Public and private language ideologies as reflected in language attitudes on the Island of Korcula.
Since languages are such powerful means of group identification, they may be considered as constitutive of communities. Attitudes expressed toward certain linguistic varieties may thus be perceived as attitudes held toward respective community-members. However, as attitudes are not always easily accessible, and are rarely one-dimensional but rather multi-layered, an insight into overt (publicly proclaimed) and covert (privately held) ideologies can enhance understanding of language attitudes and their meaning. This paper brings the analysis of these two types of attitudes held by adolescents in three most populated places on the island of Korcula, Croatia. The analysis is based on the results obtained by means of a questionnaire eliciting, among other things, overt attitudes toward six local, regional and supra-regional varieties, and covert attitudes toward judges' local speech and the Standard variety of Croatian. Although the results confirm some expected tendencies in the evaluation of different varieties, subsequently conducted analysis of speech recognition rates offers some valuable insights and interesting implications for further interpretation of the results.


Targeted Quantification of Phosphorylation Dynamics in the Context of EGFR-MAPK Pathway.
Large-scale phosphoproteomics with coverage of over 10,000 sites of phosphorylation have now been routinely achieved with advanced mass spectrometry (MS)-based workflows. However, accurate targeted MS-based quantification of phosphorylation dynamics, an important direction for gaining quantitative understanding of signaling pathways or networks, has been much less investigated. Herein, we report an assessment of the targeted workflow in the context of signal transduction pathways, using the epidermal growth factor receptor (EGFR)-mitogen-activated protein kinase (MAPK) pathway as our model. A total of 43 phosphopeptides from the EGFR-MAPK pathway were selected for the study. The recovery and sensitivity of two commonly used enrichment methods, immobilized metal affinity chromatography (IMAC) and titanium oxide (TiO2), combined with selected reaction monitoring (SRM)-MS were evaluated. The recovery of phosphopeptides by IMAC and TiO2 enrichment was quantified to be 38 ± 5% and 58 ± 20%, respectively, based on internal standards. Moreover, both enrichment methods provided comparable sensitivity from 1 to 100 μg starting peptides. Robust quantification was consistently achieved for most targeted phosphopeptides when starting with 25-100 μg peptides. However, the numbers of quantified targets significantly dropped when peptide samples were in the 1-25 μg range. Finally, IMAC-SRM was applied to quantify signaling dynamics of EGFR-MAPK pathway in Hs578T cells following 10 ng/mL EGF treatment. The kinetics of phosphorylation clearly revealed early and late phases of phosphorylation, even for very low abundance proteins. These results demonstrate the feasibility of robust targeted quantification of phosphorylation dynamics for specific pathways, even starting with relatively small amounts of protein.


The Rx for Change database: a first-in-class tool for optimal prescribing and medicines use.
Globally, suboptimal prescribing practices and medication errors are common. Guidance to health professionals and consumers alone is not sufficient to optimise behaviours, therefore strategies to promote evidence-based decision making and practice, such as decision support tools or reminders, are important. The literature in this area is growing, but is of variable quality and dispersed across sources, which makes it difficult to identify, access, and assess. To overcome these problems, by synthesizing and evaluating the data from systematic reviews, we have developed Rx for Change to provide a comprehensive, online database of the evidence for strategies to improve drug prescribing and use. We use reliable and valid methods to search and screen the literature, and to appraise and analyse the evidence from relevant systematic reviews. We then present the findings in an online format which allows users to easily access pertinent information related to prescribing and medicines use. The database is a result of the collaboration between the Canadian Agency for Drugs and Technologies in Health (CADTH) and two Cochrane review groups. To capture the body of evidence on interventions to improve prescribing and medicines use, we conduct comprehensive and regular searches in multiple databases, and hand-searches of relevant journals. We screen articles to identify relevant systematic reviews, and include them if they are of moderate or high methodological quality. Two researchers screen, assess quality, and extract data on demographic details, intervention characteristics, and outcome data. We report the results of our analysis of each systematic review using a standardised quantitative and qualitative format. Rx for Change currently contains over 200 summarised reviews, structured in a multi-level format. The reviews included in the database are diverse, covering various settings, conditions, or diseases and targeting a range of professional and consumer behaviors. Rx for Change is a novel database that synthesizes current research evidence about the effects of interventions to improve drug prescribing practices and medicines use.


Dentures discovered in larynx 8 days after general anaesthetic.
An active 72-year-old man presented to the accident and emergency department (A&E) with odynophagia, dysphagia and haemoptysis 6 days after a minor operation and was discharged after treatment for an aspiration pneumonia. He presented to A&E 2 days later with worsening symptoms and was found to have dentures lodged in his larynx which were then removed in theatre. For 6 weeks after removal, he had periodic episodes of frank haemoptysis requiring multiple blood transfusions and, after extensive investigation, was found to have an erosion into an arterial vessel on his right parapharyngeal wall, just posterior to the glossopharyngeal sulcus. This case raises questions about perioperative care in patients with dentures, diagnostic decision-making in the emergency care setting and postoperative care after delayed removal of foreign bodies from the upper aerodigestive tract.


Patient assessed health profile: a six-month quality of life questionnaire survey after day surgery.
Patient assessed quality of life is one of the principal end-points after day surgery. The aim of the present study was to describe the natural course, differences and timing of final evaluation for three common day surgical procedures; inguinal hernia repair (IHR), arthroscopic procedures (AS); and cosmetic breast augmentation (CBA). A total of 355 patients prospectively completed an extended eight-item EQ-5D questionnaire (pain, mobility, mood, self-care, activities, sleep, sex, need for analgesic), preoperatively and at one, three and six months postoperatively. Pain and mobility problems were frequently reported prior to surgery among IHR and AS patients, while CBA patients had less deviation from normal in the preoperative health profile. The proportions of patients reporting surgery-related deviations were 35%, 20% and 5% at one, three and six months respectively. After one month, 50% of AS patients still suffered subjective discomfort as compared to 13% and 20% of the IHR and CBA patients, respectively. Pain and ambulation problems were the most common symptoms in all groups. Six months after surgery, 94% of IHR, 89% of AS and 97% of CBA patients were fully recovered. No major morbidity or severe complications were observed and patients' satisfaction was high overall. We found procedure-specific changes in the postoperative health profile after day surgery. AS patients recovered more slowly compared with IHR and CBA patients. We conclude that time for final evaluation differs significantly between procedures.


Institutionalization of brief alcohol intervention in primary health care-the Finnish case.
There have been several research and practical projects to promote alcohol brief interventions (BIs) in healthcare settings, but no reports of nationwide outcome have so far been published. In Finland, these activities started in the early 1990s, and in the past years, the focus has been mainly on primary and occupational health care. The aim of the present study was to ascertain whether the extensive and long-lasting implementation efforts have led to the institutionalization of this activity among primary healthcare physicians and to the identification of factors that may be associated with it. The data were gathered by a questionnaire sent to all Finnish primary healthcare physicians in 2002 and 2007. In both years, the questionnaire contained questions on demographics, professional background and the physicians' own BI activity (regular, occasional, or none). In 2007, a question eliciting information about the change in BI activity during the past 5 years was added. The response rate was 67.1% (95% CI 65.4 to 68.8) (2,001/2,980) in 2002 and 50.9% (95% CI 49.2 to 52.6) (1,610/3,163) in 2007. The number of physicians offering BI had increased during the study years from 59.2 to 78.5%. Regular activity was reported in 2002 by 9.3% of physicians and in 2007 by 17.2% and occasional activity correspondingly by 49.9 and 61.3%. Of the physicians who offered BI in 2007, 52.4% reported increased activity and 42.6% similar activity to that reported 5 years earlier. Having a specialist's license in general practice or occupational health care or long experience as a primary healthcare physician predicted high activity. The BI activity of Finnish primary healthcare physicians is reasonably high and rising. Training and motivating those with low BI activity remains future challenge.


Reduction of photosynthetic sensitivity in response to abiotic stress in tomato is mediated by a new generation plant activator.
Yield losses as a result of abiotic stress factors present a significant challenge for the future of global food production. While breeding technologies provide potential to combat negative stress-mediated outcomes over time, interventions which act to prime plant tolerance to stress, via the use of phytohormone-based elicitors for example, could act as a valuable tool for crop protection. However, the translation of fundamental biology into functioning solution is often constrained by knowledge-gaps. Photosynthetic and transcriptomic responses were characterised in young tomato (Solanum lycopersicum L.) seedlings in response to pre-treatment with a new plant health activator technology, 'Alethea', followed by a subsequent 100 mM salinity stress. Alethea is a novel proprietary technology composed of three key constituent compounds; the hitherto unexplored compound potassium dihydrojasmonate, an analogue of jasmonic acid; sodium benzoate, a carboxylic acid precursor to salicylic acid, and the α-amino acid L-arginine. Salinity treatment led to a maximal 47% reduction in net photosynthetic rate 8 d following NaCl treatment, yet in Alethea pre-treated seedlings, sensitivity to salinity stress was markedly reduced during the experimental period. Microarray analysis of leaf transcriptional responses showed that while salinity stress and Alethea individually impacted on largely non-overlapping, distinct groups of genes, Alethea pre-treatment substantially modified the response to salinity. Alethea affected the expression of genes related to biotic stress, ethylene signalling, cell wall synthesis, redox signalling and photosynthetic processes. Since Alethea had clear effects on photosynthesis/chloroplastic function at the physiological and molecular levels, we also investigated the ability of Alethea to protect various crop species against methyl viologen, a potent generator of oxidative stress in chloroplasts. Alethea pre-treatment produced dramatic reductions in visible foliar necrosis caused by methyl viologen compared with non-primed controls. 'Alethea' technology mediates positive recovery of abiotic stress-induced photosynthetic and foliar loss of performance, which is accompanied by altered transcriptional responses to stress.


