Characterization of fortilin, a novel antiapoptotic protein.
Apoptosis is meticulously controlled in living organisms. Its dysregulation has been shown to play a key role in a number of human diseases, including neoplastic, cardiovascular, and degenerative disorders. Bcl-2 family member proteins and inhibitors of apoptosis proteins are two major negative regulators of apoptosis. We report here the characterization of novel antiapoptotic protein, fortilin, which we identified through yeast two-hybrid library screening. Sequence analysis of fortilin revealed it to be a 172-amino acid polypeptide highly conserved from mammals to plants. Fortilin is structurally unrelated to either Bcl-2 family member proteins or inhibitors of apoptosis proteins. Northern blot analysis showed the fortilin message to be ubiquitous in normal tissue but especially abundant in the liver, kidney, and small intestine. Western blot analysis using anti-fortilin antibody showed more extensive expression in cancerous cell lines (H1299, MCF-7, and A549) than in cell lines derived from normal tissue (HEK293). Immunocytochemistry using HeLa cells transiently expressing FLAG-tagged fortilin and immunohistochemistry using human breast ductal carcinoma tissue and anti-fortilin antibody both showed that fortilin is predominantly localized in the nucleus. Functionally, the transient overexpression of fortilin in HeLa cells prevented them, in a dose-dependent fashion, from undergoing etoposide-induced apoptosis. Consistently, U2OS cells stably expressing fortilin protected the cells from cell death induced by etoposide over various concentrations and durations of exposure. In addition, fortilin overexpression inhibited caspase-3-like activity as assessed by the cleavage of fluorogenic substrate benzyloxycarbonyl-DEVD-7-amido-4-(trifluoromethyl)coumarin. Furthermore, the antisense depletion of fortilin from breast cancer cell line MCF-7 was associated with massive cell death. These data suggest that fortilin represents a novel antiapoptotic protein involved in cell survival and apoptosis regulation.


In vitro drug permeation enhancement potential of aloe gel materials.
Aloe vera gel previously showed the ability to increase the bioavailability of vitamins and to enhance the in vitro transport of a macromolecular drug across intestinal epithelial cell monolayers. The purpose of this study is to investigate the potential of other species of aloe to act as drug absorption enhancement agents. The effect of gel materials from three South African aloes; Aloe ferox, A. marlothii and A. speciosa on the transepithelial electrical resistance and permeability of atenolol across excised intestinal tissue of the rat as well as the transport of FITC-dextran across Caco-2 cell monolayers was investigated. The aloe gel materials exhibited the ability to statistically significantly reduce the transepithelial electrical resistance of excised rat intestinal tissue but did not significantly increase the transport of atenolol across this in vitro tissue model at the concentrations tested. At least one concentration of each aloe gel material enhanced the transport of FITC-dextran statistically significantly across Caco-2 cell monolayers. The aloe gel materials showed potential to act as drug absorption enhancing agents across intestinal epithelia. The absorption enhancement effect was dependent on the type of in vitro model and type of drug was investigated.


Selective depletion of plasma prekallikrein or coagulation factor XII inhibits thrombosis in mice without increased risk of bleeding.
Recent studies indicate that the plasma contact system plays an important role in thrombosis, despite being dispensable for hemostasis. For example, mice deficient in coagulation factor XII (fXII) are protected from arterial thrombosis and cerebral ischemia-reperfusion injury. We demonstrate that selective reduction of prekallikrein (PKK), another member of the contact system, using antisense oligonucleotide (ASO) technology results in an antithrombotic phenotype in mice. The effects of PKK deficiency were compared with those of fXII deficiency produced by specific ASO-mediated reduction of fXII. Mice with reduced PKK had ∼ 3-fold higher plasma levels of fXII, and reduced levels of fXIIa-serpin complexes, consistent with fXII being a substrate for activated PKK in vivo. PKK or fXII deficiency reduced thrombus formation in both arterial and venous thrombosis models, without an apparent effect on hemostasis. The amount of reduction of PKK and fXII required to produce an antithrombotic effect differed between venous and arterial models, suggesting that these factors may regulate thrombus formation by distinct mechanisms. Our results support the concept that fXII and PKK play important and perhaps nonredundant roles in pathogenic thrombus propagation, and highlight a novel, specific and safe pharmaceutical approach to target these contact system proteases.


Activated Notch1 target genes during embryonic cell differentiation depend on the cellular context and include lineage determinants and inhibitors.
Notch receptor signaling controls developmental cell fates in a cell-context dependent manner. Although Notch signaling directly regulates transcription via the RBP-J/CSL DNA binding protein, little is known about the target genes that are directly activated by Notch in the respective tissues. To analyze how Notch signaling mediates its context dependent function(s), we utilized a Tamoxifen-inducible system to activate Notch1 in murine embryonic stem cells at different stages of mesodermal differentiation and performed global transcriptional analyses. We find that the majority of genes regulated by Notch1 are unique for the cell type and vary widely dependent on other signals. We further show that Notch1 signaling regulates expression of genes playing key roles in cell differentiation, cell cycle control and apoptosis in a context dependent manner. In addition to the known Notch1 targets of the Hes and Hey families of transcriptional repressors, Notch1 activates the expression of regulatory transcription factors such as Sox9, Pax6, Runx1, Myf5 and Id proteins that are critically involved in lineage decisions in the absence of protein synthesis. We suggest that Notch signaling determines lineage decisions and expansion of stem cells by directly activating both key lineage specific transcription factors and their repressors (Id and Hes/Hey proteins) and propose a model by which Notch signaling regulates cell fate commitment and self renewal in dependence of the intrinsic and extrinsic cellular context.


Marine natural products.
This review covers the literature published in 2003 for marine natural products, with 619 citations (413 for the period January to December 2003) referring to compounds isolated from marine microorganisms and phytoplankton, green algae, brown algae, red algae, sponges, coelenterates, bryozoans, molluscs, tunicates and echinoderms. The emphasis is on new compounds (656 for 2003), together with their relevant biological activities, source organisms and country or origin. Biosynthetic studies or syntheses that lead to the revision of structures or stereochemistries have been included (78), including any first total syntheses of a marine natural product.


Patients' experiences and perceived causes of persisting discomfort following day surgery.
The aim of this study was to describe patients' experiences and perceived causes of persisting discomfort following day surgery. Earlier research has mainly covered symptoms and signs during a recovery period of up to one month, and not dealt with patients' perceptions of what causes persisting, longer-term discomfort. This study is a part from a study carried out during the period May 2006 to May 2007 with a total of 298 day surgery patients. Answers were completed by 118 patients at 48 hours, 110 at seven days and 46 at three months to one open-ended question related to discomfort after day surgery constructed as follows: If you are still experiencing discomfort related to the surgery, what is the reason, in your opinion? Data was processed, quantitatively and qualitatively. Descriptive, inferential, correlation and content analyses were performed. The results suggest that patients suffer from remaining discomfort e.g. pain and wound problem, with effects on daily life following day surgery up to three months. Among patients' perceptions of factors leading to discomfort may be wrongful or suboptimal treatment, type of surgery or insufficient access to provider/information. The results have important implications for preventing and managing discomfort at home following day surgery, and for nursing interventions to help patients handle the recovery period better.


Screening for Exotic Forest Pathogens to Increase Survey Capacity Using Metagenomics.
Anthropogenic activities have a major impact on the global environment. Canada's natural resources are threatened by the spread of fungal pathogens, which is facilitated by agricultural practices and international trade. Fungi are introduced to new environments and sometimes become established, in which case they can cause disease outbreaks resulting in extensive forest decline. Here, we describe how a nationwide sample collection strategy coupled to next-generation sequencing (NGS) (i.e., metagenomics) can achieve fast and comprehensive screening for exotic invasive species. This methodology can help provide guidance to phytopathology stakeholders such as regulatory agencies. Several regulated invasive species were monitored by processing field samples collected over 3 years (2013 to 2015) near high-risk areas across Canada. Fifteen sequencing runs were required on the Ion Torrent platform to process 398 samples that yielded 45 million reads. High-throughput screening of fungal and oomycete operational taxonomic units using customized fungi-specific ribosomal internal transcribed spacer 1 barcoded primers was performed. Likewise, Phytophthora-specific barcoded primers were used to amplify the adenosine triphosphate synthase subunit 9-nicotinamide adenine dinucleotide dehydrogenase subunit 9 spacer. Several Phytophthora spp. were detected by NGS and confirmed by species-specific quantitative polymerase chain reaction (qPCR) assays. The target species Heterobasidion annosum sensu stricto could be detected only through metagenomics. We demonstrated that screening target species using a variety of sampling techniques and NGS-the results of which were validated by qPCR-has the potential to increase survey capacity and detection sensitivity, reduce hands-on time and costs, and assist regulatory agencies to identify ports of entry. Considering that early detection and prevention are the keys in mitigating invasive species damage, our method represents a substantial asset in plant pathology management.


Drug repurposing screens identify compounds that inhibit α-synuclein oligomers' membrane disruption and block antibody interactions.
Small soluble oligomers of the protein α-synuclein (αSO) have been linked to disruptions in neuronal homeostasis, contributing to the development of Parkinson's Disease (PD). While this makes αSO an obvious drug target, the development of effective therapeutics against αSO is challenged by its low abundance and structural and morphological complexity. Here, we employ two different approaches to neutralize toxic interactions made by αSOs with different cellular components. First, we use available data to identify four neuronal proteins as likely candidates for αSO interactions, namely Cfl1, Uchl1, Sirt2 and SerRS. However, despite promising results when immobilized, all 4 proteins only bind weakly to αSO in solution in microfluidic assays, making them inappropriate for screening. In contrast, the formation of stable contacts formed between αSO and vesicles consisting of anionic lipids not only mimics a likely biological role of αSO but also provided a platform to screen two small molecule libraries for disruptors of these contacts. Of the 7 best leads obtained in this way, 2 significantly impaired αSO contacts with other proteins in a sandwich ELISA assay using αSO-binding monoclonal antibodies and nanobodies. In addition, 5 of these leads suppressed α-synuclein amyloid formation. Thus, a repurposing screening that directly targets a key culprit in PD pathogenesis shows therapeutic potential.


