Immunosuppressive agents for treating IgA nephropathy.
IgA nephropathy is the most common glomerulonephritis world-wide. IgA nephropathy causes end-stage kidney disease (ESKD) in 15% to 20% of affected patients within 10 years and in 30% to 40% of patients within 20 years from the onset of disease. This is an update of a Cochrane review first published in 2003 and updated in 2015. To determine the benefits and harms of immunosuppression strategies for the treatment of IgA nephropathy. We searched the Cochrane Kidney and Transplant Register of Studies up to 9 September 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. We included randomised controlled trials (RCTs) and quasi-RCTs of treatment for IgA nephropathy in adults and children and that compared immunosuppressive agents with placebo, no treatment, or other immunosuppressive or non-immunosuppressive agents. Two authors independently assessed study risk of bias and extracted data. Estimates of treatment effect were summarised using random effects meta-analysis. Treatment effects were expressed as relative risk (RR) and 95% confidence intervals (95% CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Risks of bias were assessed using the Cochrane tool. Evidence certainty was evaluated using GRADE methodology. Fifty-eight studies involving 3933 randomised participants were included. Six studies involving children were eligible. Disease characteristics (kidney function and level of proteinuria) were heterogeneous across studies. Studies evaluating steroid therapy generally included patients with protein excretion of 1 g/day or more. Risk of bias within the included studies was generally high or unclear for many of the assessed methodological domains. In patients with IgA nephropathy and proteinuria > 1 g/day, steroid therapy given for generally two to four months with a tapering course probably prevents the progression to ESKD compared to placebo or standard care (8 studies; 741 participants: RR 0.39, 95% CI 0.23 to 0.65; moderate certainty evidence). Steroid therapy may induce complete remission (4 studies, 305 participants: RR 1.76, 95% CI 1.03 to 3.01; low certainty evidence), prevent doubling of serum creatinine (SCr) (7 studies, 404 participants: RR 0.43, 95% CI 0.29 to 0.65; low certainty evidence), and may lower urinary protein excretion (10 studies, 705 participants: MD -0.58 g/24 h, 95% CI -0.84 to -0.33;low certainty evidence). Steroid therapy had uncertain effects on glomerular filtration rate (GFR), death, infection and malignancy. The risk of adverse events with steroid therapy was uncertain due to heterogeneity in the type of steroid treatment used and the rarity of events. Cytotoxic agents (azathioprine (AZA) or cyclophosphamide (CPA) alone or with concomitant steroid therapy had uncertain effects on ESKD (7 studies, 463 participants: RR 0.63, 95% CI 0.33 to 1.20; low certainty evidence), complete remission (5 studies; 381 participants: RR 1.47, 95% CI 0.94 to 2.30; very low certainty evidence), GFR (any measure), and protein excretion. Doubling of serum creatinine was not reported. Mycophenolate mofetil (MMF) had uncertain effects on the progression to ESKD, complete remission, doubling of SCr, GFR, protein excretion, infection, and malignancy. Death was not reported. Calcineurin inhibitors compared with placebo or standard care had uncertain effects on complete remission, SCr, GFR, protein excretion, infection, and malignancy. ESKD and death were not reported. Mizoribine administered with renin-angiotensin system inhibitor treatment had uncertain effects on progression to ESKD, complete remission, GFR, protein excretion, infection, and malignancy. Death and SCr were not reported. Leflunomide followed by a tapering course with oral prednisone compared to prednisone had uncertain effects on the progression to ESKD, complete remission, doubling of SCr, GFR, protein excretion, and infection. Death and malignancy were not reported. Effects of other immunosuppressive regimens (including steroid plus non-immunosuppressive agents or mTOR inhibitors) were inconclusive primarily due to insufficient data from the individual studies in low or very low certainty evidence. The effects of treatments on death, malignancy, reduction in GFR at least of 25% and adverse events were very uncertain. Subgroup analyses to determine the impact of specific patient characteristics such as ethnicity or disease severity on treatment effectiveness were not possible. In moderate certainty evidence, corticosteroid therapy probably prevents decline in GFR or doubling of SCr in adults and children with IgA nephropathy and proteinuria. Evidence for treatment effects of immunosuppressive agents on death, infection, and malignancy is generally sparse or low-quality. Steroid therapy has uncertain adverse effects due to a paucity of studies. Available studies are few, small, have high risk of bias and generally do not systematically identify treatment-related harms. Subgroup analyses to identify specific patient characteristics that might predict better response to therapy were not possible due to a lack of studies. There is no evidence that other immunosuppressive agents including CPA, AZA, or MMF improve clinical outcomes in IgA nephropathy.


Skin aging as a mechanical phenomenon: The main weak links.
From a mechanical point of view, human skin appears as a layered composite containing the stiff thin cover layer presented by the stratum corneum, below which are the more compliant layers of viable epidermis and dermis and further below the much more compliant adjacent layer of subcutaneous white adipose tissue (sWAT). Upon exposure to a strain, such a multi-layer system demonstrates structural instabilities in its stiffer layers, which in its simplest form is the wrinkling. These instabilities appear hierarchically when the mechanical strain in the skin exceeds some critical values. Their appearance is mainly dependent on the mismatch in mechanical properties between adjacent skin layers or between the skin and sWAT, on the adhesive strength and thickness ratios between the layers, on their bending and tensile stiffness as well as on the value of the stress existing in single layers. Gradual reduction of elastic fibers in aging significantly reduces the skin's ability to bend, prompting an up to 4-fold reduction of its stability against wrinkling, thereby explaining the role of these fibers in skin aging. While chronological and extrinsic aging differently modify these parameters, they lead to the same end result, reducing the critical strain required for the onset of instabilities. Comparing of mechanical properties of the skin presented as a bi-, tri- or tetra-layer structure demonstrates the particular importance of the papillary dermis in skin aging and provides the arguments to consider the undulations on the dermal-epidermal and dermal-sWAT interfaces as the result of mechanical bifurcation, leading to structural instabilities inside of the skin. According to this model, anti-aging strategies should focus not as much on the reinforcement of the dermis, but rather aim to treat the elastic mismatch between different adjacent layers in the skin and sWAT as well as the adhesion between these layers.


Updated Reference Genome Sequence and Annotation of Mycobacterium bovis AF2122/97.
We report here an update to the reference genome sequence of the bovine tuberculosis bacillus Mycobacterium bovis AF2122/97, generated using an integrative multiomics approach. The update includes 42 new coding sequences (CDSs), 14 modified annotations, 26 single-nucleotide polymorphism (SNP) corrections, and disclosure that the RD900 locus, previously described as absent from the genome, is in fact present.


Mapping from frame-driven to frame-free event-driven vision systems by low-rate rate coding and coincidence processing--application to feedforward ConvNets.
Event-driven visual sensors have attracted interest from a number of different research communities. They provide visual information in quite a different way from conventional video systems consisting of sequences of still images rendered at a given "frame rate." Event-driven vision sensors take inspiration from biology. Each pixel sends out an event (spike) when it senses something meaningful is happening, without any notion of a frame. A special type of event-driven sensor is the so-called dynamic vision sensor (DVS) where each pixel computes relative changes of light or "temporal contrast." The sensor output consists of a continuous flow of pixel events that represent the moving objects in the scene. Pixel events become available with microsecond delays with respect to "reality." These events can be processed "as they flow" by a cascade of event (convolution) processors. As a result, input and output event flows are practically coincident in time, and objects can be recognized as soon as the sensor provides enough meaningful events. In this paper, we present a methodology for mapping from a properly trained neural network in a conventional frame-driven representation to an event-driven representation. The method is illustrated by studying event-driven convolutional neural networks (ConvNet) trained to recognize rotating human silhouettes or high speed poker card symbols. The event-driven ConvNet is fed with recordings obtained from a real DVS camera. The event-driven ConvNet is simulated with a dedicated event-driven simulator and consists of a number of event-driven processing modules, the characteristics of which are obtained from individually manufactured hardware modules.


Effect of organic and inorganic ions on the lower critical solution transition and aggregation of PNIPAM.
We have studied the effect of different ions belonging to the extended Hofmeister series on the thermosensitive polymer poly(N-isopropylacrylamide) (PNIPAM), by combining Differential Scanning Calorimetry (DSC) and Dynamic Light Scattering (DLS). The variations in the lower critical solution temperature (TLCS) and enthalpy change during PNIPAM phase separation evidence the importance of considering both hydration and hydrophobicity to explain the interaction of ions with interfaces. The results obtained in the presence of inorganic ions can be explained by the tendency of water molecules to preferentially hydrate the PNIPAM chains or the ions, depending on the kosmotropic (highly hydrated) or chaotropic (poorly hydrated) character of the ions. On the contrary, tetraphenyl organic ions (Ph4B- and Ph4As+) interact with the hydrophobic moieties of PNIPAM chains, inducing a significant reduction of the TLCS. DLS results show that the aggregation state of PNIPAM above the TLCS is also strongly influenced by the presence of ions. While macroscopic phase separation (formation of a polymer-rich phase insoluble in water) was apparent in the presence of inorganic ions, we observed the formation of submicron PNIPAM aggregates at temperatures above the TLCS in the presence of the hydrophobic ions. Kinetically arrested monodisperse PNIPAM nanoparticles were formed in the presence of the Ph4B- anion, while a rather polydisperse distribution of particle sizes was observed in the presence of Ph4As+. These results show that ionic specificity influences both the static (thermodynamic) and dynamic (kinetically controlled aggregation) states of PNIPAM in an aqueous environment.