Imaging of acute pelvic pain.
Determining the cause of acute pelvic pain in the female patient is often a clinical challenge. Diagnostic imaging can be invaluable in this situation. Ectopic pregnancy, pelvic inflammatory disease, and hemorrhagic ovarian cysts are the most commonly diagnosed gynecologic conditions presenting with acute pelvic pain. Ovarian torsion and degenerating fibroids occur less frequently. Other causes to consider include endometriosis, and postpartum causes such as endometritis, or ovarian vein thrombosis. Finally, nongynecologic conditions may overlap in their presentation of acute pelvic pain and should also be considered. The most important of these is acute appendicitis.


Near-zero dispersion, highly nonlinear lead-silicate W-type fiber for applications at 1.55 microm.
We report the design, fabrication and characterization of a lead-silicate glass highly nonlinear W-type fiber with a flattened and near-zero dispersion profile in the 1.55 microm region. The fiber was composed of three types of commercial lead silicate glasses. Effectively single-mode guidance was observed in the fiber at 1550 nm. The nonlinear coefficient and the propagation loss at this wavelength were measured to be 820 W(-1)km(-1) and 2.1 dB/m, respectively. Investigations of the Brillouin threshold revealed no evidence of stimulated Brillouin scattering for continuous wave signal powers up to 29 dBm in a 2m sample of the fiber. A broadband dispersion measurement confirmed the near-zero dispersion values and the flat dispersion profile around 1550 nm, in good agreement with our simulations. Efficient four-wave-mixing, tunable across the whole C-band, was demonstrated in a 2.2m length of the fiber.


Vertigo in downhill mountain biking and road cycling.
Vertigo has been described after the practice of mountain bike. This study aimed to investigate the prevalence of vertigo following competitions or training sessions of downhill mountain biking (DMB) or road cycling (RC). One hundred and two DMB riders, 79 road cyclists and 73 control participants filled in a survey intended to evaluate the prevalence of vertigo in daily living activities and following competitions or training sessions. Vertigo causal factors (crashes, head trauma, fatigue, characteristics of the path/road ridden) were recorded. DMB riders and road cyclists did not report more vertigo during daily living activities than controls. But DMB riders older than 30 had more risk to report vertigo than age-matched road cyclists (OR: 5.06, 95% CI: 1.23-20.62). Road cyclists aged between 20 and 29 were 2.59-fold (95% CI: 1.06-6.27) more likely to report vertigo than controls. After competitions and training sessions, DMB riders were 2.33-fold (95% CI: 1.22-4.41) more likely to report vertigo than road cyclists. Vertigo causal factors were crash with head trauma in DMB riders and fatigue in road cyclists. Vertigo during daily living activities may be of concern for cyclists, particularly older DMB riders. The accumulation of impacts (crashes, vibrations) during the career of a DMB rider may generate micro-traumatisms of the central nervous system and/or peripheral vestibular structures, particularly the otolith organs. In RC, the pathophysiological mechanisms generating vertigo might be effort-related disturbance of homeostasis. To avoid injuries, DMB riders should be aware that vertigo may occur at the end of training sessions or competitions.


Human platelets contain SNARE proteins and a Sec1p homologue that interacts with syntaxin 4 and is phosphorylated after thrombin activation: implications for platelet secretion.
In response to thrombin and other extracellular activators, platelets secrete molecules from large intracellular vesicles (granules) to initiate thrombosis. Little is known about the molecular machinery responsible for vesicle docking and secretion in platelets and the linkage of that machinery to cell activation. We found that platelet membranes contain a full complement of interacting proteins-VAMP, SNAP-25, and syntaxin 4-that are necessary for vesicle docking and fusion with the plasma membrane. Platelets also contain an uncharacterized homologue of the Sec1p family that appears to regulate vesicle docking through its binding with a cognate syntaxin. This platelet Sec1 protein (PSP) bound to syntaxin 4 and thereby excluded the binding of SNAP-25 with syntaxin 4, an interaction critical to vesicle docking. As predicted by its sequence, PSP was detected predominantly in the platelet cytosol and was phosphorylated in vitro by protein kinase C (PKC), a secretion-linked kinase, incorporating 0.87 +/- 0.11 mol of PO4 per mole of protein. PSP was also specifically phosphorylated in permeabilized platelets after cellular stimulation by phorbol esters or thrombin and this phosphorylation was blocked by the PKC inhibitor Ro-31-8220. Phosphorylation by PKC in vitro inhibited PSP from binding to syntaxin 4. Taken together, these studies indicate that platelets, like neurons and other cells capable of regulated secretion, contain a unique complement of interacting vesicle docking proteins and PSP, a putative regulator of vesicle docking. The PKC-dependent phosphorylation of PSP in activated platelets and its inhibitory effects on syntaxin 4 binding provide a novel functional link that may be important in coupling the processes of cell activation, intracellular signaling, and secretion.


Slow intestinal transit contributes to elevate urinary p-cresol level in Italian autistic children.
The uremic toxin p-cresol (4-methylphenol) is either of environmental origin or can be synthetized from tyrosine by cresol-producing bacteria present in the gut lumen. Elevated p-cresol amounts have been previously found in the urines of Italian and French autism spectrum disorder (ASD) children up until 8 years of age, and may be associated with autism severity or with the intensity of abnormal behaviors. This study aims to investigate the mechanism producing elevated urinary p-cresol in ASD. Urinary p-cresol levels were thus measured by High Performance Liquid Chromatography in a sample of 53 Italian ASD children assessed for (a) presence of Clostridium spp. strains in the gut by means of an in vitro fecal stool test and of Clostridium difficile-derived toxin A/B in the feces, (b) intestinal permeability using the lactulose/mannitol (LA/MA) test, (c) frequent use of antibiotics due to recurrent infections during the first 2 years of postnatal life, and (d) stool habits with the Bristol Stool Form Scale. Chronic constipation was the only variable significantly associated with total urinary p-cresol concentration (P < 0.05). No association was found with presence of Clostridium spp. in the gut flora (P = 0.92), augmented intestinal permeability (P = 0.18), or frequent use of antibiotics in early infancy (P = 0.47). No ASD child was found to carry C. difficile in the gut or to release toxin A/B in the feces. In conclusion, urinary p-cresol levels are elevated in young ASD children with increased intestinal transit time and chronic constipation. Autism Res 2016, 9: 752-759. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.


Determinants of angiotensin II generation during converting enzyme inhibition.
The reaction of the renin-angiotensin system to acute angiotensin converting enzyme inhibition was investigated in a single-blind, crossover study in nine normal volunteers receiving two out of three regimens in random order: the new converting enzyme inhibitor benazepril (20 mg once or 5 mg four times at 6-hour intervals) or enalapril (20 mg). Plasma converting enzyme activity, drug levels, angiotensin I and angiotensin II, active renin, and aldosterone were measured before and 1-4 hours and 14-30 hours after drug intake. Baseline in vitro plasma converting enzyme activity was 97 +/- 15 nmol/ml/min (mean +/- SD) when Hip-Gly-Gly was used as substrate, but with carbobenzoxy-Phe-His-Leu (Z-Phe-His-Leu) or angiotensin I as substrate it was only 20 +/- 4 and 1.7 +/- 0.3 nmol/ml/min, respectively. Discriminating power at peak converting enzyme inhibition was enhanced with the two latter substrates. In vivo converting enzyme activity was estimated by the plasma angiotensin II/angiotensin I ratio, which correlated well with in vitro converting enzyme activity using Z-Phe-His-Leu as substrate (r = 0.76, n = 252). Angiotensin II levels returned to baseline less than 24 hours after drug administration, whereas in vitro and in vivo converting enzyme activity remained considerably inhibited and active renin together with angiotensin I levels were still elevated. A close linear relation was found between plasma angiotensin II and the angiotensin I/drug level ratio (r = 0.91 for benazeprilat and r = 0.88 for enalaprilat, p less than 0.001). Thus, plasma angiotensin II truly reflects the resetting of the renin-angiotensin system at any degree of converting enzyme inhibition. The ratio of plasma angiotensin II to angiotensin I represents converting enzyme inhibition more accurately than in vitro assays, which vary considerably depending on substrates and assay conditions used.


Acetylsalicylic acid and ascorbic acid combination improves cognition; via antioxidant effect or increased expression of NMDARs and nAChRs?
Chronic inflammation occurs systematically in the central nervous system during ageing, it has been shown that neuroinflammation plays an important role in the pathogenesis of many neurodegenerative disorders. Aspirin, a nonselective COX inhibitor, as well as ascorbic acid, has been purported to protect cerebral tissue. We investigated the effects of subchronic aspirin and ascorbic acid usage on spatial learning, oxidative stress and expressions of NR2A, NR2B, nAChRα7, α4 and β2. Forty male rats (16-18 months) were divided into 4 groups, namely, control, aspirin-treated, ascorbic acid-treated, aspirin+ascorbic acid-treated groups. Following 10-weeks administration period, rats were trained and tested in the Morris water maze. 8-Hydroxy-2-deoxyguanosine and malondialdehyde were evaluated by ELISA and HPLC, respectively. Receptor expressions were assessed by western blotting of hippocampi. Spatial learning performance improved partially in the aspirin group, but significant improvement was seen in the aspirin+ascorbic acid group (p < 0.05). While 8-hydroxy-2-deoxyguanosine and malondialdehyde levels were significantly decreased, NR2B and nAChRα7 expressions were significantly increased in the aspirin+ascorbic acid group as compared to the control group (p < 0.05). Subchronic treatment with aspirin+ascorbic acid in aged rats was shown to enhance cognitive performance and increase the expressions of several receptors related to learning and memory process.


Neuronal diversity and temporal dynamics: the unity of hippocampal circuit operations.
In the cerebral cortex, diverse types of neurons form intricate circuits and cooperate in time for the processing and storage of information. Recent advances reveal a spatiotemporal division of labor in cortical circuits, as exemplified in the CA1 hippocampal area. In particular, distinct GABAergic (gamma-aminobutyric acid-releasing) cell types subdivide the surface of pyramidal cells and act in discrete time windows, either on the same or on different subcellular compartments. They also interact with glutamatergic pyramidal cell inputs in a domain-specific manner and support synaptic temporal dynamics, network oscillations, selection of cell assemblies, and the implementation of brain states. The spatiotemporal specializations in cortical circuits reveal that cellular diversity and temporal dynamics coemerged during evolution, providing a basis for cognitive behavior.


