Effects of a Mediterranean-style diet on cardiovascular risk factors: a randomized trial.
The Mediterranean diet has been shown to have beneficial effects on cardiovascular risk factors. To compare the short-term effects of 2 Mediterranean diets versus those of a low-fat diet on intermediate markers of cardiovascular risk. Substudy of a multicenter, randomized, primary prevention trial of cardiovascular disease (Prevención con Dieta Mediterránea [PREDIMED] Study). Primary care centers affiliated with 10 teaching hospitals. 772 asymptomatic persons 55 to 80 years of age at high cardiovascular risk who were recruited from October 2003 to March 2004. Participants were assigned to a low-fat diet (n = 257) or to 1 of 2 Mediterranean diets. Those allocated to Mediterranean diets received nutritional education and either free virgin olive oil, 1 liter per week (n = 257), or free nuts, 30 g/d (n = 258). The authors evaluated outcome changes at 3 months. Body weight, blood pressure, lipid profile, glucose levels, and inflammatory molecules. The completion rate was 99.6%. Compared with the low-fat diet, the 2 Mediterranean diets produced beneficial changes in most outcomes. Compared with the low-fat diet, the mean changes in the Mediterranean diet with olive oil group and the Mediterranean diet with nuts group were -0.39 mmol/L (95% CI, -0.70 to -0.07 mmol/L) and -0.30 mmol/L (CI, -0.58 to -0.01 mmol/L), respectively, for plasma glucose levels; -5.9 mm Hg (CI, -8.7 to -3.1 mm Hg) and -7.1 mm Hg (CI, -10.0 to -4.1 mm Hg), respectively, for systolic blood pressure; and -0.38 (CI, -0.55 to -0.22) and - 0.26 (CI, -0.42 to -0.10), respectively, for the cholesterol-high-density lipoprotein cholesterol ratio. The Mediterranean diet with olive oil reduced C-reactive protein levels by 0.54 mg/L (CI, 1.04 to 0.03 mg/L) compared with the low-fat diet. This short-term study did not focus on clinical outcomes. Nutritional education about low-fat diet was less intense than education about Mediterranean diets. Compared with a low-fat diet, Mediterranean diets supplemented with olive oil or nuts have beneficial effects on cardiovascular risk factors.


Use of isotopically labeled substrates reveals kinetic differences between human and bacterial serine palmitoyltransferase.
Isotope labels are frequently used tools to track metabolites through complex biochemical pathways and to discern the mechanisms of enzyme-catalyzed reactions. Isotopically labeled l-serine is often used to monitor the activity of the first enzyme in sphingolipid biosynthesis, serine palmitoyltransferase (SPT), as well as labeling downstream cellular metabolites. Intrigued by the effect that isotope labels may be having on SPT catalysis, we characterized the impact of different l-serine isotopologues on the catalytic activity of recombinant SPT isozymes from humans and the bacterium Sphingomonas paucimobilis Our data show that S. paucimobilis SPT activity displays a clear isotope effect with [2,3,3-D]l-serine, whereas the human SPT isoform does not. This suggests that although both human and S. paucimobilis SPT catalyze the same chemical reaction, there may well be underlying subtle differences in their catalytic mechanisms. Our results suggest that it is the activating small subunits of human SPT that play a key role in these mechanistic variations. This study also highlights that it is important to consider the type and location of isotope labels on a substrate when they are to be used in in vitro and in vivo studies.


Contractile properties of the elasmobranch rectal gland.
The importance of the rectal gland in elasmobranch osmoregulation is well established. The rate of secretion by the gland is under the control of a variety of secretagogues and inhibitors. Early morphological work suggested that a band of smooth muscle cells surrounds the periphery of the shark rectal gland between the secretory tubules and the connective tissue capsule. To confirm the presence of the muscle ring, we examined histological sections from two species of shark, Squalus acanthias and Carcharodon carcharius, and from the stingray Dasyatis sabina and stained sections from S. acanthias with the actin-specific ligand phalloidin. In all three species, a distinct band of what appeared to be smooth muscle cells was evident, and the putative muscle ring in S. acanthias stained specifically with phalloidin. Moreover, isolated rings of rectal gland tissue from S. acanthias constricted when acetylcholine or endothelin was applied and responded to nitric oxide with an initial dilation, followed by a more substantial constriction. Subsequent addition of porcine C-type natriuretic peptide dilated the rings, but two prostanoids (carbaprostacyclin and prostaglandin E(1)) did not change ring tension significantly. The rings did not respond to the endothelin-B-specific agonist sarafotoxoin S6c, suggesting that the response to endothelin was mediated via endothelin-A-type receptors. Our data confirm the presence of a smooth muscle ring in the periphery of the elasmobranch rectal gland and demonstrate that the gland responds to a suite of smooth muscle agonists, suggesting that changes in the dimensions of the whole rectal gland may play a role in its secretory function.


Dissociating breathlessness symptoms from mood in asthma.
It is poorly understood why asthma symptoms are often discordant with objective medical tests. Differences in interoception (perception of internal bodily processes) may help explain symptom discordance, which may be further influenced by mood and attention. We explored inter-relationships between interoception, mood and attention in 63 individuals with asthma and 30 controls. Questionnaires, a breathing-related interoception task, two attention tasks, and standard clinical assessments were performed. Questionnaires were analysed using exploratory factor analysis, and linear regression examined relationships between measures. K-means clustering also defined asthma subgroups. Two concordant asthma subgroups (symptoms related appropriately to pathophysiology, normal mood) and one discordant subgroup (moderate symptoms, minor pathophysiology, low mood) were found. In all participants, negative mood correlated with decreased interoceptive ability and faster reaction times in an attention task. Our findings suggest that interpreting bodily sensations relates to mood, and this effect may be heightened in subgroups of individuals with asthma.


Microbiota-Produced N-Formyl Peptide fMLF Promotes Obesity-Induced Glucose Intolerance.
The composition of the gastrointestinal microbiota and associated metabolites changes dramatically with diet and the development of obesity. Although many correlations have been described, specific mechanistic links between these changes and glucose homeostasis remain to be defined. Here we show that blood and intestinal levels of the microbiota-produced N-formyl peptide, formyl-methionyl-leucyl-phenylalanine, are elevated in high-fat diet-induced obese mice. Genetic or pharmacological inhibition of the N-formyl peptide receptor Fpr1 leads to increased insulin levels and improved glucose tolerance, dependent upon glucagon-like peptide 1. Obese Fpr1 knockout mice also display an altered microbiome, exemplifying the dynamic relationship between host metabolism and microbiota. Overall, we describe a new mechanism by which the gut microbiota can modulate glucose metabolism, providing a potential approach for the treatment of metabolic disease.


Overview of membranes and membrane plates used in research and diagnostic ELISPOT assays.
Polyvinylidene fluoride (PVDF) membrane-bottomed, 96-well plates and 8-well strips constitute the formats in which the overwhelming majority of ELISPOT assays used in research and diagnostic applications are performed. PVDF is well suited for ELISPOT because it has a high antibody-binding capacity and because its white color provides an excellent backdrop for ELISPOT enumeration. Nitrocellulose (NC) and PVDF membranes and 96-well plates containing those membranes used in ELISPOT assays were initially commercialized for filtration applications and later optimized for a range of different protein analytical applications. An overview of the development and biotechnology applications of PVDF membrane is provided. Characteristics and attributes of the membrane that are relevant to ELISPOT are summarized. Enhancements in PVDF membrane performance and optimization of devices for automation compatible and diagnostic ELISPOT applications are presented.


Update on allergy immunotherapy: American Academy of Allergy, Asthma & Immunology/European Academy of Allergy and Clinical Immunology/PRACTALL consensus report.
Allergy immunotherapy (AIT) is an effective treatment for allergic asthma and rhinitis, as well as venom-induced anaphylaxis. In addition to reducing symptoms, AIT can change the course of allergic disease and induce allergen-specific immune tolerance. In current clinical practice immunotherapy is delivered either subcutaneously or sublingually; some allergens, such as grass pollen, can be delivered through either route, whereas others, such as venoms, are only delivered subcutaneously. Both subcutaneous and sublingual immunotherapy appear to have a duration of efficacy of up to 12 years, and both can prevent the development of asthma and new allergen sensitivities. In spite of the advances with AIT, safer and more effective AIT strategies are needed, especially for patients with asthma, atopic dermatitis, or food allergy. Novel approaches to improve AIT include use of adjuvants or recombinant allergens and alternate routes of administration. As part of the PRACTALL initiatives, the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology nominated an expert team to develop a comprehensive consensus report on the mechanisms of AIT and its use in clinical practice, as well as unmet needs and ongoing developments in AIT. This resulting report is endorsed by both academies.


Basigin mediates pulmonary hypertension by promoting inflammation and vascular smooth muscle cell proliferation.
Cyclophilin A (CyPA) is secreted from vascular smooth muscle cells (VSMCs) by oxidative stress and promotes VSMC proliferation. However, the role of extracellular CyPA and its receptor Basigin (Bsg, encoded by Bsg) in the pathogenesis of pulmonary hypertension (PH) remains to be elucidated. To determine the role of CyPA/Bsg signaling in the development of PH. In the pulmonary arteries of patients with PH, immunostaining revealed strong expression of CyPA and Bsg. The pulmonary arteries of CyPA(±) and Bsg(±) mice exposed to normoxia did not differ in morphology compared with their littermate controls. In contrast, CyPA(±) and Bsg(±) mice exposed to hypoxia for 4 weeks revealed significantly reduced right ventricular systolic pressure, pulmonary artery remodeling, and right ventricular hypertrophy compared with their littermate controls. These features were unaltered by bone marrow reconstitution. To further evaluate the role of vascular Bsg, we harvested pulmonary VSMCs from Bsg(+/+) and Bsg(±) mice. Proliferation was significantly reduced in Bsg(±) compared with Bsg(+/+) VSMCs. Mechanistic studies demonstrated that Bsg(±) VSMCs revealed reduced extracellular signal-regulated kinase 1/2 activation and less secretion of cytokines/chemokines and growth factors (eg, platelet-derived growth factor-BB). Finally, in the clinical study, plasma CyPA levels in patients with PH were increased in accordance with the severity of pulmonary vascular resistance. Furthermore, event-free curve revealed that high plasma CyPA levels predicted poor outcome in patients with PH. These results indicate the crucial role of extracellular CyPA and vascular Bsg in the pathogenesis of PH.


