Development of a Bayesian based adaptive optimisation algorithm for the thermostat settings in agile open plan offices.
The development of a Bayesian based adaptive optimisation algorithm for optimising the indoor thermostat settings in a large agile open plan office is presented. Occupant expressions of thermal dissatisfaction and indoor environmental conditions were collected using densely-placed devices over a period of approximately 19 months. A logistic regression model was employed to identify the optimal settings, using regression coefficients that were estimated using Bayesian inference. A series of optimisation scenarios with and without considering the temporal variations of occupant thermal preferences and the spatial deviation of the indoor conditions was designed and implemented to evaluate their potential benefit in terms of overall occupant thermal dissatisfaction reduction. We developed two metrics that were tailored to quantify the overall reduction of thermal dissatisfaction when using optimal air temperature and PMV thermostat settings. These two metrics represented the average reduction of overall indoor thermal dissatisfaction each time a thermostat value was updated. The results showed that it was useful to consider the temporal variations of occupant thermal preferences to reduce the overall occupant thermal dissatisfaction in the office, and that using the same approach on individual zones within the open plan office would lead to further improvements. The case study demonstrated that the optimal adaptive temperature and PMV thermostat settings led to an overall thermal dissatisfaction reduction of 1.47% and 1.21% in the whole office, respectively (as opposed to 0.25% and 0.19% when single fixed temperature-based and PMV-based thermostat settings were used). By applying the proposed adaptive optimisation algorithm on individual zones in the office, the occupant thermal dissatisfaction reductions ranged from 0.88% to 5.17% for PMV-based settings, and from 1.20% to 5.19% for temperature-based settings.


Adhesion of enteroaggregative Escherichia coli to pediatric intestinal mucosa in vitro.
Organ cultures of small- and large-intestinal mucosa from children were used to examine the interactions of enteroaggregative Escherichia coli (EAEC) with human intestine. Mucosae from patients aged between 3 and 190 months were cultured with five EAEC strains isolated from infants with diarrhea in the United Kingdom and with two well-described prototype EAEC strains, 17-2 and 221. The prototype strains adhered to jejunal, ileal, and colonic mucosae. The wild-type strains also adhered to this tissue but showed a variable pattern of adhesion: two adhered to all intestinal levels, one adhered to jejunum and ileum, one adhered to ileum only, and one adhered to ileum and colon. Adherence was in an aggregative or stacked-brick pattern, resembling that seen on HEp-2 cells. Electron microscopy of infected small intestinal mucosa revealed bacteria in association with a thick mucus layer above an intact enterocyte brush border, which contained extruded cell fragments. This mucus layer was not present on controls. EAEC adherence to colonic mucosa was associated with cytotoxic effects including microvillous vesiculation (but without evidence of an attaching/effacing lesion), enlarged crypt openings, the presence of intercrypt crevices, and increased epithelial cell extrusion. These results demonstrate that in vitro organ culture of intestinal mucosa from children can be used to investigate EAEC pathogenesis in childhood directly. EAEC strains appear able to colonize many regions of the gastrointestinal tract, without overt changes to small intestinal mucosa but with cytotoxic effects on colonic mucosa.


A mechanism of susceptibility to mucormycosis in diabetic ketoacidosis: transferrin and iron availability.
The defect in host defense that makes the diabetic ketoacidotic (DKA) patient susceptible to mucormycosis has not been identified. Sera from 10 DKA patients and three normal volunteers were tested for their capacity to support the in vitro growth of a common etiologic agent of mucormycosis, Rhizopus oryzae. After equilibration with room air none of the normal or DKA sera, each of which was now extremely alkaline, supported growth of R. oryzae. When the sera were placed in a CO2 atmosphere that permitted simulation of the in vivo clinical pH (normal 7.40 and DKA 7.3-6.6), four of seven DKA sera supported profuse fungal growth. No growth occurred in normal serum. The three DKA sera that did not support fungal growth at pH less than or equal to 7.3 contained less iron (x = 13 micrograms/dl) than the four sera that supported profuse fungal growth (x = 69 micrograms/dl). Increasing the iron content of iron-poor DKA serum that did not support R. oryzae growth allowed profuse growth at acidotic conditions but not at pH greater than or equal to 7.4. Simulated acidotic conditions (pH 7.3-6.6) also decreased the iron-binding capacity of normal serum stepwise from 266 micrograms/dl to 0. Our data indicate that acidosis temporarily disrupts the capacity of transferrin to bind iron and suggest that this alteration abolishes an important host defense mechanism that permits growth of R. oryzae.


Synthesis and evaluation of novel 7H-pyrrolo-[2,3-d]pyrimidine derivatives as potential anticancer agents.
Aim: Bladder cancer is a highly recurrent urologic malignancy with limited treatment approaches. Previously, we reported compound 11 is a FGFR3 inhibitor with significant antibladder cancer activity. Materials & methods: In this study, a series of 7H-pyrrolo-[2,3-d]pyrimidine derivatives were synthesized through ring formation and modification of compound 11 for anticancer activity evaluation. Results: Compound 13i is the most effective agent against human RT-112 bladder cancer cells. Notably, 13i strongly inhibits CK1δ without affecting FGFR3 activity. We generated 13i HCl to increase solubility and showed profound cell cycle accumulation at the sub-G1 phase and apoptosis in CK1δ-overexpressed bladder and ovarian cancer cells. Conclusion: These results indicate that compound 13i could be a lead compound for further development of novel anticancer agents.


Structural proteins of equine arteritis virus.
We have recently shown that the genome of equine arteritis virus (EAV) contains seven open reading frames (ORFs). We now present data on the structural proteins of EAV and the assignment of their respective genes. Virions are composed of a 14-kDa nucleocapsid protein (N) and three membrane proteins designated M, GS, and GL. M is an unglycosylated protein of 16 kDa, and GS and GL are N-glycosylated proteins of 25 and 30 to 42 kDa, respectively. The broad size distribution of GL results from heterogeneous N-acetyllactosamine addition since it is susceptible to digestion by endo-beta-galactosidase. Using monospecific antisera as well as an antivirion serum, and by expression of individual ORFs, the genes for the structural proteins were identified: ORF 7 codes for N, ORF 6 for M, ORF 5 for GL, and ORF 2 for GS. With the exception of GS, the proteins are about equally abundant in EAV virions, being present at a molar ratio of 3 (N):2 (M):3 (GL). The GS protein, which is expressed at a level similar to that of M in infected cells, is strikingly underrepresented in virus particles (1 to 2%). Our data justify a distinct taxonomic position for EAV, together with lactate dehydrogenase-elevating virus and simian hemorrhagic fever virus; although coronavirus- and toroviruslike in features of transcription and translation, the virion architecture of EAV is fundamentally different.


Neural integration of top-down spatial and feature-based information in visual search.
Visual search is aided by previous knowledge regarding distinguishing features and probable locations of a sought-after target. However, how the human brain represents and integrates concurrent feature-based and spatial expectancies to guide visual search is currently not well understood. Specifically, it is not clear whether spatial and feature-based search information is initially represented in anatomically segregated regions, nor at which level of processing expectancies regarding target features and locations may be integrated. To address these questions, we independently and parametrically varied the degree of spatial and feature-based (color) cue information concerning the identity of an upcoming visual search target while recording blood oxygenation level-dependent (BOLD) responses in human subjects. Search performance improved with the amount of spatial and feature-based cue information, and cue-related BOLD responses showed that, during preparation for visual search, spatial and feature cue information were represented additively in shared frontal, parietal, and cingulate regions. These data show that representations of spatial and feature-based search information are integrated in source regions of top-down biasing and oculomotor planning before search onset. The purpose of this anticipatory integration could lie with the generation of a "top-down salience map," a search template of primed target locations and features. Our results show that this role may be served by the intraparietal sulcus, which additively integrated a spatially specific activation gain in relation to spatial cue information with a spatially global activation gain in relation to feature cue information.


Fast and non-destructive Raman spectroscopic determination of multi-walled carbon nanotube (MWCNT) contents in MWCNT/polydimethylsiloxane composites.
A versatile Raman spectroscopic method to determine the contents of carbon nanotubes (CNTs) in CNT/polydimethylsiloxane (PDMS) composites is demonstrated, and important issues directly related to the accuracy of the measurement have been investigated. Initially, Raman microscopic mappings over an area of 6.0 × 6.0 mm2 were carried out on CNT/PDMS composites, which revealed the existence of the partial localization of CNTs on a microscopic scale. Therefore, a laser illumination scheme covering a large sample area of 28.3 mm2 was employed to acquire a sample spectrum representative of the whole CNT concentration. The peak area ratio between the CNT and PDMS peaks clearly varied with the CNT concentration, whereas the reproducibility of measurements was degraded for the composites containing more than 3.0 wt% CNTs because of the decreased Raman sampling volume arising from the absorption of laser radiation by the CNTs. The laser penetration depth was semi-quantitatively investigated by observing the spectra of thin-sliced samples collected by positioning a Teflon disk behind the sample, and Monte Carlo simulations were employed to examine the internal photon propagation as well as explain the experimental observation. In summary, the fundamental issues affecting the Raman measurement of the CNT containing polymer matrix have been clearly addressed, and the finding here will be a beneficial basis for successful Raman spectroscopic analysis of different CNT-containing composites.


HPV-DNA testing for cervical cancer precursors: from evidence to clinical practice.
The large amount of literature published over the last two decades on human papillomavirus (HPV)-DNA testing has definitely demonstrated the association between high-risk viral genotypes (hrHPV) and cervical cancer. Moreover, hrHPV-DNA testing has shown excellent performance in several clinical applications, from screening settings to the follow-up of treated patients, compared to conventional cytology or colposcopy options. On the other hand, when a huge number of reports are published on the same subject in a relatively short period of time, with many variations in settings, study designs and applications, the result is often confusion and decreased comprehension by readers. In daily office practice, several different situations (in symptomatic or asymptomatic women) can be positively managed by the correct use of hrHPV-DNA testing. Validated hrHPV-DNA testing and, specifically, the HC2® assay, due to its excellent sensitivity and negative predictive value together with optimal reproducibility, currently represent a powerful tool in the clinician's hands to optimally manage several situations related to HPV infection and the potential development of cervical cancer.


Seasonal variation in human births.
During the first half of this century, the seasonal pattern of births in European countries showed a major peak in the spring and a minor peak in the autumn. In contrast, the pattern in the US was of a minor peak in spring and a major peak in autumn. Over the last 20 years, the pattern in England and Wales has changed to resemble the US pattern, and the same seems to be true of several other European countries. A hypothesis is offered to account for the difference between the European and the US patterns and for the change from one to the other in some countries. The magnitude of seasonality correlates positively with latitude: it is suggested that this is partially consequent on variation in luminosity.