Sensorimotor adaptation as a behavioural biomarker of early spinocerebellar ataxia type 6.
Early detection of the behavioural deficits of neurodegenerative diseases may help to describe the pathogenesis of such diseases and establish important biomarkers of disease progression. The aim of this study was to identify how sensorimotor adaptation of the upper limb, a cerebellar-dependent process restoring movement accuracy after introduction of a perturbation, is affected at the pre-clinical and clinical stages of spinocerebellar ataxia type 6 (SCA6), an inherited neurodegenerative disease. We demonstrate that initial adaptation to the perturbation was significantly impaired in the eighteen individuals with clinical motor symptoms but mostly preserved in the five pre-clinical individuals. Moreover, the amount of error reduction correlated with the clinical symptoms, with the most symptomatic patients adapting the least. Finally both pre-clinical and clinical individuals showed significantly reduced de-adaptation performance after the perturbation was removed in comparison to the control participants. Thus, in this large study of motor features in SCA6, we provide novel evidence for the existence of subclinical motor dysfunction at a pre-clinical stage of SCA6. Our findings show that testing sensorimotor de-adaptation could provide a potential predictor of future motor deficits in SCA6.


Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial.
Patients with dilated cardiomyopathy whose symptoms and cardiac function have recovered often ask whether their medications can be stopped. The safety of withdrawing treatment in this situation is unknown. We did an open-label, pilot, randomised trial to examine the effect of phased withdrawal of heart failure medications in patients with previous dilated cardiomyopathy who were now asymptomatic, whose left ventricular ejection fraction (LVEF) had improved from less than 40% to 50% or greater, whose left ventricular end-diastolic volume (LVEDV) had normalised, and who had an N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) concentration less than 250 ng/L. Patients were recruited from a network of hospitals in the UK, assessed at one centre (Royal Brompton and Harefield NHS Foundation Trust, London, UK), and randomly assigned (1:1) to phased withdrawal or continuation of treatment. After 6 months, patients in the continued treatment group had treatment withdrawn by the same method. The primary endpoint was a relapse of dilated cardiomyopathy within 6 months, defined by a reduction in LVEF of more than 10% and to less than 50%, an increase in LVEDV by more than 10% and to higher than the normal range, a two-fold rise in NT-pro-BNP concentration and to more than 400 ng/L, or clinical evidence of heart failure, at which point treatments were re-established. The primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02859311. Between April 21, 2016, and Aug 22, 2017, 51 patients were enrolled. 25 were randomly assigned to the treatment withdrawal group and 26 to continue treatment. Over the first 6 months, 11 (44%) patients randomly assigned to treatment withdrawal met the primary endpoint of relapse compared with none of those assigned to continue treatment (Kaplan-Meier estimate of event rate 45·7% [95% CI 28·5-67·2]; p=0·0001). After 6 months, 25 (96%) of 26 patients assigned initially to continue treatment attempted its withdrawal. During the following 6 months, nine patients met the primary endpoint of relapse (Kaplan-Meier estimate of event rate 36·0% [95% CI 20·6-57·8]). No deaths were reported in either group and three serious adverse events were reported in the treatment withdrawal group: hospital admissions for non-cardiac chest pain, sepsis, and an elective procedure. Many patients deemed to have recovered from dilated cardiomyopathy will relapse following treatment withdrawal. Until robust predictors of relapse are defined, treatment should continue indefinitely. British Heart Foundation, Alexander Jansons Foundation, Royal Brompton Hospital and Imperial College London, Imperial College Biomedical Research Centre, Wellcome Trust, and Rosetrees Trust.


Cumulative Blood Pressure Exposure During Young Adulthood and Mobility and Cognitive Function in Midlife.
High blood pressure (BP) is a known risk factor for mobility and cognitive impairment in older adults. This study tested the association of cumulative BP exposure from young adulthood to midlife with gait and cognitive function in midlife. Furthermore, we tested whether these associations were modified by cerebral white matter hyperintensity (WMH) burden. We included 191 participants from the CARDIA study (Coronary Artery Risk Development in Young Adults), a community-based cohort of young individuals followed over 30 years. Cumulative BP was calculated as the area under the curve (mm Hg×years) from baseline up to year 30 examination. Gait and cognition were assessed at the year 30 examination. Cerebral WMH was available at year 30 in a subset of participants (n=144) who underwent magnetic resonance imaging. Multiple linear regression models were used to assess the association of cumulative BP exposure with gait and cognition. To test effect modification by WMH burden, participants were stratified at the median of WMH and tested for interaction. Higher cumulative systolic and diastolic BPs were associated with slower walking speed (both P=0.010), smaller step length (P=0.011 and 0.005, respectively), and higher gait variability (P=0.018 and 0.001, respectively). Higher cumulative systolic BP was associated with lower cognitive performance in the executive (P=0.021), memory (P=0.015), and global domains (P=0.010), and higher cumulative diastolic BP was associated with lower cognitive performance in the memory domain (P=0.012). All associations were independent of socio-demographics and vascular risk factors (body mass index, smoking, diabetes mellitus and total cholesterol). The association between cumulative BP and gait was moderated by WMH burden (interaction P<0.05). However, the relation between cumulative BP and cognitive function was not different based on the WMH burden (interaction P>0.05). Exposure to higher BP levels from young to midlife is associated with worse gait and cognitive performance in midlife. Furthermore, WMH moderates the association of cumulative BP exposure with gait, but not with cognitive function in midlife. The mechanisms underpinning the impact of BP exposure on brain structure and function must be investigated in longitudinal studies using a life course approach.


Impact of PSA screening on the incidence of advanced stage prostate cancer in the United States: a surveillance modeling approach.
and objective. Both the detection and the treatment of prostate cancer have undergone important clinical advances. Simultaneously, both distant stage incidence and disease-specific mortality have fallen in the United States. A recent study suggests that if prostate-specific antigen (PSA) testing explains the decline in distant stage incidence, then it may be largely responsible for the decline in mortality. The objective was to quantify this link between PSA screening and the decline in distant stage incidence. A fixed-cohort simulation model of prostate cancer progression and screening was adapted to a population-based model that integrates new data on trends in testing and biopsy practices. The model was calibrated to pre-PSA incidence and then screening was superimposed, obtaining incidence projections in the absence and presence of testing. This approach permits calculation of clinically relevant measures for model validation and direct assessment of the role of testing in the distant stage incidence decline. The model validated well with prior studies of natural history, and the sensitivity analysis indicated that the findings were robust to variation in model parameters. Model results indicate that PSA screening accounts for approximately 80% of the observed decline in distant stage incidence. PSA screening contributed to the observed declines in distant stage incidence and mortality in the 1990s. However, additional factors, such as increasing awareness of prostate cancer and advances in treatment, have probably also played a role in these trends.


[Cytochrome P-450 and the response to antimalarial drugs].
To assess the relationship between the genetic and phenotypic factors linked to the cytochrome P-450 enzyme system and the response to the antimalarial drugs chloroquine, amodiaquine, mefloquine, and proguanil, as well as to determine how certain biological and social factors of the host influence the behavior of this enzymatic complex. We performed a systematic review of the medical bibliographic databases PubMed, Excerpta Medica, LILACS, and SciELO by using the following Spanish and English descriptors: "CYP-450" and "citocromo P-450" in combination with "proguanil" (and with "mefloquina," "cloroquina," and "amodiaquina"), "farmacocinética de proguanil" (and the same using "mefloquina," "cloroquina," and "amodiaquina"), "resistencia a proguanil" (and the same using "mefloquina," "cloroquina," and "amodiaquina"), "metabolismo," "farmacogenética," "enfermedad," "inflamación," "infección," "enfermedad hepática," "malaria," "nutrición," and "desnutrición." The same terms were used in English. The search included only articles published in Spanish, English, and Portuguese on or before 30 June 2005 that dealt with only four antimalarial drugs: amodiaquine, chloroquine, mefloquine, and proguanil. Some genetic factors linked to human cytochrome P-450 (mainly its polymorphism), as well as other biological and social factors (the presence of disease itself, or of inflammation and infection, the use of antimalarials in their various combinations, and the patient's nutritional status) influence the behavior of this complex enzymatic system. It has only been in the last decade that the genetics of the cytochromes has been explored and that the mechanisms underlying some therapeutic interactions and aspects of drug metabolism have been uncovered, making it possible to characterize the biotransformation pathway of amodiaquine and chloroquine. Hopefully new research will help answer the questions that still remain, some of which pertain to the metabolism of other antimalarial drugs, the distribution in the population of the genetic alleles linked to the enzymes involved in their metabolism, the contribution of these genetic mutations to therapeutic failure, and the possibility of predicting the response to antimalarial therapy. The therapeutic response to antimalarial drugs is a multifactorial process that is poorly understood, so that it is not possible to ascribe to a specific phenotype or genotype a role in the response to antimalarial therapy. Attention should be given to biological and social factors, such as diet, nutritional status, and inflammatory and infectious processes that are often present in areas where malaria is endemic.


Establishing the Bioequivalence Safe Space for Immediate-Release Oral Dosage Forms using Physiologically Based Biopharmaceutics Modeling (PBBM): Case Studies.
For oral drug products, in vitro dissolution is the most used surrogate of in vivo dissolution and absorption. In the context of drug product quality, safe space is defined as the boundaries of in vitro dissolution, and relevant quality attributes, within which drug product variants are expected to be bioequivalent to each other. It would be highly desirable if the safe space could be established via a direct link between available in vitro data and in vivo pharmacokinetics. In response to the challenges with establishing in vitro-in vivo correlations (IVIVC) with traditional modeling approaches, physiologically based biopharmaceutics modeling (PBBM) has been gaining increased attention. In this manuscript we report five case studies on using PBBM to establish a safe space for BCS Class 2 and 4 across different companies, including applications in an industrial setting for both internal decision making or regulatory applications. The case studies provide an opportunity to reflect on practical vs. ideal datasets for safe space development, the methodologies for incorporating dissolution data in the model and the criteria used for model validation and application. PBBM and safe space, still represent an evolving field and more examples are needed to drive development of best practices.


