Functional multi-locus QTL mapping of temporal trends in Scots pine wood traits.
Quantitative trait loci (QTL) mapping of wood properties in conifer species has focused on single time point measurements or on trait means based on heterogeneous wood samples (e.g., increment cores), thus ignoring systematic within-tree trends. In this study, functional QTL mapping was performed for a set of important wood properties in increment cores from a 17-yr-old Scots pine (Pinus sylvestris L.) full-sib family with the aim of detecting wood trait QTL for general intercepts (means) and for linear slopes by increasing cambial age. Two multi-locus functional QTL analysis approaches were proposed and their performances were compared on trait datasets comprising 2 to 9 time points, 91 to 455 individual tree measurements and genotype datasets of amplified length polymorphisms (AFLP), and single nucleotide polymorphism (SNP) markers. The first method was a multilevel LASSO analysis whereby trend parameter estimation and QTL mapping were conducted consecutively; the second method was our Bayesian linear mixed model whereby trends and underlying genetic effects were estimated simultaneously. We also compared several different hypothesis testing methods under either the LASSO or the Bayesian framework to perform QTL inference. In total, five and four significant QTL were observed for the intercepts and slopes, respectively, across wood traits such as earlywood percentage, wood density, radial fiberwidth, and spiral grain angle. Four of these QTL were represented by candidate gene SNPs, thus providing promising targets for future research in QTL mapping and molecular function. Bayesian and LASSO methods both detected similar sets of QTL given datasets that comprised large numbers of individuals.


Seeing the oceans in the shadow of Bergen values.
Although oceanographers such as Roger Revelle are typically associated with key indicators of anthropogenic change, he and other scientists at midcentury had very different scientific priorities and ways of seeing the oceans. How can we join the narrative of the triumph of mathematical, dynamic oceanography with the environmental narrative? Dynamic methods entailed a broad set of values that touched the professional lives of marine scientists in a variety of disciplines all over the world, for better or for worse. The present essay highlights three aspects of "Bergen values" in need of greater exploration by scholars. First, how did the dominance of Scandinavian outlooks influence scientific questions across the broad spectrum of oceanography? Second, did oceanographers' particular means of making the oceans legible through instrumentation challenge their ability to perceive the oceans differently? Third, given the immense quantity of data, was the historical legacy of the dynamic oceanographers more descriptive than they imagined?


Diet Quality and Bone Measurements Using HRpQCT and pQCT in Older Community-Dwelling Adults from the Hertfordshire Cohort Study.
There are few data describing associations between dietary patterns and bone microarchitecture. This study investigated the relationship between diet quality and HRpQCT and pQCT measures in older adults. Data were available for 184 men and 166 women. Dietary data were collected at baseline (1998-2003) using an administered food frequency questionnaire. A 'prudent' diet score (PDS) was identified using principal component analysis and used as an indicator of dietary quality. HRpQCT and pQCT images were acquired at follow-up in 2012, from the non-dominant distal radius and tibia using Scanco XtremeCT and Stratec XCT2000 instrument scanners, respectively. The mean (SD) PDS was - 0.24 (1.23) for men and 0.62 (1.14) for women. In women, a significant positive relationship was found between baseline dietary pattern and total and trabecular area at both the radius and the tibia, measured by HRpQCT. Similar trends were observed with pQCT parameters. Positive associations were observed for tibia total area (38% slice). At the radius, significant positive associations were found for total area (4% slice) and polar strength strain index (33% slice). All relationships remained robust to adjustment. For men, although patterns were similar, there were no significant associations for HRpQCT outcomes. Significant associations were observed for baseline PDS and polar strength strain and total area (66% slice) at the radius, measured by pQCT. Our data suggest that diets high in fruit, vegetables, oily fish and whole grain cereals in early old age are associated with greater bone size but not volumetric bone density or microarchitecture in later life in women.


Evidence for secular trends in children's physical activity behaviour.
It is not clear whether the global increase in weight problems in children is the result of excessive energy intake or decreasing energy expenditure. Methodological limitations have made it difficult to analyse. There is evidence that at least part of the problem may lie with increasing energy consumption, but it is important to examine the other side of the energy equation also. However, it is not possible to conclusively describe physical activity trends because of the absence of suitable baseline data. One solution is to summate all available evidence in as many areas of daily activities as possible and then draw tentative conclusions. This review summarises available trend data on direct representations of physical activity in a range of contexts, together with indirect measures such as sedentariness, fitness, and attitudes. The conclusions drawn are: physical activity in clearly defined contexts such as active transport, school physical education, and organised sports is declining in many countries; young people would like to be active but are often constrained by external factors such as school policy or curricula, parental rules in relation to safety and convenience, and physical environmental factors.


Comparison of HE4 and CA125 levels in women with benign gynecologic disorders : Does age or menopausal status matter?
The aim of this study was to measure serum concentrations of human epididymis protein 4 (HE4) in premenopausal and postmenopausal women with benign adnexal tumors and compare HE4 levels with those of cancer antigen 125 (CA125) measured in the same samples. In a retrospectively designed, monocentric study (Department of Gynecology & Obstetrics, General Hospital, Celje, Slovenia, EU), 147 women diagnosed with various benign adnexal tumors were included. Preoperative HE4 and CA125 levels were obtained and analyzed with regard to histopathological classification, menopausal status, and age distribution. A marked difference was observed in patients with endometriomas in which mean CA125 was elevated above the reference range in the premenopausal (mean 90.1 U/ml) and postmenopausal groups (mean 48.5 U/ml), while HE4 levels were within the reference range, irrespective of age or menopausal status. Inflammatory adnexal tumors were associated with elevated levels of CA125 (mean 142.2 U/ml, premenopausal and mean 62.4 U/ml, postmenopausal patients); HE4 levels were not elevated regardless of age or menopausal status. HE4 is elevated less frequently than CA125 in benign adnexal tumors, regardless of age or menopausal status.


Material wealth in 3D: Mapping multiple paths to prosperity in low- and middle- income countries.
Material wealth is a key factor shaping human development and well-being. Every year, hundreds of studies in social science and policy fields assess material wealth in low- and middle-income countries assuming that there is a single dimension by which households can move from poverty to prosperity. However, a one-dimensional model may miss important kinds of prosperity, particularly in countries where traditional subsistence-based livelihoods coexist with modern cash economies. Using multiple correspondence analysis to analyze representative household data from six countries-Nepal, Bangladesh, Ethiopia, Kenya, Tanzania and Guatemala-across three world regions, we identify a number of independent dimension of wealth, each with a clear link to locally relevant pathways to success in cash and agricultural economies. In all cases, the first dimension identified by this approach replicates standard one-dimensional estimates and captures success in cash economies. The novel dimensions we identify reflect success in different agricultural sectors and are independently associated with key benchmarks of food security and human growth, such as adult body mass index and child height. The multidimensional models of wealth we describe here provide new opportunities for examining the causes and consequences of wealth inequality that go beyond success in cash economies, for tracing the emergence of hybrid pathways to prosperity, and for assessing how these different pathways to economic success carry different health risks and social opportunities.


Cannabidiol provides long-lasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis: a role for A2A receptors.
Inflammation in the central nervous system (CNS) is a complex process that involves a multitude of molecules and effectors, and it requires the transmigration of blood leukocytes across the blood-brain barrier (BBB) and the activation of resident immune cells. Cannabidiol (CBD), a non-psychotropic cannabinoid constituent of Cannabis sativa, has potent anti-inflammatory and immunosuppressive properties. Yet, how this compound modifies the deleterious effects of inflammation in TMEV-induced demyelinating disease (TMEV-IDD) remains unknown. Using this viral model of multiple sclerosis (MS), we demonstrate that CBD decreases the transmigration of blood leukocytes by downregulating the expression of vascular cell adhesion molecule-1 (VCAM-1), chemokines (CCL2 and CCL5) and the proinflammatory cytokine IL-1β, as well as by attenuating the activation of microglia. Moreover, CBD administration at the time of viral infection exerts long-lasting effects, ameliorating motor deficits in the chronic phase of the disease in conjunction with reduced microglial activation and pro-inflammatory cytokine production. Adenosine A2A receptors participate in some of the anti-inflammatory effects of CBD, as the A2A antagonist ZM241385 partially blocks the protective effects of CBD in the initial stages of inflammation. Together, our findings highlight the anti-inflammatory effects of CBD in this viral model of MS and demonstrate the significant therapeutic potential of this compound for the treatment of pathologies with an inflammatory component.


Human U6 promoter drives stronger shRNA activity than its schistosome orthologue in Schistosoma mansoni and human fibrosarcoma cells.
Blood flukes or schistosomes are the causative agents of human schistosomiasis, one of the major neglected tropical diseases. Draft genome sequences have been reported for schistosomes, but functional genomics tools are needed to investigate the role and essentiality of the newly reported genes. Vector based RNA interference can contribute to functional genomics analysis for schistosomes. Using mRNA encoding reporter firefly luciferase as a model target, we compared the performance of a schistosome and a human promoter from the U6 gene in driving shRNA in human fibrosarcoma cells and in cultured schistosomes. Further, both a retroviral [Murine leukemia virus (MLV)] and plasmid (piggyBac, pXL-Bac II) vector were utilized. The schistosome U6 gene promoter was 270 bp in length, the human U6 gene promoter was 264 bp; they shared 41% identity. Following transduction of both HT1080 fibrosarcoma cells and schistosomules of Schistosoma mansoni with pseudotyped MLV virions, stronger knockdown of luciferase activity was seen with the virions encoding the human U6 promoter driven shRNA than the schistosome U6 promoter. A similar trend was seen after transfection of HT1080 cells and schistosomules with the pXL-Bac-II constructs-stronger knockdown of luciferase activity was seen with constructs encoding the human compared to schistosome U6 promoter. The findings indicate that a human U6 gene promoter drives stronger shRNA activity than its schistosome orthologue, not only in a human cancer cell line but also in larval schistosomes. This RNA polymerase III promoter represents a potentially valuable component for vector based RNA interference studies in schistosomes and related platyhelminth parasites.