Effect of a selective 5-hydroxytryptamine reuptake inhibitor on brain extracellular noradrenaline: microdialysis studies using paroxetine.
The clinical efficacy of selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (SSRIs) is normally attributed to their ability to increase brain 5-HT function although recent preclinical findings indicate that their selectivity for 5-HT over noradrenaline may be less evident in vivo. The present study investigated the effects of the SSRI, paroxetine, on extracellular levels of noradrenaline. Microdialysis was carried out in the hippocampus of the awake rat. In rats treated twice daily for 14 days with paroxetine (5 mg/kg s.c.), dialysate levels of noradrenaline showed a maintained two-fold increase compared to saline-injected controls. Paroxetine (5 mg/kg s.c.) administered once daily for 14 days did not cause a sustained increase in noradrenaline but levels showed a moderate (+58%) increase in response to a paroxetine challenge. Acute injection of paroxetine (5 mg/kg s.c.) did not elevate noradrenaline levels. Paroxetine (5 mg/kg s.c.) elevated dialysate 5-HT after both acute and repeated (twice daily for 14 days) treatment. The paroxetine-induced increase in noradrenaline (and 5-HT) was positively correlated with plasma concentrations of the drug, which were around the therapeutic range. In comparison to paroxetine, desipramine (10 mg/kg s.c.) caused a four-fold increase in dialysate noradrenaline (but did not change 5-HT) following repeated (once daily for 14 days) treatment and a two-fold increase at for acute treatment. In summary, despite its selectivity as a 5-HT reuptake inhibitor, paroxetine increased extracellular levels of noradrenaline in rat hippocampus following repeated administration. We discuss the possibility that a facilitation of noradrenaline function might be involved in the antidepressant effect of paroxetine, and possibly other SSRIs.


Organizational interventions employing principles of complexity science have improved outcomes for patients with Type II diabetes.
Despite the development of several models of care delivery for patients with chronic illness, consistent improvements in outcomes have not been achieved. These inconsistent results may be less related to the content of the models themselves, but to their underlying conceptualization of clinical settings as linear, predictable systems. The science of complex adaptive systems (CAS), suggests that clinical settings are non-linear, and increasingly has been used as a framework for describing and understanding clinical systems. The purpose of this study is to broaden the conceptualization by examining the relationship between interventions that leverage CAS characteristics in intervention design and implementation, and effectiveness of reported outcomes for patients with Type II diabetes. We conducted a systematic review of the literature on organizational interventions to improve care of Type II diabetes. For each study we recorded measured process and clinical outcomes of diabetic patients. Two independent reviewers gave each study a score that reflected whether organizational interventions reflected one or more characteristics of a complex adaptive system. The effectiveness of the intervention was assessed by standardizing the scoring of the results of each study as 0 (no effect), 0.5 (mixed effect), or 1.0 (effective). Out of 157 potentially eligible studies, 32 met our eligibility criteria. Most studies were felt to utilize at least one CAS characteristic in their intervention designs, and ninety-one percent were scored as either "mixed effect" or "effective." The number of CAS characteristics present in each intervention was associated with effectiveness (p = 0.002). Two individual CAS characteristics were associated with effectiveness: interconnections between participants and co-evolution. The significant association between CAS characteristics and effectiveness of reported outcomes for patients with Type II diabetes suggests that complexity science may provide an effective framework for designing and implementing interventions that lead to improved patient outcomes.


Predictors of vitamin A rich food consumption among women living in households growing orange-fleshed sweetpotatoes in selected regions in Uganda.
Vitamin A deficiency (VAD) has serious public health consequences including morbidity and mortality for populations in low and middle-income countries (LMICs), especially for children under 5 years and pregnant women. LMICs are at greater risk of VAD, in part due to low levels of consumption of vitamin A-rich foods most of which are plant-based, such as orange-fleshed sweet potatoes (OFSP), with lower bioavailability than animal sources of the vitamin A. Food-based approaches such as biofortification of OFSP, including promoting the consumption of vitamin A-rich biofortified staple crops, has been shown to be potentially effective in improving the status of vitamin A and other micronutrients. This study examined vitamin A-rich food consumption and its predictors among women of reproductive age from OFSP-growing households in two regions of Uganda. A cross-sectional survey was conducted among 617 OFSP growing households, focusing on women in the reproductive age group from the northern and eastern regions of Uganda. Households were not receiving any VAD-related intervention at the time of the survey. Quantitative data included vitamin A-rich food consumption, knowledge on vitamin A, and rich food sources dietary intake, using a 7-day food frequency questionnaire. Vitamin A consumption and risk of deficiency were estimated using the Hellen Keller International guide. The majority of women in this study were either pregnant (80%) or lactating (17%). More than 70% of the study population had a weighted vitamin A rich food consumption mean score of <6 days per week, indicating a high risk of VAD. Knowledge about vitamin A [b (SE) = -0.18 (0.50), p < 0.001] was significantly and inversely associated with vitamin A rich food consumption. Components of food insecurity such as availability, affordability, utilization, and changing food preferences may contribute to the unexpected inverse relationship between knowledge and consumption of vitamin A rich foods. Scaling up biofortified food initiatives, including OFSP, can improve consumption of vitamin A rich foods with effective strategies to comprehensively address consumption barriers such as lack of nutrition education, cooking skills, and storage facilities, as well as low production levels and perceived contamination of biofortified foods.


Global and regional left ventricular systolic performance in the in situ ejecting canine heart. Importance of the mitral apparatus.
The importance of the intact mitral apparatus in left ventricular (LV) systolic performance has been indirectly suggested by clinical studies of chordal-preserving mitral valve replacement (MVR) or reconstruction. The importance of the intact mitral apparatus has been clearly demonstrated in isovolumic experimental preparations but has not been demonstrated unequivocally in ejecting hearts. Therefore, this question was assessed independently of load in an in situ, open-chest ejecting canine heart preparation (n = 9). Three orthogonal LV dimensions were measured by sonomicrometry. During MVR with complete chordal preservation, snares were placed around the anterior and posterior papillary muscles. After the hearts were weaned from cardiopulmonary bypass, LV function was assessed by caval occlusion to alter LV preload abruptly. The slopes of the end-systolic--pressure-volume (end-systolic elastance, Ees) and stroke-work--end-diastolic volume (preload-recruitable stroke work, PRSW) relations were used to measure global LV systolic function; similarly, the slopes of the end-systolic--pressure-dimension (regional end-systolic elastance, rEes) and stroke-work--end-diastolic dimension changes in regional LV systolic performance. All chordae were then divided by pulling the snares. Immediate reassessment revealed deterioration of global LV function: Ees declined by 72% (14.1 +/- 11.2 mm Hg/ml [mean +/- SD] vs. 3.9 +/- 3.5 mm Hg/ml, p less than 0.001), and PRSW declined by 39% (129 +/- 37 vs. 79 +/- 29 mm Hg, p = 0.0001). Regional LV function was also adversely affected but somewhat selectively: rEes decreased significantly in all three LV dimensions (p less than or equal to 0.03), but rPRSW decreased significantly (-21%) only in the anteroposterior minor LV axis (89 +/- 19 vs. 70 +/- 15 mm Hg, p = 0.005) and in the septal-lateral axis (-19%, p = NS). These data demonstrate the importance of the intact mitral apparatus on LV systolic performance in ejecting hearts, particularly in the LV regions subtended by the papillary muscles.


3D proteome-wide scale screening and activity evaluation of a new ALKBH5 inhibitor in U87 glioblastoma cell line.
The imidazobenzoxazin-5-thione MV1035, synthesized as a new sodium channel blocker, has been tested on tumoral cells that differ for origin and for expressed NaV pool (U87-MG, H460 and A549). In this paper we focus on the effect of MV1035 in reducing U87 glioblastoma cell line migration and invasiveness. Since the effect of this compound on U87-MG cells seemed not dependent on its sodium channel blocking capability, alternative off-target interaction for MV1035 have been identified using SPILLO-PBSS software. This software performs a structure-based in silico screening on a proteome-wide scale, that allows to identify off-target interactions. Among the top-ranked off-targets of MV1035, we focused on the RNA demethylase ALKBH5 enzyme, known for playing a key role in cancer. In order to prove the effect of MV1035 on ALKBH5 in vitro coincubation of MV1035 and ALKBH5 has been performed demonstrating a consequent increase of N6-methyladenosine (m6A) RNA. To further validate the pathway involving ALKBH5 inhibition by MV1035 in U87-MG reduced migration and invasiveness, we evaluated CD73 as possible downstream protein. CD73 is an extrinsic protein involved in the generation of adenosine and is overexpressed in several tumors including glioblastoma. We have demonstrated that treating U87-MG with MV1035, CD73 protein expression was reduced without altering CD73 transcription. Our results show that MV1035 is able to significantly reduce U87 cell line migration and invasiveness inhibiting ALKBH5, an RNA demethylase that can be considered an interesting target in fighting glioblastoma aggressiveness. Our data encourage to further investigate the MV1035 inhibitory effect on glioblastoma.


Asian infants show preference for own-race but not other-race female faces: the role of infant caregiving arrangements.
Previous studies have reported that 3- to 4-month-olds show a visual preference for faces of the same gender as their primary caregiver (e.g., Quinn et al., 2002). In addition, this gender preference has been observed for own-race faces, but not for other-race faces (Quinn et al., 2008). However, most of the studies of face gender preference have focused on infants at 3-4 months. Development of gender preference in later infancy is still unclear. Moreover, all of these studies were conducted with Caucasian infants from Western countries. It is thus unknown whether a gender preference that is limited to own-race faces can be generalized to infants from other racial groups and different cultures with distinct caregiving practices. The current study investigated the face gender preferences of Asian infants presented with male versus female face pairs from Asian and Caucasian races at 3, 6, and 9 months and the role of caregiving arrangements in eliciting those preferences. The results showed an own-race female face preference in 3- and 6-month-olds, but not in 9-month-olds. Moreover, the downturn in the female face preference correlated with the cumulative male face experience obtained in caregiving practices. In contrast, no gender preference or correlation between gender preference and face experience was found for other-race Caucasian faces at any age. The data indicate that the face gender preference is not specifically rooted in Western cultural caregiving practices. In addition, the race dependency of the effect previously observed for Caucasian infants reared by Caucasian caregivers looking at Caucasian but not Asian faces extends to Asian infants reared by Asian caregivers looking at Asian but not Caucasian faces. The findings also provide additional support for an experiential basis for the gender preference, and in particular suggest that cumulative male face experience plays a role in inducing a downturn in the preference in older infants.