Review of Aboriginal child health services in remote Western Australia identifies challenges and informs solutions.
Despite a national focus on closing the gap between Aboriginal and non-Aboriginal child health outcomes in Australia, there remain significant challenges, including provision of health services in very remote communities. We aimed to identify and map child health services in the very remote Fitzroy Valley, West Kimberley, and document barriers to effective service delivery. Identification and review of all regional child health services and staffing in 2013. Verification of data by interview with senior managers and staff of key providers in the Western Australian Country Health Service, Kimberley Population Health Unit, Nindilingarri Cultural Health Services and non-government providers. We identified no document providing a comprehensive overview of child health services in the Fitzroy Valley. There were inadequate numbers of health professionals, facilities and accommodation; high staff turnover; and limited capacity and experience of local health professionals. Funding and administrative arrangements were complex and services poorly coordinated and sometimes duplicated. The large geographic area, distances, extreme climate and lack of public and private transport challenge service delivery. The need to attend to acute illness acts to deprioritise crucial primary and preventative health care and capacity for dealing with chronic, complex disorders. Some services lack cultural safety and there is a critical shortage of Aboriginal Health Workers (AHW). Services are fragmented and variable and would benefit from a coordinated approach between government, community-controlled agencies, health and education sectors. A unifying model of care with emphasis on capacity-building in Aboriginal community members and training and support for AHW and other health professionals is required but must be developed in consultation with communities. Innovative diagnostic and care models are needed to address these challenges, which are applicable to many remote Australian settings outside the Fitzroy Valley, as well as other countries globally. Our results will inform future health service planning and strategies to attract and retain health professionals to work in these demanding settings. A prospective audit of child health services is now needed to inform improved planning of child health services with a focus on identifying service gaps and training needs and better coordinating existing services to improve efficiency and potentially also efficacy.


Reproducibility of masked hypertension determined from morning and evening home blood pressure measurements over a 6-month period.
Recently, the existence of so-called masked hypertension has attracted attention. In this study, the reproducibility of masked hypertension determined from morning and evening home blood pressure measurements was examined over a 6-month period. Home blood pressure measurements were taken consecutively for 7 days in volunteers at a company in 2002 and again in 2003. The 503 Japanese subjects (329 male, 174 female, mean age: 39.4 years), who were not taking antihypertensive drugs, were asked to measure their home blood pressure three times every morning and three times every evening. We defined casual blood pressure > or =140 (systolic) or > or =90 (diastolic) mmHg and home blood pressure > or =135 or > or =85 mmHg as hypertension. We also defined normotension as <140 and <90 mmHg in casual blood pressure and <135 and <85 mmHg in home blood pressure. We examined the reproducibility of four blood pressure categories (normotension, hypertension, white-coat hypertension, and masked hypertension) over a 6-month period. When measured in morning home blood pressure, the reproducibility of masked hypertension (59.1%) was significantly higher than that of white-coat hypertension (25.0%) and similar to that of hypertension (67.6%). However, the reproducibility of masked hypertension (23.5%) was similar to that of white-coat hypertension (32.0%) and significantly lower than that of hypertension (66.7%) when determined using evening home blood pressure. The concordances in the four blood pressure categories between the two periods were 0.582 (kappa coefficient) and 0.463 when determined using morning and evening home blood pressure data, respectively. In conclusion, the reproducibility of masked hypertension over a 6-month period was moderate in an urban Japanese population when evaluated by morning home blood pressure.


Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis.
Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. To identify the genetic variants associated with juvenile ALS. In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism. De novo variants present only in the index case and not in unaffected family members. Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway. These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.


Documenting an EBP project: guidelines for what to include and why.
In increasing numbers, nurses as members of intradisciplinary and transdisciplinary teams are implementing evidence-based practice (EBP) changes. These variations result in demonstrated improvement in outcomes for the patient and family, staff, organization, and community. Many of these EBP activities remain an untapped resource; however, they have potential for improving practice beyond a single facility or local area. Descriptions of EBP projects that dofind their way into the literature have yet to include detail on all of the steps of the EBP process from problem identification through critical appraisal and synthesis of relevant literature to development, implementation, and evaluation of the practice change. In this article, the authors aim to provide guidance to clinicians on how to document an EBP project. Guidelines addressed in the article are also included as criteria for the Evidence-Based Practice Award, as established by the Foundation of New York State Nurses Center for Nursing Research Planning Committee.


Neonatal Exposure to Amoxicillin Alters Long-Term Immune Response Despite Transient Effects on Gut-Microbiota in Piglets.
Antibiotic exposure during neonatal development may result in transient or persistent alterations of key microbes that are vital for normal development of local and systemic immunity, potentially impairing immune competence later in life. To further elucidate the relationship between antibiotic exposure and immune development, newborn pigs were exposed to a therapeutic pediatric dose (30 mg/kg/day) of amoxicillin (AB) or placebo (PL) from post-natal day (PND) 0-14. Subsequently, immune cell phenotype, microbial composition, and immune response to an intraperitoneal (IP) challenge with Salmonella enterica serovar Typhimurium were evaluated. AB exposure caused significant changes in fecal microbial composition on PND 3 (P = 0.025). This stemmed from a 2-fold increase in Enterobacteriaceae with live cecal coliforms on PND 7 indicating at 10-fold increase (P = 0.036). Alterations in microbial composition were transient, and successional patterns were normalizing by PND 14 (P = 0.693). Differences in PBMC (peripheral blood mononuclear cell) immune cell subtypes were detected, with the percentage of CD3+CD4+ T cells among the broader T cell population (CD3+CD4+/CD3+) being significantly higher (P = 0.031) in AB pigs and the numbers of CD4+CD45RA+ (naïve) T cells per liter of blood were lower on PND 21 in AB pigs (P = 0.036). Meanwhile, PBMCs from AB pigs produced significantly more IFNγ upon stimulation with a T-cell mitogen on PND 21 and 49 (P = 0.021). When AB pigs were challenged with heat-killed Salmonella (IP) on PND 49, IFNγ gene expression in peripheral blood was upregulated compared to those treated with PL (P = 0.043). Additionally, AB pigs showed stronger activation among neutrophils infiltrating the peritoneal cavity after in vivo immune challenge, based on higher levels of NF-κB nuclear translocation (P = 0.001). Overall, our results indicate that early life treatment with a therapeutically relevant dose of a commonly prescribed antibiotic has a programming effect on the immune system. Despite antibiotics only causing a transient disruption in gut-associated microbial communities, implications were long-term, with antibiotic treated pigs mounting an upregulated response to an immune challenge. This research adds to the growing body of evidence indicating adverse immune outcomes of early life antibiotic exposures.


