Improving health-related quality of life in single-sided deafness: a systematic review and meta-analysis.
Unilateral severe-to-profound hearing loss, or single-sided deafness (SSD), impairs listening abilities supported by the use of two ears, including speech perception in background noise and sound localisation. Hearing-assistive devices can aid listening by re-routing sounds from the impaired to the non-impaired ear or by restoring input to the impaired ear. A systematic review of the literature examined the impact of hearing-assistive devices on the health-related quality of life (HRQoL) of adults with SSD as measured using generic and disease-specific instruments. A majority of studies used observational designs, and the quality of the evidence was low to moderate. Only two studies used generic instruments. A mixed-effect meta-analysis of disease-specific measures suggested that hearing-assistive devices have a small-to-medium impact on HRQoL. The Speech, Spatial and Qualities of Hearing Scale and the Health Utilities Index Mark 3 (HUI3) were identified as instruments that are sensitive to device-related changes in disease-specific and generic HRQoL, respectively.


Modified Delphi study of decision-making around treatment sequencing in relapsing-remitting multiple sclerosis.
Existing effectiveness models of disease-modifying drugs (DMDs) for relapsing-remitting multiple sclerosis (RRMS) evaluate a single line of treatment; however, RRMS patients often receive more than one lifetime DMD. To develop treatment sequencing models grounded in clinical reality, a detailed understanding of the decision-making process regarding DMD switching is required. Using a modified Delphi approach, this study attempted to reach consensus on modelling assumptions. A modified Delphi technique was conducted based on three rounds of discussion amongst an international group of 10 physicians with expertise in RRMS. The panel agreed that the expected time from disease onset to Expanded Disability Status Scale 6.0 is a proxy for disease severity as well as suitable for classifying severity into three groups. A modelled clinical decision rule regarding the timing of switching should contain at least the time between relapses, magnetic resonance imaging outcomes and the occurrence/risk of adverse events. The experts agreed that the assessment of adverse event risk for a DMD is dependent on disease severity, with more risks accepted when the patient's disease is more severe. The effectiveness of DMDs conditional on their position in a sequence and/or disease duration was discussed: there was consensus on some statements regarding this topic but these were accompanied by a high degree of uncertainty due to considerable knowledge gaps. Useful insights into the medical decision-making process regarding treatment sequencing in RRMS were obtained. The knowledge gained has been used to validate the main modelling concepts and to further generate clinically meaningful results.


Nitroxyl Anion Mediates Relaxation in Mesenteric Arteries from Angiotensin II Hypertensive Mice.
Nitroxyl anion (HNO) has recently become an emerging candidate in vascular regulation. NO- is a potent vasodilator of both conduit and small resistance vessels and mediates relaxation in a soluble guanylate cyclase-dependent manner. Interestingly, HNO activates voltage-dependent K+ (K+ V) channels, whereas Nitric Oxide (NO) activates calcium-activated K+ Ca channels. To date, there are few studies investigating the role of HNO in hypertension, and the possible mechanisms, which may be altered during this condition. We hypothesized that mesenteric arteries from angiotensin II-induced (AngII) hypertensive mice would exhibit an increased dependence upon NO- for relaxation, which may be mediated through K+ V channels. Methods and Key Results: C57/Bl6 mice, aged 12-14 weeks were implanted with mini-pumps containing angiotensin II (AngII, 3600ng/kg/min) for 14 days. For this study, we proposed to investigate the role of HNO in the resistance vasculature, and so first order mesenteric arteries were isolated and used in functional studies, or were frozen for Western blot analysis. We observed that mesenteric arteries from AngII mice (AngII) exhibited a decrease in HNO-mediated relaxation, which was endotheliumindependent. With HNO scavenging by L-cysteine [3mM], the maximal acetylcholine (ACh)-mediated relaxation response was decreased in sham, whereas mesenteric arteries from AngII exhibited a decrease in sensitivity. Incubation with the K+ V channel inhibitor, 4-aminopyridine [1mM], decreased AChmediated relaxation responses in sham, but almost completely abolished relaxation in AngII. We reveal that exogenous HNO-mediated relaxation, via Angeli's Salt, is impaired in mesenteric arteries from AngII-treated mice, yet endogenous HNO-mediated relaxation may be more important during hypertension.


Marital quality among couples living under the threat of forced relocation: the case of families in the Golan Heights.
This study aims to explore how the long period of uncertainty about possible relocation affects the marital quality of the population in the Golan Heights and what forms of coping with this ongoing stress are used. The results, based on both quantitative and qualitative data, indicate a circular process in which the level of stress generated by the uncertainty varies with marital quality and with other personal and family resources, such as potency and an appreciation of the spouse's ability to cope with the stress. Four ways of coping with the uncertainty were observed in in-depth interviews: fighting, ignoring, postponing, and planning. The results are discussed in terms of their meaning for possible systemic interventions.


Altered expression of gap junction connexin proteins may partly underlie heart rhythm disturbances in the streptozotocin-induced diabetic rat heart.
Previous studies in isolated perfused heart and in atrial preparations have demonstrated significant reductions in beating rate in STZ-induced diabetic rats, which suggests that sinus arrhythmias in diabetes mellitus may be partly caused by intrinsic alteration of sino-atrial node (SAN) function. The effects of diabetes on electrical activity and expression levels of mRNA for gap junction proteins in the SAN have been investigated. Diabetes was induced by a single intraperitoneal injection of STZ (60 mg/kg) administered to young male Wistar rats (200-250 g). Experiments were performed 8-10 weeks after treatment. Conduction time and pacemaker cycle length were measured in sino-atrial node preparations with extracellular electrodes. Expression levels of mRNA for Gja5 (Cx40), Gja1 (Cx43) and Gja7 (Cx45) were measured in SAN and compared with right atrium and right ventricle with real-time quantitative reverse transcription-polymerase chain reaction. Diabetes was confirmed by a significant elevation of blood glucose (356+/-21 mg/dl) compared to age-matched controls (66+/-2 mg/dl). Pacemaker cycle length was significantly prolonged in diabetic heart (415+/-43 ms, n=6) compared to controls (255+/-7 ms, n=6). Sino-atrial conduction time was also significantly prolonged in diabetic hearts (12+/-2 ms) compared to controls (7+/-1 ms). Expression levels of mRNA for Gja5 (Cx40) and Gja1 (Cx43) were moderately increased and for Gja7 (Cx45) was significantly increased in SAN from diabetic heart compared to controls. Expression levels for gap junction connexin proteins were not significantly altered in right atrium or right ventricle from diabetic heart compared to controls. Structural remodelling of gap junction connexin proteins may partly underlie electrophysiological defects in STZ-induced diabetic rat SAN.


The chemical constituents and biological activity of essential oil of Lavandula stoechas ssp. stoechas.
The composition of essential oil of the leaves of Lavandula stoechas ssp. stoechas, was analyzed by means of capillary GC-MS. The main components of L. stoechas ssp. stoechas oil were pulegone (40.4%), menthol (18.1%), menthone (12.6%). The essential oil of the plant was evaluated for antibacterial and a panel cytotoxic activities.


Human muscle power output during upper- and lower-body exercises.
The purpose of this study was to evaluate the use of traditional resistance training equipment in the measurement of muscular power. This was accomplished by measuring the velocity of movement through a measured distance during maximal effort lifts using a Smith rack. The reliability of the method was established using 10 male volunteers who performed both bench press and squat exercises in a Smith rack. Maximal power output was determined at 30, 40, 50, 60, 70, 80, and 90% of the subject's 1 repetition maximum (1RM). Test-retest power values were not statistically different. Another 15 male volunteers who had previous muscle biopsy data from the vastus lateralis muscle performed the same maximal power output evaluation. There were no significant relationships between peak power outputs and fiber-type expressions when linear regressions were performed. The power curve produced by graphing power output vs. the percentage of 1RM indicates that peak power output occurs between 50 and 70% of 1RM for the squat and between 40 and 60% of 1RM for the bench press. These data indicate that this method of evaluation of muscle power is reliable, although it is not predictive of muscle fiber-type percentages.


Nucleotide sequence of the Akv env gene.
The sequence of 2,191 nucleotides encoding the env gene of murine retrovirus Akv was determined by using a molecular clone of the Akv provirus. Deduction of the encoded amino acid sequence showed that a single open reading frame encodes a 638-amino acid precursor to gp70 and p15E. In addition, there is a typical leader sequence preceding the amino terminus of gp70. The locations of potential glycosylation sites and other structural features indicate that the entire gp70 molecule and most of p15E are located on the outer side of the membrane. Internal cleavage of the env precursor to generate gp70 and p15E occurs immediately adjacent to several basic amino acids at the carboxyl terminus of gp70. This cleavage generates a region of 42 uncharged, relatively hydrophobic amino acids at the amino terminus of p15E, which is located in a position analogous to the hydrophobic membrane fusion sequence of influenza virus hemagglutinin. The mature polypeptides are predicted to associate with the membrane via a region of 30 uncharged, mostly hydrophobic amino acids located near the carboxyl terminus of p15E. Distal to this membrane association region is a sequence of 35 amino acids at the carboxyl terminus of the env precursor, which is predicted to be located on the inner side of the membrane. By analogy to Moloney murine leukemia virus, a proteolytic cleavage in this region removes the terminal 19 amino acids, thus generating the carboxyl terminus of p15E. This leaves 15 amino acids at the carboxyl terminus of p15E on the inner side of the membrane in a position to interact with virion cores during budding. The precise location and order of the large RNase T(1)-resistant oligonucleotides in the env region were determined and compared with those from several leukemogenic viruses of AKR origin. This permitted a determination of how the differences in the leukemogenic viruses affect the primary structure of the env gene products.


Lessons From a Care Management Pilot Program for People With Acquired Brain Injury.
From November 2010 to August 2013, 161 adults with acquired brain injury in Massachusetts transitioned from long-term care settings to the community through a Medicaid-funded waiver. Most participants transitioned with minimal risk; for some, the transition resulted in an increase in risk incidents above the rest. Specifically, despite risk mitigation efforts, 11% of the participants accounted for more than 75% of the reported first year incidents. A registered nurse Care Manager was engaged in a pilot program to address the needs of participants at the highest risk. Based on incidents or potential for incidents, 30 participants were enrolled in care management (CM). Secondary data analysis, interviews, and surveys assessed whether CM was associated with a decrease in incidents and to what extent participants and providers were satisfied with CM. Care management was significantly associated with a decrease in incidents including hospitalizations and emergency room visits. Participants, Case Managers, and service providers were highly satisfied with the Care Manager. Focusing on a specific population with increased risk, clearly explaining the purpose of CM, and remaining flexible when addressing the complex and individual nature of risk management are important strategies to ensure an effective CM program.