Review: cerebral amyloid angiopathy, prion angiopathy, CADASIL and the spectrum of protein elimination failure angiopathies (PEFA) in neurodegenerative disease with a focus on therapy.
Failure of elimination of proteins from the brain is a major feature in many neurodegenerative diseases. Insoluble proteins accumulate in brain parenchyma and in walls of cerebral capillaries and arteries. Cerebral amyloid angiopathy (CAA) is a descriptive term for amyloid in vessel walls. Here, we adopt the term protein elimination failure angiopathy (PEFA) to focus on mechanisms involved in the pathogenesis of a spectrum of disorders that exhibit both unique and common features of protein accumulation in blood vessel walls. We review (a) normal pathways and mechanisms by which proteins and other soluble metabolites are eliminated from the brain along 100- to 150-nm-thick basement membranes in walls of cerebral capillaries and arteries that serve as routes for lymphatic drainage of the brain; (b) a spectrum of proteins involved in PEFA; and (c) changes that occur in artery walls and contribute to failure of protein elimination. We use accumulation of amyloid beta (Aβ), prion protein and granular osmiophilic material (GOM) in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) as examples of different factors involved in the aetiology and pathogenesis of PEFA. Finally, we discuss how knowledge of factors involved in PEFA may help to focus on new therapies for neurodegenerative diseases. When Aβ (following immunotherapy) and prion protein are released from brain parenchyma they deposit in walls of cerebral capillaries and arteries; GOM in CADASIL accumulates primarily in artery walls. Therefore, the focus of therapy for protein clearance in neurodegenerative disease should perhaps be on facilitating perivascular elimination of proteins and reducing PEFA.


Noninvasive positive pressure ventilation to treat respiratory failure.
To review the clinical use of noninvasive positive pressure ventilation, including its efficacy with acute and chronic forms of respiratory failure, its mechanism of action, and its implementation. Studies were identified through a MEDLINE search using the key words respiratory failure and mechanical ventilation and through a manual review of reference lists of published articles. All original studies relating to the use of noninvasive positive pressure ventilation in respiratory failure were included. Because of the paucity of controlled trials, cohort studies were not excluded. Study design, numbers and diagnoses of patients, ventilator modes, and success and complication rates were extracted and compiled. For acute respiratory failure, studies report improved gas exchange and avoidance of intubation in 60% to 80% of patients with chronic obstructive pulmonary disease, restrictive thoracic disease, congestive heart failure, pneumonia, or postoperative extubation failure. However, the patients were highly selected, and relatively few studies have been published, only one of which was a randomized controlled trial. For chronic respiratory failure due to restrictive thoracic disease, all studies report improved gas exchange and symptoms of hypoventilation after prolonged nocturnal use, although no study was controlled. Some cohort studies of patients with severe chronic obstructive pulmonary disease yielded favorable results, but longer-term, randomized, controlled studies showed minimal, if any, benefit. Noninvasive positive pressure ventilation is effective in the treatment of chronic respiratory failure due to restrictive thoracic diseases. The routine use of such treatment for chronic respiratory failure due to chronic obstructive pulmonary disease and for acute respiratory failure needs to be studied in randomized controlled trials in better-defined patient subsets.


Differential association of cytoplasmic signalling molecules SHP-1, SHP-2, SHIP and phospholipase C-gamma1 with PECAM-1/CD31.
Recent studies have shown that, in addition to its role as an adhesion receptor, platelet endothelial cell adhesion molecule 1/CD31 becomes phosphorylated on tyrosine residues Y663 and Y686 and associates with protein tyrosine phosphatases SHP-1 and SHP-2. In this study, we screened for additional proteins which associate with phosphorylated platelet endothelial cell adhesion molecule 1, using surface plasmon resonance. We found that, besides SHP-1 and SHP-2, platelet endothelial cell adhesion molecule 1 binds the cytoplasmic signalling proteins SHIP and PLC-gamma1 via their Src homology 2 domains. Using two phosphopeptides, NSDVQpY663TEVQV and DTETVpY686SEVRK, we demonstrate differential binding of SHP-1, SHP-2, SHIP and PLC-gamma1. All four cytoplasmic signalling proteins directly associate with cellular platelet endothelial cell adhesion molecule 1, immunoprecipitated from pervanadate-stimulated THP-1 cells. These results suggest that overlapping immunoreceptor tyrosine-based inhibition motif/immunoreceptor tyrosine-based activation motif-like motifs within platelet endothelial cell adhesion molecule 1 mediate differential interactions between the Src homology 2 containing signalling proteins SHP-1, SHP-2, SHIP and PLC-gamma1.


The anatomy of health care in the United States.
Health care in the United States includes a vast array of complex interrelationships among those who receive, provide, and finance care. In this article, publicly available data were used to identify trends in health care, principally from 1980 to 2011, in the source and use of funds ("economic anatomy"), the people receiving and organizations providing care, and the resulting value created and health outcomes. In 2011, US health care employed 15.7% of the workforce, with expenditures of $2.7 trillion, doubling since 1980 as a percentage of US gross domestic product (GDP) to 17.9%. Yearly growth has decreased since 1970, especially since 2002, but, at 3% per year, exceeds any other industry and GDP overall. Government funding increased from 31.1% in 1980 to 42.3% in 2011. Despite the increases in resources devoted to health care, multiple health metrics, including life expectancy at birth and survival with many diseases, shows the United States trailing peer nations. The findings from this analysis contradict several common assumptions. Since 2000, (1) price (especially of hospital charges [+4.2%/y], professional services [3.6%/y], drugs and devices [+4.0%/y], and administrative costs [+5.6%/y]), not demand for services or aging of the population, produced 91% of cost increases; (2) personal out-of-pocket spending on insurance premiums and co-payments have declined from 23% to 11%; and (3) chronic illnesses account for 84% of costs overall among the entire population, not only of the elderly. Three factors have produced the most change: (1) consolidation, with fewer general hospitals and more single-specialty hospitals and physician groups, producing financial concentration in health systems, insurers, pharmacies, and benefit managers; (2) information technology, in which investment has occurred but value is elusive; and (3) the patient as consumer, whereby influence is sought outside traditional channels, using social media, informal networks, new public sources of information, and self-management software. These forces create tension among patient aims for choice, personal care, and attention; physician aims for professionalism and autonomy; and public and private payer aims for aggregate economic value across large populations. Measurements of cost and outcome (applied to groups) are supplanting individuals' preferences. Clinicians increasingly are expected to substitute social and economic goals for the needs of a single patient. These contradictory forces are difficult to reconcile, creating risk of growing instability and political tensions. A national conversation, guided by the best data and information, aimed at explicit understanding of choices, tradeoffs, and expectations, using broader definitions of health and value, is needed.


Pharmacokinetic optimisation in the treatment of Parkinson's disease : an update.
Pharmacotherapy for Parkinson's disease is focused on dopaminergic drugs, mainly the dopamine precursor levodopa and dopamine receptor agonists. The elimination half-life (t(1/2)) of levodopa from plasma (in combination with a decarboxylase inhibitor) of about 1.5 hours becomes more influential as the disease progresses. The long-duration of response to levodopa, which is evident in early Parkinson's disease, diminishes and after a few years of treatment motor performance is closely correlated to the fluctuating plasma concentrations of levodopa. Absorption of levodopa in the proximal small intestine depends on gastric emptying, which is erratic and may be slowed in Parkinson's disease. The effects of levodopa on motor function are dependent on gastric emptying in patients in the advanced stages of disease. The current treatment concept is continuous dopaminergic stimulation (CDS). Sustained-release formulations of levodopa may provide more stable plasma concentrations. Oral liquid formulations shorten the time to reach peak concentration and onset of effect but do not affect plasma levodopa variability. The t(1/2) of levodopa can be prolonged by adding a catechol-O-methyltransferase inhibitor (entacapone or tolcapone), which may reduce fluctuations in plasma concentrations, although both peak and trough concentrations are increased with frequent administration. Intravenous and enteral (duodenal/jejunal) infusions of levodopa yield stable plasma levodopa concentrations and motor performance. Enteral infusion is feasible on a long-term basis in patients with severe fluctuations. Among the dopamine receptor agonists the ergot derivatives bromocriptine, cabergoline, dihydroergocryptine and pergolide, and the non-ergot derivatives piribedil, pramipexole and ropinirole, have longer t(1/2) compared with levodopa. Thus, they stimulate dopamine receptors in a less pulsatile manner, yet pharmacokinetic studies of repeated doses of dopamine receptor agonists are few. Optimisation of these drugs is often performed with standardised titration schedules. Apomorphine and lisuride have short t(1/2) and are suitable for subcutaneous infusion, with results similar to those of levodopa infusion. Transdermal administration of dopamine receptor agonists such as rotigotine might be an alternative in the future. In general, initial dopamine receptor agonist monotherapy is associated with poorer motor performance and lower incidence of motor complications compared with levodopa. Buccal administration of the monoamine oxidase-B inhibitor selegiline (deprenyl) provides better absorption and less formation of metabolites compared with standard tablets. To conclude, several new drugs, formulations and routes of administration have been introduced in the treatment of Parkinson's disease during the last decade, mainly with CDS as the aim. CDS can be approached by optimising the use of dopaminergic drugs based on pharmacokinetic data.


Combined Effects of UV-B and Drought on Native and Exotic Populations of Verbascum thapsus L.
During plant invasions, exotic species have to face new environmental challenges and are affected by interacting components of global change, which may include more stressful environmental conditions. We investigated an invasive species of New Zealand grasslands, commonly exposed to two concomitant and limiting abiotic factors-high levels of ultraviolet-B radiation and drought. The extent to which Verbascum thapsus may respond to these interacting stress factors via adaptive responses was assessed in a greenhouse experiment comprising native German plants and plants of exotic New Zealand origins. Plants from both origins were grown within four treatments resulting from the crossed combinations of two levels of UV-B and drought. Over twelve weeks, we recorded growth, morphological characteristics, physiological responses and productivity. The results showed that drought stress had the strongest effect on biomass, morphology and physiology. Significant effects of UV-B radiation were restricted to variables of leaf morphology and physiology. We found neither evidence for additive effects of UV-B and drought nor origin-dependent stress responses that would indicate local adaptation of native or exotic populations. We conclude that drought-resistant plant species might be predisposed to handle high UV-B levels, but emphasize the importance of setting comparable magnitudes in stress levels when testing experimentally for antagonistic interaction effects between two manipulated factors.