Immediate delivery compared with expectant management after preterm pre-labour rupture of the membranes close to term (PPROMT trial): a randomised controlled trial.
Preterm pre-labour ruptured membranes close to term is associated with increased risk of neonatal infection, but immediate delivery is associated with risks of prematurity. The balance of risks is unclear. We aimed to establish whether immediate birth in singleton pregnancies with ruptured membranes close to term reduces neonatal infection without increasing other morbidity. The PPROMT trial was a multicentre randomised controlled trial done at 65 centres across 11 countries. Women aged over 16 years with singleton pregnancies and ruptured membranes before the onset of labour between 34 weeks and 36 weeks and 6 days weeks who had no signs of infection were included. Women were randomly assigned (1:1) by a computer-generated randomisation schedule with variable block sizes, stratified by centre, to immediate delivery or expectant management. The primary outcome was the incidence of neonatal sepsis. Secondary infant outcomes included a composite neonatal morbidity and mortality indicator (ie, sepsis, mechanical ventilation ≥24 h, stillbirth, or neonatal death); respiratory distress syndrome; any mechanical ventilation; and duration of stay in a neonatal intensive or special care unit. Secondary maternal outcomes included antepartum or intrapartum haemorrhage, intrapartum fever, postpartum treatment with antibiotics, and mode of delivery. Women and caregivers could not be masked, but those adjudicating on the primary outcome were masked to group allocation. Analyses were by intention to treat. This trial is registered with the International Clinical Trials Registry, number ISRCTN44485060. Between May 28, 2004, and June 30, 2013, 1839 women were recruited and randomly assigned: 924 to the immediate birth group and 915 to the expectant management group. One woman in the immediate birth group and three in the expectant group were excluded from the primary analyses. Neonatal sepsis occurred in 23 (2%) of 923 neonates whose mothers were assigned to immediate birth and 29 (3%) of 912 neonates of mothers assigned to expectant management (relative risk [RR] 0·8, 95% CI 0·5-1·3; p=0·37). The composite secondary outcome of neonatal morbidity and mortality occurred in 73 (8%) of 923 neonates of mothers assigned to immediate delivery and 61 (7%) of 911 neonates of mothers assigned to expectant management (RR 1·2, 95% CI 0·9-1·6; p=0·32). However, neonates born to mothers in the immediate delivery group had increased rates of respiratory distress (76 [8%] of 919 vs 47 [5%] of 910, RR 1·6, 95% CI 1·1-2·30; p=0·008) and any mechanical ventilation (114 [12%] of 923 vs 83 [9%] of 912, RR 1·4, 95% CI 1·0-1·8; p=0·02) and spent more time in intensive care (median 4·0 days [IQR 0·0-10·0] vs 2·0 days [0·0-7·0]; p<0·0001) compared with neonates born to mothers in the expectant management group. Compared with women assigned to the immediate delivery group, those assigned to the expectant management group had higher risks of antepartum or intrapartum haemorrhage (RR 0·6, 95% CI 0·4-0·9), intrapartum fever (0·4, 0·2-0·9), and use of postpartum antibiotics (0·8, 0·7-1·0), and longer hospital stay (p<0·0001), but a lower risk of caesarean delivery (RR 1·4, 95% CI 1·2-1·7). In the absence of overt signs of infection or fetal compromise, a policy of expectant management with appropriate surveillance of maternal and fetal wellbeing should be followed in pregnant women who present with ruptured membranes close to term. Australian National Health and Medical Research Council, the Women's and Children's Hospital Foundation, and The University of Sydney.


The Neuro-Immuno-Senescence Integrative Model (NISIM) on the Negative Association Between Parasympathetic Activity and Cellular Senescence.
There is evidence that accumulated senescent cells drive age-related pathologies, but the antecedents to the cellular stressors that induce senescence remain poorly understood. Previous research suggests that there is a relationship between shorter telomere length, an antecedent to cellular senescence, and psychological stress. Existing models do not sufficiently account for the specific pathways from which psychological stress regulation is converted into production of reactive oxygen species. We propose the neuro-immuno-senescence integrative model (NISIM) suggesting how vagally mediated heart rate variability (HRV) might be related to cellular senescence. Prefrontally modulated, and vagally mediated cortical influences on the autonomic nervous system, expressed as HRV, affects the immune system by adrenergic stimulation and cholinergic inhibition of cytokine production in macrophages and neutrophils. Previous findings indicate that low HRV is associated with increased production of the pro-inflammatory cytokines IL-6 and TNF-α. IL-6 and TNF-α can activate the NFκB pathway, increasing production of reactive oxygen species that can cause DNA damage. Vagally mediated HRV has been related to an individual's ability to regulate stress, and is lower in people with shorter telomeres. Based on these previous findings, the NISIM suggest that the main pathway from psychological stress to individual differences in oxidative telomere damage originates in the neuroanatomical components that modulate HRV, and culminates in the cytokine-induced activation of NFκB. Accumulated senescent cells in the brain is hypothesized to promote age-related neurodegenerative disease, and previous reports suggest an association between low HRV and onset of Alzheimer's and Parkinson's disease. Accumulating senescent cells in peripheral tissues secreting senescence-associated secretory phenotype factors can alter tissue structure and function which can induce cancer and promote tumor growth and metastasis in old age, and previous research suggested that ability to regulate psychological stress has a negative association with cancer onset. We therefore conclude that the NISIM can account for a large proportion of the individual differences in the psychological stress-related antecedents to cellular senescence, and suggest that it can be useful in providing a dynamic framework for understanding the pathways by which psychological stress induce pathologies in old age.


Socioeconomic status, asthma and chronic bronchitis in a large community-based study.
The present study investigated the relationship between socioeconomic status, using measures of occupational class and education level, and the prevalence and incidence of asthma (with and without atopy) and chronic bronchitis using data from the European Community Respiratory Health Survey (ECRHS). Asthma and chronic bronchitis were studied prospectively within the ECRHS (n = 9,023). Incidence analyses comprised subjects with no history of asthma or bronchitis at baseline. Asthma symptoms were also assessed as a continuous score. Bronchitis risk was associated with low educational level (prevalence odds ratio (POR) 1.9; 95% confidence interval (CI) 1.4-2.8) and occupational class (1.8; 1.2-2.7). Incident bronchitis also increased with low educational level (risk ratio (RR) 2.8; 95%CI 1.5-5.4). Prevalent and incident asthma with no atopy were associated with low educational level. Subjects in the low occupational class (incident risk ratio (IRR) 1.4; 95%CI 1.2-1.7) and education group (IRR 1.3; 95% CI 1.1-1.6) had higher mean asthma scores than those in higher socioeconomic groups. Lower educational level was associated with increased risk of prevalent and incident chronic bronchitis and asthma with no atopy. Lower socioeconomic groups tended to have a higher prevalence and incidence of asthma, particularly higher mean asthma scores. Adjustment for variables associated with asthma and bronchitis explained little of the observed health differences by socioeconomic status.


Achyranthes bidentata root extract prevent OVX-induced osteoporosis in rats.
The objective of the present study was to systematically investigate the effects of Achyranthes bidentata root extract (ABRE) on postmenopausal osteoporosis. Eighty 3-month-old female Sprague-Dawley rats were used and randomly assigned into sham-operated group (SHAM) and five ovariectomy (OVX) subgroups, i.e. OVX with vehicle (OVX); OVX with 17 β-ethinylestradiol (E(2), 25 μg/kg/day); OVX with ABRE of graded doses (100, 300, or 500 mg/kg/day). Daily oral administration of ABRE or E(2) started on week 4 after OVX for 16 weeks. Bone mass, bone turnover and strength were analyzed by dual-energy X-ray absorptiometry (DEXA), biochemical markers and three-point bending test. The trabecular bone microarchitecture was evaluated by microcomputed tomography (μCT). 16 weeks treatment of ABRE slowed down the body weight gain and prevented the loss of bone mass induced by the OVX. The prevention effect on bone loss was due to altering the rate of bone remodeling, which could be inferred from the decreased level of bone turnover markers, such as serum alkaline phosphatase (ALP), osteocalcin (OC) and urinary deoxypyridinoline (DPD). The changes of urinary calcium and phosphorus excretion provided the same evidence. The treatment could also enhance the bone strength and prevent the deterioration of trabecular microarchitecture. We conclude that 16 weeks of ABRE treatment improve bone biomechanical quality through modifications of bone mineral density (BMD), and trabecular microarchitecture without hyperplastic effect on uterus, and it might be a potential alternative medicine for treatment of postmenopausal osteoporosis.


Prevention of bacterial endocarditis. Recommendations by the American Heart Association.
To update recommendations issued by the American Heart Association last published in 1990 for the prevention of bacterial endocarditis in individuals at risk for this disease. An ad hoc writing group appointed by the American Heart Association for their expertise in endocarditis and treatment with liaison members representing the American Dental Association, the Infectious Diseases Society of America, the American Academy of Pediatrics, and the American Society for Gastrointestinal Endoscopy. The recommendations in this article reflect analyses of relevant literature regarding procedure-related endocarditis, in vitro susceptibility data of pathogens causing endocarditis, results of prophylactic studies in animal models of endocarditis, and retrospective analyses of human endocarditis cases in terms of antibiotic prophylaxis usage patterns and apparent prophylaxis failures. MEDLINE database searches from 1936 through 1996 were done using the root words endocarditis, bacteremia, and antibiotic prophylaxis. Recommendations in this document fall into evidence level III of the US Preventive Services Task Force categories of evidence. The recommendations were formulated by the writing group after specific therapeutic regimens were discussed. The consensus statement was subsequently reviewed by outside experts not affiliated with the writing group and by the Science Advisory and Coordinating Committee of the American Heart Association. These guidelines are meant to aid practitioners but are not intended as the standard of care or as a substitute for clinical judgment. Major changes in the updated recommendations include the following: (1) emphasis that most cases of endocarditis are not attributable to an invasive procedure; (2) cardiac conditions are stratified into high-, moderate-, and negligible-risk categories based on potential outcome if endocarditis develops; (3) procedures that may cause bacteremia and for which prophylaxis is recommended are more clearly specified; (4) an algorithm was developed to more clearly define when prophylaxis is recommended for patients with mitral valve prolapse; (5) for oral or dental procedures the initial amoxicillin dose is reduced to 2 g, a follow-up antibiotic dose is no longer recommended, erythromycin is no longer recommended for penicillin-allergic individuals, but clindamycin and other alternatives are offered; and (6) for gastrointestinal or genitourinary procedures, the prophylactic regimens have been simplified. These changes were instituted to more clearly define when prophylaxis is or is not recommended, improve practitioner and patient compliance, reduce cost and potential gastrointestinal adverse effects, and approach more uniform worldwide recommendations.