Blinking statistics correlated with nanoparticle number.
We report fluorescence of single semiconductor nanorods (NRs) and few-NR clusters, correlated with transmission electron microscopy for direct determination of the number of NRs present in a single fluorescent source. For samples drop-cast from dilute solutions, we show that the majority of the blinking sources (approximately 75%) are individual NRs while the remaining sources are small clusters consisting of up to 15 NRs. Clusters containing two or three NRs exhibit intermittent fluorescence intensity trajectories, I(t), similar to those of individual NRs. The associated statistical parameters of on- and off-time probability densities for two- and three-NR clusters are indistinguishable from those of individual NRs. In contrast, statistically distinguishable blinking parameters are observed for clusters of five or more particles. In particular, the "truncation time" of the on-time probability density, i.e., the time characterizing the transition from a power law to an exponential decay, was found to increase superlinearly with the number of particles. Our long (2.4 x 10(4) s) blinking measurements also directly reveal the previously unobserved truncation of the power law distribution of the off-times for single nanoparticles.


Strategies used by critical care nurses to identify, interrupt, and correct medical errors.
Medical errors are common in intensive care units. Nurses are uniquely positioned to identify, interrupt, and correct medical errors and to minimize preventable adverse outcomes. Nurses are increasingly recognized as playing a role in reducing medical errors, but only recently have their error-recovery strategies been described. To describe error-recovery strategies used by critical care nurses. Data were collected by audio taping focus groups with 20 nurses from 5 critical care units at 2 urban university medical centers and 2 community hospitals on the East and West coasts of the United States. Transcript content was analyzed as recommended by Krueger and Casey. Analysis of focus group data revealed that nurses in critical care settings use 17 strategies to identify, interrupt, and correct errors. Nurses used 8 strategies to identify errors: knowing the patient, knowing the "players," knowing the plan of care, surveillance, knowing policy/procedure, double-checking, using systematic processes, and questioning. Nurses used 3 strategies to interrupt errors: offering assistance, clarifying, and verbally interrupting. Nurses used 6 strategies to correct errors: persevering, being physically present, reviewing or confirming the plan of care, offering options, referencing standards or experts, and involving another nurse or physician. These results reflect the pivotal role that critical care nurses play in the recovery of medical errors and ensuring patient safety. Several error-recovery strategies identified in this study were also reported by emergency nurses, providing further empirical support for nurses' role in the recovery of medical errors as proposed in the Eindhoven model.


Extracellular nicotinamide phosphoribosyltransferase (NAMPT) promotes M2 macrophage polarization in chronic lymphocytic leukemia.
Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in nicotinamide adenine dinucleotide biosynthesis. In the extracellular compartment, it exhibits cytokine-/adipokinelike properties, suggesting that it stands at the crossroad between metabolism and inflammation. Here we show that both intracellular and extracellular NAMPT levels are increased in cells and plasma of chronic lymphocytic leukemia (CLL) patients. The extracellular form (eNAMPT) is produced by CLL lymphocytes upon B-cell receptor, Toll-like receptor, and nuclear factor κB (NF-κB) signaling pathway activation. eNAMPT is important for differentiation of resting monocytes, polarizing them toward tumor-supporting M2 macrophages. These cells express high levels of CD163, CD206, and indoleamine 2,3-dioxygenase and secrete immunosuppressive (interleukin [IL] 10, CC chemokine ligand 18) and tumor-promoting (IL-6, IL-8) cytokines. NAMPT-primed M2 macrophages activate extracellular-regulated kinase 1/2, signal transducer and activator of transcription 3, and NF-κB signaling; promote leukemic cell survival; and reduce T-cell responses. These effects are independent of the enzymatic activity of NAMPT, as inferred from the use of an enzymatically inactive mutant. Overall, these results reveal that eNAMPT is a critical element in the induction of an immunosuppressive and tumor-promoting microenvironment of CLL.


Acanthamoeba produces disseminated infection in locusts and traverses the locust blood-brain barrier to invade the central nervous system.
Many aspects of Acanthamoeba granulomatous encephalitis remain poorly understood, including host susceptibility and chronic colonization which represent important features of the spectrum of host-pathogen interactions. Previous studies have suggested locusts as a tractable model in which to study Acanthamoeba pathogenesis. Here we determined the mode of parasite invasion of the central nervous system (CNS). Using Acanthamoeba isolates belonging to the T1 and T4 genotypes, the findings revealed that amoebae induced sickness behaviour in locusts, as evidenced by reduced faecal output and weight loss and, eventually, leading to 100% mortality. Significant degenerative changes of various tissues were observed by histological sectioning. Both isolates produced disseminated infection, with viable amoebae being recovered from various tissues. Histological examination of the CNS showed that Acanthamoeba invaded the locust CNS, and this is associated with disruption of the perineurium cell/glial cell complex, which constitutes the locust blood-brain barrier. This is the first study to demonstrate that Acanthamoeba invades locust brain by modulating the integrity of the insect's blood-brain barrier, a finding that is consistent with the human infection. These observations support the idea that locusts provide a tractable model to study Acanthamoeba encephalitis in vivo. In this way the locust model may generate potentially useful leads that can be tested subsequently in mammalian systems, thus replacing the use of vertebrates at an early stage, and reducing the numbers of mammals required overall.


STAT5 activation is critical for the transformation mediated by myeloproliferative disorder-associated JAK2 V617F mutant.
It has been well established that disruption of JAK2 signaling regulation is involved in various hematopoietic disorders; however, the detailed mechanism by which abnormal activation of JAK2 exhibits transforming activity remains to be elucidated. Here, to clarify the functional role of the erythropoietin receptor (EpoR) and its downstream transcription factor STAT5 in the abnormal activation of JAK2-induced hematopoietic diseases, we generated a stable transfectant of Ba/F3 cells expressing EpoR and analyzed the molecular mechanism of how JAK2 mutation induces cell growth disorder. JAK2 V617F mutant exhibited transforming activity when EpoR was coexpressed. According to a study utilizing several truncated mutants of EpoR, the ability of EpoR to facilitate the transforming activity of JAK2 V617F mutant required the intracellular domain to interact with STAT5. Strikingly, once the truncated EpoR (EpoR-H) was mutated on Tyr-343, the phosphorylation of which is known to be important for interaction with STAT5, JAK2 V617F mutant failed to exhibit transforming activity, suggesting that STAT5 is critical for JAK2 mutant-induced hematopoietic disorder. Furthermore, the expression of the constitutively active STAT5 mutant exhibited transforming activity in Ba/F3 cells, and short hairpin RNA-mediated knockdown of STAT5 significantly inhibited the transforming activity of JAK2 V617F mutant. Taking these observations together, STAT5 plays an essential role in EpoR-JAK2 V617F mutant-induced hematopoietic disorder. Although it remains unclear why the presence of EpoR is required to activate oncogenic signaling via the JAK2 mutant and STAT5, its interacting ability is a target for the treatment of these hematopoietic diseases.


A review of injection and antibiotic use at primary health care (public and private) centers in Africa.
We conducted a review to study antibiotic and injections use at primary care centers (PHCs) within the World Health Organization African region. This was part of a larger study on prescribing indicators at PHCs within the region. We analyzed antibiotic and injection use reported in studies published between 1993 and June 2013, which were identified through searches conducted in PubMed, Scopus, Web of science, Africa-Wide NiPAD, Africa Journals Online, Google Scholar, and International Network for Rational Use of Drugs bibliography databases. Sub-group analysis was carried out for private and public centers. Data were retrieved from 18 studies in 6 countries involving 21,283 patient encounters across 338 PHCs. The percentage of patient encounters with antibiotics prescribed was 51.5% (IQR 41.1-63.3%). The percentage of patient encounters which resulted in the prescription of an injection was 36.8% (IQR 20.7-57.6%). Injection use rate at private facilities was 38% (IQR 19.1-42.7) while that of the public was 32.3% (IQR 20.6-57.6). Rate of antibiotic prescribing at public centers was 49.7% (IQR 51.1-75.7) and that of private facilities 57.6 (IQR 39.0-69.5). The percentage use of injections and antibiotics is high in Africa. The excessive use of antibiotics and injections are particularly more problematic in private than public facilities. Further research is needed to understand fully the underlying factors for the observed patterns and ways of improving medicines use.


Rehabilitating the health system after conflict in East Timor: a shift from NGO to government leadership.
Efforts to rehabilitate health systems after periods of prolonged conflict have often been characterized by poor coordination of external actors - multilateral agencies, donors and non-governmental organizations (NGOs). This paper describes the process and analyses the roles of the different stakeholders in the establishment of a government-led district health system in East Timor, between 1999 and 2002, after decades of chronic conflict and Indonesian occupation. Future East Timorese policy-makers and health professionals began to mobilize in May 1999, in preparation for independence. During the emergency phase, from September 1999, when violence erupted, to March 2000, NGOs played a major role in the provision of relief to the population, coordinated by United Nations agencies. An Interim Health Authority, led by local Timorese, was established in March and the major donors began to shift funding from NGOs to the newly established Ministry of Health. A rapid phasing-out of NGOs, accompanied by a sequence of steps to build the capacity of Timorese to manage the new district health system, was implemented. Early evidence shows that health service utilization continued to grow during and after implementation.


Characterization of the basal angiosperm Aristolochia fimbriata: a potential experimental system for genetic studies.
Previous studies in basal angiosperms have provided insight into the diversity within the angiosperm lineage and helped to polarize analyses of flowering plant evolution. However, there is still not an experimental system for genetic studies among basal angiosperms to facilitate comparative studies and functional investigation. It would be desirable to identify a basal angiosperm experimental system that possesses many of the features found in existing plant model systems (e.g., Arabidopsis and Oryza). We have considered all basal angiosperm families for general characteristics important for experimental systems, including availability to the scientific community, growth habit, and membership in a large basal angiosperm group that displays a wide spectrum of phenotypic diversity. Most basal angiosperms are woody or aquatic, thus are not well-suited for large scale cultivation, and were excluded. We further investigated members of Aristolochiaceae for ease of culture, life cycle, genome size, and chromosome number. We demonstrated self-compatibility for Aristolochia elegans and A. fimbriata, and transformation with a GFP reporter construct for Saruma henryi and A. fimbriata. Furthermore, A. fimbriata was easily cultivated with a life cycle of just three months, could be regenerated in a tissue culture system, and had one of the smallest genomes among basal angiosperms. An extensive multi-tissue EST dataset was produced for A. fimbriata that includes over 3.8 million 454 sequence reads. Aristolochia fimbriata has numerous features that facilitate genetic studies and is suggested as a potential model system for use with a wide variety of technologies. Emerging genetic and genomic tools for A. fimbriata and closely related species can aid the investigation of floral biology, developmental genetics, biochemical pathways important in plant-insect interactions as well as human health, and various other features present in early angiosperms.