Phenylthiocarbamide (PTC) perception in ultra-high risk for psychosis participants who develop schizophrenia: testing the evidence for an endophenotypic marker.
Reports suggesting that schizophrenia participants are more likely to be phenylthiocarbamide (PTC) non-tasters when compared to controls have recently been controversial. If supported, a genetic-based phenotypic variation in PTC taster status is implicated, suggesting a greater illness risk for those participants with recessive alleles for the TAS2R38 receptor. Should PTC insensitivity be a schizophrenia endophenotype, then it would be expected in follow-up of ultra high-risk for psychosis participants who later develop schizophrenia (UHR-S). UHR-S was hypothesised to show reduced PTC sensitivity compared to those who were previously at risk, but did not transition (UHR-NP). PTC perception was assessed in 219 UHR participants at long-term follow-up, of whom 53 had transitioned to psychosis (UHR-P) during the follow-up period. Fifteen of the 219 participants were diagnosed with schizophrenia. Seventy-eight had a family history of psychotic disorder. No differences in PTC taster status were found in UHR participants based upon transition to psychosis status, schizophrenia diagnosis, or family history of schizophrenia. This report indicates that schizophrenia development among UHR participants is not associated with PTC tasting deficits and fails to support previous findings that inability to detect the bitter taste of PTC is a schizophrenia endophenotype.


The impact of age on the incidence and severity of post-endoscopic retrograde cholangiopancreatography pancreatitis.
With advancing age there is progressive pancreatic atrophy and fibrosis, leading to tissue destruction and chronic pancreatitis that has been found to be protective against post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). However, there are no reports regarding the potential effect of the aging pancreatic changes on the incidence and severity of PEP. Therefore, the aim of the present study was to investigate the impact of senile changes in the pancreas on the incidence and severity of PEP. A total of 2688 patients who underwent the first therapeutic ERCP at a single center were included in the final analysis of the study. Patients were classified into two groups: 1644 patients aged ≤75 years (mean age 61.56+1.26 years), group A; and 1044 patients aged >75 years (mean age 81.97+4.29 years), group B. Patients' files were identified using a retrospective database linked to the endoscopy reporting system. Patients' characteristic, endoscopic findings, details of intervention and rate and severity of PEP were evaluated. No significant differences between the two groups were observed with regard to ERCP indication, patient- and technique-related risk factors for PEP, presence of periampullary diverticulum, and type of therapeutic intervention. The incidence of PEP was 5.2% in group A and 4% in group B (P=NS) with comparable grades of severity. All episodes of pancreatitis had full recovery with conventional treatment. One death occurred from respiratory arrest in each group of patients. This study shows that the pancreatic changes associated with aging do not influence the incidence and severity of PEP.


Dispersing nano- and micro-sized portlandite particulates via electrosteric exclusion at short screening lengths.
In spite of their high surface charge (zeta potential ζ = +34 mV), aqueous suspensions of portlandite (calcium hydroxide: Ca(OH)2) exhibit a strong tendency to aggregate, and thereby present unstable suspensions. While a variety of commercial dispersants seek to modify the suspension stability and rheology (e.g., yield stress, viscosity), it remains unclear how the performance of electrostatically and/or electrosterically based additives is affected in aqueous environments having either a high ionic strength and/or a pH close to the particle's isoelectric point (IEP). We show that the high native ionic strength (pH ≈ 12.6, IEP: pH ≈ 13) of saturated portlandite suspensions strongly screens electrostatic forces (Debye length: κ-1 = 1.2 nm). As a result, coulombic repulsion alone is insufficient to mitigate particle aggregation and affect rheology. However, a longer-range geometrical particle-particle exclusion that arises from electrosteric hindrance caused by the introduction of comb polyelectrolyte dispersants is very effective at altering the rheological properties and fractal structuring of suspensions. As a result, comb-like dispersants that stretch into the solvent reduce the suspension's yield stress by 5× at similar levels of adsorption as compared to linear dispersants, thus enhancing the critical solid loading (i.e., at which jamming occurs) by 1.4×. Significantly, the behavior of diverse dispersants is found to be inherently related to the thickness of the adsorbed polymer layer on particle surfaces. These outcomes inform the design of dispersants for concentrated suspensions that present strong charge screening behavior.


Comparative effectiveness of pharmacotherapies for prevention of atrial fibrillation following coronary artery bypass surgery.
Risk of atrial fibrillation (AF) after coronary artery bypass grafting (CABG) is high, yet the effectiveness of guideline-recommended preoperative prophylaxis in clinical practice remains uncertain. We determined the utilization and variation of preoperative AF prevention and assessed the comparative effectiveness of alternative drugs using the Society of Thoracic Surgeons multicenter Contemporary Analysis of Perioperative Cardiovascular Surgical Care (CAPS-Care) registry. Among 2,177 patients who underwent high-risk CABG and/or valve surgery, the mean age was 71 ± 9, 66% were men, 26% had chronic lung disease, and 21% had cerebrovascular disease. Overall use of AF prophylaxis was 84% and varied across sites (range 52% to 100%). The most common preventive agents were beta blockers (72%), followed by calcium antagonists (17%). Postoperatively, 30% (n = 646) developed AF at a median of 2 (25th to 75th percentiles: 1 to 3) days after surgery. Increasing age, height, white race, body mass index >35, New York Heart Association class IV heart failure, preoperative dialysis, and concomitant aortic valve replacement were associated with greater odds of postoperative AF (p <0.05 for all). Preoperative amiodarone use was associated with a trend to reduction of postoperative AF (26%, adjusted odds ratio 0.72 [95% confidence interval 0.51 to 1.00], p = 0.052). After adjustment, the odds of postoperative AF were not statistically different across agents. In conclusion, use of AF prophylaxis before surgery varied significantly. In this high-risk population, we were unable to demonstrate that any of the commonly used preventive agents were associated with lower rates of AF compared with alternatives or no treatment.


The ETO protein disrupted in t(8;21)-associated acute myeloid leukemia is a corepressor for the promyelocytic leukemia zinc finger protein.
The ETO protein was originally identified by its fusion to the AML-1 transcription factor in translocation (8;21) associated with the M2 form of acute myeloid leukemia (AML). The resulting AML-1-ETO fusion is an aberrant transcriptional regulator due to the ability of ETO, which does not bind DNA itself, to recruit the transcriptional corepressors N-CoR, SMRT, and Sin3A and histone deacetylases. The promyelocytic leukemia zinc finger (PLZF) protein is a sequence-specific DNA-binding transcriptional factor fused to retinoic acid receptor alpha in acute promyelocytic leukemia associated with the (11;17)(q23;q21) translocation. PLZF also mediates transcriptional repression through the actions of corepressors and histone deacetylases. We found that ETO is one of the corepressors recruited by PLZF. The PLZF and ETO proteins associate in vivo and in vitro, and ETO can potentiate transcriptional repression by PLZF. The N-terminal portion of ETO forms complexes with PLZF, while the C-terminal region, which was shown to bind to N-CoR and SMRT, is required for the ability of ETO to augment transcriptional repression by PLZF. The second repression domain (RD2) of PLZF, not the POZ/BTB domain, is necessary to bind to ETO. Corepression by ETO was completely abrogated by histone deacetylase inhibitors. This identifies ETO as a cofactor for a sequence-specific transcription factor and indicates that, like other corepressors, it functions through the action of histone deactylase.


Challenges and Enablers of Deprescribing: A General Practitioner Perspective.
Deprescribing is the process of reducing or discontinuing medicines that are unnecessary or deemed to be harmful. We aimed to investigate general practitioner (GP) perceived challenges to deprescribing in residential care and the possible enablers that support GPs to implement deprescribing. A qualitative study was undertaken using semi-structured, face-to-face interviews from two cities in New Zealand and a purpose-developed pilot-tested interview schedule. Interviews were recorded with permission and transcribed verbatim. Transcripts were read and re-read and themes were identified with iterative building of a coding list until all data was accounted for. Interviews continued until saturation of ideas occurred. Analysis was carried out with the assistance of a Theoretical Domains Framework (TDF) and constant comparison techniques. Several themes were identified. Challenges and enablers of deprescribing were determined based on participants' answers. Ten GPs agreed to participate. Four themes were identified to define the issues around prescribing for older people, from the GPs' perspectives. Theme 1, the 'recognition of the problem', discusses the difficulties involved with prescribing for older people. Theme 2 outlines the identified behaviour change factors relevant to the problem. Deprescribing challenges were drawn from these factors and summarised in Theme 3 under three major headings; 'prescribing factors', 'social influences' and 'policy and processes'. Deprescribing enablers, based on the opinions and professional experience of GPs, were retrieved and summarised in Theme 4. The process of deprescribing is laced with many challenges for GPs. The uncertainty of research evidence in older people and social factors such as specialists' and nurses' influences were among the major challenges identified. Deprescribing enablers encompassed support for GPs' awareness and knowledge, improvement of communication between multiple prescribers, adequate reimbursement and pharmacists being involved in the multidisciplinary team.


Comparative study of isolates from community-acquired and catheter-associated urinary tract infections with reference to biofilm-producing property, antibiotic sensitivity and multi-drug resistance.
Urinary tract infection (UTI) can be community-acquired (Com-UTI) or catheter-associated (CAUTI) and may be associated with biofilm-producing organisms. A comparative analysis of biofilm-producing property (BPP), antibiotic-sensitivity and multi-drug resistance (MDR) and their relation with the BPP of isolates from Com-UTI and CAUTI has not yet been performed and necessitated this study. (1) isolation of bacteria from CAUTI and Com-UTI and identification of their BPP, antibiotic-sensitivity and MDR status; (2) comparison of the isolates from CAUTI and Com-UTI as regards BPP, MDR status and their relation with BPP. isolates from 100 cases each of Com-UTI and CAUTI were subjected to Congo redagar (CRA) and Safranin tube tests. Antibiotic susceptibility was investigated using the disc diffusion method. Both groups were compared regarding BPP, drug sensitivity and MDR status. Statistical analyses were performed using χ2 and Fisher's exact tests. 76.19 % of isolates from Com-UTI and 60.72 % from CAUTI had BPP (P=0.0252; significant). The Safranin tube test detected more isolates with BPP than the CRA test. MDR is greater in CAUTI than Com-UTI (83.33 % versus 64.76 %; P=0.0039; significant). MDR is greater in isolates with BPP in both Com-UTI and CAUTI (76.47 and 62.35 %; non-significant). BPP was found in both Com-UTI and CAUTI. When used together, the Safranin tube test and the CRA test increased the sensitivity of detecting BPP. MDR was higher in CAUTI than Com-UTI. MDR and BPP are not interrelated or associated, especially in settings where it is not certain that isolates were obtained from a well-formed biofilm. However, this does not rule out a higher incidence or prevalence of MDR in isolates with BPP taken directly from the biofilms.


