward-associated distractors in the occipital stimulation group, demonstrating that plasticity in visual cortex contributes to value-driven attentional capture.


Effect of 6 weeks wobble board exercises on static and dynamic balance of stroke survivors.
Balance is a complex motor skill and it is frequently disturbed among stroke survivors. Rehabilitation experts are still facing challenges in achieving good stability. The primary aim of this study was to determine the effect of a wobble board exercise program on static and dynamic balance of hemiplegic subjects. Seventeen (17) stroke survivors were randomly selected into two groups. The subjects in the experimental group were trained on wobble board for six weeks while the control group received only the baseline treatment programs. The modified version of the timed balance test was used to assess balance while the foursquare step test was used to assess dynamic balance. Descriptive statistics and Analysis of variance (ANOVA) were used to analyze the data obtained. The result showed that there was significant difference in the static balance (eye closed) (F=7.49, P< 0.05) and dynamic balance (F3.20, P< 0.05) between the groups but there was no significant difference in static balance (eye opened) (F= 1.75, P> 0.05). The study concluded that wobble board exercise improved both static (eye closed) and dynamic balance of stroke survivor used in this study.


The MARINER trial of rivaroxaban after hospital discharge for medical patients at high risk of VTE. Design, rationale, and clinical implications.
Hospital-associated venous thromboembolism (VTE) is a leading cause of premature death and disability worldwide. Evidence-based guidelines recommend that anticoagulant thromboprophylaxis be given to hospitalised medical patients at risk of VTE, but suggest against routine use of thromboprophylaxis beyond the hospital stay. The MARINER study is a randomised, double-blind, placebo-controlled trial to evaluate the efficacy and safety of thromboprophylaxis using rivaroxaban, begun at hospital discharge and continued for 45 days, for preventing symptomatic VTE in high-risk medical patients. Eligible patients are identified using the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE VTE) risk score, combined with a laboratory test, D-dimer. The rivaroxaban regimen is 10 mg once daily for patients with CrCl ≥ 50 ml/min, or 7.5 mg once daily for patients with CrCl ≥ 30 ml/min and < 50 ml/min. The primary efficacy outcome is the composite of symptomatic VTE (lower extremity deep-vein thrombosis and non-fatal pulmonary embolism) and VTE-related death. The principal safety outcome is major bleeding. A blinded clinical events committee adjudicates all suspected outcome events. The sample size is event-driven with an estimated total of 8,000 patients to acquire 161 primary outcome events. Study design features that distinguish MARINER from previous and ongoing thromboprophylaxis trials in medically ill patients are: (i) use of a validated risk assessment model (IMPROVE VTE) and D-dimer determination for identifying eligible patients at high risk of VTE, (ii) randomisation at the time of hospital discharge, (iii) a 45-day treatment period and (iv) restriction of the primary efficacy outcome to symptomatic VTE events.


Lizard and frog prestin: evolutionary insight into functional changes.
The plasma membrane of mammalian cochlear outer hair cells contains prestin, a unique motor protein. Prestin is the fifth member of the solute carrier protein 26A family. Orthologs of prestin are also found in the ear of non-mammalian vertebrates such as zebrafish and chicken. However, these orthologs are electrogenic anion exchangers/transporters with no motor function. Amphibian and reptilian lineages represent phylogenic branches in the evolution of tetrapods and subsequent amniotes. Comparison of the peptide sequences and functional properties of these prestin orthologs offer new insights into prestin evolution. With the recent availability of the lizard and frog genome sequences, we examined amino acid sequence and function of lizard and frog prestins to determine how they are functionally and structurally different from prestins of mammals and other non-mammals. Somatic motility, voltage-dependent nonlinear capacitance (NLC), the two hallmarks of prestin function, and transport capability were measured in transfected human embryonic kidney cells using voltage-clamp and radioisotope techniques. We demonstrated that while the transport capability of lizard and frog prestin was compatible to that of chicken prestin, the NLC of lizard prestin was more robust than that of chicken's and was close to that of platypus. However, unlike platypus prestin which has acquired motor capability, lizard or frog prestin did not demonstrate motor capability. Lizard and frog prestins do not possess the same 11-amino-acid motif that is likely the structural adaptation for motor function in mammals. Thus, lizard and frog prestins appear to be functionally more advanced than that of chicken prestin, although motor capability is not yet acquired.


Left ventricular dysfunction in patients with angina pectoris and normal coronary angiograms.
Left ventricular function was assessed in 201 patients who presented with angina pectoris and who were subsequently found to have completely normal coronary angiograms. Left ventricular angiograms from 187 patients were suitable for analysis of systolic regional wall motion; 121 were found to be normal and 66 had a total of 115 hypokinetic segments. Patients with hypokinesia had a significantly higher left ventricular end systolic volume and a significantly lower left ventricular ejection fraction and exercise capacity than those in whom regional wall motion was normal. Thirty one per cent of patients with normal wall motion and 30% of those with hypokinesia had a resting left ventricular end diastolic pressure greater than 15 mm Hg. There were significantly more smokers in the group with hypokinetic segments. Thus of patients with angina and normal coronary angiograms, 25% had evidence of left ventricular systolic dysfunction, 20% had evidence of diastolic dysfunction, and 11% had evidence of both systolic and diastolic dysfunction. The results suggest that smoking may be associated with left ventricular regional wall motion abnormalities.