Comorbid diseases as risk factors for incident posttraumatic stress disorder (PTSD) in a large community cohort (KCIS no.PSY4).
Nature disasters and terrorist attacks have occurred globally in recent years. Posttraumatic stress disorder (PTSD) has gained increasing attention, but its incidence and comorbidities in the general population are different from those inside the disaster areas. The present study estimated incident PTSD and comorbid diseases for over a decade in a cohort from a community-based integrated screening program. Factors associated with the incidence of PTSD were analyzed using Cox regression models. PTSD incidence was estimated as 81 per 105 person-years. Incidence was higher in females than in males and one-year increments in age lowered the risk for PTSD by 3%. Adjusting for other factors, cardiovascular heart disease (adjusted hazard ratio (aHR) = 1.45, 95% confidence interval (CI): 1.03-2.04), bipolar disorder (aHR = 1.86, 95% CI: 1.07-3.24) and major depressive disorder (aHR = 7.03, 95% CI: 5.02-9.85) all significantly increased 45%, 86% and 603%, respectively, the risk of developing PTSD. The low rate of people with incident PTSD receiving treatment in this community health screening population implies there is room for improvement in terms of early detection and intervention. Clinical preventive efforts may be made for patients seeking general medical help, especially those with cardiovascular disorders or mood disorders.


Patient predictors of caregiver burden, optimism, and pessimism in rheumatoid arthritis.
The authors of the present study investigated the relationship between rheumatoid arthritis (RA) patients' demographic, medical, and functional status and caregivers' burden, optimism, and pessimism. Subjects were 65 RA patients and their caregivers who were recruited from an outpatient rheumatology clinic. Each caregiver completed the Burden Interview to measure caregiver burden and the Life Orientation Test to measure optimism and pessimism. Each RA patient completed the Arthritis Impact Measurement Scale to measure pain and physical disability as well as a number of cognitive measures to assess two summary psychological cognitive factors labeled self-efficacy expectations and distorted cognitions. These cognitive factors were based on the following commonly used measures in RA research: the Cognitive Errors Questionnaire, the Arthritis Self-Efficacy Scale, the Coping Strategies Questionnaire, and the Pain Beliefs and Perceptions Inventory. Correlational analyses indicated that patients' functional and psychological measures (including poor self-efficacy expectations regarding symptoms) were related to caregiver burden, that patient self-efficacy expectations were related to caregiver optimism, and that patient physical disability was related to caregiver pessimism. Regression analyses revealed that, when competing with other demographic and disease severity variables, the relationships between patient self-efficacy expectations and caregiver burden and caregiver optimism, and patient physical function and caregiver pessimism remained significant. Taken together, these findings suggest that patient expectancies about control over arthritis-related symptoms (including pain) are strongly related to caregiver burden and caregiver optimism and that patient physical status is strongly related to caregiver pessimism.


Megaesophagus in 15 llamas: a retrospective study (1985-1993).
Megaesophagus was diagnosed in 15 llamas on the basis of survey and contrast radiography. Age of onset ranged from 13 months to 9.5 years. Clinical signs varied, with salivation being the most common; regurgitation or dysphagia were noted in only 33% of the cases. Duration of the disorder ranged from 1 week to 5 years. Organophosphate toxicity was the cause of megaesophagus in 1 llama. While most cases were of unknown etiology, the 3 with histological abnormalities included 1 with vagal neuropathy and 2 with a degenerative myopathy of esophageal muscles. The causes in most were undetermined.


In vivo activation of gene transcription via oestrogen response elements by a raloxifene analogue.
Raloxifene is a selective oestrogen receptor modulator with tissue-specific effects. The mechanisms behind the effects of raloxifene are partly unclear, and the aim of the present study was to investigate whether raloxifene can activate the classical oestrogen-signalling pathway in vivo in three known oestrogen-responsive organs, uterus (reproductive organ), bone (non-reproductive organ) and thymus (immune organ). For this purpose, we have used reporter mice with a luciferase gene under control of oestrogen-responsive elements (EREs), enabling detection of in vivo activation of gene transcription via the classical oestrogen pathway. Three-month-old ovariectomized ERE-luciferase mice were treated with the raloxifene analogue (LY117018), oestradiol (OE(2)) or vehicle for 3 weeks. Luciferase activation was measured in bone, uterus and thymus, and compared to bone parameters, and uterus and thymus weights. The raloxifene analogue affected bone mineral density (BMD) to the same extent as OE(2), and both treatments resulted in increased luciferase activity in bone. As expected, OE(2) treatment resulted in increased uterus weight and increased uterine luciferase activity, while the effect of LY117018 on uterus weight and luciferase activity was modest and significantly lower than the effect of OE(2). LY117018 and OE(2) treatment resulted in similar luciferase activation in thymus. However, only OE(2) treatment resulted in thymic atrophy, while no effect on thymus weight was seen after LY117018 treatment. In summary, the raloxifene analogue LY117018 can activate the classical oestrogen pathway in bone, uterus and thymus in vivo, and this activation is associated with BMD and uterus weight, but not thymus weight.


Cooperative carotid artery centerline extraction in MRI.
Centerline extraction of the carotid artery in MRI is important to analyze the artery geometry and to provide input for further processing such as registration and segmentation. The centerline of the artery bifurcation is often extracted by means of two independent minimum cost paths ranging from the common to the internal and the external carotid artery. Often the cost is not well defined at the artery bifurcation, leading to centerline errors. To solve this problem, we developed a method to cooperatively extract both centerlines, where in the cost to extract each centerline, we integrate a constraint region derived from the estimated position of the neighbor centerline. This method avoids that both centerlines follow the same cheapest path after the bifurcation, which is a common error when the paths are extracted independently. We show that this method results in less error compared to extracting them independently: 10 failed centerlines Vs. 3 failures in a data set of 161 arteries with manual annotations. Additionally, we show that the new method improves the non-cooperative approach in 28 cases (p < 0.0001) in a data set of 3,904 arteries.


Carotenoid excited-state properties in photosynthetic purple bacterial reaction centers: effects of the protein environment.
Carotenoid excited-state properties are characterized and compared in reaction centers (RCs) of wild-type (WT) Rhodobacter (Rb.) sphaeroides , and a mutant VR(L157), in which the near-infrared absorbance band associated with the primary electron donor, P, is missing. Energy transfer from the carotenoid (spheroidenone) S(2) and relaxed S(1) excited states to an adjacent monomeric-bacteriochlorophyll is unchanged between WT and the mutant RC samples. However, two other excited states, including a vibrationally hot S(1) state and a state referred to as S*, have distinct properties in the two RCs. The lifetime of the hot S(1) state is significantly shortened in the P-less mutant compared to WT RCs (450 fs vs 800 fs, respectively), and there is a nearly 2-fold decrease in the efficiency of energy transfer from the carotenoid to bacteriochlorophyll in the P-less mutant relative to WT RCs. The fact that both the observed hot S(1) excited state lifetime and the energy transfer efficiency decrease in the mutant implies that the intrinsic lifetime of the hot S(1) state in the P-less mutant has decreased. Interestingly, the S* state is observed only in the P-less mutant, and it is not present in the WT. The change in the hot S(1) lifetime between WT and mutant RCs, and the formation of the S* state only in the mutant, suggests that the carotenoid binding pocket in the P-less mutant is substantially altered. The excited-state behavior of spheroidene in WT RCs isolated from anaerobically grown cells was also characterized and compared with previous studies of spheroidene in the light-harvesting complex II (LH2) from Rb. sphaeroides . Differences in the photophysical properties of spheroidene between WT RCs and LH2 parallel those observed for spheroidenone between WT and VR(L157) mutant RCs. On the basis of the structural information available for both RCs and LH2, it appears that the hot S(1) state and the S* state are sensitive to the structural constraints imposed by protein-carotenoid interactions. Finally, in the VR(L157) mutant, it is possible to directly observe the carotenoid triplet state, likely formed via quenching of the bacteriochlorophyll triplet state. This provides direct experimental evidence for triplet energy transfer to the carotenoid, a process that is integral to the photoprotective role of carotenoids in bacterial RCs.


Proposal for the management of the unexpected difficult pediatric airway.
The incidence of unanticipated difficult or failed airway in otherwise healthy children is rare, and routine airway management in pediatric patients is easy in experienced hands. However, difficulties with airway management in healthy children are not infrequent in nonpediatric anesthetists and are a main reason for pediatric anesthesia-related morbidity and mortality. Clear concepts and strategies are, therefore, required to maintain oxygenation and ventilation in children. Several complicated algorithms for the management of the unanticipated difficult adult and pediatric airway have been proposed, but a simple structured algorithm for the pediatric patient with unanticipated difficult airway is missing. This paper proposes a simple step-wise algorithm for the unexpected difficult pediatric airway based on an adult Difficult Airway Society (DAS) protocol, discusses the role of recently introduced airway devices, and suggests a content of a pediatric airway trolley. It is intended as an easy to memorize and a practical guide for the anesthetist only occasionally involved in pediatric anesthesia care as well as a call to stimulate discussion about the management of the unanticipated difficult pediatric airway.


