Nocturnal temperature-controlled laminar airflow device for adults with severe allergic asthma: the LASER RCT.
Severe asthma exacerbations are costly to patients and the NHS, and occur frequently in severely allergic patients. To ascertain whether or not nocturnal temperature-controlled laminar airflow (TLA) device usage over 12 months can reduce severe exacerbations and improve asthma control and quality of life compared with a placebo device, while being cost-effective and acceptable to adults with severe allergic asthma. A pragmatic, multicentre, randomised, double-blind, placebo-controlled, parallel-group, superiority trial with qualitative interviews. The trial included an internal pilot with qualitative focus groups. Fourteen hospitals in the UK that manage patients with severe asthma. Adults (16-75 years) with severe, poorly controlled, exacerbation-prone asthma despite high-intensity treatment, and who are sensitised to a perennial indoor aeroallergen. Nocturnal, home-based TLA treatment using an Airsonett® (Airsonett AB, Ängelholm, Sweden) device. The comparator was a placebo device that was identical to the active device except that it did not deliver the laminar airflow. Participants were allocated 1 : 1 to TLA therapy or placebo, minimised by site, origin of case, baseline severe exacerbation frequency, maintenance oral corticosteroid use and pre-bronchodilator forced expiratory volume in 1 second. Primary outcome - frequency of severe asthma exacerbations occurring within the 12-month follow-up period, defined as worsening of asthma requiring systemic corticosteroids [≥ 30 mg of prednisolone or equivalent daily (or ≥ 50% increase in dose if on maintenance dose of ≥ 30 mg of prednisolone)] for ≥ 3 days. Secondary outcomes - changes in asthma control, lung function, asthma-specific and global quality of life for participants, adherence to the intervention, device acceptability, health-care resource use and cost-effectiveness. Between May 2014 and January 2016, 489 patients consented to participate in the trial, of whom 249 failed screening and 240 were randomised (n = 119 in the treatment group and n = 121 in the placebo group); all were analysed. In total, 202 participants (84%) reported use of the device for 9-12 months. Qualitative analyses showed high levels of acceptability. The mean [standard deviation (SD)] rate of severe exacerbations did not differ between groups [active 1.39 (1.57), placebo 1.48 (2.03); risk ratio 0.92, 95% CI 0.66 to 1.27; p = 0.616]. There were no significant differences in secondary outcomes for lung function, except for a reduction in mean daily peak expiratory flow [mean (SD) difference 14.7 l/minute (7.35 l/minute), 95% CI 0.32 to 29.1 l/minute; p = 0.045) for those in the active device group. There were no differences in asthma control or airway inflammation and no serious harms related to the device. No significant difference between the groups in quality-adjusted life-years gained over 1 year was observed. In addition, there was no difference in generic or disease-specific health-related quality of life overall, although statistically significant higher quality of life at month 6 was observed. Increases in quality of life were not sufficient to offset the annual costs associated with use of the TLA device. Missing outcome data could have resulted in an underestimation of exacerbations and rendered the study inconclusive. Within the limits of the data, no consistent benefits of the active device were demonstrated, and the differences observed were not sufficient to make the device cost-effective. The types of patients who may benefit from the TLA device, and the reasons for large reductions in exacerbation frequency in severe asthma trials, which also incorporate other methods of recording exacerbations, need to be explored. Current Controlled Trials ISRCTN46346208. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 29. See the NIHR Journals Library website for further project information.


How public catering accelerates sustainability: a German case study.
Public catering has become increasingly important in recent years. With increasing annual customers, the sector's impact on the environment is also growing continuously. At the same time, public catering offers a lever to promote sustainable nutrition that has rarely been used so far. Small changes in kitchen practices and food offers can thus be multiplied into a significant positive impact on environmental challenges, such as climate change or loss of biodiversity due to the large number of servings. In contrast to private households, management decisions in public catering can influence the food-related environmental impact of thousands of customers. This article deals with the nationwide level of greenhouse gas (GHG) emissions and resource use in the German public catering segment "business" and its saving potentials by different scenarios of unsupported and supported recipe revision. In this paper, we define "unsupported" as the intuitive optimization of recipes by employees of public catering businesses. In contrast, "supported" approaches had to meet specific target goals, for example of the Deutsche Gesellschaft für Ernährung; engl. German Nutrition Society or the sustainable level. Specifically, we will test how (A) an unsupported recipe revision, (B) a recipe revision based on dietary recommendations and (C) a recipe revision using scientific guidance affect the environmental impact of a dish. As a methodological framework, an online survey of public catering companies was conducted as well as a scenario analysis at menu level and at nationwide level. The results are based on empirical data on the one hand, and on extrapolations on the other. The results show that the nationwide implementation of recipe revision according to scientific guidance-such as concrete target goals for the GHG emissions per serving-can save up to 44% of resource use in the German business catering sector (which corresponds to 3.4 million tons of resources per year) and as much as 40% of GHG emissions (0.6 million tons GHG emissions per year). Even in the scenario of unsupported recipe revision, GHG and resource savings of up to 20% can be realized. The results show that public catering can reduce its material and carbon footprint by 20% overnight. Moreover, the findings show indications for the sustainable transformation of public catering. Nevertheless, it must be noted that these are some first steps of the transformation, which will require further changes with even greater impacts and political activities. The online version contains supplementary material available at 10.1007/s11625-022-01183-2.


Blast-1 possesses a glycosyl-phosphatidylinositol (GPI) membrane anchor, is related to LFA-3 and OX-45, and maps to chromosome 1q21-23.
Blast-1 is a human activation-associated glycoprotein expressed on the surface of leukocytes. Analysis of a translated sequence from a Blast-1 cDNA reveals a single hydrophobic sequence which could traverse the plasma membrane, but is devoid of charged residues that might represent a cytoplasmic tail. Consistent with this characteristic, Blast-1 is demonstrated here to be anchored to the cell surface through a glycosyl-phosphatidylinositol (GPI)-containing lipid. Comparison of Blast-1 to other GPI-anchored membrane proteins revealed a striking primary and secondary structure similarity with MRC OX45 and the lymphocyte function antigen LFA-3. The degree of overall amino acid sequence homology reveals that OX45 is a rat homologue of Blast-1. The greatest homology to LFA-3 occurs between their NH2-terminal Ig-like domains. Evidence is presented that demonstrates that Blast-1 and LFA-3 possess a disulfide-bonded second domain. These common characteristics demonstrate a structural and evolutionary relationship between Blast-1, OX45, LFA-3, and CD2, which in turn suggests a functional role for Blast-1 in cell-cell interactions in the immune response. The gene for Blast-1 has been localized to chromosome 1 q21-q23, indistinguishable from the CD1 cluster of Ig superfamily genes, raising the possibility that they may be linked.


Lifestyle factors and prostate-specific antigen (PSA) testing in UK Biobank: Implications for epidemiological research.
The central role of prostate-specific antigen (PSA) testing in the diagnosis of prostate cancer leads to the possibility that observational studies that report associations between risk factors and prostate cancer could be affected by detection bias. This study aims to investigate whether reported risk factors for prostate cancer are associated with PSA testing in a large middle-aged population-based cohort in the UK. The cross-sectional association between a wide range of sociodemographic, lifestyle, dietary and health characteristics with PSA testing was examined in 212,039 men aged 40-69 years in UK Biobank. A total of 62,022 (29%) men reported they had ever had a PSA test. A wide range of factors was associated with a higher likelihood of PSA testing including age, height, education level, family history of prostate cancer, black ethnic origin, not being in paid/self-employment, living with a wife or partner, having had a vasectomy, being diagnosed with cancer or hypertension and having a high dietary intake of cereal, cooked and salad/raw vegetables, fresh fruit and tea. Conversely, socioeconomic deprivation, Asian ethnic origin, current smoking, low alcohol intake, high body-mass index, high coffee consumption and being diagnosed with diabetes, heart disease or stroke were associated with a lower likelihood of PSA testing. A variety of sociodemographic, lifestyle and health-related characteristics are associated with PSA testing, suggesting that observed associations of some of these traits with risk for prostate cancer in epidemiological studies may be, at least partially, due to detection bias.


Breaking down protein degradation mechanisms in cardiac muscle.
Regulated protein degradation through the ubiquitin-proteasome and lysosomal/autophagy systems is critical for homeostatic protein turnover in cardiac muscle and for proper cardiac function. The discovery of muscle-specific components in these systems has illuminated how aberrations in their levels are pivotal to the development of cardiac stress and disease. New evidence suggests that equal importance in disease development should be given to ubiquitously expressed degradation components. These are compartmentalized within cardiac muscles and, when mislocalized, can be critical in the development of specific cardiac diseases. Here, we discuss how alterations in the compartmentalization of degradation components affect disease states, the tools available to investigate these mechanisms, as well as recent discoveries that highlight the therapeutic value of targeting these pathways in disease.


Constraining the chlorine monoxide (ClO)/chlorine peroxide (ClOOCl) equilibrium constant from Aura Microwave Limb Sounder measurements of nighttime ClO.
The primary ozone loss process in the cold polar lower stratosphere hinges on chlorine monoxide (ClO) and one of its dimers, chlorine peroxide (ClOOCl). Recently, analyses of atmospheric observations have suggested that the equilibrium constant, K(eq), governing the balance between ClOOCl formation and thermal decomposition in darkness is lower than that in the current evaluation of kinetics data. Measurements of ClO at night, when ClOOCl is unaffected by photolysis, provide a useful means of testing quantitative understanding of the ClO/ClOOCl relationship. Here we analyze nighttime ClO measurements from the National Aeronautics and Space Administration Aura Microwave Limb Sounder (MLS) to infer an expression for K(eq). Although the observed temperature dependence of the nighttime ClO is in line with the theoretical ClO/ClOOCl equilibrium relationship, none of the previously published expressions for K(eq) consistently produces ClO abundances that match the MLS observations well under all conditions. Employing a standard expression for K(eq), A x exp(B/T), we constrain the parameter A to currently recommended values and estimate B using a nonlinear weighted least squares analysis of nighttime MLS ClO data. ClO measurements at multiple pressure levels throughout the periods of peak chlorine activation in three Arctic and four Antarctic winters are used to estimate B. Our derived B leads to values of K(eq) that are approximately 1.4 times smaller at stratospherically relevant temperatures than currently recommended, consistent with earlier studies. Our results are in better agreement with the newly updated (2009) kinetics evaluation than with the previous (2006) recommendation.