Effects of antenatal corticosteroids given prior to 26 weeks' gestation: a systematic review of randomized controlled trials.
Although it is generally accepted that antenatal corticosteroids reduce neonatal complications after preterm labor, it is unclear at what gestational age this effect starts to occur. We conducted a systematic review of the literature to determine the effects of antenatal corticosteroids given to women at risk of preterm birth <26 weeks' gestation. Two reviewers independently searched electronic databases and the Cochrane Library for randomized controlled trials including women at imminent birth at a gestational age <26 weeks. Nine randomized trials were included. Meta-analyses and meta-regression of trials including participants with a lower gestational age revealed no significant reduction of neonatal mortality and morbidity in the corticosteroid group as compared with nonintervention, in contrast to clear evidence of beneficial effects in trials including women given corticosteroids at a later gestational age. A gestational age-dependent effect of antenatal corticosteroids on neonatal outcomes with lesser treatment benefits in patients <26 weeks' gestational age appears to exist. There is no evidence from randomized controlled trials to support or refute the recommendation of administrating antenatal corticosteroids to women at risk of preterm birth <26 weeks' gestation.


The effect of splanchnic viscera removal upon canine liver regeneration.
The influence of portal blood factors on canine liver regeneration was studied with graded nonhepatic splanchnic evisceration, coupled with 44 and 72 per cent hepatectomies. In one type of experiment, the pancreas was retained while the rest of the intra-abdominal gastrointestinal tract was removed. In a second variety, total pancreatectomy was performed with preservation of the intra-abdominal organs. In a third kind of experiment, total nonhepatic splanchnic evisceration was performed. Liver regeneration after hepatectomy was decreased by all three kinds of viscera removed as judged by deoxyribonucleic acid synthesis, autoradiography and mitotic index. Pancreatectomy and nonpancreatic splanchnic evisceration caused almost equal decreases in the regenerative response. Total nonhepatic splanchnic evisceration essentially halted regeneration during the first three postoperative days and intraportal infusions of insulin or glucagon, or both together, did not reverse this effect. The decrease in liver membrane bound adenyl cyclase activity and biphasic change in liver cyclic 3', 5' -adenosine monophosphate concentrations normally seen after partial hepatectomy were disrupted after the various eviscerations. Adenyl cyclase activity and cyclic 3', 5' -adenosine monophosphate concentrations tended to be higher than normal in the eviscerated dogs. These observations provide more support for our previously proposed hypothesis that control of liver regeneration is by multiple factors. Pancreatic hormones are important modifiers of this response but, by no means, exercise exclusive control. Other substances of gastrointestinal origin, presumably including hormones and nutrient supply apparently play important specific roles. The volume of portal flow is a secondary and nonspecific, but possibly significant, factor.


Flux response of glycolysis and storage metabolism during rapid feast/famine conditions in Penicillium chrysogenum using dynamic (13)C labeling.
The scale-up of fermentation processes frequently leads to a reduced productivity compared to small-scale screening experiments. Large-scale mixing limitations that lead to gradients in substrate and oxygen availability could influence the microorganism performance. Here, the impact of substrate gradients on a penicillin G producing Penicillium chrysogenum cultivation was analyzed using an intermittent glucose feeding regime. The intermittent feeding led to fluctuations in the extracellular glucose concentration between 400 μM down to 6.5 μM at the end of the cycle. The intracellular metabolite concentrations responded strongly and showed up to 100-fold changes. The intracellular flux changes were estimated on the basis of dynamic (13) C mass isotopomer measurements during three cycles of feast and famine using a novel hybrid modeling approach. The flux estimations indicated a high turnover of internal and external storage metabolites in P. chrysogenum under feast/famine conditions. The synthesis and degradation of storage requires cellular energy (ATP and UTP) in competition with other cellular functions including product formation. Especially, 38% of the incoming glucose was recycled once in storage metabolism. This result indicated that storage turnover is increased under dynamic cultivation conditions and contributes to the observed decrease in productivity compared to reference steady-state conditions.


Resveratrol protects against acute chemotherapy toxicity induced by doxorubucin in rat erythrocyte and plasma.
Doxorubicin (Dox), a widely used antitumor anthracycline antibiotic, plays an undisputed key role in the treatment of many neoplasic diseases. In this study, the protective role of resveratrol against Dox-induced erythrocytes and plasma toxicity has been evaluated in rats. Animals were treated with resveratrol (25 mg/kg b.w.) by intraperitoneal injection during 8 days. At the 4(th) day of treatment, rats were intraperitoneally injected with a single dose of Dox (20 mg/kg b.w.). At the end of the treatment, blood samples were collected following standard procedure and processed for oxidative stress parameters (malondialdehyde (MDA), carbonyl protein, free iron, calcium and H(2)O(2) levels), transaminases and antioxidant enzymes as catalase (CAT), peroxidase (POD) and superoxide dismutase (SOD). Data showed that Dox drastically increased erythrocytes and plasma MDA, free iron, H(2)O(2) and carbonyl proteins but decreased calcium levels and also decreased erythrocytes CAT, POD and SOD activity. Besides, Dox decreased plasma CAT and SOD but unexpectedly increased POD activity. Dox also increased plasma ALT and AST levels and decreased them into erythrocytes. Co-treatment with resveratrol counteracted almost all Dox's effects. In conclusion, Dox induced a pro-oxidative stress into erythrocytes and resveratrol exerted real antioxidant properties which can be attributed, at least in part, to free iron and calcium modulation.


The Saccharomyces cerevisiae DNA polymerase alpha catalytic subunit interacts with Cdc68/Spt16 and with Pob3, a protein similar to an HMG1-like protein.
We have used DNA polymerase alpha affinity chromatography to identify factors involved in eukaryotic DNA replication in the yeast Saccharomyces cerevisiae. Two proteins that bound to the catalytic subunit of DNA polymerase alpha (Pol1 protein) are encoded by the essential genes CDC68/SPT16 and POB3. The binding of both proteins was enhanced when extracts lacking a previously characterized polymerase binding protein, Ctf4, were used. This finding suggests that Cdc68 and Pob3 may compete with Ctf4 for binding to Pol1. Pol1 and Pob3 were coimmunoprecipitated from whole-cell extracts with antiserum directed against Cdc68, and Pol1 was immunoprecipitated from whole-cell extracts with antiserum directed against the amino terminus of Pob3, suggesting that these proteins may form a complex in vivo. CDC68 also interacted genetically with POL1 and CTF4 mutations; the maximum permissive temperature of double mutants was lower than for any single mutant. Overexpression of Cdc68 in a pol1 mutant strain dramatically decreased cell viability, consistent with the formation or modulation of an essential complex by these proteins in vivo. A mutation in CDC68/SPT16 had previously been shown to cause pleiotropic effects on the regulation of transcription (J. A. Prendergrast et al., Genetics 124:81-90, 1990; E. A. Malone et al., Mol. Cell. Biol. 11:5710-5717, 1991; A. Rowley et al., Mol. Cell. Biol. 11:5718-5726, 1991), with a spectrum of phenotypes similar to those caused by mutations in the genes encoding histone proteins H2A and H2B (Malone et al., Mol. Cell. Biol. 11:5710-5717, 1991). We show that at the nonpermissive temperature, cdc68-1 mutants arrest as unbudded cells with a 1C DNA content, consistent with a possible role for Cdc68 in the prereplicative stage of the cell cycle. The cdc68-1 mutation caused elevated rates of chromosome fragment loss, a phenotype characteristic of genes whose native products are required for normal DNA metabolism. However, this mutation did not affect the rate of loss or recombination for two intact chromosomes, nor did it affect the retention of a low-copy-number plasmid. The previously uncharacterized Pob3 sequence has significant amino acid sequence similarity with an HMG1-like protein from vertebrates. Based on these results and because Cdc68 has been implicated as a regulator of chromatin structure, we postulate that polymerase alpha may interact with these proteins to gain access to its template or to origins of replication in vivo.


Functional analysis of the Antirrhinum floral homeotic DEFICIENS gene in vivo and in vitro by using a temperature-sensitive mutant.
Flowers of the temperature-sensitive DEFICIENS (DEF) mutant, def-101, display sepaloid petals and carpelloid stamens when grown at 26 degrees C, the non-permissive temperature. In contrast, when cultivated under permissive conditions at 15 degrees C, the morphology of def-101 flowers resembles that of the wild type. Temperature shift experiments during early and late phases of flower development revealed that second and third whorl organ development is differentially sensitive to changes in DEF expression. In addition, early DEF expression seems to control the spatially correct initiation of fourth whorl organ development. Reduction of the def-101 gene dosage differentially affects organogenesis in adjacent whorls: at the lower temperature development of petals in the second whorl and initiation of carpels in the centre of the flower is not affected while third whorl organogenesis follows the mutant (carpelloid) pattern. The possible contribution of accessory factors to organ-specific DEF functions is discussed. In situ analyses of mRNA and protein expression patterns during def-101 flower development at 15 degrees C and at 26 degrees C support previously proposed combinatorial regulatory interactions between the MADS-box proteins DEF and GLOBOSA (GLO), and provide evidence that the autoregulatory control of DEF and GLO expression by the DEF/GLO heterodimer starts after initiation of all organ primordia. Immunolocalisation revealed that both proteins are located in the nucleus. Interestingly, higher growth temperature affects the stability of both the DEF-101 and GLO proteins in vivo. In vitro DNA binding studies suggest that the temperature sensitivity of the def-101 mutant is due to an altered heterodimerisation/DNA-binding capability of the DEF-101 protein, conditioned by the deletion of one amino acid within the K-box, a protein region thought to be involved in protein-protein interaction. In addition, we introduce a mutant allele of GLO, glo-confusa, where insertion of one amino acid impairs the hydrophobic carboxy-terminal region of the MADS-box, but which confers no strong phenotypic changes to the flower. The strong mutant phenotype of flowers of def-101/glo-conf double mutants when grown in the cold represents genetic evidence for heterodimerisation between DEF and GLO in vivo. The potential to dissect structural and functional domains of MADS-box transcription factors is discussed.