Structure of HoxA9 and Pbx1 bound to DNA: Hox hexapeptide and DNA recognition anterior to posterior.
The HOX/HOM superfamily of homeodomain proteins controls cell fate and segmental embryonic patterning by a mechanism that is conserved in all metazoans. The linear arrangement of the Hox genes on the chromosome correlates with the spatial distribution of HOX protein expression along the anterior-posterior axis of the embryo. Most HOX proteins bind DNA cooperatively with members of the PBC family of TALE-type homeodomain proteins, which includes human Pbx1. Cooperative DNA binding between HOX and PBC proteins requires a residue N-terminal to the HOX homeodomain termed the hexapeptide, which differs significantly in sequence between anterior- and posterior-regulating HOX proteins. We report here the 1.9-A-resolution structure of a posterior HOX protein, HoxA9, complexed with Pbx1 and DNA, which reveals that the posterior Hox hexapeptide adopts an altered conformation as compared with that seen in previously determined anterior HOX/PBC structures. The additional nonspecific interactions and altered DNA conformation in this structure account for the stronger DNA-binding affinity and altered specificity observed for posterior HOX proteins when compared with anterior HOX proteins. DNA-binding studies of wild-type and mutant HoxA9 and HoxB1 show residues in the N-terminal arm of the homeodomains are critical for proper DNA sequence recognition despite lack of direct contact by these residues to the DNA bases. These results help shed light on the mechanism of transcriptional regulation by HOX proteins and show how DNA-binding proteins may use indirect contacts to determine sequence specificity.


Photosynthetic Responses to High Temperature and Strong Light Suggest Potential Post-flowering Drought Tolerance of Sorghum Japanese Landrace Takakibi.
Sorghum [Sorghum bicolor (L.) Moench] is a C4 crop known to be adaptable to harsh environments such as those under high temperature and water deficit. In this study, we focused on a Japanese sorghum landrace Takakibi (NOG) and employed chlorophyll fluorescence measurements to assess its response to environmental stress. Comparison of photosynthetic rate evaluated using two parameters (effective quantum yield and electron transfer rate) indicated that NOG showed less activity than BTx623 in the pre-flowering stage, which was consistent with the higher susceptibility of NOG seedlings to drought than BTx623. The observed differences in photosynthetic activity between the two cultivars were detectable without drought conditions on days with high temperature and strong light. Interestingly, the photosynthetic activity of NOG leaves in stress conditions increased soon after heading, and the trend was similar to that in BTx642, a well-characterized post-flowering drought-tolerant cultivar. In contrast, BTx623 showed a gradual decline in photosynthetic rate. Thus, we inferred that Japanese Takakibi has the potential to show pre-flowering drought susceptibility and post-flowering drought tolerance, through which it adapts to local climates with high temperature and strong light at harvest.


Pharmacology and pharmacogenetics of prednisone and prednisolone in patients with nephrotic syndrome.
Nephrotic syndrome is one of the most common glomerular disorders in childhood. Glucocorticoids have been the cornerstone of the treatment of childhood nephrotic syndrome for several decades, as the majority of children achieves complete remission after prednisone or prednisolone treatment. Currently, treatment guidelines for the first manifestation and relapse of nephrotic syndrome are mostly standardized, while large inter-individual variation is present in the clinical course of disease and side effects of glucocorticoid treatment. This review describes the mechanisms of glucocorticoid action and clinical pharmacokinetics and pharmacodynamics of prednisone and prednisolone in nephrotic syndrome patients. However, these mechanisms do not account for the large inter-individual variability in the response to glucocorticoid treatment. Previous research has shown that genetic factors can have a major influence on the pharmacokinetic and dynamic profile of the individual patient. Therefore, pharmacogenetics may have a promising role in personalized medicine for patients with nephrotic syndrome. Currently, little is known about the impact of genetic polymorphisms on glucocorticoid response and steroid-related toxicities in children with nephrotic syndrome. Although the evidence is limited, the data summarized in this study do suggest a role for pharmacogenetics to improve individualization of glucocorticoid therapy. Therefore, studies in larger cohorts with nephrotic syndrome patients are necessary to draw final conclusions about the influence of genetic polymorphisms on the glucocorticoid response and steroid-related toxicities to ultimately implement pharmacogenetics in clinical practice.


Operational use of neem oil as an alternative anopheline larvicide. Part B: Environmental impact and toxicological potential.
This study was conducted to investigate the preliminary environmental and mammalian toxicology of neem oil, temephos and chlorpyriphos-methyl/fenitrothion. Culex pipiens, Daphnia magna and Gambusia affinis were used to study environmental impact. A high level of toxicity was observed, with slight differences between organisms. The emulsifiers individually also displayed toxicity towards the tested organisms. Up to 90 days daily oral crude neem oil treatment (5 g/kg body weight) of laboratory mice did not cause any significant changes in weekly body weight gain, nor in serum liver damage indicators, direct bilirubin or total bilirubin. Blood parameters of treated mice up to 90 days were not statistically different from those of control mice. Neem oil could be used as an environmentally friendly alternative to the traditional chemical anopheline larvicides.


Comparing and combining chunkers of biomedical text.
Text chunking is an essential pre-processing step in information extraction systems. No comparative studies of chunking systems, including sentence splitting, tokenization and part-of-speech tagging, are available for the biomedical domain. We compared the usability (ease of integration, speed, trainability) and performance of six state-of-the-art chunkers for the biomedical domain, and combined the chunker results in order to improve chunking performance. We investigated six frequently used chunkers: GATE chunker, Genia Tagger, Lingpipe, MetaMap, OpenNLP, and Yamcha. All chunkers were integrated into the Unstructured Information Management Architecture framework. The GENIA Treebank corpus was used for training and testing. Performance was assessed for noun-phrase and verb-phrase chunking. For both noun-phrase chunking and verb-phrase chunking, OpenNLP performed best (F-scores 89.7% and 95.7%, respectively), but differences with Genia Tagger and Yamcha were small. With respect to usability, Lingpipe and OpenNLP scored best. When combining the results of the chunkers by a simple voting scheme, the F-score of the combined system improved by 3.1 percentage point for noun phrases and 0.6 percentage point for verb phrases as compared to the best single chunker. Changing the voting threshold offered a simple way to obtain a system with high precision (and moderate recall) or high recall (and moderate precision). This study is the first to compare the performance of the whole chunking pipeline, and to combine different existing chunking systems. Several chunkers showed good performance, but OpenNLP scored best both in performance and usability. The combination of chunker results by a simple voting scheme can further improve performance and allows for different precision-recall settings.


Engineering Hydrophobic Organosilica Nanoparticle-Doped Nanofibers for Enhanced and Fouling Resistant Membrane Distillation.
Engineering and scaling-up new materials for better water desalination are imperative to find alternative fresh water sources to meet future demands. Herein, the fabrication of hydrophobic poly(ether imide) composite nanofiber membranes doped with novel ethylene-pentafluorophenylene-based periodic mesoporous organosilica nanoparticles is reported for enhanced and fouling resistant membrane distillation. Novel organosilica nanoparticles were homogeneously incorporated into electrospun nanofiber membranes depicting a proportional increase of hydrophobicity to the particle contents. Direct contact membrane distillation experiments on the organosilica-doped membrane with only 5% doping showed an increase of flux of 140% compared to commercial membranes. The high porosity of organosilica nanoparticles was further utilized to load the eugenol antimicrobial agent which produced a dramatic enhancement of the antibiofouling properties of the membrane of 70% after 24 h.


[Efficacy of neoadjuvant chemotherapy for resectable pancreatic carcinoma].
Surgery followed by adjuvant chemotherapy is standard care for resectable pancreatic carcinoma. The maximum estimated 2-year survival rate associated with this strategy is nearly 50%. The use of neoadjuvant therapy for pancreatic cancer remains controversial, and its efficacy has not been elucidated. To evaluate the efficacy of neoadjuvant chemotherapy for planned pancreatic cancer resection, the oncological outcomes of neoadjuvant gemcitabine plus S-1 combination therapy( GS therapy) and a surgery-first approach were retrospectively compared. Patients with planned pancreatic cancer resection and without major artery abutments were enrolled in this study. There were 39 cases of neoadjuvant GS therapy (N group) and 93 cases of the surgery-first approach( S group). Survival and surrogate markers, including the R0 rate, the "true R0 rate"( R0 with tumor marker normalization after resection), and N0 rate, were compared. The groups did not differ significantly in terms of age, gender, or tumor location. The resection rates of the N and S groups were similar (92% and 86%, respectively). The median survival of the N group (39.4 months) was significantly longer than that of the S group (20.8 months) in intention-to-treat analysis (p=0.0009). The R0, true R0, and N0 rates of the N group (85%, 69%, and 44%, respectively) were higher than those of the S group( 72%, 48%, and 24%, respectively). In conclusion, this retrospective analysis showed that neoadjuvant GS therapy might be more effective than the standard surgery-first strategy in terms of oncological outcomes for resectable pancreatic cancer. A prospective randomized study, Prep-02/JSAP-05, which compares neoadjuvant therapy to the surgery-first approach, is ongoing (UMIN-No. 000009634).