Electronic and plasmonic phenomena at graphene grain boundaries.
Graphene, a two-dimensional honeycomb lattice of carbon atoms of great interest in (opto)electronics and plasmonics, can be obtained by means of diverse fabrication techniques, among which chemical vapour deposition (CVD) is one of the most promising for technological applications. The electronic and mechanical properties of CVD-grown graphene depend in large part on the characteristics of the grain boundaries. However, the physical properties of these grain boundaries remain challenging to characterize directly and conveniently. Here we show that it is possible to visualize and investigate the grain boundaries in CVD-grown graphene using an infrared nano-imaging technique. We harness surface plasmons that are reflected and scattered by the graphene grain boundaries, thus causing plasmon interference. By recording and analysing the interference patterns, we can map grain boundaries for a large-area CVD graphene film and probe the electronic properties of individual grain boundaries. Quantitative analysis reveals that grain boundaries form electronic barriers that obstruct both electrical transport and plasmon propagation. The effective width of these barriers (∼10-20 nm) depends on the electronic screening and is on the order of the Fermi wavelength of graphene. These results uncover a microscopic mechanism that is responsible for the low electron mobility observed in CVD-grown graphene, and suggest the possibility of using electronic barriers to realize tunable plasmon reflectors and phase retarders in future graphene-based plasmonic circuits.


Crushed tablets: does the administration of food vehicles and thickened fluids to aid medication swallowing alter drug release?
To evaluate the influence of co-administered vehicles on in vitro dissolution in simulated gastric fluid of crushed immediate release tablets as an indicator for potential drug bioavailability compromise. Release and dissolution of crushed amlodipine, atenolol, carbamazepine and warfarin tablets were tested with six foods and drinks that are frequently used in the clinical setting as mixers for crushed medications (water, orange juice, honey, yoghurt, strawberry jam and water thickened with Easythick powder) in comparison to whole tablets. Five commercial thickening agents (Easythick Advanced, Janbak F, Karicare, Nutilis, Viscaid) at three thickness levels were tested for their effect on the dissolution of crushed atenolol tablets. Atenolol dissolution was unaffected by mixing crushed tablets with thin fluids or food mixers in comparison to whole tablets or crushed tablets in water, but amlodipine was delayed by mixing with jam. Mixing crushed warfarin and carbamazepine tablets with honey, jam or yoghurt caused them to resemble the slow dissolution of whole tablets rather than the faster dissolution of crushed tablets in water or orange juice. Crushing and mixing any of the four medications with thickened water caused a significant delay in dissolution. When tested with atenolol, all types of thickening agents at the greatest thickness significantly restricted dissolution, and products that are primarily based on xanthan gum also delayed dissolution at the intermediate thickness level. Dissolution testing, while simplistic, is a widely used and accepted method for comparing drug release from different formulations as an indicator for in vivo bioavailability. Thickened fluids have the potential to retard drug dissolution when used at the thickest levels. These findings highlight potential clinical implications of the addition of these agents to medications for the purpose of dose delivery and indicate that further investigation of thickened fluids and their potential to influence therapeutic outcomes is warranted.


[Relationship between smoking and risk of esophageal cancer in 103 areas in China: a large-scale case-control study incorporated into a nationwide survey of mortality].
To examine the relationship between smoking and risk of esophageal cancer (EC), and present a theoretical framework of control selection in population-based case-control study which was incorporated into a nationwide retrospective survey of mortality in China. A large-scale population-based case-control study was incorporated into the nationwide retrospective survey of mortality conducted 1989 - 1991 in 24 urban cities selected by non-random sampling and 79 rural counties selected from 3000 counties included in the 1973 - 1975 cancer distribution survey by random sampling during. A questionnaire survey was conducted by home visit to investigate the death causes and smoking history of 19 734 deceased male adults who died of esophageal cancer during 1986 - 1988 at the age >or= 35. Two control groups were set up to undergo questionnaire survey by home visit to investigate the smoking history of the deceased persons and the informants. Control group I included the surviving spouses or other informants of 31 989 male adults who died of non-malignant digestive diseases during 1986 - 1988 at the age >or= 35, and control group II included 104 846 male spouses of the deceased female adults who died of different causes during 1986 - 1989 at the age >or= 35. The relative risks and population smoking attributable risks for EC were calculated using non-conditional logistic model, and the results were compared for consistency between the analyses using two different control groups. The EC absolute death rates were higher in the smokers than in the non-smokers in all urban and rural area groups. The total EC absolute death rate per 1000 among the non-smokers vs. smokers was 0.37:0.65 in the urban areas, 0.99:1.29 in the inland rural areas, and 1.09:1.62 in the coastal rural areas in the control group I, and there was a similar trend in the control group II. There was a significant dose-response relation between the period of smoking and the death risk of EC and between the daily cigarette consumption and the death risk of EC. The risk ratios, for example, for cigarette per day < 10, 10-, and 20- in the urban men were 1.42, 1.82, 2.22 in the control group I (trend test P < 0.01), and 1.57, 1.95, and 3.18 in the control group II (trend test P < 0.01). Smoking is an important risk factor for mortality from EC in China. Investigating the surviving spouses of the deceased patients is a creative, effective, and feasible trial, with the prerequisite of whole population-based survey, in study of the main types of death and the relevant risk factors.


Preventive effects of selenium yeast, chromium picolinate, zinc sulfate and their combination on oxidative stress, inflammation, impaired angiogenesis and atherogenesis in myocardial infarction in rats.
Accumulating evidences suggest a critical role of trace metal dyshemostasis in oxidative stress and cardiac dysfunction after myocardial infarction (MI). This study investigated the cardioprotective effects of selenium yeast (Se), chromium picolinate Cr(pic)3, zinc sulfate (Zn) and their combination on isoproterenol (ISO)-induced MI. Rats were divided into six groups: normal control, ISO control, Se-pretreated (0.1 mg/kg), Cr(pic)3-pretreated (400 µg/kg), Zn-pretreated (30 mg/kg) and metal combination-pretreated groups. All metals were administered for 28 days and at the 27th day, MI was induced by subcutaneous injection of ISO (85 mg/kg) once for two consecutive days. ISO control group showed hyperlipidemia, elevation of cardiac biomarkers and lipid peroxidation and increased immunostaining of p47 phox NADPH oxidase subunit in addition to decreased levels of glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). Cardiac levels of tumor necrosis factor-α (TNF-α) were increased, while vascular endothelial growth factor (VEGF, the major angiogenic factor) was decreased. Pretreatment with Se normalized the cardiac enzymes, lipid peroxidation, GSH, SOD, CAT, GPx, TNF-α and VEGF (P<0.001) and reduced the immunostaining of p47 phox subunit. However, Se failed to correct the dyslipidemia. Cr(pic)3 significantly improved lipid profile (P<0.001) and all other biochemical deviations except for VEGF. Zn, but to lesser extent, reduced the oxidative damage and TNF-α levels and improved both dyslipidemia and angiogenesis. Combination therapy exhibited less prominent protection compared to individual metals. Daily supplementation with trace metals is promising for improving myocardial performance via preventing oxidative damage, induction of angiogenesis, anti-inflammatory and/or anti-hyperlipidemic mechanisms.


A rare case of hypercalcemia-induced pancreatitis in a first trimester pregnant woman.
The objective of the study is to report a case of acute pancreatitis secondary to hypercalcemia induced by primary hyperparathyroidism in a pregnant woman at the end of the first trimester. The case included a 32-year-old woman who was diagnosed with acute pancreatitis and severe hypercalcemia refractory to many regimens of medical therapy in the first trimester of pregnancy. She was successfully treated with parathyroidectomy in the early second trimester with complete resolution of hypercalcemia and pancreatitis. Neonatal course was unremarkable. To our best knowledge, this is a rare case when primary hyperparathyroidism and its complications are diagnosed in the first trimester of pregnancy. In conclusion, primary hyperparathyroidism is a rare life-threatening condition to the fetus and mother especially when associated with complications such as pancreatitis. Early therapeutic intervention is important to reduce the morbidity and mortality. Parathyroidectomy performed in the second trimester can be the only solution. Learning how to make diagnosis of primary hyperparathyroidism in a woman during the first trimester of pregnancy.Understanding the complications of hypercalcemia and be aware of the high mortality and sequelae in both fetus and mother.Providing the adequate treatment in such complicated cases with coordinated care between endocrinologists and obstetricians to ensure optimal outcomes.


Pituitary gland volumes in bipolar disorder.
Bipolar disorder has been associated with increased Hypothalamic-Pituitary-Adrenal axis function. The mechanism is not well understood, but there may be associated increases in pituitary gland volume (PGV) and these small increases may be functionally significant. However, research investigating PGV in bipolar disorder reports mixed results. The aim of the current study was twofold. First, to assess PGV in two novel samples of patients with bipolar disorder and matched healthy controls. Second, to perform a meta-analysis comparing PGV across a larger sample of patients and matched controls. Sample 1 consisted of 23 established patients and 32 matched controls. Sample 2 consisted of 39 medication-naïve patients and 42 matched controls. PGV was measured on structural MRI scans. Seven further studies were identified comparing PGV between patients and matched controls (total n; 244 patients, 308 controls). Both novel samples showed a small (approximately 20mm(3) or 4%), but non-significant, increase in PGV in patients. Combining the two novel samples showed a significant association of age and PGV. Meta-analysis showed a trend towards a larger pituitary gland in patients (effect size: .23, CI: -.14, .59). While results suggest a possible small difference in pituitary gland volume between patients and matched controls, larger mega-analyses with sample sizes greater even than those used in the current meta-analysis are still required. There is a small but potentially functionally significant increase in PGV in patients with bipolar disorder compared to controls. Results demonstrate the difficulty of finding potentially important but small effects in functional brain disorders.


Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief.
Typically considered to be cell surface sensors of extracellular signals, heterotrimeric GTP-binding protein (G protein)-coupled receptors (GPCRs) control many pathophysiological processes and are the target of 30% of therapeutic drugs. Activated receptors redistribute to endosomes, but researchers have yet to explore whether endosomal receptors generate signals that control complex processes in vivo and are viable therapeutic targets. We report that the substance P (SP) neurokinin 1 receptor (NK1R) signals from endosomes to induce sustained excitation of spinal neurons and pain transmission and that specific antagonism of the NK1R in endosomes with membrane-anchored drug conjugates provides more effective and sustained pain relief than conventional plasma membrane-targeted antagonists. Pharmacological and genetic disruption of clathrin, dynamin, and β-arrestin blocked SP-induced NK1R endocytosis and prevented SP-stimulated activation of cytosolic protein kinase C and nuclear extracellular signal-regulated kinase, as well as transcription. Endocytosis inhibitors prevented sustained SP-induced excitation of neurons in spinal cord slices in vitro and attenuated nociception in vivo. When conjugated to cholestanol to promote endosomal targeting, NK1R antagonists selectively inhibited endosomal signaling and sustained neuronal excitation. Cholestanol conjugation amplified and prolonged the antinociceptive actions of NK1R antagonists. These results reveal a critical role for endosomal signaling of the NK1R in the complex pathophysiology of pain and demonstrate the use of endosomally targeted GPCR antagonists.


Mutation Detection in Patients with Retinal Dystrophies Using Targeted Next Generation Sequencing.
Retinal dystrophies (RD) constitute a group of blinding diseases that are characterized by clinical variability and pronounced genetic heterogeneity. The different nonsyndromic and syndromic forms of RD can be attributed to mutations in more than 200 genes. Consequently, next generation sequencing (NGS) technologies are among the most promising approaches to identify mutations in RD. We screened a large cohort of patients comprising 89 independent cases and families with various subforms of RD applying different NGS platforms. While mutation screening in 50 cases was performed using a RD gene capture panel, 47 cases were analyzed using whole exome sequencing. One family was analyzed using whole genome sequencing. A detection rate of 61% was achieved including mutations in 34 known and two novel RD genes. A total of 69 distinct mutations were identified, including 39 novel mutations. Notably, genetic findings in several families were not consistent with the initial clinical diagnosis. Clinical reassessment resulted in refinement of the clinical diagnosis in some of these families and confirmed the broad clinical spectrum associated with mutations in RD genes.


Language-related field potentials in the anterior-medial temporal lobe: II. Effects of word type and semantic priming.
Field potentials were recorded from intracranial electrodes in humans to study the role of the anterior medial temporal lobe (AMTL) in language-related processing. Subjects viewed lists of words in which orthography and word type varied, or in which words were primed by semantic associates. Large negative field potentials were elicited within the AMTL by isolated words. The amplitude and intracranial distribution of these AMTL field potentials were consistent with those in our previous study in which anomalous sentence-ending words were used as stimuli (McCarthy et al., in press). The neocortex, in the region of the collateral sulcus and anterior fusiform gyrus, was identified as the likely neural generator of this field potential. The AMTL field potential was diminished by semantic priming, and was larger for words with semantic content than for words serving grammatical function. Orthographically illegal nonwords did not elicit this field potential. The N400 scalp event-related potential (ERP) has been shown to respond in the same manner to these task manipulations (Nobre and McCarthy, 1994), and, thus, the AMTL field potential was proposed to contribute to the generation of N400. The possible roles in language processing reflected by the AMTL field potential were considered.


Fibroblast growth factor 2: good or bad guy in the joint?
Fibroblast growth factor 2 (FGF2) is a highly abundant growth factor found within the pericellular matrix of articular chondrocytes, but studies investigating its role have been conflicting. The paper reported by Yan and colleagues in the previous issue of Arthritis Research & Therapy proposes that differences in responses to FGF2 are most likely due to changes in the balance between the two major articular cartilage FGF receptors, FGFR1 and FGFR3. They show that the catabolic and anti-anabolic effects of FGF2 are mediated primarily through FGFR1 whereas the beneficial effects are through FGFR3. This balance is dynamic and is altered in disease and following growth factor stimulation in vitro.


Clinical associations between gout and multiple sclerosis, Parkinson's disease and motor neuron disease: record-linkage studies.
Uric acid has antioxidant effects on neurons. Abnormally high levels of uric acid are, however, associated with gout. Previous studies have suggested that high levels of uric acid (and the presence of gout) may exert a protective effect against the risk of developing some neurological diseases. We aimed to investigate this hypothesis in a large database of hospital admissions in England. We analysed a database of linked statistical records of hospital admissions and death registrations in England (1999-2012). A cohort of people with gout was constructed and followed for development of multiple sclerosis (MS), Parkinson's disease (PD) or motor neuron disease (MND). Then, conversely, cohorts of all people in the database with MS, PD or MND were constructed and followed for subsequent gout. Rate ratios (RRs) were determined, comparing these cohorts with people in a reference cohort. In the gout cohort, we observed a modest elevation of the overall risk of subsequent MS, PD and MND (respectively, RR = 1.27 (95% confidence interval 1.03-1.55), 1.11 (1.05-1.17) and 1.28 (1.11-1.48) which was largely attributable to an increased risk observed in the early years after hospitalisation for gout. The increased risk of neurological disease did not remain after 5 years. In the cohorts of people with MS or PD, there was a significantly reduced risk of subsequent gout admission (RR = 0.79 (0.69-0.89) and 0.83 (0.79-0.87), respectively). This inverse association was sustained over time. There was also a reduced risk of MND following gout which only emerged more than five years following initial gout admission (RR at 5+ years 0.35 (0.15-0.68)). This study investigated the epidemiological evidence for a protective role of high serum concentration of uric acid, for which we used gout as a proxy, in the aetiology of MS, PD or MND. Our observations do not support this hypothesis. However, when the order was reversed, and we retrospectively followed up patients with MS, PD and MND for a number of years, we found a statistically significant deficit of gout. This suggests that there is relationship between some aspects of these neurodegenerative diseases and metabolism of uric acid.


College student drinking: perception of the norm and behavioral intentions.
Social norm campaigns assume that college students desire to increase their drinking, and may eventually do so, to match inflated perceptions of peer drinking. We assessed 171 college students on self-reported drinking, desired drinking and perception of peer drinking at baseline, and assessed 139 of those students one month later. Participants who believed their peers drank more than they were hypothesized to desire to increase their alcohol consumption to match the perceived norm. This hypothesis was not supported; however, 91% of participants believed their peers drank more than themselves. It was also hypothesized that participants who wished to drink more would drink more in the future. Participants who desired to increase their drinking did not report a significant change in drinking behavior one month later, but participants who initially desired to maintain or decrease their drinking reported significant decreases across the following month. College student overestimation of peer drinking and the college environment are discussed. Social norm campaigns should consider behavioral intentions, and the underlying assumptions of these campaigns should be further tested.


German evidence-based guidelines for the treatment of Psoriasis vulgaris (short version).
Psoriasis vulgaris is a common and chronic inflammatory skin disease which has the potential to significantly reduce the quality of life in severely affected patients. The incidence of psoriasis in Western industrialized countries ranges from 1.5 to 2%. Despite the large variety of treatment options available, patient surveys have revealed insufficient satisfaction with the efficacy of available treatments and a high rate of medication non-compliance. To optimize the treatment of psoriasis in Germany, the Deutsche Dermatologische Gesellschaft and the Berufsverband Deutscher Dermatologen (BVDD) have initiated a project to develop evidence-based guidelines for the management of psoriasis. The guidelines focus on induction therapy in cases of mild, moderate, and severe plaque-type psoriasis in adults. The short version of the guidelines reported here consist of a series of therapeutic recommendations that are based on a systematic literature search and subsequent discussion with experts in the field; they have been approved by a team of dermatology experts. In addition to the therapeutic recommendations provided in this short version, the full version of the guidelines includes information on contraindications, adverse events, drug interactions, practicality, and costs as well as detailed information on how best to apply the treatments described (for full version, please see Nast et al., JDDG, Suppl 2:S1-S126, 2006; or http://www.psoriasis-leitlinie.de ).


Small-molecule inhibitors targeting INK4 protein p18(INK4C) enhance ex vivo expansion of haematopoietic stem cells.
Among cyclin-dependent kinase inhibitors that control the G1 phase in cell cycle, only p18 and p27 can negatively regulate haematopoietic stem cell (HSC) self-renewal. In this manuscript, we demonstrate that p18 protein is a more potent inhibitor of HSC self-renewal than p27 in mouse models and its deficiency promoted HSC expansion in long-term culture. Single-cell analysis indicated that deleting p18 gene favoured self-renewing division of HSC in vitro. Based on the structure of p18 protein and in-silico screening, we further identified novel smallmolecule inhibitors that can specifically block the activity of p18 protein. Our selected lead compounds were able to expand functional HSCs in a short-term culture. Thus, these putative small-molecule inhibitors for p18 protein are valuable for further dissecting the signalling pathways of stem cell self-renewal and may help develop more effective chemical agents for therapeutic expansion of HSC.


The burden of adverse events during treatment of drug-resistant tuberculosis in Namibia.
Namibia faces a dual burden of HIV/AIDS and tuberculosis (TB). In 2010, HIV prevalence was 18.8%, the TB case notification rate was 634 cases per 100,000 population and the TB/HIV co-infection rate was 58%. There were 372 cases of drug-resistant TB (DR-TB) in 2009. The objective of this study was to assess the prevalence, profile and outcome of adverse events (AEs) associated with treatment of DR-TB and to explore possible influences of HIV disease on the occurrence of adverse events. This was a cross-sectional descriptive study. After ethical approval, data were collected from treatment records of all patients treated for DR-TB at the study facility between January 2008 and February 2010 using a structured data collection form. A total of 141 adverse events of varying severity were experienced in 90% (53/59) of patients.The TB/HIV co-infection rate was 53% (n=31). The prevalence of gastrointestinal tract adverse events (abdominal pains, constipation, diarrhea, nausea and vomiting) was 64%, tinnitus 45%, joint pain 28%and decreased hearing 25%. Abdominal pains, rash, nausea, decreased hearing and joint pain were more common in HIV infected than in HIV uninfected patients. Adverse events of varying severity are common during treatment of DR-TB, particularly in the intensive phase of therapy. Some adverse events were more prevalent in DR-TB patients co-infected with HIV. The study concludes that the characteristics and risk factors of serious adverse events should be further examined.