The functional promoter polymorphism of the coagulation factor XII gene is not associated with peripheral arterial disease.
Coagulation factor XII (FXII) plays a key role in both coagulation and fibrinolysis and has been associated with cardiovascular disease in some studies. Plasma FXIIa levels are strongly determined by a common functional polymorphism in the promoter of the FXII gene (F12-4C>T). To investigate the potential association of this polymorphism with peripheral arterial disease (PAD), we performed a case-control study including 668 patients with PAD and 762 controls participants without cardiovascular disease. F12 genotype frequencies were not significantly different between patients with PAD and control participants. After adjustment for classical risk factors, the odds ratio of carriers of a F12 -4T allele for PAD was 1.06 (95% confidence interval 0.86-1.32). F12 genotypes were associated with a modest increase of the mean-activated partial thromboplastin time but not with PAD stage or severity. We conclude that the functional F124C>T polymorphism is not associated with PAD.


Using pre-existing microarray datasets to increase experimental power: application to insulin resistance.
Although they have become a widely used experimental technique for identifying differentially expressed (DE) genes, DNA microarrays are notorious for generating noisy data. A common strategy for mitigating the effects of noise is to perform many experimental replicates. This approach is often costly and sometimes impossible given limited resources; thus, analytical methods are needed which increase accuracy at no additional cost. One inexpensive source of microarray replicates comes from prior work: to date, data from hundreds of thousands of microarray experiments are in the public domain. Although these data assay a wide range of conditions, they cannot be used directly to inform any particular experiment and are thus ignored by most DE gene methods. We present the SVD Augmented Gene expression Analysis Tool (SAGAT), a mathematically principled, data-driven approach for identifying DE genes. SAGAT increases the power of a microarray experiment by using observed coexpression relationships from publicly available microarray datasets to reduce uncertainty in individual genes' expression measurements. We tested the method on three well-replicated human microarray datasets and demonstrate that use of SAGAT increased effective sample sizes by as many as 2.72 arrays. We applied SAGAT to unpublished data from a microarray study investigating transcriptional responses to insulin resistance, resulting in a 50% increase in the number of significant genes detected. We evaluated 11 (58%) of these genes experimentally using qPCR, confirming the directions of expression change for all 11 and statistical significance for three. Use of SAGAT revealed coherent biological changes in three pathways: inflammation, differentiation, and fatty acid synthesis, furthering our molecular understanding of a type 2 diabetes risk factor. We envision SAGAT as a means to maximize the potential for biological discovery from subtle transcriptional responses, and we provide it as a freely available software package that is immediately applicable to any human microarray study.


Comparison of the effects of TiF4 and NaF solutions at pH 1.2 and 3.5 on enamel erosion in vitro.
This study aimed to analyse and compare the protective effect of buffered (pH 3.5) and native (pH 1.2) TiF(4) in comparison with NaF solutions on enamel erosion. Bovine samples were pretreated with 1.50% TiF(4) or 2.02% NaF (both 0.48 M F) solutions, each at a pH of 1.2 and 3.5. The control group received no fluoride pretreatment. Twenty samples per group were eroded with HCl (pH 2.6) for 10 x 60 s. Erosion was either investigated by profilometry (n = 10) or by determination of calcium release into the acid (n = 10). Additionally, the elemental surface composition was quantified by X-ray energy-dispersive spectroscopy in fluoridated but not eroded samples (6 samples per group). Scanning electron microscopy was performed prior and after erosion (2 samples per group). Cumulative enamel loss (mum) and calcium release (nmol/mm(2)) were analysed by repeated-measures ANOVA. The Ti and F surface composition was analysed by one-way ANOVA separately for each element. Only TiF(4) at pH 1.2 reduced enamel surface loss significantly. Calcium release was significantly reduced by TiF(4) and NaF at pH 1.2, but not by the solutions at pH 3.5. Samples pretreated with TiF(4) at pH 1.2 showed a significant increase in Ti, while NaF increased F concentration significantly. Only TiF(4) at pH 1.2 induced the formation of a glaze-like layer, which was still present after erosion. Enamel erosion can be significantly reduced by TiF(4) at pH 1.2 but not at pH 3.5. TiF(4) at pH 1.2 was more effective in protecting against enamel erosion than NaF.


Modelling the impact of a healthy diet on cardiovascular disease and cancer mortality.
Quantifying the potential health benefits of improvements in the nutritional quality of the average diet of a population would provide evidence for resource allocation between population-level interventions aimed at reducing chronic disease. A model was built linking consumption of food components with biological risk factors (blood pressure, serum cholesterol and obesity) and subsequent mortality from coronary heart disease, stroke and cancer. Meta-analyses of individual-level studies that quantified the RR of increased consumption/increased risk factor level on disease outcomes were used to build the model. The sensitivity of the model to the results from the meta-analyses was assessed with Monte Carlo simulations. Country-specific estimates of current nutrient intake compared against dietary recommendations for the UK were used to demonstrate the model. Approximately 33 000 deaths per year would be avoided if UK dietary recommendations were met. The modelled reduction in deaths for coronary heart disease was 20 800 (95% credible interval 17 845-24 069), for stroke 5876 (3856-7364) and for cancer 6481 (4487-8353). Over 15 000 of the avoided deaths would be due to increased consumption of fruit and vegetables. The developed model estimates the impact of population-level dietary changes and is robust. Achieving UK dietary recommendations for fruit and vegetable consumption (five portions a day) would result in substantial health benefits-equivalent benefits would be achieved if salt intakes were lowered to 3.5 g per day or saturated fat intakes were lowered to 3% of total energy.


Long-term follow-up of the surgical management of neuropathic arthropathy of the spine.
No studies have discussed the long-term surgical management and outcomes of Charcot arthropathy of the spine. This case series presents nine patients treated over 30 years. The study hypothesis was that surgery would reduce instability, pain, recurrence, and the need for revision surgery in the long-term, given previous study findings of successful fusion of Charcot spine in the short-term. To evaluate the long-term outcomes of surgery for Charcot spine. Retrospective case series. Cases took place at Stanford University Medical Center and Santa Clara Valley Medical Center. All patients had either complete paraplegia or dense paraparesis with both major motor and sensory deficits. Seven patients developed Charcot spine after spinal instrumentation for trauma, one after scoliosis repair for meningomyelocele, and one after spinal instrumentation for neuromuscular scoliosis caused by birth injury resulting in C6-C7 quadraplegia. Average time between initial instrumentation and development of Charcot spine was 7.6 years. Two patients underwent posterior fusion alone, six had anterior-posterior fusion, and one was managed with thoracolumbar orthosis. Average follow-up was 14.3 years. Revisions were necessary in 75% (6 of 8) of patients for complications including nonunion, new Charcot joints, recurrent hardware failure, and osteomyelitis. Achieving fusion often required multiple operations, and there were no deaths or neurologic complications. Long-term follow-up showed a high rate of revision surgery. Solid fusions often resulted in late breakdown or new junctional Charcot arthropathies. Patients initially fused to the lumbar spine instead of the sacrum or pelvis had a higher rate of developing another Charcot joint. Fusion was often difficult with persistent nonunions and functional deficits because of decreased mobility. We recommend that Charcot spine well tolerated without skin, seating problems, or dysreflexia should be cautiously observed with conservative management. For surgical care, we recommend three-column stabilization with either combined anterior-posterior or all posterior approaches with anterior support to obtain and secure greater long-term stability.


Blood-based biomarkers of human papillomavirus-associated cancers: A systematic review and meta-analysis.
Despite the significant societal burden of human papillomavirus (HPV)-associated cancers, clinical screening interventions for HPV-associated noncervical cancers are not available. Blood-based biomarkers may help close this gap in care. Five databases were searched, 5687 articles were identified, and 3631 unique candidate titles and abstracts were independently reviewed by 2 authors; 702 articles underwent a full-text review. Eligibility criteria included the assessment of a blood-based biomarker within a cohort or case-control study. One hundred thirty-seven studies were included. Among all biomarkers assessed, HPV-16 E seropositivity and circulating HPV DNA were most significantly correlated with HPV-associated cancers in comparison with cancer-free controls. In most scenarios, HPV-16 E6 seropositivity varied nonsignificantly according to tumor type, specimen collection timing, and anatomic site (crude odds ratio [cOR] for p16+ or HPV+ oropharyngeal cancer [OPC], 133.10; 95% confidence interval [CI], 59.40-298.21; cOR for HPV-unspecified OPC, 25.41; 95% CI, 8.71-74.06; cOR for prediagnostic HPV-unspecified OPC, 59.00; 95% CI, 15.39-226.25; cOR for HPV-unspecified cervical cancer, 12.05; 95% CI, 3.23-44.97; cOR for HPV-unspecified anal cancer, 73.60; 95% CI, 19.68-275.33; cOR for HPV-unspecified penile cancer, 16.25; 95% CI, 2.83-93.48). Circulating HPV-16 DNA was a valid biomarker for cervical cancer (cOR, 15.72; 95% CI, 3.41-72.57). In 3 cervical cancer case-control studies, cases exhibited unique microRNA expression profiles in comparison with controls. Other assessed biomarker candidates were not valid. HPV-16 E6 antibodies and circulating HPV-16 DNA are the most robustly analyzed and most promising blood-based biomarkers for HPV-associated cancers to date. Comparative validity analyses are warranted. Variations in tumor type-specific, high-risk HPV DNA prevalence according to anatomic site and world region highlight the need for biomarkers targeting more high-risk HPV types. Further investigation of blood-based microRNA expression profiling appears indicated.


Persons living on a disability grant in Mpumalanga province: An insider perspective.
In Mpumalanga province, more than 45 000 persons with disability receive a disability grant. Although research regarding social grants in general and disability grants specifically had previously been conducted from various perspectives, none has been carried out in Mpumalanga and none to explore the impact of the disability grant on the lives of the recipients. The objective of the study was to gain an understanding of the impact of the disability grant on the lives of recipients living in Mpumalanga. The study was conducted as a contextual, exploratory and qualitative study. The target population was persons with a disability receiving a disability grant. Data gathering was conducted in October 2010 using a semi-structured interview technique. The data were analysed in terms of the social and economic impact of the disability grant in the life of the participant. A combination of three qualitative data analysis methods was used to analyse the data. The qualitative findings indicate that although it is an individual grant, the disability grant was used to support the whole family and was frequently the family's only income. Food, clothes and electricity was most frequently bought with the disability grant. Food often did not last for a month. The families were living precariously and any crisis, for example lapsing of the grant, would result in hunger and desperation as a result of their complete dependence on the disability grant.Without insight in how people live their lives, registered nurses may give health education to patients that they cannot implement, perpetuating the burden of disease in South Africa.