Merbarone induces activation of caspase-activated DNase and excision of chromosomal DNA loops from the nuclear matrix.
Studies were carried out to address possible cellular mechanisms by which merbarone, a catalytic inhibitor of DNA topoisomerase II, can block tumor cell growth without inducing extensive DNA cleavage. Merbarone induced the release of high molecular weight DNA fragments from the nuclear matrix of HL-60 leukemia cells, which preceded the internucleosomalsize DNA fragmentation characteristic of late-stage apoptosis. The chromatin fragments were enriched in a matrix attachment region (MAR) sequence compared with a non-MAR sequence and were similar in size to DNA loops extracted from nuclear matrices. However, merbarone did not directly induce the excision of high molecular weight DNA fragments from the nuclear matrix by promoting topoisomerase II-catalyzed DNA cleavage, because the drug inhibited topoisomerase II-mediated cleavage in isolated nuclear matrix preparations. Instead, merbarone induced rapid activation of the mitochondrial apoptosis pathway, which included the following temporal sequence of events: dissipation of the mitochondrial transmembrane potential within 30 min, release of mitochondrial cytochrome c, and activation of caspase-activated DNase (CAD) by its inhibitor ICAD. The excision of high molecular weight DNA was inhibited at least 80% in merbarone-treated cells preincubated with the pan-caspase inhibitor z-VAD-fmk [Z-Val-Ala-Asp(OMe)-fluoromethyl ketone] and in caspase-resistant Jurkat cells (ICAD/double-mutated) that express a mutant form of ICAD. These results provide evidence that merbarone can induce rapid disorganization of DNA in tumor cells that have a functional mitochondrial apoptosis pathway without inducing extensive DNA cleavage.


Conservation of coevolving protein interfaces bridges prokaryote-eukaryote homologies in the twilight zone.
Protein-protein interactions are fundamental for the proper functioning of the cell. As a result, protein interaction surfaces are subject to strong evolutionary constraints. Recent developments have shown that residue coevolution provides accurate predictions of heterodimeric protein interfaces from sequence information. So far these approaches have been limited to the analysis of families of prokaryotic complexes for which large multiple sequence alignments of homologous sequences can be compiled. We explore the hypothesis that coevolution points to structurally conserved contacts at protein-protein interfaces, which can be reliably projected to homologous complexes with distantly related sequences. We introduce a domain-centered protocol to study the interplay between residue coevolution and structural conservation of protein-protein interfaces. We show that sequence-based coevolutionary analysis systematically identifies residue contacts at prokaryotic interfaces that are structurally conserved at the interface of their eukaryotic counterparts. In turn, this allows the prediction of conserved contacts at eukaryotic protein-protein interfaces with high confidence using solely mutational patterns extracted from prokaryotic genomes. Even in the context of high divergence in sequence (the twilight zone), where standard homology modeling of protein complexes is unreliable, our approach provides sequence-based accurate information about specific details of protein interactions at the residue level. Selected examples of the application of prokaryotic coevolutionary analysis to the prediction of eukaryotic interfaces further illustrate the potential of this approach.


Secondhand smoke exposure and asthma outcomes among African-American and Latino children with asthma.
Secondhand smoke (SHS) exposures have been linked to asthma-related outcomes but quantitative dose-responses using biomarkers of exposure have not been widely reported. Assess dose-response relationships between plasma cotinine-determined SHS exposure and asthma outcomes in minority children, a vulnerable population exposed to higher levels of SHS and under-represented in the literature. We performed analyses in 1172 Latino and African-American children with asthma from the mainland USA and Puerto Rico. We used logistic regression to assess relationships of cotinine levels ≥0.05 ng/mL with asthma exacerbations (defined as asthma-related hospitalisations, emergency room visits or oral steroid prescription) in the previous year and asthma control. The shape of dose-response relationships was assessed using a continuous exposure variable in generalised additive logistic models with penalised splines. The OR for experiencing asthma exacerbations in the previous year for cotinine levels ≥0.05 ng/mL, compared with <0.05 ng/mL, was 1.40 (95% CI 1.03 to 1.89), while the OR for poor asthma control was 1.53 (95% CI 1.12 to 2.13). Analyses for dose-response relationships indicated increasing odds of asthma outcomes related with increasing exposure, even at cotinine levels associated with light SHS exposures. Exposure to SHS was associated with higher odds of asthma exacerbations and having poorly controlled asthma with an increasing dose-response even at low levels of exposure. Our results support the conclusion that there are no safe levels of SHS exposures.


Management of Verticillium Wilt of Potato with Disease-Suppressive Green Manures and as Affected by Previous Cropping History.
The ability of disease-suppressive rotation crops to reduce potato disease problems and increase crop productivity in a field with prior severe Verticillium wilt, as well as the potential influence of previous cropping history on disease suppression, was evaluated over three field seasons in Maine. Disease-suppressive rotations consisted of: (i) a high-glucosinolate mustard blend ('Caliente 119') as a mixture of white mustard (Sinapis alba) and oriental mustard (Brassica juncea) with known biofumigation potential and (ii) a sorghum-sudangrass hybrid. Each were grown as single-season green manures followed by a subsequent potato crop. These rotations were compared with a standard barley rotation and a barley rotation followed by chemical fumigation with metam sodium as controls. Both green manure rotations significantly reduced (average reductions of 25 and 18%, respectively) Verticillium wilt in the subsequent potato crop compared with the standard barley control but were not as effective as chemical fumigation (35% reduction). The mustard blend also reduced other soilborne diseases (black scurf and common scab) better than all other rotations. Mustard blend and chemical fumigation treatments increased tuber yield relative to the barley control by 12 and 18%, respectively. However, by the second rotation cycle, disease levels were high in all rotations, and only chemical fumigation resulted in substantial disease reduction (35%). Rotations also had significant effects on soil microbiology, including soil bacterial and fungal populations and microbial community characteristics based on fatty acid profiles. However, only chemical fumigation significantly reduced soil populations of Verticillium spp. and increased general soil microbial activity. Previous cropping history did not significantly affect disease reduction, tuber yield, or soil microbial communities. This research indicates the potential for using disease-suppressive rotations for managing Verticillium wilt and other soilborne diseases but also indicates that multiple years of disease-suppressive crops may be needed to substantially reduce disease in heavily infested fields.


Cerebellar re-encoding of self-generated head movements.
Head movements are primarily sensed in a reference frame tied to the head, yet they are used to calculate self-orientation relative to the world. This requires to re-encode head kinematic signals into a reference frame anchored to earth-centered landmarks such as gravity, through computations whose neuronal substrate remains to be determined. Here, we studied the encoding of self-generated head movements in the rat caudal cerebellar vermis, an area essential for graviceptive functions. We found that, contrarily to peripheral vestibular inputs, most Purkinje cells exhibited a mixed sensitivity to head rotational and gravitational information and were differentially modulated by active and passive movements. In a subpopulation of cells, this mixed sensitivity underlay a tuning to rotations about an axis defined relative to gravity. Therefore, we show that the caudal vermis hosts a re-encoded, gravitationally polarized representation of self-generated head kinematics in freely moving rats.


Short report: surveillance of Leishmania sp. among sand flies in Sicily (Italy) using a fluorogenic real-time polymerase chain reaction.
Leishmaniasis caused by Leishmania infantum is a complex zoonotic disease, resulting in cutaneous and visceral manifestations in both dogs and humans. The present study involved a published Taqman fluorogenic real-time polymerase chain reaction (PCR) assay for surveillance of Leishmania sp. parasites among sand flies trapped in two provinces in Sicily, Catania and Agrigento, during the summer and fall of 2003. Only male specimens were identified to species level, while females were used to evaluate Leishmania sp. infection by PCR testing. The two most prevalent sand fly species found were Phlebotomus perfiliewi and P. perniciosus. Of the female sand flies tested, 2.9% were positive for Leishmania sp. DNA by the PCR.