Effects of p47phox C terminus phosphorylations on binding interactions with p40phox and p67phox. Structural and functional comparison of p40phox and p67phox SH3 domains.
The neutrophil NADPH oxidase produces superoxide anions in response to infection. This reaction is activated by association of cytosolic factors, p47phox and p67phox, and a small G protein Rac with the membranous flavocytochrome b558. Another cytosolic factor, p40phox, is associated to the complex and is reported to play regulatory roles. Initiation of the NADPH oxidase activation cascade has been reported as consecutive to phosphorylation on serines 359/370 and 379 of the p47phox C terminus. These serines surround a polyproline motif that can interact with the Src homology 3 (SH3) module of p40phox (SH3p40) or the C-terminal SH3 of p67phox (C-SH3p67). The latter one presents a higher affinity in the resting state for p47phox. A change in SH3 binding preference following phosphorylation has been postulated earlier. Here we report the crystal structures of SH3p40 alone or in complex with a 12-residue proline-rich region of p47phox at 1.46 angstrom resolution. Using intrinsic tryptophan fluorescence measurements, we compared the affinity of the strict polyproline motif and the whole C terminus peptide with both SH3p40 and C-SH3p67. These data reveal that SH3p40 can interact with a consensus polyproline motif but also with a noncanonical motif of the p47phox C terminus. The electrostatic surfaces of both SH3 are very different, and therefore the binding preference for C-SH3p67 can be attributed to the polyproline motif recognition and particularly to the Arg-368p47 binding mode. The noncanonical motif contributes equally to interaction with both SH3. The influence of serine phosphorylation on residues 359/370 and 379 on the affinity for both SH3 domains has been checked. We conclude that contrarily to previous suggestions, phosphorylation of Ser-359/370 does not modify the SH3 binding affinity for both SH3, whereas phosphorylation of Ser-379 has a destabilizing effect on both interactions. Other mechanisms than a phosphorylation induced switch between the two SH3 must therefore take place for NADPH oxidase activation cascade to start.


T-cell responses in children to internal influenza antigens, 1 year after immunization with pandemic H1N1 influenza vaccine, and response to revaccination with seasonal trivalent-inactivated influenza vaccine.
During seasonal influenza epidemics, 5-15% of the population are affected with an illness having a nontrivial mortality, morbidity and economic burden. Inactivated influenza vaccines are routinely used to prevent influenza infection, primarily by inducing humoral immunity. In addition, trivalent-inactivated influenza vaccines have previously been shown to boost influenza-specific T-cell responses in a small percentage of adults. We investigate here the influenza-specific T-cell response, in children, 1 year after pandemic H1N1 vaccination and the ability to boost the T-cell response with trivalent-inactivated influenza immunization. Peripheral blood mononuclear cells (PBMCs) were isolated from children previously vaccinated with pandemic H1N1 vaccine, pre- and postseasonal 2010-2011 trivalent influenza vaccine (TIV) vaccination. Samples were analyzed by interferon-gamma enzyme-linked immunosorbent spot for reactogenicity toward internal influenza antigens (nucleoprotein, matrix protein 1 and nonstructural protein 1). Basal ex vivo T-cell responses to nucleoprotein, matrix protein 1 and nonstructural protein 1 measured by interferon-gamma enzyme-linked immunosorbent spot assay were significantly higher in those children who had previously received an AS03B-adjuvanted split virion pandemic vaccine 12 months earlier rather than a nonadjuvanted whole virion vaccine. Boosting of these responses, 21 days after 2010/2011 seasonal TIV vaccination was observed regardless of age or prior pandemic vaccination regime, although boosting was greater in those groups with the lowest initial response. We show here that children previously vaccinated with the 2009 pandemic H1N1 vaccine have measurable T-cell responses 1 year after vaccination. The magnitudes of these responses are dependent on both age of vaccine and type of pandemic H1N1 vaccine used. After 2010/2011 seasonal TIV vaccination, these T-cell responses undergo a small but significant boost.


Feature-based attentional weighting and spreading in visual working memory.
Attention can be directed at features and feature dimensions to facilitate perception. Here, we investigated whether feature-based-attention (FBA) can also dynamically weight feature-specific representations within multi-feature objects held in visual working memory (VWM). Across three experiments, participants retained coloured arrows in working memory and, during the delay, were cued to either the colour or the orientation dimension. We show that directing attention towards a feature dimension (1) improves the performance in the cued feature dimension at the expense of the uncued dimension, (2) is more efficient if directed to the same rather than to different dimensions for different objects, and (3) at least for colour, automatically spreads to the colour representation of non-attended objects in VWM. We conclude that FBA also continues to operate on VWM representations (with similar principles that govern FBA in the perceptual domain) and challenge the classical view that VWM representations are stored solely as integrated objects.


A randomized, placebo-controlled trial of acupuncture in patients with chronic obstructive pulmonary disease (COPD): the COPD-acupuncture trial (CAT).
Dyspnea on exertion (DOE) is a major symptom of chronic obstructive pulmonary disease (COPD) and is difficult to control. This study was performed to determine whether acupuncture is superior to placebo needling in improving DOE in patients with COPD who are receiving standard medication. Sixty-eight of 111 patients from the Kansai region of Japan who were diagnosed as having COPD and were receiving standard medication participated in a randomized, parallel-group, placebo-controlled trial (July 1, 2006, through March 31, 2009) in which the patients, evaluators, and statistician were unaware of the random allocation. Participants were randomly assigned to traditional acupuncture (real acupuncture group, n=34) or placebo needling (placebo acupuncture group, n=34). Both groups received real or placebo needling at the same acupoints once a week for 12 weeks. The primary end point was the modified Borg scale score evaluated immediately after the 6-minute walk test. Measurements were obtained at baseline and after 12 weeks of treatment. After 12 weeks, the Borg scale score after the 6-minute walk test was significantly better in the real acupuncture group compared with the placebo acupuncture group (mean [SD] difference from baseline by analysis of covariance, -3.6 [1.9] vs 0.4 [1.2]; mean difference between groups by analysis of covariance, -3.58; 95% CI, -4.27 to -2.90). Patients with COPD who received real acupuncture also experienced improvement in the 6-minute walk distance during exercise, indicating better exercise tolerance and reduced DOE. This study clearly demonstrates that acupuncture is a useful adjunctive therapy in reducing DOE in patients with COPD. umin.ac.jp/ctr Identifier: UMIN000001277.


Comparison of MRI and CT for detection of acute intracerebral hemorrhage.
Noncontrast computed tomography (CT) is the standard brain imaging study for the initial evaluation of patients with acute stroke symptoms. Multimodal magnetic resonance imaging (MRI) has been proposed as an alternative to CT in the emergency stroke setting. However, the accuracy of MRI relative to CT for the detection of hyperacute intracerebral hemorrhage has not been demonstrated. To compare the accuracy of MRI and CT for detection of acute intracerebral hemorrhage in patients presenting with acute focal stroke symptoms. A prospective, multicenter study was performed at 2 stroke centers (UCLA Medical Center and Suburban Hospital, Bethesda, Md), between October 2000 and February 2003. Patients presenting with focal stroke symptoms within 6 hours of onset underwent brain MRI followed by noncontrast CT. Acute intracerebral hemorrhage and any intracerebral hemorrhage diagnosed on gradient recalled echo (GRE) MRI and CT scans by a consensus of 4 blinded readers. The study was stopped early, after 200 patients were enrolled, when it became apparent at the time of an unplanned interim analysis that MRI was detecting cases of hemorrhagic transformation not detected by CT. For the diagnosis of any hemorrhage, MRI was positive in 71 patients with CT positive in 29 (P<.001). For the diagnosis of acute hemorrhage, MRI and CT were equivalent (96% concordance). Acute hemorrhage was diagnosed in 25 patients on both MRI and CT. In 4 other patients, acute hemorrhage was present on MRI but not on the corresponding CT--each of these 4 cases was interpreted as hemorrhagic transformation of an ischemic infarct. In 3 patients, regions interpreted as acute hemorrhage on CT were interpreted as chronic hemorrhage on MRI. In 1 patient, subarachnoid hemorrhage was diagnosed on CT but not on MRI. In 49 patients, chronic hemorrhage, most often microbleeds, was visualized on MRI but not on CT. MRI may be as accurate as CT for the detection of acute hemorrhage in patients presenting with acute focal stroke symptoms and is more accurate than CT for the detection of chronic intracerebral hemorrhage.


Rethinking HIV exceptionalism: the ethics of opt-out HIV testing in sub-Saharan Africa.
Opt-out testing for the human immunodeficiency virus (HIV) incorporates testing as a routine part of health care for all patients unless they refuse. The ethics of this approach to testing in sub-Saharan Africa is a source of controversy. Opt-out HIV testing is expected to improve survival by increasing case detection and thus linking more HIV-infected people to earlier treatment, provided there is effective patient follow-up and programme sustainability. At the population level, these benefits will likely outweigh the potential negative consequences of individuals experiencing HIV-related stigma. These justifications appeal to consequentialist moral theories that the acceptability of an action depends upon its outcomes. On the other hand, liberal moral theories state that the autonomy of individuals should always be protected unless restricting autonomy is necessary to protect the welfare of others. Opt-out consent may restrict autonomy and it is unclear whether it would benefit people other than those being tested. Yet, the doctrine of libertarian paternalism proposes that it is justifiable and desirable to use unobtrusive mechanisms to help individuals make choices to maximize their own welfare. Central to this idea are the premises featured by supporters of opt-out consent that individuals will not always make the best choices for their own welfare but they may be influenced to do so in ways that will not compromise their freedom of choice. Also important is the premise that all policies inevitably exert some such influence: opt-in consent encourages test refusal just as opt-out consent encourages acceptance. Based on these premises, opt-out testing may be an effective and ethically acceptable policy response to Africa's HIV epidemic.


Consent and community engagement in diverse research contexts.
Consent and community engagement (CE) in health research are two aspects of a single concern-that research is carried out in a respectful manner where social value is maximized. There are important overlaps and interdependencies between consent and CE; for example, CE can provide insights into how best to tailor consent to context and can be an important component of consent processes. Engaging communities can also have intrinsic and instrumental value beyond consent; for example, as a means of showing respect and identifying appropriate ways of working respectfully. In this paper we critically examine how CE and consent processes are characterized, conducted, and evaluated in diverse health research contexts, and propose a preliminary research agenda to support future learning in these critical areas.