Family environment as a predictor of psychiatric rehospitalization.
The Family Environment Scale scores and demographic characteristics of 108 discharged psychiatric patients were used to predict outcome at 3 months and 1 year. Higher ratings of family expressiveness predicted fewer days of rehospitalization, especially among schizophrenic patients. Higher family cohesion scores predicted better family-rated patient adjustment. The patients were more likely to rate themselves as better adjusted if they had higher incomes, lived with parents rather than a spouse, and came from families with less emphasis on independence. Family environment was a better predictor of rehospitalization than baseline ratings of clinical status, indicating the importance of family support in the community adjustment of chronic psychiatric patients.


Typical electrocardiographic deviations after cessation of physical activities in elite sportsmen.
We observed that ECG changes associated with high levels of sporting activity are reversible in the majority of cases after cessation of the sports career. This is probably related to the normalization of the raised vagal tone and diminution of the effort-related heart hypertrophy and chamber dilatation in ex-sportsmen. The persistent ECG changes observed in some of the ex-sportsmen could be related to the ageing processes observed in the general population as well. It is important that all ECG deviations in ex-sportsmen be considered seriously and interpreted in the context of the ECGs obtained during the active sports career.


The impact of modifiable risk factors on mortality from prostate cancer in populations of the Asia-Pacific region.
Mortality from cancer of the prostate is increasing in the Asia-Pacific, when much of this region is undergoing a transition to a Western lifestyle. The role that lifestyle factors play in prostate cancer appears limited, but existing data mainly are from the West. We conducted an individual participant data analysis of 24 cohort studies involving 320,852 men (83% in Asia). Cox proportional hazard models were used to quantify associations between risk factors and mortality from prostate cancer. There were 308 deaths from prostate cancer (14% in Asia) during 2.1 million person-years of follow-up. The age-adjusted hazard ratio (95% confidence interval; CI) for men with body mass index (BMI) 28 kg/m2 or more, compared with below 25, was 1.55 (1.12 - 2.16); no such significant relationship was found for height or waist circumference. The BMI result was unchanged after adjustment for other variables, was consistent between Asia and Australia/New Zealand (ANZ) and did not differ with age. There was no significant relationship with diabetes, glucose or total cholesterol (p > or = 0.18). Smoking, alone, showed different effects in the two regions, possibly due to the relative immaturity of the smoking epidemic in Asia. In ANZ, the multiple-adjusted hazard ratio for an extra 5 cigarettes per day was 1.12 (95%CI: 1.03 - 1.22), whereas in Asia it was 0.77 (0.56 - 1.05). Body size is an apparently important determinant of prostate cancer in the Asia-Pacific. Evidence of an adverse effect of smoking is conclusive only in the predominantly Caucasian parts of the region.


Antisense COOLAIR mediates the coordinated switching of chromatin states at FLC during vernalization.
Long noncoding RNAs (lncRNAs) have been proposed to play important roles in gene regulation. However, their importance in epigenetic silencing and how specificity is determined remain controversial. We have investigated the cold-induced epigenetic switching mechanism involved in the silencing of Arabidopsis thaliana Flowering Locus C (FLC), which occurs during vernalization. Antisense transcripts, collectively named COOLAIR, are induced by prolonged cold before the major accumulation of histone 3 lysine 27 trimethylation (H3K27me3), characteristic of Polycomb silencing. We have found that COOLAIR is physically associated with the FLC locus and accelerates transcriptional shutdown of FLC during cold exposure. Removal of COOLAIR disrupted the synchronized replacement of H3K36 methylation with H3K27me3 at the intragenic FLC nucleation site during the cold. Consistently, genetic analysis showed COOLAIR and Polycomb complexes work independently in the cold-dependent silencing of FLC. Our data reveal a role for lncRNA in the coordinated switching of chromatin states that occurs during epigenetic regulation.


Factors determining case fatality in myocardial infarction "who dies in a heart attack"?
To examine the determinants of case fatality in the first major ischaemic heart disease event (heart attack) after screening. Prospective study of 7735 middle aged men drawn from general practices in 24 British towns. During 11.5 years follow up there were 743 major ischaemic heart disease events of which 302 (40.6%) were fatal within 28 days of onset. Previous definite myocardial infarction or stroke and age at time of event were most strongly associated with case fatality. In men with no previous myocardial infarction or stroke, after adjustment for a range of risk factors, antihypertensive treatment (odds ratio (OR) = 1.97, P < 0.05), arrhythmia (OR = 1.93, P = 0.06), increased heart rate (OR = 2.03, P = 0.06), and diabetes (OR = 2.61, P = 0.07) were associated with increased case fatality. High levels of physical activity (OR = 0.53, P < 0.05) and moderate drinking (16-42 units/week) (OR = 0.61, P < 0.05) were associated with lower case fatality, although moderate drinking was not associated with a lower incidence of major ischaemic heart disease events. Current smoking, serum total cholesterol, and systolic blood pressure were not significantly associated with case fatality. In men with previous myocardial infarction or stroke, arrhythmia and to a lesser degree antihypertensive treatment, moderate or heavy drinking, and diabetes were associated with higher case fatality. These findings suggest that physical activity may be an important modifiable factor influencing the incidence of ischaemic heart disease and the chance of survival in men without a previous heart attack or stroke. Arrhythmia, increased heart rate, diabetes, and treatment for hypertension are also areas of concern.


Bringing accommodation into focus: the several discoveries of the ciliary muscle.
Since at least the 16th century, many investigators have speculated on the presence of a specialized muscle in the front of the eye designed to somehow alter its disposition to bring about changes in focus. By the 1850s, when Hermann von Helmholtz offered the first plausible theory of accommodation, the anatomy of the ciliary muscle was well known. The credit for this knowledge is generally given to Ernst Brücke and William Bowman, who published their observations on the muscle independently in the 1840s. In fact, not only were Bowman and Brücke wrong about the role of the ciliary muscle in accommodation, and for different reasons, but they shared this distinction with at least 3 investigators who came before them. In the 3 decades before 1840, Philip Crampton, Robert Knox, and William Wallace had all zeroed in on the ciliary muscle, describing its anatomy in varying detail. If none understood its precise role in accommodation--all ignored the work of Thomas Young, who by 1800 had proved that the lens must somehow round up to achieve near vision--each deserves a share of the credit for its discovery.


ASMase regulates autophagy and lysosomal membrane permeabilization and its inhibition prevents early stage non-alcoholic steatohepatitis.
Acid sphingomyelinase (ASMase) is activated in non-alcoholic steatohepatitis (NASH). However, the contribution of ASMase to NASH is poorly understood and limited to hepatic steatosis and glucose metabolism. Here we examined the role of ASMase in high fat diet (HFD)-induced NASH. Autophagy, endoplasmic reticulum (ER) stress and lysosomal membrane permeabilization (LMP) were determined in ASMase(-/-) mice fed a HFD. The impact of pharmacological ASMase inhibition on NASH was analyzed in wild type mice fed a HFD. ASMase deficiency determined resistance to hepatic steatosis mediated by a HFD or methionine-choline deficient diet. ASMase(-/-) mice were resistant to HFD-induced hepatic ER stress, but sensitive to tunicamycin-mediated ER stress, indicating selectivity in the resistance of ASMase(-/-) mice to ER stress and steatosis. Autophagic flux, determined in the presence of rapamycin and/or chloroquine, was lower in primary mouse hepatocytes (PMH) from ASMase(-/-) mice and accompanied by increased p62 levels, suggesting autophagic impairment. Moreover, autophagy suppression by chloroquine and brefeldin A caused ER stress in PMH from ASMase(+/+) mice but not in ASMase(-/-) mice. ASMase(-/-) PMH exhibited increased lysosomal cholesterol loading, decreased LMP and apoptosis resistance induced by O-methyl-serine dodecylamide hydrochloride or palmitic acid, effects that were reversed by decreasing cholesterol levels by oxysterol 25-hydroxycholesterol. In vivo pharmacological ASMase inhibition by amitriptyline, a widely used tricyclic antidepressant, protected wild type mice against HFD-induced hepatic steatosis, fibrosis, and liver damage, effects indicative of early-stage NASH. These findings underscore a critical role for ASMase in diet-induced NASH and suggest the potential of amitriptyline as a treatment for patients with NASH.


Factors associated with negative co-parenting experiences in families of a child with autism spectrum disorder.
The purpose of this study was to identify key factors associated with negative co-parenting experiences in parents raising a child with autism spectrum disorder. Questionnaires were sent to families with one or more children with a diagnosis of autism spectrum disorder. Parents of 142 children with autism spectrum disorder indicated that the diagnosis had a very negative impact on their co-parent relationship. A multivariate logistic regression model was run to analyze the association of these experiences with various demographic, family and community factors. Three factors were associated with negative co-parenting relationships: (1) family stress due to the child's diagnosis, (2) effects of the diagnosis on parents' relationship with their other children and (3) distance travelled to the nearest medical facility. Findings highlight the need to further explore family dynamics, particularly the relationships between the co-parenting alliance, other family members and the extra-familial environment.


Secondary metabolites and nutrients of woody plants in relation to browsing intensity in African savannas.
Carbon-based secondary metabolites (CBSMs) are assumed to function as defences that contribute to herbivore-avoidance strategies of woody plants. Severe browsing has been reported to reduce concentrations of CBSMs and increase N concentrations in individual plants, causing heavily browsed plants to be characterised by N-rich/C-poor tissues. We hypothesised that concentrations of condensed tannins (CT) and total polyphenols (TP) should decrease, or N increase, in relation to increasing intensity of browsing, rendering severely browsed plants potentially more palatable (increased N:CT) and less N-limited (increased N:P) than lightly browsed ones. We sampled naturally browsed trees (taller than 2 m) of four abundant species in southern Kruger National Park, South Africa. Species-specific relationships between N:CT, CT, TP and P concentrations and increasing browsing intensity were detected, but N and N:P were consistently invariable. We developed a conceptual post-hoc model to explain diverse species-specific CBSM responses on the basis of relative allocation of C to total C-based defence traits (e.g. spines/thorns, tough/evergreen leaves, phenolic compounds). The model suggests that species with low allocation of C to C-based defence traits become C-limited (potentially more palatable) at higher browsing intensity than species with high allocation of C to C-based defences. The model also suggests that when N availability is high, plants become C-limited at higher browsing intensity than when N availability is low.