A Curriculum to Increase Empathy and Reduce Burnout.
Empathy is essential for good patient care. It underpins effective communication and high-quality, relationship-centered care. Empathy skills have been shown to decline with medical training, concordant with increasing physician distress and burnout. We piloted a 6-month curriculum for interns (N = 27) during the 2015-2016 academic year at the University of Wisconsin-Madison. The course included: (1) review of literature on physician well-being and clinical empathy, (2) instruction on the neurobiology of empathy and compassion, (3) explanation of stress physiology and techniques for mitigating its effects, (4) humanities-informed techniques, and (5) introductions to growth mindset and mindful awareness. To measure effectiveness, we compared empathy and burnout scores before and after the course. The course was well-attended. Intern levels of burnout and empathy remained stable over the study period. In multivariable modeling, we found that for each session an intern attended, their emotional exhaustion declined by 3.65 points (P = 0.007), personal accomplishment increased by 2.69 points (P = 0.001), and empathic concern improved by 0.82 points (P = 0.066). The course was well-liked. Learners reported applying course content inside and outside of work and expressed variable preferences for content and teaching methods. Skills in empathic and self-care can be taught together to reduce the decline of empathy and well-being that has been seen during internship. In this single-center pilot, resident physicians reported using these skills both inside and outside of work. Our curriculum has the potential to be adopted by other residency programs.


Real-world risk exposure in older drivers with cognitive and visual dysfunction.
Objective: This study addresses the need to measure and monitor objective, real-world driver safety behavior in at-risk drivers with age-related dysfunction. Older drivers are at risk for age-related cognitive and visual dysfunction, which may reduce mobility and increase errors that lead to crashes. Understanding patterns of real-world behavior, exposure, and cognitive-perceptual processes underlying risk in environmental context and in older drivers requires new approaches.Methods: We assessed patterns of objective, real-world driver risk exposure and vehicle control related to steering, braking, and accelerating in older adults with a range of cognitive and visual functional abilities. Real-world driver behavior was collected from passive-monitoring systems installed in 77 drivers' vehicles and analyzed across 242,153 km (150,467 miles) driven. Driver behavior was assessed cross-sectionally in relationship to driver functional abilities and safety-critical environmental contexts (roadway type and visibility condition).Results: Results suggest that cognitive dysfunction impairs vehicle control across wide-ranging environments. Drivers with greater cognitive dysfunction showed more erratic braking and accelerating during daytime commercial and interstate driving. Drivers with less cognitive dysfunction showed more erratic braking and accelerating on residential roadways regardless of visibility condition. Greater cognitive dysfunction predicted more erratic steering on commercial and interstate roadways and less erratic steering on residential roadways. Greater visual dysfunction impaired braking and accelerating during nighttime and interstate driving, but not on residential or commercial roadways. Steering behavior was unaffected by visual abilities. Drivers with greater cognitive dysfunction did not appear to reduce driving frequency in higher-risk environments. Visually impaired drivers drove more on residential roadways and less on commercial roadways, but did not reduce driving on interstates, where they showed the greatest risk per mile driven.Conclusions: Results successfully mapped driver cognitive and visual profiles onto contemporaneous, real-world behavior and risk loci. Results link age-related dysfunction to real-world vehicle control and show that drivers may not sufficiently reduce exposure to higher-risk driving environments. Employing naturalistic observation to monitor and measure patterns of driver behavior can inform methods for early detection of age-related risk, fitness-to-drive assessments, and interventions to preserve safety, mobility, and quality of life in aging or other at-risk populations.


Front propagation in a vortex lattice: dependence on boundary conditions and vortex depth.
We experimentally address the propagation of reaction-diffusion fronts in vortex lattices by combining, in a Hele-Shaw cell and at low Reynolds number, forced electroconvective flows and an autocatalytic reaction in solution. We consider both vortex chains and vortex arrays, the former referring to mixed free/rigid boundary conditions for vortices and the latter to free boundary conditions. Varying the depth of the fluid layer, we observe no variation of the mean front velocities for vortex arrays and a noticeable variation for vortex chains. This questions the two-dimensional character of front propagation in low Reynolds number vortex lattices, as well as the mechanisms of this dependence.


Phylogenomic evidence for a myxococcal contribution to the mitochondrial fatty acid beta-oxidation.
The origin of eukaryotes remains a fundamental question in evolutionary biology. Although it is clear that eukaryotic genomes are a chimeric combination of genes of eubacterial and archaebacterial ancestry, the specific ancestry of most eubacterial genes is still unknown. The growing availability of microbial genomes offers the possibility of analyzing the ancestry of eukaryotic genomes and testing previous hypotheses on their origins. Here, we have applied a phylogenomic analysis to investigate a possible contribution of the Myxococcales to the first eukaryotes. We conducted a conservative pipeline with homologous sequence searches against a genomic sampling of 40 eukaryotic and 357 prokaryotic genomes. The phylogenetic reconstruction showed that several eukaryotic proteins traced to Myxococcales. Most of these proteins were associated with mitochondrial lipid intermediate pathways, particularly enzymes generating reducing equivalents with pivotal roles in fatty acid β-oxidation metabolism. Our data suggest that myxococcal species with the ability to oxidize fatty acids transferred several genes to eubacteria that eventually gave rise to the mitochondrial ancestor. Later, the eukaryotic nucleocytoplasmic lineage acquired those metabolic genes through endosymbiotic gene transfer. Our results support a prokaryotic origin, different from α-proteobacteria, for several mitochondrial genes. Our data reinforce a fluid prokaryotic chromosome model in which the mitochondrion appears to be an important entry point for myxococcal genes to enter eukaryotes.


Nutritional interventions in sarcopenia: a critical review.
The aim of the present paper is to critically review the details of the published nutrition intervention trials, with and without exercise, targeting sarcopenia. Sarcopenia is the loss of muscle mass, strength and/or performance with age. Since amino acids and energy are required for muscle synthesis it is possible that nutritional intake influences sarcopenia. Nutritional studies are challenging to carry out because of the complexity of modulating dietary intake. It is very difficult to change one nutrient without influencing many others, which means that many of the published studies are problematic to interpret. The studies included evaluate whole protein, essential amino acids and β-hydroxyl β-methylbutyrate (HMB). Whole-protein supplementation failed to show a consistent effect on muscle mass, strength or function. This can be explained by the variations in study design, composition of the protein supplement and the failure to monitor voluntary food intake, adherence and baseline nutritional status. Essential amino-acid supplements showed an inconsistent effect but there are only two trials that have significant differences in methodology and the supplement used. The HMB studies are suggestive of a beneficial effect on older adults, but larger well-controlled studies are required that measure outcomes relevant to sarcopenia, ideally in sarcopenic populations. The issues of timing and distribution of protein intake, and increased splanchnic amino-acid sequestration are discussed, and recommendations for future trials are made.


A novel measurement method for the morphology of the mandibular ramus using homologous modelling.
It is important to assess the mandibular morphology when orthognathic surgery, especially mandibular ramus osteotomy, is performed. Several studies on three-dimensional (3D) facial asymmetry have reported differences in linear and angle measurements between the deviated and contralateral sides in asymmetric mandibles. However, methods used in these studies cannot analyse the 3D morphology of the ramus. In this study, we aimed to evaluate the differences in mandibular ramus between the deviated and contralateral sides in asymmetric mandibles using traditional measurements as well as 3D shape analysis. 15 Japanese females with jaw deformities treated by orthodontic surgery were enrolled. 3D CT images were reconstructed, and 14 landmarks were identified on the model surface. Ten linear and four angle measurements were calculated using these landmarks. Homologous ramus models were constructed for each sample, and after converting all homologous models to the right side, 30 homologous models of the ramus were analysed using principal component analysis. Firstly, eight principal components explained >80% of the total variance. Differences between the deviated and contralateral sides in measurements and scores of the eight principal components were tested. Significant difference at the 5% level between the deviated and contralateral sides was observed in five linear measurements, three angle measurements and the third principal component. The variance of the deviated side was significantly larger in the diameter between the mandibular notch and coronoid process, horizontal dilated angle of the mandibular ramus and vertical dilated angle of the mandibular ramus. The variance of the contralateral side was significantly larger in the height of mandibular ramus, height of posterior of mandibular ramus, condylar width, height of condylar head and mandibular angle. The squared multiple correlation coefficient adjusted for the degrees of freedom was 0.815. The third principal component showed the difference between the deviated and contralateral sides. Shape variation represented by the third principal component visually indicated that the contralateral side was larger and had inwardly directed coronoid process and the deviated side had a mandibular angle that was turned inwards to a greater extent. In conclusion, we successfully created a homologous model of the mandibular ramus and demonstrated the effectiveness of this model in the 3D comparison of the ramus morphology between the contralateral and deviated sides in asymmetric mandibles.