Immediate impact of minimum unit pricing on alcohol purchases in Scotland: controlled interrupted time series analysis for 2015-18.
To assess the immediate impact of the introduction of minimum unit pricing in Scotland on household alcohol purchases. Controlled interrupted time series analysis. Purchase data from Kantar Worldpanel's household shopping panel for 2015-18. 5325 Scottish households, 54 807 English households as controls, and 10 040 households in northern England to control for potential cross border effects. Introduction of a minimum price of 50p (€0.55; $0.61) per UK unit (6.25p per gram) for the sale of alcohol in Scotland on 1 May 2018. Price per gram of alcohol, number of grams of alcohol purchased from off-trade by households, and weekly household expenditure on alcohol. The introduction of minimum unit pricing in Scotland was associated with an increase in purchase price of 0.64p per gram of alcohol (95% confidence interval 0.54 to 0.75), a reduction in weekly purchases of 9.5 g of alcohol per adult per household (5.1 to 13.9), and a non-significant increase in weekly expenditure on alcohol per household of 61p (-5 to 127). The increase in purchase price was higher in lower income households and in households that purchased the largest amount of alcohol. The reduction in purchased grams of alcohol was greater in lower income households and only occurred in the top fifth of households by income that purchased the greatest amount of alcohol, where the reduction was 15 g of alcohol per week (6 to 24). Changes in weekly expenditure were not systematically related to household income but increased with increasing household purchases. In terms of immediate impact, the introduction of minimum unit pricing appears to have been successful in reducing the amount of alcohol purchased by households in Scotland. The action was targeted, in that reductions of purchased alcohol only occurred in the households that bought the most alcohol.


Supramolecular assembly of a thermoresponsive steroidal surfactant with an oppositely charged thermoresponsive block copolymer.
Supramolecular rearrangements are crucial in determining the response of stimuli sensitive soft matter systems such as those formed by mixtures of oppositely charged amphiphiles. Here mixtures of this kind were prepared by mixing the cationic block copolymer pAMPTMA30-b-pNIPAAM120 and an anionic surfactant obtained by the modification of the bile salt sodium cholate. As pure components, the two compounds presented a thermoresponsive self-assembly at around 30-35 °C; a micelle formation in the case of the copolymer and a transition from fibers to tubes in the case of the bile salt derivative. When both were present in the same solution they associated into mixed aggregates that showed complex thermoresponsive features. At room temperature, the core of the aggregate was comprised of a supramolecular twisted ribbon of the bile salt derivative. The block copolymers were anchored on the surface of this ribbon through electrostatic interactions between their charged blocks and the oppositely charged heads of the bile salt molecules. The whole structure was stabilized by a corona of the uncharged blocks that protruded into the surrounding solvent. By increasing the temperature to 30-34 °C the mixed aggregates transformed into rods with smooth edges that associated into bundles and clusters, which in turn induced clouding of the solution. Circular dichroism allowed us to follow progressive rearrangements of the supramolecular organization within the complex, occurring in the range of temperature of 20-70 °C.


Implementing knowledge into practice for improved neonatal survival; a cluster-randomised, community-based trial in Quang Ninh province, Vietnam.
Globally, almost 4 million newborns die during the first 4 weeks of life every year. By increased use of evidence-based knowledge in the healthcare system a large proportion of these neonatal deaths could be prevented. But there is a severe lack of knowledge on effective methods for successful implementation of evidence into practice, particularly in low- and middle-income countries. Recent studies have demonstrated promising results with increased survival among both mothers and newborns using community-based approaches. In Vietnam evidence-based guidelines on reproductive health were launched in 2003 and revised in 2009. The overall objective of the current project is to evaluate if a facilitation intervention on the community level, with a problem-solving approach involving local representatives if the healthcare system and the community, results in improvements of neonatal health and survival. The study, which has been given the acronym NeoKIP (Neonatal Health - Knowledge Into Practice), took place in 8 districts composed by 90 communes in a province in northern Vietnam, where neonatal mortality rate was 24/1000 in 2005. A cluster randomised design was used, allocating clusters, as defined as a commune and its correponding Commune Health Center (CHC) to either intervention or control arm. The facilitation intervention targeted staff at healthcare centres and key persons in the communes. The facilitator role was performed by lay women (Women's Union representatives) using quality improvement techniques to initiate and sustain improvement processes targeting identified problem areas. The intervention has been running over 3 years and data were collected on the facilitation process, healthcare staff knowledge in neonatal care and their behaviour in clinical practice, and reproductive and perinatal health indicators. Primary outcome is neonatal mortality. The intervention is participatory and dynamic, focused on developing a learning process and a problem-solving cycle. The study recognises the vital role of the local community as actors in improving their own and their newborns' health, and applies a bottom-up approach where change will be accomplished by an increasing awareness at and demand from grass root level. By utilising the existing healthcare structure this intervention may, if proven successful, be well suited for scaling up. Current Controlled Trials ISRCTN44599712.


Biophysical analysis and small-angle X-ray scattering-derived structures of MeCP2-nucleosome complexes.
MeCP2 is a highly abundant chromatin architectural protein with key roles in post-natal brain development in humans. Mutations in MeCP2 are associated with Rett syndrome, the main cause of mental retardation in girls. Structural information on the intrinsically disordered MeCP2 protein is restricted to the methyl-CpG binding domain; however, at least four regions capable of DNA and chromatin binding are distributed over its entire length. Here we use small angle X-ray scattering (SAXS) and other solution-state approaches to investigate the interaction of MeCP2 and a truncated, disease-causing version of MeCP2 with nucleosomes. We demonstrate that MeCP2 forms defined complexes with nucleosomes, in which all four histones are present. MeCP2 retains an extended conformation when binding nucleosomes without extra-nucleosomal DNA. In contrast, nucleosomes with extra-nucleosomal DNA engage additional DNA binding sites in MeCP2, resulting in a rather compact higher-order complex. We present ab initio envelope reconstructions of nucleosomes and their complexes with MeCP2 from SAXS data. SAXS studies also revealed unexpected sequence-dependent conformational variability in the nucleosomes themselves.


Hypothalamus-hippocampus circuitry regulates impulsivity via melanin-concentrating hormone.
Behavioral impulsivity is common in various psychiatric and metabolic disorders. Here we identify a hypothalamus to telencephalon neural pathway for regulating impulsivity involving communication from melanin-concentrating hormone (MCH)-expressing lateral hypothalamic neurons to the ventral hippocampus subregion (vHP). Results show that both site-specific upregulation (pharmacological or chemogenetic) and chronic downregulation (RNA interference) of MCH communication to the vHP increases impulsive responding in rats, indicating that perturbing this system in either direction elevates impulsivity. Furthermore, these effects are not secondary to either impaired timing accuracy, altered activity, or increased food motivation, consistent with a specific role for vHP MCH signaling in the regulation of impulse control. Results from additional functional connectivity and neural pathway tracing analyses implicate the nucleus accumbens as a putative downstream target of vHP MCH1 receptor-expressing neurons. Collectively, these data reveal a specific neural circuit that regulates impulsivity and provide evidence of a novel function for MCH on behavior.


A Narrative Review of Meaningful Use and Anesthesia Information Management Systems.
The US federal government has enacted legislation for a federal incentive program for health care providers and hospitals to implement electronic health records. The primary goal of the Meaningful Use (MU) program is to drive adoption of electronic health records nationwide and set the stage to monitor and guide efforts to improve population health and outcomes. The MU program provides incentives for the adoption and use of electronic health record technology and, in some cases, penalties for hospitals or providers not using the technology. The MU program is administrated by the Department of Health and Human Services and is divided into 3 stages that include specific reporting and compliance metrics. The rationale is that increased use of electronic health records will improve the process of delivering care at the individual level by improving the communication and allow for tracking population health and quality improvement metrics at a national level in the long run. The goal of this narrative review is to describe the MU program as it applies to anesthesiologists in the United States. This narrative review will discuss how anesthesiologists can meet the eligible provider reporting criteria of MU by applying anesthesia information management systems (AIMS) in various contexts in the United States. Subsequently, AIMS will be described in the context of MU criteria. This narrative literature review also will evaluate the evidence supporting the electronic health record technology in the operating room, including AIMS, independent of certification requirements for the electronic health record technology under MU in the United States.


Immune Alterations Following Neurological Disorders: A Comparison of Stroke and Seizures.
Background: Granulocytes and monocytes are the first cells to invade the brain post stroke and are also being discussed as important cells in early neuroinflammation after seizures. We aimed at understanding disease specific and common pathways of brain-immune-endocrine-interactions and compared immune alterations induced by stroke and seizures. Therefore, we compared granulocytic and monocytic subtypes between diseases and investigated inflammatory mediators. We additionally investigated if seizure type determines immunologic alterations. Material and Methods: We included 31 patients with acute seizures, 17 with acute stroke and two control cohorts. Immune cells were characterized by flow cytometry from blood samples obtained on admission to the hospital and the following morning. (i) Monocytes subpopulations were defined as classical (CD14++CD16-), (ii) intermediate (CD14++CD16+), and (iii) non-classical monocytes (CD14dimCD16+), while granulocyte subsets were characterized as (i) "classical granulocytes" (CD16++CD62L+), (ii) pro-inflammatory (CD16dimCD62L+), and (iii) anti-inflammatory granulocytes (CD16++CD62L-). Stroke patient's blood was additionally drawn on days 3 and 5. Cerebrospinal fluid mitochondrial DNA was quantified by real-time PCR. Plasma High-Mobility-Group-Protein-B1, metanephrine, and normetanephrine were measured by ELISA. Results: HLA-DR expression on monocytes and their subpopulations (classical, intermediate, and non-classical monocytes) was reduced after stroke or seizures. Expression of CD32 was increased on monocytes and subtypes in epilepsy patients, partly similar to stroke. CD32 and CD11b regulation on granulocytes and subpopulations (classical, anti-inflammatory, pro-inflammatory granulocytes) was more pronounced after stroke compared to seizures. On admission, normetanephrine was upregulated in seizures, arguing for the sympathetic nervous system as inducer of immune alterations similar to stroke. Compared to partial seizures, immunologic changes were more pronounced in generalized tonic-clonic seizures. Conclusion: Seizures lead to immune alterations within the immediate postictal period similar but not identical to stroke. The type of seizures determines the extent of immune alterations.