Naringenin ameliorates learning and memory impairment following systemic lipopolysaccharide challenge in the rat.
Systemic inflammation following infection is usually associated with long-term complications including cognitive deficit and dementia. Neuroinflammation and cognitive decline are also main hallmarks of several neurological conditions. Naringenin is a citrus flavanone with anti-inflammatory, neuroprotective, and antioxidant potential. In this study, the protective effect of naringenin against lipopolysaccharide (LPS)-induced cognitive decline was evaluated in the rat. LPS was daily injected at a dose of 167 μg/kg for 1 week and naringenin was administered p.o. at doses of 25, 50, or 100 mg/kg/day. Treatment of LPS-injected rats with naringenin dose-dependently improved spatial recognition memory in Y maze, discrimination ratio in novel object discrimination task, and retention and recall capability in passive avoidance test. Furthermore, naringenin lowered hippocampal malondialdehyde (MDA) as an index of lipid peroxidation and improved antioxidant defensive system comprising superoxide dismutase (SOD), catalase, and glutathione (GSH) in addition to decreasing acetylcholinesterase (AChE) activity. Additionally, naringenin was able to lower hippocampal nuclear factor-kappaB (NF-κB), toll-like receptor 4 (TLR4), tumor necrosis factor α (TNFα), cyclooxygenase-2 (COX2), inducible nitric oxide synthase (iNOS), glial fibrillary acidic protein (GFAP) level and its immunoreactivity, and to elevate nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Taken together, naringenin could alleviate LPS-induced cognitive deficits and neuroinflammation, as was evident from attenuation of oxidative stress and AChE and modulation of Nrf2/NF-κB/TNFα/COX2/iNOS/TLR4/GFAP.


Reduction of serum matrix metalloproteinase 1 and matrix metalloproteinase 3 in rheumatoid arthritis patients following anti-tumour necrosis factor-alpha (cA2) therapy.
Matrix metalloproteinase (MMP)-1 and MMP-3 levels were measured in serum samples from rheumatoid arthritis (RA) patients undergoing a double-blinded placebo-controlled trial with the chimaeric anti-tumour necrosis factor (TNF)-alpha antibody cA2. Both MMP-1 (P < 0.015), but to a larger extent MMP-3 (P < 0.001) levels were elevated in all RA patients prior to the commencement of the trial compared with normal control sera. Following cA2 therapy, MMP-1 and MMP-3 levels were assessed in the placebo, and 1 and 10 mg/kg cA2-treated groups at 7, 14, 21 and 28 days. In both the 1 and the 10 mg/kg cA2-treated groups, a significant decrease in serum MMP-3 levels at all time points was observed, reducing maximally to 41% of pre-infusion values at day 7. MMP-1 levels were also reduced, but less dramatically than MMP-3, to 85% of pre-infusion values after 14 days in the 10 mg/kg cA2 treated group. In a separate non-placebo-controlled study, we also evaluated the tissue inhibitor of metalloproteinase (TIMP)-1 levels in plasma following cA2 infusion. Pre-infusion TIMP-1 levels were above the normal control range, but were significantly reduced (P < 0.035) 14 days after infusion to 72% of pre-infusion values. This study confirms previous reports that MMP-3 levels are elevated and correlate with measures of inflammation in RA, and furthermore demonstrate that serum MMP-3 and MMP-1 levels are downmodulated following anti-TNF-alpha antibody therapy. Whilst serum MMP-3 levels correlated with C-reactive protein (CRP) both prior to and following anti-TNF-alpha antibody therapy, it remains to be demonstrated that serum MMP-3 and/or MMP-1 levels reflect the cartilage and bone resorptive processes which are evident in this disease.


Towards agreement on best practice for publishing raw clinical trial data.
Many research-funding agencies now require open access to the results of research they have funded, and some also require that researchers make available the raw data generated from that research. Similarly, the journal Trials aims to address inadequate reporting in randomised controlled trials, and in order to fulfil this objective, the journal is working with the scientific and publishing communities to try to establish best practice for publishing raw data from clinical trials in peer-reviewed biomedical journals. Common issues encountered when considering raw data for publication include patient privacy - unless explicit consent for publication is obtained - and ownership, but agreed-upon policies for tackling these concerns do not appear to be addressed in the guidance or mandates currently established. Potential next steps for journal editors and publishers, ethics committees, research-funding agencies, and researchers are proposed, and alternatives to journal publication, such as restricted access repositories, are outlined.


The genome of the yellow potato cyst nematode, Globodera rostochiensis, reveals insights into the basis of parasitism and virulence.
The yellow potato cyst nematode, Globodera rostochiensis, is a devastating plant pathogen of global economic importance. This biotrophic parasite secretes effectors from pharyngeal glands, some of which were acquired by horizontal gene transfer, to manipulate host processes and promote parasitism. G. rostochiensis is classified into pathotypes with different plant resistance-breaking phenotypes. We generate a high quality genome assembly for G. rostochiensis pathotype Ro1, identify putative effectors and horizontal gene transfer events, map gene expression through the life cycle focusing on key parasitic transitions and sequence the genomes of eight populations including four additional pathotypes to identify variation. Horizontal gene transfer contributes 3.5 % of the predicted genes, of which approximately 8.5 % are deployed as effectors. Over one-third of all effector genes are clustered in 21 putative 'effector islands' in the genome. We identify a dorsal gland promoter element motif (termed DOG Box) present upstream in representatives from 26 out of 28 dorsal gland effector families, and predict a putative effector superset associated with this motif. We validate gland cell expression in two novel genes by in situ hybridisation and catalogue dorsal gland promoter element-containing effectors from available cyst nematode genomes. Comparison of effector diversity between pathotypes highlights correlation with plant resistance-breaking. These G. rostochiensis genome resources will facilitate major advances in understanding nematode plant-parasitism. Dorsal gland promoter element-containing effectors are at the front line of the evolutionary arms race between plant and parasite and the ability to predict gland cell expression a priori promises rapid advances in understanding their roles and mechanisms of action.


Evaluation of a tobacco prevention programme among teenagers in Sweden.
To study the prevalence of tobacco use among teenagers, to evaluate a tobacco prevention programme and to study factors related to participation in the prevention programme. Population-based prospective cohort study. Within the Obstructive Lung disease in Northern Sweden (OLIN) studies, a cohort study about asthma in schoolchildren started in 2006. All children aged 7-8 years in three municipalities were invited to a questionnaire survey and 2585 (96%) participated. The cohort was followed up at age 11-12 years (n=2612, 95% of invited) and 14-15 years (n=2345, 88% of invited). In 2010, some of the children in the OLIN cohort (n=447) were invited to a local tobacco prevention programme and 224 (50%) chose to participate. At the age of 14-15 years, the prevalence of daily smoking was 3.5%. Factors related to smoking were female sex, having a smoking mother, participation in sports and lower parental socioeconomic status (SES). The prevalence of using snus was 3.3% and risk factors were male sex, having a smoking mother, having a snus-using father and non-participation in the prevention programme. In the prevention programme, the prevalence of tobacco use was significantly lower among the participants compared with the controls in the cohort. Factors related to non-participation were male sex, having a smoking mother, lower parental SES and participation in sports. The prevalence of tobacco use was lower among the participants in the tobacco prevention programme compared with the non-participants as well as with the controls in the cohort. However, the observed benefit of the intervention may be overestimated as participation was biased by selection.


Quinine pharmacokinetics and toxicity in pregnant and lactating women with falciparum malaria.
Quinine dihydrochloride (10 mg or, in two patients, a loading dose of 20 mg kg-1) was infused intravenously over 4 h in ten severely ill but conscious women with falciparum malaria complicating the third trimester of pregnancy. Plasma quinine concentrations, measured spectrophotofluorimetrically after benzene extraction, fitted closely a single exponential decline after the intravenous infusion. These data were therefore fitted to a one compartment model: total apparent volume of distribution, V, 0.96 +/- 0.27 l kg-1 (+/- s.d.), elimination half-time (t1/2,z), 11.3 +/- 4.3 h, total clearance, 1.22 +/- 0.77 ml min-1 kg-1. There was no relationship between arterial blood pressure and plasma quinine concentrations. Eight women delivered of live infants while taking quinine, had placental cord plasma quinine concentrations from 1.0 to 4.6 mg l-1 (mean 2.4) which correlated significantly with maternal plasma quinine concentrations (r = 0.78, t = 3.06, P less than 0.05). The mean (+/- s.d.) ratio of cord plasma to maternal plasma quinine concentration was 0.32 +/- 0.14. Heart blood from a foetus aborted at term had a plasma quinine concentration of 2.8 mg l-1; simultaneous maternal plasma quinine was 7.1 mg l-1 (ratio 0.39). Breast milk quinine concentrations and milk to plasma ratios were 0.5-3.6 mg l-1 (mean 2.6) and 0.11-0.53 (mean 0.31) in twenty-five women who were breast-feeding and had taken oral quinine sulphate for 1-10 days (mean 4.0). Five women with more serious infections received intravenous quinine; breast milk quinine concentrations ranged between 0.5 and 8.0 mg l-1 (mean 3.4).(ABSTRACT TRUNCATED AT 250 WORDS)


Population differences in the International Multi-Centre ADHD Gene Project.
The International Multi-Centre ADHD Gene sample consists of 674 families from eight countries (Belgium, England, Germany, Holland, Ireland, Israel, Spain, and Switzerland) ascertained from clinics for combined-type attention definity hyperactivity disorder in an offspring. 863 SNPs were successfully genotyped across 47 autosomal genes implicated in psychiatric disorders yielding a single nucleotide polymorphism (SNP) density of approximately one SNP per 2.5 kb. A global test of heterogeneity showed 269 SNPs nominally significant (expected 43). Inclusion of the Israeli population accounted for approximately 70% of these nominally significant tests. Hardy-Weinberg equilibrium tests suggest that combining all these populations would induce stratification, but that the Northern European populations (Belgium, England, Germany, Holland, and Ireland) could be appropriate. Tag SNPs were generated using pair-wise and aggressive tagging from Carlson et al. [2004] and de Bakker et al. [2005], respectively, in each population and applied to the other populations. Cross-population performance across Northern Europe was consistent with within population comparisons. Smaller sample size for each population tended to yield more problems for the generation of aggressive tags and the application of pair-wise tags. Any case-control sample employing an Israeli sample with Northern Europeans must consider stratification. A Northern European tag set, however, appears to be appropriate for capturing the variation across populations.


