Impact of monovalent rotavirus vaccine on diarrhoea-associated post-neonatal infant mortality in rural communities in Malawi: a population-based birth cohort study.
Rotavirus is a major contributor to child mortality. The effect of rotavirus vaccine on diarrhoea mortality has been estimated in middle-income but not low-income settings, where mortality is high and vaccine effectiveness in reducing admissions to hospital is lower. Empirical population-based mortality studies have not been done in any setting. Malawi introduced monovalent rotavirus vaccine (RV1) in October, 2012. We aimed to investigate the impact and effectiveness of the RV1 vaccine in reducing diarrhoea-associated mortality in infants aged 10-51 weeks. In this population-based cohort study, we included infants born between Jan 1, 2012, and June 1, 2015, in Mchinji, Central Malawi and analysed data on those surviving 10 weeks. Individual vaccination status was extracted from caregiver-held records or report at home visits at 4 months and 1 year of age. Survival to 1 year was confirmed at home visit, or cause of death ascertained by verbal autopsy. We assessed impact (1 minus mortality rate ratio following vs before vaccine introduction) using Poisson regression. Among vaccine-eligible infants (born from Sept 17, 2012), we assessed effectiveness (1 minus hazard ratio) using Cox regression. Between Jan 1, 2012, and June 1, 2015, we recruited 48 672 livebirths in Mchinji, among whom 38 518 were vaccine-eligible and 37 570 survived to age 10 weeks. Two-dose versus zero-dose effectiveness analysis included 28 141 infants, of whom 101 had diarrhoea-associated death before 1 year of age. Diarrhoea-associated mortality declined by 31% (95% CI 1-52; p=0·04) after RV1 introduction. Effectiveness against diarrhoea-mortality was 34% (95% CI -28 to 66; p=0·22). RV1 was associated with substantial reduction in diarrhoea-associated deaths among infants in this rural sub-Saharan African setting. These data add considerable weight to evidence showing the impact of rotavirus vaccine programmes. Wellcome Trust and GlaxoSmithKline Biologicals.


Plasma biomarker profiles differ depending on breast cancer subtype but RANTES is consistently increased.
Current biomarkers for breast cancer have little potential for detection. We determined whether breast cancer subtypes influence circulating protein biomarkers. A sandwich ELISA microarray platform was used to evaluate 23 candidate biomarkers in plasma samples that were obtained from subjects with either benign breast disease or invasive breast cancer. All plasma samples were collected at the time of biopsy, after a referral due to a suspicious screen (e.g., mammography). Cancer samples were evaluated on the basis of breast cancer subtypes, as defined by the HER2 and estrogen receptor statuses. Ten proteins were statistically altered in at least one breast cancer subtype, including four epidermal growth factor receptor ligands, two matrix metalloproteases, two cytokines, and two angiogenic factors. Only one cytokine, RANTES, was significantly increased (P < 0.01 for each analysis) in all four subtypes, with areas under the curve (AUC) for receiver operating characteristic values that ranged from 0.76 to 0.82, depending on cancer subtype. The best AUC values were observed for analyses that combined data from multiple biomarkers, with values ranging from 0.70 to 0.99, depending on the cancer subtype. Although the results for RANTES are consistent with previous publications, the multi-assay results need to be validated in independent sample sets. Different breast cancer subtypes produce distinct biomarker profiles, and circulating protein biomarkers have potential to differentiate between true- and false-positive screens for breast cancer. Subtype-specific biomarker panels may be useful for detecting breast cancer or as an adjunct assay to improve the accuracy of current screening methods.


Effects of hydrogen plasma treatment on the electrical and optical properties of ZnO films: identification of hydrogen donors in ZnO.
Wurtzite ZnO has many potential applications in optoelectronic devices, and the hydrogenated ZnO exhibits excellent photoelectronic properties compared to undoped ZnO; however, the structure of H-related defects is still unclear. In this article, the effects of hydrogen-plasma treatment and subsequent annealing on the electrical and optical properties of ZnO films were investigated by a combination of Hall measurement, Raman scattering, and photoluminescence. It is found that two types of hydrogen-related defects, namely, the interstitial hydrogen located at the bond-centered (H(BC)) and the hydrogen trapped at a O vacancy (H(O)), are responsible for the n-type background conductivity of ZnO films. Besides introducing two hydrogen-related donor states, the incorporated hydrogen passivates defects at grain boundaries. With increasing annealing temperatures, the unstable H(BC) atoms gradually diffuse out of the ZnO films and part of them are converted into H(O), which gives rise to two anomalous Raman peaks at 275 and 510 cm(-1). These results help to clarify the relationship between the hydrogen-related defects in ZnO described in various studies and the free carriers that are produced by the introduction of hydrogen.


A practice change intervention to improve antenatal care addressing alcohol consumption by women during pregnancy: research protocol for a randomised stepped-wedge cluster trial.
Despite clinical guideline recommendations, implementation of antenatal care addressing alcohol consumption by pregnant women is limited. Implementation strategies addressing barriers to such care may be effective in increasing care provision. The aim of this study is to examine the effectiveness, cost and cost-effectiveness of a multi-strategy practice change intervention in increasing antenatal care addressing the consumption of alcohol by pregnant women. The study will be a randomised, stepped-wedge controlled trial conducted in three sectors in a health district in New South Wales, Australia. Stepped implementation of a practice change intervention will be delivered to sectors in a random order to support the introduction of a model of care for addressing alcohol consumption by pregnant women. A staged process was undertaken to develop the implementation strategies, which comprise of: leadership support, local clinical practice guidelines, electronic prompts and reminders, opinion leaders, academic detailing (audit and feedback), educational meetings and educational materials, and performance monitoring. Repeated cross-sectional outcome data will be gathered weekly across all sectors for the study duration. The primary outcome measures are the proportion of antenatal appointments at 'booking in', 27-28 weeks gestation and 35-36 weeks gestation for which women report (1) being assessed for alcohol consumption, (2) being provided with brief advice related to alcohol consumption during pregnancy, (3) receiving relevant care for addressing alcohol consumption during pregnancy, and (4) being assessed for alcohol consumption and receiving relevant care. Data on resources expended during intervention development and implementation will be collected. The proportion of women who report consuming alcohol since knowing they were pregnant will be measured as a secondary outcome. This will be the first randomised controlled trial to evaluate the effectiveness, cost and cost-effectiveness of implementation strategies in improving antenatal care that addresses alcohol consumption by pregnant women. If positive changes in clinical practice are found, this evidence will support health service adoption of implementation strategies to support improved antenatal care for this recognised risk to the health and wellbeing of the mother and child. Australian and New Zealand Clinical Trials Registry, No. ACTRN12617000882325 (date registered: 16/06/2017).


Prognostic factors for the development of fibromyalgia in women with self-reported musculoskeletal pain. A prospective study.
To estimate the risk of developing fibromyalgia (FM) in women with self-reported pain and to estimate the relative risk of a series of variables. As part of a population study, 214 women with self-reported pain were interviewed and examined in 1990 and 1995. In 1990, 39 of these women fulfilled the American College of Rheumatology criteria for FM. The other 175 women represented a continuum of pain extent from nonchronic pain to chronic widespread pain, and were assessed as individuals at risk for developing FM. Potential risk factors for FM were registered in 1990 and analyzed by bivariate and multiple statistical methods in the total sample and also in a subgroup of 115 women with limited pain. Forty-three (25%) women developed FM. Having > or = 4 associated symptoms, pain of > or = 6 years' duration, back pain, alternately hard/loose stools, and self-assessed depression were found to be predictors. Pain in the lower arm and a feeling of swelling were more weakly associated. In women with limited pain, pain > or = 6 years' duration, > or = 4 associated symptoms, not feeling refreshed in the morning, and paresthesia were found to be predictors. A weaker association was found with self-assessed depression and a lack of formal education. A high cumulative incidence of FM was found and a diversity of predictors for FM were identified in the total sample and also in women with limited pain. Of the variables that were part of the FM syndrome, back pain predicted FM, while tender points and pain in the neck did not. Moreover, > or = 4 associated symptoms, self-assessed depression, and longlasting pain were shown to be important predictors.


Design or screening of drugs for the treatment of Chagas disease: what shows the most promise?
Endemic in Latin America, Chagas disease is now becoming a serious global health problem, and yet has no financial viability for the pharmaceutical industry and remains incurable. In 2012, two antimycotic drugs inhibitors of fungal sterol 14α-demethylase (CYP51) - posaconazole and ravuconazole - entered clinical trials. Availability of the X-ray structure of the orthologous enzyme from the causative agent of the disease, protozoan parasite Trypanosoma cruzi, determined in complexes with posaconazole as well as with several experimental protozoa-specific CYP51 inhibitors opens an excellent opportunity to improve the situation. This article summarizes the information available in PubMed and Google on the outcomes of treatment of the chronic Chagas disease. It also outlines the major features of the T. cruzi CYP51 structure and the possible structure-based strategies for rational design of novel T. cruzi specific drugs. There is no doubt that screenings for alternative drug-like molecules as well as mining the T. cruzi genome for novel drug targets are of great value and might eventually lead to groundbreaking discoveries. However, all newly identified molecules must proceed through the long, expensive and low-yielding drug optimization process, and all novel potential drug targets must be validated in terms of their essentiality and druggability. CYP51 is already a well-validated and highly successful target for clinical and agricultural antifungals. With minimal investments into the final stages of their development/trials, T. cruzi-specific CYP51 inhibitors can provide an immediate treatment for Chagas disease, either on their own or in combination with the currently available drugs.


Attentional changes in pre-stimulus oscillatory activity within early visual cortex are predictive of human visual performance.
Physiological and neuroimaging studies provide evidence to suggest that attentional mechanisms operating within the fronto-parietal network may exert top-down control on early visual areas, priming them for forthcoming sensory events. The believed consequence of such priming is enhanced task performance. Using the technique of magnetoencephalography (MEG), we investigated this possibility by examining whether attention-driven changes in cortical activity are correlated with performance on a line-orientation judgment task. We observed that, approximately 200 ms after a covert attentional shift towards the impending visual stimulus, the level of phase-resetting (transient neural coherence) within the calcarine significantly increased for 2-10 Hz activity. This was followed by a suppression of alpha activity (near 10 Hz) which persisted until the onset of the stimulus. The levels of phase-resetting, alpha suppression and subsequent behavioral performance varied between subjects in a systematic fashion. The magnitudes of phase-resetting and alpha-band power were negatively correlated, with high levels of coherence associated with high levels of performance. We propose that top-down attentional control mechanisms exert their initial effects within the calcarine through a phase-resetting within the 2-10 Hz band, which in turn triggers a suppression of alpha activity, priming early visual areas for incoming information and enhancing behavioral performance.