Variability of breast sucking, associated milk transfer and the duration of lactational amenorrhoea.
Quantitative relationships between physical parameters of sucking, milk transfer and the duration of amenorrhoea were examined in normal mother-baby pairs under exclusive breastfeeding. Sucking pressures were recorded twice on the second and once on the fifth month after birth, during complete breastfeeding episodes, by means of a catheter attached to the nipple and connected to a pressure transducer, the signals of which were analysed by computer. Babies were weighed before and after each sucking episode to estimate milk transfer. In the first nursing episode after noon, 2-month-old babies sucked from 140 to > 800 times during 4-15 min from the first breast, obtaining from 20 to > 100 g milk. The physical parameters of sucking and milk transfer exhibited high inter-individual but low intra-individual variabilities. There were significant differences in the physical parameters of sucking and milk transfer efficiency between first and second breast and between the second and fifth months after birth. Milk transfer efficiency was inversely correlated with time occupied by non-sucking pauses > or = 1.5 s, and was directly correlated with mean intersuck intervals in the first breast and with duration of the sucking episode, number of sucks, mean pressure and area under the pressure curve in the second breast. There was no correlation between the physical parameters of sucking and duration of lactational amenorrhoea (n = 62). However, significantly more mothers had amenorrhoea lasting > 180 days among those whose babies spent a longer proportion of the nursing episode in non-sucking pauses > or = 1.5 s. This finding indicates that sensory stimulation of the nipple produced during a nursing episode by stimuli other than sucking itself may have an important role in sustaining lactational amenorrhoea. It is concluded that nursing episodes have a complex structure that allows the development of a breastfeeding phenotype in each mother-baby pair, exhibiting important inter-individual variability. The present analysis does not support the contention that this source of variability accounts for the variability in the duration of lactational amenorrhoea.


Impact of weight reduction on pericardial adipose tissue and cardiac structure in patients with atrial fibrillation.
Obesity and pericardial adipose tissue are independent risk factors for atrial fibrillation (AF) and adverse cardiac structural remodeling. The effect of weight reduction on pericardial adipose tissue and cardiac structure remains unknown. We prospectively performed cardiac magnetic resonance imaging on 87 participants with AF undergoing either structured weight management (intervention) or general lifestyle advice (control). We measured pericardial adipose tissue, atrial and ventricular volumes, and myocardial mass at baseline and 12 months. In total, 69 participants underwent baseline and 12-month follow-up cardiac magnetic resonance imaging (intervention n = 36 and controls n = 33). From baseline to 12 months, weight loss (kg, mean [95% CI]) was greater in the intervention group from 101.5 kg (97.2-105.8 kg) to 86.5 kg (81.2-91.9 kg) as compared with controls from 102.6 kg (97.2-108.1 kg) to 98.7 kg (91.0-106.3 kg) (time-group interaction P < .001). The intervention group showed a reduction in left atrial volumes (mL) from 105.0 mL (98.9-111.1 mL) to 96.4 mL (91.6-101.1 mL), whereas the change in the control group was from 108.8 mL (99.6-117.9 mL) to 108.9 mL (99.8-118.0 mL) (time-group interaction P < .001). There was a decline in pericardial adipose tissue (cm(3)) from 140.9 cm(3) (129.3-152.4 cm(3)) to 118.8 cm(3) (108.1-129.6 cm(3)) and myocardial mass (g) from 137.6 g (128.1-147.2 g) to 123.1 g (114.5-131.7 g) in the intervention group, whereas the change in the control group was from 143.2 cm(3) (124.6-161.7 cm(3)) to 147.2 cm(3) (128.9-165.4 cm(3)) for pericardial adipose tissue and 138.3 g (124.8-151.8 g) to 140.7 g (127.4-154.1 g) for myocardial mass (both variables, time-group interaction P < .001). Weight reduction results in favorable structural remodeling and a reduction in pericardial adipose tissue burden.


Japanese phase I study of cabazitaxel in metastatic castration-resistant prostate cancer.
We previously reported the pharmacokinetic profile and preliminary tolerability of cabazitaxel in a phase I study in Japanese patients with metastatic castration-resistant prostate cancer (mCRPC). Here we report the final safety profile and anti-tumor activity of cabazitaxel in a larger population, including all patients enrolled in the expansion cohort of the study. Japanese patients with mCRPC previously treated with docetaxel received cabazitaxel intravenously every 3 weeks plus daily prednisolone. In patients treated with the maximum tolerated dose of 25 mg/m(2) we evaluated adverse events including treatment-related neutropenia, prostate-specific antigen (PSA) response and objective response. In total, 44 patients were treated with the maximum tolerated dose. The most frequent adverse events (any grade) were neutropenia (100 %), febrile neutropenia (54.5 %), fatigue (54.5 %), nausea (52.3 %) and diarrhea (50.0 %). There were no deaths due to treatment-related adverse events. Neutropenia with prior docetaxel did not appear to influence the probability of febrile neutropenia with cabazitaxel. Most patients received therapeutic granulocyte colony-stimulating factor (G-CSF; cycle 1: 86.4 %; cycle 2 or later: 81.8 %). In the efficacy population, two of 12 patients with measurable disease had partial response (objective response rate: 16.7 %), while 10 had stable disease. PSA response rate was 29.3 % (12/41 patients). Median time to PSA progression was 3.68 months (95 % confidence interval 1.35-4.63). In this heavily pretreated Japanese population, the occurrence of neutropenia and febrile neutropenia was high, suggesting G-CSF prophylaxis may be required as part of toxicity management. However, the efficacy of cabazitaxel was consistent with global studies. ClinicalTrials.gov identifier: NCT01324583.


Dimerized linear mimics of a natural cyclopeptide (TMC-95A) are potent noncovalent inhibitors of the eukaryotic 20S proteasome.
Noncovalent proteasome inhibitors introduce an alternative mechanism of inhibition to that of covalent inhibitors used in cancer therapy. Starting from a noncovalent linear mimic of TMC-95A, a series of dimerized inhibitors using polyaminohexanoic acid spacers has been designed and optimized to target simultaneously two of the six active sites of the eukaryotic 20S proteasome. The homodimerized compounds actively inhibited chymotrypsin-like (Ki = 6-11 nM) and trypsin-like activities, whereas postacid activity was poorly modified. The noncovalent binding mode was ascertained by X-ray crystallography of the inhibitors complexed with the yeast 20S proteasome. The inhibition of proteasomal activities in human cells was evaluated. The use of the multivalency inhibitor concept has produced highly efficient and selective noncovalent compounds (no inhibition of calpain and cathepsin) that have potential therapeutic advantages compared to covalent binders such as bortezomib and carfilzomib.


An online survey of tobacco smoking cessation associated with naturalistic psychedelic use.
Data suggest psychedelics such as psilocybin and lysergic acid diethylamide (LSD) may hold therapeutic potential in the treatment of addictions, including tobacco dependence. This retrospective cross-sectional anonymous online survey characterized 358 individuals (52 females) who reported having quit or reduced smoking after ingesting a psychedelic in a non-laboratory setting ⩾1 year ago. On average, participants smoked 14 cigarettes/day for 8 years, and had five previous quit attempts before their psychedelic experience. Of the 358 participants, 38% reported continuous smoking cessation after psychedelic use (quitters). Among quitters, 74% reported >2 years' abstinence. Of the 358 participants, 28% reported a persisting reduction in smoking (reducers), from a mode of 300 cigarettes/month before, to a mode of 1 cigarette/month after the experience. Among reducers, 62% reported >2 years of reduced smoking. Finally, 34% of the 358 participants (relapsers) reported a temporary smoking reduction before returning to baseline smoking levels, with a mode time range to relapse of 3-6 months. Relapsers rated their psychedelic experience significantly lower in personal meaning and spiritual significance than both other groups. Participants across all groups reported less severe affective withdrawal symptoms (e.g. depression, craving) after psychedelic use compared with previous quit attempts, suggesting a potential mechanism of action for psychedelic-associated smoking cessation/reduction. Changes in life priorities/values were endorsed as the most important psychological factor associated with smoking cessation/reduction. Results suggest psychedelics may hold promise in treating tobacco addiction as potentially mediated by spiritual experience, changed priorities/values, and improved emotional regulation.


Expanding biohybrid-mediated asymmetric catalysis into the realm of RNA.
The recent development of biohybrid catalytic systems has allowed synthetic chemists to reach high levels of selectivity on a wide variety of valuable synthetic transformations. In this context, DNA-based catalysts have emerged as particularly appealing tools. Interestingly, while long RNA sequences (ribozymes) are known to catalyse specific biochemical reactions with remarkable efficiencies, RNA-based catalysts involving a catalytically active metal complex interacting in a non-covalent fashion with short sequences have never been evaluated to date. We report here our results, which have led to the first example involving a short RNA-based catalyst.


Photocontrol of cell adhesion and proliferation by a photoinduced cationic polymer surface.
In this study photoinduced cation generation, based on the photochemical properties of malachite green (MG), was used for the surface design and in vitro photochemical control of cell adhesion and proliferation. The MG-derivatized surface was prepared by coating a photoreactive polymer as a substrate onto a poly(ethylene terephthalate) (PET) sheet. The photoreactive polymer was radical copolymer of styrene with the MG-derivatized monomer diphenyl(4-vinylphenyl)methane leucohydroxide (degree of substitution of MG unit: 12.4 mol%). Water contact angle measurements and X-ray photoelectron spectroscopy revealed high hydrophobicity and homogeneous distribution of the MG groups on the outermost surface of the coated film, respectively. When the coated film was exposed to ultraviolet light (UV) irradiation at wavelengths of 290-410 nm, a time-dependent color change of the film was observed from pale yellow, before irradiation, to green. These results indicated generation of cations on the film surface by photochemical cation generation of the MG groups, which was quantitatively characterized by force versus distance curves measurements in atomic force microscopic (AFM) observation using a carboxylated AFM tip. The seeding and culture of endothelial cells showed a marked reduction in adhesion on the nonirradiated coated film surface, whereas the UV-irradiated surface promoted cell adhesion and proliferation except for incubation in serum-free medium, which was similar to commercial tissue culture PET sheet. These observations may be due to adsorption of cell adhesive proteins, typified by fibronectin, in serum-containing medium onto the cationized photoreactive copolymer surface by electrostatic interactions.