SU-E-T-543: Beam Attenuation Characteristics of Treatment Couches.
Measure photon beam attenuation characteristics of the Varian EXACT, Varian IGRT treatment couches and two CIVCO Universal extensions; and assess accuracy of Varian's Eclipse treatment planning system in modeling the beam attenuation of each couch. Dose Measurements were taken using a Farmer ion chamber inside a cylindrical acrylic phantom. They were taken for two photon energies (6MV and 15MV), at three different field sizes, for various gantry angles through the couch. EXACT couch was tested both with the adjustable rails pushed to the outside of the couch, and pushed to the center of the couch. IGRT couch was divided by thickness into three sections. Effects on surface dose were measured using a Tissue Maximum Ratio or Percent Depth Dose curve. CIVCO extensions were CT scanned for inclusion in the planning system. All measurements were modeled in the Eclipse treatment planning system for comparison. Maximum attenuation was measured at 6MV with the smallest field for all couch setups. The EXACT couch produced a maximum attenuation of 19.2% and a surface dose increase of 47% of Dmax through the couch. Maximum attenuation for the IGRT couch and both CIVCO extensions were between 6-8%. Through the couch, the IGRT couch showed a surface dose increase of 29% of Dmax,; the CIVCO extensions produced a surface dose increase of 33% and 7% of Dmax. Maximum difference between measured and planned dose was 7%, for the EXACT couch, 1.9% for the IGRT couch and 2.4% for both CIVCO extensions. These treatment couches were shown to affect delivered and surface dose. Including the couch structure during treatment planning can account for the couch attenuation in most cases, but some attenuation values are underestimated in the planning software. Largest effects are for oblique treatment angles using low energy and small field sizes.


Recent advances in photoresponsive supramolecular self-assemblies.
Construction of supramolecular self-assemblies whose self-assembling process and self-assembled architectures can be controlled by external stimuli is a fascinating and challenging topic for supramolecular chemists. The modification of photochromic molecules with noncovalent interaction sites or the incorporation of photochromic molecules into self-assembling modules makes light an ideal external input, providing high-performance photoresponsive multicomponent self-assemblies. Among such systems, in this tutorial review we deal with several photoresponsive supramolecular self-assemblies showing a unique mechanism and/or type of photoresponse. These examples illustrate that we would be able to produce further new photoresponsive molecular ensembles if one can elaborately hybridize photochromic molecules to specifically-designed supramolecular self-assemblies. We believe that the accumulation of insight into the construction principle, mechanism and concept of such smart supramolecular self-assemblies should realize practical smart functional materials.


The impact of adopting stress-tolerant maize on maize yield, maize income, and food security in Tanzania.
Productivity growth emanating from scientific advances offered by biotechnology and other plant breeding initiatives offers great promise for meeting the growing food demand worldwide. This justifies investments in agricultural research and development that have led to the development of stress-tolerant maize varieties (STMVs) in Africa. While most literature has documented the average impacts of STMVs on productivity, this paper is premised on the fact that benefits from technology adoption are not the same across household. The paper addresses this information gap by examining potential heterogeneity in yield, income, and food security benefits from of adopting STMVs using a sample of 720 maize-producing households from Tanzania. The dose-response continuous treatment effect method supported by an endogenous switching probit model was used to estimate the heterogenous impact of STMV adoption on the three outcomes of interest. Results show that, overall, the adoption of stress-tolerant maize varieties increased maize grain yield by about 1 ton/ha, maize income by about $62/ha. The adoption of STMVs also reduced the propensity to report mild, moderate, and severe food insecurity by 34%, 17%, and 6%, respectively. There are substantial idiosyncratic variations in the productivity, income, and food security effects depending on the scale of adoption, with a higher impact at lower dose levels of adoption. The heterogenous and pro-poor nature of STMV adoption is also revealed through nonparametric results showing higher productivity benefits among households that are less endowed with wealth and knowledge. These findings underscore the need for further scaling of stress-tolerant maize varieties for greater impact on the livelihoods of poor small-scale farmers in Tanzania.


Willingness to Participate in Passive Mobile Data Collection.
The rising penetration of smartphones now gives researchers the chance to collect data from smartphone users through passive mobile data collection via apps. Examples of passively collected data include geolocation, physical movements, online behavior and browser history, and app usage. However, to passively collect data from smartphones, participants need to agree to download a research app to their smartphone. This leads to concerns about nonconsent and nonparticipation. In the current study, we assess the circumstances under which smartphone users are willing to participate in passive mobile data collection. We surveyed 1,947 members of a German nonprobability online panel who own a smartphone using vignettes that described hypothetical studies where data are automatically collected by a research app on a participant's smartphone. The vignettes varied the levels of several dimensions of the hypothetical study, and respondents were asked to rate their willingness to participate in such a study. Willingness to participate in passive mobile data collection is strongly influenced by the incentive promised for study participation but also by other study characteristics (sponsor, duration of data collection period, option to switch off the app) as well as respondent characteristics (privacy and security concerns, smartphone experience).


Distinguishing state variability from trait change in longitudinal data: the role of measurement (non)invariance in latent state-trait analyses.
Researchers analyzing longitudinal data often want to find out whether the process they study is characterized by (1) short-term state variability, (2) long-term trait change, or (3) a combination of state variability and trait change. Classical latent state-trait (LST) models are designed to measure reversible state variability around a fixed set-point or trait, whereas latent growth curve (LGC) models focus on long-lasting and often irreversible trait changes. In the present article, we contrast LST and LGC models from the perspective of measurement invariance testing. We show that establishing a pure state-variability process requires (1) the inclusion of a mean structure and (2) establishing strong factorial invariance in LST analyses. Analytical derivations and simulations demonstrate that LST models with noninvariant parameters can mask the fact that a trait-change or hybrid process has generated the data. Furthermore, the inappropriate application of LST models to trait change or hybrid data can lead to bias in the estimates of consistency and occasion specificity, which are typically of key interest in LST analyses. Four tips for the proper application of LST models are provided.


Magnesium in metabolic syndrome: a review based on randomized, double-blind clinical trials.
A growing body of evidence shows the effect of magnesium on serum glucose, HDL-cholesterol, and triglycerides levels, as well as on blood pressure, which strongly suggests that magnesium might play an important role in metabolic syndrome (MetS), a cluster of risk factors for cardiovascular disease and type 2 diabetes. We performed a systematic review of clinical evidence derived from randomized, double-blind, controlled clinical trials, regarding the efficacy of magnesium supplementation on the components of MetS. Using the electronic databases of Medline, Embase, and the Cochrane Controlled Trials Register up to May 2016, we looked for randomized controlled trials focused on the effects of oral magnesium supplementation on insulin sensitivity, glucose, triglyceride and HDL-cholesterol levels, as well as its effects on high blood pressure, irrespective of the magnesium salt used, and with a duration of at least four weeks. Crossover studies, irrespective of blinding criteria, were not included. Results of this review show that magnesium supplementation in individuals with hypomagnesemia can be effective in the treatment of MetS.


Olanzapine oro-dispersible (Velotab TM ) - an alternative to depot?
Olanzapine oro-dispersible (Velotab TM ) was introduced to the United Kingdom in May 2000. It rapidly dissolves in the mouth, and therefore patients may find it preferable to swallowing tablets. Another advantage is that the opportunity to hide the medication is much reduced. The study examined the usage of Velotab TM in a forensic psychiatry setting. Drug expenditure for different classes of antipsychotic was examined for 6 months before and 7 months after the introduction of olanzapine Velotab TM . The results showed a change in prescribing practice, with a significant inverse correlation between the use of Velotab TM and depot medication. This suggests that forensic psychiatrists, who may have particular concerns about compliance, had confidence in oro-dispersible administration as an alternative to depot medication. It is suggested that making other neuroleptics available in an oro-dispersible form would allow for a wider choice of atypicals in populations in whom there are significant compliance problems. (Int J Psych Clin Pract 2002; 6: 163-165).


Papilloedema, a complication of progressive diaphyseal dysplasia: a series of three case reports.
Progressive diaphyseal dysplasia (PDD) is a rare, autosomal dominant, osteosclerotic dysplasia affecting both endochondrally and intramembranously derived bones. Severely affected patients can develop progressive stenosis of the optic canals and compressive optic neuropathy. Although raised intracranial pressure (ICP) has been described in patients with PDD in whom visual loss has occurred, the elevation of ICP in those patients has been thought to be either non-contributory or only partially responsible for the accompanying visual loss. Three cases were reviewed and the clinical and radiological characteristics are described here. All three patients had bilateral optic disc swelling with no radiological evidence of either compressive optic neuropathy or thrombosis of the intracranial venous sinuses. The aetiology of the disc swelling was proved to be papilloedema in the first two cases and was probably the dominant cause in the third case. The visual loss documented in at least two of the three patients reported appears to be solely attributable to raised ICP. Normalisation of the ICP has led to an improvement and stabilisation of the visual function in all three patients. Patients with PDD probably require periodic ophthalmic assessments.


Independent variation and positive selection in env V1 and V2 domains within maternal-infant strains of human immunodeficiency virus type 1 in vivo.
Multiple targets for immune recognition and cellular tropism are localized to the V1 and V2 hypervariable regions in the amino portion of human immunodeficiency virus type 1 (HIV-1) gp120env. We have assessed genetic diversity in env V1 and V2 hypervariable domains in vivo within epidemiologically related strains of HIV-1. Our strategy was to analyze longitudinal samples from two seropositive mothers and multiple children infected by perinatal transmission. Although the V1 and V2 domains are closely linked in the HIV-1 genome, nucleotide sequences in V1 and in V2 evolved independently in maternal-infant viruses in vivo. A high proportion of the nucleotide substitutions would introduce amino acid diversity in V1 and in V2. A significant excess of nonsynonymous over synonymous substitutions was identified in HIV-1 env V1 and V2 peptides in the mothers and in two older children but was not generally apparent in HIV-1 sequences in infants. An excess of nonsynonymous over synonymous substitutions indicated that there is positive selection for independent genetic variation in the V1 and V2 domains in vivo. It is likely that there are host responses to complex determinants in the V1 or V2 hypervariable domain of HIV-1 gp120.