The effect of antihypertensive treatment on headache and blood pressure variability in randomized controlled trials: a systematic review.
Antihypertensive drugs reduce headache but it is unclear whether there are differences between drug classes. Calcium channel blockers (CCBs) decrease variability in systolic blood pressure (SBPV) and stroke risk more than other classes, possibly due to decreased vascular tone. If so, there might be a correlation between drug-class effects on variability in SBP and on headache. We determined antihypertensive class effects on SBPV and headache during follow-up in a systematic review of randomized controlled trials. We determined pooled estimates of treatment effect on group variability in BP (variance ratio, VR) and on the odds ratio for headache (OR) by random-effects meta-analysis. Antihypertensive drugs reduced the incidence of headache compared to placebo (OR = 0.75, 95% CI 0.69-0.82, p < 0.0001, 198 comparisons, 43,672 patients), but there was significant heterogeneity between drug classes (p = 0.0007) with a greater effect of beta-blockers compared to placebo (VR = 0.49, 0.33-0.68, p < 0.0001, 16 trials) or all other drug classes (OR = 0.73, 0.62-0.85, p = 0.0002, 49 trials) and a lack of effectiveness of CCBs (vs. placebo-OR = 0.95, 0.79-1.15, 65 trials; vs. other drugs-OR = 1.19, 1.05-1.35, p = 0.009, 101 trials). Drug-class effects on headache were opposite to effects on variability in SBP (vs. other drugs: CCB-VR = 0.81, 0.71-0.85, p < 0.0001; beta-blocker VR = 1.17, 1.07-1.28, p < 0.0001), but were unrelated to differences in mean SBP. Antihypertensive drugs reduce headache but the effect differs between classes, corresponding to their effects on SBPV and the risk of stroke. This may partly be explained by consistent antihypertensive class effects on vascular tone in the peripheral (variability) and cerebrovascular circulations (headache).


Nudging Immunity: The Case for Vaccinating Children in School and Day Care by Default.
Many parents are hesitant about, or face motivational barriers to, vaccinating their children. In this paper, we propose a type of vaccination policy that could be implemented either in addition to coercive vaccination or as an alternative to it in order to increase paediatric vaccination uptake in a non-coercive way. We propose the use of vaccination nudges that exploit the very same decision biases that often undermine vaccination uptake. In particular, we propose a policy under which children would be vaccinated at school or day-care by default, without requiring parental authorization, but with parents retaining the right to opt their children out of vaccination. We show that such a policy is (1) likely to be effective, at least in cases in which non-vaccination is due to practical obstacles, rather than to strong beliefs about vaccines, (2) ethically acceptable and less controversial than some alternatives because it is not coercive and affects individual autonomy only in a morally unproblematic way, and (3) likely to receive support from the UK public, on the basis of original empirical research we have conducted on the lay public.


Genome-wide enrichment analysis between endometriosis and obesity-related traits reveals novel susceptibility loci.
Endometriosis is a chronic inflammatory condition in women that results in pelvic pain and subfertility, and has been associated with decreased body mass index (BMI). Genetic variants contributing to the heritable component have started to emerge from genome-wide association studies (GWAS), although the majority remain unknown. Unexpectedly, we observed an intergenic locus on 7p15.2 that was genome-wide significantly associated with both endometriosis and fat distribution (waist-to-hip ratio adjusted for BMI; WHRadjBMI) in an independent meta-GWAS of European ancestry individuals. This led us to investigate the potential overlap in genetic variants underlying the aetiology of endometriosis, WHRadjBMI and BMI using GWAS data. Our analyses demonstrated significant enrichment of common variants between fat distribution and endometriosis (P = 3.7 × 10(-3)), which was stronger when we restricted the investigation to more severe (Stage B) cases (P = 4.5 × 10(-4)). However, no genetic enrichment was observed between endometriosis and BMI (P = 0.79). In addition to 7p15.2, we identify four more variants with statistically significant evidence of involvement in both endometriosis and WHRadjBMI (in/near KIFAP3, CAB39L, WNT4, GRB14); two of these, KIFAP3 and CAB39L, are novel associations for both traits. KIFAP3, WNT4 and 7p15.2 are associated with the WNT signalling pathway; formal pathway analysis confirmed a statistically significant (P = 6.41 × 10(-4)) overrepresentation of shared associations in developmental processes/WNT signalling between the two traits. Our results demonstrate an example of potential biological pleiotropy that was hitherto unknown, and represent an opportunity for functional follow-up of loci and further cross-phenotype comparisons to assess how fat distribution and endometriosis pathogenesis research fields can inform each other.


CATALISE: A Multinational and Multidisciplinary Delphi Consensus Study. Identifying Language Impairments in Children.
Delayed or impaired language development is a common developmental concern, yet there is little agreement about the criteria used to identify and classify language impairments in children. Children's language difficulties are at the interface between education, medicine and the allied professions, who may all adopt different approaches to conceptualising them. Our goal in this study was to use an online Delphi technique to see whether it was possible to achieve consensus among professionals on appropriate criteria for identifying children who might benefit from specialist services. We recruited a panel of 59 experts representing ten disciplines (including education, psychology, speech-language therapy/pathology, paediatrics and child psychiatry) from English-speaking countries (Australia, Canada, Ireland, New Zealand, United Kingdom and USA). The starting point for round 1 was a set of 46 statements based on articles and commentaries in a special issue of a journal focusing on this topic. Panel members rated each statement for both relevance and validity on a seven-point scale, and added free text comments. These responses were synthesised by the first two authors, who then removed, combined or modified items with a view to improving consensus. The resulting set of statements was returned to the panel for a second evaluation (round 2). Consensus (percentage reporting 'agree' or 'strongly agree') was at least 80 percent for 24 of 27 round 2 statements, though many respondents qualified their response with written comments. These were again synthesised by the first two authors. The resulting consensus statement is reported here, with additional summary of relevant evidence, and a concluding commentary on residual disagreements and gaps in the evidence base.


Orienting attention to locations in mental representations.
Many cognitive processes depend on our ability to hold information in mind, often well beyond the offset of the original sensory input. The capacity of this visual short-term memory (VSTM) is limited to around three to four items. Recent research has demonstrated that the content of VSTM can be modulated by top-down attentional biases. This has been demonstrated using retrodictive spatial cues, termed "retro-cues," which orient subjects' attention to spatial locations within VSTM. In the present article, we tested whether the use of these cues is modulated by memory load and cue delay. There are a number of important conclusions: (1) Top-down biases can operate on very brief iconic traces as well as on older VSTM representations (Exp. 1). (2) When operating within capacity, subjects use the cue to prioritise where they initiate their memory search, rather than to discard uncued items (Exps. 2 and 3). (3) When capacity is exceeded, there is little benefit to top-down biasing relative to a neutral condition; however, unattended items are lost, with there being a substantial cost of invalid spatial cueing (Exp. 3). (4) These costs and benefits of orienting spatial attention differ across iconic memory and VSTM representations when VSTM capacity is exceeded (Exp. 4).


A systematic review of xuezhikang, an extract from red yeast rice, for coronary heart disease complicated by dyslipidemia.
Objective. This systematic review aims to evaluate the benefit and side effect of Xuezhikang for coronary heart disease (CHD) complicated by dyslipidemia. Methods. All randomized clinical trials (RCTs) with Xuezhikang as a treatment for CHD combined with dyslipidemia were considered for inclusion. Data extraction and analyses and quality assessment were conducted according to the Cochrane standards. Results. We included 22 randomized trials. Xuezhikang showed significant benefit on the incidence of all-cause deaths, CHD deaths, myocardial infarction, and revascularization as compared with placebo based on conventional treatment for CHD. It remarkably lowered total cholesterol (TC), triglyceride (TG), and low-density lipoprotein-cholesterol (LDL-C) as compared with the placebo or inositol nicotinate group, which was similar to statins group. Xuezhikang also raised high-density lipoprotein cholesterol (HDL-C) compared to placebo or no intervention, which was similar to Inositol nicotinate and slightly inferior to statins. The incidence of adverse events did not differ between the Xuezhikang and control group. Conclusions. Xuezhikang showed a comprehensive lipid-regulating effect and was safe and effective in reducing cardiovascular events in CHD patients complicated by dyslipidemia. However, more rigorous trials with high quality are needed to give high level of evidence.


Usefulness of vegetarian and vegan diets for treating type 2 diabetes.
Significant benefits for diabetes prevention and management have been observed with vegetarian and especially vegan diets. This article reviews observational studies and intervention trials on such diets, and discusses their efficacy, nutritional adequacy, acceptability, and sustainability. Research to date has demonstrated that a low-fat, plant-based nutritional approach improves control of weight, glycemia, and cardiovascular risk. These studies have also shown that carefully planned vegan diets can be more nutritious than diets based on more conventional diet guidelines, with an acceptability that is comparable with that of other therapeutic regimens. Current intervention guidelines from professional organizations offer support for this approach. Vegetarian and vegan diets present potential advantages in managing type 2 diabetes that merit the attention of individuals with diabetes and their caregivers.


Pomegranate juice consumption for 3 years by patients with carotid artery stenosis reduces common carotid intima-media thickness, blood pressure and LDL oxidation.
Dietary supplementation with polyphenolic antioxidants to animals was shown to be associated with inhibition of LDL oxidation and macrophage foam cell formation, and attenuation of atherosclerosis development. We investigated the effects of pomegranate juice (PJ, which contains potent tannins and anthocyanins) consumption by atherosclerotic patients with carotid artery stenosis (CAS) on the progression of carotid lesions and changes in oxidative stress and blood pressure. Ten patients were supplemented with PJ for 1 year and five of them continued for up to 3 years. Blood samples were collected before treatment and during PJ consumption. In the control group that did not consume PJ, common carotid intima-media thickness (IMT) increased by 9% during 1 year, whereas, PJ consumption resulted in a significant IMT reduction, by up to 30%, after 1 year. The patients' serum paraoxonase 1 (PON 1) activity was increased by 83%, whereas serum LDL basal oxidative state and LDL susceptibility to copper ion-induced oxidation were both significantly reduced, by 90% and 59%, respectively, after 12 months of PJ consumption, compared to values obtained before PJ consumption. Furthermore, serum levels of antibodies against oxidized LDL were decreased by 19%, and in parallel serum total antioxidant status (TAS) was increased by 130% after 1 year of PJ consumption. Systolic blood pressure was reduced after 1 year of PJ consumption by 12% [corrected] and was not further reduced along 3 years of PJ consumption. For all studied parameters, the maximal effects were observed after 1 year of PJ consumption. Further consumption of PJ, for up to 3 years, had no additional beneficial effects on IMT and serum PON1 activity, whereas serum lipid peroxidation was further reduced by up to 16% after 3 years of PJ consumption. The results of the present study thus suggest that PJ consumption by patients with CAS decreases carotid IMT and systolic blood pressure and these effects could be related to the potent antioxidant characteristics of PJ polyphenols.