Opitutus terrae gen. nov., sp. nov., to accommodate novel strains of the division 'Verrucomicrobia' isolated from rice paddy soil.
Three strains of obligately anaerobic bacteria were isolated from rice paddy soil microcosms. Comparative analysis of the 16S rRNA genes showed that these novel isolates have identical gene sequences and are members of the division 'Verrucomicrobia'. The novel strains are phenotypically and phylogenetically distinct from species described previously. One strain, PB90-1T, was characterized in more detail. The cells are cocci and are motile by means of a flagellum. Catalase and oxidase activities are absent. Growth-supporting substrates include mono-, di- and polysaccharides, while alcohols, amino acids and organic acids do not support growth. Propionate and acetate are the major end-products of fermentation. Nitrate is reduced to nitrite, but other external electron acceptors are not utilized. The G+C content of the genomic DNA is 74 mol%. This strain represents a taxon that has not yet been formally recognized, for which the name Opitutus terrae gen. nov., sp. nov. is proposed. The type strain is PB90-1T (= DSM 11246T).


Proton magnetic resonance spectroscopy (1H-MRS) findings for the brain in patients with liver cirrhosis reflect the hepatic functional reserve.
Proton magnetic resonance spectroscopy (1H-MRS) has been used to assess the metabolic changes in the brain in patients with liver cirrhosis. Decreased myo-inositol and increased glutamine levels were noted to be the most sensitive spectroscopic markers for cirrhotic patients with hepatic encephalopathy (HE). The purpose of this study was to assess how the abnormalities seen on the 1H-MRS of the brain in patients with liver cirrhosis are related to clinical and laboratory parameters. In a prospective study, localized 1H-MRS was performed in the basal ganglia and parietal white matter regions in liver cirrhosis patients with (n = 48) and without (n = 52) HE and chronic hepatitis (CH) (n = 15), and in normal controls (n = 20). Among cirrhotic patients, the myo-inositol levels were significantly lower (p < 0.01) and the glutamine levels were higher (p < 0.05) for patients with HE than for those without HE. The myo-inositol and glutamine levels, respectively, were inversely (r = -0.50; p < 0.001) and linearly (r = 0.50; p < 0.001) related to the Child-Pugh score. However, by subgroup analysis of Child-Pugh class C patients, there were no significant differences in the myo-inositol and glutamine levels between cirrhotic patients with (n = 40) and without HE (n = 24). A follow-up study of eight cirrhotic patients with HE showed no significant differences in the myo-inositol and glutamine levels after clinical improvement of HE. The abnormalities seen on the 1H-MRS of the brain of patients with liver cirrhosis are not likely to reflect the severity of HE or acute alteration in the level of consciousness. Rather, we believe they represent the chronic metabolic derangement of the brain associated with hepatic functional reserve.


Neurobiological Basis of Language Learning Difficulties.
In this paper we highlight why there is a need to examine subcortical learning systems in children with language impairment and dyslexia, rather than focusing solely on cortical areas relevant for language. First, behavioural studies find that children with these neurodevelopmental disorders perform less well than peers on procedural learning tasks that depend on corticostriatal learning circuits. Second, fMRI studies in neurotypical adults implicate corticostriatal and hippocampal systems in language learning. Finally, structural and functional abnormalities are seen in the striatum in children with language disorders. Studying corticostriatal networks in developmental language disorders could offer us insights into their neurobiological basis and elucidate possible modes of compensation for intervention.


Otoacoustic emission responses of the cochlea to acute and total ischemia.
In the present experimental study, we sought to monitor distortion product otoacoustic emissions (DPOAEs) as an indicator of cochlear function, after sudden, total, and irreversible interruption of cochlear blood flow, to provide information on the time course of cochlear response to ischemia. Twenty rats with normal hearing function were included. Complete and abrupt ischemia was provided by decapitation. DPOAEs at 3-8 kHz frequencies were recorded at baseline and exactly every consecutive minute after decapitation, until emissions in all frequencies disappeared completely. Mean DPOAE values decreased significantly and progressively after decapitation for all frequencies. The mean duration of emissions was 8.20 ± 1.96 min (minimum 3 min, maximum 11 min). The longest durations of DPOAEs were observed with 4 and 5 kHz frequencies, and 3 and 6 kHz had the shortest durations. The outer hair cells exposed to acute ischemia seem to exhibit a rapid functional loss; thus, cautious handling of the cochlear vasculature and surrounding structures is necessary in surgical interventions. Additionally, our results provide some idea of the normal tolerance range of the cochlea to ischemia, which could be useful for future studies.


IL-2 therapy: potential impact of the CD4 cell count at initiation on clinical efficacy--results from the ANRS CO4 cohort.
We investigated why, despite its beneficial effect on the CD4 cell count, IL-2 therapy had no clinical benefit as shown in the ESPRIT and SILCAAT trials. We focused on subgroups of patients defined according to CD4 cell counts at baseline and over time to assess the threshold above which IL-2 therapy was no longer beneficial in a large cohort of HIV-1 infected patients. Within the French Hospital Database on HIV, a total of 953 IL-2-treated patients were compared with 27 750 IL-2-untreated patients, matched for the date of enrolment, sex, age, and the baseline CD4 cell count and plasma HIV-1 RNA level. The risk of clinical progression, defined as the occurrence of a new AIDS-defining event or death, was studied with multivariable Cox proportional hazards models and Poisson regression models. We found no clinical benefit in patients starting IL-2 with CD4 count ≥200 cells/mm(3) [hazard ratio (HR) =1.13; 95% confidence interval (CI), 0.81-1.57], while a benefit was observed in patients with CD4 count <200 cells/mm(3) (HR=0.64; 95% CI, 0.48-0.86). The observed benefit was due to the risk reduction in the 100-350/mm(3) stratum of updated CD4 cell counts (relative rate=0.30; 95% CI, 0.09-1.03). Higher CD4 cell counts at enrolment and shorter follow-up with low to intermediate CD4 cell counts may explain why IL-2 therapy had no observed clinical benefit in the SILCAAT study. Our findings suggest that the benefit of IL-2 is restricted to a narrow range of CD4 cell counts, arguing against the use of IL-2 in HIV infection to reduce the risk of clinical events.


Volume-of-interest cone-beam CT using a 2.35 MV beam generated with a carbon target.
This is a proof-of-concept study addressing volume of interest (VOI) cone beam CT (CBCT) imaging using an x-ray beam produced by 2.35 MeV electrons incident on a carbon linear accelerator target. Methodology is presented relevant to VOI CBCT image acquisition and reconstruction. Sample image data are given to demonstrate and compare two approaches to minimizing artifacts arising from reconstruction with truncated projections. Dosimetric measurements quantify the potential dose reduction of VOI acquisition relative to full-field CBCT. The dependence of contrast-to-noise ratio (CNR) on VOI dimension is investigated. A paradigm is presented linking the treatment planning process with the imaging technique, allowing definition of an imaging VOI to be tailored to the geometry of the patient. Missing data in truncated projection images are completed using a priori information in the form of digitally reconstructed radiographs (DRRs) generated from the planning CT set. This method is compared to a simpler technique of extrapolating truncated projection data prior to reconstruction. The utility of these approaches is shown through imaging of a geometric phantom and the head-and-neck section of a lamb. The total scatter factor of the 2.35 MV∕carbon beam on field size is measured and compared to a standard therapeutic beam to estimate the comparative dose reduction inside the VOI. Thermoluminescent dosimeters and Gafchromic film measurements are used to compare the imaging dose distributions for the 2.35 MV∕carbon beam between VOI and full-field techniques. The dependence of CNR on VOI dimension is measured for VOIs ranging from 4 to 15 cm diameter. Without compensating for missing data outside of truncated projections prior to reconstruction, pronounced boundary artifacts are present, in three dimensions, within 2-3 cm of the edges of the VOI. These artifacts, as well as cupping inside the VOI, can be reduced substantially using either the DRR filling or extrapolation techniques presented. Compared to 6 MV, the 2.35 MV∕carbon beam shows a substantially greater dependence of total scatter factor on field size, indicating a comparative advantage of the VOI approach when combined with the low-Z target beam. Dosimetric measurements in the anthropomorphic head phantom demonstrate a dose reduction by up to 15% and 75% inside and outside of the VOI, respectively, compared to full-field imaging. For the 2.35 MV∕carbon beam, CNR was shown to be approximately invariant with VOI dimension for bone and lung objects. The low-Z target, VOI CBCT technique appears to be feasible and combines the desirable characteristics of the low-Z target beam with regard to CNR, with the capacity to localize the imaging dose to the anatomy relevant to the image guidance task.


Rapid changes in the gut microbiome during human evolution.
Humans are ecosystems containing trillions of microorganisms, but the evolutionary history of this microbiome is obscured by a lack of knowledge about microbiomes of African apes. We sequenced the gut communities of hundreds of chimpanzees, bonobos, and gorillas and developed a phylogenetic approach to reconstruct how present-day human microbiomes have diverged from those of ancestral populations. Compositional change in the microbiome was slow and clock-like during African ape diversification, but human microbiomes have deviated from the ancestral state at an accelerated rate. Relative to the microbiomes of wild apes, human microbiomes have lost ancestral microbial diversity while becoming specialized for animal-based diets. Individual wild apes cultivate more phyla, classes, orders, families, genera, and species of bacteria than do individual humans across a range of societies. These results indicate that humanity has experienced a depletion of the gut flora since diverging from Pan.