Alzheimer's disease is type 3 diabetes-evidence reviewed.
Alzheimer's disease (AD) has characteristic histopathological, molecular, and biochemical abnormalities, including cell loss; abundant neurofibrillary tangles; dystrophic neurites; amyloid precursor protein, amyloid-beta (APP-Abeta) deposits; increased activation of prodeath genes and signaling pathways; impaired energy metabolism; mitochondrial dysfunction; chronic oxidative stress; and DNA damage. Gaining a better understanding of AD pathogenesis will require a framework that mechanistically interlinks all these phenomena. Currently, there is a rapid growth in the literature pointing toward insulin deficiency and insulin resistance as mediators of AD-type neurodegeneration, but this surge of new information is riddled with conflicting and unresolved concepts regarding the potential contributions of type 2 diabetes mellitus (T2DM), metabolic syndrome, and obesity to AD pathogenesis. Herein, we review the evidence that (1) T2DM causes brain insulin resistance, oxidative stress, and cognitive impairment, but its aggregate effects fall far short of mimicking AD; (2) extensive disturbances in brain insulin and insulin-like growth factor (IGF) signaling mechanisms represent early and progressive abnormalities and could account for the majority of molecular, biochemical, and histopathological lesions in AD; (3) experimental brain diabetes produced by intracerebral administration of streptozotocin shares many features with AD, including cognitive impairment and disturbances in acetylcholine homeostasis; and (4) experimental brain diabetes is treatable with insulin sensitizer agents, i.e., drugs currently used to treat T2DM. We conclude that the term "type 3 diabetes" accurately reflects the fact that AD represents a form of diabetes that selectively involves the brain and has molecular and biochemical features that overlap with both type 1 diabetes mellitus and T2DM.


Inactivation of heat shock factor Hsf4 induces cellular senescence and suppresses tumorigenesis in vivo.
Studies suggest that Hsf4 expression correlates with its role in cell growth and differentiation. However, the role of Hsf4 in tumorigenesis in vivo remains unexplored. In this article, we provide evidence that absence of the Hsf4 gene suppresses evolution of spontaneous tumors arising in p53- or Arf-deficient mice. Furthermore, deletion of hsf4 alters the tumor spectrum by significantly inhibiting development of lymphomas that are normally observed in the majority of mice lacking p53 or Arf tumor suppressor genes. Using mouse embryo fibroblasts deficient in the hsf4 gene, we have found that these cells exhibit reduced proliferation that is associated with induction of senescence and senescence-associated β-galactosidase (SA-β-gal). Cellular senescence in hsf4-deficient cells is associated with the increased expression of the cyclin-dependent kinase inhibitors, p21 and p27 proteins. Consistent with the cellular senescence observed in vitro, specific normal tissues of hsf4(-/-) mice and tumors that arose in mice deficient in both hsf4 and p53 genes exhibit increased SA-β-gal activity and elevated levels of p27 compared with wild-type mice. These results suggest that hsf4 deletion-induced senescence is also present in vivo. Our results therefore indicate that Hsf4 is involved in modulation of cellular senescence, which can be exploited during cancer therapy.


Defect-Mediated Charge-Carrier Trapping and Nonradiative Recombination in WSe2 Monolayers.
Nonradiative charge-carrier recombination in transition-metal dichalcogenide (TMD) monolayers severely limits their use in solar energy conversion technologies. Because defects serve as recombination sites, developing a quantitative description of charge-carrier dynamics in defective TMD monolayers can shed light on recombination mechanisms. Herein we report a first-principles investigation of charge-carrier dynamics in pristine and defective WSe2 monolayers with three of the most probable defects, namely, Se vacancies, W vacancies, and SeW antisites. We predict that Se vacancies slow down recombination by nearly an order of magnitude relative to defect-free samples by breaking the monolayer's symmetry and thereby reducing the spectral intensity of the A1g phonon mode that promotes recombination in the pristine monolayer. By contrast, we find W vacancies accelerate recombination by more than an order of magnitude, with half of the recombination events bypassing charge traps. The subsequent dynamics feature both charge trapping and charge-trap-assisted recombination. Although SeW antisites also slightly accelerate recombination, the predicted mechanism is different from the W vacancy case. First, a shallow energy level traps a photoexcited electron. Then, both shallow- and deep-trap-assisted recombination can occur simultaneously. Accelerated recombination arises for W vacancies and SeW antisites because they introduce new phonon modes that strongly couple to electron and hole dynamics. This work thus provides a detailed understanding of the mechanisms behind charge-carrier recombination in WSe2 monolayers with distinct defects. Thus, materials engineering, particularly to avoid W vacancies, could advance this technology. The insights derived are important for future design of high-performance photoactive devices based on WSe2 monolayers.


Human male recombination maps for individual chromosomes.
Meiotic recombination is essential for the segregation of chromosomes and the formation of normal haploid gametes, yet we know very little about the meiotic process in humans. We present the first (to our knowledge) recombination maps for every autosome in the human male obtained by new immunofluorescence techniques followed by centromere-specific multicolor fluorescence in situ hybridization in human spermatocytes. The mean frequency of autosomal recombination foci was 49.8+/-4.3, corresponding to a genetic length of 2,490 cM. All autosomal bivalents had at least one recombination focus. In contrast, the XY bivalent had a recombination focus in 73% of nuclei, suggesting that a relatively large proportion of spermatocytes may be at risk for nondisjunction of the XY bivalent or elimination by meiotic arrest. There was a very strong correlation between mean length of the synaptonemal complex (SC) and the number of recombination foci per SC. Each bivalent presented a distinct distribution of recombination foci, but in general, foci were near the distal parts of the chromosome, with repression of foci near the centromere. The position of recombination foci demonstrated positive interference, but, in rare instances, foci were very close to one another.


Impact of financial agreements in European chronic care on health care expenditure growth.
Various types of financial agreements have been implemented in Europe to reduce health care expenditure by stimulating integrated chronic care. This study used difference-in-differences (DID) models to estimate differences in health care expenditure trends before and after the introduction of a financial agreement between 9 intervention countries and 16 control countries. Intervention countries included countries with pay-for-coordination (PFC), pay-for-performance (PFP), and/or all inclusive agreements (bundled and global payment) for integrated chronic care. OECD and WHO data from 1996 to 2013 was used. The results from the main DID models showed that the annual growth of outpatient expenditure was decreased in countries with PFC (by 21.28 US$ per capita) and in countries with all-inclusive agreements (by 216.60 US$ per capita). The growth of hospital and administrative expenditure was decreased in countries with PFP by 64.50 US$ per capita and 5.74 US$ per capita, respectively. When modelling impact as a non-linear function of time during the total 4-year period after implementation, PFP decreased the growth of hospital and administrative expenditure and all-inclusive agreements reduced the growth of outpatient expenditure. Financial agreements are potentially powerful tools to stimulate integrated care and influence health care expenditure growth. A blended payment scheme that combines elements of PFC, PFP, and all-inclusive payments is likely to provide the strongest financial incentives to control health care expenditure growth.


Focal cerebral ischemic tolerance and change in blood-brain barrier permeability after repetitive pure oxygen exposure preconditioning in a rodent model.
OBJECTIVE The goal of this study was to demonstrate that repetitive pure oxygen exposure preconditioning (O2PC) for 8 hours per day for 3 or 7 days, a practicable preconditioning for clinical use, is able to induce cerebral ischemic tolerance (IT) and further clarify the accompanying changes in the blood-brain barrier (BBB) that may be involved. METHODS A total of 68 adult male Sprague-Dawley rats and eight 1-day-old rat pups were used in this study. The adult rats were exposed to pure O2 (38 rats) 8 hours a day for 3 or 7 days or to room air (in an identical setup) for 8 hours a day for 7 days as controls (30 rats). Arterial O2 tension (PaO2) was measured in 6 rats exposed to O2 and 3 controls. Focal cerebral ischemia was elicited by middle cerebral artery occlusion (MCAO) in 37 rats, of which 21 had been exposed to pure O2 for 3 or 7 days and 16 to room air for 7 days as controls. Neurological behavior was scored with the Garcia score in 15 MCAO rats, of which 10 had been exposed to pure O2 for 3 or 7 days and 5 to room air for 7 days as controls, and cerebral infarct volumes were assessed with TTC (2,3,5-triphenyltetrazolium chloride) staining in 10 rats (5 from each group) after 7 days of exposure. Formamide-extraction method was used to detect leakage of Evans blue (EB) dye in 7 rats exposed to pure O2 for 7 days and 7 exposed to room air for 7 days. Fluorescence microscopy was used to analyze the leaked EB in the nonischemic areas of 4 rats exposed to pure O2 for 7 days and 4 exposed to room air for 7 days before MCAO and the brain of the rats that had not been subjected to MCAO. Astrocyte changes associated with O2PC were evaluated by means of fluorescence microscopy and electron microscopy in 14 rats that were exposed to the same O2 or control conditions as the MCAO rats but without MCAO. Astrocytes were also obtained from 8 rat pups and cultured; levels of AQP4 and VEGF were detected by Western blot and ELISA in cells with and without O2 treatment. RESULTS A significant increase in PaO2 was seen after O2PC. The neurological score was significantly increased in the O2PC groups (10.6 ± 0.6 in the 3-day O2PC group, p < 0.05; 12 ± 0.84 in the 7-day O2PC group, p < 0.05) compared with the control group (7 ± 0.55). The ratio of cerebral infarct volume to contralateral cerebral hemisphere volume was significantly lower in the O2PC group than in the control group (0.204 ± 0.03 vs 0.48 ± 0.05, p < 0.05). The amount of leaked EB in the ischemic cerebral hemisphere was also lower in the O2-treated rats than in controls (7.53 ± 1.4 vs 11.79 ± 3.3 μg EB/g brain weight, p < 0.05). However, fluorescence microscopy showed significantly greater BBB permeability in the nonischemic areas in the O2PC group than in controls (p < 0.05). More red fluorescence could be observed in the nonischemic areas in both the ipsilateral and contralateral sides of the ischemic brain in the O2PC animals than in the nonischemic areas in the corresponding sides of the controls. Further investigation of the effect of the O2PC itself on the BBB of rats that were not subjected to MCAO showed that there was no EB leakage in the brain parenchyma in the rats exposed to room air, but some red fluorescence patches were noticed in the normal brain from the rats in the O2PC group. Astrocytes, including those from areas around the BBB, were activated in the O2PC group. Levels of both aquaporin 4 (AQP4) and vascular endothelial growth factor (VEGF) were significantly increased in cultured astrocytes after O2PC. CONCLUSIONS These findings suggest that O2PC is able to induce IT, which makes it a strong candidate for clinical use. Moreover, O2PC can also promote BBB opening, which may contribute to the induction of IT as well as representing a possible strategy for promoting drug transportation into the CNS. Activated astrocytes are likely to be involved in these processes through astrocyte-derived factors, such as AQP4 and VEGF.