Integrated genomic study of quadruple-WT GIST (KIT/PDGFRA/SDH/RAS pathway wild-type GIST).
About 10-15% of adult gastrointestinal stromal tumors (GIST) and the vast majority of pediatric GIST do not harbour KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutations (J Clin Oncol 22:3813-3825, 2004; Hematol Oncol Clin North Am 23:15-34, 2009). The molecular biology of these GIST, originally defined as KIT/PDGFRA wild-type (WT), is complex due to the existence of different subgroups with distinct molecular hallmarks, including defects in the succinate dehydrogenase (SDH) complex and mutations of neurofibromatosis type 1 (NF1), BRAF, or KRAS genes (RAS-pathway or RAS-P).In this extremely heterogeneous landscape, the clinical profile and molecular abnormalities of the small subgroup of WT GIST suitably referred to as quadruple wild-type GIST (quadrupleWT or KITWT/PDGFRAWT/SDHWT/RAS-PWT) remains undefined. The aim of this study is to investigate the genomic profile of KITWT/PDGFRAWT/SDHWT/RAS-PWT GIST, by using a massively parallel sequencing and microarray approach, and compare it with the genomic profile of other GIST subtypes. We performed a whole genome analysis using a massively parallel sequencing approach on a total of 16 GIST cases (2 KITWT/PDGFRAWT/SDHWT and SDHBIHC+/SDHAIHC+, 2 KITWT/PDGFRAWT/SDHAmut and SDHBIHC-/SDHAIHC- and 12 cases of KITmut or PDGFRAmut GIST). To confirm and extend the results, whole-genome gene expression analysis by microarray was performed on 9 out 16 patients analyzed by RNAseq and an additional 20 GIST patients (1 KITWT/PDGFRAWTSDHAmut GIST and 19 KITmut or PDGFRAmut GIST). The most impressive data were validated by quantitave PCR and Western Blot analysis. We found that both cases of quadrupleWT GIST had a genomic profile profoundly different from both either KIT/PDGFRA mutated or SDHA-mutated GIST. In particular, the quadrupleWT GIST tumors are characterized by the overexpression of molecular markers (CALCRL and COL22A1) and of specific oncogenes including tyrosine and cyclin- dependent kinases (NTRK2 and CDK6) and one member of the ETS-transcription factor family (ERG). We report for the first time an integrated genomic picture of KITWT/PDGFRAWT/SDHWT/RAS-PWT GIST, using massively parallel sequencing and gene expression analyses, and found that quadrupleWT GIST have an expression signature that is distinct from SDH-mutant GIST as well as GIST harbouring mutations in KIT or PDGFRA. Our findings suggest that quadrupleWT GIST represent another unique group within the family of gastrointestintal stromal tumors.


Inducing nematic ordering of cellulose nanofibers using osmotic dehydration.
The formation of nematically-ordered cellulose nanofiber (CNF) suspensions with an order parameter fmax≈ 0.8 is studied by polarized optical microscopy, small-angle X-ray scattering (SAXS), and rheological measurements as a function of CNF concentration. The wide range of CNF concentrations, from 0.5 wt% to 4.9 wt%, is obtained using osmotic dehydration. The rheological measurements show a strong entangled network over all the concentration range whereas SAXS measurements indicate that at concentrations >1.05 wt% the CNF suspension crosses an isotropic-anisotropic transition that is accompanied by a dramatic increase of the optical birefringence. The resulting nanostructures are modelled as mass fractal structures that converge into co-existing nematically-ordered regions and network-like regions where the correlation distances decrease with concentration. The use of rapid, upscalable osmotic dehydration is an effective method to increase the concentration of CNF suspensions while partly circumventing the gel/glass formation. The facile formation of highly ordered fibers can result in materials with interesting macroscopic properties.


The positive association of obesity variants with adulthood adiposity strengthens over an 80-year period: a gene-by-birth year interaction.
To test the hypothesis that the statistical effect of obesity-related genetic variants on adulthood adiposity traits depends on birth year. The study sample included 907 related, non-Hispanic White participants in the Fels Longitudinal Study, born between 1901 and 1986, and aged 25-64.99 years (474 females; 433 males) at the time of measurement. All had both genotype data from which a genetic risk score (GRS) composed of 32 well-replicated obesity-related common single nucleotide polymorphisms was created, and phenotype data [including body mass index (BMI), waist circumference, and the sum of four subcutaneous skinfolds]. Maximum likelihood-based variance components analysis was used to estimate trait heritabilities, main effects of GRS and birth year, GRS-by-birth year interaction, sex, and age. Positive GRS-by-birth year interaction effects were found for BMI (p < 0.001), waist circumference (p = 0.007), and skinfold thickness (p < 0.007). For example, each one-allele increase in GRS was estimated to result in a 0.16 increase in BMI among males born in 1930 compared to a 0.47 increase among those born in 1970. These novel findings suggest the influence of common obesity susceptibility variants has increased during the obesity epidemic.


Complementing Operating Room Teaching With Video-Based Coaching.
Surgical expertise demands technical and nontechnical skills. Traditionally, surgical trainees acquired these skills in the operating room; however, operative time for residents has decreased with duty hour restrictions. As in other professions, video analysis may help maximize the learning experience. To develop and evaluate a postoperative video-based coaching intervention for residents. In this mixed methods analysis, 10 senior (postgraduate year 4 and 5) residents were videorecorded operating with an attending surgeon at an academic tertiary care hospital. Each video formed the basis of a 1-hour one-on-one coaching session conducted by the operative attending; although a coaching framework was provided, participants determined the specific content collaboratively. Teaching points were identified in the operating room and the video-based coaching sessions; iterative inductive coding, followed by thematic analysis, was performed. Teaching points made in the operating room were compared with those in the video-based coaching sessions with respect to initiator, content, and teaching technique, adjusting for time. Among 10 cases, surgeons made more teaching points per unit time (63.0 vs 102.7 per hour) while coaching. Teaching in the video-based coaching sessions was more resident centered; attendings were more inquisitive about residents' learning needs (3.30 vs 0.28, P = .04), and residents took more initiative to direct their education (27% [198 of 729 teaching points] vs 17% [331 of 1977 teaching points], P < .001). Surgeons also more frequently validated residents' experiences (8.40 vs 1.81, P < .01), and they tended to ask more questions to promote critical thinking (9.30 vs 3.32, P = .07) and set more learning goals (2.90 vs 0.28, P = .11). More complex topics, including intraoperative decision making (mean, 9.70 vs 2.77 instances per hour, P = .03) and failure to progress (mean, 1.20 vs 0.13 instances per hour, P = .04) were addressed, and they were more thoroughly developed and explored. Excerpts of dialogue are presented to illustrate these findings. Video-based coaching is a novel and feasible modality for supplementing intraoperative learning. Objective evaluation demonstrates that video-based coaching may be particularly useful for teaching higher-level concepts, such as decision making, and for individualizing instruction and feedback to each resident.


Synthetic mRNA-based differentiation method enables early detection of Parkinson's phenotypes in neurons derived from Gaucher disease-induced pluripotent stem cells.
Gaucher disease, the most prevalent metabolic storage disorder, is caused by mutations in the glucocerebrosidase gene GBA1, which lead to the accumulation of glucosylceramide (GlcCer) in affected cells. Gaucher disease type 1 (GD1), although defined as a nonneuronopathic subtype, is accompanied by an increased risk of Parkinson's disease. To gain insights into the association of progressive accumulation of GlcCer and the Parkinson's disease phenotypes, we generated dopaminergic (DA) neurons from induced pluripotent stem cells (iPSCs) derived from a GD1 patient and a healthy donor control, and measured GlcCer accumulation by liquid chromatography-mass spectrometry. We tested two DA neuron differentiation methods: a well-established method that mimics a step-wise developmental process from iPSCs to neural progenitor cells, and to DA neurons; and a synthetic mRNA-based method that overexpresses a transcription factor in iPSCs. GD1-specific accumulation of GlcCer was detected after 60 days of differentiation by the former method, whereas it was detected after only 10 days by the latter method. With this synthetic mRNA-based rapid differentiation method, we found that the metabolic defect in GD1 patient cells can be rescued by the overexpression of wild-type GBA1 or the treatment with an inhibitor for GlcCer synthesis. Furthermore, we detected the increased phosphorylation of α-synuclein, a biomarker for Parkinson's disease, in DA neurons derived from a GD1 patient, which was significantly decreased by the overexpression of wild-type GBA1. These results suggest that synthetic mRNA-based method accelerates the analyses of the pathological mechanisms of Parkinson's disease in GD1 patients and possibly facilitates drug discovery processes.