The Analysis of Poisoning Cases Presented to the Emergency Department within a One-Year Period.
Intoxication is the emergence of unwanted signs and symptoms in an organism after exposure to potentially harmful chemical, physical or organic materials. In our study, we evaluated demographic and etiological factors of adult patients admitted to the emergency department with suicidal or accidental poisoning. This study was conducted retrospectively by using data from the forensics books, protocol notebooks and patient files. Patients over the age of 14 years that were admitted to the Goztepe Training and Research Hospital during a 1-year period (September 2011-September 2012) with poisoning were included in the study. A total of 430 patients were included in the study and 278 of those patients were females (64.7%). The male/female (F/M) ratio was 1.82/1 and the mean age of the patients was 27.4±11.75 years. The analyses showed that in 348 patients (80.93%) the cause of poisoning was medicine, in 39 patients (9.06%) alcohol and drugs, in 37 patients (8.6%) rat poison, in 4 patients (0.93%) a caustic substance and organophosphates in 2 patients (0.46%). The highest rate of admittance due to poisoning was seen in July, followed by August and September. When the frequency of admittance was evaluated in terms of seasons: summer had the highest frequency with 35.6%, then autumn with 29.1%, spring with 19.8% and winter with 15.6%. The results of our studies are similar to previously reported studies in Turkey. Poisoning cases are more common in women and the most common way of poisoning is by medication. Unlike previous reports from the literature, we found that poisoning was most frequent in the summer.


Expert consensus document: Advances in the diagnosis and classification of gastric and intestinal motility disorders.
Disturbances of gastric, intestinal and colonic motor and sensory functions affect a large proportion of the population worldwide, impair quality of life and cause considerable health-care costs. Assessment of gastrointestinal motility in these patients can serve to establish diagnosis and to guide therapy. Major advances in diagnostic techniques during the past 5-10 years have led to this update about indications for and selection and performance of currently available tests. As symptoms have poor concordance with gastrointestinal motor dysfunction, clinical motility testing is indicated in patients in whom there is no evidence of causative mucosal or structural diseases such as inflammatory or malignant disease. Transit tests using radiopaque markers, scintigraphy, breath tests and wireless motility capsules are noninvasive. Other tests of gastrointestinal contractility or sensation usually require intubation, typically represent second-line investigations limited to patients with severe symptoms and are performed at only specialized centres. This Consensus Statement details recommended tests as well as useful clinical alternatives for investigation of gastric, small bowel and colonic motility. The article provides recommendations on how to classify gastrointestinal motor disorders on the basis of test results and describes how test results guide treatment decisions.


Phase shift of the circannual reproductive rhythm in European hamsters by 2 days of long photoperiod.
In European hamsters a circannual clock drives the seasonal changes in the reproductive state. Its resetting by photoperiod is clearly phase dependent. In mid subjective winter a 1-month pulse of long photoperiod (LP) advances the onset of the reproductive phase of animals maintained in constant short photoperiod (SP) by up to 1.5 months. The present study investigated whether shorter pulses, i.e. 8, 4 or 2 days LP-pulses are still effective to phase shift the circannual rhythm. All pulses induced gonadal development after a similar time relative to the offset of the pulse and earlier than in the control group. Thus, they all shared a similar effectiveness. In European hamsters a very brief LP-pulse can phase shift the reproductive rhythm but its strength is not determined by its duration at least not in the tested range.


Does who you marry matter for your health? Influence of patients' and spouses' personality on their partners' psychological well-being following coronary artery bypass surgery.
Research suggests that presurgical personality attributes influence postsurgical well-being in both patients and their spouses in the context of coronary artery bypass grafting (CABG) surgery. The authors hypothesized that a spouse's characteristics would influence a partner's psychological well-being, regardless of whether he or she was the patient or the caregiver. In this study, 111 male patients and their caregiver spouses completed measures of neuroticism, optimism, perceived marital satisfaction, and depression prior to elective CABG. Follow-up was conducted at 18 months. As expected, higher caregiver presurgical neuroticism predicted higher patient depressive symptoms at follow-up, with caregiver's concurrent 18-month affect controlled for. Likewise, higher patient presurgical neuroticism predicted higher caregiver depressive symptoms at follow-up. Additionally, higher patient presurgical depressive symptoms and lower presurgical optimism contributed to greater caregiving burden. Relationship satisfaction moderated these effects. These results suggest that partners' personality traits are important determinants of both patients' and their caregiving spouses' well-being.


Cold snare polypectomy with pull technique of flat colonic polyps up to 12 mm: a porcine model.
Most colonoscopic complications are polypectomy-related and occur more frequently during the removal of numerous small polyps. Therefore, it is important to have the best polypectomy approach of small polyps. The aim of the present animal study was to investigate the effectiveness and safety of cold snare polypectomy (CSP) technique combined with light pull of the snare in order to peel the mucosal and upper submucosal layer, namely pull CSP (PCSP), for the removal of polyps sized up to 12 mm in porcine models. We performed a series of polypectomies in the pig colon with a double-channel experimental gastroscope using PCSP technique. Thirty cases of "polyps" larger than 7 mm and up to 12 mm were treated using PCSP technique. No sign of perforation or bleeding was observed in all cases performed with PCSP. According to our preliminary results in this animal model, PCSP could be a safe and effective technique for flat colonic polyp removal up to 12 mm in size consistent with the basic polypectomy principles.


A checklist to improve reporting of group-based behaviour-change interventions.
Published descriptions of group-based behaviour-change interventions (GB-BCIs) often omit design and delivery features specific to the group setting. This impedes the ability to compare behaviour-change interventions, synthesise evidence on their effectiveness and replicate effective interventions. The aim of this study was to develop a checklist of elements that should be described to ensure adequate reporting of GB-BCIs. A range of characteristics needed to replicate GB-BCIs were extracted from the literature and precisely defined. An abbreviated checklist and a coder manual were developed, pilot tested and refined. The final checklist and coder manual were used to identify the presence or absence of specified reporting elements in 30 published descriptions of GB-BCIs by two independent coders. Reliability of coding was assessed. The checklist comprises 26 essential reporting elements, covering intervention design, intervention content, participant characteristics, and facilitator characteristics. Inter-rater reliability for identification of reporting elements was high (95% agreement, Mean AC1 = 0.89). The checklist is a practical tool that can be used, alongside other reporting guidelines, to ensure comprehensive description and to assess reporting quality of GB-BCIs. It can also be helpful for designing group-based health interventions.


Recognition Receiver Operating Characteristic Curves: The Complex Influence of Input Statistics, Memory, and Decision-making.
Receiver operating characteristic (ROC) analysis is the standard tool for studying recognition memory. In particular, the curvilinearity and the y-offset of recognition ROC curves have been interpreted as indicative of either memory strength (single-process models) or different memory processes (dual-process model). The distinction between familiarity and recollection has been widely studied in cognitive neuroscience in a variety of conditions, including lesions of different brain regions. We develop a computational model that explicitly shows how performance in recognition memory is affected by a complex and, as yet, underappreciated interplay of various factors, such as stimulus statistics, memory processing, and decision-making. We demonstrate that (1) the factors in the model affect recognition ROC curves in unexpected ways, (2) fitting R and F parameters according to the dual-process model is not particularly useful for understanding the underlying processes, and (3) the variability of recognition ROC curves and the controversies they have caused might be due to the uncontrolled variability in the contributing factors. Although our model is abstract, its functional components can be mapped onto brain regions, which are involved in corresponding functions. This enables us to reproduce and interpret in a coherent framework the diverse effects on recognition memory that have been reported in patients with frontal and hippocampal lesions. To conclude, our work highlights the importance of the rich interplay of a variety of factors in driving recognition memory performance, which has to be taken into account when interpreting recognition ROC curves.


Parent-child bed-sharing: The good, the bad, and the burden of evidence.
The practice of parent and child sharing a sleeping surface, or 'bed-sharing', is one of the most controversial topics in parenting research. The lay literature has popularized and polarized this debate, offering on one hand claims of dangers, and on the other, of benefits - both physical and psychological - associated with bed-sharing. To address the scientific evidence behind such claims, we systematically reviewed 659 published papers (peer-reviewed, editorial pieces, and commentaries) on the topic of parent-child bed-sharing. Our review offers a narrative walkthrough of the many subdomains of bed-sharing research, including its many correlates (e.g., socioeconomic and cultural factors) and purported risks or outcomes (e.g., sudden infant death syndrome, sleep problems). We found general design limitations and a lack of convincing evidence in the literature, which preclude making strong generalizations. A heat-map based on 98 eligible studies aids the reader to visualize world-wide prevalence in bed-sharing and highlights the need for further research in societies where bed-sharing is the norm. We urge for multiple subfields - anthropology, psychology/psychiatry, and pediatrics - to come together with the aim of understanding infant sleep and how nightly proximity to the parents influences children's social, emotional, and physical development.


Light scattering characteristics of various aerosol types derived from multiple wavelength lidar observations.
The present study demonstrates the potential of a multiple wavelength lidar for discriminating between several aerosol types such as maritime, continental, stratospheric, and desert aerosols on the basis of wavelength dependence of the aerosol backscatter coefficient. In the analysis of lidar signals, the two-component lidar equation was solved under the assumption of similarity in the derived profiles of backscatter coefficients for each wavelength, and this made it possible to reduce the uncertainty in the extinction/backscatter ratio, which is a key parameter in the lidar solution. It is shown that a three-wavelength lidar system operating at 300, 600, and 1064 nm can provide unique information for discriminating between various aerosol types such as continental, maritime, Saharan dust, stratospheric aerosols in a tropopause fold event, and tropical forest aerosols. Measurement error estimation was also made through numerical simulations. Mie calculations were made using in situ aerosol data and aerosol models to compare with the lidar results. There was disagreement between the theoretical and empirical results, which in some cases was substantial. These differences may be partly due to uncertainties in the lidar data analysis and aerosol characteristics and also due to the conventional assumption of aerosol sphericity for the aerosol Mie calculations.