The mechanism underlying defective Fcgamma receptor-mediated phagocytosis by HIV-1-infected human monocyte-derived macrophages.
Clearance of IgG-opsonized erythrocytes is impaired in HIV-1-infected patients, suggesting defective FcgammaR-mediated phagocytosis in vivo. We have previously shown defective FcgammaR-mediated phagocytosis in HIV-1-infected human monocyte-derived macrophages (MDM), establishing an in vitro model for defective tissue macrophages. Inhibition was associated with decreased protein expression of FcR gamma-chain, which transduces immune receptor signals via ITAM motifs. FcgammaRI and FcgammaRIIIa signal via gamma-chain, whereas FcgammaRIIa does not. In this study, we showed that HIV-1 infection inhibited FcgammaRI-, but not FcgammaRIIa-dependent Syk activation in MDM, showing that inhibition was specific for gamma-chain-dependent signaling. HIV-1 infection did not impair gamma-chain mRNA levels measured by real-time PCR, suggesting a posttranscriptional mechanism of gamma-chain depletion. HIV-1 infection did not affect gamma-chain degradation (n = 7, p = 0.94) measured in metabolic labeling/chase experiments, whereas gamma-chain biosynthesis was inhibited (n = 12, p = 0.0068). Using an enhanced GFP-expressing HIV-1 strain, we showed that FcgammaR-mediated phagocytosis inhibition is predominantly due to a bystander effect. Experiments in which MDM were infected in the presence of the antiretroviral drug 3TC suggest that active viral replication is required for inhibition of phagocytosis in MDM. These data suggest that HIV-1 infection may affect only gamma-chain-dependent FcgammaR functions, but that this is not restricted to HIV-1-infected cells.


Cross-modal integration in the brain is related to phonological awareness only in typical readers, not in those with reading difficulty.
Fluent reading requires successfully mapping between visual orthographic and auditory phonological representations and is thus an intrinsically cross-modal process, though reading difficulty has often been characterized as a phonological deficit. However, recent evidence suggests that orthographic information influences phonological processing in typical developing (TD) readers, but that this effect may be blunted in those with reading difficulty (RD), suggesting that the core deficit underlying reading difficulties may be a failure to integrate orthographic and phonological information. Twenty-six (13 TD and 13 RD) children between 8 and 13 years of age participated in a functional magnetic resonance imaging (fMRI) experiment designed to assess the role of phonemic awareness in cross-modal processing. Participants completed a rhyme judgment task for word pairs presented unimodally (auditory only) and cross-modally (auditory followed by visual). For typically developing children, correlations between elision and neural activation were found for the cross-modal but not unimodal task, whereas in children with RD, no correlation was found. The results suggest that elision taps both phonemic awareness and cross-modal integration in typically developing readers, and that these processes are decoupled in children with reading difficulty.


Classification of advanced stages of Parkinson's disease: translation into stratified treatments.
Advanced stages of Parkinson's disease (advPD) still impose a challenge in terms of classification and related stage-adapted treatment recommendations. Previous concepts that define advPD by certain milestones of motor disability apparently fall short in addressing the increasingly recognized complexity of motor and non-motor symptoms and do not allow to account for the clinical heterogeneity that require more personalized approaches. Therefore, deep phenotyping approaches are required to characterize the broad-scaled, continuous and multidimensional spectrum of disease-related motor and non-motor symptoms and their progression under real-life conditions. This will also facilitate the reasoning for clinical care and therapeutic decisions, as neurologists currently have to refer to clinical trials that provide guidance on a group level; however, this does not always account for the individual needs of patients. Here, we provide an overview on different classifications for advPD that translate into critical phenotypic patterns requiring the differential therapeutic adjustments. New concepts refer to precision medicine approaches also in PD and first studies on genetic stratification for therapeutic outcomes provide a potential for more objective treatment recommendations. We define novel treatment targets that align with this concept and make use of emerging device-based assessments of real-life information on PD symptoms. As these approaches require empowerment of patients and integration into treatment decisions, we present communication strategies and decision support based on new technologies to adjust treatment of advPD according to patient demands and safety.


Ontology alignment architecture for semantic sensor Web integration.
Sensor networks are a concept that has become very popular in data acquisition and processing for multiple applications in different fields such as industrial, medicine, home automation, environmental detection, etc. Today, with the proliferation of small communication devices with sensors that collect environmental data, semantic Web technologies are becoming closely related with sensor networks. The linking of elements from Semantic Web technologies with sensor networks has been called Semantic Sensor Web and has among its main features the use of ontologies. One of the key challenges of using ontologies in sensor networks is to provide mechanisms to integrate and exchange knowledge from heterogeneous sources (that is, dealing with semantic heterogeneity). Ontology alignment is the process of bringing ontologies into mutual agreement by the automatic discovery of mappings between related concepts. This paper presents a system for ontology alignment in the Semantic Sensor Web which uses fuzzy logic techniques to combine similarity measures between entities of different ontologies. The proposed approach focuses on two key elements: the terminological similarity, which takes into account the linguistic and semantic information of the context of the entity's names, and the structural similarity, based on both the internal and relational structure of the concepts. This work has been validated using sensor network ontologies and the Ontology Alignment Evaluation Initiative (OAEI) tests. The results show that the proposed techniques outperform previous approaches in terms of precision and recall.


Structure of the complex between the Fab fragment of a neutralizing antibody for type 1 poliovirus and its viral epitope.
The crystal structure of the complex between the Fab fragment of C3, a neutralizing antibody for poliovirus, and a peptide corresponding to the viral epitope has been determined at 3.0 A resolution. Although this antibody was originally raised to heat inactivated (noninfectious) virus particles, it strongly neutralizes the Mahoney strain of type 1 poliovirus. Eleven peptide residues are well-defined in the electron-density map and form two type I beta-turns in series. At the carboxyl end, the peptide is bound snugly in the antibody-combining site and adopts a conformation that differs significantly from the structure of the corresponding residues in the virus. Structural comparisons between the peptide in the complex and the viral epitope suggests that on binding to infectious virions, this antibody may induce structural changes important for neutralization.


Transurethral ventral buccal mucosa graft inlay for treatment of distal urethral strictures: international multi-institutional experience.
To critically evaluate a multi-institutional patient cohort undergoing single-stage distal urethral repair using a novel transurethral buccal mucosa graft inlay urethroplasty technique (TBMGI). A retrospective multi-institutional review of consecutive patients with fossa navicularis (FN) strictures treated with a single-stage TBMGI technique at 12 institutions from March 2014-March 2018 was performed. Patient demographics, stricture characteristics, clinical and patient-reported outcomes were analyzed. The primary outcomes were stricture recurrence and complications. Secondary outcomes were change in maximum urinary flow rate (Qmax), PVR, and changes in IPSS, SHIM and global response assessment (GRA) questionnaire responses. Descriptive statistical analysis was used for evaluation of outcomes. Sixty-eight men met inclusion criteria. Median age and stricture length were 60 years (IQR 48-69) and 2 cm (IQR 2-3), respectively. Most common stricture etiology was lichen sclerosus (34%). Median operative time and EBL were 72 min (IQR 50-120) and 20 mL (IQR 10-43), respectively. Fifty-seven men completed ≥ 12-month follow-up. At a median follow-up of 17 months (IQR 13-22), 54 patients (95%) remained stricture-free. Median Qmax improved from 5 to 18 mL/s (p < 0.0001), PVR 76-21 mL (p < 0.0001), and IPSS 15-5 (p < 0.0001); IPSS-QOL score: 5-1 (p < 0.0001). SHIM score did not significantly change following repair (median 22-21 p = 0.85). On GRA assessment, a majority of men reported "marked" (64%) or "moderate" (28%) overall improvement. No patient developed fistula, glanular dehiscence, graft necrosis or chordee. This novel minimally invasive transurethral urethroplasty technique is feasible and has demonstrated generalizable outcomes in a multi-institutional cohort with varying etiologies.


Amphibian malformations and body condition across an agricultural landscape of northwest Argentina.
Agricultural landscapes support large amphibian populations because they provide habitat for many species, although agriculture affects amphibians through various mechanisms. Pollution with agrochemicals is the major threat to amphibian populations after habitat loss, as chemicals alter the ecophysiology of amphibians, putting their health and survival at risk. We aimed to assess the effect of different environments, sites, width of forest buffers and sampling years on the health of amphibians, which was estimated through the prevalence of malformations and body condition. During 3 yr of pitfall trapping, we captured 4491 amphibians. The prevalence of malformations was higher in the croplands than in the forests, while the body condition was better within forests. The prevalence of malformations was higher in the narrower forest site than in the wider forest site. The prevalence of malformations and the body condition were higher in the third year. The prevalence of malformations differed by species. We found 11 types of malformation, which mainly affected limbs and were unilateral or bilaterally asymmetrical. Our results showed that the prevalence of malformations and body condition reflect different aspects of the health of amphibians and that forest individuals are healthier than those from croplands. The results also highlight the importance of spatial configuration besides the conservation of natural habitats to preserve healthy amphibians in agricultural landscapes. The types of malformation that we found suggest that agrochemicals could be an important cause of malformations.


Catalyst-free synthesis of 3-sulfone nitrile from sulfonyl hydrazides and acrylonitrile in water.
A novel catalyst-free sulfonation reaction for synthesizing 3-sulfone nitrile compounds from sulfonyl hydrazides and acrylonitriles in water, without any metal catalyst, ligand or organic solvent, was demonstrated. This catalyst-free protocol provides a new synthetic method for the construction of 3-sulfone nitrile compounds with excellent yields. The D2O experiment adequately proved that the catalyst-free sulfonation reaction occurs via a Michael addition mechanism and that the hydrogen of 3-sulfone nitrile comes from water.


Thioarsenates in geothermal waters of Yellowstone National Park: determination, preservation, and geochemical importance.
Mono-, di-, tri-, and tetrathioarsenate, as well as methylated arsenic oxy- and thioanions, were determined besides arsenite and arsenate in geothermal waters of Yellowstone National Park using anion-exchange chromatography inductively coupled plasma mass spectrometry. Retention time match with synthetic standards, measured S:As ratios, and molecular electrospray mass spectra support the identification. Acidification was unsuitable for arsenic species preservation in sulfidic waters, with HCI addition causing loss of total dissolved arsenic, presumably by precipitation of arsenic-sulfides. Flash-freezing is preferred for the preservation of arsenic species for several weeks. After thawing, samples must be analyzed immediately. Thioarsenates occurred over a pH range of 2.1 to 9.3 in the geothermal waters. They clearly predominated under alkaline conditions (up to 83% of total arsenic), but monothioarsenate also was detected in acidic waters (up to 34%). Kinetic studies along a drainage channel showed the importance of thioarsenates for the fate of arsenic discharged from the sulfidic hot spring. The observed arsenic speciation changes suggest three separate reactions: the transformation of trithioarsenate to arsenite (major initial reaction), the stepwise ligand exchange from tri- via di- and monothioarsenate to arsenate (minor reaction), and the oxidation of arsenite to arsenate, which only becomes quantitatively important after thioarsenates have disappeared.