Three-dimensional volumetric study with VOCAL in normal and abnormal posterior fossa fetuses.
Purpose: The aim of this study was to compare volumetric parameters in the abnormal and normal posterior fossa using the Virtual Organ Computer-aided AnaLysis (VOCAL™) technique to determine whether fetuses with an abnormal posterior fossa have different volumes.Methods: A prospective study was conducted on 17 fetuses with an abnormal posterior fossa including, Dandy Walker malformation (DWM) (n = 6), vermian hypoplasia (VH) (n = 3), mega cisterna magna (MCM) (n = 8), and 99 healthy control fetuses from 20 to 34 weeks' gestation. Measurement of the fetal cisterna magna and cerebellar volume was performed in the standard transcerebellar plane through the VOCAL™ method. To establish the correlation of volumes with gestational age, polynomial regression analysis was performed. For comparison between groups, univariate ANCOVA was performed using gestational age as a covariate. The reliability was analyzed by the intraclass correlation coefficient (ICC).Results: Cerebellar volume and cisterna magna volume were correlated with gestational age. Posterior fossa volume was significantly larger in DWM (p < .0001) and MCM (p < .0001) in comparison to the control group. In VH group, cisterna magna volume does not seem to expand (p = .298). Cerebellar volume does not seem to change in subgroups when the influence of gestational age is discarded (p = .09). The ratio of cerebellar volume to the cisterna magna volume decreases significantly in abnormal fetuses (p < .0001). Good intraobserver and interobserver reliabilities were found for both cerebellum and cisterna magna measurements.Conclusions: Volume analysis may have a role in discrimination of different posterior fossa pathologies.


Identification and molecular characterization of the mammalian α-kleisin RAD21L.
Meiosis is a fundamental process that generates new combinations between maternal and paternal genomes and haploid gametes from diploid progenitors. Many of the meiosis-specific events stem from the behavior of the cohesin complex (CC), a proteinaceous ring structure that entraps sister chromatids until the onset of anaphase. CCs ensure chromosome segregation, participate in DNA repair, regulate gene expression, and also contribute to synaptonemal complex (SC) formation at meiosis by keeping long-range distant DNA interactions through its conserved structure. Studies from yeast to humans have led to the assumption that Scc1/RAD21 is the α-kleisin that closes the tripartite CC that entraps two DNA molecules in mitosis, while its paralog REC8 is essential for meiosis. Here we describe the identification of RAD21L, a novel mammalian CC subunit with homology to the RAD21/REC8 α-kleisin subfamily, which is expressed in mouse testis. RAD21L interacts with other cohesin subunits such as SMC1α, SMC1b, SMC3 and with the meiosis-specific STAG3 protein. Thus, our results demonstrate the existence of a new meiotic-specific CC constituted by this α-kleisin and expand the view of REC8 as the only specific meiotic α-kleisin.


Pig Skin Gelatin Hydrolysates Attenuate Acetylcholine Esterase Activity and Scopolamine-induced Impairment of Memory and Learning Ability of Mice.
The protective effect of pig skin gelatin water extracts (PSW) and the low molecular weight hydrolysates of PSW generated via enzymatic hydrolysis with Flavourzyme® 1000L (LPSW) against scopolamine-induced impairment of cognitive function in mice was determined. Seventy male ICR mice weighing 20-25 g were randomly assigned to seven groups: Control (CON); scopolamine (SCO, 1 mg/kg B.W., intraperitoneally (i.p.); tetrahydroaminoacridine 10 [THA 10, tacrine; 10 mg/kg B.W. per oral (p.o.) with SCO (i.p.)]; PSW 10 (10 mg/kg B.W. (p.o.) with SCO (i.p.); PSW 40 (40 mg/kg B.W. (p.o.) with SCO (i.p.); LPSW 100 (100 mg/kg B.W. (p.o.) with SCO (i.p.); LPSW 400 (400 mg/kg B.W. (p.o.) with SCO (i.p.). All treatment groups, except CON, received scopolamine on the day of the experiment. The oxygen radical absorbance capacity of LPSW 400 at 1 mg/mL was 154.14 μM Trolox equivalent. Administration of PSW and LPSW for 15 weeks did not significantly affect on physical performance of mice. LPSW 400 significantly increased spontaneous alternation, reaching the level observed for THA and CON. The latency time of animals receiving LPSW 400 was higher than that of mice treated with SCO alone in the passive avoidance test, whereas it was shorter in the water maze test. LPSW 400 increased acetylcholine (ACh) content and decreased ACh esterase activity (p<0.05). LPSW 100 and LPSW 400 reduced monoamine oxidase-B activity. These results indicated that LPSW at 400 mg/kg B.W. is a potentially strong antioxidant and contains novel components for the functional food industry.


Cardiac mass in glucocorticoid-hypertensive rats with and without circulating adrenaline.
There is evidence that catecholamines may promote the development of cardiac hypertrophy in hypertension. To test the hypothesis that adrenaline directly determines left ventricular mass, normotensive Wistar rats were made adrenaline-deficient by adrenalectomy and hypertensive by administration of glucocorticoid. Blood pressure, heart rate, and body weight of the adrenalectomised group were not significantly different from a glucocorticoid treated control group with intact adrenals. Heart weight was significantly lower in the adrenalectomised rats, but this difference disappeared when heart weight was adjusted for body weight. It appears therefore that the presence or absence of adrenaline does not significantly affect cardiac mass in the presence of hypertension in this animal model.


[Clinicopathologic features and differential diagnoses of non-involuting congenital hemangioma in children].
To investigate the clinicopathologic features and differential diagnoses of non-involuting congenital hemangioma (NICH) in children. The clinical, morphologic and immunophenotypic characteristics of 22 cases of NICH were retrospectively analyzed. The mean patients' age at diagnosis was 4.2 years, with a male to female ratio of 1.75:1. The tumors were located in the head and face (5 cases), neck (3 cases), body (6 cases), upper limbs (5 cases), and lower limbs (3 cases). Histologically, the tumor was dominated by rather large lobules of small vessels that were mostly rounded, curved, small and thin-walled, and were lined by endothelial cells surrounded by one or more layers of pericytes. The center of the lobules was occupied by one or more thin or thick walled vessels, which were surrounded by fibrous and fatty tissue, which contained abnormal arterial and venous structures. At the edge of the lobules there were lymphatic vessels. Immunohsitochemical study showed that tumor cells in NICH were positive for CD34 (22/22), CD31 (22/22), SMA (22/22), vimentin (22/22) and Glut1 (0/22). D2-40 expression was located at the edge of the capillary lobules. NICH is a benign lesion. Clinically and pathologically, it needs to be differentiated from rapidly involuting congenital hemangioma, infantile hemangiomas, tufted angioma, vascular malformation, and others.


Prefrontal neuronal activity encodes spatial target representations sequentially updated after nonspatial target-shift cues.
We examined prefrontal neuronal activity while monkeys performed a sequential target-shift task, in which, after a positional cue indicated the initial saccade target among 8 peripheral positions, the monkeys were required to internally shift the target by one position on every flash of a target-shift cue. The target-shift cue appeared in the center 0 to 3 times within a single trial and was always the same in shape, size, and color. We found selective neuronal activity related to the target position: when the target-shift cue implied the target shift to particular peripheral positions, neurons exhibited early-dominant and late-dominant activity during the following delay period. The early-dominant target-selective activity emerged early in the delay just after the presentation of the target-shift cue, whereas the late-dominant activity gradually built up toward the end of the delay. Because the target-shift cue was not related to any specific target location, the early-dominant target-selective activity could not be a mere visual response to the target-shift cue. We suggest that the early-dominant activity reflects the transitory representation for the saccade target that was triggered by the nonspatial target-shift cue, whereas the late-dominant activity reflects the target representation in the spatial working memory or the preparatory set for the possible impending saccade, being repeatedly updated during sequential target shifts.


Urban green space and mental health among people living alone: The mediating roles of relational and collective restoration in an 18-country sample.
Rates of living alone, especially in more urbanised areas, are increasing across many industrialised countries, with associated increases in feelings of loneliness and poorer mental health. Recent studies have suggested that access to nature (e.g. parks and green spaces) can reduce the stressors associated with loneliness, partly through providing opportunities to nurture personal relationships (relational restoration) and engage in normative community activities (collective restoration). Such associations might vary across different household compositions and socio-demographic or geographical characteristics, but these have not been thoroughly tested. Using data collected across 18 countries/territories in 2017-2018, we grouped urban respondents into those living alone (n = 2062) and those living with a partner (n = 6218). Using multigroup path modelling, we tested whether the associations between neighbourhood greenspace coverage (1-km-buffer from home) and mental health are sequentially mediated by: (a) visits to greenspace; and subsequently (b) relationship and/or community satisfaction, as operationalisations of relational and collective restoration, respectively. We also tested whether any indirect associations varied among subgroups of respondents living alone. Analyses showed that visiting green space was associated with greater mental well-being and marginally lower odds of using anxiety/depression medication use indirectly, mediated via both relationship and community satisfaction. These indirect associations were equally strong among respondents living alone and those living with a partner. Neighbourhood green space was, additionally, associated with more visits among respondents living with a partner, whereas among those living alone, this was sensitive to the green space metric. Within subgroups of people living alone, few overall differences were found. Some indirect pathways were, nevertheless, stronger in males, under 60-year-olds, those with no financial strain, and residents in warmer climates. In conclusion, supporting those living alone, as well as those living with a partner, to more frequently access their local greenspaces could help improve mental health via promoting relational and collective restoration.


Clinical use of potassium supplements.
The clinical use of potassium supplements is reviewed. Included is a discussion of the measurement of potassium status, oral and intravenous potassium therapy, intraperitoneal potassium administration, and hazards of potassium supplements. It is concluded that the potential hazards of potassium indicate a need for a more rational approach to potassium therapy.