Oral ketamine analgesia in chronic pain and problematic rise in blood pressure.
Hospitals and specialists in the UK are increasingly prescribing and dispensing off-license drugs such as ketamine which are not routinely included in the prescribing record of the general practitioner (GP). We present the case of a 67-year-old woman who developed an episode of uncontrolled raised blood pressure (BP) (224/124 mm Hg) following hospital introduction of oral ketamine for chronic pain. This raised BP was not followed up, and she was then found to be persistently hypertensive in the community some months later. No obvious cause for the patient's increase in BP could be identified. Only on reduction of the ketamine dose and introduction of additional antihypertensive medication, did her BP normalise. We postulate that long-term ketamine use may have been associated with this unexpected and persistent rise in BP. Clinicians should monitor BP closely during ketamine therapy and be wary of new hypertension associated with its long-term use. Further research is needed on the long-term effects of ketamine on BP.


Truly distributed birefringence measurement of polarization-maintaining fibers based on transient Brillouin grating.
We report on what we believe to be the first truly distributed birefringence measurement of polarization-maintaining fibers (PMFs) based on transient Brillouin grating (TBG). A TBG is created by two short pump pulses in the slow axis of the PMF, and then the birefringence-related TBG spectrum is mapped by scanning a probe pulse launched in the fast axis, where the local birefringence can be calculated using the birefringence induced frequency shift. Two types of widely used PMFs, bow-tie and panda, with a length of 8 m were measured at a spatial resolution of 20 cm, and the results show that the birefringence features a periodic variation, and their variation ranges are approximately 2.4x10(-6) and 1.3x10(-6) along the test fibers, respectively.


Malaria vaccines: past, present and future.
The currently available malaria control tools have allowed malaria elimination in many regions but there remain many regions where malaria control has made little progress. A safe and protective malaria vaccine would be a huge asset for malaria control. Despite the many challenges, efforts continue to design and evaluate malaria vaccine candidates. These candidates target different stages in the life cycle of Plasmodia. The most advanced vaccine candidates target the pre-erythrocytic stages in the life cycle of the parasite and include RTS,S/AS01, which has progressed through clinical development to the stage that it may be licensed in 2015. Attenuated whole-parasite vaccine candidates are highly protective, but there are challenges to manufacture and to administration. Cellular immunity is targeted by the prime-boost approach. Priming vectors trigger only modest responses but these are focused on the recombinant antigen. Boosting vectors trigger strong but broad non-specific responses. The heterologous sequence produces strong immunological responses to the recombinant antigen. Candidates that target the blood stages of the parasite have to result in an immune response that is more effective than the response to an infection to abort or control the infection of merozoites and hence disease. Finally, the sexual stages of the parasite offer another target for vaccine development, which would prevent the transmission of malaria. Today it seems unlikely that any candidate targeting a single antigen will provide complete protection against an organism of the complexity of Plasmodium. A systematic search for vaccine targets and combinations of antigens may be a more promising approach.


Invariances, Laplacian-like wavelet bases, and the whitening of fractal processes.
In this contribution, we study the notion of affine invariance (specifically, invariance to the shifting, scaling, and rotation of the coordinate system) as a starting point for the development of mathematical tools and approaches useful in the characterization and analysis of multivariate fractional Brownian motion (fBm) fields. In particular, using a rigorous and powerful distribution theoretic formulation, we extend previous results of Blu and Unser (2006) to the multivariate case, showing that polyharmonic splines and fBm processes can be seen as the (deterministic vs stochastic) solutions to an identical fractional partial differential equation that involves a fractional Laplacian operator. We then show that wavelets derived from polyharmonic splines have a behavior similar to the fractional Laplacian, which also turns out to be the whitening operator for fBm fields. This fact allows us to study the probabilistic properties of the wavelet transform coefficients of fBm-like processes, leading for instance to ways of estimating the Hurst exponent of a multiparameter process from its wavelet transform coefficients. We provide theoretical and experimental verification of these results. To complement the toolbox available for multiresolution processing of stochastic fractals, we also introduce an extended family of multidimensional multiresolution spaces for a large class of (separable and nonseparable) lattices of arbitrary dimensionality.


Minimally Invasive Plate Osteosynthesis of Humeral Shaft Fractures: Current State of the Art.
Most closed humeral shaft fractures can be successfully managed nonsurgically. However, fractures for which closed treatment is unsuccessful are stabilized using either plates or intramedullary nails. There are shortcomings associated with each technique, including the potential complications of nonunion, infection, shoulder pain, and radial nerve injury. Minimally invasive plate osteosynthesis (MIPO), an innovative alternative treatment, is gaining in popularity. This technique is based on the anterior humeral shaft providing a relatively safe surface for plate application, and limited open exposures proximally and distally allow percutaneous insertion of the necessary implant. More than 40 articles have been published regarding MIPO, and it compares favorably to other available forms of treatment with excellent functional outcomes and a lower rate of iatrogenic radial nerve injury. Larger randomized controlled trials comparing this method with other accepted techniques, including nonsurgical management, are necessary to better define the role of MIPO in the management of humeral shaft fractures.


Lossy-to-lossless compression of medical volumetric data using three-dimensional integer wavelet transforms.
We study lossy-to-lossless compression of medical volumetric data using three-dimensional (3-D) integer wavelet transforms. To achieve good lossy coding performance, it is important to have transforms that are unitary. In addition to the lifting approach, we first introduce a general 3-D integer wavelet packet transform structure that allows implicit bit shifting of wavelet coefficients to approximate a 3-D unitary transformation. We then focus on context modeling for efficient arithmetic coding of wavelet coefficients. Two state-of-the-art 3-D wavelet video coding techniques, namely, 3-D set partitioning in hierarchical trees (Kim et al., 2000) and 3-D embedded subband coding with optimal truncation (Xu et al., 2001), are modified and applied to compression of medical volumetric data, achieving the best performance published so far in the literature-both in terms of lossy and lossless compression.


A novel degron-mediated degradation of the RTG pathway regulator, Mks1p, by SCFGrr1.
Yeast cells respond to mitochondrial dysfunction by altering the expression of a subset of nuclear genes, a process known as retrograde signaling (RS). RS terminates with two transcription factors, Rtg1p and Rtg3p. One positive regulator, Rtg2p, and four negative regulators, Lst8p, Mks1p, and the redundant 14-3-3 proteins, Bmh1p and Bmh2p, control RS upstream of Rtg1/3p. Mks1p is negatively regulated by binding to Rtg2p and positively regulated when bound to Bmh1/2p. Here we report that Grr1p, a component of the SCF(Grr1) E3 ubiquitin ligase, modulates RS by affecting Mks1p levels. Grr1p polyubiquitinates Mks1p not bound to either Rtg2p or to Bmh1/2p, targeting it for degradation. An acidic domain region of Mks1p constitutes the portable Mks1p degron sequence. We have isolated dominant mutations in Grr1p leading to increased Mks1p degradation. These mutations result in a gain of positive charge on the concave surface of the leucine rich repeat (LRR) domain of Grr1p, the proposed substrate binding site. We propose that Mks1p is a central player of RS and is acted upon by multiple regulators of the pathway.


Association between magnesium intake and risk of colorectal cancer among postmenopausal women.
Data relating to magnesium intake and colorectal cancer (CRC) risk in postmenopausal women are incomplete. We investigated the association between total magnesium intake and the risk of CRC in an ethnically diverse cohort of postmenopausal women enrolled in the Women's Health Initiative. Self-reported dietary and supplemental magnesium were combined to form total magnesium intake. Invasive incident CRC was the primary outcome. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). During an average follow-up of 13 years (1,832,319 person-years), of the 140,601 women included for analysis, 2,381 women were diagnosed with CRC (1,982 colon cancer and 438 rectal cancer). After adjustment for potential confounding variables, an inverse association was observed in the highest quintile of total magnesium intake compared to the lowest quintile for risk of CRC (HR 0.79, 95% CI 0.67, 0.94, p trend < 0.0001) and colon cancer (HR 0.80, 95% CI 0.66, 0.97, p trend < 0.0001). A borderline significant inverse association was detected in the highest versus the lowest quintile of total magnesium intake for rectal cancer (HR 0.76, 95% CI 0.51, 1.13, p trend < 0.001). Findings from this study support the hypothesis that magnesium intake around 400 mg/day from both dietary and supplemental sources is associated with a lower incidence of CRC in postmenopausal women.


Loads and Movement Speeds Dictate Differences in Power Output During Circuit Training.
Power training has become a common exercise intervention for improving muscle strength, power, and physical function while reducing injury risk. Few studies, however, have evaluated acute load changes on power output during traditional resistance training protocols. Therefore, the aim of this study was to quantify the effects of different loading patterns on power output during a single session of circuit resistance training (CRT). Nine male (age = 19.4 ± 0.9 years) and 11 female participants (age = 20.6 ± 1.6 years) completed 3 CRT protocols during separate testing sessions using 7 pneumatic exercises. Protocols included heavy load explosive contraction (HLEC: 80% one repetition maximum [1RM], maximum speed concentric-2 seconds eccentric), heavy load controlled contraction (HLCC: 80% 1RM, 2 seconds concentric-2 seconds eccentric), and moderate load explosive contraction (MLEC: 50% 1RM, maximum speed concentric-2 seconds eccentric). Protocols were assigned randomly using a counterbalanced design. Power for each repetition and set were determined using computerized software interfaced with each machine. Blood lactate was measured at rest and immediately postexercise. For male and female participants, average power was significantly greater during all exercises for HLEC and MLEC than HLCC. Average power was greatest during the HLEC for leg press (LP), hip adduction (ADD), and hip abduction (ABD) (p ≤ 0.05), whereas male participants alone produced their greatest power during HLEC for leg curl (LC) (p < 0.001). For male and female participants, significantly greater power was detected by set for LP, lat pull-down (LAT), ADD, LC, and ABD for the MLEC protocol (p < 0.02) and for LP, LAT, CP, and LC for the HLEC protocol (p < 0.03). A condition × sex interaction was seen for blood lactate changes ((Equation is included in full-text article.)= 0.249; p = 0.024), with female participants producing a significantly greater change for MLEC than HLEC (Mdiff = 1.61 ± 0.35 mmol·L; p = 0.011), whereas male participants showed no significant differences among conditions. Performing a CRT protocol using explosive training patterns, especially at high loads for lower-body exercises and moderate loads for upper-body exercises, produces significantly higher power than controlled speed training in most exercises. These results provide exercisers, personal trainers, and strength coaches with information that can assist in the design of training protocols to maximize power output during CRT.