Matrix metalloproteinase-9 is a diagnostic marker of heterotopic ossification in a murine model.
Heterotopic ossification (HO) is a serious disorder that occurs when there is aberrant bone morphogenic protein (BMP) signaling in soft tissues. Currently, there are no methods to detect HO before mineralization occurs. Yet once mineralization occurs, there are no effective treatments, short of surgery, to reverse HO. Herein, we used in vivo molecular imaging and confirmatory ex vivo tissue analyses of an established murine animal model of BMP-induced HO to show that matrix metalloproteinase-9 (MMP-9) can be detected as an early-stage biomarker before mineralization. Ex vivo analyses show that active MMP-9 protein is significantly elevated within tissues undergoing HO as early as 48 h after BMP induction, with its expression co-localizing to nerves and vessels. In vivo molecular imaging with a dual-labeled near-infrared fluorescence and micro-positron emission tomography (μPET) agent specific to MMP-2/-9 expression paralleled the ex vivo observations and reflected the site of HO formation as detected from microcomputed tomography 7 days later. The results suggest that the MMP-9 is a biomarker of the early extracellular matrix (ECM) re-organization and could be used as an in vivo diagnostic with confirmatory ex vivo tissue analysis for detecting HO or conversely for monitoring the success of tissue-engineered bone implants that employ ECM biology for engraftment.


Nile red fluorescence for quantitative monitoring of micropolarity and microviscosity of pluronic F127 in aqueous media.
The photophysical behaviour and excited state decay kinetics of the fluorescent probe Nile red were used for quantitative monitoring of micropolarity, microviscosity and the sol-gel transition temperature of a copolymer hydrogel, pluronic F127. There was considerable enhancement of the emission intensity with a large blue shift in emission and an absorption maximum at and above the sol-gel transition temperature (20 °C), showing the sensitivity of Nile red fluorescence to the sol-gel transition. The estimation of micropolarity by comparing the Nile red emission maximum in dioxane-water mixtures suggested a considerable decrease in the polarity of the PF127 microenvironment from less polar (20% dioxane-water) in its sol phase to almost non-polar (90% dioxane-water) microenvironments in the gel phase. The thermotropic response of the wavelength dependent fluorescence lifetime of the probe with a rise time in the longer wavelength region has enabled monitoring of the microheterogeneity of the gel medium. With an increase in temperature, the microviscosity progressively increases from ∼10 mPa s (sol state) to ∼23 mPa s (gel state). The mismatch between microviscosity as estimated by the Nile red and the corresponding bulk viscosity reflected the microheterogeneity of the pluronic medium and its sensitivity towards PF127 microenvironments.


Teen smoking behavior and the regulatory environment.
Professor Hersch argues that most state regulations aimed at fighting teen smoking have had little or no effect. She provides evidence that despite widespread age restrictions on purchasing tobacco, most teens do not consider it difficult for minors to purchase tobacco products within their community. She also presents evidence demonstrating a strong correlation between smoking rates and perceptions about the addictive nature of smoking. These findings suggest that facilitating greater awareness of the addictive power of cigarettes could be effective in curbing teen smoking. She explores the potential for parental restrictions on limiting teen smoking, but provides indications that parents are not well informed about their children's smoking behavior. Finally, she examines the recent FDA regulations, which, she says, are merely a continuation of the traditional methods of attacking adolescent smoking, and are unlikely to have a significant effect.


Neuroprotective Effects of Emodin against Ischemia/Reperfusion Injury through Activating ERK-1/2 Signaling Pathway.
Stroke is one of the leading causes of death and disability worldwide and places a heavy burden on the economy in our society. Current treatments, such as the use of thrombolytic agents, are often limited by a narrow therapeutic time window. However, the regeneration of the brain after damage is still active days, even weeks, after stroke occurs, which might provide a second window for treatment. Emodin, a traditional Chinese medicinal herb widely used to treat acute hepatitis, has been reported to possess antioxidative capabilities and protective effects against myocardial ischemia/reperfusion injury. However, the underlying mechanisms and neuroprotective functions of Emodin in a rat middle cerebral artery occlusion (MCAO) model of ischemic stroke remain unknown. This study investigates neuroprotective effects of Emodin in ischemia both in vitro and in vivo. PC12 cells were exposed to oxygen-glucose deprivation to simulate hypoxic injury, and the involved signaling pathways and results of Emodin treatment were evaluated. The therapeutic effects of Emodin in ischemia animals were further investigated. Emodin reduced infarct volume and cell death following focal cerebral ischemia injury. Emodin treatment restored PC12 cell viability and reduced reactive oxygen species (ROS) production and glutamate release under conditions of ischemia/hypoxia. Emodin increased Bcl-2 and glutamate transporter-1 (GLT-l) expression but suppressed activated-caspase 3 levels through activating the extracellular signal-regulated kinase (ERK)-1/2 signaling pathway. Emodin induced Bcl-2 and GLT-1 expression to inhibit neuronal apoptosis and ROS generation while reducing glutamate toxicity via the ERK-1/2 signaling pathway. Furthermore, Emodin alleviated nerve cell injury following ischemia/reperfusion in a rat MCAO model. Emodin has neuroprotective effects against ischemia/reperfusion injury both in vitro and in vivo, which may be through activating the ERK-1/2 signaling pathway.


Anterior Fixation of Floating Facet Fractures in the Cervical Spine: A Prospective Case Series and Biomechanical Analysis.
Unilateral fractures involving complete separation of the lateral mass from the vertebra and lamina (floating lateral mass fractures) are a unique subset of cervical spine fractures. These injuries are at significant risk for displacement without operative fixation. Posterior fixation has proven to facilitate adequate fusion. However, there are few data supporting the clinical success of single-level anterior fixation. Biomechanical evaluation of floating lateral mass fractures and a consecutive case series of patients with rotationally unstable floating lateral mass fractures treated with anterior fixation using an integrated cage-screw device with anterior plating (ICSD) was performed. The study comprised 7 fresh human cadaver cervical spines (C2-C7), and 11 patients with floating lateral mass fractures. Segmental flexibility testing evaluating axial rotation, flexion/extension, and lateral bending was performed in a cadaveric model after 2 types of single-level anterior fixation and 1 type of 2-level posterior fixation. Eleven patients with a floating lateral mass fracture of the cervical spine underwent anterior fixation with an ICSD. Radiographs and clinical outcomes were retrospectively reviewed. Compared with the intact condition, posterior instrumentation significantly (P < .05) reduced range of motion (ROM) in all 3 planes; anterior fixation with cervical plate and interbody spacer significantly reduced ROM in lateral bending only; and the ICSD significantly reduced ROM in flexion/extension and lateral bending. In the clinical arm, there were no long-term complications, subsidence >2 mm, failure of fixation, reoperation, pseudoarthrosis, or listhesis at final follow-up. The addition of 2 screws placed through a cervical cage can improve anterior fixation in a human cadaveric model of floating lateral mass fractures. Early clinical results demonstrate a low complication rate and a high rate of healing with single-level anterior fixation using this technique.


Effect of buffer general acid-base catalysis on the stereoselectivity of ester and thioester H/D exchange in D2O.
As part of a comprehensive investigation on the stereochemistry of base-catalyzed 1,2-elimination and H/D exchange reactions of carbonyl compounds, we have found that the stereoselectivity of H/D exchange of 3-hydroxybutyryl N-acetylcysteamine (3) in D(2)O is strongly influenced by the presence of buffers. This buffer effect is also operative with a simple acyclic ester, ethyl 3-methoxybutanoate (7). Buffers whose general-acid components are cyclic tertiary ammonium ions are particularly effective in changing the stereoselectivity. (2)H NMR analysis showed that without buffer, H/D exchange of 3 produces 81-82% of the 2R*, 3R* diastereomer of 2-deuterio 3 (the anti product). In the presence of 0.33 M 3-quinuclidinone buffer, only 44% of the 2R*, 3R* diastereomer was formed. With ester 7, the stereoselectivity went from 93-94% in DO(-)/D(2)O to 60% in the presence of buffer. Phosphate buffer, as well as others, also showed substantial effects. The results are put into the context of what is known about the mechanism of H/D exchange of esters and thioesters, and the relevance of the buffer effect on the mechanism of the enoyl-CoA hydratase reaction is discussed. It is likely that hydrogen bonding in the enolate-buffer acid encounter complex is an important stereochemical determinant in producing a greater amount of the 2R*, 3S* diastereomer (the syn product). Studies that involve the protonation of enolate anions in D(2)O need to include the buffer general acid in any understanding of the stereoselectivity.


From nonconjugation to conjugation: novel meso-OH substituted dipyrromethanes as fluorescence turn-on Zn2+ probes.
Most reported Zn(2+) probes suffer from the interference of background fluorescence originated from the conjugated structures of commonly utilized fluorophores. In this work, three novel meso-hydroxyl group substituted dipyrromethanes DPMOH1-DPMOH3 were synthesized and found to be colourless and nonfluorescent due to the interruption of the conjugated π system by an sp(3) carbon between the two pyrrolic units. Interestingly, only the addition of Zn(2+) to the solutions of DPMOH1-DPMOH3 promoted their oxidation to dipyrrin forms, and bright fluorescence "turn on" was observed due to the formation of corresponding dipyrrin complexes with the dipyrrin : zinc stoichiometry of 2 : 1. Zn(2+) detection mechanism was investigated by UV-Vis, fluorescence, (1)H NMR and HRMS analyses, which can be ascribed to the CHEF type fluorescence enhancement, resulting from good rigidity of the dipyrrin complexes. Hence, DPMOH1-DPMOH3 can be used as fluorescence turn-on Zn(2+) probes with the advantage of no background fluorescence.


imDC: an ensemble learning method for imbalanced classification with miRNA data.
Imbalances typically exist in bioinformatics and are also common in other areas. A drawback of traditional machine learning methods is the relatively little attention given to small sample classification. Thus, we developed imDC, which uses an ensemble learning concept in combination with weights and sample misclassification information to effectively classify imbalanced data. Our method showed better results when compared to other algorithms with UCI machine learning datasets and microRNA data.


beta-Scruin, a homologue of the actin crosslinking protein scruin, is localized to the acrosomal vesicle of Limulus sperm.
Scruin (alpha-scruin) is an actin bundling protein found in the acrosomal process of Limulus polyhemus sperm. We have cloned and sequenced a second scruin isoform from Limulus, beta-scruin, that is 67% identical to alpha-scruin. Northern and Southern analyses confirm that beta-scruin and alpha-scruin are encoded by distinct genes. The sequence of beta-scruin, like alpha-scruin, is organized into N- and C-terminal superbarrel domains that are characterized by a six-fold repeat of a 50 residue motif. Western analysis using rabbit polyclonal antisera specific for alpha- and beta-scruin indicate that beta-scruin, like alpha-scruin, is found in Limulus sperm but not blood or muscle. Both immunofluorescence microscopy and immunogold-EM localize beta-scruin within the acrosomal vesicle at the anterior of sperm but not in the acrosomal process. The function of beta-scruin in this membrane-bounded compartment that is devoid of actin is unknown. However, the location of beta-scruin together with the fact that it contains two putative beta-superbarrel structural folds, which are known to be catalytic domains in a number of proteins, suggests it may have a possible enzymatic role.