Quantum dot conjugated saporin activates microglia and induces selective substantia nigra degeneration.
Parkinson's disease (PD) is characterized by profound microglial driven inflammatory processes and the loss of dopamine neurons of the substantia nigra (SNc). Both microglia and dopamine neurons that are affected in the SNc are particularly vulnerable to environmental toxicants and finding more selective ways of targeting these cell types is of importance. Quantum dots (QDs) might be a useful vehicle for selectively delivering toxicants to microglia and owing to their fluorescent capability, they can be microscopically tracked within the cell. Accordingly, we assessed the impact of QDs alone and QDs conjugated to the ribosomal toxin, saporin, upon SNc microglia and dopamine neurons. We found that intra-SNc infused QDs selectively entered microglia and induced morphological changes consistent with an activated state. QDs conjugated to saporin also caused a significant loss of dopamine neurons and motor coordination (on a rotarod test) deficits, along with an increase in the inflammatory microglial actin regulatory factors, WAVE2. These data suggest that QDs might be a viable route for toxicant delivery and also has an added advantage of being fluorescently visible. Ultimately, we found SNc neurons to be exceptionally vulnerable to QD-saporin and suggest that this could be a novel targeted approach to model PD-like inflammatory pathology.


Small intestinal bacterial overgrowth in patients with inflammatory bowel disease: A case-control study.
Though small intestinal bacterial overgrowth (SIBO) is known in inflammatory bowel disease (IBD), the data on it are scanty and have limitations. Data on IBD patients undergoing glucose hydrogen breath test (GHBT) were retrospectively analyzed to evaluate the frequency and risk factors of SIBO in IBD compared to 66 healthy controls. Patients with IBD (n=86; 45 ulcerative colitis [UC] and 41 Crohn's disease [CD]) more often had SIBO on GHBT than the healthy subjects (16/86 [18.6%] vs. 1/66 [1.5%]; p=0.002). SIBO was commoner among patients with CD than UC (14/41 [34.1%] vs. 2/45 [4.4%]; p=0.001). The frequency of SIBO among UC patients was comparable to healthy subjects (2/45 [4.4%] vs. 1/66 [1.5%]; p=not significant [NS]). Patients with CD than those with UC had higher values of maximum breath hydrogen and a greater area under the curve for breath hydrogen. Other factors associated with SIBO included female gender (11/16 [68.8%] with vs. 21/70 [30%] without SIBO; p=0.003), and having undergone surgery (8/16 [50%] vs. 6/70 [8.6%]; p=0.0002). SIBO patients had lower levels of total serum protein and albumin than those without SIBO (6.2 ± 1.5 g/dL vs. 7.0 ± 0.9 g/dL, respectively; p=0.009 and 3.5 ± 0.9 g/dL vs. 4.0 ± 0.6 g/dL, respectively; p=0.02). CD, female gender, and surgery for IBD tended to be the independent factors associated with SIBO among IBD patients on multivariate analysis. Patients with IBD, particularly CD, female, and those having undergone surgery, have a higher risk of SIBO than the healthy controls.


N-acetyltransferase 2 polymorphisms, tobacco smoking, and breast cancer risk in the breast and prostate cancer cohort consortium.
Common polymorphisms in the N-acetyltransferase 2 gene (NAT2) modify the association between cigarette smoking and bladder cancer and have been hypothesized to determine whether active cigarette smoking increases breast cancer risk. The authors sought to replicate the latter hypothesis in a prospective analysis of 6,900 breast cancer cases and 9,903 matched controls drawn from 6 cohorts (1989-2006) in the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium. Standardized methods were used to genotype the 3 most common polymorphisms that define NAT2 acetylation phenotype (rs1799930, rs1799931, and rs1801280). In unconditional logistic regression analyses, breast cancer risk was higher in women with more than 20 pack-years of active cigarette smoking than in never smokers (odds ratio (OR) = 1.28, 95% confidence interval (CI): 1.17, 1.39), after controlling for established risk factors other than alcohol consumption and physical inactivity. However, associations were similar for the slow (OR = 1.25, 95% CI: 1.11, 1.39) and rapid/intermediate (OR = 1.24, 95% CI: 1.08, 1.42) acetylation phenotypes, with no evidence of interaction (P = 0.87). These results provide some support for the hypothesis that long-term cigarette smoking may be causally associated with breast cancer risk but underscore the need for caution when interpreting sparse data on gene-environment interactions.