Isorhamnetin, a 3'-methoxylated flavonol, enhances the lysosomal proteolysis in J774.1 murine macrophages in a TFEB-independent manner.
Lysosome is the principal organelle for the ultimate degradation of cellular macromolecules, which are delivered through endocytosis, phagocytosis, and autophagy. The lysosomal functions have been found to be impaired by fatty foods and aging, and more importantly, the lysosomal dysfunction in macrophages has been reported as a risk of atherosclerosis development. In this study, we searched for dietary polyphenols which possess the activity for enhancing the lysosomal degradation in J774.1, a murine macrophage-like cell line. Screening test utilizing DQ-BSA digestion identified isorhamnetin (3'-O-methylquercetin) as an active compound. Interestingly, structural comparison to inactive flavonols revealed that the chemical structure of the B-ring moiety in isorhamnetin is the primary determinant of its lysosome-enhancing activity. Unexpectedly isorhamnetin failed to inhibit mTORC1-TFEB signaling, a master regulator of lysosomal biogenesis and function. Our data suggested that the other molecular mechanism might be critical for the regulation of lysosomes in macrophages.Abbreviations: ANOVA: analysis of variance; ApoE: apolipoprotein E; ATP6V0D2: ATPase H+ transporting V0 subunit d2; BAF: bafilomycin A1; BODIPY: boron dipyrromethene; BSA: bovine serum albumin; CTSD: cathepsin D; CTSF: cathepsin F; DMEM: Dulbecco's modified eagle medium; DMSO: dimethyl sulfoxide; EGCG: epigallocatechin-3-gallate; FBS: fetal bovine serum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HPLC: high-performance liquid chromatography; LAMP1: lysosomal-associated membrane protein 1; LAMP2A: lysosomal-associated membrane protein 2A; LC-MS/MS: liquid chromatography tandem mass spectrometry; MITF: microphthalmia-associated transcription factor; MRM: multiple reaction monitoring; mTORC1: mechanistic target of rapamycin complex 1; PBS: phosphate-buffered saline; PPARγ: peroxisome proliferator-activated receptor γ; RT-qPCR: reverse transcription quantitative polymerase chain reaction; SDS: sodium dodecyl sulfate; SNARE: soluble N-ethylmaleimide-sensitive-factor attachment protein receptor; TBS: Tris-buffered saline; TFA: trifluoroacetic acid; TFE3: transcription factor binding to IGHM enhancer 3; TFEB: transcriptional factor EB; TFEC: transcription factor EC; V-ATPase: vacuolar-type proton ATPase.


pHi, contractility and Ca-balance under hypercapnic acidosis in the myocardium of different vertebrate species.
The influence of hypercapnic acidosis upon the heart was examined in four vertebrate species. The CO2 in the tissue bath was increased from 2.7 to 15% at 12 degrees C for flounder (Platichthys flesus) and cod (Gadus morhua) and from 3 to 13% at 22 degrees C for turtle (Pseudemys scripta) and rainbow trout (Salmo gairdneri). During hypercapnia, as previously described, there was a decline and recovery of contractility in heart strips of flounder and turtle, and a sustained decrease in cod and rainbow trout. At high CO2 the increase in contractile force following increases in the extracellular Ca-concentration were smaller for the cod myocardium than for the other myocardia. The intracellular pH (pHi), measured with the DMO method, in heart strips of turtle and trout was significantly lower at high than at low CO2. This acidifying effect expressed as the increase in the intracellular concentration of hydrogen ions was larger in the turtle than in the trout myocardium. Intracellular Ca-activity, measured by efflux of 45Ca from preloaded heart strips, was unaffected by high CO2 in trout, but was raised in the other three species. Thus the ability to counteract the negative inotropic effect of hypercapnia is apparently not due to cellular buffering or extrusion of hydrogen ions. More probably it involves (a) a release of intracellular Ca; (b) a positive inotropic effect of an increase in intracellular Ca-activity.


Cholesterol affects the interaction between an ionic liquid and phospholipid vesicles. A study by differential scanning calorimetry and nanoplasmonic sensing.
The present work aims at studying the interactions between cholesterol-rich phosphatidylcholine-based lipid vesicles and trioctylmethylphosphonium acetate ([P8881][OAc]), a biomass dissolving ionic liquid (IL). The effect of cholesterol was assayed by using differential scanning calorimetry (DSC) and nanoplasmonic sensing (NPS) measurement techniques. Cholesterol-enriched dipalmitoyl-phosphatidylcholine vesicles were exposed to different concentrations of the IL, and the derived membrane perturbation was monitored by DSC. The calorimetric data could suggest that the binding and infiltration of the IL are delayed in the vesicles containing cholesterol. To clarify our findings, NPS was applied to quantitatively follow the resistance of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine incorporating 0, 10, and 50mol% of cholesterol toward the IL exposure over time. The membrane perturbation induced by different concentrations of IL was found to be a concentration dependent process on cholesterol-free lipid vesicles. Moreover, our results showed that lipid depletion in cholesterol-enriched lipid vesicles is inversely proportional to the increasing amount of cholesterol in the vesicles. These findings support that cholesterol-rich lipid bilayers are less susceptible toward membrane disrupting agents as compared to membranes that do not incorporate any sterols. This probably occurs because cholesterol tightens the phospholipid acyl chain packing of the plasma membranes, increasing their resistance and reducing their permeability.


Three-dimensional cell and tissue patterning in a strained fibrin gel system.
Techniques developed for the in vitro reproduction of three-dimensional (3D) biomimetic tissue will be valuable for investigating changes in cell function in tissues and for fabricating cell/matrix composites for applications in tissue engineering techniques. In this study, we show that the simple application of a continuous strain to a fibrin gel facilitates the development of fibril alignment and bundle-like structures in the fibrin gel in the direction of the applied strain. Myoblasts cultured in this gel also exhibited well-aligned cell patterning in a direction parallel to the direction of the strain. Interestingly, the direction of cell proliferation was identical to that of cell alignment. Finally, the oriented cells formed linear groups that were aligned parallel to the direction of the strain and replicated the native skeletal muscle cell patterning. In addition, vein endothelial cells formed a linear, aligned vessel-like structure in this system. Thus, the system enables the in vitro reproduction of 3D aligned cell sets replicating biological tissue patterns.


Effectiveness of the 2009 seasonal influenza vaccine against pandemic influenza A(H1N1)2009 in healthcare workers in New Zealand, June-August 2009.
There is uncertainty whether the 2009 seasonal influenza vaccination influences the risk of infection with the 2009 pandemic influenza A(H1N1) virus. This issue was investigated in 548 healthcare workers from Capital and Coast District Health Board, Wellington, New Zealand, presenting with influenza-like illness during the influenza pandemic between June and August 2009. All workers completed an assessment sheet and had a nasopharyngeal swab tested by real-time RT-PCR. The risk of pandemic influenza A(H1N1) infection associated with the 2009 seasonal inactivated trivalent influenza vaccine was determined by logistic regression, with adjustment for potential confounding variables. In 96 workers pandemic influenza A(H1N1) RNA was detected and 452 tested negative. The multivariate analysis did not show any effect of vaccination on PCR-confirmed influenza A(H1N1)2009 infection (odds ratio 1.2, 95% confidence interval 0.7–1.9, p=0.48). We conclude that 2009 seasonal influenza vaccination had no protective effect against influenza A(H1N1)2009 infection amongst healthcare workers. To protect against further waves of the current pandemic influenza or future pandemics in which the influenza virus is antigenically distinct from contemporary seasonal influenza viruses, it would be necessary to vaccinate with a specific pandemic influenza vaccine, or a seasonal influenza vaccine that includes the pandemic influenza serotype.


Functional characterization of a new human melanocortin-4 receptor homozygous mutation (N72K) that is associated with early-onset obesity.
The melanocortin 4 receptor (MC4R) is expressed in the hypothalamus and is essential for regulation of appetite and energy expenditure. MC4R dysfunction in humans causes hyperphagia, impaired satiety and obesity. We have identified a novel c.216C>A (N72 K) homozygous mutation in MC4R in a girl with severe obesity. The patient presented with early-onset obesity and hyperphagia indicating an effect of the homozygous mutation on her phenotype. In silico analyses indicate a damaging effect on receptor function, and the mutation is unusual in occurring in the first intra-cellular loop of the receptor. Site-directed mutagenesis was used to generate plasmid constructs expressing wild-type and mutant MC4R. These were transfected into HEK293 cells and assessed for cAMP responsiveness to α-MSH. Cells expressing N-terminal HA and C-terminal GFP-tagged MC4R were assessed by immunofluorescence confocal microscopy and flow cytometry for correct cell-surface localization. The maximal response of the mutant MC4R to α-MSH was decreased to 20 ± 1 % of the wild type receptor response, and the EC50 was increased from 16.5 ± 5.4 nM to 37.0 ± 8.3 nM. Localization of N- and C-terminally tagged MC4R by confocal microscopy and flow cytometry showed aberrant retention of the mutant receptor in the cytoplasm. Our data describe a rare homozygous inactivating mutation in the first intra-cellular loop of MC4R that markedly impairs its function and is associated with early-onset obesity and hyperphagia.


Reductions in parietal and temporal cerebral metabolic rates for glucose are not specific for Alzheimer's disease.
Reduction in the regional cerebral metabolic rate for glucose (rCMRglc) in the parietal and temporal regions has been shown in Alzheimer's disease (AD). The specificity of these findings for this disease state is uncertain. We repeatedly measured rCMRglc with positron emission tomography and [18F]2-fluoro-2-deoxy-D-glucose in the resting state in a 68 year old man with slowly progressive dementia who, during life, was initially diagnosed as having dementia of the Alzheimer type, then Parkinson disease with dementia, but was found to have only Parkinson's disease at necropsy. Metabolic ratios (rCMRglc/mean grey CMRglc) were significantly (p < 0.05) reduced in parietal and temporal regions, as well as in the prefrontal and premotor areas. This pattern was similar in regional distribution and magnitude of the defect to that seen in patients with probable AD. These results suggest that reductions of glucose metabolism in association neocortex in AD are not specific to the disease process, but may be related to the dementia state.


Interplay between Nanoparticle Wrapping and Clustering of Inner Anchored Membrane Proteins.
The receptor-mediated endocytosis of nanoparticles (NPs) is known to be size and shape dependent but regulated by membrane properties, like tension, rigidity, and especially membrane proteins. Compared with transmembrane receptors, which directly bind ligands coated on NPs to provide the driving force for passive endocytosis, the hidden role of inner anchored membrane proteins (IAMPs), however, has been grossly neglected. Here, by applying the N-varied dissipative particle dynamics (DPD) techniques, we present the first simulation study on the interplay between wrapping of NPs and clustering of IAMPs. Our results suggest that the wrapping dynamics of NPs can be regulated by clustering of IAMPs, but in a competitive way. In the early stage, the dispersed IAMPs rigidify the membrane and thus restrain NP wrapping by increasing the membrane bending energy. However, once the clustering completes, the rigidifying effect is reduced. Interestingly, the clustering of longer IAMPs can sense NP wrapping. They are found to locate preferentially at the boundary region of NP wrapping. More importantly, the adjacent IAMP clustering produces a late membrane monolayer protrusion, which finally wraps the NP from the top side. Our findings regarding the competitive effects of IAMP clustering on NP wrapping facilitate the molecular understanding of endocytosis and establish fundamental principles for design of NPs for widespread biomedical applications.