History of domestic violence and physical health in midlife.
The association between domestic violence and physical health in middle-aged Australian women is investigated via a cross-sectional survey of 14,100 women (45 to 50 years old) who responded to the first Australian Longitudinal Study on Women's Health survey. After adjustment for demographic and health behavior characteristics and menopause status in multivariate analyses, various physical conditions (allergies or breathing problems, pain or fatigue, bowel problems, vaginal discharge, eyesight and hearing problems, low iron, asthma, bronchitis or emphysema, cervical cancer) were associated with domestic violence. The results highlight the link between health and domestic violence in middle-aged women and underscore the need for health professionals to take a full social history from women presenting with physical symptoms.


Recent advances in processing and presentation of CD1 bound lipid antigens.
It is well established that different populations of alphabeta T lymphocytes can recognize not only peptides in the context of MHC class I and class II molecules, but also foreign and self-lipids in association with CD1 proteins, which share structural similarities with MHC class I molecules. CD1 molecules are comprised of five isoforms, known as group 1 (CD1a, b, c, e) and group 2 (CD1d) CD1, presenting lipid antigens to conventional T lymphocytes or innate-like T cells bearing an invariant T cell receptor (TCR) and known as invariant NKT (iNKT) cells. During the last couple of years, several papers have been published describing important aspects of the mechanisms controlling the processing and presentation of endogenous and exogenous CD1 lipid antigens, which will be the main focus of this review.


Microlessons: Toward a History of Information-Age Cuisine.
This essay proposes that critiques of the industrial food system have not kept pace with its rapid transformation through information technologies, and returns to the emergence of microwave cooking during the 1970s for an illustrative case study. Not just the appliances but also their related cookbooks were produced by corporations heavily invested in electronics. Peculiar convergences suggest that a more encompassing approach to the new cuisine is imperative if we are to understand its complex ecology and phenomenology. In deference to a term from one such cookbook published by General Electric, my history is organized around eight related "Microlessons"-each an invented culinary technique, procedure, or adaptation responding to challenges posed by the new technology-that in hindsight are difficult to confine under the rubric of food studies. The aim is to articulate a new perspective on the post-industrial food system and its many consequences.


Laryngomalacia and Swallow Dysfunction.
Laryngomalacia is an established cause of stridor and sleep-disordered breathing in children. However, the relationship between laryngomalacia and dysphagia has not been well characterized. The objectives of this study were to (1) describe the patient characteristics, symptoms, and prevalence of dysphagia in children with laryngomalacia and (2) examine the effectiveness of supraglottoplasty in improving feeding. This was a retrospective study of patients with laryngomalacia who underwent a modified barium swallow study (MBSS) at a tertiary academic pediatric medical center between March 1, 2014, and March 1, 2018. Patients were excluded if they did not undergo a MBSS. Comorbidities, airway and feedings symptoms, MBSS results, and surgical history were recorded from each patient's electronic medical record. Forty-four children met inclusion/exclusion criteria. The median age at presentation was 96 days. There was a male predominance (66%). About one-third had a genetic or neuromuscular comorbidity. Most children had stridor (93%) and feeding difficulty (86%), while 50% had parent-reported poor weight gain. Fifty-seven percent of patients had evidence of penetration or aspiration on MBSS. All patients with a positive MBSS had dysphagia symptoms. Fifty-seven percent of patients underwent supraglottoplasty. Postoperatively, 92% reported improvement in dysphagia symptoms. Dysphagia is prevalent among a subset of children with laryngomalacia. Symptomatic children may benefit from a swallow evaluation to help determine the need for further intervention. Children who undergo supraglottoplasty for laryngomalacia have improved dysphagia at follow-up, though the amount of improvement directly attributable to surgery is unclear and warrants further investigation.


Kinetic energy-induced growth regimes of nanocolumnar Ti thin films deposited by evaporation and magnetron sputtering.
We experimentally analyze different growth regimes of Ti thin films associated to the existence of kinetic energy-induced relaxation mechanisms in the material's network when operating at oblique geometries. For this purpose, we have deposited different films by evaporation and magnetron sputtering under similar geometrical arrangements and at low temperatures. With the help of a well-established growth model we have found three different growth regimes: (i) low energy deposition, exemplified by the evaporation technique, carried out by species with typical energies in the thermal range, where the morphology and density of the film can be explained by solely considering surface shadowing processes, (ii) magnetron sputtering under weak plasma conditions, where the film growth is mediated by surface shadowing mechanisms and kinetic-energy-induced relaxation processes, and (iii) magnetron sputtering under intense plasma conditions, where the film growth is highly influenced by the plasma, and whose morphology is defined by nanocolumns with similar tilt than evaporated films, but with much higher density. The existence of these three regimes explains the variety of morphologies of nanocolumnar Ti thin films grown at oblique angles under similar conditions in the literature.


Reflechi twòp--thinking too much: description of a cultural syndrome in Haiti's Central Plateau.
A rich Haitian ethnopsychology has been described, detailing concepts of personhood, explanatory models of illness, and links between mind and body. However, little research has engaged explicitly with mental illness, and that which does focuses on the Kreyòl term fou (madness), a term that psychiatrists associate with schizophrenia and other psychoses. More work is needed to characterize potential forms of mild-to-moderate mental illness. Idioms of distress provide a promising avenue for exploring common mental disorders. Working in Haiti's Central Plateau, we aimed to identify idioms of distress that represent cultural syndromes. We used ethnographic and epidemiologic methods to explore the idiom of distress reflechi twòp (thinking too much). This syndrome is characterized by troubled rumination at the intersection of sadness, severe mental disorder, suicide, and social and structural hardship. Persons with "thinking too much" have greater scores on the Beck Depression Inventory and Beck Anxiety Inventory. "Thinking too much" is associated with 8 times greater odds of suicidal ideation. Untreated "thinking too much" is sometimes perceived to lead to psychosis. Recognizing and understanding "thinking too much" may allow early clinical recognition and interventions to reduce long-term psychosocial suffering in Haiti's Central Plateau.


Complex roles of the actin-binding protein Girdin/GIV in DNA damage-induced apoptosis of cancer cells.
The actin-binding protein Girdin is a hub protein that interacts with multiple proteins to regulate motility and Akt and trimeric G protein signaling in cancer cells. Girdin expression correlates with poor outcomes in multiple human cancers. However, those findings are not universal, as they depend on study conditions. Those data suggest that multiple aspects of Girdin function and its role in tumor cell responses to anticancer therapeutics must be reconsidered. In the present study, we found that Girdin is involved in DNA damage-induced cancer cell apoptosis. An esophageal cancer cell line that exhibited high Girdin expression showed a marked sensitivity to UV-mediated DNA damage compared to a line with low Girdin expression. When transcriptional activation of endogenous Girdin was mediated by an engineered CRISPR/Cas9 activation system, sensitivity to DNA damage increased in both stationary and migrating HeLa cancer cells. High Girdin expression was associated with dysregulated cell cycle progression and prolonged G1 and M phases. These features were accompanied by p53 activation, which conceivably increases cancer cell vulnerability to UV exposure. These data highlight the importance of understanding complex Girdin functions that influence cancer cell sensitivity to therapeutics.


Selective inhibition of endothelium-dependent relaxation by sympathectomy in rabbit carotid artery rings in vitro.
The influence of cervical and periarterial sympathectomy on endothelium-dependent relaxation of the rabbit common carotid artery was studied in vitro. Noradrenaline, serotonin, acetylcholine and papaverine concentration-response curves of sympathectomized and control rabbit common carotid artery rings were recorded and analyzed and effects of endothelium removal were investigated. Endothelium-dependent relaxation was selectively and significantly inhibited in 3 weeks postsympathectomy arterial preparations. Alterations in acetylcholine receptors of endothelial cells, decrease in endothelium-derived relaxing factor synthesis, or desensitization of medial muscular cells to endothelium-derived relaxing factor are hypothetical causes of this phenomenon.


Crystal structures of the kinase domain of the sulfate-activating complex in Mycobacterium tuberculosis.
In Mycobacterium tuberculosis the sulfate activating complex provides a key branching point in sulfate assimilation. The complex consists of two polypeptide chains, CysD and CysN. CysD is an ATP sulfurylase that, with the energy provided by the GTPase activity of CysN, forms adenosine-5'-phosphosulfate (APS) which can then enter the reductive branch of sulfate assimilation leading to the biosynthesis of cysteine. The CysN polypeptide chain also contains an APS kinase domain (CysC) that phosphorylates APS leading to 3'-phosphoadenosine-5'-phosphosulfate, the sulfate donor in the synthesis of sulfolipids. We have determined the crystal structures of CysC from M. tuberculosis as a binary complex with ADP, and as ternary complexes with ADP and APS and the ATP mimic AMP-PNP and APS, respectively, to resolutions of 1.5 Å, 2.1 Å and 1.7 Å, respectively. CysC shows the typical APS kinase fold, and the structures provide comprehensive views of the catalytic machinery, conserved in this enzyme family. Comparison to the structure of the human homolog show highly conserved APS and ATP binding sites, questioning the feasibility of the design of specific inhibitors of mycobacterial CysC. Residue Cys556 is part of the flexible lid region that closes off the active site upon substrate binding. Mutational analysis revealed this residue as one of the determinants controlling lid closure and hence binding of the nucleotide substrate.