Postoperative complications following colectomy for ulcerative colitis: a validation study.
Ulcerative colitis (UC) patients failing medical management require colectomy. This study compares risk estimates for predictors of postoperative complication derived from administrative data against that of chart review and evaluates the accuracy of administrative coding for this population. Hospital administrative databases were used to identify adults with UC undergoing colectomy from 1996-2007. Medical charts were reviewed and regression analyses comparing chart versus administrative data were performed to assess the effect of age, emergent operation, and Charlson comorbidities on the occurrence of postoperative complications. Sensitivity, specificity, and positive/negative predictive values of administrative coding for identifying the study population, Charlson comorbidities, and postoperative complications were assessed. Compared to chart review, administrative data estimated a higher magnitude of effect for emergent admission (OR 2.52 [95% CI: 1.80-3.52] versus 1.49 [1.06-2.09]) and Charlson comorbidities (OR 2.91 [1.86-4.56] versus 1.50 [1.05-2.15]) as predictors of postoperative complications. Administrative data correctly identified UC and colectomy in 85.9% of cases. The administrative database was 37% sensitive in identifying patients with ≥ 1Charlson comorbidity. Restricting analysis to active comorbidities increased the sensitivity to 63%. The sensitivity of identifying patients with at least one postoperative complication was 68%; restricting analysis to more severe complications improved the sensitivity to 84%. Administrative data identified the same risk factors for postoperative complications as chart review, but overestimated the magnitude of risk. This discrepancy may be explained by coding inaccuracies that selectively identifying the most serious complications and comorbidities.


[Development and institutionalization of the first online certificate and Master Program of Biomedical Informatics in global health in Peru].
Training in Biomedical Informatics is essential to meet the challenges of a globalized world. However, the development of postgraduate training and research programs in this area are scarce in Latin America. Through QUIPU: Andean Center for Training and research in Iformatics for Global Health, has developed the first Certificate and Master's Program on Biomedical Informatics in the Andean Region. The aim of this article is to describe the experience of the program. To date, 51 students from Peru, Chile, Ecuador, Colombia and Venezuela have participated; they come from health ministries, hospitals, universities, research centers, professional associations and private companies. Seventeen courses were offered with the participation of faculty from Argentina, Chile, Colombia, USA, Mexico and Peru. This program is already institutionalized at the School of Public Health and Administration from the Universidad Peruana Cayetano Heredia.


Atonal, rough and the resolution of proneural clusters in the developing Drosophila retina.
In the developing Drosophila retina, the proneural gene for photoreceptor neurons is atonal, a basic helix-loop-helix transcription factor. Using atonal as a marker for proneural maturation, we examine the stepwise resolution of proneural clusters during the initiation of ommatidial differentiation in the developing eye disc. In addition, evidence is provided that atonal is negatively regulated by rough, a homeobox-containing transcription factor expressed exclusively in the retina. This interaction leads to the refinement of proneural clusters to specify R8, the first neuron to emerge in the retinal neuroepithelium. Ectopic expression of atonal or removal of rough results in the transformation of a discrete 'equivalence group' of cells into R8s. In addition, ectopic expression of rough blocks atonal expression and proneural cluster formation within the morphogenetic furrow. Thus, rough provides retina-specific regulation to the more general atonal-mediated proneural differentiation pathway. The opposing roles of atonal and rough are not mediated through the Notch pathway, as their expression remains complementary when Notch activity is reduced. These observations suggest that homeobox-containing genes can provide tissue-specific regulation to bHLH factors.


Using PacBio Long-Read High-Throughput Microbial Gene Amplicon Sequencing To Evaluate Infant Formula Safety.
Infant formula (IF) requires a strict microbiological standard because of the high vulnerability of infants to foodborne diseases. The current study used the PacBio single-molecule real-time (SMRT) sequencing platform to generate full-length 16S rRNA-based bacterial microbiota profiles of 30 Chinese domestic and imported IF samples. A total of 600 species were identified, dominated by Streptococcus thermophilus, Lactococcus lactis, and Lactococcus piscium. Distinctive bacterial profiles were observed between the two sample groups, as confirmed with both principal coordinate analysis and multivariate analysis of variance. Moreover, the product whey protein nitrogen index (WPNI), representing the degree of preheating, negatively correlated with the relative abundances of the Bacillus genus. This study has demonstrated the application of the PacBio SMRT sequencing platform in assessing the bacterial contamination of IF products, which is of interest to the dairy industry for effective monitoring of microbial quality and safety during production.


Enrollment Trends and Disparity Among Patients With Lung Cancer in National Clinical Trials, 1990 to 2012.
Purpose Under-representation of elderly, women, and racial/ethnic minority patients with cancer in clinical trials is of national concern. The goal of this study was to characterize enrollment trends and disparities by age, sex, and race/ethnicity in lung cancer trials. Methods We analyzed data for 23,006 National Cancer Institute cooperative group lung cancer trial participants and 578,476 patients with lung cancer from the SEER registry from 1990 to 2012. The enrollment disparity difference (EDD) and enrollment disparity ratio (EDR) were calculated on the basis of the proportion of each subgroup in the trial population and the US lung cancer population. Annual percentage changes (APCs) in the subgroup proportions in each population were compared over time. Results Enrollment disparity for patients ≥ 70 years of age with non-small-cell lung cancer improved from 1990 to 2012 (test of parallelism, P = .020), with a remaining EDD of 0.22 (95% CI, 0.19 to 0.25) and EDR of 1.65 (95% CI, 1.51 to 1.82) in 2010 to 2012. No improvement was seen for elderly patients with small-cell lung cancer (SCLC), with an APC of 0.20 ( P = .714) among trial participants, despite a rising proportion of elderly patients with SCLC in the US population (APC, 0.32; P = .020). Enrollment disparity for women with lung cancer improved overall, with the gap closing by 2012 (EDD, 0.03 [95% CI, 0.00 to 0.06]; EDR, 1.07 [95% CI, 1.00 to 1.16]). Enrollment disparities persisted without significant improvement for elderly women, blacks, Asians/Pacific Islanders, and Hispanics. Conclusion Under-representation in lung cancer trials improved significantly from 1990 to 2012 for elderly patients with non-small-cell lung cancer and for women, but ongoing efforts to improve the enrollment of elderly patients with SCLC and minorities are needed. Our study highlights the importance of addressing enrollment disparities by demographic and disease subgroups to better target under-represented groups of patients with lung cancer.


Four cone types characterized by anti-visual pigment antibodies in the pigeon retina.
Using three antibodies to visual pigments (monoclonal antibodies COS-1 and OS-2, and a polyclonal anti-opsin serum), four different types of cone cells could be distinguished in the red area (dorsoposterior part with the highest density of cones) of the pigeon retina. Both members of the double cone and the single cone with the red oil droplet were labelled with our monoclonal antibody COS-1 (type I cone). The single cone with the orange oil droplet was positive both with anti-opsin and monoclonal antibody OS-2 (type II cone). The single cone exhibiting a yellowish-green oil droplet, fluorescent in ultraviolet light, also reacted with anti-opsin but lacked the antigenic determinant recognized by OS-2 (type III cone). The thin cone with the small colorless oil droplet was negative with both COS-1 and anti-rhodopsin (type IV cone). We propose that the four immunologically distinguishable cone types correspond to cones expressing visual pigments with different (long-, middle-, short-wavelength and ultraviolet) color sensitivities.


Joint Coordinate System Using Functional Axes Achieves Clinically Meaningful Kinematics of the Tibiofemoral Joint as Compared to the International Society of Biomechanics Recommendation.
Quantification of clinically meaningful tibiofemoral motions requires a joint coordinate system (JCS) with motions free from kinematic crosstalk errors. The objectives were to use a JCS with literature-backed functional axes (FUNC) and a JCS recommended by the International Society of Biomechanics (ISB) to determine tibiofemoral kinematics of the native (i.e., healthy) knee, determine variability associated with each JCS, and determine whether the FUNC JCS significantly reduced kinematic crosstalk errors compared to the ISB JCS. Based on a kinematic model consisting of a three-cylindric joint chain, the FUNC JCS included functional flexion-extension (F-E) and internal-external (I-E) tibial rotation axes. In contrast, the ISB JCS included F-E and I-E axes defined using anatomic landmarks. Single-plane fluoroscopic images in 13 subjects performing a weighted deep knee bend were analyzed. Tibiofemoral kinematics using the FUNC JCS fell within the physiological range of motion in all six degrees-of-freedom. Internal tibial rotation averaged 13 deg for the FUNC JCS versus 10 deg for the ISB JCS and motions in the other four degrees-of-freedom (collectively termed off-axis motions) were minimal as expected based on biomechanical constraints. Off-axis motions for the ISB JCS were significantly greater; maximum valgus rotation was 4 deg and maximum anterior and distraction translations were 9 mm and 25 mm, respectively, which is not physiologic. Variabilities in off-axis motions were significantly greater with the ISB JCS (p < 0.0002). The FUNC JCS achieved clinically meaningful kinematics by significantly reducing kinematic crosstalk errors and is the more suitable coordinate system for quantifying tibiofemoral motions.


Aldehyde Dehydrogenase 2 Family Member (ALDH2) Is a Therapeutic Index for Oxaliplatin Response on Colorectal Cancer Therapy with Dysfunction p53.
Oxaliplatin resistance is a major issue in the treatment of p53 mutant colorectal cancer (CRC). Finding the specific biomarkers would improve therapeutic efficacy of patients with CRC. In order to figure out the biomarker for CRC patients with mutant p53 access oxaliplatin, a Gene Expression Omnibus dataset (GSE42387) was used to determine differentially expressed genes (DEGs). The Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape software were used to predict protein-protein interactions. The Database for Annotation, Visualization, and Integrated Discovery online tool was used to group the DEGs into their common pathways. 138 DEGs were identified with 46 upregulated and 92 downregulated. In the PPI networks, 7 of the upregulated genes and 13 of the downregulated genes were identified as hub genes (high degrees). Four hub genes, aldehyde dehydrogenase 2 family member (ALDH2), aldo-keto reductase family 1 member B1 (AKR1B1), aldo-keto reductase family 1 member B10 (AKR1B10), and monoglyceride lipase (MGLL) were enriched in the most significant pathway, glycerolipid metabolism. Further, we found that low expression of ALDH2 is correlated with poor overall survival and oxaliplatin resistance. Finally, we found that combined treatment with ALDH2 inhibitor and oxaliplatin will reduce the sensitivity to oxaliplatin in p53 mutant HT29 cells. In conclusion, we demonstrate that ALDH2 may be a biomarker for oxaliplatin resistance status in CRC patients and bring new insight into treatment strategy for p53 mutant CRC patients.