Expression of mutant Sftpc in murine alveolar epithelia drives spontaneous lung fibrosis.
Epithelial cell dysfunction is postulated as an important component in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Mutations in the surfactant protein C (SP-C) gene (SFTPC), an alveolar type II (AT2) cell-restricted protein, have been found in sporadic and familial IPF. To causally link these events, we developed a knockin mouse model capable of regulated expression of an IPF-associated isoleucine-to-threonine substitution at codon 73 (I73T) in Sftpc (SP-CI73T). Tamoxifen-treated SP-CI73T cohorts developed rapid increases in SftpcI73T mRNA and misprocessed proSP-CI73T protein accompanied by increased early mortality (days 7-14). This acute phase was marked by diffuse parenchymal lung injury, tissue infiltration by monocytes, polycellular alveolitis, and elevations in bronchoalveolar lavage and AT2 mRNA content of select inflammatory cytokines. Resolution of alveolitis (2-4 weeks), commensurate with a rise in TGF-β1, was followed by aberrant remodeling marked by collagen deposition, AT2 cell hyperplasia, α-smooth muscle actin-positive (α-SMA-positive) cells, and restrictive lung physiology. The translational relevance of the model was supported by detection of multiple IPF biomarkers previously reported in human cohorts. These data provide proof of principle that mutant SP-C expression in vivo causes spontaneous lung fibrosis, strengthening the role of AT2 cell dysfunction as a key upstream driver of IPF pathogenesis.


Adsorbate-induced lifting of substrate relaxation is a general mechanism governing titania surface chemistry.
Under ambient conditions, almost all metals are coated by an oxide. These coatings, the result of a chemical reaction, are not passive. Many of them bind, activate and modify adsorbed molecules, processes that are exploited, for example, in heterogeneous catalysis and photochemistry. Here we report an effect of general importance that governs the bonding, structure formation and dissociation of molecules on oxidic substrates. For a specific example, methanol adsorbed on the rutile TiO2(110) single crystal surface, we demonstrate by using a combination of experimental and theoretical techniques that strongly bonding adsorbates can lift surface relaxations beyond their adsorption site, which leads to a significant substrate-mediated interaction between adsorbates. The result is a complex superstructure consisting of pairs of methanol molecules and unoccupied adsorption sites. Infrared spectroscopy reveals that the paired methanol molecules remain intact and do not deprotonate on the defect-free terraces of the rutile TiO2(110) surface.


Prioritizing Information during Working Memory: Beyond Sustained Internal Attention.
Working memory (WM) has limited capacity. This leaves attention with the important role of allowing into storage only the most relevant information. It is increasingly evident that attention is equally crucial for prioritizing representations within WM as the importance of individual items changes. Retrospective prioritization has been proposed to result from a focus of internal attention highlighting one of several representations. Here, we suggest an updated model, in which prioritization acts in multiple steps: first orienting towards and selecting a memory, and then reconfiguring its representational state in the service of upcoming task demands. Reconfiguration sets up an optimized perception-action mapping, obviating the need for sustained attention. This view is consistent with recent literature, makes testable predictions, and links WM with task switching and action preparation.


The benefits of using patient-based methods of assessment. Medium-term results of an observational study of shoulder surgery.
We carried out a prospective study of 93 patients undergoing surgery for conditions of the rotator cuff during 1994 and 1995. They were assessed before operation and after six months, and four years, using the patient-based Oxford Shoulder Score (OSS), the SF-36 questionnaire and the Constant shoulder score. The response rates were higher for the OSS and SF-36. The correlation coefficients were high (r > 0.5) between all scores at each stage of the study. While all scores improved substantially at six months, the Constant score was reduced significantly at four years. This did not correlate with the patients' judgement of the change in symptoms or of the success of the operation. Our study suggests that patient-based measures of pain and function can reliably assess outcomes in the medium term after surgery to the shoulder.


Noninvasive disconnection of targeted neuronal circuitry sparing axons of passage and nonneuronal cells.
Surgery can be highly effective for the treatment of medically intractable, neurological disorders, such as drug-resistant focal epilepsy. However, despite its benefits, surgery remains substantially underutilized due to both surgical concerns and nonsurgical impediments. In this work, the authors characterized a noninvasive, nonablative strategy to focally destroy neurons in the brain parenchyma with the goal of limiting collateral damage to nontarget structures, such as axons of passage. Low-intensity MR-guided focused ultrasound (MRgFUS), together with intravenous microbubbles, was used to open the blood-brain barrier (BBB) in a transient and focal manner in rats. The period of BBB opening was exploited to focally deliver to the brain parenchyma a systemically administered neurotoxin (quinolinic acid) that is well tolerated peripherally and otherwise impermeable to the BBB. Focal neuronal loss was observed in targeted areas of BBB opening, including brain regions that are prime objectives for epilepsy surgery. Notably, other structures in the area of neuronal loss, including axons of passage, glial cells, vasculature, and the ventricular wall, were spared with this procedure. These findings identify a noninvasive, nonablative approach capable of disconnecting neural circuitry while limiting the neuropathological consequences that attend other surgical procedures. Moreover, this strategy allows conformal targeting, which could enhance the precision and expand the treatment envelope for treating irregularly shaped surgical objectives located in difficult-to-reach sites. Finally, if this strategy translates to the clinic, the noninvasive nature and specificity of the procedure could positively influence both physician referrals for and patient confidence in surgery for medically intractable neurological disorders.


Shape-specific preparatory activity mediates attention to targets in human visual cortex.
The mechanisms of attention prioritize sensory input for efficient perceptual processing. Influential theories suggest that attentional biases are mediated via preparatory activation of task-relevant perceptual representations in visual cortex, but the neural evidence for a preparatory coding model of attention remains incomplete. In this experiment, we tested core assumptions underlying a preparatory coding model for attentional bias. Exploiting multivoxel pattern analysis of functional neuroimaging data obtained during a non-spatial attention task, we examined the locus, time-course, and functional significance of shape-specific preparatory attention in the human brain. Following an attentional cue, yet before the onset of a visual target, we observed selective activation of target-specific neural subpopulations within shape-processing visual cortex (lateral occipital complex). Target-specific modulation of baseline activity was sustained throughout the duration of the attention trial and the degree of target specificity that characterized preparatory activation patterns correlated with perceptual performance. We conclude that top-down attention selectively activates target-specific neural codes, providing a competitive bias favoring task-relevant representations over competing representations distributed within the same subregion of visual cortex.


Beta-oestradiol rescues DeltaF508CFTR functional expression in human cystic fibrosis airway CFBE41o- cells through the up-regulation of NHERF1.
CF (cystic fibrosis) is a disease caused by mutations within the CFTR (CF transmembrane conductance regulator) gene. The most common mutation, DeltaF508 (deletion of Phe-508), results in a protein that is defective in folding and trafficking to the cell surface but is functional if properly localized in the plasma membrane. We have recently demonstrated that overexpression of the PDZ protein NHERF1 (Na(+)/H(+)-exchanger regulatory factor 1) in CF airway cells induced both a redistribution of DeltaF508CFTR from the cytoplasm to the apical membrane and the PKA (protein kinase A)-dependent activation of DeltaF508CFTR-dependent chloride secretion. In view of the potential importance of the targeted up-regulation of NHERF1 in a therapeutic context, and since it has been demonstrated that oestrogen treatment increases endogenous NHERF1 expression, we tested the hypothesis that oestrogen treatment can increase NHERF1 expression in a human bronchiolar epithelial CF cell line, CFBE41o(-), with subsequent rescue of apical DeltaF508CFTR chloride transport activity. We found that CFBE41o(-) cells do express ERs (oestrogen receptors) in the nuclear fraction and that beta-oestradiol treatment was able to significantly rescue DeltaF508CFTR-dependent chloride secretion in CFBE41o(-) cell monolayers with a peak between 6 and 12 h of treatment, demonstrating that the DeltaF508CFTR translocated to the apical membrane can function as a cAMP-responsive channel, with a significant increase in chloride secretion noted at 1 nM beta-oestradiol and a maximal effect observed at 10 nM. Importantly, knock-down of NHERF1 expression by transfection with siRNA (small interfering RNA) for NHERF1 inhibited the beta-oestradiol-dependent increase in DeltaF508CFTR protein expression levels and completely prevented the beta-oestradiol-dependent rescue of DeltaF508CFTR transport activity. These results demonstrate that beta-oestradiol-dependent up-regulation of NHERF1 significantly increases DeltaF508CFTR functional expression in CFBE41o(-) cells.


Negative epistasis between the malaria-protective effects of alpha+-thalassemia and the sickle cell trait.
The hemoglobinopathies, disorders of hemoglobin structure and production, protect against death from malaria. In sub-Saharan Africa, two such conditions occur at particularly high frequencies: presence of the structural variant hemoglobin S and alpha(+)-thalassemia, a condition characterized by reduced production of the normal alpha-globin component of hemoglobin. Individually, each is protective against severe Plasmodium falciparum malaria, but little is known about their malaria-protective effects when inherited in combination. We investigated this question by studying a population on the coast of Kenya and found that the protection afforded by each condition inherited alone was lost when the two conditions were inherited together, to such a degree that the incidence of both uncomplicated and severe P. falciparum malaria was close to baseline in children heterozygous with respect to the mutation underlying the hemoglobin S variant and homozygous with respect to the mutation underlying alpha(+)-thalassemia. Negative epistasis could explain the failure of alpha(+)-thalassemia to reach fixation in any population in sub-Saharan Africa.