Pharmacokinetics of ingested fluoride: lack of effect of chemical compound.
Fluoride in drinking water may be present from natural sources or added as sodium fluoride (NaF), sodium silicofluoride (Na(2)SiF(6)) or fluorosilicic acid (H(2)SiF(6)). Results from an early study with rats suggested that, when ingested as Na(2)SiF(6), the absorption and excretion of fluoride were greater than when ingested as NaF. The present single-blind, crossover study with 10 adults was done to determine three key pharmacokinetic parameters: the maximum plasma fluoride concentrations (C(max)), the elapsed time to reach the maximum concentrations (T(max)) and the 6-h areas under the time-plasma concentration curves (AUCs) after ingestion of 500 mL of water containing 0.67 or 5.45 mg F/L present naturally or added as NaF or H(2)SiF(6). Blood was collected prior to and at nine time points during 6h after ingestion of the test solutions. Plasma was analysed by electrode after HMDS-facilitated diffusion and the data were analysed for statistically significant differences using repeated measures ANOVA. The C(max), T(max) and AUC values after ingestion of the solutions containing natural fluoride, NaF or H(2)SiF(6) did not differ significantly at either dose level. Further, the T(max) values associated with the 0.67 and 5.45 mg/L solutions did not differ significantly indicating that the absorption, distribution and elimination rates were not affected by the dose size. Considered together with published reports, the present findings support the conclusion that the major features of fluoride metabolism are not affected differently by the chemical compounds commonly used to fluoridate water nor are they affected by whether the fluoride is present naturally or added artificially.


Clinical and bacteriological evaluation of nadifloxacin 1% cream in patients with acne vulgaris: a double-blind, phase III comparison study versus erythromycin 2% cream.
The aim of this double-blind, multinational, phase III study was to investigate the clinical and bacteriological efficacy of nadifloxacin 1% cream compared with erythromycin 2% cream in 474 European patients with predominantly inflamed slight-to-moderate acne vulgaris. During 12 weeks of treatment both nadifloxacin and erythromycin caused significant reduction in the number of inflamed papulo-pustular lesions (66.7% and 64.7%, respectively) and open and closed comedones. The microbiological evaluation showed a significant reduction of coagulase negative staphylococci (CNS) only in the nadifloxacin group, while Propionibacterium acnes was significantly reduced by both formulations. A significantly higher resistance and the extent of resistant of P. acnes and CNS against erythromycin compared to nadifloxacin were also evidenced. All adverse events reported were minor in both groups. This pivotal erythromycin-controlled study has demonstrated that nadifloxacin 1% cream was as efficacious and safe as erythromycin 2% and extremely low numbers of nadifloxacin-resistant microorganisms were detected in the treatment period.


Skeletal muscle PGF(2)(alpha) and PGE(2) in response to eccentric resistance exercise: influence of ibuprofen acetaminophen.
PGs have been shown to modulate skeletal muscle protein metabolism as well as inflammation and pain. In nonskeletal muscle tissues, the over the counter analgesic drugs ibuprofen and acetaminophen function through suppression of PG synthesis. We previously reported that ibuprofen and acetaminophen inhibit the normal increase in skeletal muscle protein synthesis after high intensity eccentric resistance exercise. The current study examined skeletal muscle PG levels in the same subjects to further investigate the mechanisms of action of these drugs in exercised skeletal muscle. Twenty-four males (25 +/- 3 yr) were assigned to 3 groups that received the maximal over the counter dose of ibuprofen (1200 mg/d), acetaminophen (4000 mg/d), or a placebo after 10-14 sets of 10 eccentric repetitions at 120% of concentric 1 repetition maximum using the knee extensors. Preexercise and 24 h postexercise biopsies of the vastus lateralis revealed that the exercise-induced change in PGF(2alpha) in the placebo group (77%) was significantly different (P < 0.05) from those in the ibuprofen (-1%) and acetaminophen (-14%) groups. However, the exercise-induced change in PGE(2) in the placebo group (64%) was only significantly different (P < 0.05) from that in the acetaminophen group (-16%). The exercise-induced changes in PGF(2alpha) and PGE(2) were not different between the ibuprofen and acetaminophen groups. These results suggest that ibuprofen and acetaminophen have a comparable effect on suppressing the normal increase in PGF(2alpha) in human skeletal muscle after eccentric resistance exercise, which may profoundly influence the anabolic response of muscle to this form of exercise.


Increased hypoxia-inducible factor 1α expression in lung cells of horses with recurrent airway obstruction.
Recurrent airway obstruction (RAO, also known as equine heaves) is an inflammatory condition caused by exposure of susceptible horses to organic dusts in hay. The immunological processes responsible for the development and the persistence of airway inflammation are still largely unknown. Hypoxia-inducible factor (Hif) is mainly known as a major regulator of energy homeostasis and cellular adaptation to hypoxia. More recently however, Hif also emerged as an essential regulator of innate immune responses. Here, we aimed at investigating the potential involvement of Hif1-α in myeloid cells in horse with recurrent airway obstruction. In vitro, we observed that Hif is expressed in equine myeloid cells after hay dust stimulation and regulates genes such as tumor necrosis factor alpha (TNF-α), interleukin-8 (IL-8) and vascular endothelial growth factor A (VEGF-A). We further showed in vivo that airway challenge with hay dust upregulated Hif1-α mRNA expression in myeloid cells from the bronchoalveolar lavage fluid (BALF) of healthy and RAO-affected horses, with a more pronounced effect in cells from RAO-affected horses. Finally, Hif1-α mRNA expression in BALF cells from challenged horses correlated positively with lung dysfunction. Taken together, our results suggest an important role for Hif1-α in myeloid cells during hay dust-induced inflammation in horses with RAO. We therefore propose that future research aiming at functional inactivation of Hif1 in lung myeloid cells could open new therapeutic perspectives for RAO.


Effects of high-sugar ryegrass silage and mixtures with red clover silage on ruminant digestion. 1. In vitro and in vivo studies of nitrogen utilization.
Two experiments were carried out to determine the effects of feeding grass silages differing in their water-soluble carbohydrate content, with or without red clover silage, on the efficiency of nutrient use. High-sugar grass, control grass, and red clover were ensiled in laboratory silos for use in an in vitro experiment (Exp. 1). For an in vivo experiment (Exp. 2), the same forage types were baled and ensiled. All silages were well preserved; within experiments the grass silages had similar composition, except for greater (P < 0.05) water-soluble carbohydrate concentrations in the high-sugar than the control grass silage. In Exp. 1, high-sugar grass, control grass, and red clover silages were fed alone or as mixtures (30:70, 50:50, or 70:30 on a DM basis, respectively) of each grass with the red clover silage to a simulated rumen culture system. There were no significant differences in microbial N flow or efficiency of microbial protein synthesis between individual forages. However, the corresponding values for the 70:30 ratio of high-sugar grass:red clover silage were greater (P < 0.05) than for the red clover silage. The value for the efficiency of N use (g of microbial N/g of feed N) was greater (0.86; P < 0.05) for high-sugar grass silage than the control grass silage. In addition, the high-sugar grass:red clover silage mixtures all gave greater (P < 0.05) values for the efficiency of N use than red clover silage alone; this difference was not achieved with the control grass mixture. Experiment 2 was an incomplete Latin square design conducted with 6 Here-ford x Friesian steers (163 +/- 5.9 kg of BW) with rumen and duodenal cannulas fed the following 5 silage diets: high-sugar grass silage; control grass silage; high-sugar grass and red clover silage (50:50 DM basis); control grass and red clover silage (50:50 DM basis); and red clover silage. Rumen NH3-N concentration was lowest (P < 0.05) with the high-sugar grass silage. Microbial N flows to the duodenum and efficiency of microbial protein synthesis were greater (P < 0.05) for steers fed the high-sugar grass silage than for control grass and red clover silages, and mixing red clover with grass silages increased (P < 0.05) these values compared with red clover silage alone. In both experiments, the efficiency of incorporation of silage N into microbial N was more than 20% greater (P < 0.05) for high-sugar grass than for control grass silage. These data suggest that grass silage with high-sugar content provides a forage-based strategy for balancing N and energy supply and improving the efficiency of use of grass silage N in the rumen.


[Adverse events associated with the treatment of inflammatory bowel disease].
The purpose of inflammatory bowel disease (IBD) treatment is to achieve resolution of symptoms and remission of disease with a minimum of adverse events (AE). To report AE of different prescriptions used for the treatment of IBD. Analysis of a registry of patients with IBD held at a private clinic from 1976 to 2013. All used medications, the occurrence and severity of AE were recorded. The records of 346 patients aged 16 to 86 years, 74% with ulcerative colitis, were analyzed. The most commonly type of medications prescribed were 5-aminosalicylates (5-ASAs) in 329 patients (92%), followed by adrenal steroids in 218 (61%). Forty nine AE were recorded in the same number of patents (14%). These were more common in patients with Crohn disease (n = 19, 21%). An univariate analysis, demonstrated that extra-intestinal manifestations, hospitalizations secondary to IBD crisis, requirement of surgery and treatment with steroids, immunosuppressants or biologic agents were significantly associated with the presence of AE. AEs were more common with immunosuppressants, followed by 5-ASAs and steroids. Discontinuation of therapy was required in 79, 100 and 43% of patients taking these medications, respectively. Twenty percent of AEs were severe. Leukopenia and pancytopenia along with alopecia were the most common AEs attributable to azathioprine. The occurrence of AEs in patients with IBD is uncommon. Even inmunosuppressants or biologic agents have a low rate of AE and most of them mild.


Bruton tyrosine kinase deficiency augments NLRP3 inflammasome activation and causes IL-1β-mediated colitis.
Bruton tyrosine kinase (BTK) is present in a wide variety of cells and may thus have important non-B cell functions. Here, we explored the function of this kinase in macrophages with studies of its regulation of the NLR family, pyrin domain-containing 3 (NLRP3) inflammasome. We found that bone marrow-derived macrophages (BMDMs) from BTK-deficient mice or monocytes from patients with X-linked agammaglobulinemia (XLA) exhibited increased NLRP3 inflammasome activity; this was also the case for BMDMs exposed to low doses of BTK inhibitors such as ibrutinib and for monocytes from patients with chronic lymphocytic leukemia being treated with ibrutinib. In mechanistic studies, we found that BTK bound to NLRP3 during the priming phase of inflammasome activation and, in doing so, inhibited LPS- and nigericin-induced assembly of the NLRP3 inflammasome during the activation phase of inflammasome activation. This inhibitory effect was caused by BTK inhibition of protein phosphatase 2A-mediated (PP2A-mediated) dephosphorylation of Ser5 in the pyrin domain of NLRP3. Finally, we show that BTK-deficient mice were subject to severe experimental colitis and that such colitis was normalized by administration of anti-IL-β or anakinra, an inhibitor of IL-1β signaling. Together, these studies strongly suggest that BTK functions as a physiologic inhibitor of NLRP3 inflammasome activation and explain why patients with XLA are prone to develop Crohn's disease.