Defective ribosomal products (DRiPs): a major source of antigenic peptides for MHC class I molecules?
MHC class I molecules predominantly bind to peptides derived from a cytosolic pool of polypeptides. Little is known about the nature of the polypeptides that serve as substrates for peptidogenic cytosolic proteases. We propose that a significant source of self and viral peptides are defective ribosomal products (DRiPs), which consist of prematurely terminated polypeptides and misfolded polypeptides produced from translation of bona fide mRNAs in the proper reading frame. DRiPs are produced entropically, due to the inevitable imperfections inherent to protein synthesis or folding. To accelerate recognition of cells harboring intracellular parasites such as viruses, DRiP formation may be enhanced by changes in the cellular physiology induced by infection or by exposure of cells to cytokines released at the site of inflammation.


Integral optical digital computers.
The specific features of optical digital computers in integrated circuit form, whose principle of operation is based on electrooptic light modulation, are considered. The design of an array processor unit is described. It is shown that the optical communication channels introduced into integrated circuit structures with the help of thin film light modulators enable one to reduce, compared to electronics with equivalent functional capability, the total number of device components by 2 orders of magnitude, the interconnections area by an order of magnitude, and to increase performance by a factor of m (m is the image dimension). The experimental results of studying a cell of dynamic memory constructed with the above components are presented.


Analysis of T-cell proliferation and cytokine secretion in the individuals exposed to arsenic.
Over six million people in nine districts of West Bengal, India are exposed to very high levels of arsenic primarily through their drinking water. More than 300,000 people showed arsenic-induced skin lesions in these districts. This is regarded as the greatest arsenic calamity in the world. Chronic arsenicosis causes varied dermatological signs ranging from pigmentation changes, hyperkeratosis to non-melanocytic cancer of skin, and also malignancies in different internal organs. Higher incidences of opportunistic infections are found in the arsenic-exposed individuals, indicating that their immune systems may be impaired somehow. We have thus investigated the effect of arsenic on T-cell proliferation and cytokine secretion in 20 individuals with arsenic-induced skin lesions and compared the results with 18 arsenic-unexposed individuals. A marked dose-dependent suppression of Concanavalin A (Con A) induced T-cell proliferation was observed in the arsenic-exposed individuals compared with the unexposed (P < 0.001) individuals. This correlated with a significant decrease in the levels of secreted cytokines by the T cells (TNF-alpha, IFN-gamma, IL2, IL10, IL5, and IL4) in the exposed individuals (P < 0.001). Thus it can be inferred that arsenic exposure can cause immunosuppression in humans.


The Experience of Caring For or Living with an Individual with an Eating Disorder: A Meta-Synthesis of Qualitative Studies.
Eating disorders (ED) has the highest mortality rate of psychiatric disorders and a high incidence of comorbidity. Because of the average age of onset, care typically befalls family members. However, despite the severity of the disorder and the burden placed on the family, research into the caregiving experience is still developing. Studies have shown caregivers of individuals with ED to experience high levels of distress, burden and expressed emotion. Recent theoretical models have underscored the importance of caregivers' responses as a maintenance factor for the ED, and family therapy has proved efficacious. However, the literature pertaining to the experience of family members living with or caring for an individual with an ED has not been systematically reviewed. This review aimed to synthesize qualitative studies relating to the caring experience and its impact, thereby gaining an understanding from the perspective of the individuals themselves. Relevant search terms were utilized to systematically search key databases. Twenty studies, with a total sample of 239 participants, met the inclusion criteria. Nine core themes emerged from the synthesis, forming the basis of an explanatory theory. The ED was found to have a pervasive impact upon family members, mediated by a number of factors. Cognitive appraisals affected the caregiving experience and responses to the individual. The experience of caregiving was continually reappraised leading to a process of adaptation. The majority of studies identified unmet carer needs. The implications of the findings are discussed with reference to existing theoretical models and in terms of clinical practice. Copyright © 2015 John Wiley & Sons, Ltd. Carers experience a significant amount of guilt and distress once they have found out about their loved one's eating disorder. Across the studies, there were many themes of unmet need for carers. Siblings have often been overlooked by both clinicians and researchers. Interventions for people with eating disorders should also acknowledge carers and close family members.


Conformational and biochemical characterization of a biologically active rat recombinant Protease Nexin-1 expressed in E. coli.
Protease Nexin-1, a 43-kDa glycoprotein, is a major physiological thrombin inhibitor involved in the modulation of nerve cell plasticity. Recombinant rat Protease Nexin-1 (rPN-1) was efficiently produced in Escherichia coli using a T7 RNA polymerase based expression system and purified by heparin-sepharose affinity chromatography yielding 3 mg of protein per liter of cell culture. The purity and chemical identity of rPN-1 were assessed by SDS-PAGE, Reverse Phase- High Performance Liquid Chromatography, mass spectrometry and two-dimensional-gel electrophoresis. Conformational analysis by circular dichroism and fluorescence spectroscopy revealed the presence of mixed alpha/beta secondary structure and the prevailing localization of Trp-residues in rather polar environments. Fluorescence titration of rPN-1 with heparin indicated that rPN-1 binds heparin with high affinity. Furthermore, the formation of a SDS-stable 1:1 thrombin-rPN-1 complex, monitored by SDS-PAGE, confirmed the native-like structure of rPN-1. Finally, the cellular effects of rPN-1, such as its ability to promote neurite outgrowth in neuroblastoma cells, were found to be very similar to those elicited by natural PN-1. Altogether, our results demonstrate that glycosylation does not alter neither structure nor function of PN-1 and that E. coli is a suitable expression system for obtaining milligram quantities of pure and fully active rPN-1 for structural and functional studies.


Exploring qualitative research synthesis: the role of patients' perspectives in health policy design and decision making.
Health systems are placing more and more emphasis on the design and delivery of services that are focused on the patient, and there is a growing interest in patient involvement in health policy research and health technology assessment (HTA). Furthermore, there is a growing research interest in eliciting patients' views, not only on 'what works' for patients but also on the need for intervention and on factors influencing the implementation of particular health technologies, their appropriateness and acceptability. This article focuses on qualitative research synthesis in eliciting patients' perspectives. Its aim is to bring research closer to policy development and decision making, to facilitate better use of research findings for health and welfare, to generate a body of evidence, and to ensure that effective and appropriate information is used in health policy decision design. A variety of synthesizing approaches in qualitative research are explored, such as meta-synthesis, meta-summary, meta-ethnography, and meta-study, focusing especially on methodology. Meta-synthesis and meta-ethnography are probably the most frequently cited approaches in qualitative research synthesis and have perhaps the most developed methodology. The implications of these various synthesizing approaches in relation to health policy and HTA are discussed, and we suggest that meta-synthesis and meta-summary are particularly useful approaches. They have an explicit focus on 'evidence synthesis', fairly clear methodologies, and they are designed to not only present interpretations of the findings but also integrate research findings. Qualitative research synthesis enables researchers to synthesize findings from multiple qualitative studies on patients' perspectives instead of establishing new, expensive, and perhaps redundant studies that might intrude on the lives of patients. Qualitative research synthesis is highly recommended by decision makers and in health policy research and HTA. In cases where patient assessment is important to overall success, it can provide those responsible for policy and decision making with a broad and varied range of knowledge about patients' perspectives before they make decisions on the application of health technologies.


Gram-negative sepsis: a dilemma of modern medicine.
Gram-negative sepsis is an increasingly common problem, with up to 300,000 cases occurring each year in the United States alone. Despite the ongoing development of new antibiotics, mortality from gram-negative sepsis remains unacceptably high. To stimulate earlier therapeutic intervention by physicians, a new set of broad definitions has been proposed to define the systemic inflammatory response characteristic of sepsis. In this review, the signs and symptoms of this progressive, injurious process are reviewed and its management is discussed, as are the mechanisms by which bacterial endotoxin triggers the biochemical events that lead to such serious complications as shock, adult respiratory distress syndrome, and disseminated intravascular coagulation. These events often occur even when appropriate antimicrobial therapy has been instituted. An increased understanding of the structure of endotoxin and its role in the development of sepsis, together with advances in hybridoma technology, has led to the development of monoclonal antibodies that bind to endotoxin and significantly attenuate its adverse effects. These agents promise to substantially reduce the morbidity and mortality associated with gram-negative sepsis.


Population promotion of informal self-help strategies for early intervention against depression and anxiety.
Much of the burden of depression and anxiety in the population is attributable to subclinical symptoms. Broadening formal health-care systems to treat subclinical depression and anxiety is not the answer to reducing this burden, because health-care systems lack the resources even to provide optimal care to clinical cases. The solution proposed is the population-wide dissemination of informal self-help strategies that have evidence for effectiveness. These are highly acceptable to the public, easily applied, inexpensive and may avert the development of many clinical cases.


Predicting motivational regulations in physical education: the interplay between dispositional goal orientations, motivational climate and perceived competence.
In this study, we examined the main and interactive effects of students' goal orientations, perceived competence and perceptions of the motivational climate on the motivational styles advanced by self-determination theory. The participants were 328 British secondary school students aged 13.6 +/- 0.6 years (mean +/- s). Moderated hierarchical regression analyses revealed task orientation, perceived competence and perceptions of a mastery climate to be positive predictors of self-determined styles of motivation. Perceived competence in physical education was negatively associated with amotivation. Significant interaction effects for mastery climate x task orientation and for ego orientation x perceived competence emerged. The results indicate that: (1) for students endorsing a high task orientation, the perception that the class climate was high in mastery cues was associated with increased intrinsic motivation; and (2) for students high in ego orientation, the belief that one was competent increased, while perceptions of incompetence attenuated intrinsic motivation. Additionally, a three-way interaction between ego orientation, performance climate and perceived competence emerged. In light of achievement goal and self-determination frameworks, we propose that studying the potential interplay between both individual and situational goal perspectives and the moderating effect of perceived competence may further enhance our understanding of motivation in physical education.