Perceptual switch rates with ambiguous structure-from-motion figures in bipolar disorder.
Slowing of the rate at which a rivalrous percept switches from one configuration to another has been suggested as a potential trait marker for bipolar disorder. We measured perceptual alternations for a bistable, rotating, structure-from-motion cylinder in bipolar and control participants. In a control task, binocular depth rendered the direction of cylinder rotation unambiguous to monitor participants' performance and attention during the experimental task. A particular direction of rotation was perceptually stable, on average, for 33.5s in participants without psychiatric diagnosis. Euthymic, bipolar participants showed a slightly slower rate of switching between the two percepts (percept duration 42.3s). Under a parametric analysis of the best-fitting model for individual participants, this difference was statistically significant. However, the variability within groups was high, so this difference in average switch rates was not big enough to serve as a trait marker for bipolar disorder. We also found that low-level visual capacities, such as stereo threshold, influence perceptual switch rates. We suggest that there is no single brain location responsible for perceptual switching in all different ambiguous figures and that perceptual switching is generated by the actions of local cortical circuitry.


Y-chromosome distributions among populations in Northwest China identify significant contribution from Central Asian pastoralists and lesser influence of western Eurasians.
Northwest China is closely adjacent to Central Asia, an intermediate region of the Eurasian continent. Moreover, the Silk Road through the northwest of China once had a vital role in the east-west intercommunications. Nevertheless, little has been known about the genetic makeup of populations in this region. We collected 503 male samples from 14 ethnic groups in the northwest of China, and surveyed 29 Y-chromosomal biallelic markers and 8 short tandem repeats (STRs) loci to reconstruct the paternal architecture. Our results illustrated obvious genetic difference among these ethnic groups, and in general their genetic background is more similar with Central Asians than with East Asians. The ancestors of present northwestern populations were the admixture of early East Asians peopling northwestward and later Central Asians immigrating eastward. This population mixture was dated to occur within the past 10 000 years. The J2-M172 lineages likely entered China during the eastward migration of Central Asians. The influence from West Eurasia through gene flows on the extant ethnic groups in Northwest China was relatively weak.


Peripheral pre-synaptic pathway reduces the heart rate response to sympathetic activation following exercise training: role of NO.
We tested the hypothesis that the attenuated heart rate (HR) response to sympathetic activation following swim training in the guinea pig (Cavia porcellus) results from a peripheral modulation of pacemaking by nitric oxide (NO). Nitric oxide synthase (NOS) inhibition on the increase in heart rate with sympathetic nerve stimulation (SNS) was investigated in the isolated guinea pig double atrial/right stellate ganglion preparation from exercise trained (6-weeks swimming, n=20) and sedentary animals (n=20). Western blot analysis for neuronal nitric oxide synthase (nNOS) was performed on the stellate ganglion from both groups. Relative to the control group, the exercise group demonstrated typical exercise adaptations of increased ventricular weight/body weight ratio, enhanced skeletal muscle citrate synthase activity and higher concentrations of [3H]ouabain binding sites in both skeletal and cardiac tissue (P<0.05). The increase in heart rate (bpm) with SNS significantly decreased in the exercise group (n=16) compared to the sedentary group (n=16) from 30+/-5 to 17+/-3 bpm at 1 Hz; 67+/-7 to 47+/-4 bpm at 3 Hz; 85+/-9 to 63+/-4 bpm at 5 Hz and 101+/-9 to 78+/-5 bpm at 7 Hz stimulation (P<0.05). The increase in heart rate with cumulative doses (0.1-10 microM) or a single dose (0.1 microM) of bath-applied norepinephrine expressed as the effective doses at which the HR response was 50% of the maximum response (EC50) were similar in both exercise (EC50 -6.08+/-0.16 M, n=8) and sedentary groups (EC50 -6.18+/-0.07 M, n=7). Trained animals had significantly more nNOS protein in left stellate ganglion compared to the sedentary group. In the exercise group, the non-isoform selective NOS inhibitor, N-omega nitro-L-arginine (L-NA, 100 microM) caused a small but significant increase in the heart rate response to SNS. However, the positive chronotropic response to sympathetic nerve stimulation remained significantly attenuated in the exercise group compared to the sedentary group during NOS inhibition (P<0.05). Our results indicate that there is a significant peripheral pre-synaptic component reducing the HR response to sympathetic activation following training, although NO does not play a dominant role in this response.


Obese subjects show sex-specific differences in right ventricular hypertrophy.
As right ventricular (RV) remodeling in obesity remains underinvestigated, and the impact of left ventricular (LV) diastolic dysfunction on RV hypertrophy is unknown, we aimed to investigate whether (1) sex-specific patterns of RV remodeling exist in obesity and (2) LV diastolic dysfunction in obesity is related to RV hypertrophy. Seven hundred thirty-nine subjects (women, n=345; men, n=394) without identifiable cardiovascular risk factors (body mass index [BMI], 15.3-59.2 kg/m2) underwent cardiovascular magnetic resonance (1.5 T) to measure RV mass (g), RV end-diastolic volume (mL), RV mass/volume ratio, and LV diastolic peak filling rate (mL/s). All subjects were normotensive (average, 119±11/73±8 mm Hg), normoglycaemic (4.8±0.5 mmol/L), and normocholesterolaemic (4.8±0.9 mmol/L) at the time of scanning. Across both sexes, there was a moderately strong positive correlation between BMI and RV mass (men, +0.8 g per BMI point increase; women, +1.0 g per BMI point increase; both P<0.001). Whereas women exhibited RV cavity dilatation (RV end-diastolic volume, +1.0 mL per BMI point increase; P<0.001), BMI was not correlated with RV end-diastolic volume in men (R=0.04; P=0.51). Concentric RV remodeling was present in both sexes, with RV mass/volume ratio being positively correlated to BMI (men, R=0.41; women, R=0.51; both P<0.001). Irrespective of sex, the LV peak filling rate was negatively correlated with both RV mass (men, R=-0.43; women, R=-0.44; both P<0.001) and RV mass/volume ratio (men, R=-0.37; women, R=-0.35; both P<0.001). A sex difference in RV remodeling exists in obesity. Whereas men exhibit concentric RV remodeling, women exhibit a mixed pattern of eccentric and concentric remodeling. Regardless of sex, reduced LV diastolic function is associated with concentric RV remodeling.


Analgesic effects of mad honey (grayanotoxin) in mice models of acute pain and painful diabetic neuropathy.
The aim of this experimental study was to investigate the effects of mad honey (grayanotoxin, GTX), used in complementary medicine for a variety of purposes besides being food, on pain thresholds in normal mice as model for acute pain and diabetic mouse as model for neuropathic pain. Hind paw withdrawal pain threshold to thermal stimulus was measured with a plantar analgesia meter in a mice model using healthy intact animals for acute pain and streptozotocin-induced diabetic animals for chronic neuropathic pain. Time and dose-dependent effects of intraperitoneally (i.p.) administered GTX were investigated in both acute and neuropathic pain. In the acute pain model, administration of GTX caused a dose- and time-dependent marked increase in the pain latency values. In diabetic mice, which had markedly increased threshold to pain, GTX (0.1 mg/kg, i.p.) restored the mean pain latencies by decreasing from the pre-GTX treatment values of 3.2 ± 0.6 to 3.0 ± 0.9s at 10 min, 3.2 ± 0.6s at 20 min, 3.4 ± 0.6s at 30 min, 2.6 ± 0.5s at 60 min and 2.4 ± 0.6s (p < 0.05) at 100 min. The results from this experimental study indicate that GTX exhibits significant analgesic activity and has potential benefits against painful diabetic neuropathy. This is compatible with the widespread use of GTX containing mad honey for alleviating pain. Further studies involving long-term applications are needed for a more decisive conclusion regarding the usefulness of GTX as an analgesic, especially in the treatment of painful neuropathy.


Robotic multiwell planar patch-clamp for native and primary mammalian cells.
Robotic multiwell planar patch-clamp has become common in drug development and safety programs because it enables efficient and systematic testing of compounds against ion channels during voltage-clamp. It has not, however, been adopted significantly in other important areas of ion channel research, where conventional patch-clamp remains the favored method. Here, we show the wider potential of the multiwell approach with the ability for efficient intracellular solution exchange, describing protocols and success rates for recording from a range of native and primary mammalian cells derived from blood vessels, arthritic joints and the immune and central nervous systems. The protocol involves preparing a suspension of single cells to be dispensed robotically into 4-8 microfluidic chambers each containing a glass chip with a small aperture. Under automated control, giga-seals and whole-cell access are achieved followed by preprogrammed routines of voltage paradigms and fast extracellular or intracellular solution exchange. Recording from 48 chambers usually takes 1-6 h depending on the experimental design and yields 16-33 cell recordings.


Scaffold Generator: a Java library implementing molecular scaffold functionalities in the Chemistry Development Kit (CDK).
The concept of molecular scaffolds as defining core structures of organic molecules is utilised in many areas of chemistry and cheminformatics, e.g. drug design, chemical classification, or the analysis of high-throughput screening data. Here, we present Scaffold Generator, a comprehensive open library for the generation, handling, and display of molecular scaffolds, scaffold trees and networks. The new library is based on the Chemistry Development Kit (CDK) and highly customisable through multiple settings, e.g. five different structural framework definitions are available. For display of scaffold hierarchies, the open GraphStream Java library is utilised. Performance snapshots with natural products (NP) from the COCONUT (COlleCtion of Open Natural prodUcTs) database and drug molecules from DrugBank are reported. The generation of a scaffold network from more than 450,000 NP can be achieved within a single day.