Generation of a cylindrically symmetric, polarized laser beam with narrow linewidth and fine tunability.
We demonstrated a generation of cylindrically symmetric, polarized laser beams with narrow linewidth and fine tunability. Since an LP11 mode beam in an optical fiber is a superposition of an HE21 (hybrid) mode beam and a TE01 or TM01 mode beam, firstly, a higher order transverse (TEM01 or TEM10) mode laser beam with narrow linewidth and fine tunability was generated from an external cavity diode laser (ECDL) in conjunction with a phase adjustment plate. Then the beam generated was passed in a two mode optical fiber. A doughnut shaped laser beam with the cylindrically symmetric polarization (a radially or azimuthally polarized beam) was obtained by properly adding stress-induced birefringence in the optical fiber.


Glomerular sclerosis is prevented during urinary tract obstruction due to podocyte protection.
Urine outflow obstruction activates a variety of profibrotic factors, including the intrarenal renin-angiotensin system. However, the obstruction also nullifies the transmural hydraulic pressure difference across the glomerular capillary wall, an established inducer of glomerulosclerosis. In the present study, we investigated whether, and by what mechanism, urine outflow obstruction affects the process of progressive glomerulosclerosis. For this purpose, we tested the effect of unilateral ureteral obstruction (UUO) of 7 days duration in two distinct mouse models of glomerulosclerosis. In the human immunodeficiency virus (HIV) nephropathy model, where HIV-1 genes are selectively expressed in podocytes and develop progressive podocyte damage and glomerulosclerosis, UUO protected against sclerosis with preservation of podocytes morphologically and immunohistochemically. In contrast, the nonobstructed contralateral kidneys of these mice, as well as sham-operated HIV-1 mouse kidneys, developed severe podocyte injury and glomerulosclerosis. The protection against glomerulosclerosis imparted by ureteral obstruction was also documented in the NEP25 model of podocyte injury, in which a single injection of immunotoxin, LMB2, triggers selective podocyte injury followed by glomerulosclerosis, both of which were protected by UUO. Notably, intervention with an angiotensin II type 1 receptor antagonist provided only a partial protective effect in each of the models. These results demonstrate that urine outflow obstruction protects the glomerulus from progressive sclerosis. The results further reveal that this protection occurs at a very early stage of the pathologic process, namely, damage of podocytes.


Dietary effects on dental diseases.
Dental caries is a highly prevalent chronic disease and its consequences cause a lot of pain and suffering. Sugars, particularly sucrose, are the most important dietary aetiological cause of caries. Both the frequency of consumption and total amount of sugars is important in the aetiology of caries. The evidence establishing sugars as an aetiological factor in dental caries is overwhelming. The foundation of this lies in the multiplicity of studies rather than the power of any one. That statement by the British Nutrition Foundation's Task Force on Oral Health, Diet and Other Factors, sums up the relationship between sugars and caries in Europe. There is no evidence that sugars naturally incorporated in the cellular structure of foods (intrinsic sugars) or lactose in milk or milk products (milk sugars) have adverse effects on health. Foods rich in starch, without the addition of sugars, play a small role in coronal dental caries. The intake of extrinsic sugars beyond four times a day leads to an increase risk of dental caries. The current dose-response relationship between caries and extrinsic sugars suggests that the sugars levels above 60 g/person/day for teenagers and adults increases the rate of caries. For pre-school and young children the intakes should be proportional to those for teenagers; about 30 g/person/day for pre-school children. Fluoride, particularly in toothpastes, is a very important preventive agent against dental caries. Toothbrushing without fluorides has little effect on caries. As additional fluoride to that currently available in toothpaste does not appear to be benefiting the teeth of the majority of people, the main strategy to further reduce the levels of caries, is reducing the frequency of sugars intakes in the diet. Dental erosion rates are considered to be increasing. The aetiology is acids in foods and drinks and to a much lesser extent from regurgitation.


Cyclic ADP-ribose, the ADP-ribosyl cyclase pathway and calcium signalling.
Cyclic adenosine diphosphate-ribose, an endogenous metabolite of nicotinamide adenine dinucleotide was first characterized as a potent Ca2+ mobilizing agent in sea urchin eggs. Mounting evidence points to it being an endogenous activator of Ca(2+)-induced Ca2+ release by non-skeletal muscle ryanodine receptors in several invertebrate and mammalian cell types. Cyclic adenosine diphosphate-ribose is synthesized by adenosine diphosphate-ribosyl cyclases, which have been found to be widespread enzymes. Recent data suggests that cyclic adenosine diphosphate-ribose may function as a second messenger in sea urchin eggs at fertilization and in stimulus secretion coupling in pancreatic beta-cells. A second messenger role for cyclic adenosine diphosphate-ribose requires that its intracellular levels be under the control of extracellular stimuli. Another second messenger, cGMP, stimulates the synthesis of cyclic adenosine diphosphate-ribose from nicotinamide adenine dinucleotide by activating the adenosine diphosphate-ribosyl cyclase pathway in sera urchin eggs and egg homogenates, suggesting that cyclic adenosine diphosphate-ribose may be an intracellular messenger for cell surface receptors or nitric oxide, which activate cGMP-producing guanylate cyclases. Cyclic adenosine diphosphate-ribose may have a similar role to inositol trisphosphate in controlling intracellular calcium signalling with these two calcium-mobilizing second messengers activating ryanodine receptors and inositol trisphosphate receptors respectively.


Childhood epilepsy recorded in primary care in the UK.
To examine temporal trends in the incidence of epilepsy recorded in UK primary care and to evaluate the impact of recent efforts to improve the specificity of diagnosis in children. Birth cohort study using primary care data from The Health Improvement Network, which includes a representative sample of the UK population of approximately 5%. We identified epilepsy recorded in primary care using relatively specific through to relatively sensitive indicators to identify epilepsy. Incidence estimates were based on 344 718 children aged 0-14 years with 1 447 760 years' follow-up between 1994 and 2008. Trends in cumulative incidence were explored with stratified analysis by year-of-birth. Trends in annual incidence were investigated using Poisson regression with adjustment for age, gender and deprivation. Cumulative incidence of recorded epilepsy at age 5 years ranged from 0.38% to 0.68% and annual incidence ranged from 71 to 116/100 000 person-years-at-risk, depending on the indicator used to identify epilepsy. With the most specific indicator for epilepsy, cumulative incidence was 33% lower among children born in 2003-2005 than in children born in 1994-1996, and annual incidence declined by 4% per annum between 2001 and 2008, after adjusting for age, gender and deprivation. Using a more sensitive indicator for epilepsy, the equivalent declines were 47% in cumulative incidence and 9% in annual incidence. The decline since the mid-1990s in epilepsy recorded in primary care may be due to more specific diagnosis, cessation of treatment for some forms of epilepsy, reduced exposure to risk factors or all of these factors.


Methods of anorectal manometry vary widely in clinical practice: Results from an international survey.
Ano-rectal manometry (ARM) is the most commonly performed investigation for assessment of anorectal dysfunction. Its use is supported by expert consensus documents and international guidelines. Variation in technology, data acquisition, and analysis affect results and clinical interpretation. This study examined variation in ARM between institutions to establish the status of current practice. A 50-item web-based questionnaire assessing analysis and interpretation of ARM was distributed by the International Anorectal Physiology Working Group via societies representing practitioners that perform ARM. Study methodology and performance characteristics between institutions were compared. One hundred and seven complete responses were included from 30 countries. Seventy-nine (74%) institutions performed at least two studies per week. Forty-nine centers (47%) applied conventional ARM (≤8 pressure sensors) and 57 (53%) high-resolution ARM (HR-ARM). Specialist centers were most likely to use HR-ARM compared to regional hospitals and office-based practice (63% vs 37%). Most conventional ARM systems used water-perfused technology (34/49); solid-state hardware was more frequently used in centers performing HR-ARM (44/57). All centers evaluated rest and squeeze. There was marked variation in the methods used to report results of maneuvers. No two centers had identical protocols for patient preparation, setup, study, and data interpretation, and no center fully complied with published guidelines. There is significant discrepancy in methods for data acquisition, analysis, and interpretation of ARM. This is likely to impact clinical interpretation, transfer of data between institutions, and research collaboration. There is a need for expert international co-operation to standardize ARM.


Analgesic adherence measurement in cancer patients: comparison between electronic monitoring and diary.
Adherence to analgesics in cancer patients has scarcely been studied. In this study, the Medication Event Monitoring System (MEMS) and medication diaries were compared with respect to feasibility and adherence measurements. Forty-six outpatients with nociceptive pain caused by cancer were asked to use MEMS for their analgesics and to record their medication usage in a diary for four weeks. Seventy-nine percent of the patients used MEMS for the full four-week period; 70% did so for the diary. The majority of patients were satisfied with both MEMS and diary. Adherence data assessed by MEMS and diary were comparable. Patients used the amount of analgesics adequately (taking adherence: 87%) but took them irregularly (timing adherence: 53%). Subgroup analyses in patients using single and multiple analgesic regimens confirmed the comparable suitability of both methods. MEMS and a medication diary are equally useful for analgesic adherence measurement in cancer patients with pain.