Pregnancy in a patient with 47,XX,i(Xq) karyotype.
A phenotypically normal woman with a 47,XX,i(Xq) karyotype is reported. She has had two successful pregnancies monitored by prenatal diagnosis with the delivery of normal offspring. The presence of a structurally abnormal third X chromosome has not demonstrably affected this patient or her reproduction. The importance of the human X and Y chromosomes in sexual differentiation is readily apparent. Patients with anomalies of the X chromosome most frequently have clinical features of Turner's syndrome. Much less clearly defined are patients who possess additional X chromosome material. For example, triple X females are not easily distinguishable from 46,XX females. Only a few cases have been reported of patients who have a 47,XXX karyotype with the third X chromosome being structurally abnormal. This report describes a patient with a 47,XX,i(Xq) (qter leads to cen leads to qter) karyotype.


Genetic polymorphisms of alcohol and aldehyde dehydrogenases and glutathione S-transferase M1 and drinking, smoking, and diet in Japanese men with esophageal squamous cell carcinoma.
The genetic polymorphisms of aldehyde dehydrogenase-2 (ALDH2), alcohol dehydrogenase-2 (ADH2), ADH3, and glutathione S-transferase M1 (GSTM1) influence the metabolism of alcohol and other carcinogens. The ALDH2*1/2*2 genotype, which encodes inactive ALDH2, and ADH2*1/2*1, which encodes the low-activity form of ADH2, enhance the risk for esophageal cancer in East Asian alcoholics. This case-control study of whether the enzyme-related vulnerability for esophageal cancer can be extended to a general population involved 234 Japanese men with esophageal squamous cell carcinoma and 634 cancer-free Japanese men who received annual health checkups. The GSTM1 genotype was not associated with the risk for this cancer. Light drinkers (1-8.9 units/week) with ALDH2*1/2*2 had an esophageal cancer risk 5.82 times that of light drinkers with ALDH2*1/2*1 (reference category), and their risk was similar to that of moderate drinkers (9-17.9 units/week) with ALDH2*1/2*1 (odds ratio = 5.58). The risk for moderate drinkers with ALDH2*1/2*2 (OR = 55.84) exceeded that for heavy drinkers (18+ units/week) with ALDH2*1/2*1 (OR = 10.38). Similar increased risks were observed for those with ADH2*1/2*1. A multiple logistic model including ALDH2, ADH2, and ADH3 genotypes showed that the ADH3 genotype does not significantly affect the risk for esophageal cancer. For individuals with both ALDH2*1/2*2 and ADH2*1/2*1, the risk of esophageal cancer was enhanced in a multiplicative fashion (OR = 30.12), whereas for those with either ALDH2*1/2*2 or ADH2*1/2*1 alone the ORs were 7.36 and 4.11. In comparison with the estimated population-attributable risks for preference for strong alcoholic beverages (30.7%), smoking (53.6%) and for lower intake of green and yellow vegetables (25.7%) and fruit (37.6%), an extraordinarily high proportion of the excessive risk for esophageal cancer in the Japanese males can be attributed to drinking (90.9%), particularly drinking by persons with inactive heterozygous ALDH2 (68.5%). Education regarding these risky conditions in connection with ALDH2 and ADH2 is vitally important in a new strategic approach aimed at preventing esophageal cancer in East Asians.


A global compendium of human dengue virus occurrence.
A global geographic database of human dengue virus occurrence was produced to generate a global risk map and associated burden estimates(1). Herein we present the database, which comprises occurrence data linked to point or polygon locations, derived from peer-reviewed literature and case reports as well as informal online sources. Entries date from 1960 to 2012. We describe all data collection processes in full, as well as geo-positioning, database management and quality-control procedures. This is the most comprehensive database of confirmed human dengue infection to-date, consisting of 8,309 geo-positioned occurrences in total.


Hepatic injury in adult coeliac disease.
In an attempt to determine the frequency of liver injury in adult coeliac disease (A.C.D.) the case records of 74 consecutive patients were examined. In 13 cases histological sections of the liver were available and in 5 of these there were signs of reactive hepatitis. Histological signs of distinct hepatic injury with cirrhosis and/or chronic active hepatitis were found in 7 other patients. In 5 of these serum-IgA was normal, whereas 16 out of 20 control patients with liver cirrhosis not associated with A.C.D. had raised serum-IgA. Serum-aspartate-aminotransferase and serum-alanine-aminotransferase were determined in 53 patients; 29 had raised concentrations. In 19 patients serum-aminotransferases were repeatedly determined before and during the dietary regimen and there was a significant reduction in enzyme concentrations during treatment. The median concentration of serum-alkaline-phosphatase was also reduced during treatment but not significantly. The histological evidence of liver injury in 16% and the abnormal liver-function tests in 39% of the patients indicate that hepatic injury is common in A.C.D. Since liver-function tests or liver biopsy specimens were available for only about two-thirds of the patients, liver damage in A.C.D. may be more common than indicated by these results. The effect of a gluten-free diet on aminotransferase concentrations indicates that the liver injury may be reversible and suggests that in some A.C.D. patients progressive liver damage may be prevented by suitable treatment. Since A.C.D. is not always recognised, the diagnosis should be considered in patients with liver disease of unknown aetiology.


Generation of transmitted/founder HIV-1 infectious molecular clones and characterization of their replication capacity in CD4 T lymphocytes and monocyte-derived macrophages.
Genome sequences of transmitted/founder (T/F) HIV-1 have been inferred by analyzing single genome amplicons of acute infection plasma viral RNA in the context of a mathematical model of random virus evolution; however, few of these T/F sequences have been molecularly cloned and biologically characterized. Here, we describe the derivation and biological analysis of ten infectious molecular clones, each representing a T/F genome responsible for productive HIV-1 clade B clinical infection. Each of the T/F viruses primarily utilized the CCR5 coreceptor for entry and replicated efficiently in primary human CD4(+) T lymphocytes. This result supports the conclusion that single genome amplification-derived sequences from acute infection allow for the inference of T/F viral genomes that are consistently replication competent. Studies with monocyte-derived macrophages (MDM) demonstrated various levels of replication among the T/F viruses. Although all T/F viruses replicated in MDM, the overall replication efficiency was significantly lower compared to prototypic "highly macrophage-tropic" virus strains. This phenotype was transferable by expressing the env genes in an isogenic proviral DNA backbone, indicating that T/F virus macrophage tropism mapped to Env. Furthermore, significantly higher concentrations of soluble CD4 were required to inhibit T/F virus infection compared to prototypic macrophage-tropic virus strains. Our findings suggest that the acquisition of clinical HIV-1 subtype B infection occurs by mucosal exposure to virus that is not highly macrophage tropic and that the generation and initial biological characterization of 10 clade B T/F infectious molecular clones provides new opportunities to probe virus-host interactions involved in HIV-1 transmission.


MicroRNA-29 in aortic dilation: implications for aneurysm formation.
Aging represents a major risk factor for coronary artery disease and aortic aneurysm formation. MicroRNAs (miRs) have emerged as key regulators of biological processes, but their role in age-associated vascular pathologies is unknown. We aim to identify miRs in the vasculature that are regulated by age and play a role in age-induced vascular pathologies. Expression profiling of aortic tissue of young versus old mice identified several age-associated miRs. Among the significantly regulated miRs, the increased expression of miR-29 family members was associated with a profound downregulation of numerous extracellular matrix (ECM) components in aortas of aged mice, suggesting that this miR family contributes to ECM loss, thereby sensitizing the aorta for aneurysm formation. Indeed, miR-29 expression was significantly induced in 2 experimental models for aortic dilation: angiotensin II-treated aged mice and genetically induced aneurysms in Fibulin-4(R/R) mice. More importantly, miR-29b levels were profoundly increased in biopsies of human thoracic aneurysms, obtained from patients with either bicuspid (n=79) or tricuspid aortic valves (n=30). Finally, LNA-modified antisense oligonucleotide-mediated silencing of miR-29 induced ECM expression and inhibited angiotensin II-induced dilation of the aorta in mice. In conclusion, miR-29-mediated downregulation of ECM proteins may sensitize the aorta to the formation of aneurysms in advanced age. Inhibition of miR-29 in vivo abrogates aortic dilation in mice, suggesting that miR-29 may represent a novel molecular target to augment matrix synthesis and maintain vascular wall structural integrity.


Big Data, Efficient Markets, and the End of Daily Fantasy Sports As We Know It?
Fantasy sports are a popular way for individuals to add another layer of enjoyment to their interest in sports. While fantasy sports have been around for many years, access to big data sets and computer power to process them is a relatively new phenomenon, as well as the ability to compete in daily competitions and not just season-long campaigns. We posit that access to new and yet unforeseen data, models, and computing power to manage it, when viewed through the lens of efficient market hypothesis, will cause the daily fantasy sports market to change dramatically. We compare with several other markets to show the effects, when similar technologies become available.


Fixed holograms in iron-doped lithium niobate: simultaneous self-stabilized recording and compensation.
We analyze the mechanisms leading to a highly diffractive fixed hologram in photorefractive Fe-doped lithium niobate crystals by simultaneous self-stabilized holographic recording and compensation at moderately high temperatures. We show that a partially compensated running hologram is produced during recording under this condition and discuss the performance of the process in terms of the operating temperature, the degree of oxidation ([Fe(3+)]/[Fe(2+)] ratio) of the sample, and the effect of the absorption grating arising from the spatial modulation of the Fe(2+) concentration produced during photorefractive recording. We experimentally measure the evolution of the uncompensated remaining hologram during recording and the evolution of the diffraction efficiency of the fixed hologram during white-light development and show that the maximum fixed grating modulation to be achieved is roughly limited by Fe-dopant saturation. A reproducible eta approximately 66% efficiency fixed grating was obtained on a sample exhibiting an otherwise maximum fixed eta approximately 3% when using the classical three-step (recording at room temperature--compensating at high temperature--developing at room temperature) process.