Waiting times in the ambulatory sector--the case of chronically ill patients.
First, the influence of determinants on the waiting times of chronically ill patients in the ambulatory sector is investigated. The determinants are subdivided into four groups: (1) need, (2) socio-economic factors, (3) health system and (4) patient time pressures. Next, the influence of waiting times on the annual number of consultations is examined to assess whether the existing variation in waiting times influences the frequency of medical examinations. The waiting times of chronically ill patients are analysed since regular ambulatory care for this patient group could both improve treatment outcomes and lower costs. Individual data from the 2010 Representative Survey conducted by the National Association of Statutory Health Insurance Physicians (KBV) together with regional data from the Federal Office of Construction and Regional Planning. This is a retrospective observational study. The dependent variables are waiting times in the ambulatory sector and the number of consultations of General Practitioners (GPs) and specialist physicians in the year 2010. The explanatory variables of interest are 'need' and 'health system' in the first model and 'length of waiting times' in the second. Negative binomial models with random effects are used to estimate the incidence rate ratios of increased waiting times and number of consultations. Subsequently, the models are stratified by urban and rural areas. In the pooled regression the factor 'privately insured' shortens the waiting time for treatment by a specialist by approximately 28% (about 3 days) in comparison with members of the statutory health insurance system. The category of insurance has no influence on the number of consultations of GPs. In addition, the regression results stratified by urban and rural areas show that in urban areas the factor 'privately insured' reduces the waiting time for specialists by approximately 35% (about 3.3 days) while in rural areas there is no evidence of statistical influence. In neither of the models, however, does the waiting time have a documentable effect on the number of consultations in the ambulatory sector. In our random sample, characteristics of the health care system have an influence on the waiting time for specialists, but the waiting time has no documentable effect on the number of consultations in the ambulatory sector. In the present analysis this applies to consultations of both GPs and specialists. Nevertheless, it does not rule out the possibility that the length of waiting times might influence the treatment outcomes of certain patient populations.


Long-term effect of neuronal nitric oxide synthase over-expression on cardiac neurotransmission mediated by a lentiviral vector.
Short-term over-expression of neuronal nitric oxide synthase (nNOS) with adenoviral gene transfer into peripheral cardiac autonomic neurons can facilitate cholinergic neurotransmission, and inhibit sympathetic transmission, by regulating cyclic nucleotide-dependent pathways coupled to neuronal calcium entry. We tested the idea whether cardiac neuromodulation by nNOS could be sustained by long-term over-expression of the enzyme following lentiviral gene transfer. We developed a lentiviral vector with an elongation factor 1 (EF1alpha) promoter to drive nNOS or enhanced green fluorescent protein (eGFP) expression. Lenti.EF1alpha-nNOS or Lenti.EF1alpha-eGFP was transferred to the right atrium of Spague-Dawley (SD) rats and acetylcholine (ACh) or noradrenaline (NA) release to field stimulation was measured 4 months after gene transfer. Atria transduced with Lenti.EF1alpha-nNOS had higher nNOS expression compared to the atria treated with Lenti.EF1alpha-eGFP (P < 0.05). We also detected significant increases (P < 0.05) in atrial cGMP and cAMP levels in the same tissue. Immunohistochemistry revealed co-localisation of eGFP in intrinsic cholinergic neurons (choline acetyltransferase positive) and intrinsic adrenergic neurons (tyrosine hydroxylase positive) following gene transfer. nNOS-transduced animals displayed enhanced ACh release (P < 0.05) and reduced NA release (P < 0.05) compared to the eGFP-treated group. nNOS-specific inhibition reversed the enhanced ACh release. Persistent nNOS over-expression mediated by a lentiviral vector can modulate sympatho-vagal control of cardiac excitability. This approach may provide a new tool to target impaired cardiac autonomic phenotypes that are disrupted by several cardiovascular pathologies.


The neural system of language: structure and development.
Recent neuroimaging and neuropsychological research in adults and infants suggests that the neural system for language is widely distributed and shares organizational principles with other cognitive systems in the brain. Connectionist modelling has clarified that networks operating with associative mechanisms can display properties typically associated with genetically predetermined and dedicated symbolic functions.


Infant feeding patterns and risks of death and hospitalization in the first half of infancy: multicentre cohort study.
To determine the association of different feeding patterns for infants (exclusive breastfeeding, predominant breastfeeding, partial breastfeeding and no breastfeeding) with mortality and hospital admissions during the first half of infancy. This paper is based on a secondary analysis of data from a multicentre randomized controlled trial on immunization-linked vitamin A supplementation. Altogether, 9424 infants and their mothers (2919 in Ghana, 4000 in India and 2505 in Peru) were enrolled when infants were 18-42 days old in two urban slums in New Delhi, India, a periurban shanty town in Lima, Peru, and 37 villages in the Kintampo district of Ghana. Mother-infant pairs were visited at home every 4 weeks from the time the infant received the first dose of oral polio vaccine and diphtheria-pertussis-tetanus at the age of 6 weeks in Ghana and India and at the age of 10 weeks in Peru. At each visit, mothers were queried about what they had offered their infant to eat or drink during the past week. Information was also collected on hospital admissions and deaths occurring between the ages of 6 weeks and 6 months. The main outcome measures were all-cause mortality, diarrhoea-specific mortality, mortality caused by acute lower respiratory infections, and hospital admissions. There was no significant difference in the risk of death between children who were exclusively breastfed and those who were predominantly breastfed (adjusted hazard ratio (HR) = 1.46; 95% confidence interval (CI) = 0.75-2.86). Non-breastfed infants had a higher risk of dying when compared with those who had been predominantly breastfed (HR = 10.5; 95% CI = 5.0-22.0; P < 0.001) as did partially breastfed infants (HR = 2.46; 95% CI = 1.44-4.18; P = 0.001). There are two major implications of these findings. First, the extremely high risks of infant mortality associated with not being breastfed need to be taken into account when informing HIV-infected mothers about options for feeding their infants. Second, our finding that the risks of death are similar for infants who are predominantly breastfed and those who are exclusively breastfed suggests that in settings where rates of predominant breastfeeding are already high, promotion efforts should focus on sustaining these high rates rather than on attempting to achieve a shift from predominant breastfeeding to exclusive breastfeeding.


Evaluation of the protective effects of quercetin, rutin, naringenin, resveratrol and trolox against idarubicin-induced DNA damage.
Idarubicin is a synthetic anthracycline anticancer drug widely used in the treatment of some hematological malignancies. The studies in our laboratory have clearly demonstrated that idarubicin can undergo reductive bioactivation by NADPH-cytochrome P450 reductase to free radicals with resulting formation of DNA strand breaks, which can potentially contribute to its genotoxic effects [Celik, H., Arinç, E., Bioreduction of idarubicin and formation of ROS responsible for DNA cleavage by NADPH-cytochrome P450 reductase and its potential role in the antitumor effect. J Pharm Pharm Sci, 11(4):68-82, 2008]. In the current study, our aim was to investigate the possible protective effects of several phenolic antioxidants, quercetin, rutin, naringenin, resveratrol and trolox, against the DNA-damaging effect of idarubicin originating from its P450 reductase-catalyzed bioactivation. DNA damage was measured by detecting single-strand breaks in plasmid pBR322 DNA using a cell-free agarose gel method. Our results indicated that, among the compounds tested, quercetin was the most potent antioxidant in preventing DNA damage. Quercetin significantly decreased the extent of DNA strand breaks in a dose-dependent manner; 100 microM of quercetin almost completely inhibited the DNA strand breakage. Unlike quercetin, its glycosidated conjugate rutin, failed to provide any significant protection against idarubicin-induced DNA strand breaks except at the highest concentration tested (2 mM). The protective effects of other antioxidants were significantly less than that of quercetin even at high concentrations. Quercetin was found to be also an effective protector against DNA damage induced by mitomycin C. We conclude that quercetin, one of the most abundant flavonoids in the human diet, is highly effective in reducing the DNA damage caused by the antitumor agents, idarubicin and mitomycin C, following bioactivation by P450 reductase.


Cannabis and tobacco smoke are not equally carcinogenic.
More people are using the cannabis plant as modern basic and clinical science reaffirms and extends its medicinal uses. Concomitantly, concern and opposition to smoked medicine has occurred, in part due to the known carcinogenic consequences of smoking tobacco. Are these reactions justified? While chemically very similar, there are fundamental differences in the pharmacological properties between cannabis and tobacco smoke. Cannabis smoke contains cannabinoids whereas tobacco smoke contains nicotine. Available scientific data, that examines the carcinogenic properties of inhaling smoke and its biological consequences, suggests reasons why tobacco smoke, but not cannabis smoke, may result in lung cancer.


A randomised, blinded, placebo-controlled trial in dementia patients continuing or stopping neuroleptics (the DART-AD trial).
There have been increasing concerns regarding the safety and efficacy of neuroleptics in people with dementia, but there are very few long-term trials to inform clinical practice. The aim of this study was to determine the impact of long-term treatment with neuroleptic agents upon global cognitive decline and neuropsychiatric symptoms in patients with Alzheimer disease. Randomised, blinded, placebo-controlled parallel two-group treatment discontinuation trial. Oxfordshire, Newcastle and Gateshead, London and Edinburgh, United Kingdom. Patients currently prescribed the neuroleptics thioridazine, chlorpromazine, haloperidol trifluoperazine or risperidone for behavioural or psychiatric disturbance in dementia for at least 3 mo. Continue neuroleptic treatment for 12 mo or switch to an identical placebo. Primary outcome was total Severe Impairment Battery (SIB) score. Neuropsychiatric symptoms were evaluated with the Neuropsychiatric Inventory (NPI). 165 patients were randomised (83 to continue treatment and 82 to placebo, i.e., discontinue treatment), of whom 128 (78%) commenced treatment (64 continue/64 placebo). Of those, 26 were lost to follow-up (13 per arm), resulting in 51 patients per arm analysed for the primary outcome. There was no significant difference between the continue treatment and placebo groups in the estimated mean change in SIB scores between baseline and 6 mo; estimated mean difference in deterioration (favouring placebo) -0.4 (95% confidence interval [CI] -6.4 to 5.5), adjusted for baseline value (p = 0.9). For neuropsychiatric symptoms, there was no significant difference between the continue treatment and placebo groups (n = 56 and 53, respectively) in the estimated mean change in NPI scores between baseline and 6 mo; estimated mean difference in deterioration (favouring continue treatment) -2.4 (95% CI -8.2 to 3.5), adjusted for baseline value (p = 0.4). Both results became more pronounced at 12 mo. There was some evidence to suggest that those patients with initial NPI >/= 15 benefited on neuropsychiatric symptoms from continuing treatment. For most patients with AD, withdrawal of neuroleptics had no overall detrimental effect on functional and cognitive status. Neuroleptics may have some value in the maintenance treatment of more severe neuropsychiatric symptoms, but this benefit must be weighed against the side effects of therapy. Cochrane Central Registry of Controlled Trials/National Research Register (#ISRCTN33368770).