Osteopathic Medical Care With and Without Osteopathic Manipulative Treatment in Patients With Chronic Low Back Pain: A Pain Registry-Based Study.
The OSTEOPATHIC Trial demonstrated substantial improvement in pain intensity, decreased need for rescue medication for pain, and greater likelihood of recovery in patients with chronic low back pain who received 6 osteopathic manipulative treatment (OMT) sessions over 3 months. To assess osteopathic medical care and the effectiveness of OMT for chronic low back pain in a real-world setting without the constraints of a rigid research protocol. An observational study of 445 adults with chronic low back pain who had an established osteopathic physician (ie, DO) or allopathic physician (ie, MD) was conducted within the PRECISION Pain Research Registry from April 2016 through February 2019. Primary outcome measures included a numerical rating scale for low back pain intensity, the Roland-Morris Disability Questionnaire for back-related functioning, and use of nonsteroidal anti-inflammatory drugs or opioids for low back pain. A total of 79, 48, and 318 patients, respectively, were treated by DOs who used OMT, DOs who did not use OMT, or MDs. Patients treated by DOs who used OMT reported significantly lesser low back pain intensity (mean numerical rating score, 5.6; 95% CI, 5.1-6.1 vs 6.1; 95% CI, 5.9-6.3; P=.04) and back-related disability (mean Roland-Morris Disability score, 12.4; 95% CI, 11.1-13.8 vs 14.4; 95% CI, 13.7-15.0; P=.009) than patients treated by MDs. Patients treated by DOs who used OMT also reported less frequent use of nonsteroidal anti-inflammatory drugs (multivariate odds ratio, 0.41; 95% CI, 0.24-0.70; P=.001) or opioids (multivariate odds ratio, 0.52; 95% CI, 0.28-0.98; P=.04). There were no significant differences in primary outcomes between DOs who did not use OMT and MDs. This study of community-based patients in a pain research registry supports the effectiveness of OMT as an integral component of osteopathic medical care for chronic low back pain. Patients treated by DOs who did not use OMT did not experience better results than patients treated by MDs in any primary outcome measure. Further research is needed to more specifically compare the effects of OMT with other treatment effects that may be attributed to patient-DO interactions during medical encounters.


Learning with multiple pairwise kernels for drug bioactivity prediction.
Many inference problems in bioinformatics, including drug bioactivity prediction, can be formulated as pairwise learning problems, in which one is interested in making predictions for pairs of objects, e.g. drugs and their targets. Kernel-based approaches have emerged as powerful tools for solving problems of that kind, and especially multiple kernel learning (MKL) offers promising benefits as it enables integrating various types of complex biomedical information sources in the form of kernels, along with learning their importance for the prediction task. However, the immense size of pairwise kernel spaces remains a major bottleneck, making the existing MKL algorithms computationally infeasible even for small number of input pairs. We introduce pairwiseMKL, the first method for time- and memory-efficient learning with multiple pairwise kernels. pairwiseMKL first determines the mixture weights of the input pairwise kernels, and then learns the pairwise prediction function. Both steps are performed efficiently without explicit computation of the massive pairwise matrices, therefore making the method applicable to solving large pairwise learning problems. We demonstrate the performance of pairwiseMKL in two related tasks of quantitative drug bioactivity prediction using up to 167 995 bioactivity measurements and 3120 pairwise kernels: (i) prediction of anticancer efficacy of drug compounds across a large panel of cancer cell lines; and (ii) prediction of target profiles of anticancer compounds across their kinome-wide target spaces. We show that pairwiseMKL provides accurate predictions using sparse solutions in terms of selected kernels, and therefore it automatically identifies also data sources relevant for the prediction problem. Code is available at https://github.com/aalto-ics-kepaco. Supplementary data are available at Bioinformatics online.


Gene targeting of GAN in mouse causes a toxic accumulation of microtubule-associated protein 8 and impaired retrograde axonal transport.
Mutations in gigaxonin were identified in giant axonal neuropathy (GAN), an autosomal recessive disorder. To understand how disruption of gigaxonin's function leads to neurodegeneration, we ablated the gene expression in mice using traditional gene targeting approach. Progressive neurological phenotypes and pathological lesions that developed in the GAN null mice recapitulate characteristic human GAN features. The disruption of gigaxonin results in an impaired ubiquitin-proteasome system leading to a substantial accumulation of a novel microtubule-associated protein, MAP8, in the null mutants. Accumulated MAP8 alters the microtubule network, traps dynein motor protein in insoluble structures and leads to neuronal death in cultured wild-type neurons, which replicates the process occurring in GAN null mutants. Defective axonal transport is evidenced by the in vitro assays and is supported by vesicular accumulation in the GAN null neurons. We propose that the axonal transport impairment may be a deleterious consequence of accumulated, toxic MAP8 protein.


A profile of Australian adults who have discussed their posthumous organ donation wishes with family members.
Next of kin who are aware of the deceased's organ donation wishes usually will honor those wishes, while next of kin who are unaware of these wishes typically withhold consent for posthumous donation. Encouraging individuals to communicate or register their organ donation wishes is therefore important. Using a sample of 409 participants, the current study sought to develop a profile of Australian adults who had communicated their organ donation wishes to family members. Christian participants and those who had a higher income were more likely to have communicated their donation wishes. Conversely, participants were less likely to have communicated their donation wishes if they were unregistered and undecided/opposed to organ donation, unregistered but willing to donate, or fearful of death. Finally, whether participants had communicated, registered, or communicated and registered their donation wishes was associated with their age, religion, attitude toward organ donation, and recall of media content about organ donation. Messages encouraging the communication of organ donation wishes to family members should therefore be targeted toward those individuals who are most likely to be receptive toward enacting this behavior.


Endocrine control of steroidogenesis in granulosa cells.
This review offers a summary of an increasingly complex literature which exists on the specific endocrine control of granulosa cell steroidogenesis. Further developments in cell biology will ultimately aid our greater understanding of pathophysiological regulation of the ovarian events underlying the human menstrual cycle. While we are beginning to unravel many of the important operational facets of this integrated process, our knowledge is still limited. Important questions remain to many clinical syndromes involving altered ovarian function, for example primary ovarian failure, polycystic ovary disease, resistant ovary syndrome, and so on. However, with the rapid continuing expansion of cellular and molecular technologies gaps in our understanding may be bridged in the near future, and thus enable physicians to evaluate better and treat disorders of ovarian function.


Prognostic value of innate and adaptive immunity in colorectal cancer.
Colorectal cancer (CRC) remains one of the major public health problems throughout the world. Originally depicted as a multi-step dynamical disease, CRC develops slowly over several years and progresses through cytologically distinct benign and malignant states, from single crypt lesions through adenoma, to malignant carcinoma with the potential for invasion and metastasis. Moving from histological observations since a long time, it has been recognized that inflammation and immunity actively participate in the pathogenesis, surveillance and progression of CRC. The advent of immunohistochemical techniques and of animal models has improved our understanding of the immune dynamical system in CRC. It is well known that immune cells have variable behavior controlled by complex interactions in the tumor microenvironment. Advances in immunology and molecular biology have shown that CRC is immunogenic and that host immune responses influence survival. Several lines of evidence support the concept that tumor stromal cells, are not merely a scaffold, but rather they influence growth, survival, and invasiveness of cancer cells, dynamically contributing to the tumor microenvironment, together with immune cells. Different types of immune cells infiltrate CRC, comprising cells of both the innate and adaptive immune system. A relevant issue is to unravel the discrepancy between the inhibitory effects on cancer growth exerted by the local immune response and the promoting effects on cancer proliferation, invasion, and dissemination induced by some types of inflammatory cells. Here, we sought to discuss the role played by innate and adaptive immune system in the local progression and metastasis of CRC, and the prognostic information that we can currently understand and exploit.


Experimental food supplementation reveals habitat-dependent male reproductive investment in a migratory bird.
Environmental factors can shape reproductive investment strategies and influence the variance in male mating success. Environmental effects on extrapair paternity have traditionally been ascribed to aspects of the social environment, such as breeding density and synchrony. However, social factors are often confounded with habitat quality and are challenging to disentangle. We used both natural variation in habitat quality and a food supplementation experiment to separate the effects of food availability-one key aspect of habitat quality-on extrapair paternity (EPP) and reproductive success in the black-throated blue warbler, Setophaga caerulescens. High natural food availability was associated with higher within-pair paternity (WPP) and fledging two broods late in the breeding season, but lower EPP. Food-supplemented males had higher WPP leading to higher reproductive success relative to controls, and when in low-quality habitat, food-supplemented males were more likely to fledge two broods but less likely to gain EPP. Our results demonstrate that food availability affects trade-offs in reproductive activities. When food constraints are reduced, males invest in WPP at the expense of EPP. These findings imply that environmental change could alter how individuals allocate their resources and affect the selective environment that drives variation in male mating success.


Maturation of the humoral autoimmune response to epitopes of GAD in preclinical childhood type 1 diabetes.
GAD is a major target of autoimmunity in preclinical type 1 diabetes. Here we examine the maturation of the humoral response to GAD epitopes sequentially from birth to diabetes onset or current follow-up in 29 GAD antibody (GADA)+ offspring of parents with diabetes from the BABYDIAB Study. Antibodies were measured against GAD65, GAD67, and GAD65/67 chimeras by radiobinding assay. In 28 of 29 offspring, the first GADAs contained reactivity against epitopes within GAD65 residues 96-444, suggesting that the middle GAD65 region is a primary target of GAD humoral autoimmunity. In 7 of these 28 offspring, initial antibody reactivity was against all epitope regions tested (middle GAD65, COOH-terminal GAD65 residues 445-585, NH2-terminal GAD65 residues 1-95, and GAD67); in 16 offspring, reactivity was to middle and COOH-terminal GAD65 epitopes, and in 5 offspring, reactivity was only to the middle GAD65 epitopes. The single offspring without middle GAD65 reactivity had antibodies to the NH2-terminal epitopes in the absence of all other islet autoimmunity. Subsequent GADA epitope spreading was frequent and seen in 10 of 15 offspring with informative follow-up samples. Spreading was mostly (eight cases) to NH2-terminal GAD65 epitopes. In two offspring, spreading to new epitopes was found when antibody titers to GAD65 and early epitopes were declining, suggesting determinant-specific regulation of the humoral response. None of the GADA reactivities nor any changes in reactivity over time were specifically associated with diabetes onset. The findings suggest that the humoral autoimmune response to GAD found in childhood is dynamic, is initially against epitopes within the middle portion of GAD65, and spreads to epitopes in other regions of GAD65 and GAD67.