Two-dimensional noise reconstruction in proton computed tomography using distance-driven filtered back-projection of simulated projections.
We present a formalism for two-dimensional (2D) noise reconstruction in proton computed tomography (pCT). This is necessary for the application of fluence modulated pCT (FMpCT) since it permits image noise prescription and the corresponding proton fuence optimization. We aimed at extending previously published formalisms to account for the impact of multiple Coulomb scattering (MCS) on projection noise, and the use of filtered back projection (FBP) reconstruction along curved paths with distance driven binning (DDB). 2D noise reconstruction for a beam of protons with parallel initial momentum vectors, and for projections binned both at the rear tracker and with DDB, was established. Monte Carlo (MC) simulations of pCT scans of a water cylinder were employed to generate pCT projections and to calculate their noise for use in 2D noise reconstruction. These were compared to results from an analytical model accounting for MCS for rear tracker binning as well as against the previously published central pixel model which ignores MCS. Image noise reconstructed with the formalism for rear tracker binning and DDB were compared to MC results using annular regions of interest (ROIs). Agreement better than 8% was obtained between the noise of projections calculated with MC simulation and our model. Noise from annular ROIs agreed with our noise reconstructions for rear tracker binning and DDB. The central pixel model ignoring MCS underestimated projection and thus image noise by up to 40% towards the object's edge. The use of DDB decreased the image noise towards the object's edge when compared to rear tracker binning and yielded more uniform noise throughout the image. MCS should not be neglected when predicting image noise for pixels away from the center of an object in a pCT scan due to the increasing influence of the gradient of the object's hull closer to the edges.


Routine assessment of family and community health risks: parent views and what they receive.
To examine the prevalence of parent-provider discussions of family and community health risks during well-child visits and the gaps between which issues are discussed and which issues parents would like to discuss. Data came from the National Survey of Early Childhood Health, a nationally representative sample of parents of 2068 children aged 4 to 35 months. The outcome measures were 1) the reported discussions with pediatric clinicians about 7 family and community health risks and 2) whether the parent believes that pediatric clinicians should ask parents about each risk. Most parents believe that pediatric providers should discuss topics such as smoking in the household, financial difficulties, and emotional support available to the parent. However, with the exception of "household smoking," fewer than half of parents have been asked about these topics by their child's clinician. Parents of black and Hispanic children were more likely than parents of white children to be asked about several of these issues, as were parents of the youngest children and those with publicly financed health insurance. The greatest gap between parents' views and their reports of discussion with the clinician occur for parents of white children and older children. Among parents who hold the view that a topic should be discussed, parents of white and older children are less likely than others to report discussing some or all family and community health risks. The low frequency of discussions for many topics indicates potential unmet need. More universal surveillance of parents with young children might ensure that needs are not missed, particularly given that strong majorities of parents view family and community topics, with the exception of community violence, as appropriate for discussion in clinic visits.


Model selection and averaging in the assessment of the drivers of household food waste to reduce the probability of false positives.
Food waste from households contributes the greatest proportion to total food waste in developed countries. Therefore, food waste reduction requires an understanding of the socio-economic (contextual and behavioural) factors that lead to its generation within the household. Addressing such a complex subject calls for sound methodological approaches that until now have been conditioned by the large number of factors involved in waste generation, by the lack of a recognised definition, and by limited available data. This work contributes to food waste generation literature by using one of the largest available datasets that includes data on the objective amount of avoidable household food waste, along with information on a series of socio-economic factors. In order to address one aspect of the complexity of the problem, machine learning algorithms (random forests and boruta) for variable selection integrated with linear modelling, model selection and averaging are implemented. Model selection addresses model structural uncertainty, which is not routinely considered in assessments of food waste in literature. The main drivers of food waste in the home selected in the most parsimonious models include household size, the presence of fussy eaters, employment status, home ownership status, and the local authority. Results, regardless of which variable set the models are run on, point toward large households as being a key target element for food waste reduction interventions.


Induction of osteopenia during experimental tooth movement in the rat: alveolar bone remodelling and the mechanostat theory.
Increases in bone strains above a certain threshold have a positive effect on bone mass, whereas reductions in strain magnitude lead to bone loss and osteopenia; the term 'mechanostat' has been introduced to describe this tissue-level negative feedback mechanism. The mechanobiology of bone and particularly alveolar bone is poorly understood, and whether the mechanostat theory has any relevance to explaining the osseous changes that occur during orthodontic tooth movement remains unclear. To investigate the relationship further, an expansile force of 0.2 N was applied to the maxillary molars of 36, 6-week-old Wistar rats by helical coil springs. The animals were sacrificed at 1, 2, 4, and 8 days and the tissue response analyzed by histological, biochemical, and finite element (FE) methods. Differences between groups were determined by Student's t-test (two-tailed). The appliance produced an increase in the intermolar width averaging 0.5 mm after 8 days. Tetracycline uptake in the control rats suggested a rapid turnover of bone in both the interradicular domain and the bone-periodontal ligament interface. In the experimental group, however, incorporation of tetracycline into the interradicular domain was reduced and conventional histology revealed evidence of bone loss and osteopenia, in both the experimental and a group of sham-treated positive controls (with inactive, annealed springs). Serum alkaline phosphatase declined significantly in both experimental and sham-treated groups over the 8-day time course, indicating decreased bone formation. Serum acid phosphatase also declined, suggesting a concomitant decrease in bone resorption. Three-dimensional FE analysis of the stresses generated in the bone following occlusal (2 N) and orthodontic loading showed that the orthodontic force created a constant loading condition shielding some areas of bone from mechanical stress. Areas of low mechanical stimulation were coincident with sites of bone loss observed histologically, while bone mass was preserved in areas with higher levels of loading. These findings suggest that (1) the osteopenia resulted from stress shielding of the interradicular bone by the appliance, and a consequent reduction in occlusal loading below the critical threshold required for maintaining normal osseous architecture and (2) the mechanostat model can be employed to explain, at least in part, the response of the bone to orthodontic loading.


Somatotropin-dependent decrease in fatty acid synthase mRNA abundance in 3T3-F442A adipocytes is the result of a decrease in both gene transcription and mRNA stability.
Somatotropin (ST) markedly decreases lipogenesis, fatty acid synthase (FAS) enzyme activity and mRNA abundance in pig adipocytes. The present study was conducted to determine whether the decrease in FAS mRNA in 3T3-F442A adipocytes was the result of a decrease in transcription of the FAS gene and/or a change in FAS mRNA stability. Insulin increased the abundance of FAS mRNA 2-13-fold and fatty acid synthesis 3-7-fold. Somatotropin decreased the stimulatory effect of insulin on the abundance of FAS mRNA and lipogenesis by 40-70% and 20-60% respectively. Subsequent run-on analyses demonstrated that the decrease observed in FAS mRNA in response to ST was associated with an 82% decrease in transcription; ST significantly shortened the half-life of FAS mRNA from 35 to 11 h. To corroborate the run-on analyses, cells were stably transfected with a pFAS-CAT5 (in which CAT stands for chloramphenicol acetyltransferase) reporter construct that contained 2195 bp of the 5' flanking region of the rat FAS gene. Insulin treatment increased FAS-CAT activity 4.7-fold. When ST was added to the insulin-containing medium there was an approx. 60% reduction in FAS-CAT activity. In summary, our results indicate that ST decreases FAS mRNA levels and that this is the result of a marked decrease in both transcription of the FAS gene and stability of the FAS mRNA.


CGTase-catalysed cis-glucosylation of L-rhamnosides for the preparation of Shigella flexneri 2a and 3a haptens.
We report the enzymatic synthesis of α-D-glucopyranosyl-(1→4)-α-L-rhamnopyranoside and α-D-glucopyranosyl-(1→3)-α-L-rhamnopyranoside by using a wild-type transglucosidase in combination with glucoamylase and glucose oxidase. It was shown that Bacillus circulans 251 cyclodextrin glucanotransferase (CGTase, EC 18.104.22.168) can efficiently couple an α-L-rhamnosyl acceptor to a maltodextrin molecule with an α-(1→4) linkage, albeit in mixture with the α-(1→3) regioisomer, thus giving two glucosylated acceptors in a single reaction. Optimisation of the CGTase coupling reaction with β-cyclodextrin as the donor substrate and methyl or allyl α-L-rhamnopyranoside as acceptors resulted in good conversion yields (42-70%) with adjustable glycosylation regioselectivity. Moreover, the efficient chemical conversion of the products of CGTase-mediated cis-glucosylation into protected building blocks (previously used in the synthesis of O-antigen fragments of several Shigella flexneri serotypes) was substantiated. These novel chemoenzymatic strategies towards useful, convenient intermediates in the synthesis of S. flexneri serotypes 2a and 3a oligosaccharides might find applications in developments towards synthetic carbohydrate-based vaccine candidates against bacillary dysentery.


Transcriptome Analysis Reveals Cr(VI) Adaptation Mechanisms in Klebsiella sp. Strain AqSCr.
Klebsiella sp. strain AqSCr, isolated from Cr(VI)-polluted groundwater, reduces Cr(VI) both aerobically and anaerobically and resists up 34 mM Cr(VI); this resistance is independent of the ChrA efflux transporter. In this study, we report the whole genome sequence and the transcriptional profile by RNA-Seq of strain AqSCr under Cr(VI)-adapted conditions and found 255 upregulated and 240 downregulated genes compared to controls without Cr(VI) supplementation. Genes differentially transcribed were mostly associated with oxidative stress response, DNA repair and replication, sulfur starvation response, envelope-osmotic stress response, fatty acid (FA) metabolism, ribosomal subunits, and energy metabolism. Among them, genes not previously associated with chromium resistance, for example, cybB, encoding a putative superoxide oxidase (SOO), gltA2, encoding an alternative citrate synthase, and des, encoding a FA desaturase, were upregulated. The sodA gene encoding a manganese superoxide dismutase was upregulated in the presence of Cr(VI), whereas sodB encoding an iron superoxide dismutase was downregulated. Cr(VI) resistance mechanisms in strain AqSCr seem to be orchestrated by the alternative sigma factors fecl, rpoE, and rpoS (all of them upregulated). Membrane lipid analysis of the Cr(IV)-adapted strain showed a lower proportion of unsaturated lipids with respect to the control, which we hypothesized could result from unsaturated lipid peroxidation followed by degradation, together with de novo synthesis mediated by the upregulated FA desaturase-encoding gene, des. This report helps to elucidate both Cr(VI) toxicity targets and global bacterial response to Cr(VI).