Characterization of the small RNA component of the transcriptome from grain and sweet sorghum stems.
Sorghum belongs to the tribe of the Andropogoneae that includes potential biofuel crops like switchgrass, Miscanthus and successful biofuel crops like corn and sugarcane. However, from a genomics point of view sorghum has compared to these other species a simpler genome because it lacks the additional rounds of whole genome duplication events. Therefore, it has become possible to generate a high-quality genome sequence. Furthermore, cultivars exists that rival sugarcane in levels of stem sugar so that a genetic approach can be used to investigate which genes are differentially expressed to achieve high levels of stem sugar. Here, we characterized the small RNA component of the transcriptome from grain and sweet sorghum stems, and from F2 plants derived from their cross that segregated for sugar content and flowering time. We found that variation in miR172 and miR395 expression correlated with flowering time whereas variation in miR169 expression correlated with sugar content in stems. Interestingly, genotypic differences in the ratio of miR395 to miR395* were identified, with miR395* species expressed as abundantly as miR395 in sweet sorghum but not in grain sorghum. Finally, we provided experimental evidence for previously annotated miRNAs detecting the expression of 25 miRNA families from the 27 known and discovered 9 new miRNAs candidates in the sorghum genome. Sequencing the small RNA component of sorghum stem tissue provides us with experimental evidence for previously predicted microRNAs in the sorghum genome and microRNAs with a potential role in stem sugar accumulation and flowering time.


Femtosecond-pulse cavity-dumped solid-state oscillator design and application to ultrafast microscopy.
The construction, modeling, and performance characteristics of a new resonator design for ultrafast cavity-dumped oscillators are presented. An acousto-optic Bragg cell was incorporated at the end of the longer arm of a Ti:sapphire oscillator rather than in the shorter arm as in several recent studies. The new arrangement improves the pulse intensity stability of the oscillator and significantly reduces the effort required in construction. The experimental findings are supported by comparison of the stability regions of the laser cavities based on the two different designs. To demonstrate the potential of cavity-dumped oscillators for spatially resolved ultrafast spectroscopy studies, the pulse duration is characterized at the focal plane of two achromatic high-N.A. oil-immersion objectives with different amounts of flat-field correction. Transform-limited pulse widths as short as 15 fs are obtained. To our knowledge, this is the shortest pulse duration measured with true high-N.A. (N.A. > 1) focusing conditions.


Prevalence of HIV, hepatitis B, and hepatitis C in people with severe mental illness: a systematic review and meta-analysis.
Although people with serious mental illnesses have a high risk of contracting blood-borne viral infections, sexual health has largely been neglected by researchers and policy makers involved in mental health. Failure to address this shortcoming could increase morbidity and mortality as a result of undetected and untreated infection. We did a systematic review and meta-analysis to estimate the prevalence of blood-borne viral infection in people with serious mental illness. We searched the Cochrane Library, Medline, Embase, PsycInfo, CINAHL, and DARE for studies of the prevalence of HIV, hepatitis B virus, and hepatitis C virus in people with serious mental illness, published between Jan 1, 1980, and Jan 1, 2015. We group prevalence data by region and by virus and estimated pooled prevalence. We did a sensitivity analysis of the effect of study quality on prevalence. After removal of duplicates, we found 373 abstracts, 91 of which met our eligibility criteria. The prevalences of blood-borne viral infections in people with serious mental illness were higher than in the general population in places with low prevalence of blood-borne viruses, such as the USA and Europe, and on par with the general population in regions with high prevalence of blood-borne viruses (Africa for HIV and southeast Asia for hepatitis B virus and hepatitis C virus). Pooled prevalence of HIV in people with serious mental illness in the USA was 6·0% (95% CI 4·3-8·3). Sensitivity analysis showed that quality scores did not significantly affect prevalence. People with serious mental illness are at risk of blood-borne viral infections. However, because of methodological limitations of the studies the prevalence might be overestimated. Serious mental illness is unlikely to be a sole risk factor and risk of blood-borne viral infection is probably multifactorial and associated with low socioeconomic status, drug and alcohol misuse, ethnic origin, and sex. Health providers should routinely discuss sexual health and risks for blood-borne viruses (including risks related to drug misuse) with people who have serious mental illness, as well as offering testing and treatment for those at risk. Wellcome Trust.


Linkage analysis of autopsy-confirmed familial Alzheimer disease supports an Alzheimer disease locus in 8q24.
We have previously reported the results of an extended genome-wide scan of Swedish Alzheimer disease (AD)-affected families; in this paper, we analyzed a subset of these families with autopsy-confirmed AD. We report the fine-mapping, using both microsatellite markers and single-nucleotide polymorphisms (SNPs), in the observed maximum logarithm of the odds (LOD)-2 unit (LOD(max)-2) region under the identified linkage peak, linkage analysis of the fine-mapping data with additionally analyzed pedigrees, and association analysis of SNPs selected from candidate genes in the linked interval. The subset was made on the criterion of at least one autopsy-confirmed AD case per family, resulting in 24 families. Linkage analysis of a family subset having at least one autopsy-confirmed AD case showed a significant nonparametric single-point LOD score of 4.4 in 8q24. Fine-mapping under the linkage peak with 10 microsatellite markers yielded an increase in the multipoint (mpt) LOD score from 2.1 to 3.0. SNP genotyping was performed on 21 selected candidate transcripts of the LOD(max)-2 region. Both family-based association and linkage analysis were performed on extended material from 30 families, resulting in a suggestive linkage at peak marker rs6577853 (mpt LOD score = 2.4). The 8q24 region has been implicated to be involved in AD etiology.


TDDFT studies of absorption and SERS spectra of pyridine interacting with Au20.
We present time dependent density functional theory (TDDFT) calculations for a tetrahedral Au20 complex interacting with pyridine for the purpose of modeling absorption and surface enhanced Raman scattering, with emphasis on chemical and electrodynamic enhancement effects. These calculations are done using the ADF code with the BP86 functional, the zeroth-order regular approximation and with the resonant electronic response modeled using a short time approximation expression for the perturbed density matrix, with a damping factor that is empirically chosen. The absorption spectrum of bare Au20 shows strong intraband (sp-sp) and interband (sp-d) coupling with a low-energy peak at 2.89 eV that is mostly intraband and other peaks at 3.94 and 4.70 eV that have mixed intra- and interband character. SERS spectra are calculated for pyridine/Au20 for both vertex (V) and surface (S) configurations at their respective lowest energy absorption maxima (near 2.89 eV), and we find that the V configuration has higher intensities that correspond to SERS enhancements of 10(3)-10(4), whereas S has an enhancement of 10(2)-10(3). These enhancement values are significantly lower than the analogous results for pyridine/Ag20 primarily because of reduced oscillator strength associated with the intraband transition in Au20. Decomposition of the pyridine/Au20 enhancement factor into chemical and electromagnetic contributions (through an analysis of the static SERS intensities) shows enhanced chemical enhancements compared to Ag20 but reduced electromagnetic enhancements.


Dose-dependent anti-inflammatory effect of inhaled mometasone furoate/formoterol in subjects with asthma.
A well-controlled study in patients with allergic asthma was warranted to assess dose-dependency between fractional concentration of exhaled nitric oxide (FeNO) and sputum eosinophils to a combination of an inhaled corticosteroid plus a long-acting β2-agonist. We sought to characterize the dose-dependency of mometasone furoate/formoterol (MF/F) using FeNO and sputum eosinophil percentage as surrogates of airway inflammation in subjects with allergic asthma. Following a 2-week, open-label run-in, 93 subjects (≥12 y) using only short-acting beta agonist reliever medication as needed, were randomized to twice daily (BID) placebo; MF/F 100/10 μg, 200/10 μg, or 400/10 μg (via pressurized metered-dose inhaler [MDI]); MF-MDI 200 μg; or MF 200 μg via dry powder inhaler (DPI) during a 2-week, double-blind treatment period. All active treatments demonstrated significant percentage reductions from baseline in FeNO compared with placebo at all time points (P ≤ 0.034). At endpoint, mean MF/F treatment group FeNO reductions ranged from -35.3% to -61.4%. Sputum eosinophil percentage reductions from baseline were significant compared with placebo for the MF/F 200/10 μg, MF/F 400/10 μg, and MF-DPI 200 μg groups at endpoint (P ≤ 0.023). Escalating MF/F doses significantly reduced both FeNO (P ≤ 0.001) and sputum eosinophil (P ≤ 0.022) levels in a dose-dependent manner at all time points. All treatments were well tolerated; no serious adverse events were observed. All 3 MF/F doses demonstrated pronounced, clinically meaningful, dose-dependent reductions in FeNO, with reduced sputum eosinophil levels for MF/F 200/10 μg and MF/F 400/10 μg. These findings suggest both inflammatory markers may be useful in assessing corticosteroid responsiveness in asthma patients, and perhaps identifying the same asthma subphenotype. Clinical Trials.gov: NCT00635882.


Africa's oesophageal cancer corridor: Do hot beverages contribute?
Hot beverage consumption has been linked to oesophageal squamous cell cancer (EC), but its contribution to the poorly understood East African EC corridor is not known. In a cross-sectional study of general-population residents in Kilimanjaro, North Tanzania, tea drinking temperatures and times were measured. Using linear regression models, we compared drinking temperatures to those in previous studies, by socio-demographic factors and tea type ("milky tea" which can be 50 % or more milk and water boiled together vs "black tea" which has no milk). Participants started drinking at a mean of 70.6 °C (standard deviation 3.9, n = 188), which exceeds that in all previous studies (p ≤ 0.01 for each). Tea type, gender and age were associated with drinking temperatures. After mutual adjustment for each other, milky tea drinkers drank their tea 1.9 °C (95 % confidence interval: 0.9, 2.9) hotter than drinkers of black tea, largely because black tea cooled twice as fast as milky tea. Men commenced drinking tea 0.9 °C (-0.2, 2.1) hotter than women did and finished their cups 30 (-9, 69) seconds faster. 70 % and 39 % of milky and black tea drinkers, respectively, reported a history of tongue burning. Hot tea consumption, especially milky tea, may be an important and modifiable risk factor for EC in Tanzania. The contribution of this habit to EC risk needs to be evaluated in this setting, jointly with that of the many risk factors acting synergistically in this multi-factorial disease.