Polyphenolics from peach (Prunus persica var. Rich Lady) inhibit tumor growth and metastasis of MDA-MB-435 breast cancer cells in vivo.
The tumor growth inhibition and anti-metastatic effects of peach polyphenolics were investigated in vivo using a xenograft model and MDA-MB-435 breast cancer cells. Results showed that tumor growth and lung metastasis were inhibited in vivo by peach polyphenolics in a dose range of 0.8-1.6 mg/day, and these effects were mediated by inhibition of metalloproteinases gene expression. Modulation of metalloproteinase-2, metalloproteinase-3 and metalloproteinase-13 gene expression may be some of the molecular targets for anti-metastatic activity of peach polyphenolics. Therefore, these compounds may constitute a novel chemopreventive tool to reduce the risk of metastasis in the combination therapy when primary cancer is diagnosed. Conversion to equivalent human intake for future clinical studies using the body surface area normalization method gave a dose of ~370.6 mg/day for a human adult of 60 kg, which can be supplied by consuming two to three peach fruit per day or alternatively using a dietary supplement peach polyphenol extract powder.


Somatostatin receptor expression in Merkel cell carcinoma as target for molecular imaging.
Merkel cell carcinoma (MCC) is a rare cutaneous neoplasm with increasing incidence, aggressive behavior and poor prognosis. Somatostatin receptors (SSTR) are expressed in MCC and represent a potential target for both imaging and treatment. To non-invasively assess SSTR expression in MCC using PET and the radiotracers [68Ga]DOTA-D-Phe1-Tyr3-octreotide (DOTATOC) or -octreotate (DOTATATE) as surrogate for tumor burden. In 24 patients with histologically proven MCC SSTR-PET was performed and compared to results of computed tomography (CT). SSTR-PET detected primary and metastatic MCC lesions. On a patient-based analysis, sensitivity of SSTR-PET was 73% for nodal metastases, 100% for bone, and 67% for soft-tissue metastases, respectively. Notably, brain metastases were initially detected by SSTR-PET in 2 patients, whereas liver and lung metastases were diagnosed exclusively by CT. SSTR-PET showed concordance to CT results in 20 out of 24 patients. Four patients (17%) were up-staged due to SSTR-PET and patient management was changed in 3 patients (13%). SSTR-PET showed high sensitivity for imaging bone, soft tissue and brain metastases, and particularly in combination with CT had a significant impact on clinical stage and patient management.


Women's experiences with oral and vaginal pre-exposure prophylaxis: the VOICE-C qualitative study in Johannesburg, South Africa.
In VOICE, a multisite HIV pre-exposure prophylaxis (PrEP) trial, plasma drug levels pointed to widespread product nonuse, despite high adherence estimated by self-reports and clinic product counts. Using a socio-ecological framework (SEF), we explored socio-cultural and contextual factors that influenced participants' experience of daily vaginal gel and oral tablet regimens in VOICE. In Johannesburg, a qualitative ancillary study was concurrently conducted among randomly selected VOICE participants assigned to in-depth interviews (n = 41), serial ethnographic interviews (n = 21), or focus group discussions (n = 40). Audiotaped interviews were transcribed, translated, and coded thematically for analysis. Of the 102 participants, the mean age was 27 years, and 96% had a primary sex partner with whom 43% cohabitated. Few women reported lasting nonuse, which they typically attributed to missed visits, lack of product replenishments, and family-related travel or work. Women acknowledged occasionally skipping or mistiming doses because they forgot, were busy, felt lazy or bored, feared or experienced side effects. However, nearly all knew or heard of other study participants who did not use products daily. Three overarching themes emerged from further analyses: ambivalence toward research, preserving a healthy status, and managing social relationships. These themes highlighted the profound and complex meanings associated with participating in a blinded HIV PrEP trial and taking antiretroviral-based products. The unknown efficacy of products, their connection with HIV infection, challenges with daily regimen given social risks, lack of support-from partners and significant others-and the relationship tradeoffs entailed by using the products appear to discourage adequate product use. Personal acknowledgment of product nonuse was challenging. This qualitative inquiry highlighted key influences at all SEF levels that shaped women's perceptions of trial participation and experiences with investigational products. Whether these impacted women's behaviors and may have contributed to ineffective trial results warrants further investigation.


[Estimation of scatter component in SPECT planar image using a Monte Carlo method].
A Monte Carlo simulation was performed to estimate quantitatively the scattered photons in planar images of SPECT. As a phantom we used a water-filled cylinder with a line source and calculated the energy spectra of primary and multiple scattered photons separately at each pixel of the planar images. The energy spectra of primary and scattered photons were studied on following parameters: the size of the phantom; the location of the source; the width of the energy window centered at 72.3 (Tl-201), 141 (Tc-99m), and 159 keV (I-123); and the view angle of the planar images. Obtained results were; (1) the energy spectra of Compton scattered photon varied with the phantom size, the source location, and the photopeak energy, (2) the scattered photons within energy windows of 10-30% centered at the photopeak energy were mainly composed by Compton scatter of the first order, (3) the higher order scattering component of the Compton photons did not represent the location of the line source on the planar image, and (4) the scatter fraction defined by the ratio of the scattered photons to the primary photons increased with increasing the size of the phantom and the width of energy window at the low photopeak energy. From the results, we discussed on the scatter subtraction methods.


Rho-associated kinase II (ROCKII) limits axonal growth after trauma within the adult mouse spinal cord.
Rho GTPases are thought to mediate the action of several axonal growth inhibitors in the adult brain and spinal cord. RhoA has been targeted pharmacologically in both humans and animals to promote neurite outgrowth and functional recovery following CNS trauma. However, rat spinal cord injury studies suggest a complicated and partial benefit of inhibiting Rho or its downstream effector, Rho-associated kinase (ROCKII). This limited benefit may reflect inhibition of other kinases, poor access, or a minimal role of ROCKII in vivo. Therefore, we studied ROCKII mutant mice to probe this pathway genetically. ROCKII(-/-) dorsal root ganglion neurons are less sensitive to inhibition by Nogo protein or by chondroitin sulfate proteoglycan in vitro. We examined adult ROCKII(-/-) mice in two injury paradigms, cervical multilevel dorsal rhizotomy and midthoracic dorsal spinal cord hemisection. After dorsal root crush injury, the ROCKII(-/-) mice recovered use of the affected forepaw more quickly than did controls. Moreover, multiple classes of sensory axons regenerated across the dorsal root entry zone into the spinal cord of mice lacking ROCKII. After the spinal cord injury, ROCKII(-/-) mice showed enhanced local growth of raphespinal axons in the caudal spinal cord and corticospinal axons into the lesion site. Improved functional recovery was not observed by Basso Mouse Scale score following dorsal hemisection, likely due to developmental defects in the nervous system. Together, these findings demonstrate that the ROCKII gene product limits axonal growth after CNS trauma.


Non-invasively assessing disturbance and stress in laboratory rats by scoring chromodacryorrhoea.
In rats, like many rodents, Harderian glands next to the orbits secrete porphyrins, lipids and other compounds. High levels of secretion lead to chromodacryorrhoea (red or "bloody" tears), often taken as a sign of stress or disease. Here, we developed a scoring system for recording chromodacryorrhoea in a quantitative way, and investigated whether the low-level, transient Harderian secretions of normal, healthy rats correlate with low to moderate levels of stress or disturbance. Rather than exposing our subjects (24 Lister Hoodeds, housed in 11 single-sex cages) experimentally to stressors, we made opportunistic use of three likely sources of low-level stress within the unit: 1) building maintenance work, taking several hours and involving several potential stressors; 2) visits by unfamiliar humans, and the other mild sources of disturbance normal in an animal unit; and 3) social status within the cage. The mean daily chromodacryorrhoea score increased most with the severe disturbance of building maintenance work (F1,9 = 602.67, p < < 0.0001), and also increased--though to a lesser extent--with the mild disturbance of visitors and similar (F1,9 = 8.77, p = 0.008), while being the subordinate member of a cage-group had a smaller effect still (F1,6 = 7.86, p = 0.03). Individual rats scored consistently across treatment conditions, and there was also significant inter-observer reliability between independent scorers. We therefore suggest that scoring chromodacryorrhoea could be a simple, practical and non-invasive way of sensitively assessing the impact on rats of housing, husbandry, or procedures.


Differing associations for sport versus occupational physical activity and cardiovascular risk.
We investigate the independent and interacting long-term associations of occupational physical activity (OPA) and sport physical activity (SpPA) with the incidence of coronary heart disease (CHD) and cardiovascular diseases (CVD; CHD plus ischaemic stroke) in North Italian male workers. 3574 employed men aged 25-64 years, free of CVD at baseline, recruited in three population-based and one factory-based cohorts, were included in the analysis. The Baecke Questionnaire was used to assess OPA and SpPA in 'minutes per week' of moderate or vigorous PA. We estimated the associations between different domains of PA and the endpoints, adjusting for major CVD risk factors, using Cox models. During a median follow-up of 14 years, 135 and 174 first CHD and CVD events, fatal and non-fatal, occurred. Compared with the intermediate OPA tertile, the HRs for CHD among low and high OPA workers were 1.66 (95% CI 1.06 to 2.59) and 1.18 (0.72 to 1.94), respectively (P value=0.07). Decreasing trends in CHD and CVD rates across increasing levels of SpPA were also found, with an HR for CVD of 0.68 (0.46 to 0.98) for intermediate/recommended SpPA compared with poor SpPA. We also found a statistically significant SpPA-OPA interaction, and the protective effect of SpPA was only found among sedentary workers, for both endpoints. Conversely, high OPA workers with intermediate/recommended SpPA levels had increased CHD and CVD rates compared with the poor SpPA category. Our results provide further evidence on the health paradox of OPA, with higher CVD rates among workers with intense PA at work. Moreover, the protective effect on CVDs of SpPA is prominent in sedentary workers, but it attenuates and even reverses in moderate and strenuous OPA workers.


Medium term endoscopic assessment of the surgical outcome following laryngeal saccule resection in brachycephalic dogs.
Laryngeal saccule eversion has been widely reported as an important component of brachycephalic airway obstructive syndrome (BAOS). The authors hypothesised that saccules affected by acute histological changes in patients showing marked improvement following palate and nares surgery might spontaneously return to normal; moreover, spontaneous resolution of the eversion in patients with fibrotic saccules and/or without clinical improvement following BAOS surgery might be impossible and, on the contrary, the persistence of turbulent airflow and associated ongoing inflammation might lead to aberrant tissue proliferation after resection. In order to demonstrate our hypotheses, the authors decided to perform a unilateral sacculectomy and to postpone and assess the need for the execution of the contralateral saccule resection according to the findings of a second-look laryngoscopy. Ten dogs were enrolled. None of the saccules left in situ underwent spontaneous resolution of the eversion. In one dog, after sacculectomy, proliferation of a soft tissue lesion endoscopically similar to a newly formed saccule occurred. The results of the present study suggest that spontaneous resolution of saccule eversion is uncommon, even after the correction of the primary abnormalities (palate, nares). Resection of the saccules can relieve ventral rima glottidis obstruction; however, secondary intention healing might occasionally result in the recurrence of the obstruction.