Combination of sacral-alar-iliac screw and cortical bone trajectory screw techniques for lumbosacral fixation: technical note.
Lumbosacral fixation plays an important role in the management of devastating spinal pathologies, including osteoporosis, fracture, infection, tumor resection, and spinal deformities, which require long-segment fusion constructs to the sacrum. The sacral-alar-iliac (SAI) screw technique has been developed as a promising solution to facilitate both minimal invasiveness and strong fixation. The rationale for SAI screw insertion is a medialized entry point away from the ilium and in line with cranial screws. The divergent screw path of the cortical bone trajectory (CBT) provides a higher amount of cortical bone purchase and strong screw fixation and has the potential to harmoniously align with SAI screws due to its medial starting point. However, there has been no report on the combination of these two techniques. The objective of this study was to assess the feasibility of this combination technique. The subjects consisted of 17 consecutive patients with a mean age of 74.2 ± 4.7 years who underwent posterior lumbosacral fixation for degenerative spinal pathologies using the combination of SAI and CBT fixation techniques. There were 8 patients with degenerative scoliosis, 7 with degenerative kyphosis, 1 with an osteoporotic vertebral fracture at L5, and 1 with vertebral metastasis at L5. Fusion zones included T10-sacrum in 13 patients, L2-sacrum in 2, and L4-sacrum in 2. No patients required complicated rod bending or the use of a connector for rod assembly in the lumbosacral region. Postoperative CT performed within a week after surgery showed that all lumbosacral screws were in correct positions and there was no incidence of neurovascular injuries. The lumbosacral bone fusion was confirmed in 81.8% of patients at 1-year follow-up based on fine-cut CT scanning. No patient showed a significant loss of spinal alignment or rod fracture in the lumbosacral transitional region. This is the first paper on the feasibility of a combination technique using SAI and CBT screws. This technique could be a valid option for lumbosacral fixation due to the ease of rod placement with potential reductions in operative time and blood loss.


Maternal sevoflurane exposure affects differentiation of hippocampal neural stem cells by regulating miR-410-3p and ATN1.
Currently, numerous animal studies have shown that exposure to commonly used general anesthetics during pregnancy may cause neurocognitive impairment in the offspring. Reportedly, exposure to sevoflurane during mid-trimester of pregnancy can inhibit proliferation of neural stem cells (NSCs) and lead to early apoptosis. Whether exposure to sevoflurane during pregnancy affects the differentiation of NSCs remains unclear. In the present study, pregnant rats were exposed to 3% sevoflurane once for 2 h on gestational day 14 (G14) or 3 times for 2 h on G13, G14, and G15. Next, the differentiation of NSCs was measured using neuron marker β-tubulin III and astrocyte marker glial fibrillary acidic protein (GFAP) in fetal brain tissues 24 h and 72 h after anesthesia and in hippocampus on postnatal day 28. Primary cultured rat NSCs were exposed to 4.1% sevoflurane to explore the mechanism. The results showed that during mid-trimester, multiple exposures to sevoflurane can cause premature differentiation of NSCs in developing brains of offspring and lead to long-term neuron reduction and astrocyte proliferation in hippocampus. The data from the present study indicated that repeated exposure to sevoflurane downregulated atrophin-1 (ATN1) expression and caused early differentiation of NSCs. Overexpression of ATN1 via lentivirus transfection attenuated the influence of sevoflurane. Using dual luciferase assay, ATN1 was found to be a target gene of microRNA-410-3p (miR-410-3p). MiR-410-3p suppression via lentivirus transfection recovered the ATN1 expression and differentiation of NSCs. The results from the present study demonstrated that repeated exposure to sevoflurane leads to early differentiation of NSCs and long-term effects via the miR-410-3p/ATN1 pathway.


First Report of Banana bunchy top virus in Banana and Plantain (Musa spp.) in Nigeria.
Plantain and banana (Musa spp.) are among the most important staple crops for food and income generation for the rural and urban populations in the humid forest agroecological zone of West Africa. Until recently, Cucumber mosaic virus (genus Cucumovirus) and Banana streak virus (genus Badnavirus) were the only viruses reported to occur in Musa spp. in West Africa. In 2011, an outbreak of banana bunchy top disease (BBTD) caused by Banana bunchy top virus (BBTV; genus Babuvirus, family Nanoviridae) was reported in Ouémé Département (6°30'N and 2°36'E) in the Republic of Benin (2). BBTV is one of the most economically important pathogens of Musa spp. It is well established in Central Africa and also in Angola, Malawi, and Zambia in Southern Africa (2). Plants infected at early growth stages are severely dwarfed and do not bear fruit. BBTV is transmitted by the banana aphid Pentalonia nigronervosa, which is widespread in Africa (1). The regions in the Republic of Benin affected by BBTV border Ogun State (7°00'N and 3°35'E) of Nigeria. Epidemiological investigations were conducted during May 2012 at 31 locations in Ogun State to determine the potential risk of BBTV spreading into Nigeria. Plants with typical symptoms of BBTD (stunting, narrow and shortened leaves, chlorotic streaks on petioles and pseudostem) were observed in four locations: Ilashe, Odan-Itoro, Ido-Ologun, and Igbogila. Total DNA was extracted from 90 leaf samples randomly collected from symptomatic and asymptomatic banana and plantain plants in these areas. Samples were tested for BBTV by polymerase chain reaction (PCR) using primer pairs, mREP-F and mREP-R, which amplifies a 241-bp of BBTV DNA-mRep segment (1), and Scp-F and Scp-R specific for approximately 1075-bp BBTV DNA-S that encodes coat protein gene (1). The amplicons of expected size were obtained from 17 of 90 samples analyzed (18.8%). BBTV in the symptomatic plants was further confirmed by nucleic acid spot hybridization (NASH) assay using DIG-labeled 1,075-bp probe corresponding to coat protein gene and chromogenic detection as per the previously described protocol (3). The DIG-probe specifically reacted with nucleic acid from the symptomatic plants, but not with negative controls, providing conclusive evidence for the BBTV. The PCR products of DNA-mRep segment amplified from three banana plants infected with BBTV collected in Ilashe (Ipokia Local Government Area) were purified and sequenced in both directions. The sequences of these isolates were 100% identical with each other (GenBank Accession Nos. JX290301, JX290302, and JX290303). A BLASTn search revealed 100% nucleotide sequence identity with a BBTV isolate from Benin (JQ437548) and 99 to 100% identity with DNA-mRep sequences of several other BBTV isolates from Africa, Australia, India, and the South Pacific. Further analysis of the 241-bp mRep gene sequences with Neighbor-Joining phylogenetic analysis grouped the BBTV isolate with the South Pacific isolates. To our knowledge, this is the first report of BBTV in Nigeria. This underscores need for surveys to assess the extent of BBTV spread in Nigeria and strict implementation of phytosanitary measures, including restrictions on the movement of planting material from disease-affected regions, to prevent further spread of this important disease. References: (1) P. L. Kumar et al. Virus Res. 159:171, 2011. (2) B. Lokossou et al. New Dis. Rep. 25:13, 2012. (3) W. S. Xie and J. S. Hu. Phytopathol. 85:339, 1995.


Appropriateness of antimicrobial prescribing in a Swiss tertiary care hospital: a repeated point prevalence survey.
Inappropriate use of antimicrobials is associated with the emergence of antimicrobial resistance and adverse events. Antimicrobial stewardship programmes may both optimise treatment of infections and reduce antimicrobial resistance but are implemented in only a minority of Swiss hospitals. In addition, data on prescribing patterns and quality are scarce. We conducted a repeated point prevalence survey to evaluate the quality of antimicrobial prescribing in a single tertiary care centre. Antimicrobial use was audited twice (summer 2017 and winter 2018) among all patients admitted to the University Hospital Basel, Switzerland. Data were collected from the electronic health record. Appropriateness of antimicrobial use was evaluated according to previously published rules and local national guidelines. We evaluated 1112 patients of whom 378 (34%) received 548 prescriptions in total (30% for prophylaxis). Penicillins with β-lactamase inhibitors were most commonly used (30%), followed by cotrimoxazole (12%) and ceftriaxone (7%). Intravenous administration was chosen in 56% of patients. Prior to antimicrobial therapy, blood cultures were collected in 69% of patients. Overall, 182 (33%) prescriptions were not appropriate; reasons included lack of indication (11%), incorrect dosing (7%), delay in intravenous to oral switch (9%) or non-adherence to local guidelines (15%). A minority of patients received antimicrobials despite documented allergies (2%). Almost 38% of empirical prescriptions were inappropriate, compared with only 19% of prophylactic and 20% of targeted prescriptions. Penicillins with β-lactamase inhibitors and cephalosporins were most commonly involved in inappropriate prescribing (>50%) followed by carbapenems (30%), narrow-spectrum penicillins (17%) and cotrimoxazole (6%), with oral administration being involved less frequently than intravenous administration (15 vs 37%). Infectious diseases consultation and presence of immunosuppression were associated with reduced odds (odds ratio [OR] 0.38, 95% confidence interval [CI] 0.21–0.70 and OR 0.31, 95% CI 0.17–0.54, respectively) of inappropriate prescription in the per-patient multivariable analysis, whereas being admitted to a surgical or intensive care unit was associated with increased odds (OR 1.83 and 5.67) compared with a medical unit. Almost one third of prescriptions were inappropriate in our tertiary care centre despite local guidelines and an on-demand infectious diseases consultation service. Our results underscore the need for expanding current antimicrobial stewardship efforts, including national initiatives such as stewardship and prescribing guidelines, repeated surveys and identification of areas for improvement including timely intravenous to oral switches in order to reduce the consequences of inappropriate prescribing and of multidrug resistant organisms.


Time-resolved optical imaging of a solid tissue-equivalent phantom.
A solid plastic phantom has been developed with optical properties that closely match those of human breast tissue at near-IR wavelengths. The phantom is a 54-mm-thick slab containing four small cylinders of contrasting scatter and absorption. A detailed description of the phantom is followed by an account of an attempt to image the phantom by a time-resolved imaging technique. Images generated with transmitted light with the shortest flight times revealed the embedded cylinders with greater visibility than images obtained with continuous light transillumination. However, images corresponding to flight times of less than ~700 ps were severely degraded from a lack of detected photons. An attempt was made to overcome this degradation by extrapolating the measured temporal distributions with an analytic model of photon transport. Results suggest that subcentimeter resolution imaging of low-contrast tumors in the breast is scientifically possible. Our phantom is available to any other research groups wishing to evaluate their systems.