Revolutionizing KRAS p.G12C therapy in metastatic colorectal cancer: The triumph of dual inhibition.
The management of refractory metastatic colorectal cancer patients with the KRAS p.G12C mutation presents a significant unmet need, with limited success using standard therapies. The study by Fakih et al. highlights the potential of sotorasib and panitumumab combination therapy in this clinical context, paving the way for a promising personalized therapeutic approach.1.


Nonlinear dynamics of cortical responses to color in the human cVEP.
The main finding of this paper is that the human visual cortex responds in a very nonlinear manner to the color contrast of pure color patterns. We examined human cortical responses to color checkerboard patterns at many color contrasts, measuring the chromatic visual evoked potential (cVEP) with a dense electrode array. Cortical topography of the cVEPs showed that they were localized near the posterior electrode at position Oz, indicating that the primary cortex (V1) was the major source of responses. The choice of fine spatial patterns as stimuli caused the cVEP response to be driven by double-opponent neurons in V1. The cVEP waveform revealed nonlinear color signal processing in the V1 cortex. The cVEP time-to-peak decreased and the waveform's shape was markedly narrower with increasing cone contrast. Comparison of the linear dynamics of retinal and lateral geniculate nucleus responses with the nonlinear dynamics of the cortical cVEP indicated that the nonlinear dynamics originated in the V1 cortex. The nature of the nonlinearity is a kind of automatic gain control that adjusts cortical dynamics to be faster when color contrast is greater.


Gene expression in extratumoral microenvironment predicts clinical outcome in breast cancer patients.
A gene expression signature indicative of activated wound responses is common to more than 90% of non-neoplastic tissues adjacent to breast cancer, but these tissues also exhibit substantial heterogeneity. We hypothesized that gene expression subtypes of breast cancer microenvironment can be defined and that these microenvironment subtypes have clinical relevance. Gene expression was evaluated in 72 patient-derived breast tissue samples adjacent to invasive breast cancer or ductal carcinoma in situ. Unsupervised clustering identified two distinct gene expression subgroups that differed in expression of genes involved in activation of fibrosis, cellular movement, cell adhesion and cell-cell contact. We evaluated the prognostic relevance of extratumoral subtype (comparing the Active group, defined by high expression of fibrosis and cellular movement genes, to the Inactive group, defined by high expression of claudins and other cellular adhesion and cell-cell contact genes) using clinical data. To establish the biological characteristics of these subtypes, gene expression profiles were compared against published and novel tumor and tumor stroma-derived signatures (Twist-related protein 1 (TWIST1) overexpression, transforming growth factor beta (TGF-β)-induced fibroblast activation, breast fibrosis, claudin-low tumor subtype and estrogen response). Histological and immunohistochemical analyses of tissues representing each microenvironment subtype were performed to evaluate protein expression and compositional differences between microenvironment subtypes. Extratumoral Active versus Inactive subtypes were not significantly associated with overall survival among all patients (hazard ratio (HR) = 1.4, 95% CI 0.6 to 2.8, P = 0.337), but there was a strong association with overall survival among estrogen receptor (ER) positive patients (HR = 2.5, 95% CI 0.9 to 6.7, P = 0.062) and hormone-treated patients (HR = 2.6, 95% CI 1.0 to 7.0, P = 0.045). The Active subtype of breast microenvironment is correlated with TWIST-overexpression signatures and shares features of claudin-low breast cancers. The Active subtype was also associated with expression of TGF-β induced fibroblast activation signatures, but there was no significant association between Active/Inactive microenvironment and desmoid type fibrosis or estrogen response gene expression signatures. Consistent with the RNA expression profiles, Active cancer-adjacent tissues exhibited higher density of TWIST nuclear staining, predominantly in epithelium, and no evidence of increased fibrosis. These results document the presence of two distinct subtypes of microenvironment, with Active versus Inactive cancer-adjacent extratumoral microenvironment influencing the aggressiveness and outcome of ER-positive human breast cancers.


High mutation detection rate in the COL4A5 collagen gene in suspected Alport syndrome using PCR and direct DNA sequencing.
Approximately 85% of patients with Alport syndrome (hereditary nephritis) have been estimated to have mutations in the X chromosomal COL4A5 collagen gene; the remaining cases are autosomal with mutations in the COL4A3 or COL4A4 genes located on chromosome 2. In the present work, the promoter sequence and previously unknown intron sequences flanking exons 2 and 37 of COL4A5 were determined. Furthermore, intron sequences flanking the other 49 exons were expanded from 35 to 190 to facilitate mutation analysis of the gene. Using this information, all 51 exons and the promoter region were PCR-amplified and sequenced from DNA of 50 randomly chosen patients with suspected Alport syndrome. Mutations were found in 41 patients, giving a mutation detection rate of 82%. Retrospective analysis of clinical data revealed that two of the cases might be autosomal. Although it could not be determined whether the remaining seven cases (14%) were autosomal or X chromosome-linked, it is likely that some of them were autosomal. It is concluded that PCR amplification and direct DNA sequencing of the promoter and exons is currently the best procedure to detect mutations in COL4A5 in Alport syndrome.


Determining the Replication Kinetics and Cellular Tropism of Influenza D Virus on Primary Well-Differentiated Human Airway Epithelial Cells.
Influenza viruses are notorious pathogens that frequently cross the species barrier with often severe consequences for both animal and human health. In 2011, a novel member of the Orthomyxoviridae family, Influenza D virus (IDV), was identified in the respiratory tract of swine. Epidemiological surveys revealed that IDV is distributed worldwide among livestock and that IDV-directed antibodies are detected in humans with occupational exposure to livestock. To identify the transmission capability of IDV to humans, we determined the viral replication kinetics and cell tropism using an in vitro respiratory epithelium model of humans. The inoculation of IDV revealed efficient replication kinetics and apical progeny virus release at different body temperatures. Intriguingly, the replication characteristics of IDV revealed higher replication kinetics compared to Influenza C virus, despite sharing the cell tropism preference for ciliated cells. Collectively, these results might indicate why IDV-directed antibodies are detected among humans with occupational exposure to livestock.


Genotype-phenotype correlations of mutations and polymorphisms in HSD11B2, the gene encoding the kidney isozyme of 11beta-hydroxysteroid dehydrogenase.
Mutations in the HSD11B2 gene encoding the kidney (11-HSD2) isozyme of 11beta-hydroxysteroid dehydrogenase cause the syndrome of apparent mineralocorticoid excess, a form of salt-sensitive hypertension. Enzymatic activities of mutant enzymes measured in cultured cells are correlated with several parameters of clinical severity including urinary steroid product:precursor ratios, age at diagnosis, birth weight and potassium levels, but not with blood pressure. In normals or in subjects with essential hypertension, sensitivity of blood pressure to salt loading is correlated with activity of renal 11-HSD2, as measured by an increase in the ratio of urinary free cortisol/urinary free cortisone (UFF/UFE), and also correlated with length of a CA repeat polymorphism in the first intron of HSD11B2. A functional explanation for these associations remains to be elucidated.


Use of mesalazine in diverticular disease.
Diverticular disease includes a spectrum of conditions sharing the underlying pathology of acquired diverticula of the colon: symptomatic uncomplicated diverticular disease, recurrent symptomatic uncomplicated diverticular disease, and complicated diverticular disease. Goals of therapy in diverticular disease should be to improve symptoms and to prevent recurrent attacks in symptomatic uncomplicated diverticular disease, and to prevent the complications of disease such as diverticulitis. Inflammation seems to play a key role in all forms of the disease. This is the rationale for the use of anti-inflammatory drugs such as mesalazine. Inflammation in such diseases seems to be generated by a heightened production of proinflammatory cytokines, reduced anti-inflammatory cytokines, and enhanced intramucosal synthesis of nitric oxide. The mechanisms of action of mesalazine are not yet well understood. It is an anti-inflammatory drug that inhibits factors of the inflammatory cascade (such as cyclooxygenase) and free radicals, and has an intrinsic antioxidant effect. Some recent studies confirm the efficacy of mesalazine in diverticular disease both in relief of symptoms in symptomatic uncomplicated forms and in prevention of recurrence of symptoms and main complications.


Comparison of current US risk strategy to screen for hepatitis C virus with a hypothetical targeted birth cohort strategy.
We compared the theoretical performance of a 1-time, birth cohort strategy with the currently recommended risk strategy for screening for hepatitis C virus (HCV) infection, which is undetected in an estimated 75% of 4 million affected people in the United States. We applied current American Association for the Study of Liver Disease risk screening guidelines and a targeted birth cohort strategy to National Health and Nutrition Examination Survey data from 2003 to 2006 to estimate their performance in identifying HCV cases. Risk guidelines would recommend testing 25% of the US population aged 20 years or older and, if fully implemented, identify 82% of the projected HCV-exposed population. A targeted birth cohort (1946-1964) strategy would test 45% of the same population and identify 76% of the projected HCV population. In this ideal-world simulation, birth year and risk screening had similar theoretical performances for predicting HCV infection. However, actual implementation of risk screening has not achieved its theoretical performance, and birth cohort screening might increase HCV testing rates.


Man-Made Climatic Changes: Man's activities have altered the climate of urbanized areas and may affect global climate in the future.
Natural climatic fluctuations, even those of recent years, cover a considerable range. They can be characterized as a "noise" spectrum which masks possible global effects of man-caused increases of atmospheric CO(2) and particulates. Local modifications, either deliberate or inadvertent, measurably affect the microclimate. Some artificial alterations of the microlimate are beneficial in agriculture. Among the unplanned effects, those produced by urbanization on local temperature and on wind field are quite pronounced. The influences on rainfall are still somewhat controversial, but effects may extend considerably beyond the confines of metropolitan areas. They are the result of water vapor released by human activity and of the influence of condensation and freezing nuclei produced in overabundance by motor vehicles and other combustion processes. Therefore it appears that on the local scale man-made influences on climate are substantial but that on the global scale natural forces still prevail. Obviously this should not lead to complacency. The potential for anthropogenic changes of climate on a larger and even a global scale is real. At this stage activation of an adequate worldwide monitoring system to permit early assessment of these changes is urgent. This statement applies particularly to the surveillance of atmospheric composition and radiation balance at sites remote from concentrations of population, which is now entirely inadequate. In my opinion, man-made aerosols, because of their optical properties and possible influences on cloud and precipitation processes, constitute a more acute problem than CO(2). Many of their effects are promptly reversible; hence, one should strive for elimination at the source. Over longer intervals, energy added to the atmosphere by heat rejection and CO(2) absorption remain matters of concern.