Change in health-related quality of life in patients with coronary artery disease predicts 4-year mortality.
Self-reported health-related quality of life (HRQL) and changes in HRQL have been shown to predict mortality and/or adverse events in patients with coronary artery disease. MacNew Heart Disease HRQL questionnaire scores were examined as predictors of 4-year all-cause mortality. Following referral for angioplasty in 385 patients with coronary artery disease, data were analyzed for differences in all-cause mortality by MacNew Global and subscale baseline and 1- and 3-month change scores (deteriorated ≥0.50; unchanged (-0.49 to +0.49); and improved ≥0.50 points). Mean baseline, 1-month, and 3-month MacNew Global and subscale scores were similar in survivors and non-survivors. Mean 1- and 3-month Global and emotional subscale and mean 1-month social subscale change scores decreased more in non-survivors than survivors. Compared with patients whose Global MacNew HRQL scores improved at one month, 4-year all-cause mortality hazard ratio (HR) was higher in patients whose HRQL deteriorated (HR, 1.70, 95% CI, 1.09, 2.65; p=0.021). Compared with patients whose Global MacNew HRQL improved at three months, 4-year all-cause mortality was higher in both patients whose HRQL had deteriorated (HR, 2.07, 95% CI, 1.29, 3.32; p=0.003) and patients with unchanged HRQL (HR, 2.62, 95% CI, 1.11, 6.17; p=0.028). A deterioration of ≥0.50 points in MacNew HRQL Global scores at both one and three months is predictive of 4-year all-cause mortality. Serial HRQL information may be useful to identify patients at higher risk for adverse cardiac events and mortality and may have implications for determining follow-up frequency and treatment in individual patients.


Effects of extracellular fiber architecture on cell membrane shear stress in a 3D fibrous matrix.
Interstitial fluid flow has been shown to affect the organization and behavior of cells in 3D environments in vivo and in vitro, yet the forces driving such responses are not clear. Due to the complex architecture of the extracellular matrix (ECM) and the difficulty of measuring fluid flow near cells embedded in it, the levels of shear stress experienced by cells in this environment are typically estimated using bulk-averaged matrix parameters such as hydraulic permeability. While this is useful for estimating average stresses, it cannot yield insight into how local matrix fiber architecture-which is cell-controlled in the immediate pericellular environment-affects the local stresses imposed on the cell surface. To address this, we used computational fluid dynamics to study flow through an idealized mesh constructed of a cubic lattice of fibers simulating a typical in vitro collagen gel. We found that, in such high porosity matrices, the fibers strongly affect the flow fields near the cell, with peak shear stresses up to five times higher than those predicted by the Brinkman equation. We also found that minor remodeling of the fibers near the cell surface had major effects on the shear stress profile on the cell. These findings demonstrate the importance of fiber architecture to the fluid forces on a cell embedded in a 3D matrix, and also show how small modifications in the local ECM can lead to large changes in the mechanical environment of the cell.


Suppression of NF-κB signaling by andrographolide with a novel mechanism in human platelets: regulatory roles of the p38 MAPK-hydroxyl radical-ERK2 cascade.
Andrographolide, a novel nuclear factor-κB (NF-κB) inhibitor, is isolated from leaves of Andrographis paniculata. Platelet activation is relevant to a variety of coronary heart diseases. Our recent studies revealed that andrographolide possesses potent antiplatelet activity by activating the endothelial nitric oxide synthase (eNOS)-NO-cyclic GMP pathway. Although platelets are anucleated cells, they also express the transcription factor, NF-κB, that may exert non-genomic functions in platelet activation. Therefore, we further investigated the inhibitory roles of andrographolide in NF-κB-mediated events in platelets. In this study, NF-κB signaling events, including IKKβ phosphorylation, IκBα degradation, and p65 phosphorylation, were time-dependently activated by collagen in human platelets, and these signaling events were attenuated by andrographolide (35 and 75 μM). ODQ and KT5823, respective inhibitors of guanylate cyclase and cyclic GMP-dependent kinase (PKG), strongly reversed andrographolide-mediated inhibition of platelet aggregation, relative [Ca(2+)]i mobilization, and IKKβ, and p65 phosphorylation. In addition, SB203580 (an inhibitor of p38 MAPK), but not PD98059 (an inhibitor of ERKs), markedly abolished IKKβ and p65 phosphorylation. SB203580, NAC (a free-radical scavenger), and BAY11-7082 (an inhibitor of NF-κB) all diminished ERK2 phosphorylation, whereas PD98059, BAY11-7082, and NAC had no effects on p38 MAPK phosphorylation. Furthermore, SB203580, but not BAY11-7082 or PD98059, reduced collagen-induced hydroxyl radical ((·)HO) formation. KT5823 also markedly reversed andrographolide-mediated inhibition of p38 MAPK and ERK2 phosphorylation, and hydroxyl radical formation in platelets. In conclusion, this study demonstrated that andrographolide may involve an increase in cyclic GMP/PKG, followed by inhibition of the p38 MAPK/(·)HO-NF-κB-ERK2 cascade in activated platelets. Therefore, andrographolide may have a high therapeutic potential to treat thromboembolic disorders and may also be considered for treating various inflammatory diseases.


Pontin is essential for murine hematopoietic stem cell survival.
Pontin is a highly conserved DNA helicase/ATPase which is a component of several macromolecular complexes with functions that include DNA repair, telomere maintenance and tumor suppression. While Pontin is known to be essential in yeast, fruit flies and frogs, its physiological role in mammalian organisms remains to be determined. We here find that Pontin is highly expressed in embryonic stem cells and hematopoietic tissues. Through germline inactivation of Ruvbl1, the gene encoding Pontin, we found it to be essential for early embryogenesis, as Ruvbl1 null embryos could not be recovered beyond the blastocyst stage where proliferation of the pluripotent inner cell mass was impaired. Conditional ablation of Ruvbl1 in hematopoietic tissues led to bone marrow failure. Competitive repopulation experiments showed that this included the loss of hematopoietic stem cells through apopotosis. Pontin is, therefore, essential for the function of both embryonic pluripotent cells and adult hematopoietic stem cells.


The Global Drug Facility: a unique, holistic and pioneering approach to drug procurement and management.
In January 2006, the Stop TB Partnership launched the Global Plan to Stop TB 2006-2015, which describes the actions and resources needed to reduce tuberculosis (TB) incidence, prevalence and deaths. A fundamental aim of the Global Plan is to expand equitable access to affordable high-quality anti-tuberculous drugs and diagnostics. A principal tool developed by the Stop TB Partnership to achieve this is the Global Drug Facility (GDF). This paper demonstrates the GDFs unique, holistic and pioneering approach to drug procurement and management by analysing its key achievements. One of these has been to provide 9 million patient-treatments to 78 countries in its first 6 years of operation. The GDF recognized that the incentives provided by free or affordable anti-tuberculosis drugs are not sufficient to induce governments to improve their programmes standards and coverage, nor does the provision of free or affordable drugs guarantee that there is broad access to, and use of, drug treatment in cases where procurement systems are weak, regulatory hurdles exist or there are unreliable distribution and storage systems. Thus, the paper also illustrates how the GDF has contributed towards making sustained improvements in the capacity of countries worldwide to properly manage their anti-TB drugs. This paper also assesses some of the limitations, shortcomings and risks associated with the model. The paper concludes by examining the GDFs key plans and strategies for the future, and the challenges associated with implementation.


Asymmetry of fusiform structure in autism spectrum disorder: trajectory and association with symptom severity.
While asymmetry in the fusiform gyrus (FFG) has been reported in functional and structural studies in typically developing controls (TDC), few studies have examined FFG asymmetry in autism spectrum disorder (ASD) subjects and those studies are limited by small sample sizes, and confounded by cognitive ability or handedness. No previous work has examined FFG surface area or cortical thickness asymmetry in ASD; nor do we understand the trajectory of FFG asymmetry over time. Finally, it is not known how FFG structural asymmetry relates to ASD symptom severity. In this study, we examined FFG volume, surface area, and cortical thickness asymmetry, as well as their cross-sectional trajectories in a large sample of right-handed males aged 7 to 25 years with 128 ASD and 127 TDC subjects using general linear models. In addition, we examined the relationship between FFG asymmetry and ASD severity using the Autism Diagnostic Observation Schedule (ADOS) and Gotham autism severity scores. Findings revealed that while group differences were evident with mean leftward asymmetry in ASD and mean near symmetry in TDC volume and surface area, asymmetry for both groups existed on a spectrum encompassing leftward and rightward asymmetry. In ASD subjects, volume asymmetry was negatively associated with ADOS and autism severity score symptom measures, with a subset of rightward asymmetric patients being most severely affected. We also observed differential trajectory of surface area asymmetry: ASD subjects exhibited a change from leftward asymmetry toward symmetry from age 7 to 25, whereas TDCs exhibited the reverse trend with a change from near symmetry toward leftward symmetry over the observed age range. Abnormalities in FFG structural asymmetry are related to symptom severity in ASD and show differential developmental trajectory compared to TDC. This study is the first to note these findings. These results may have important implications for understanding the role of FFG asymmetry in ASD.


Ezh2-dCas9 and KRAB-dCas9 enable engineering of epigenetic memory in a context-dependent manner.
Rewriting of the epigenome has risen as a promising alternative to gene editing for precision medicine. In nature, epigenetic silencing can result in complete attenuation of target gene expression over multiple mitotic divisions. However, persistent repression has been difficult to achieve in a predictable manner using targeted systems. Here, we report that persistent epigenetic memory required both a DNA methyltransferase (DNMT3A-dCas9) and a histone methyltransferase (Ezh2-dCas9 or KRAB-dCas9). We demonstrate that the histone methyltransferase requirement can be locus specific. Co-targeting Ezh2-dCas9, but not KRAB-dCas9, with DNMT3A-dCas9 and DNMT3L induced long-term HER2 repression over at least 50 days (approximately 57 cell divisions) and triggered an epigenetic switch to a heterochromatic environment. An increase in H3K27 trimethylation and DNA methylation was stably maintained and accompanied by a sustained loss of H3K27 acetylation. Interestingly, substitution of Ezh2-dCas9 with KRAB-dCas9 enabled long-term repression at some target genes (e.g., SNURF) but not at HER2, at which H3K9me3 and DNA methylation were transiently acquired and subsequently lost. Off-target DNA hypermethylation occurred at many individual CpG sites but rarely at multiple CpGs in a single promoter, consistent with no detectable effect on transcription at the off-target loci tested. Conversely, robust hypermethylation was observed at HER2. We further demonstrated that Ezh2-dCas9 required full-length DNMT3L for maximal activity and that co-targeting DNMT3L was sufficient for persistent repression by Ezh2-dCas9 or KRAB-dCas9. These data demonstrate that targeting different combinations of histone and DNA methyltransferases is required to achieve maximal repression at different loci. Fine-tuning of targeting tools is a necessity to engineer epigenetic memory at any given locus in any given cell type.