The Not-So-Good Prognosis of Streptococcal Periprosthetic Joint Infection Managed by Implant Retention: The Results of a Large Multicenter Study.
Streptococci are not an infrequent cause of periprosthetic joint infection (PJI). Management by debridement, antibiotics, and implant retention (DAIR) is thought to produce a good prognosis, but little is known about the real likelihood of success. A retrospective, observational, multicenter, international study was performed during 2003-2012. Eligible patients had a streptococcal PJI that was managed with DAIR. The primary endpoint was failure, defined as death related to infection, relapse/persistence of infection, or the need for salvage therapy. Overall, 462 cases were included (median age 72 years, 50% men). The most frequent species was Streptococcus agalactiae (34%), and 52% of all cases were hematogenous. Antibiotic treatment was primarily using β-lactams, and 37% of patients received rifampin. Outcomes were evaluable in 444 patients: failure occurred in 187 (42.1%; 95% confidence interval, 37.5%-46.7%) after a median of 62 days from debridement; patients without failure were followed up for a median of 802 days. Independent predictors (hazard ratios) of failure were rheumatoid arthritis (2.36), late post-surgical infection (2.20), and bacteremia (1.69). Independent predictors of success were exchange of removable components (0.60), early use of rifampin (0.98 per day of treatment within the first 30 days), and long treatments (≥21 days) with β-lactams, either as monotherapy (0.48) or in combination with rifampin (0.34). This is the largest series to our knowledge of streptococcal PJI managed by DAIR, showing a worse prognosis than previously reported. The beneficial effects of exchanging the removable components and of β-lactams are confirmed and maybe also a potential benefit from adding rifampin.


Chemical Ecology and Sociality in Aphids: Opportunities and Directions.
Aphids have long been recognized as good phytochemists. They are small sap-feeding plant herbivores with complex life cycles that can involve cyclical parthenogenesis and seasonal host plant alternation, and most are plant specialists. Aphids have distinctive traits for identifying and exploiting their host plants, including the expression of polyphenisms, a form of discrete phenotypic plasticity characteristic of insects, but taken to extreme in aphids. In a relatively small number of species, a social polyphenism occurs, involving sub-adult "soldiers" that are behaviorally or morphologically specialized to defend their nestmates from predators. Soldiers are sterile in many species, constituting a form of eusociality and reproductive division of labor that bears striking resemblances with other social insects. Despite a wealth of knowledge about the chemical ecology of non-social aphids and their phytophagous lifestyles, the molecular and chemoecological mechanisms involved in social polyphenisms in aphids are poorly understood. We provide a brief primer on aspects of aphid life cycles and chemical ecology for the non-specialists, and an overview of the social biology of aphids, with special attention to chemoecological perspectives. We discuss some of our own efforts to characterize how host plant chemistry may shape social traits in aphids. As good phytochemists, social aphids provide a bridge between the study of insect social evolution sociality, and the chemical ecology of plant-insect interactions. Aphids provide many promising opportunities for the study of sociality in insects, and to understand both the convergent and novel traits that characterize complex sociality on plants.


A systematic review of serum biomarkers anti-cyclic citrullinated Peptide and rheumatoid factor as tests for rheumatoid arthritis.
This systematic review assesses the current status of anti-cyclic citrullinated peptide (anti-CCP) and rheumatoid factor (RF) tests in the diagnosis and prognosis of rheumatoid arthritis (RA). We reviewed publications on tests and biomarkers for early diagnosis of RA from English-language MEDLINE-indexed journals and non-MEDLINE-indexed sources. 85 publications were identified and reviewed, including 68 studies from MEDLINE and 17 non-MEDLINE sources. Anti-CCP2 assays provide improved sensitivity over anti-CCP assays and RF, but anti-CCP2 and RF assays in combination demonstrate a positive predictive value (PPV) nearing 100%, greater than the PPV of either of the tests alone. The combination also appears to be able to distinguish between patients whose disease course is expected to be more severe and both tests are incorporated in the 2010 ACR Rheumatoid Arthritis Classification Criteria. While the clinical value of anti-CCP tests has been established, differences in cut-off values, sensitivities and specificities exist between first-, second- and third-generation tests and harmonization efforts are under way. Anti-CCP and RF are clinically valuable biomarkers for the diagnosis and prognosis of RA patients. The combination of the two biomarkers in conjunction with other clinical measures is an important tool for the diagnosis and management of RA patients.


Philosophy on steroids: a reply.
Brent Kious has recently attacked several arguments generally adduced to support anti-doping in sports, which are widely supported by the sports medicine fraternity, international sports federations, and international governments. We show that his attack does not succeed for a variety of reasons. First, it uses an overly inclusive definition of doping at odds with the WADA definition, which has global, if somewhat contentious, currency. Second, it seriously misconstrues the position it attacks, rendering the attack without force against a more balanced construal of an anti-doping position. Third, it makes unwarranted appeals to matters Kious considers morally 'clear', while simultaneously attacking a position many others take to be equally morally 'clear', namely that of anti-doping. Such an inconsistency, attacking and appealing to the moral status quo as befits one's argument, is not acceptable without further qualification. Fourth, his position suffers from a general methodological flaw of over-reliance upon argumentation by analogy. Moreover, it is argued that the analogies, being poorly selected and developed, fail to justify his conclusion that the anti-doping lobby lacks philosophical and moral authority for its stance. These issues are symptomatic of a more fundamental problem: any attempt at providing a blanket solution to the question of whether doping is morally acceptable or not is bound to run up against problems when applied to highly specific contexts. Thus, rather than reaching any particular conclusion for or against doping products or processes in this article, we conclude that an increased context-sensitivity will result in a more evenhanded appraisal of arguments on the matter.


Simultaneous four-photon luminescence, third-harmonic generation, and second-harmonic generation microscopy of GaN.
We demonstrate what is to our knowledge the first example of four-photon luminescence microscopy in GaN and apply it to quality mapping of bulk GaN. The simultaneously acquired second- and third-harmonic generation can be used to map the distribution of the piezoelectric field and the band-tail state density, respectively. Through spectrum- and power-dependent studies, the fourth power dependence of the band edge luminescence is confirmed. The superb spatial resolution of the four-photon luminescence modality is also demonstrated. This technique provides a high-resolution, noninvasive monitoring and tool for examining the physical properties of semiconductors.


Edge-selectively phosphorus-doped few-layer graphene as an efficient metal-free electrocatalyst for the oxygen evolution reaction.
The development of efficient, stable and cost-effective electrocatalysts for the oxygen evolution reaction (OER) is the key for water splitting. Carbon-based nanomaterials have found significant applications as metal-free OER electrocatalysts. In this study, for the first time, edge-selectively phosphorus-doped graphene (G-P) was synthesised for OER electrocatalysts. The G-P catalyst reached a current density of 10 mA cm-2 at a small overpotential of 330 mV for the OER with a Tafel slope as low as 62 mV dec-1, which is superior to most of the carbon-based electrocatalysts reported to date.


DICLENS: divisive clustering ensemble with automatic cluster number.
Clustering has a long and rich history in a variety of scientific fields. Finding natural groupings of a data set is a hard task as attested by hundreds of clustering algorithms in the literature. Each clustering technique makes some assumptions about the underlying data set. If the assumptions hold, good clusterings can be expected. It is hard, in some cases impossible, to satisfy all the assumptions. Therefore, it is beneficial to apply different clustering methods on the same data set, or the same method with varying input parameters or both. We propose a novel method, DICLENS, which combines a set of clusterings into a final clustering having better overall quality. Our method produces the final clustering automatically and does not take any input parameters, a feature missing in many existing algorithms. Extensive experimental studies on real, artificial, and gene expression data sets demonstrate that DICLENS produces very good quality clusterings in a short amount of time. DICLENS implementation runs on standard personal computers by being scalable, and by consuming very little memory and CPU.


Stromal cell-derived factor-1alpha associates with heparan sulfates through the first beta-strand of the chemokine.
Biological properties of chemokines are believed to be influenced by their association with glycosaminoglycans. Surface plasmon resonance kinetic analysis shows that the CXC chemokine stromal cell-derived factor-1alpha (SDF-1alpha), which binds the CXCR4 receptor, associates with heparin with an affinity constant of 38.4 nM (k(on) = 2.16 x 10(6) M(-1) s(-1) and k(off) = 0.083 x s(-1)). A modified SDF-1alpha (SDF-1 3/6) was generated by combined substitution of the basic cluster of residues Lys(24), His(25), and Lys(27) by Ser. SDF-1 3/6 conserves the global native structure and functional properties of SDF-1alpha, but it is unable to interact with sensor chip-immobilized heparin. The biological relevance of these in vitro findings was investigated. SDF-1alpha was unable to bind in a CXCR4-independent manner on epithelial cells that were treated with heparan sulfate (HS)-degrading enzymes or constitutively lack HS expression. The inability of SDF-1 3/6 to bind to cells underlines the importance of the identified basic cluster for the physiological interactions of SDF-1alpha with HS. Importantly, the amino-terminal domain of SDF-1alpha which is required for binding to, and activation of, CXCR4 remains exposed after binding to HS and is recognized by a neutralizing monoclonal antibody directed against the first residues of the chemokine. Overall, these findings indicate that the Lys(24), His(25), and Lys(27) cluster of residues forms, or is an essential part of, the HS-binding site which is distinct from that required for binding to, and signaling through, CXCR4.


Development of methods for cryopreservation of rooster sperm from the endangered breed "Gallina Valenciana de Chulilla" using low glycerol concentrations.
Glycerol (11%; v:v) is the cryoprotectant most often used for the cryopreservation of rooster sperm. However, chicken breeds differ in the resistance of their sperm to the cryopreservation process and endangered or local breeds usually present low fertilizing ability when conventional sperm cryopreservation protocols are used. The objective of this study was to optimize the protocol for the cryopreservation of the sperm from the endangered breed "Gallina Valenciana de Chulilla". For this purpose, 10 pools of semen from 43 roosters of this breed were cryopreserved using 8%, 7%, 6%, or 4% glycerol, and the sperm quality was determined immediately after thawing and in the insemination doses. Lohmann Brown Classic laying hens (n = 40) were used for the insemination trials. The sperm quality after cryopreservation progressively decreased as the glycerol concentration was reduced (P < 0.01); samples frozen using 4% glycerol exhibited the lowest quality (38% total motile sperm and 49% live sperm), and samples frozen using 8% glycerol exhibited the highest quality (67% total motile sperm and 66% live sperm). These differences were also observed after the glycerol was removed (P < 0.01). However, the sperm fertilizing ability was similar for all the treatments (23%-30% fertilized eggs), and increased as the glycerol concentration decreased. In conclusion, semen from roosters frozen using 4% glycerol exhibited lower sperm quality but similar fertilizing ability compared with samples processed using higher glycerol concentrations. These results may provide useful information for developing cryopreservation protocols for other breeds.