Effects of oral niacin on endothelial dysfunction in patients with coronary artery disease: results of the randomized, double-blind, placebo-controlled INEF study.
High-density-lipoproteins-cholesterol (HDL-C) is invertedly related to the incidence of cardiovascular events. Recent studies suggest that HDL-C directly improves endothelial function. Nicotinic acid (niacin) effectively raises serum HDL-C. We therefore hypothesized that treatment with niacin improves endothelial dysfunction in patients with coronary artery disease (CAD). One hundred seven patients with CAD were randomly assigned to double-blinded treatment for 12 weeks with extended-release (ER)-niacin 1000 mg/day (N) or placebo (C), respectively. Flow-mediated dilation (FMD) of the brachial artery, nitroglycerin-mediated endothelium-independent dilation (NMD) and serum lipid concentrations were measured before and after treatment. Triglycerides (P=0.013), low-density-lipoprotein-cholesterol (LDL-C) (P=0.013) and HDL-C (P<0.0001) were altered by N compared to C. Niacin treatment was without effect on FMD or NMD, respectively, compared to placebo. However, post-hoc subgroup analysis revealed an improvement in FMD in patients with low HDL-C at baseline (absolute change in FMD (mean+/-S.D.) N: +3.25+/-3.88%, C: +1.03+/-2.71% in low tertile HDL-C <or=45 mg/dl. P=0.047). The present findings indicate that ER-niacin treatment improves endothelial dysfunction in patients with CAD and low HDL-C, but not with normal HDL-C.


Differential effectiveness of the Minnesota Safe Patient Handling Act by health care setting: An exploratory study.
The Minnesota Safe Patient Handling (MN SPH) Act requires health care facilities to implement comprehensive programs to protect their workers from musculoskeletal injuries caused by lifting and transferring patients. Nursing homes, hospitals, and outpatient facilities each face unique challenges implementing and maintaining SPH programs. The objective of the study was to compare patient handling injuries in these three health care settings and determine whether change in injury rate over time differed by setting following enactment of the law. Workers' compensation data from a Minnesota-based insurer were used to describe worker and claim characteristics in nursing homes, hospitals, and outpatient facilities. Negative binomial models were used to compare claims and estimate mean annual patient handling claim rates by health care setting and time period following enactment of the law. Consistent with national data, the patient handling claim rate was highest in Minnesota nursing homes (168 claims/$100 million payroll [95% confidence interval: 163-174]) followed by hospitals (35/$100 million payroll [34-37]) and outpatient facilities (2/$100 million payroll [1.8-2.2]). Patient handling claims declined by 38% over 10 years following enactment of the law (vs. 27% for all other claims). The change in claims over time did not differ by health care setting. In this single-insurer sample, declines in workers' compensation claims for patient handling injuries were consistent across health care settings following enactment of a state SPH law. Though nursing homes experienced elevated claim rates overall, results suggest they are not lagging hospitals and outpatient facilities in reducing patient handling injuries.


[Quality of the home parenteral nutrition program: 14 years of experience at a general university hospital].
The quality of home parenteral nutrition (NPD in its Spanish acronym) depends on the frequency and type of complication associated with NPD treatment and the likelihood of survival. The present study assesses the quality of the NPD programme in place in our hospital in terms of survival, infections and mechanical complications. A retrospective study was carried out into the clinical follow-up data of all the patients (n = 24) included in our NPD programme since its start in 1985 until 1998 (14 years). An estimate is made for: a) the annual index of infectious complications (IAC in its Spanish acronym), b) the annual index of mechanical complications (MAC in its Spanish acronym) and c) the likelihood of survival by means of the Kaplan-Meier method. The quality specifications adopted are those of the literature reflecting the current provision of NPD programmes and the survival values of patients undergoing dialysis for chronic kidney failure. The most frequent pathology in our context is benign (70.8%), distributed as follows: small bowel syndrome of ischaemic origin (45.8%), small bowel syndrome of non-ischaemic origin (12.5%) and idiopathic intestinal pseudo-obstruction (12.5%). The patients with benign pathologies present a higher survival rate than patients with neoplastic disease (95% in the fifth year of treatment versus 45% at twenty months), with a statistically significant difference. The annual index of infectious complications is 0.6 (median value of the 14 years studied). Similarly, the annual indices of obstructions and thromboses are 0.11 and 0.0095, respectively. In our opinion, the quality of the NPD programme in place at our hospital is highly satisfactory because both the survival rate and the annual indices of mechanical and infectious complications are acceptable with regard to the programmes in place in the international sphere. In addition, in terms of survival, NPD seems slightly more effective than dialysis for chronic kidney disease.


Male health status, signalled by courtship display, reveals ejaculate quality and hatching success in a lekking species.
1. The information content of secondary sexual traits and the benefits gathered by choosy females are at the heart of sexual selection theory. Indicator models of sexual selection assume that secondary sexual traits reflect the phenotypic/genetic quality of their bearers and that females gather benefits from choosing these high-quality males. 2. Here, we tested the idea that courtship display reflects the health status in a bird species with a lek-based mating system, the houbara bustard (Chlamydotis undulata undulata). A group of males was treated with the lipopolysaccharide (LPS) of the cell wall of the bacterium Escherichia coli during the seasonal peak of courtship display, while another group of males was injected with a phosphate-buffered saline solution (PBS) as a control. We then monitored the effect of the treatment on both courtship display and ejaculate quality. Finally, females were artificially inseminated with semen from LPS and PBS males, which allowed us to assess the effect of the immunological treatment on reproduction. 3. We found that the inflammatory challenge reduced courtship display and semen quality compared to controls. Interestingly, males that better resisted to the immune challenge in terms of courtship display also better resisted in terms of ejaculate quality. Early reproductive failure was increased when females were artificially inseminated with semen from immune-activated males. Failure of eggs laid by females inseminated with LPS semen was due to a reduced fertilization power of sperm of LPS males or to increased embryo mortality in the very early stage of embryo development. As a consequence, hatching rate was reduced for females inseminated with semen collected from LPS males. 4. These results show that by assessing male courtship display, females may gain insight into the current phenotypic/genetic quality of mates and gather fitness benefits in terms of reproductive success.


QuantiFERON-TB Performs Better in Children, Including Infants, than in Adults with Active Tuberculosis: a Multicenter Study.
Immunological tests, including the QuantiFERON-TB Gold In-Tube (QFT-IT) assay, represent an important aid for diagnosing active tuberculosis (TB) and latent TB infections in children, but concerns about their use in children <5 years of age persist. This is a multicenter retrospective study comparing a population of 226 children to 521 adults with pulmonary or extrapulmonary TB. The aim was to evaluate the QFT-IT performance, analyzing both qualitative and quantitative results, according to age, birthplace, and disease localization. Compared to culture, QFT-IT sensitivity was 93.9%, 100%, and 94.4% in children ≤2, 2 to 5, and 5 to 16 years of age, respectively, and was significantly higher than that in adults (81.0%) (P < 0.0001). The rate of indeterminate test results for children (2.2%) was significantly lower than that for adults (5.2%) (P < 0.0001). In children, QFT-IT sensitivity was not affected by disease localization or birthplace (Italy born versus foreign born). Interferon gamma (IFN-γ) values in response to TB antigen and mitogen were significantly higher in children than in adults (TB antigen, median of 10 versus 1.66 IU IFN-γ/ml; mitogen, median of 10 versus 6.70 IU IFN-γ/ml; P < 0.0001). In summary, this study supports the use of QFT-IT as a complementary test for the diagnosis of pediatric TB even under 2 years of age. Our observations could be applicable to the new version of the test, QuantiFERON-TB Gold Plus, which has recently been shown to have similar sensitivity in active TB, although data in children are still lacking.


Long term valve-related morbidity following open-heart surgery at the Kenyatta National Hospital.
To determine the incidence of valve morbidity associated with post-operative valve patients at the Kenyatta National Hospital, Nairobi. A combined retrospective and prospective study. Restrospective period from 1973 to 31st July 1977 and prospective period from there on to 31st July 1998. Cardiothoracic outpatient clinic at Kenyatta National Hospital, Nairobi. All valve replacement patients attending the cardiothoracic outpatient clinic on follow up following discharge from the ward. Morbidity was assessed by incidence of: stroke, thromboembolism, valve thrombosis, bleeding episodes, valve endocarditis and re-operation for valve failure. For all valve surgery combined the overall follow up rate equalled 476.3 patient years. The linearised occurrence rate for thromboembolism for all valves was 1.04% per patient year. For the mechanical valves this incidence was 1.32% per patient year. The stroke free rate at one year and five years was 97.7% and 95.9% respectively. The linearised incidence rate for stroke was 0.84% per patient year for all valves. The incidence of bleeding episodes, excluding menorrhagia, for mechanical valves was 0.79% per patient year. Three episodes of valve thrombosis were observed in this study group, all occurring with mechanical valves. For mechanical valves the incidence equalled 0.79% per patient year. The incidence of prosthetic valve endocarditis equalled 0.42% per patient year for all valves combined, or 0.53% per patient year for mechanical valves. Three patients in the series had redo surgery due to valve failure (0.63%). The commutative occurrence of valve related morbidity for the study population for all valves analysed was 2.73% per patient year. The incidence of the various valve morbidity at the Kenyatta National Hospital are below the internationally quoted figures in the literature for other centres. The high incidence of drop out to clinic follow up is likely to be the main reason for this with a lot of morbidity occurring outside the hospital environment and therefore not documented. The exact estimation of this incidence is difficult to assess. To help ascertain this occurrence an accurate patient database with accurate (real time) contacts needs to be put into place.