Iatrogenic nerve injuries during shoulder surgery.
The current literature indicates that neurologic injuries during shoulder surgery occur infrequently and result in little if any morbidity. The purpose of this study was to review one institution's experience treating patients with iatrogenic nerve injuries after shoulder surgery. A retrospective review of the records of patients evaluated in a brachial plexus specialty clinic from 2000 to 2010 identified twenty-six patients with iatrogenic nerve injury secondary to shoulder surgery. The records were reviewed to determine the operative procedure, time to presentation, findings on physical examination, treatment, and outcome. The average age was forty-three years (range, seventeen to seventy-two years), and the average delay prior to referral was 5.4 months (range, one to fifteen months). Seven nerve injuries resulted from open procedures done to treat instability; nine, from arthroscopic surgery; four, from total shoulder arthroplasty; and six, from a combined open and arthroscopic operation. The injury occurred at the level of the brachial plexus in thirteen patients and at a terminal nerve branch in thirteen. Fifteen patients (58%) did not recover nerve function after observation and required surgical management. A structural nerve injury (laceration or suture entrapment) occurred in nine patients (35%), including eight of the thirteen who presented with a terminal nerve branch injury and one of the thirteen who presented with an injury at the level of the brachial plexus. Nerve injuries occurring during shoulder surgery can produce severe morbidity and may require surgical management. Injuries at the level of a peripheral nerve are more likely to be surgically treatable than injuries of the brachial plexus. A high index of suspicion and early referral and evaluation should be considered when evaluating patients with iatrogenic neurologic deficits after shoulder surgery.


Inflamm-ageing and Senescence in Gout: The Tale of an Old King's Disease.
Gout is the most common auto-inflammatory arthritis that leads to severe comorbidities such as cardiovascular diseases, renal impairment and metabolic disorders at an early age. We hypothesize that chronic as well as frequent flares of intermittent inflammation, caused by uric acid contribute to an early onset of cardiovascular-, renal- and metabolic diseases. Persistent exposure of the cells to such inflammatory events elaborates DNA damage, excessive cell turnover inconsistent with age and telomere shortening which is representative for accelerated senescence. In this review we aim to untangle the intriguing effect of inflammation-induced cellular senescence on the high prevalence of age-related cardiovascular, renal and metabolic diseases in gout.


Stargazin and other transmembrane AMPA receptor regulating proteins interact with synaptic scaffolding protein MAGI-2 in brain.
The spatial coordination of neurotransmitter receptors with other postsynaptic signaling and structural molecules is regulated by a diverse array of cell-specific scaffolding proteins. The synaptic trafficking of AMPA receptors by the stargazin protein in some neurons, for example, depends on specific interactions between the C terminus of stargazin and the PDZ [postsynaptic density-95 (PSD-95)/Discs large/zona occludens-1] domains of membrane-associated guanylate kinase scaffolding proteins PSD-93 or PSD-95. Stargazin [Cacng2 (Ca2+ channel gamma2 subunit)] is one of four closely related proteins recently categorized as transmembrane AMPA receptor regulating proteins (TARPs) that appear to share similar functions but exhibit distinct expression patterns in the CNS. We used yeast two-hybrid screening to identify MAGI-2 (membrane associated guanylate kinase, WW and PDZ domain containing 2) as a novel candidate interactor with the cytoplasmic C termini of the TARPs. MAGI-2 [also known as S-SCAM (synaptic scaffolding molecule)] is a multi-PDZ domain scaffolding protein that interacts with several different ligands in brain, including PTEN (phosphatase and tensin homolog), dasm1 (dendrite arborization and synapse maturation 1), dendrin, axin, beta- and delta-catenin, neuroligin, hyperpolarization-activated cation channels, beta1-adrenergic receptors, and NMDA receptors. We confirmed that MAGI-2 coimmunoprecipitated with stargazin in vivo from mouse cerebral cortex and used in vitro assays to localize the interaction to the C-terminal -TTPV amino acid motif of stargazin and the PDZ1, PDZ3, and PDZ5 domains of MAGI-2. Expression of stargazin recruited MAGI-2 to cell membranes and cell-cell contact sites in transfected HEK-293T cells dependent on the presence of the stargazin -TTPV motif. These experiments identify MAGI-2 as a strong candidate for linking TARP/AMPA receptor complexes to a wide range of other postsynaptic molecules and pathways and advance our knowledge of protein interactions at mammalian CNS synapses.


The role of symmetry in attraction to average faces.
Although many studies have demonstrated that average faces tend to be attractive, few studies have examined the extent to which symmetry contributes to the attractiveness of average faces. Such studies are potentially important, however, because average faces are highly symmetric and increasing the symmetry of face images increases their attractiveness. Here we demonstrate that increasing averageness of 2-D face shape independently of symmetry is sufficient to increase attractiveness, indicating that preferences for symmetry cannot solely explain the attractiveness of average faces. Additionally, we show that averageness preferences are significantly weaker when the effects of symmetry are controlled for using computer graphic methods than when the effects of symmetry are not controlled for, suggesting that symmetry contributes to the attractiveness of average faces. Importantly, this latter finding was not explained by the greater perceived similarity between versions offaces that varied in averageness, but not symmetry, than between versions of faces that varied in both averageness and symmetry.


Altered methylation pattern of the SRD5A2 gene in the cerebrospinal fluid of post-finasteride patients: a pilot study.
Post-finasteride syndrome (PFS) occurs in patients with androgenic alopecia after suspension of the finasteride treatment, leading to a large variety of persistent side effects. Despite the severity of the clinical picture, the mechanism underlying the PFS symptoms onset and persistence is still unclear. To study whether epigenetic modifications occur in PFS patients. Retrospective analysis of a multicentric, prospective, longitudinal, case-control clinical trial, enrolling 16 PFS patients, compared to 20 age-matched healthy men. Main outcomes were methylation pattern of SRD5A1 and SRD5A2 promoters and concentration of 11 neuroactive steroids, measured by liquid chromatography-tandem mass spectrometry, in blood and cerebrospinal fluid (CSF) samples. SRD5A1 and SRD5A2 methylation analysis was performed in all blood samples (n = 16 PFS patients and n = 20 controls), in 16 CSF samples from PFS patients and in 13 CSF samples from controls. The SRD5A2 promoter was more frequently methylated in CSF of PFS patients compared to controls (56.3 vs 7.7%). No promoter methylation was detected in blood samples in both groups. No methylation occurred in the SRD5A1 promoter of both groups. Unmethylated controls compared to unmethylated SRD5A2 patients showed higher pregnenolone, dihydrotestosterone and dihydroprogesterone, together with lower testosterone CSF levels. Andrological and neurological assessments did not differ between methylated and unmethylated subjects. For the first time, we demonstrate a tissue-specific methylation pattern of SRD5A2 promoter in PFS patients. Although we cannot conclude whether this pattern is prenatally established or induced by finasteride treatment, it could represent an important mechanism of neuroactive steroid levels and behavioural disturbances previously described in PFS.


Maternal near-miss case reviews: the UK approach.
The UK has a well-established programme of Confidential Enquiries into Maternal Deaths and a national system for research into near-miss maternal morbidities, the UK Obstetric Surveillance System. The addition of a programme of near-miss case reviews, the Confidential Enquiries into Maternal Morbidity, permits a complete examination of the incidence, risk factors, care and outcomes of the severest complications in pregnancy, and enables the lessons learnt to improve future care to be identified more quickly. This in turn allows for more rapid inclusion of recommendations into national guidance and hence the potential of better health for both women and babies.


Bone marrow transplantation for recessive dystrophic epidermolysis bullosa.
Recessive dystrophic epidermolysis bullosa is an incurable, often fatal mucocutaneous blistering disease caused by mutations in COL7A1, the gene encoding type VII collagen (C7). On the basis of preclinical data showing biochemical correction and prolonged survival in col7 −/− mice, we hypothesized that allogeneic marrow contains stem cells capable of ameliorating the manifestations of recessive dystrophic epidermolysis bullosa in humans. Between October 2007 and August 2009, we treated seven children who had recessive dystrophic epidermolysis bullosa with immunomyeloablative chemotherapy and allogeneic stem-cell transplantation. We assessed C7 expression by means of immunofluorescence staining and used transmission electron microscopy to visualize anchoring fibrils. We measured chimerism by means of competitive polymerase-chain-reaction assay, and documented blister formation and wound healing with the use of digital photography. One patient died of cardiomyopathy before transplantation. Of the remaining six patients, one had severe regimen-related cutaneous toxicity, with all having improved wound healing and a reduction in blister formation between 30 and 130 days after transplantation. We observed increased C7 deposition at the dermal-epidermal junction in five of the six recipients, albeit without normalization of anchoring fibrils. Five recipients were alive 130 to 799 days after transplantation; one died at 183 days as a consequence of graft rejection and infection. The six recipients had substantial proportions of donor cells in the skin, and none had detectable anti-C7 antibodies. Increased C7 deposition and a sustained presence of donor cells were found in the skin of children with recessive dystrophic epidermolysis bullosa after allogeneic bone marrow transplantation. Further studies are needed to assess the long-term risks and benefits of such therapy in patients with this disorder. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00478244.)