The moral, epistemic, and mindreading components of children's vigilance towards deception.
Vigilance towards deception is investigated in 3- to-5-year-old children: (i) In Study 1, children as young as 3 years of age prefer the testimony of a benevolent rather than of a malevolent communicator. (ii) In Study 2, only at the age of four do children show understanding of the falsity of a lie uttered by a communicator described as a liar. (iii) In Study 3, the ability to recognize a lie when the communicator is described as intending to deceive the child emerges around four and improves throughout the fifth and sixth year of life. On the basis of this evidence, we suggest that preference for the testimony of a benevolent communicator, understanding of the epistemic aspects of deception, and understanding of its intentional aspects are three functionally and developmentally distinct components of epistemic vigilance.


Intradiscal ozone therapy for lumbar disc herniation.
The rationale behind intradiscal O2-O3 therapy is the pain elicited by the mechanical compression of the nerve root, which is associated with periganglionic and periradicular inflammation. This study aimed to determine the effect of intradiscal ozone injection on pain score and satisfaction of patients with low back pain (LBP) secondary to disc herniation. Patients with LBP diagnosed with disc herniation were enrolled in this clinical trial. After prepping and draping the area, intradiscal injection of ozone/oxygen mixture (10 ml, 25μg/ml) was performed under fluoroscopy guide (c-arm). Pain score and patient satisfaction were assessed prior to the injection (baseline) and 1, 3, 6, 12 and 24 months after the injection. Sixty three patients (24 males, 39 females) with mean age of 53.3 ±2.0 y enrolled in the study. The mean±standard deviation (SD) of pain score before intervention was 6.968 ±0.11. Pain score was reduced to 4.25±0.19 at 1 month, 4.33±0.20 at 3 months, 4.87 ±0.21 at 6 months and 5.22 ±0.20 at 24 months. According to the modified MacNab scale success of pain relief was as follows: excellent: 4 (6.3%), good: 17 (26.98 %), sufficient: 13 (20.63 %), poor: 13 (20.63 %), no result: 11 (17.46%), negative: 4 (6.3 %). Intradiscal ozone therapy was determined to provide improved outcomes in patients with single level of bulging and protrusion.


Women's Experience of Facility-Based Childbirth Care and Receipt of an Early Postnatal Check for Herself and Her Newborn in Northwestern Tanzania.
Negative experiences of care may act as a deterrent to current and/or future utilization of facility-based health services. To examine the situation in Tanzania, we conducted a sub-analysis of a cross-sectional household survey conducted in April 2016 in the Mara and Kagera regions of Tanzania. The sample included 732 women aged 15⁻49 years who had given birth in a health facility during the previous two years. Log binomial regression models were used to investigate the association between women's experiences of care during childbirth and the receipt of early postnatal checks before discharge. Overall, 73.1% of women reported disrespect and abuse, 60.1% were offered a birth companion, 29.1% had a choice of birth position, and 85.5% rated facility cleanliness as good. About half of mothers (46.3%) and newborns (51.4%) received early postnatal checks before discharge. Early postnatal checks for both mothers and newborns were associated with no disrespect and abuse (RR: 1.23 and 1.14, respectively) and facility cleanliness (RR: 1.29 and 1.54, respectively). Early postnatal checks for mothers were also associated with choice of birth position (RR: 1.18). The results suggest that a missed opportunity in providing an early postnatal check is an indication of poor quality of the continuum of care for mothers and newborns. Improved quality of care at one stage can predict better care in subsequent stages.


IL-37 Causes Excessive Inflammation and Tissue Damage in Murine Pneumococcal Pneumonia.
Streptococcus pneumoniae infections can lead to severe complications with excessive immune activation and tissue damage. Interleukin-37 (IL-37) has gained importance as a suppressor of innate and acquired immunity, and its effects have been therapeutic as they prevent tissue damage in autoimmune and inflammatory diseases. By using RAW macrophages, stably transfected with human IL-37, we showed a 70% decrease in the cytokine levels of IL-6, TNF-α, and IL-1β, and a 2.2-fold reduction of the intracellular killing capacity of internalized pneumococci in response to pneumococcal infection. In a murine model of infection with S. pneumoniae, using mice transgenic for human IL-37b (IL-37tg), we observed an initial decrease in cytokine expression of IL-6, TNF-α, and IL-1β in the lungs, followed by a late-phase enhancement of pneumococcal burden and subsequent increase of proinflammatory cytokine levels. Additionally, a marked increase in recruitment of alveolar macrophages and neutrophils was noted, while TRAIL mRNA was reduced 3-fold in lungs of IL-37tg mice, resulting in necrotizing pneumonia with augmented death of infiltrating neutrophils, enhanced bacteremic spread, and increased mortality. In conclusion, we have identified that IL-37 modulates several core components of a successful inflammatory response to pneumococcal pneumonia, which lead to increased inflammation, tissue damage, and mortality.


Eating disorders throughout female adolescence.
Eating disorders (EDs) are conditions which are becoming more and more widespread among adolescents and they often lead them to seek the opinion of a professional health caregiver, including gynecologists and pediatricians. EDs, and particularly anorexia nervosa (AN), are usually classified as psychological or psychiatric disorders, but they may have major somatic implications and complications as osteoporosis, nutritional deficiencies, cerebral atrophy, cardiac and metabolic disorders. A key issue in the management is prevention or reduction of both the serious somatic consequences and the important mental health consequences (e.g. depression, psychosocial withdrawal, phobia and suicide), integrating different perspectives (psychological or psychiatric - individual and familial -, genetic, nutritional, pediatric, gynecological). Adolescence is a critical period for the onset of EDs though they may also involve younger children. In this case, the consequences on the development (height, weight, puberty) can also be significant. In this review, we will focus on eating disorders in adolescent girls with an emphasis on AN. We describe variations in ED characteristics and their management depending on age at occurrence. A possible ED should be considered by pediatricians consulted about delayed female growth and puberty as well as gynecologists in patients with primary or secondary amenorrhea or infertility.


Parents' and guardians' views and experiences of accessing routine childhood vaccinations during the coronavirus (COVID-19) pandemic: A mixed methods study in England.
To explore parents' and guardians' views and experiences of accessing National Health Service (NHS) general practices for routine childhood vaccinations during the coronavirus (COVID-19) pandemic in England. Mixed methods approach involving an online cross-sectional survey (conducted between 19th April and 11th May 2020) and semi-structured telephone interviews (conducted between 27th April and 27th May 2020). 1252 parents and guardians (aged 16+ years) who reported living in England with a child aged 18 months or under completed the survey. Nineteen survey respondents took part in follow-up interviews. The majority of survey respondents (85.7%) considered it important for their children to receive routine vaccinations on schedule during the COVID-19 pandemic; however, several barriers to vaccination were identified. These included a lack of clarity around whether vaccination services were operating as usual, particularly amongst respondents from lower income households and those self-reporting as Black, Asian, Chinese, Mixed or Other ethnicity; difficulties in organising vaccination appointments; and fears around contracting COVID-19 while attending general practice. Concerns about catching COVID-19 while accessing general practice were weighed against concerns about children acquiring a vaccine-preventable disease if they did not receive scheduled routine childhood vaccinations. Many parents and guardians felt their child's risk of acquiring a vaccine-preventable disease was low as the implementation of stringent physical distancing measures (from March 23rd 2020) meant they were not mixing with others. To promote routine childhood vaccination uptake during the current COVID-19 outbreak, further waves of COVID-19 infection, and future pandemics, prompt and sustained national and general practice level communication is needed to raise awareness of vaccination service continuation and the importance of timely vaccination, and invitation-reminder systems for vaccination need to be maintained. To allay concerns about the safety of accessing general practice, practices should communicate the measures being implemented to prevent COVID-19 transmission.


Slug-dependent upregulation of L1CAM is responsible for the increased invasion potential of pancreatic cancer cells following long-term 5-FU treatment.
Pancreatic adenocarcinoma is a lethal disease with 5-year survival of less than 5%. 5-fluorouracil (5-FU) is a principal first-line therapy, but treatment only extends survival modestly and is seldom curative. Drug resistance and disease recurrence is typical and there is a pressing need to overcome this. To investigate acquired 5-FU resistance in pancreatic adenocarcinoma, we established chemoresistant monoclonal cell lines from the Panc 03.27 cell line by long-term exposure to increasing doses of 5-FU. 5-FU-resistant cell lines exhibited increased expression of markers associated with multidrug resistance explaining their reduced sensitivity to 5-FU. In addition, 5-FU-resistant cell lines showed alterations typical for an epithelial-to-mesenchymal transition (EMT), including upregulation of mesenchymal markers and increased invasiveness. Microarray analysis revealed the L1CAM pathway as one of the most upregulated pathways in the chemoresistant clones, and a significant upregulation of L1CAM was seen on the RNA and protein level. In pancreatic cancer, expression of L1CAM is associated with a chemoresistant and migratory phenotype. Using esiRNA targeting L1CAM, or by blocking the extracellular part of L1CAM with antibodies, we show that the increased invasiveness observed in the chemoresistant cells functionally depends on L1CAM. Using esiRNA targeting β-catenin and/or Slug, we demonstrate that in the chemoresistant cell lines, L1CAM expression depends on Slug rather than β-catenin. Our findings establish Slug-induced L1CAM expression as a mediator of a chemoresistant and migratory phenotype in pancreatic adenocarcinoma cells.


Time constant/volume relationship of passive expiration in mechanically ventilated ARDS patients.
Since the adult respiratory distress syndrome (ARDS) lung is known to be inhomogeneous, one could expect an uneven distribution of expiratory time constant during uninterrupted mechanical ventilation. We investigated the time constant/volume relationship of passive expiration, and their modification by external resistive elements. In 12 paralysed intubated ARDS patients, we determined the expiratory time constant (tau E) as a function of the expired volume (VE) during uninterrupted mechanical ventilation. Mean expiratory time was 2.9 +/- 0.3 s (+/- SD). VE was divided into five equal volume slices (portions) and a mean tau E calculated from the expiratory tidal volume/flow curve for each slice. The mean values of tau E for each volume slice did not differ significantly throughout expiration, averaging 690 +/- 218 ms (mean +/- SD of five slices and 12 patients). We show that the flow-dependent resistance of the endotracheal tube (RETT) is mainly responsible for the observed time constant homogeneity. We conclude that in ARDS patients during uninterrupted mechanical ventilation the time constants of passive expiration are markedly modified by the flow-dependent resistance of the endotracheal tube (RETT), and also by the external resistance of tubing and ventilator (REX). RETT and REX render tau E about three times larger than the time constant of the patient's respiratory system alone.