Practice Considerations for Proton Beam Radiation Therapy of Uveal Melanoma During the Coronavirus Disease Pandemic: Particle Therapy Co-Operative Group Ocular Experience.
Uveal melanoma (UM) is a rare but life-threatening cancer of the eye. In light of the coronavirus disease (COVID-19) pandemic, hospitals and proton eye therapy facilities must analyze several factors to ensure appropriate treatment protocols for patients and provider teams. Practice considerations to limit COVID-19 transmission in the proton ocular treatment setting for UM are necessary. The Particle Therapy Co-Operative Group is the largest international community of particle/proton therapy providers. Participating experts have current or former affiliation with the member institutions of the Particle Therapy Co-Operative Group Ocular subcommittee with long-standing high-volume proton ocular programs. The practices reviewed in this document must be taken in conjunction with local hospital procedures, multidisciplinary recommendations, and regional/national guidelines, as each community may have its unique needs, supplies, and protocols. Importantly, as the pandemic evolves, so will the strategies and recommendations. Given the unique circumstances for UM patients, along with indications of potential ophthalmologic transmission as a result of health care providers working in close proximity to patients and intrinsic infectious risk from eyelashes, tears, and hair, practice strategies may be adapted to reduce the risk of viral transmission. Certainly, providers and health care systems will continue to examine and provide as safe and effective care as possible for patients in the current environment.


Meta-analysis of 16 studies of the association of alcohol with colorectal cancer.
Alcohol consumption is an established risk factor for colorectal cancer (CRC). However, while studies have consistently reported elevated risk of CRC among heavy drinkers, associations at moderate levels of alcohol consumption are less clear. We conducted a combined analysis of 16 studies of CRC to examine the shape of the alcohol-CRC association, investigate potential effect modifiers of the association, and examine differential effects of alcohol consumption by cancer anatomic site and stage. We collected information on alcohol consumption for 14,276 CRC cases and 15,802 controls from 5 case-control and 11 nested case-control studies of CRC. We compared adjusted logistic regression models with linear and restricted cubic splines to select a model that best fit the association between alcohol consumption and CRC. Study-specific results were pooled using fixed-effects meta-analysis. Compared to non-/occasional drinking (≤1 g/day), light/moderate drinking (up to 2 drinks/day) was associated with a decreased risk of CRC (odds ratio [OR]: 0.92, 95% confidence interval [CI]: 0.88-0.98, p = 0.005), heavy drinking (2-3 drinks/day) was not significantly associated with CRC risk (OR: 1.11, 95% CI: 0.99-1.24, p = 0.08) and very heavy drinking (more than 3 drinks/day) was associated with a significant increased risk (OR: 1.25, 95% CI: 1.11-1.40, p < 0.001). We observed no evidence of interactions with lifestyle risk factors or of differences by cancer site or stage. These results provide further evidence that there is a J-shaped association between alcohol consumption and CRC risk. This overall pattern was not significantly modified by other CRC risk factors and there was no effect heterogeneity by tumor site or stage.


The relationship between hand hygiene practices and nasal Staphylococcus aureus carriage in healthcare workers.
The nasal carriage rate of Staphylococcus aureus in healthcare workers (HCWs) is higher than the general population. Their hands serve as vectors for transmitting S.aureus colonized in the nose to patients. To determine the rate of nasal S.aureus carriage and methicillin resistance in HCWs and to evaluate the relationship between carriage and personal risk factors and hand hygiene behaviors. The questionnaire included questions about sociodemographic characteristics, occupational and personal risk factors for S.aureus carriage, the "Hand Hygiene Belief Scale (HHBS)," and "Hand Hygiene Practices Inventory (HHPI)". Nasal culture was taken from all participants. Presence of S.aureus, methicillin and mupirocin resistance were investigated in samples. The study was carried out with 269 HCWs. The prevalence of S.aureus carriage was 20.1% (n:54). Among 54 S.aureus carriers, only one person had MRSA (0.37%). All S.aureus isolates were susceptible to mupirocin. S.aureus carriage was found to be significantly lower in the smoker group (p:0.015) and in the personnel wearing gloves during the procedures of each patient (p:0.002). S.aureus culture positivity was found to decrease significantly with increasing handwashing frequency (p:0.003). The mean HHPI score was higher in women (p:0.001). The mean HHPI score was lower in the group with nasal carriers than in non-carriers (p:0.176). The knowledge of hand hygiene practices, high frequency of handwashing, and wearing different gloves during the procedure of each patient decrease S.aureus nasal carriage in HCWs. In addition mupirocin is still effective in nasal S.aureus carriers.


DNAJB3/HSP-40 cochaperone is downregulated in obese humans and is restored by physical exercise.
Obesity is a major risk factor for a myriad of disorders such as insulin resistance and diabetes. The mechanisms underlying these chronic conditions are complex but low grade inflammation and alteration of the endogenous stress defense system are well established. Previous studies indicated that impairment of HSP-25 and HSP-72 was linked to obesity, insulin resistance and diabetes in humans and animals while their induction was associated with improved clinical outcomes. In an attempt to identify additional components of the heat shock response that may be dysregulated by obesity, we used the RT(2)-Profiler PCR heat shock array, complemented with RT-PCR and validated by Western blot and immunohistochemistry. Using adipose tissue biopsies and PBMC of non-diabetic lean and obese subjects, we report the downregulation of DNAJB3 cochaperone mRNA and protein in obese that negatively correlated with percent body fat (P = 0.0001), triglycerides (P = 0.035) and the inflammatory chemokines IP-10 and RANTES (P = 0.036 and P = 0.02, respectively). DNAJB positively correlated with maximum oxygen consumption (P = 0.031). Based on the beneficial effect of physical exercise, we investigated its possible impact on DNAJB3 expression and indeed, we found that exercise restored the expression of DNAJB3 in obese subjects with a concomitant decrease of phosphorylated JNK. Using cell lines, DNAJB3 protein was reduced following treatment with palmitate and tunicamycin which is suggestive of the link between the expression of DNAJB3 and the activation of the endoplasmic reticulum stress. DNAJB3 was also shown to coimmunoprecipiate with JNK and IKKβ stress kinases along with HSP-72 and thus, suggesting its potential role in modulating their activities. Taken together, these data suggest that DNAJB3 can potentially play a protective role against obesity.


Impaired ceramide signalling in spontaneously hypertensive rat vascular smooth muscle: a possible mechanism for augmented cell proliferation.
In hypertension, the vascular wall undergoes morphological changes that alter mechanical responses to vasoactive substances. Ceramide is a recently identified second messenger synthesized in response to cytokines such as tumour necrosis factor alpha (TNF-alpha). It has been previously demonstrated that vascular smooth muscle cells (VSMC) from genetically hypertensive rats proliferate at a higher rate than those of normotensive origin. We tested the hypothesis that the ceramide pathway is impaired in VSMC from spontaneously hypertensive rats (SHR). VSMC were isolated from aortae of SHR and from Wistar-Kyoto (WKY) rats. Ceramide levels were measured under baseline and agonist-stimulated conditions and cell proliferation was monitored. Cell proliferation was determined by cell counting. Ceramide levels were determined via radioactive labelling, high-performance thin-layer chromatography and phosphorimaging. Relative mRNA levels of neutral sphingomyelinase were determined using semi-quantitative polymerase chain reaction (PCR). Basal ceramide levels in untreated cells were lower in cells from SHR compared to WKY rats. During chronic treatment with TNF-alpha, ceramide levels increased in WKY rat cells but remained unchanged in cells from SHR. TNF-alpha treatment had an inhibitory effect on WKY rat VSMC proliferation, but stimulated proliferation in cells from SHR. Short-term incubation with TNF-alpha resulted in a greater increase in ceramide in cells from WKY rats than those from SHR. Semiquantitative PCR analysis indicated that neutral sphingomyelinase mRNA may be reduced in SHR VSMC. We conclude that ceramide synthesis is impaired in vascular smooth muscle from SHR and may contribute to increased VSMC proliferation in hypertension.


Wireless magnetic-based closed-loop control of self-propelled microjets.
In this study, we demonstrate closed-loop motion control of self-propelled microjets under the influence of external magnetic fields. We control the orientation of the microjets using external magnetic torque, whereas the linear motion towards a reference position is accomplished by the thrust and pulling magnetic forces generated by the ejecting oxygen bubbles and field gradients, respectively. The magnetic dipole moment of the microjets is characterized using the U-turn technique, and its average is calculated to be 1.3x10⁻¹⁰ A.m² at magnetic field and linear velocity of 2 mT and 100 µm/s, respectively. The characterized magnetic dipole moment is used in the realization of the magnetic force-current map of the microjets. This map in turn is used for the design of a closed-loop control system that does not depend on the exact dynamical model of the microjets and the accurate knowledge of the parameters of the magnetic system. The motion control characteristics in the transient- and steady-states depend on the concentration of the surrounding fluid (hydrogen peroxide solution) and the strength of the applied magnetic field. Our control system allows us to position microjets at an average velocity of 115 µm/s, and within an average region-of-convergence of 365 µm.