Probiotic Bifidobacterium strains and galactooligosaccharides improve intestinal barrier function in obese adults but show no synergism when used together as synbiotics.
One way to improve both the ecological performance and functionality of probiotic bacteria is by combining them with a prebiotic in the form of a synbiotic. However, the degree to which such synbiotic formulations improve probiotic strain functionality in humans has not been tested systematically. Our goal was to use a randomized, double-blind, placebo-controlled, parallel-arm clinical trial in obese humans to compare the ecological and physiological impact of the prebiotic galactooligosaccharides (GOS) and the probiotic strains Bifidobacterium adolescentis IVS-1 (autochthonous and selected via in vivo selection) and Bifidobacterium lactis BB-12 (commercial probiotic allochthonous to the human gut) when used on their own or as synbiotic combinations. After 3 weeks of consumption, strain-specific quantitative real-time PCR and 16S rRNA gene sequencing were performed on fecal samples to assess changes in the microbiota. Intestinal permeability was determined by measuring sugar recovery in urine by GC after consumption of a sugar mixture. Serum-based endotoxin exposure was also assessed. IVS-1 reached significantly higher cell numbers in fecal samples than BB-12 (P < 0.01) and, remarkably, its administration induced an increase in total bifidobacteria that was comparable to that of GOS. Although GOS showed a clear bifidogenic effect on the resident gut microbiota, both probiotic strains showed only a non-significant trend of higher fecal cell numbers when administered with GOS. Post-aspirin sucralose:lactulose ratios were reduced in groups IVS-1 (P = 0.050), IVS-1 + GOS (P = 0.022), and GOS (P = 0.010), while sucralose excretion was reduced with BB-12 (P = 0.002) and GOS (P = 0.020), indicating improvements in colonic permeability but no synergistic effects. No changes in markers of endotoxemia were observed. This study demonstrated that "autochthony" of the probiotic strain has a larger effect on ecological performance than the provision of a prebiotic substrate, likely due to competitive interactions with members of the resident microbiota. Although the synbiotic combinations tested in this study did not demonstrate functional synergism, our findings clearly showed that the pro- and prebiotic components by themselves improved markers of colonic permeability, providing a rational for their use in pathologies with an underlying leakiness of the gut.


Neuroplastic Effects in Patients With Traumatic Brain Injury After Music-Supported Therapy.
Damage to the orbitofrontal cortex (OFC) often occurs following a traumatic brain injury (TBI) and can lead to complex behavioral changes, including difficulty with attention and concentration. We investigated the effects of musical training on patients with behavioral and cognitive deficits following a mild traumatic brain injury (mTBI) and found significant functional neuro-plastic changes in the OFC's networks. The results from neuropsychological tests revealed an improved cognitive performance. Moreover, six out of seven participants in this group returned to work post intervention and reported improved well-being and social behavior. In this study, we explore the functional changes in OFC following music-supported intervention in reference to connecting networks that may be responsible for enhanced social interaction. Furthermore, we discuss the factor of dopamine release during playing as an element providing a possible impact on the results. The intervention consisted of playing piano, two sessions per week in 8 weeks, 30 min each time, with an instructor. Additional playing was required with a minimum of 15 min per day at home. Mean time playing piano in reference to participant's report was 3 h per week during the intervention period. Three groups participated, one mTBI group (n = 7), two control groups consisting of healthy participants, one with music training (n = 11), and one baseline group without music training (n = 12). Participants in the clinical group had received standardized cognitive rehabilitation treatment during hospitalization without recovering from their impairments. The intervention took place 2 years post injury. All participants were assessed with neuropsychological tests and with both task and resting-state functional magnetic resonance imaging (fMRI) pre-post intervention. The results demonstrated a significant improvement of neuropsychological tests in the clinical group, consistent with fMRI results in which there were functional changes in the orbitofrontal networks (OFC). These changes were concordantly seen both in a simple task fMRI but also in resting-state fMRI, which was analyzed with dynamic causal modeling (DCM). We hypothesized that playing piano, as designed in the training protocol, may provide a positive increase in both well-being and social interaction. We suggest that the novelty of the intervention may have clinical relevance for patients with behavioral problems following a TBI.


A valid and reliable nutrition knowledge questionnaire for track and field athletes.
Establishing an understanding of an athlete's nutrition knowledge can inform the coach/practitioner and support the development of the athlete. Thus the purpose of the study was to develop a psychometrically valid and reliable tool to assess general and sport nutrition knowledge. An 85 question questionnaire was developed in consultation with a panel of experts. Ninety-eight participants from the UK completed the questionnaire, and again 3 weeks later. The participants were classified into two groups: those with nutrition (NUT, n = 53) training (sport nutritionists and dietitians who were either practicing or undertaking a postgraduate qualification in the field), and those without (NONUT, n = 48) training (professionals and postgraduate students with no exposure to any form of nutrition training). The questionnaire was then administered to a pilot cohort of UK based track and field athletes (n = 59) who were requested to time how long it took to complete the questionnaire. Psychometric statistical analysis of the results was completed, resulting in the removal of 23 questions for a total of 62 questions in the final questionnaire. The validated questionnaire was then administered to 58 track and field athletes. Internal consistency was assessed using Chronbach's alpha (α > 0.7), Pearson's correlation (p < 0.05) was used to assess reliability. Construct validity was evaluated using a t-test (p < 0.05). A total test retest correlation of 0.95 was achieved (sub-section range: 0.87-0.97). Internal consistency was accepted in each sub-section (α = 0.78-0.92) and the nutrition-trained group scored significantly higher on the overall questionnaire (80.4 vs 49.6%). The overall score for the athletic group was 61.0%. The questionnaire satisfied all psychometric measures and provides a new valid and reliable tool to assess general and sport nutrition knowledge of track and field athlete.


Sources of opioid medication for misuse in older adults: results from a nationally representative survey.
Despite increasing rates of prescription opioid (PO) misuse in adults 50 years of age and older, little research has investigated such misuse in this population. This work aimed to examine sources of misused opioid medication in adults 50 years and older, with comparisons to younger groups. Data were from the 2009 to 2014 National Survey on Drug Use and Health surveys. Prevalence rates of PO sources, misuse, and PO use disorder (POUD) symptoms were estimated. Design-based logistic regression investigated age-based differences in these factors and the association of sources with POUD symptoms and other concurrent substance use. Nearly half (47.7%) of adults 65 years and older used physician sources for past 30-day PO misuse, with the second highest rates in those 50 to 64 years old (39.2%). Conversely, use of theft (5.3%), purchases (8.5%), or friends/family (for free; 23.2%) to obtain opioids were least common in adults 65 years and older, with prevalence rates of these sources in those 50 years and older closer to those of younger groups. Across those 50 years and older, use of purchases, physician, or multiple sources were associated with elevated POUD symptom prevalence. Older adults, particularly those 65 years and older, use a different pattern of PO sources than adolescents or younger adults, and those using physician sources have elevated POUD symptoms. Physicians are a key avenue for older adults to obtain opioids for misuse, highlighting the potential role of clinicians in limiting such misuse.


Correlation of tolerogenicity of a viral antigen with its immunogenicity.
Induction of B cell tolerance or activation was analyzed with vesicular stomatitis virus (VSV) glycoprotein (G) expressed as a neo-self Ag. A membrane form of VSV-G expressed in all tissues, including the bone marrow, induced unresponsiveness at both the Th and B cell level, whereas a soluble form of VSV-G expressed peripherally in liver and kidney did not tolerize B cells and only reversibly anergized Th cells. Interestingly, a similar correlation was found for activation of mature lymphocytes. When mature normal spleen cells were transferred into the two transgenic mouse lines, the membrane form of VSV-G was strongly immunogenic for both Th and B cells, and high VSV-G-specific IgG Ab titers were induced in these transgenic mice. In contrast, spleen cells transferred into mice expressing the soluble form of VSV-G were not activated, and no VSV-G specific Abs were induced. These results indicate that highly immunogenic Ags are strongly tolerogenic for both immature B and T cells.


The folding and design of repeat proteins: reaching a consensus.
Although they are widely distributed across kingdoms and are involved in a myriad of essential processes, until recently, repeat proteins have received little attention in comparison to globular proteins. As the name indicates, repeat proteins contain strings of tandem repeats of a basic structural element. In this respect, their construction is quite different from that of globular proteins, in which sequentially distant elements coalesce to form the protein. The different families of repeat proteins use their diverse scaffolds to present highly specific binding surfaces through which protein-protein interactions are mediated. Recent studies seek to understand the stability, folding and design of this important class of proteins.


Evidence-based medicine: is it a bridge too far?
This paper aims to describe the contextual factors that gave rise to evidence-based medicine (EBM), as well as its controversies and limitations in the current health context. Our analysis utilizes two frameworks: (1) a complex adaptive view of health that sees both health and healthcare as non-linear phenomena emerging from their different components; and (2) the unified approach to the philosophy of science that provides a new background for understanding the differences between the phases of discovery, corroboration, and implementation in science. The need for standardization, the development of clinical epidemiology, concerns about the economic sustainability of health systems and increasing numbers of clinical trials, together with the increase in the computer's ability to handle large amounts of data, have paved the way for the development of the EBM movement. It was quickly adopted on the basis of authoritative knowledge rather than evidence of its own capacity to improve the efficiency and equity of health systems. The main problem with the EBM approach is the restricted and simplistic approach to scientific knowledge, which prioritizes internal validity as the major quality of the studies to be included in clinical guidelines. As a corollary, the preferred method for generating evidence is the explanatory randomized controlled trial. This method can be useful in the phase of discovery but is inadequate in the field of implementation, which needs to incorporate additional information including expert knowledge, patients' values and the context. EBM needs to move forward and perceive health and healthcare as a complex interaction, i.e. an interconnected, non-linear phenomenon that may be better analysed using a variety of complexity science techniques.