Automated detection and measurement of isolated retinal arterioles by a combination of edge enhancement and cost analysis.
Pressure myography studies have played a crucial role in our understanding of vascular physiology and pathophysiology. Such studies depend upon the reliable measurement of changes in the diameter of isolated vessel segments over time. Although several software packages are available to carry out such measurements on small arteries and veins, no such software exists to study smaller vessels (<50 µm in diameter). We provide here a new, freely available open-source algorithm, MyoTracker, to measure and track changes in the diameter of small isolated retinal arterioles. The program has been developed as an ImageJ plug-in and uses a combination of cost analysis and edge enhancement to detect the vessel walls. In tests performed on a dataset of 102 images, automatic measurements were found to be comparable to those of manual ones. The program was also able to track both fast and slow constrictions and dilations during intraluminal pressure changes and following application of several drugs. Variability in automated measurements during analysis of videos and processing times were also investigated and are reported. MyoTracker is a new software to assist during pressure myography experiments on small isolated retinal arterioles. It provides fast and accurate measurements with low levels of noise and works with both individual images and videos. Although the program was developed to work with small arterioles, it is also capable of tracking the walls of other types of microvessels, including venules and capillaries. It also works well with larger arteries, and therefore may provide an alternative to other packages developed for larger vessels when its features are considered advantageous.


Visual Responses in FEF, Unlike V1, Primarily Reflect When the Visual Context Renders a Receptive Field Salient.
When light falls within a neuronal visual receptive field (RF) the resulting activity is referred to as the visual response. Recent work suggests this activity is in response to both the visual stimulation and the abrupt appearance, or salience, of the presentation. Here we present a novel method for distinguishing the two, based on the timing of random and nonrandom presentations. We examined these contributions in frontal eye field (FEF; N = 51) and as a comparison, an early stage in the primary visual cortex (V1; N = 15) of male monkeys (Macaca mulatta). An array of identical stimuli was presented within and outside the neuronal RF while we manipulated salience by varying the time between stimulus presentations. We hypothesized that the rapid presentation would reduce salience (the sudden appearance within the visual field) of a stimulus at any one location, and thus decrease responses driven by salience in the RF. We found that when the interstimulus interval decreased from 500 to 16 ms there was an approximate 79% reduction in the FEF response compared with an estimated 17% decrease in V1. This reduction in FEF response for rapid presentation was evident even when the random sequence preceding a stimulus did not stimulate the RF for 500 ms. The time course of these response changes in FEF suggest that salience is represented much earlier (<100 ms following stimulus onset) than previously estimated. Our results suggest that the contribution of salience dominates at higher levels of the visual system.SIGNIFICANCE STATEMENT The neuronal responses in early visual processing [e.g., primary visual cortex (V1)] reflect primarily the retinal stimulus. Processing in higher visual areas is modulated by a combination of the visual stimulation and contextual factors, such as salience, but identifying these components separately has been difficult. Here we quantified these contributions at a late stage of visual processing [frontal eye field (FEF)] and as a comparison, an early stage in V1. Our results suggest that as visual information continues through higher levels of processing the neural responses are no longer driven primarily by the visual stimulus in the receptive field, but by the broader context that stimulus defines-very different from current views about visual signals in FEF.


Managing the health impacts of drought in Brazil.
Drought is often a hidden risk with the potential to become a silent public health disaster. It is difficult to define precisely when it starts or when it is over, and although it is a climatological event, its impacts depend on other human activities, and are intensified by social vulnerability. In Brazil, half of all natural disaster events are drought related, and they cause half of the impacts in number of affected persons. One large affected area is the semiarid region of Brazil's Northeast, which has historically been affected by drought. Many health and well-being indicators in this region are worse than the rest of the country, based on an analysis of 5565 municipalities using available census data for 1991, 2000 and 2010, which allowed separating the 1133 municipalities affected by drought in order to compare them with the rest of the country. Although great progress has been made in reducing social and economic vulnerability, climate change and the expected changes in the semiarid region in the next few decades call for a review of current programs, particularly in public health, and the planning of new interventions with local communities. This study reviews the literature, analyzes available data and identifies possible actions and actors. The aim is to ensure there will be sufficient and sustainable local adaptive capacity and resilience, for a population already living within the limits of environmental vulnerability.


Village sanitation and child health: Effects and external validity in a randomized field experiment in rural India.
Over a billion people worldwide defecate in the open, with important consequences for early-life health and human capital accumulation in developing countries. We report a cluster randomized controlled trial of a village sanitation intervention conducted in rural Maharashtra, India designed to identify an effect of village sanitation on average child height, an outcome of increasing importance to economists. We find an effect of approximately 0.3 height-for-age standard deviations, which is consistent with observations and hypotheses in economic and health literatures. We further exploit details of the planning and implementation of the experiment to study treatment heterogeneity and external validity.