Care of patients with a diagnosis of chronic obstructive pulmonary disease: a cluster randomised controlled trial.
To evaluate a partnership model of care for patients with a diagnosis of chronic obstructive pulmonary disease (COPD). Cluster randomised controlled trial with blinded outcome assessment of 44 general practices in south-western Sydney comprising 451 people with a diagnosis of COPD, conducted between 2006 and 2009. Participants from intervention group practices were visited at their home by a registered nurse with specific training in COPD care who worked with the general practitioner, the patient and other health professionals to develop and implement an individualised care plan based on best-practice guidelines. Participants from control group practices received usual care. The primary outcome was disease-related quality of life measured using the St George's Respiratory Questionnaire (SGRQ) at 12-month follow-up. Other outcomes were overall quality of life, lung function, smoking status, immunisation status, patient knowledge of COPD, and health service use. Of the 451 participants, 257 (57.8%) were confirmed as having COPD on post-bronchodilator spirometry. Follow-up was completed for 330 patients (73.2%). At 12 months, there was no statistically significant difference in the mean SGRQ scores between intervention and control groups (38.7 v 37.6; difference, 1.1; 95% CI, - 1.53-3.74; P = 0.41) or in measures of quality of life, lung function and smoking status. Compared with the control group, in the intervention group, attendance at pulmonary rehabilitation was more frequent (31.1% v 9.6%; OR, 5.16; 95% CI, 2.40-11.10; P = 0.002) and the mean COPD knowledge score was higher (10.5 v 9.8; difference, 0.70; CI, 0.10-1.21; P = 0.02). The nurse-GP partnership intervention did not have an impact on disease-related quality of life at 12-month follow-up. However, there was evidence of improved quality of care, in particular, in attendance at pulmonary rehabilitation and patient knowledge of COPD. Australian Clinical Trials Registry ACTRN012606000304538.


Cellulose Fibre-Reinforced Biofoam for Structural Applications.
Traditionally, polymers and macromolecular components used in the foam industry are mostly derived from petroleum. The current transition to a bio-economy creates demand for the use of more renewable feedstocks. Soybean oil is a vegetable oil, composed mainly of triglycerides, that is suitable material for foam production. In this study, acrylated epoxidized soybean oil and variable amounts of cellulose fibres were used in the production of bio-based foam. The developed macroporous bio-based architectures were characterised by several techniques, including porosity measurements, nanoindentation testing, scanning electron microscopy, and thermogravimetric analysis. It was found that the introduction of cellulose fibres during the foaming process was necessary to create the three-dimensional polymer foams. Using cellulose fibres has potential as a foam stabiliser because it obstructs the drainage of liquid from the film region in these gas-oil interfaces while simultaneously acting as a reinforcing agent in the polymer foam. The resulting foams possessed a porosity of approximately 56%, and the incorporation of cellulose fibres did not affect thermal behaviour. Scanning electron micrographs showed randomly oriented pores with irregular shapes and non-uniform pore size throughout the samples.


Extrapolation of adult data and other data in pediatric drug-development programs.
In 1994, the US Food and Drug Administration (FDA) proposed an approach, based on extrapolation of efficacy findings from adults to the pediatric population, to maximize the use of adult data and other data when designing pediatric drug-development programs. We examined the experience of the FDA in using extrapolation to evaluate how and when it was used and any changes in scientific assumptions over time. We reviewed 370 pediatric studies submitted to the FDA between 1998 and 2008 in response to 159 written requests (166 products) issued under the Pediatric Exclusivity Provision. We identified cases in which efficacy was extrapolated from adult data or other data, we categorized the type of pediatric data required to support extrapolation, and we determined whether the data resulted in new pediatric labeling. Extrapolation of efficacy from adult data occurred for 82.5% of the drug products (137 of 166). Extrapolation was defined as complete for 14.5% of the products (24 of 166) and partial for 68% of them (113 of 166). Approaches to extrapolation changed over time for 19% of the therapeutic indications studied (13 of 67). When extrapolation was used, 61% of the drug products (84 of 137) obtained a new pediatric indication or extension into a new age group; this number decreased to 34% (10 of 29) when there was no extrapolation. Extrapolating efficacy from adult data or other data to the pediatric population can streamline pediatric drug development and help to increase the number of approvals for pediatric use.


A quantum gas microscope for detecting single atoms in a Hubbard-regime optical lattice.
Recent years have seen tremendous progress in creating complex atomic many-body quantum systems. One approach is to use macroscopic, effectively thermodynamic ensembles of ultracold atoms to create quantum gases and strongly correlated states of matter, and to analyse the bulk properties of the ensemble. For example, bosonic and fermionic atoms in a Hubbard-regime optical lattice can be used for quantum simulations of solid-state models. The opposite approach is to build up microscopic quantum systems atom-by-atom, with complete control over all degrees of freedom. The atoms or ions act as qubits and allow the realization of quantum gates, with the goal of creating highly controllable quantum information systems. Until now, the macroscopic and microscopic strategies have been fairly disconnected. Here we present a quantum gas 'microscope' that bridges the two approaches, realizing a system in which atoms of a macroscopic ensemble are detected individually and a complete set of degrees of freedom for each of them is determined through preparation and measurement. By implementing a high-resolution optical imaging system, single atoms are detected with near-unity fidelity on individual sites of a Hubbard-regime optical lattice. The lattice itself is generated by projecting a holographic mask through the imaging system. It has an arbitrary geometry, chosen to support both strong tunnel coupling between lattice sites and strong on-site confinement. Our approach can be used to directly detect strongly correlated states of matter; in the context of condensed matter simulation, this corresponds to the detection of individual electrons in the simulated crystal. Also, the quantum gas microscope may enable addressing and read-out of large-scale quantum information systems based on ultracold atoms.


Balloon occlusion of the carotid artery prior to surgery for neck tumors.
We present the results of presurgical balloon occlusion of the carotid artery in 22 patients with cervical lymphadenopathy stage N3. The procedure was found to be extremely useful in preventing rupture of the carotid artery, considered the most dangerous complication of neck cancer surgery. Complications of the balloon procedure were few (10%) when compared with surgical ligation of the carotid artery (41-54% stroke frequency and 32-60% mortality). This procedure also allows testing of the collateral circulation before final detachment of the balloon, a maneuver that prevents stroke in many patients.


Human humoral responses to antigens of Mycobacterium tuberculosis: immunodominance of high-molecular-mass antigens.
The selection of antigens of Mycobacterium tuberculosis for most studies of humoral responses in tuberculosis patients has been restricted to molecules that were either immunodominant in immunized animals or amenable to biochemical purification rather than those that were reactive with the human immune system. Delineation of antigens that elicit humoral responses during the natural course of disease progression in humans has been hindered by the presence of cross-reactive antibodies to conserved regions on ubiquitous prokaryotic antigens in sera from healthy individuals and tuberculosis patients. The levels of cross-reactive antibodies in the sera were reduced by preadsorption with Escherichia coli lysates, prior to studying their reactivity against a large panel of M. tuberculosis antigens to which the human immune system may be exposed during natural infection and disease. Thus, reactivity against pools of secreted, cellular, and cell wall-associated antigens of M. tuberculosis was assessed by an enzyme-linked immunosorbent assay (ELISA). Initial results suggested that the secreted protein preparation contained antigens most frequently recognized by the humoral responses of pulmonary tuberculosis patients. The culture filtrate proteins were subsequently size fractionated by preparative polyacrylamide gel electrophoresis, characterized by reaction with murine monoclonal antibodies to known antigens of M. tuberculosis by an ELISA, and assessed for reactivity with tuberculous and nontuberculous sera. Results show that a secreted antigen of 88 kDa elicits a strong antibody response in a high percentage of patients with pulmonary tuberculosis. This and other antigens identified on the basis of their reactivity with patient sera may prove useful for developing serodiagnosis for tuberculosis.


Magnetocardiography: current status and perspectives. Part II: Clinical applications.
Magnetocardiography (MCG) is a non-invasive and risk-free technique allowing body surface recording of the magnetic fields generated by the electrical activity of the heart. The MCG recording system allows spatially and temporally accurate measurements of the very weak magnetic fields produced by currents flowing within myocardial fibers during cardiac activity. MCG has now been around for over 30 years, but only recently has progress in instrumentation put the technique on the verge of clinical applicability. This review summarizes the physical principles, instrumentation, main clinical applications and perspectives for the clinical use of MCG. This second part is devoted to the description of the main current clinical applications and perspectives.


Compliant substratum guides endothelial commitment from human pluripotent stem cells.
The role of mechanical regulation in driving human induced pluripotent stem cell (hiPSC) differentiation has been minimally explored. Although endothelial cell (EC) fate from hiPSCs has been demonstrated using small molecules to drive mesoderm induction, the effects of substrate stiffness with regard to EC differentiation efficiency have yet to be elucidated. We hypothesized that substrate compliance can modulate mesoderm differentiation kinetics from hiPSCs and affect downstream EC commitment. To this end, we used polydimethylsiloxane (PDMS)-a transparent, biocompatible elastomeric material-as a substrate to study EC commitment of hiPSCs using a stepwise differentiation scheme. Using physiologically stiff (1.7 MPa) and soft (3 kPa) PDMS substrates, compared to polystyrene plates (3 GPa), we demonstrate that mechanical priming during mesoderm induction activates the Yes-associated protein and drives Wnt/β-catenin signaling. When mesoderm differentiation was induced on compliant PDMS substrates in both serum and serum-free E6 medium, mesodermal genetic signatures (T, KDR, MESP-1, GATA-2, and SNAIL-1) were enhanced. Furthermore, examination of EC fate following stiffness priming revealed that compliant substrates robustly improve EC commitment through VECad, CD31, vWF, and eNOS marker expression. Overall, we show that substrate compliance guides EC fate by enhancing mesoderm induction through Wnt activation without the addition of small molecules. These findings are the first to show that the mechanical context of the differentiation niche can be as potent as chemical cues in driving EC identity from hiPSCs.