Long-term follow-up of antivascular endothelial growth factor treatment for diabetic macular oedema: a four-year real-world study.
To evaluate visual acuity (VA) and central retinal thickness (CRT) on optical coherence tomography during a 4-year period in patients treated for sight-threatening diabetic macular oedema (DMO) at two Swedish county hospitals. Additionally, to compare health-related quality of life and subjective visual functioning before and after 4 years of treatment. Fifty-eight patients with DMO were evaluated after 4 years of antivascular endothelial growth factor (VEGF) treatment. VA, CRT and clinical data were retrospectively reviewed. Health-related quality of life and subjective visual functioning were evaluated with Short Form Health Survey (SF-36) and National Eye Institute Vision Functioning Questionnaire 25 (VFQ-25). Comparisons between independent groups were performed using Pearson's χ2 test, Fisher's exact test or Mann-Whitney U test. Spearman's ρ was used for correlation analyses. Wilcoxon signed-rank test was used for comparison between dependent groups. Logistic regression analysis was applied for analysis of VA and CRT over 4 years. Follow-up data were obtained from 37 of 58 (63.8%) patients. Baseline characteristics were similar, regardless of follow-up. VA improvement at 1 year (mean + 4.4, SD 7.5; ETDRS letter score) was maintained over 3 years, then declined. CRT was reduced throughout the study. In the first treatment year, eyes received 5.1 (1.4) anti-VEGF injections, followed by approximately two injections yearly. Additional treatment included laser and dexamethasone implants. SF-36 showed no change at 4 years, compared with baseline. VFQ-25 demonstrated improvement in near vision activities (p = 0.036). Significant long-term improvement in visual function was present in patients with anti-VEGF-treated DMO.


Misclassification bias: diversity in conceptualisations about having 'had sex'.
Understanding the signification of the word 'sex' has implications for both medical research and clinical practice. Little is known about how people of varying ages define sex and how situational qualifiers influence definitions across age groups. To our knowledge, this is the first study of a representative sample to assess attitudes about which sexual behaviours constitute having 'had sex' and to examine possible mediating factors (gender, age, giving/receiving stimulation, male ejaculation, female orgasm, condom use or brevity). A telephone survey of English-speaking residents of Indiana (USA) using random-digit-dialling produced a final sample of 204 men and 282 women (n = 486) ranging in age from 18 to 96 years. Questions assessed the respondents' attitudes on manual-genital (MG), oral-genital (OG), penile-vaginal intercourse (PVI) and penile-anal intercourse (PAI) behaviours. There was no universal consensus on which behaviours constituted having 'had sex'. More than 90% responded 'yes' to PVI but one in five responded 'no' to PAI, three in 10 responded 'no' to OG and about half endorsed MG. Fewer endorsed PVI with no male ejaculation (89.1%) compared with PVI without a qualifier (94.8%, P < 0.001). MG was endorsed more often when received (48.1%) than given (44.9%, P < 0.001). Among men, the oldest and youngest age groups were significantly less likely to believe certain behaviours constituted having 'had sex'. These findings highlight the need to use behaviour-specific terminology in sexual history taking, sex research, sexual health promotion and sex education. Researchers, educators and medical practitioners should exercise caution and not assume that their own definitions of having 'had sex' are shared by their research participants or patients.


Experimental H-type and L-type bovine spongiform encephalopathy in cattle: observation of two clinical syndromes and diagnostic challenges.
The majority of atypical bovine spongiform encephalopathy (BSE) cases so far identified worldwide have been detected by active surveillance. Consequently the volume and quality of material available for detailed characterisation is very limiting. Here we report on a small transmission study of both atypical forms, H- and L-type BSE, in cattle to provide tissue for test evaluation and research, and to generate clinical, molecular and pathological data in a standardised way to enable more robust comparison of the two variants with particular reference to those aspects most relevant to case ascertainment and confirmatory diagnosis within existing regulated surveillance programmes. Two groups of four cattle, intracerebrally inoculated with L-type or H-type BSE, all presented with a nervous disease form with some similarities to classical BSE, which progressed to a more dull form in one animal from each group. Difficulty rising was a consistent feature of both disease forms and not seen in two BSE-free, non-inoculated cattle that served as controls. The pathology and molecular characteristics were distinct from classical BSE, and broadly consistent with published data, but with some variation in the pathological characteristics. Both atypical BSE types were readily detectable as BSE by current confirmatory methods using the medulla brain region at the obex, but making a clear diagnostic distinction between the forms was not consistently straightforward in this brain region. Cerebellum proved a more reliable sample for discrimination when using immunohistochemistry. The prominent feature of difficulty rising in atypical BSE cases may explain the detection of naturally occurring cases in emergency slaughter cattle and fallen stock. Current confirmatory diagnostic methods are effective for the detection of such atypical cases, but consistently and correctly identifying the variant forms may require modifications to the sampling regimes and methods that are currently in use.


Association of HIV infection with distribution and viral load of HPV types in Kenya: a survey with 820 female sex workers.
Human papillomavirus (HPV) and HIV are each responsible for a considerable burden of disease. Interactions between these infections pose substantial public health challenges, especially where HIV prevalence is high and HPV vaccine coverage low. Between July 2005 and January 2006, a cross-sectional community-based survey in Mombasa, Kenya, enrolled female sex workers using snowball sampling. After interview and a gynaecological examination, blood and cervical cytology samples were taken. Quantitative real-time PCR detected HPV types and viral load measures. Prevalence of high-risk HPV was compared between HIV-infected and -uninfected women, and in women with abnormal cervical cytology, measured using conventional Pap smears. Median age of the 820 participants was 28 years (inter-quartile range [IQR] = 24-36 years). One third of women were HIV infected (283/803; 35.2%) and these women were y more likely to have abnormal cervical cytology than HIV-negative women (27%, 73/269, versus 8%, 42/503; P < 0.001). Of HIV-infected women, 73.3% had high-risk HPV (200/273) and 35.5% had HPV 16 and/or 18 (97/273). Corresponding figures for HIV-negative women were 45.5% (229/503) and 15.7% (79/503). After adjusting for age, number of children and condom use, high-risk HPV was 3.6 fold more common in HIV-infected women (95%CI = 2.6-5.1). Prevalence of all 15 of the high-risk HPV types measured was higher among HIV-infected women, between 1.4 and 5.5 fold. Median total HPV viral load was 881 copies/cell in HIV-infected women (IQR = 33-12,110 copies/cell) and 48 copies/cell in HIV-uninfected women (IQR = 6-756 copies/cell; P < 0.001). HPV 16 and/or HPV 18 were identified in 42.7% of LSIL (32/75) and 42.3% of HSIL (11/26) lesions (P = 0.98). High-risk HPV types other than 16 and 18 were common in LSIL (74.7%; 56/75) and HSIL (84.6%; 22/26); even higher among HIV-infected women. HIV-infected sex workers had almost four-fold higher prevalence of high-risk HPV, raised viral load and more precancerous lesions. HPV 16 and HPV 18, preventable with current vaccines, were associated with cervical disease, though other high-risk types were commoner. HIV-infected sex workers likely contribute disproportionately to HPV transmission dynamics in the general population. Current efforts to prevent HIV and HPV are inadequate. New interventions are required and improved implementation of existing strategies.


Base-resolution analysis of 5-hydroxymethylcytosine in the mammalian genome.
The study of 5-hydroxylmethylcytosines (5hmC) has been hampered by the lack of a method to map it at single-base resolution on a genome-wide scale. Affinity purification-based methods cannot precisely locate 5hmC nor accurately determine its relative abundance at each modified site. We here present a genome-wide approach, Tet-assisted bisulfite sequencing (TAB-Seq), that when combined with traditional bisulfite sequencing can be used for mapping 5hmC at base resolution and quantifying the relative abundance of 5hmC as well as 5mC. Application of this method to embryonic stem cells not only confirms widespread distribution of 5hmC in the mammalian genome but also reveals sequence bias and strand asymmetry at 5hmC sites. We observe high levels of 5hmC and reciprocally low levels of 5mC near but not on transcription factor-binding sites. Additionally, the relative abundance of 5hmC varies significantly among distinct functional sequence elements, suggesting different mechanisms for 5hmC deposition and maintenance.


"His" and "Hers": Meeting the Economic Bar to Marriage.
Scholars have suggested that low-income parents avoid marriage because they have not met the so-called economic bar to marriage. The economic bar is multidimensional, referring to a bundle of financial achievements that determine whether couples feel ready to wed. Using the Building Strong Families data set of low-income parents (n = 4,444), we operationalized this qualitative concept into a seven-item index and examined whether couples who met the economic bar by achieving the majority of the items were more likely to marry than couples who did not. Meeting the bar was associated with a two-thirds increase in marriage likelihood. The bar was not positively associated with cohabitation, suggesting that it applies specifically to marriage. When we examined different definitions of the bar based on whether the mother, father, or both parents contributed items, all variants were associated with marriage, even if the bar was based on the mother's economic accomplishments alone. When mothers contributed to the economic bar, they reported significantly higher relationship quality. Our results reinforce the importance of the multidimensional economic bar for marriage entry, highlighting the role of maternal economic contributions in low-income relationships.


Experimental verification and clinical implementation of a commercial Monte Carlo electron beam dose calculation algorithm.
This study describes the modeling and the experimental verification and clinical implementation of the alpha release of Pinnacle3 Monte Carlo (MC) electron beam dose calculation algorithm for patient-specific treatment planning. The MC electron beam modeling was performed for beam energies ranging from 6 to 18 MeV from a Siemens (Primus) linear accelerator using standard-shaped electron applicators and 100 cm source-to-surface distance (SSD). The agreement between MC calculations and measurements was, on average, within 2% and 2 mm for all applicator sizes. However, differences of the order of 3%-4% were noted in the off-axis dose profiles for the largest applicator modeled and for all energies. Output factors were calculated for standard electron cones and square cutouts inserted in the 10 x 10 cm2 applicator for different SSDs and were found to be within 4% of measured data. Experimental verification of the MC electron beam model was carried out using an ionization chamber and film in solid-water slab and anthropomorphic phantoms containing bone and lung materials. Agreement between calculated and measured dose distributions was within +/-3%. Clinical comparison was performed in four patient treatment plans with lesions in highly irregular anatomies, such as the ear, face, and breast, where custom-designed bolus and field shaping blocks were used in the patient treatments. For comparison purposes, treatment planning was also performed using the conventional pencil beam (PB) algorithm with the Pinnacle3 treatment planning system. Differences between MC and PB dose calculations for the patient treatment plans were significant, particularly in anatomies where the target was in close proximity to low density tissues, such as lung and air cavities. Concerning monitor unit calculations, the largest differences obtained between MC and PB algorithms were between 4.0% and 5.0% for two patients treated with oblique beams and involving highly irregular surfaces, i.e., breast and cheek. Clinical results are reported for overall uncertainty values (averaged over voxels with doses >50% dosemax) ranging from 2% to 0.3% and calculations were performed using cubic voxels with side 0.3 cm. Timing values ranged from 2 min to 24.5 h, depending on the field size, beam energy, number, and thickness of computed tomography slices used to define the patient's anatomy for the overall uncertainty values mentioned above.