Thirty-year risk of ischemic stroke in individuals with sickle cell trait and modification by chronic kidney disease: The atherosclerosis risk in communities (ARIC) study.
Sickle cell trait (SCT) has been associated with hypercoagulability, chronic kidney disease (CKD), and ischemic stroke. Whether concomitant CKD modifies long-term ischemic stroke risk in individuals with SCT is uncertain. We analyzed data from 3602 genotyped black adults (female = 62%, mean baseline age = 54 years) who were followed for a median 26 years by the Atherosclerosis Risk in Communities Study. Ischemic stroke was verified by physician review. Associations between SCT and ischemic stroke were analyzed using repeat-events Cox regression, adjusted for potential confounders. SCT was identified in 236 (7%) participants, who more often had CKD at baseline than noncarriers (18% vs 13%, P = .02). Among those with CKD, elevated factor VII activity was more prevalent with SCT genotype (36% vs 22%; P = .05). From 1987-2017, 555 ischemic strokes occurred in 436 individuals. The overall hazard ratio of ischemic stroke associated with SCT was 1.31 (95% CI: 0.95-1.80) and was stronger in participants with concomitant CKD (HR = 2.18; 95% CI: 1.16-4.12) than those without CKD (HR = 1.09; 95% CI: 0.74-1.61); P for interaction = .04. The hazard ratio of composite ischemic stroke and/or death associated with SCT was 1.20 (95% CI: 1.01-1.42) overall, 1.44 (95% CI: 1.002-2.07) among those with CKD, and 1.15 (95% CI: 0.94-1.39) among those without CKD; P for interaction = .18. The long-term risk of ischemic stroke associated with SCT relative to noncarrier genotype appears to be modified by concomitant CKD.


Widespread contribution of methane-cycle bacteria to the diets of lake profundal chironomid larvae.
Reports of unexpectedly 13C-depleted chironomid larvae in lakes have led to an hypothesis that significant transfer of detrital organic matter to chironomid larvae may occur via methane-cycle bacteria. However, to date little is known of how such transfer might vary across species and lakes. We gathered data from 87 lakes to determine how widespread this phenomenon might be and to define boundaries for its likely magnitude. Carbon stable isotope values of chironomid larvae varied greatly between taxa. Very marked 13C-depletion was evident only in certain taxa, especially Chironomus plumosus, C. anthracinus, and C. tenuistylus, all characteristic of eutrophic or dystrophic lakes and known to be tolerant of low oxygen conditions. Furthermore, marked 13C-depletion was only found in larvae from lakes in which late-summer hypolimnetic oxygen depletion near the sediment surface was below an apparent threshold concentration of 2-4 mg O2/L. Similarly, application of a two-source mixing model suggested that methanotrophic bacteria made the greatest contribution to profundal chironomid growth (0-70% of larval carbon) when the late-summer oxygen concentration dropped below approximately 2 mg O2/L. Our study demonstrates that methane-derived carbon is an important, but often neglected, contribution to the flux of carbon through the food webs of many productive or dystrophic lakes.


Structural characterization of H3K56Q nucleosomes and nucleosomal arrays.
The post-translational modification of histones is a key mechanism for the modulation of DNA accessibility. Acetylated lysine 56 in histone H3 is associated with nucleosome assembly during replication and DNA repair, and is thus likely to predominate in regions of chromatin containing nucleosome-free regions. Here we show by X-ray crystallography that mutation of H3 lysine 56 to glutamine (to mimic acetylation) or glutamate (to cause a charge reversal) has no detectable effects on the structure of the nucleosome. At the level of higher order chromatin structure, the K to Q substitution has no effect on the folding of model nucleosomal arrays in cis, regardless of the degree of nucleosome density. In contrast, defects in array-array interactions in trans ('oligomerization') are selectively observed for mutant H3 lysine 56 arrays that contain nucleosome-free regions. Our data suggests that H3K56 acetylation is one of the molecular mechanisms employed to keep chromatin with nucleosome-free regions accessible to the DNA replication and repair machinery.


Prostanoid- and interleukin-1-induced primary genes in cementoblastic cells.
Cementum is a key component of a functional periodontal organ. However, regenerating lost cementum is difficult and often incomplete. Identifying molecular mediators of cementoblast differentiation and function should lead to better targeted treatment for periodontitis. Prostaglandins increase mineralization of murine cementoblastic OCCM cells and alveolar bone formation, whereas the cytokine interleukin-1 (IL-1) inhibits alveolar bone formation. We hypothesized that differentially induced primary genes in OCCM cells may mediate anabolic and catabolic responses. Our objective was to identify primary genes differentially induced by the synthetic prostanoid fluprostenol and IL-1 in cementoblastic cells. Confluent OCCM cells were pretreated with the protein synthesis inhibitor cycloheximide followed by fluprostenol or IL-1 for 1.5 hours. cDNA generated from each group was used for cDNA subtraction hybridization to identify differentially induced genes. Preferential gene induction was verified by Northern blot analysis. Thirteen fluprostenol- and seven IL-1-regulated genes were identified. Among the fluprostenol-induced genes was mitogen-activated protein (MAP) kinase phosphatase 1 (MKP1), a negative regulator of MAP kinase signaling. To verify the cDNA subtraction hybridization results, OCCM cells were treated with fluprostenol or prostaglandin F2 (PGF2), and MKP1 mRNA levels were determined. The 0.001 to 1 microM fluprostenol and 0.01 to 1 microM PGF2 significantly induced MKP1 mRNA levels, which peaked at 1 hour of treatment and returned to baseline at 2 hours. Fluprostenol enhanced, whereas IL-1 inhibited, OCCM mineralization. Using cDNA subtraction hybridization, we identified primary genes that correlate with the observed anabolic and catabolic responses. These findings further our understanding of cementoblast function and suggest that differentially induced genes may mediate cementum formation and resorption.


Prokinetic therapy for feed intolerance in critical illness: one drug or two?
To compare the efficacy of combination therapy, with erythromycin and metoclopramide, to erythromycin alone in the treatment of feed intolerance in critically ill patients. Randomized, controlled, double-blind trial. Mixed medical and surgical intensive care unit. Seventy-five mechanically ventilated, medical patients with feed intolerance (gastric residual volume > or =250 mL). Patients received either combination therapy (n = 37; 200 mg of intravenous erythromycin twice daily + 10 mg of intravenous metoclopramide four times daily) or erythromycin alone (n = 38; 200 mg of intravenous erythromycin twice daily) in a prospective, randomized fashion. Gastric feeding was re-commenced and 6-hourly gastric aspirates performed. Patients were studied for 7 days. Successful feeding was defined as a gastric residual volume <250 mL with the feeding rate > or =40 mL/hr, over 7 days. Secondary outcomes included daily caloric intake, vomiting, postpyloric feeding, length of stay, and mortality. Demographic data; use of inotropes, opioids, or benzodiazepines; and pretreatment gastric residual volume were similar between the two groups. The gastric residual volume was significantly lower after 24 hrs of treatment with combination therapy, compared with erythromycin alone (136 +/- 23 mL vs. 293 +/- 45 mL, p = .04). Over the 7 days, patients treated with combination therapy had greater feeding success, received more daily calories, and had a lower requirement for postpyloric feeding, compared with erythromycin alone. Tachyphylaxis occurred in both groups but was less with combination therapy. Sedation, higher pretreatment gastric residual volume, and hypoalbuminemia were significantly associated with a poor response. There was no difference in the length of hospital stay or mortality rate between the groups. Watery diarrhea was more common with combination therapy (20 of 37 vs. 10 of 38, p = .01) but was not associated with enteric infections, including Clostridium difficile. In critically ill patients with feed intolerance, combination therapy with erythromycin and metoclopramide is more effective than erythromycin alone in improving the delivery of nasogastric nutrition and should be considered as the first-line treatment.


STEM: An Open Source Tool for Disease Modeling.
The Spatiotemporal Epidemiologic Modeler (STEM) is an open source software project supported by the Eclipse Foundation and used by a global community of researchers and public health officials working to track and, when possible, control outbreaks of infectious disease in human and animal populations. STEM is not a model or a tool designed for a specific disease; it is a flexible, modular framework supporting exchange and integration of community models, reusable plug-in components, and denominator data, available to researchers worldwide at www.eclipse.org/stem. A review of multiple projects illustrates its capabilities. STEM has been used to study variations in transmission of seasonal influenza in Israel by strains; evaluate social distancing measures taken to curb the H1N1 epidemic in Mexico City; study measles outbreaks in part of London and inform local policy on immunization; and gain insights into H7N9 avian influenza transmission in China. A multistrain dengue fever model explored the roles of the mosquito vector, cross-strain immunity, and antibody response in the frequency of dengue outbreaks. STEM has also been used to study the impact of variations in climate on malaria incidence. During the Ebola epidemic, a weekly conference call supported the global modeling community; subsequent work modeled the impact of behavioral change and tested disease reintroduction via animal reservoirs. Work in Germany tracked salmonella in pork from farm to fork; and a recent doctoral dissertation used the air travel feature to compare the potential threats posed by weaponizing infectious diseases. Current projects include work in Great Britain to evaluate control strategies for parasitic disease in sheep, and in Germany and Hungary, to validate the model and inform policy decisions for African swine fever. STEM Version 4.0.0, released in early 2019, includes tools used in these projects and updates technical aspects of the framework to ease its use and re-use.


The spread of bluetongue virus serotype 8 in Great Britain and its control by vaccination.
Bluetongue (BT) is a viral disease of ruminants transmitted by Culicoides biting midges and has the ability to spread rapidly over large distances. In the summer of 2006, BTV serotype 8 (BTV-8) emerged for the first time in northern Europe, resulting in over 2000 infected farms by the end of the year. The virus subsequently overwintered and has since spread across much of Europe, causing tens of thousands of livestock deaths. In August 2007, BTV-8 reached Great Britain (GB), threatening the large and valuable livestock industry. A voluntary vaccination scheme was launched in GB in May 2008 and, in contrast with elsewhere in Europe, there were no reported cases in GB during 2008. Here, we use carefully parameterised mathematical models to investigate the spread of BTV in GB and its control by vaccination. In the absence of vaccination, the model predicted severe outbreaks of BTV, particularly for warmer temperatures. Vaccination was predicted to reduce the severity of epidemics, with the greatest reduction achieved for high levels (95%) of vaccine uptake. However, even at this level of uptake the model predicted some spread of BTV. The sensitivity of the predictions to vaccination parameters (time to full protection in cattle, vaccine efficacy), the shape of the transmission kernel and temperature dependence in the transmission of BTV between farms was assessed. A combination of lower temperatures and high levels of vaccine uptake (>80%) in the previously-affected areas are likely to be the major contributing factors in the control achieved in England in 2008. However, low levels of vaccination against BTV-8 or the introduction of other serotypes could result in further, potentially severe outbreaks in future.