Corticosterone after acute stress prevents the delayed effects on the amygdala.
Even a single 2-hour episode of immobilization stress is known to trigger anxiety-like behavior and increase spine-density in the basolateral amygdala (BLA) of rats 10 days later. This delayed build-up of morphological and behavioral effects offers a stress-free time window of intervention after acute stress, which we used to test a protective role for glucocorticoids against stress. We observed that post-stress corticosterone, given 1 day after acute stress in drinking water, reversed enhanced anxiety-like behavior 10 days later. Quantification of spine-density on Golgi-stained BLA principal neurons showed that the same intervention also prevented the increase in spine numbers in the amygdala, at the same delayed time-point. Further, stress elevated serum corticosterone levels in rats that received vehicle in the drinking water. However, when stress was followed 24 h later by corticosterone in the drinking water, the surge in corticosterone was prevented. Together, these observations suggest that corticosterone, delivered through drinking water even 24 h after acute stress, is capable of reversing the delayed enhancing effects on BLA synaptic connectivity and anxiety-like behavior. Strikingly, although the immobilization-induced surge in corticosterone by itself has delayed detrimental effects on amygdalar structure and function, there exists a window of opportunity even after stress to mitigate its impact with a second surge of exogenously administered corticosterone. This provides a framework in the amygdala for analyzing how the initial physiological and endocrine processes triggered by traumatic stress eventually give rise to debilitating emotional symptoms, as well as the protective effects of glucocorticoids against their development.


A deep catalog of protein-coding variation in 985,830 individuals.
Coding variants that have significant impact on function can provide insights into the biology of a gene but are typically rare in the population. Identifying and ascertaining the frequency of such rare variants requires very large sample sizes. Here, we present the largest catalog of human protein-coding variation to date, derived from exome sequencing of 985,830 individuals of diverse ancestry to serve as a rich resource for studying rare coding variants. Individuals of African, Admixed American, East Asian, Middle Eastern, and South Asian ancestry account for 20% of this Exome dataset. Our catalog of variants includes approximately 10.5 million missense (54% novel) and 1.1 million predicted loss-of-function (pLOF) variants (65% novel, 53% observed only once). We identified individuals with rare homozygous pLOF variants in 4,874 genes, and for 1,838 of these this work is the first to document at least one pLOF homozygote. Additional insights from the RGC-ME dataset include 1) improved estimates of selection against heterozygous loss-of-function and identification of 3,459 genes intolerant to loss-of-function, 83 of which were previously assessed as tolerant to loss-of-function and 1,241 that lack disease annotations; 2) identification of regions depleted of missense variation in 457 genes that are tolerant to loss-of-function; 3) functional interpretation for 10,708 variants of unknown or conflicting significance reported in ClinVar as cryptic splice sites using splicing score thresholds based on empirical variant deleteriousness scores derived from RGC-ME; and 4) an observation that approximately 3% of sequenced individuals carry a clinically actionable genetic variant in the ACMG SF 3.1 list of genes. We make this important resource of coding variation available to the public through a variant allele frequency browser. We anticipate that this report and the RGC-ME dataset will serve as a valuable reference for understanding rare coding variation and help advance precision medicine efforts.


Surface assembly and plasmonic properties in strongly coupled segmented gold nanorods.
An assembly strategy is reported such that segmented nanorods fabricated through template-assisted methods can be robustly transferred and tethered to a pre-functionalized substrate with excellent uniformity over large surface areas. After embedding the rods, sacrificial nickel segments were selectively etched leaving behind strongly coupled segmented gold nanorods with gaps between rods below 40 nm and as small as 2 nm. Hyper-spectral imaging is utilized to measure Rayleigh scattering spectra from individual and coupled nanorod elements in contrast to common bulk measurements. This approach discerns the effects of not only changing segment and gap size but also the presence of characteristic defects on the plasmonic coupling between closely spaced nanorods. Polarized hyper-spectral measurements are conducted to provide direct observation of the anisotropic plasmonic resonance modes in individual and coupled nanorods, which are close to those predicted by computer simulations for nanorods with ideal shapes. Some common deviations from ideal shape such as non-flat facets and asymmetric tails are demonstrated to result in the appearance of characteristic plasmon resonances, which have not been considered before. The large-scale assembly of coupled noble nanostructures with fine control over geometry and high uniformity provides means to strongly tune the scattering, absorption, and near-field plasmonic properties through the geometric arrangement of precisely controlled nanorod segments.


Abl tyrosine kinases are required for infection by Shigella flexneri.
Infection by the opportunistic bacterial pathogen Shigella flexneri stimulates tyrosine phosphorylation of host cell proteins, but the kinases involved and their effects on the regulation of cell signaling pathways during bacterial entry remain largely undefined. Here, we demonstrate a requirement for the Abl family of tyrosine kinases during Shigella internalization. Family members Abl and Arg are catalytically activated upon Shigella infection, accumulate at the site of bacterial entry, and are required for efficient bacterial uptake, as internalization is blocked upon targeted deletion of these kinases or treatment with a specific pharmacological inhibitor. We identify the adapter protein Crk as a target for Abl kinases during Shigella uptake, and show that a phosphorylation-deficient Crk mutant significantly inhibits bacterial uptake. Moreover, we define a novel signaling pathway activated during Shigella entry that links Abl kinase phosphorylation of Crk to activation of the Rho family GTPases Rac and Cdc42. Together, these findings reveal a new role for the Abl kinases, and suggest a novel approach to treatment of Shigella infections through inhibition of host cell signaling pathways.


Vitamin d and the risk of uterine fibroids.
Uterine leiomyomata (also known as fibroids) are benign tumors of uterine smooth muscle that are characterized by overproduction of extracellular matrix. Fibroids are the leading indication for hysterectomy in the United States. The active metabolite of vitamin D has been shown to inhibit cell proliferation and extracellular matrix production in fibroid tissue culture and to reduce fibroid volume in the Eker rat. No previous study has examined whether vitamin D is related to fibroid status in women. The National Institute of Environmental Health Sciences Uterine Fibroid Study enrolled randomly selected 35- to 49-year-old women who were members of an urban health plan during 1996-1999. Fibroid status was determined by ultrasound screening of premenopausal women (620 blacks, 416 whites). Vitamin D status was assessed in stored plasma by radioimmunoassay of 25-hydroxyvitamin D (25(OH)D) and questionnaire data on sun exposure. Associations were evaluated with logistic regression, controlling for potential confounders. Only 10% of blacks and 50% of whites had levels of 25(OH)D regarded as sufficient (>20 ng/ml). Women with sufficient vitamin D had an estimated 32% lower odds of fibroids compared with those with vitamin D insufficiency (adjusted odds ratio [aOR] = 0.68, 95% confidence interval [CI] = 0.48-0.96). The association was similar for blacks and whites. Self-reported sun exposure ≥ 1 hour per day (weather permitting) was also associated with reduced odds of fibroids (aOR = 06. [0.4-0.9]), with no evidence of heterogeneity by ethnicity. The consistency of findings for questionnaire and biomarker data, the similar patterns seen in blacks and whites, and the biological plausibility provide evidence that sufficient vitamin D is associated with a reduced risk of uterine fibroids.


Evaluation of an educational programme for socially deprived asthma patients.
The aim of this study was to evaluate the effectiveness of an asthma education programme in moderate and severe asthma patients in a longitudinal, prospective and randomized study with a control group. Fifty-three asthmatic patients were studied, 26 of whom were assigned to the educational group and 27 to the control group. The educational group attended the programme regularly for a period of 6 months. The programme included information about asthma, instruction on the appropriate use of medication and training in the metered dose inhaler (MDI) technique, and information about the identification and control of asthma attacks and the recognition of early signs of exacerbation. The control group was submitted to the routine care provided at the Asthma Clinic, with no formal instruction regarding asthma control. The groups were identical with regard to severity parameters, skills, lung function and quality of life at the beginning of the trial. At the end of the study, the education group showed significant differences when compared with the control group (education/control (mean values)) with respect to: visits to the asthma emergency room over the previous 6 months, 0.7/2 (p=0.03); nocturnal symptoms, 0.3/0.7 (p=0.04); score of symptoms, 1.3/2 (p=0.04). Improvements were also observed in skills and quality of life, knowledge of how to deal with attacks and how to control the environmental triggering factors, 73/35 (<0.05); correct use of the MDI, 8/4 (0.001); understanding of the difference between relief and anti-inflammatory medication, 86/20 (<0.05); and in the global limitation quality of life score, 28/50 (0.02). It is concluded that the educational programme led to a significant improvement in asthma morbidity and that the implantation of educational programmes is possible for special populations when these programmes are adapted to the socioeconomic profile of the patients, with a significant gain in terms of the reduction of symptoms and improved pulmonary function and quality of life of asthmatics.


TAp63, a methotrexate target in CD4+ T cells, suppresses Foxp3 expression and exacerbates autoimmune arthritis.
Methotrexate (MTX) is a standard, first-line therapy for rheumatoid arthritis (RA); however, its precise mechanisms of action other than antifolate activity are largely unknown. We performed DNA microarray analyses of CD4+ T cells in patients with RA before and after MTX treatment and found that TP63 was the most significantly downregulated gene after MTX treatment. TAp63, an isoform of TP63, was highly expressed in human IL-17-producing Th (Th17) cells and was suppressed by MTX in vitro. Murine TAp63 was expressed at high levels in Th cells and at lower levels in thymus-derived Treg cells. Importantly, TAp63 knockdown in murine Th17 cells ameliorated the adoptive transfer arthritis model. RNA-Seq analyses of human Th17 cells overexpressing TAp63 and those with TAp63 knockdown identified FOXP3 as a possible TAp63 target gene. TAp63 knockdown in CD4+ T cells cultured under Th17 conditions with low-dose IL-6 increased Foxp3 expression, suggesting that TAp63 balances Th17 cells and Treg cells. Mechanistically, TAp63 knockdown in murine induced Treg (iTreg) cells promoted hypomethylation of conserved noncoding sequence 2 (CNS2) of the Foxp3 gene and enhanced the suppressive function of iTreg cells. Reporter analyses revealed that TAp63 suppressed the activation of the Foxp3 CNS2 enhancer. Collectively, TAp63 suppresses Foxp3 expression and exacerbates autoimmune arthritis.