A wireless brain-machine interface for real-time speech synthesis.
Brain-machine interfaces (BMIs) involving electrodes implanted into the human cerebral cortex have recently been developed in an attempt to restore function to profoundly paralyzed individuals. Current BMIs for restoring communication can provide important capabilities via a typing process, but unfortunately they are only capable of slow communication rates. In the current study we use a novel approach to speech restoration in which we decode continuous auditory parameters for a real-time speech synthesizer from neuronal activity in motor cortex during attempted speech. Neural signals recorded by a Neurotrophic Electrode implanted in a speech-related region of the left precentral gyrus of a human volunteer suffering from locked-in syndrome, characterized by near-total paralysis with spared cognition, were transmitted wirelessly across the scalp and used to drive a speech synthesizer. A Kalman filter-based decoder translated the neural signals generated during attempted speech into continuous parameters for controlling a synthesizer that provided immediate (within 50 ms) auditory feedback of the decoded sound. Accuracy of the volunteer's vowel productions with the synthesizer improved quickly with practice, with a 25% improvement in average hit rate (from 45% to 70%) and 46% decrease in average endpoint error from the first to the last block of a three-vowel task. Our results support the feasibility of neural prostheses that may have the potential to provide near-conversational synthetic speech output for individuals with severely impaired speech motor control. They also provide an initial glimpse into the functional properties of neurons in speech motor cortical areas.


The effect of simple heat treatment on apatite formation on grit-blasted/acid-etched dental Ti implants already in clinical use.
Grit-blasted/acid-etched titanium dental implants have a moderately roughened surface that is suitable for cell adhesion and exhibits faster osseointegration. However, the roughened surface does not always maintain stable fixation over a long period. In this study, a simple heat treatment at 600°C was performed on a commercially available dental Ti implant with grit-blasting/acid-etching, and its effect on mineralization capacity was assessed by examining apatite formation in a simulated body fluid (SBF). The as-purchased implant displayed a moderately roughened surface at the micrometer scale. Its surface was composed of titanium hydride accompanied by a small amount of alumina particles derived from the grit-blasting. Heat treatment transformed the titanium hydride into rutile without evidently changing the surface morphology. The immersion in SBF revealed that apatite formed on the heated implant at 7 days. Furthermore, apatite formed on the Ti rod surface within 1 day when the metal was subjected to acid and heat treatment without blasting. These indicate that apatite formation was conferred on the commercially available dental implant by simple heat treatment, although its induction period was slightly affected by alumina particles remaining on the implant surface. The heat-treated implant should achieve stronger and more stable bone bonding due to its apatite formation.


Incidence of Spontaneous Resorption of Lumbar Disc Herniation: A Meta-Analysis.
Lumbar disc herniation (LDH), a common disease, is often treated conservatively, frequently resulting in spontaneous resorption of the herniated disc. The incidence of this phenomenon, however, remains unknown. To analyze the incidence of spontaneous resorption after conservative treatment of LDH using computed tomography and magnetic resonance imaging. Meta-analysis and systematic review of cohort studies. The work was performed at The Suzhou Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine. We initiated a search for the period from January 1990 to December 2015 using PubMed, Embase, and the Cochrane Library. Two independent reviewers examined the relevant reports. The references from these reports were also searched for additional trials using the criteria established in the PRISMA statement. Our results represent the pooled results from 11 cohort studies. The overall incidence of spontaneous resorption after LDH was 66.66% (95% CI 51% - 69%). The incidence in the United Kingdom was 82.94% (95% CI 63.77% - 102.11%). The incidence in Japan was 62.58% (95% CI 55.71% - 69.46%). Our study was limited because there were few sources from which to extract data, either in abstracts or published studies. There were no randomized, controlled trials that met our criteria. The phenomenon of LDH reabsorption is well recognized. Because its overall incidence is now 66.66% according to our results, conservative treatment may become the first choice of treatment for LDH. More large-scale, double-blinded, randomized, controlled trials are necessary to study the phenomenon of spontaneous resorption of LDH.Key words: Lumbar, disc herniation, spontaneous resorption, conservative treatment, incidence, country, meta-analysis, systematic review, observational studies, study designs.


Taxonomic studies of extremely barophilic bacteria isolated from the Mariana Trench and description of Moritella yayanosii sp. nov., a new barophilic bacterial isolate.
We have isolated two strains of extremely barophilic bacteria from sediment collected from the world's deepest ocean floor in the Mariana Trench, Challenger Deep, at a depth of 10898m [Kato C, Li L, Nogi Y, Nakamura Y, Tamaoka J, Horikoshi K (1998) Appl Environ Microbiol 64:1510-1513]. One strain, DB21MT-2, was identified as a strain of Shewanella benthica, and the other strain, DB21MT-5, is closely affiliated with members of the genus Moritella on the basis of 16S rDNA sequence analysis. The hybridization values for DNA-DNA relatedness between DB21MT-5 and the Moritella reference strains were significantly lower than that accepted as the phylogenetic definition of a species. Based on this and other taxonomic differences, strain DB21MT-5 appears to represent a novel obligately barophilic deep-sea Moritella species. The name Moritella yaynanosii (JCM 10263) is proposed. This is the first proposed species of obligately barophilic bacteria of the genus Moritella.


Infiltrating monocytes in liver injury and repair.
Noninfectious liver injury causes many acute and chronic liver diseases around the globe, and particularly in developed nations. Bone marrow-derived monocytes infiltrate the damaged liver tissue and are a critical component of the innate immune response that may drive injury resolution or host death in the short term or chronic inflammation, fibrosis and hepatocellular carcinoma in the long term. Monocytes often play dual roles in liver injury-both perpetuating inflammation and promoting resolution of inflammation and fibrosis. Thus, we will address the role that monocytes play in different experimental forms of noninfectious liver injury; considering in particular the importance of the transition from inflammatory Ly6Chi monocytes to pro-resolution Ly6Clo monocyte-derived macrophages and the consequences of this transition for disease progression and resolution.


Light propagation in a birefringent plate with topological charge.
We calculated the Fresnel paraxial propagator in a birefringent plate having topological charge q at its center, named "q-plate." We studied the change of the beam transverse profile when it traverses the plate. An analytical closed form of the beam profile propagating in the q-plate can be found for many important specific input beam profiles. We paid particular attention to the plate having a topological unit charge and found that if small losses due to reflection, absorption, and scattering are neglected, the plate can convert the photon spin into orbital angular momentum with up to 100% efficiency provided the thickness of the plate is less than the Rayleigh range of the incident beam.


Carbon storage in US wetlands.
Wetland soils contain some of the highest stores of soil carbon in the biosphere. However, there is little understanding of the quantity and distribution of carbon stored in our remaining wetlands or of the potential effects of human disturbance on these stocks. Here we use field data from the 2011 National Wetland Condition Assessment to provide unbiased estimates of soil carbon stocks for wetlands at regional and national scales. We find that wetlands in the conterminous United States store a total of 11.52 PgC, much of which is within soils deeper than 30 cm. Freshwater inland wetlands, in part due to their substantial areal extent, hold nearly ten-fold more carbon than tidal saltwater sites-indicating their importance in regional carbon storage. Our data suggest a possible relationship between carbon stocks and anthropogenic disturbance. These data highlight the need to protect wetlands to mitigate the risk of avoidable contributions to climate change.


Treatment of nonconvergence of Fourier modal method arising from irregular field singularities at lossless metal-dielectric right-angle edges.
In a recent work [J. Opt. Soc. Am. A28, 738 (2011)], Lifeng Li and Gerard Granet investigate nonconvergence cases of the Fourier modal method (FMM). They demonstrate that the nonconvergence is due to the irregular field singularities at lossless metal-dielectric right-angle edges. Here we make further investigations on the problem and find that the FMM surprisingly converges for deep sub-wavelength gratings (grating period being much smaller than the illumination wavelength). To overcome the nonconvergence for gratings that are not deep sub-wavelength, we approximately replace the lossless metal-dielectric right-angle edges by a medium with a gradually varied refraction index, so as to remove the irregular field singularities. With such treatment, convergence is observed as the region of the approximate medium approaches vanishing.


Towards highly accelerated Cartesian time-resolved 3D flow cardiovascular magnetic resonance in the clinical setting.
The clinical applicability of time-resolved 3D flow cardiovascular magnetic resonance (CMR) remains compromised by the long scan times associated with phase-contrast imaging. The present work demonstrates the applicability of 8-fold acceleration of Cartesian time-resolved 3D flow CMR in 10 volunteers and in 9 patients with different congenital heart diseases (CHD). It is demonstrated that accelerated 3D flow CMR data acquisition and image reconstruction using k-t PCA (principal component analysis) can be implemented into clinical workflow and results are sufficiently accurate relative to conventional 2D flow CMR to permit for comprehensive flow quantification in CHD patients. The fidelity of k-t PCA was first investigated on retrospectively undersampled data for different acceleration factors and compared to k-t SENSE and fully sampled reference data. Subsequently, k-t PCA with 8-fold nominal undersampling was applied on 10 healthy volunteers and 9 CHD patients on a clinical 1.5 T MR scanner. Quantitative flow validation was performed in vessels of interest on the 3D flow datasets and compared to 2D through-plane flow acquisitions. Particle trace analysis was used to qualitatively visualise flow patterns in patients. Accelerated time-resolved 3D flow data were successfully acquired in all subjects with 8-fold nominal scan acceleration. Nominal scan times excluding navigator efficiency were on the order of 6 min and 7 min in patients and volunteers. Mean differences in stroke volume in selected vessels of interest were 2.5 ± 8.4 ml and 1.63 ± 4.8 ml in volunteers and patients, respectively. Qualitative flow pattern analysis in the time-resolved 3D dataset revealed valuable insights into hemodynamics including circular and helical patterns as well as flow distributions and origin in the Fontan circulation. Highly accelerated time-resolved 3D flow using k-t PCA is readily applicable in clinical routine protocols of CHD patients. Nominal scan times of 6 min are well tolerated and allow for quantitative and qualitative flow assessment in all great vessels.