[Canine parvovirus infection in dogs: a consideration].
The current knowledge of canine parvovirus (CPV) and the clinical symptoms associated with CPV infection within seven years after the first outbreaks of the disease are reviewed in the present paper. The most important symptoms result from the occurrence of acute enteritis and/or acute myocarditis. Besides characteristics of the virus, symptoms of disease and (histo)pathological findings, particular attention is focussed on recent developments in diagnosis and prevention. A protocol for the prevention of CPV infections in situations in kennels, consisting of combined vaccination and hygienic procedures is presented.


Effect of Self-efficacy Intervention on Quality of Life of Patients With Intestinal Stoma.
Colorectal carcinoma is one of the most common malignancies worldwide and the most prevalent cause of cancer mortality in China. The Miles operation and permanent colostomy are effective treatment. However, these affect the quality of life of patients as they alter normal defecation. Self-efficacy is used to define an individuals' assessments of their ability to perform a specific behavior successfully. It is regarded as an important belief that can predict health behaviors. The aim of this study was to explore the effect of a self-efficacy intervention on the quality of life of patients with a permanent colostomy. Forty-eight patients in treatment for permanent colostomy surgery were divided into the control and intervention groups. The control group received routine nursing; the intervention group was exposed to a 3-month self-efficacy intervention, as well as routine nursing. The two groups completed the Chinese version of a self-efficacy questionnaire at 10 days, 1 month, and 3 months after surgery. Three months after surgery, the two groups also completed a quality-of-life questionnaire. There were significant differences in the quality of life between the two groups. The self-efficacy intervention nursing method improved self-efficacy and the quality of life of patients with intestinal stoma and is worthy of clinical utilization and application.


Dam methyltransferase is required for stable lysogeny of the Shiga toxin (Stx2)-encoding bacteriophage 933W of enterohemorrhagic Escherichia coli O157:H7.
Shiga toxin 2 (Stx2), one of the principal virulence factors of enterohemorrhagic Escherichia coli, is encoded by 933W, a lambda-like prophage. 933W prophage induction contributes to Stx2 production, and here, we provide evidence that Dam methyltransferase is essential for maintenance of 933W lysogeny. Our findings are consistent with the idea that the 933W prophage has a relatively low threshold for induction, which may promote Stx2 production during infection.


[Unilateral voluntary exophthalmos. A peculiar complication of ethmoidal disease].
A few cases have been reported wherein an exophthalmos can be induced voluntarily and spontaneously. In most cases these have been due to the protrusion of the eye by pressure from behind by blood or air. In many of these cases relaxation of the fascial supports and atrophy of the orbital tissue make enophthalmos alternate with the protrusion. A dehiscence of the medial orbital wall or the establishment of emphisema may also produce a voluntary proptosis, the eye being propelled forwards by air when the intranasal pressure is voluntarily raised. We present here two cases of this peculiar complication of ethmoidal disease, discussing several aspects from the etiology and differential diagnosis of this condition.


L-selenomethionine reduces platinum(IV) anticancer model compounds at strikingly faster rates than L-methionine.
L-Selenomethionine (SeMet), the predominant form of selenium acquired from the diet by humans, has been used as a supplement, and exhibit some important functions like cancer prevention and antioxidative defense. Its interactions with Pt(II) anticancer drugs have been characterized, but its redox reactions with platinum(IV) anticancer prodrugs have not been exploited. In this work, the oxidation of SeMet by Pt(IV) anticancer model compounds trans-[PtX2(CN)4](2-) (X = Cl, Br) was characterized. A stopped-flow spectrometer was used to record the rapid scan spectra and to follow the reaction kinetics over a wide pH range. An overall second-order rate law was derived: -d[Pt(IV)]/dt = k'[Pt(IV)][SeMet], where k' pertains to the observed second-order rate constants. The k'-pH profiles showed that k' increased only about 6 times even though the solution pH was varied from 0.25 to 10.5. The redox stoichiometry was determined as Δ[Pt(IV)]/Δ[SeMet] = 1 : (1.07 ± 0.07), suggesting that SeMet was oxidized to selenomethionine selenoxide. The selenoxide together with its hydrated form was identified explicitly by high resolution mass spectral analysis. A reaction mechanism was proposed which encompassed three parallel rate-determining steps relying on the protolytic species of SeMet. Rate constants of the rate-determining steps were obtained from the simulations of the k'-pH profiles. Activation parameters were determined for the reactions of the zwitterionic form of SeMet with the Pt(IV) complexes. A bridged electron transfer process is delineated in the rate-determining steps and several lines of evidence support the bridged electron transfer mode. Strikingly, reduction of [PtX2(CN)4](2-) by SeMet is 3.7 × 10(3)-5.7 × 10(4) times faster than that by L-methionine. Some potential biological consequences resulting from the strikingly fast reduction are discussed.


Enhanced Electrocatalytic Activity of Ethanol Oxidation Reaction on Palladium-Silver Nanoparticles via Removable Surface Ligands.
This work developed a facile colloidal route to synthesize BH4--capped PdxAgy nanoparticles (NPs) in water using the reducing ionic liquids of [Cnmim]BH4, and the resulting NPs were prone to form the nanocomposites with [amim]+-modified reduced graphene (RG). The removal of the metal-free inorganic ions of BH4- can create the profoundly exposed interfaces on the PdxAgy NPs during the electrooxidation, and favor the ethanol oxidation reaction (EOR) in lowering energy barrier. The counterions of [Cnmim]+ can gather ethanol, OH- ions, and the reaction intermediates on catalysts, and synergistically interact with RG to facilitate the charge transfer in nanocomposites. The interface-modified RG nanosheets can effectively segregate the PdxAgy NPs from aggregation during the EOR. Along with the small size of 4.7 nm, the high alloying degree of 60.2%, the large electrochemical active surface area of 64.1 m2 g-1, and the great peak current density of 1501 mA cm-2 mg-1, Pd1Ag2@[C2mim]BH4-amimRG nanocomposite exhibits the low oxidation potentials, strong poison resistance, and stable catalytic activity for EOR in alkaline media, and hence can be employed as a promising anodic catalyst in ethanol fuel cells.


Key clinical activities for quality asthma care. Recommendations of the National Asthma Education and Prevention Program.
In 1997, the National Asthma Education and Prevention Program (NAEPP), coordinated by the National Heart, Lung, and Blood Institute, published the second Expert Panel Report (EPR-2): Guidelines for the Diagnosis and Management of Asthma (National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program. Expert Panel Report 2: Guidelines for the diagnosis and management of asthma. Bethesda MD: US Department of Health and Human Services, National Institutes of Health, 1997; publication no. 97-4051. Available at http://www.nhlbi.nih.gov/guidelines/ asthma/asthgdln.pdf). Subsequently, the NAEPP Expert Panel identified key questions regarding asthma management that were submitted to an evidence practice center of the Agency for Healthcare Research and Quality to conduct a systematic review of the evidence. The resulting evidence report was used by the Expert Panel to update recommendations for clinical practice on selected topics. These recommendations (EPR-Update 2002) were published in 2002. (National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program. Guidelines for the diagnosis and management of asthma--update on selected topics 2002. J Allergy Clin Immunol 2002;110[November 2002, part 2]. Available at http://www.nhlbi.nih.gov/guidelines/asthma/index.htm). To improve the implementation of these guidelines, a working group of the Professional Education Subcommittee of the NAEPP extracted key clinical activities that should be considered as essential for quality asthma care in accordance with the EPR-2 guidelines and the EPR-Update 2002. The purpose was to develop a report that would help purchasers and planners of health care define the activities that are important to quality asthma care, particularly in reducing symptoms and preventing exacerbations, and subsequently reducing the overall national burden of illness and death from asthma. This report is intended to help employer health benefits managers and other health-care planners make decisions regarding delivery of health care for persons with asthma. Although this report is based on information directed to clinicians; it is not intended to substitute for recommended clinical practices for caring for persons with asthma, nor is it intended to replace the clinical decision-making required to meet individual patient needs. Readers are referred to the EPR-2 for the full asthma guidelines regarding diagnosis and management of asthma or to the abstracted Practical Guide (National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program. Practical guide for the diagnosis and management of asthma. Bethesda MD: US Department of Health and Human Services, National Institutes of Health, 1997; publication no. 97-4053. Available at http://www.nhlbi.nih.gov/health/prof/lung/asthma/practgde.htm) and to the EPR-Update 2002. The 1997 EPR-2 guidelines and EPR-Update 2002 were derived from a consensus of leading asthma researchers from academic, clinical, federal and voluntary institutions and based on scientific evidence supported by the literature. The 10 key activities highlighted here correspond to the four recommended-as-essential components of asthma management: assessment and monitoring, control of factors contributing to asthma severity, pharmacotherapy and education for a partnership in care. The key clinical activities are not intended for acute or hospital management of patients with asthma but rather for the preventive aspects of managing asthma long term. This report was developed as a collaborative activity between CDC and the NAEPP.


Infrared Thermal Imaging of Patients With Acute Upper Respiratory Tract Infection: Mixed Methods Analysis.
Upper respiratory tract infection is a common disease of the respiratory system. Its incidence is very high, and it can even cause pandemics. Infrared thermal imaging (IRTI) can provide an objective and quantifiable reference for the visual diagnosis of people with acute respiratory tract infection, and it can function as an effective indicator of clinical diagnosis. The aims of this study are to observe and analyze the infrared expression location and characteristics of patients with acute upper respiratory tract infection through IRTI technology and to clearly express the quantification of temperature, analyze the role of IRTI in acute upper respiratory tract diagnostic research, and understand the impact of IRTI in qualitative and quantitative research. From December 2018 to February 2019, 154 patients with acute upper respiratory tract infection were randomly selected from the emergency department of the First Affiliated Hospital of Guangzhou Medical University. Among these patients, 73 were men and 81 were women. The subjects were divided into two groups according to the presence of fever, namely, fever and nonfever groups. Qualitative and quantitative analyses of the infrared thermal images were performed to compare the results before and after application of the technology. Using the method described in this paper, through the analysis of experimental data, we elucidated the role of IRTI in the diagnosis of acute upper respiratory tract infection, and we found that qualitative and quantitative IRTI analyses play important roles. Through the combination of theory and experimental data, the IRTI analysis showed good results in identifying acute upper respiratory tract infection. IRTI technology plays an important role in identifying the infrared expression location and characteristics of patients with acute upper respiratory tract infection as well as in the quantification of clear expression of body temperature, and it provides an objective and quantifiable reference basis for elucidating the pathogenesis of these patients.


Real-Time Epileptic Seizure Detection Based on Deep Learning.
Epilepsy is one of the most common neurological diseases, and video EEG is the most commonly used examination method for epilepsy diagnosis. However, since the video EEG examination lasts for hours, the escort has a heavy burden, and the large amount of video EEG data needs to be visually checked by the doctor. The real-time detection of epileptic seizures can reduce the stress of the escort and provide a mark for the doctor to check the EEG efficiently. In this paper, we propose a deep neural network with specified signal representation for real-time seizure detection and add a smoothing filter on the model output to enhance performance. First, we compare the performance of real-time epileptic seizure detection model under different signal representations. Then we use the best signal representation for further analysis in real-time scenario. In the experiment, the EEG data of 9 patients in the CHB-MIT public data set was used, and a patient-specific neural network was trained for each individual. The recall was 97%, the false alarm was 0.219 times per hour, and the latency time was 3.4s for real-time seizure event detection. The results show that this method can realize the real-time detection of epileptic seizures, which is of great significance to the subsequent system design combined with actual scenes.


Stumbling across the Same Phage: Comparative Genomics of Widespread Temperate Phages Infecting the Fish Pathogen Vibrio anguillarum.
Nineteen Vibrio anguillarum-specific temperate bacteriophages isolated across Europe and Chile from aquaculture and environmental sites were genome sequenced and analyzed for host range, morphology and life cycle characteristics. The phages were classified as Siphoviridae with genome sizes between 46,006 and 54,201 bp. All 19 phages showed high genetic similarity, and 13 phages were genetically identical. Apart from sporadically distributed single nucleotide polymorphisms (SNPs), genetic diversifications were located in three variable regions (VR1, VR2 and VR3) in six of the phage genomes. Identification of specific genes, such as N6-adenine methyltransferase and lambda like repressor, as well as the presence of a tRNAArg, suggested a both mutualistic and parasitic interaction between phages and hosts. During short term phage exposure experiments, 28% of a V. anguillarum host population was lysogenized by the temperate phages and a genomic analysis of a collection of 31 virulent V. anguillarum showed that the isolated phages were present as prophages in >50% of the strains covering large geographical distances. Further, phage sequences were widely distributed among CRISPR-Cas arrays of publicly available sequenced Vibrios. The observed distribution of these specific temperate Vibriophages across large geographical scales may be explained by efficient dispersal of phages and bacteria in the marine environment combined with a mutualistic interaction between temperate phages and their hosts which selects for co-existence rather than arms race dynamics.


The experience of Australian aged care workers during a trial implementation of a palliative care outcomes programme.
End of life care is an essential part of the role of Australian aged care homes (ACHs). However, there is no national framework to support aged care staff in systematically identifying residents with palliative care needs or to routinely assess, respond to, and measure end of life needs. The Palliative Care Outcomes Collaboration (PCOC) is a national outcomes and benchmarking programme which aims to systematically improve palliative care for people who are approaching the end of life, and for their families and carers. The PCOC Wicking Model for Residential Aged Care was developed and piloted in four Australian ACHs. This paper reports on the qualitative findings from semi-structured interviews and focus groups conducted with ACH staff (N = 37) to examine feasibility. Thematic analysis identified three overarching themes about the pilot: (i) processes to successfully prepare and support ACHs; (ii) appropriateness of PCOC tools for the ACH setting; and (iii) realised and potential benefits of the model for ACHs. The lessons presented valuable insights to refine the PCOC Wicking Model and enrich understanding of the potential challenges and solutions for implementing similar programs within ACHs in future. The results suggest that key to successfully preparing ACHs for implementation of the PCOC Wicking Model is an authentic and well-paced collaborative approach with ACHs to ensure the resources, structures and systems are in place and appropriate for the setting. The PCOC Wicking Model for Residential Aged Care is a promising prototype to support ACHs in improving palliative and end of life care outcomes for residents and their carers.


Comparison of 3 clinical models for predicting the probability of pulmonary embolism.
Two clinical models have been described to predict the probability of pulmonary embolism: the Canadian (or Wells) model, and the Geneva model. A third model has been developed recently at our institution (the Pisa model). We compared the performance of the 3 models in 215 consecutive patients with suspected pulmonary embolism. The clinical probability predicted by the models was categorized as low, intermediate, or high. In all patients, pulmonary angiography was used as the reference diagnostic standard. In patients with pulmonary embolism, the extent of pulmonary embolization was assessed on the lung scan as an index of disease severity. The prevalence of pulmonary embolism was 43.3%, and the median extent of pulmonary embolization at diagnosis was 39.8% (range, 4.5%-75.3%). The proportions of patients categorized as having low, intermediate, or high probability were, respectively: 12%, 60%, and 28%, for the Geneva model; 30%, 55%, and 15%, for the Wells model; 37%, 37%, and 26% for the Pisa model. The frequencies of pulmonary embolism in the low, intermediate, and high probability categories were, respectively: 50%, 39%, and 49% for the Geneva model; 12%, 54%, and 64% for the Wells model; 5%, 42%, and 98% for the Pisa model. Among patients with pulmonary embolism, there was a strong, positive relation between clinical probability predicted by the Pisa model and the extent of pulmonary embolization. The Pisa model proved more accurate than the 2 other models. It may be useful to physicians in defining precisely the pretest probability of pulmonary embolism.


Legacies of more frequent drought in ponderosa pine across the western United States.
Despite widespread interest in drought legacies-multiyear impacts of drought on tree growth-the key implication of reported drought legacies remains unaddressed: as impaired growth and slow recovery associated with drought legacies are pervasive across forest ecosystems, what is the impact of more frequent drought conditions? We investigated the assumption that either multiple drought years occurring during a short period (multiyear droughts), or droughts occurring during the recovery period from previous drought (compounded droughts), are detrimental to subsequent growth. There is evidence that drought responses may vary among populations of widespread species, leading us to examine regional differences in responses of the conifer Pinus ponderosa to historic drought frequency in the western United States. More frequent drought conditions incurred additional growth declines and shifts in growth-climate sensitivities in the years following drought relative to single-drought events, with 'triple-droughts' being worse than 'double-droughts'. Notably, prediction skill was not strongly reduced when ignoring compounded droughts, a consequence of the temporally comprehensive formulation of our stochastic antecedent model that accounts for the climatic memory of tree growth. We argue that incorporating drought-induced temporal variability in tree growth sensitivities can aid inference gained from statistical models, where more simplistic models could overestimate the severity of drought legacies. We also found regional differences in response to repeated drought, and suggest plastic post-drought sensitivities and climatic memory may represent beneficial physiological adjustments in interior regions. Within-species variability may thus mediate forest responses to increasing drought frequency under future climate change, but experimental approaches using more species are necessary to improve our understanding of the mechanisms that underlie drought legacy effects on tree growth.


Weight, height and puberty in a cohort of Macedonian girls.
Obesity is becoming a growing problem in developed and developing countries. Many studies report an increasing incidence of obesity in the last decade. The aim of our transversal epidemiological study was to evaluate the prevalence of overweight children, auxological characteristics and pubertal stage in healthy girls from first (200 girls), third (209), fifth (290) and seventh (223) grade of school. In this study 928 girls were evaluated through systematic school examinations in the ambulance of municipality of Karposh, Skopje. The Rome and Turkish nationality, as well as Serbian were present in a small percentage, while detailed analysis was performed in the Macedonian and Albanian population of girls. The initiation of puberty (stage M2 or P2 by Tanner) was present in Macedonian girls: 4.3% of children in first grade, 23% in third grade, and 51.7% in fifth grade. In Albanians, in first grade M2 is present in 2.7%, in third grade 5.2%, and in fifth grade 46.9%. Body mass index (BMI SDS) was +3.5 +/- 1.5 in 35% of Macedonian girls and only 5% of Albanian girls. The Macedonian girls were also significantly higher (p < 0.01) and more obese than the Albanian girls. The pubertal stage was also more advanced in Macedonian girls. Most of the obese children who were included in the study reported increased consumption of fast food. Although in the past years obesity was not a problem in our country, it is becoming more severe with every year.


Energy-crises in well-aerated and anoxic tissue: does tolerance require the same specific proteins and energy-efficient transport?
Many of the profound changes in metabolism that are caused by O2 deficiency also occur in well-aerated tissues when oxidative phosphorylation is partially or wholly inhibited. For these well-aerated tissues, reduction in energy formation occurs during exposure to inhibitors of oxidative phosphorylation, cold/chilling and wounding, so we prefer the term 'energy crisis' metabolism over 'anaerobic' metabolism. In this review, we note that the overwhelming body of data on energy crises has been obtained by exposure to hypoxia-anoxia, which we will indicate when discussing the particular experiments. We suggest that even transient survival of an energy crisis requires a network of changes common to a large number of conditions, ranging from changes in development to various adverse conditions such as high salinity, drought and nutrient deficiency, all of which reduce growth. During an energy crisis this general network needs to be complemented by energy specific proteins, including the so called 'anaerobic proteins' and the group of ERFVII transcription factors, which induces the synthesis of these proteins. Crucially, the difference between anoxia-intolerant and -tolerant tissues in the event of a severe energy crisis would mainly depend on changes in some 'key' energy crisis proteins: we suggest these proteins would include phytoglobin, the V-H+PPiase and pyruvate decarboxylase. A second characteristic of a high tolerance to an energy crisis is engagement of energy efficient transport. This feature includes a sharp reduction in rates of solute transport and use of energy-efficient modifications of transport systems by primary H+ transport and secondary H+-solute transport systems. Here we also discuss the best choice of species to study an energy crisis. Further, we consider confounding of the acclimative response by responses to injury, be it due to the use of tissues intolerant to an energy crisis, or to faulty techniques.


High incidence of community-acquired pneumonia among rapidly aging population in Japan: a prospective hospital-based surveillance.
The age-group-specific incidence and etiological patterns of community-acquired pneumonia (CAP) have not been fully established in Japan. A 2-year prospective surveillance was conducted in Kochi city, Western Japan. All CAP patients aged ≥15 years who visited a community-based hospital were enrolled in the study. Clinical samples were examined by conventional bacterial culture and urinary antigen tests, and 6 bacterial pathogens and 16 respiratory viruses were identified from sputum samples by multiplex polymerase chain reaction assays. The age-group-specific incidence of CAP was estimated using a population-based data set of the total number of outpatients in the whole city. Ninety of the 131 enrolled patients, 68.7% were positive for respiratory pathogens. Streptococcus pneumoniae was the leading bacterial pathogen identified (28.2%). Respiratory viruses were identified in 36 patients (27.5%), and human entero-rhinovirus was the most common (13.3%) among them. The estimated overall incidence of adult CAP in Kochi was 9.6 per 1,000 person-years (PY); the estimated age group-specific incidence was 3.4, 10.7, and 42.9 per 1,000 PY for those aged 15-64, 65-74, and ≥75 years, respectively. The high incidence of CAP in these rural city of Japan, probably reflects the substantial aged population. S. pneumoniae and respiratory viruses play important roles in CAP in all age groups.


Genetic relations between varicella-zoster virus and Epstein-Barr virus.
Varicella-zoster virus (VZV) and Epstein-Barr virus (EBV) are important human pathogens which belong to different subfamilies of the herpesviruses: the Alpha- and Gammaherpesvirinae, respectively. Computer comparisons of the amino acid sequences of proteins predicted from the published complete VZV and EBV DNA sequences resulted in the detection of EBV counterparts to 29 of the 67 unique VZV genes. Conserved genes were detected only in the UL component of each genome, and are located in three major regions, within which conserved genes are generally colinear. However, the three regions are arranged differently in the two genomes. These results make it possible in principle to propose the functions of EBV genes on the basis of the functions of their VZV counterparts. The data also allow identification of the types of events which may have occurred during divergence of VZV and EBV, as representatives of the Alpha- and Gammaherpesvirinae, from a common ancestor.


[Strategies avoiding inertia and non compliance in clinical trials].
Randomised controlled trials play a key role in evidence-based medicine as far as the assessment of both efficacy and safety of drugs is concerned. Various strategies are used to avoid physician's inertia and to combat patient's non compliance, two pitfalls that may hinder the demonstration of the therapeutic efficacy of the drug. Clinical inertia may be limited by titration, forced or optional, driven by therapeutic targets, or by the use, if necessary, of rescue medications. Compliance may be verified by "pill count". This simple technique allows to exclude non compliant patients when they are detected during the placebo run-in period before randomisation or not to take into account patients with poor compliance in the final evaluation by using a statistical analysis restricted to individuals who have strictly adhered to the study protocol ("per protocol analysis"). Self-monitoring and patient's empowerment in the treatment also contribute to improve drug compliance. Clinicians may take advantage of these approaches derived from clinical trials to improve their daily practice.


Roles of the α1B-Adrenergic Receptor Phosphorylation Domains in Signaling and Internalization.
The function of the α1B-adrenergic receptor phosphorylation sites previously detected by mass spectrometry was evaluated by employing mutants, substituting them with non-phosphorylatable amino acids. Substitution of the intracellular loop 3 (IL3) sites did not alter baseline or stimulated receptor phosphorylation, whereas substitution of phosphorylation sites in the carboxyl terminus (Ctail) or both domains (IL3/Ctail) markedly decreased receptor phosphorylation. Cells expressing the IL3 or Ctail receptor mutants exhibited a noradrenaline-induced calcium-maximal response similar to those expressing the wild-type receptor, and a shift to the left in the concentration-response curve to noradrenaline was also noticed. Cells expressing the IL3/Ctail mutant exhibited higher apparent potency and increased maximal response to noradrenaline than those expressing the wild-type receptor. Phorbol ester-induced desensitization of the calcium response to noradrenaline was reduced in cells expressing the IL3 mutant and abolished in cells in which the Ctail or the IL3/Ctail were modified. In contrast, desensitization in response to preincubation with noradrenaline was unaffected in cells expressing the distinct receptor mutants. Noradrenaline-induced ERK phosphorylation was surprisingly increased in cells expressing IL3-modified receptors but not in those expressing receptors with the Ctail or IL3/Ctail substitutions. Our data indicate that phosphorylation sites in the IL3 and Ctail domains mediate and regulate α1B-adrenergic receptor function. Phorbol ester-induced desensitization seems to be closely associated with receptor phosphorylation, whereas noradrenaline-induced desensitization likely involves other elements.


Influence of photon energy cuts on PET Monte Carlo simulation results.
The purpose of this work is to study the influence of photon energy cuts on the results of positron emission tomography (PET) Monte Carlo (MC) simulations. MC simulations of PET scans of a box phantom and the NEMA image quality phantom are performed for 32 photon energy cut values in the interval 0.3-350 keV using a well-validated numerical model of a PET scanner. The simulations are performed with two MC codes, egs_pet and GEANT4 Application for Tomographic Emission (GATE). The effect of photon energy cuts on the recorded number of singles, primary, scattered, random, and total coincidences as well as on the simulation time and noise-equivalent count rate is evaluated by comparing the results for higher cuts to those for 1 keV cut. To evaluate the effect of cuts on the quality of reconstructed images, MC generated sinograms of PET scans of the NEMA image quality phantom are reconstructed with iterative statistical reconstruction. The effects of photon cuts on the contrast recovery coefficients and on the comparison of images by means of commonly used similarity measures are studied. For the scanner investigated in this study, which uses bismuth germanate crystals, the transport of Bi X(K) rays must be simulated in order to obtain unbiased estimates for the number of singles, true, scattered, and random coincidences as well as for an unbiased estimate of the noise-equivalent count rate. Photon energy cuts higher than 170 keV lead to absorption of Compton scattered photons and strongly increase the number of recorded coincidences of all types and the noise-equivalent count rate. The effect of photon cuts on the reconstructed images and the similarity measures used for their comparison is statistically significant for very high cuts (e.g., 350 keV). The simulation time decreases slowly with the increase of the photon cut. The simulation of the transport of characteristic x rays plays an important role, if an accurate modeling of a PET scanner system is to be achieved. The simulation time decreases slowly with the increase of the cut which, combined with the accuracy loss at high cuts, means that the usage of high photon energy cuts is not recommended for the acceleration of MC simulations.


Glucococorticoid-induced death of pancreatic Beta cells: an organized chaos.
Glucocorticoids (GC) are renowned for their pleiotropic effects in all organ systems, their ubiquitous use in numerous clinical settings, and the abundant adverse effects they may exert, particularly in the endocrine-metabolic sphere. Although hyperglycemia and insulin resistance are well-defined GC-induced diabetogenic phenomena, an added component of direct injury to pancreatic β cells (PBC) may also participate in this scenario. Indeed, the apoptotic capacity of GC is widely recognized, and PBC do not escape this situation. No unified pathway has been characterized regarding GC-induced cell death; instead, it appears to depend on the specific machinery of each cell type, determining a great heterogeneity in GC-dependent apoptotic mechanisms among different tissues. In PBC, GC can induce the expression or activation of pro-apoptotic proteins (Bax, BAD, p38), repress anti-apoptotic proteins (Bcl-2), deactivate pro-survival mechanisms (cAMP-PKA signaling) and sensitize the cell to death induced by oxidative stress, fatty acids, hyperglycemia and cytokines. Although proliferative pathways (TGF-β, H-ras) are activated simultaneously - and an increase in PBC mass may be observed initially - pro-apoptotic and anti-proliferative mechanisms appear to eventually overcome their pro-survival counterparts, due to their synergic and aggregative action. Key molecules such as p38 and the cAMP-PKA system may be promising therapeutic targets in the prevention of GC-induced cell death.


Employment among users of a medically supervised safer injection facility.
A supervised injection facility (SIF), where individuals can inject drugs under medical supervision, opened in Vancouver in 2003. The scientific evaluation of the SIF has demonstrated positive public health-related outcomes. However, the influence of supervised injection facilities on individual efforts to reintegrate into mainstream society has not been studied. We examined for a possible relationship between use of the SIF and employment among a cohort of 1090 SIF users using generalized estimating equations (GEE). In a multivariate analysis of factors associated with employment, using the SIF for >or= 25% of injections (versus > 25% of injections) was not statistically significant (AOR = 1.05, 95% CI: 0.88-1.27). These findings suggest that the SIF is not having an adverse impact on efforts to seek employment.


Creative alternatives in mental health.
With budgets being cut universally, all types of patients face new challenges in obtaining care. When states began to release patients from state hospitals, those patients often had nowhere to turn for the basics. One demonstration program, however, strives to take them beyond the basics so they can be fully integrated members of the community.


Stevens's brightness law, contrast gain control, and edge integration in achromatic color perception: a unified model.
The brightness of an isolated test patch is related to its luminance by a power law having an exponent of about 1/3, a result known as Stevens's brightness law. The brightness law exponent characterizes the rate at which brightness grows with luminance and can thus be thought of as an "exponential" gain factor. We studied changes in this gain factor for incremental and decremental test squares as a function of the size of a surrounding frame of homogeneous luminance. For incremental targets, the gain decreased as an approximately linear function of the frame width. For decremental targets, the gain increased as an approximately linear function of the frame width. We modeled the brightness of the frame-embedded target with a quantitative theory based on the assumption that the target brightness is determined by the sum of achromatic color induction signals originating from the inner and outer edges of the surround, a theory that has previously been used to account for the results of several other brightness matching experiments. To account for the frame-width-dependent gain changes observed in the present study, we elaborate this edge integration theory by proposing the existence of a cortical contrast gain control mechanism by which the gains applied to neural edge detectors are influenced by the responses of other edge detectors responding to the nearby edges.