Evaluation of the phenotypic performance of a Red Maasai and Dorper double backcross resource population: indoor trickle challenge with Haemonchus contortus.
Six F(1) Dorper (D) x Red Maasai (R) rams were mated to both D and R ewes to produce backcross lambs. These six double backcross resource families are being analysed to identify quantitative trait loci that may be controlling resistance to gastro-intestinal (GI) nematode parasites, mainly Haemonchus contortus. After assessing the phenotypic performance of the lambs following exposure to natural infections, the surviving lambs were drenched and moved indoors for an artificial challenge with H. contortus along with straightbred D and R lambs. A total of 1317 lambs were included in the analyses consisting of 523 3/4D, 580 3/4R, 87 D and 127 R. The D lambs were significantly and consistently heavier than R lambs and 3/4D were significantly heavier than the 3/4R lambs. The difference between the backcrosses was about half of that between the straightbreds. Resistance was assessed in terms of faecal egg counts (FEC) and total worm counts (TWC) at necropsy while packed cell volume (PCV) was used to assess resilience to weekly oral doses of 2500 infective larvae of H. contortus. No significant breed differences were observed for log transformed FEC (LFEC). A significant breed difference in PCV was recorded. The backcrosses had the higher values and while no differences were observed between the straightbreds, 3/4D had significantly higher PCV than the 3/4R. Despite the absence of breed differences in FEC the R and the 3/4R had significantly fewer worms than the D and the 3/4D. The D had significantly longer worms than the R and the 3/4D had significantly longer worms than the 3/4R. Worms recovered from D had more eggs than those recovered from R. Similarly worms from 3/4D contained more eggs than those from 3/4R. Thus, on a breed basis the breed with more worms had longer worms. In contrast, when, in a small part of the experiment two doses of larvae were used to check for any breed by dose interactions, worms from the low dose (and hence fewer worms) animals were longer. We postulate that in fast growing hosts like the D, worms also have a better potential for growth and reproduction than in hosts that have less potential for growth. The overall correlation coefficient between PCV and LFEC was -0.67 while that between LFEC and LTWC was 0.72. From these results it is clear that the R do not respond to the artificial challenge the way they do to natural infection suggesting that phenotyping of R and R cross lambs for purposes of selecting those that are resistant or susceptible is best done under natural challenge.


Mouse Models of Human Proprotein Convertase Insufficiency.
The kexin-like proprotein convertases perform the initial proteolytic cleavages that ultimately generate a variety of different mature peptide and proteins, ranging from brain neuropeptides to endocrine peptide hormones, to structural proteins, among others. In this review, we present a general introduction to proprotein convertase structure and biochemistry, followed by a comprehensive discussion of each member of the kexin-like subfamily of proprotein convertases. We summarize current knowledge of human proprotein convertase insufficiency syndromes, including genome-wide analyses of convertase polymorphisms, and compare these to convertase null and mutant mouse models. These mouse models have illuminated our understanding of the roles specific convertases play in human disease and have led to the identification of convertase-specific substrates; for example, the identification of procorin as a specific PACE4 substrate in the heart. We also discuss the limitations of mouse null models in interpreting human disease, such as differential precursor cleavage due to species-specific sequence differences, and the challenges presented by functional redundancy among convertases in attempting to assign specific cleavages and/or physiological roles. However, in most cases, knockout mouse models have added substantively both to our knowledge of diseases caused by human proprotein convertase insufficiency and to our appreciation of their normal physiological roles, as clearly seen in the case of the furin, proprotein convertase 1/3, and proprotein convertase 5/6 mouse models. The creation of more sophisticated mouse models with tissue- or temporally-restricted expression of specific convertases will improve our understanding of human proprotein convertase insufficiency and potentially provide support for the emerging concept of therapeutic inhibition of convertases.


Lack of association of the vitamin D receptor gene with Graves' disease in UK Caucasians.
Vitamin D modulates the immune system by suppressing the proliferation of activated T cells, with its actions being directed through the vitamin D receptor (VDR). A number of single nucleotide polymorphisms (SNPs) have been identified in the VDR gene, of which several have been associated with autoimmune diseases, including type 1 diabetes and Graves' disease (GD) in Japanese females. The aim of this study was to test for association of polymorphisms of the VDR gene in the genetic susceptibility to GD in UK Caucasians. Target DNA for five previously published SNPs, four novel SNPs and one microsatellite marker was amplified by the polymerase chain reaction (PCR). Subsequent genotyping was performed using restriction fragment length polymorphism (RFLP) or microsatellite genotyping analysis, according to the type of VDR polymorphism. We obtained DNA from a case-control dataset consisting of 768 patients with GD and 864 control subjects. All patients and control subjects were Caucasians born in the UK, and all gave informed, written consent. Frequencies of the alleles and genotypes of the ten VDR gene polymorphisms were compared between patients and control subjects using the chi2 test. Odds ratios were calculated using Woolf's method with Haldane's modification for small numbers and D prime (D') was calculated to assess the level of linkage disequilibrium (LD) between the ten polymorphisms. No differences in allele or genotype frequencies were observed between GD cases and control subjects for any of the nine SNPs studied. The S allele of the PolyA microsatellite marker was slightly more frequent in GD cases when compared with control subjects (chi2= 4.364, P = 0.04). Strongest LD between markers was observed towards the 3' end of the VDR gene but there was no evidence of association with disease. This is the largest and most comprehensive study of the VDR gene in GD to date and these data suggest that these polymorphisms of the VDR gene do not contribute to GD susceptibility in the UK.


Predictors of survival after hepatic resection among patients with colorectal liver metastasis.
Studies suggest improved survival following resection of colorectal cancer liver metastases (CLMs). We investigated predictors of survival among patients with CLM who underwent hepatic resection using the SEER-Medicare database to identify patients >/=65 years diagnosed with CLM, 1991-2003, who underwent hepatectomy. Cox proportional hazards models were used to identify factors associated with survival after hepatectomy. Of 923 patients with CLM who underwent hepatectomy, 514 were stages I-III and developed CLM>6 months after diagnosis (metachronous), and 409 were stage IV with CLM at diagnosis (synchronous). From the date of hepatectomy, 5 year survival was 22%; younger age, being married, female gender, surgery in an NCI-designated cancer centre, fewer comorbidities, fewer positive lymph nodes, and lower grade were associated with improved survival. Both 5-fluorouracil (5FU)-based chemotherapy and hepatic arterial infusion (HAI) of floxuridine-based chemotherapy following hepatectomy improved survival (HR=0.62, 95% CI: 0.50-0.78; HR=0.51, 95% CI: 0.28-0.97, respectively) in the synchronous, but not metachronous, group. The HR for overall mortality was higher in hospitals with a high vs low procedure volume (0.75, 95% CI: 0.58-0.94). A substantial subgroup of patients with CLM who undergo hepatectomy experiences long-term survival. High hospital procedure volume and use of 5FU-based or HAI-based chemotherapy after resection were associated with improved prognosis.


Early detection of psychosocial problems in adolescents: how useful is the Dutch short indicative questionnaire (KIVPA)?
Psychosocial problems, such as behavioural, emotional, and educational problems, are highly prevalent among children and adolescents. Early treatment may reduce these problems, if accurately identified. Validated questionnaires may support identification. The aim of this study is to assess the psychometric qualities of such a questionnaire, the Short Indicative Questionnaire for Psychosocial problems among Adolescents (KIVPA,) and to determine whether it is suitable for and adds to the early detection of psychosocial problems among adolescents. Data came from a national sample of 1,440 Dutch adolescents, using the KIVPA, the Child Behavior Checklist (CBCL), and the Youth Self-Report (YSR). Of these, 1,248 provided data on all questionnaires (77.8%). The scale structure of the KIVPA was assessed; its sensitivity and specificity using CBCL, YSR and referral for psychosocial problems as criteria; and its contribution to detecting CBCL and YSR problems. The KIVPA is mostly uni-dimensional but the variance explained by its main factor is relatively low. The total KIVPA score discriminates between adolescents with and without problems on the three criteria. Using a clinical YSR total problem score as criterion, sensitivity and specificity are 0.82 and 0.85, respectively, at the proposed cut-off (area under the ROC curve: 0.92; 95% confidence interval (CI) 0.90-0.95). The odds ratio of a clinical YSR score for an elevated KIVPA score is 29.1 (95% CI: 14.4-59.1), although the KIVPA mainly covers internalizing problems. The KIVPA has added value in the early detection of internalizing psychosocial problems, but is not sufficiently efficient.


Effects of moderate red wine consumption on liver fat and blood lipids: a prospective randomized study.
There have been no human prospective randomized studies of the amount of alcohol that can induce hepatic steatosis. Thirty-two healthy women and twelve healthy men (34 ± 9 years of age) were randomized to consume 150 ml of red wine/day for women (16 g ethanol/day) or double that amount for men (33 g ethanol/day), or to alcohol abstention for 90 days. Participants underwent proton-nuclear magnetic-resonance spectroscopy for measurement of hepatic triglyceride content (HTGC). Blood samples for assessment of cardiovascular risk were drawn before and after the intervention. After exclusion of three subjects with steatosis at baseline a trend towards increased HTGC was apparent for red wine (before median: 1.1%, range 0.2-3.9%, after median: 1.1%, range 0.5-5.2 %, P = 0.059) a difference that was statistically significant compared with abstainers (p = 0.02). However, no subject developed hepatic steatosis. Low-density lipoprotein (LDL)-cholesterol was lowered by red wine (-0.3 mmol/l, SE -0.1, 95% CI -0.6 to -0.04). Moderate consumption of red wine during three months increased HTGC in subjects without steatosis at baseline. However, since not a single participant developed steatosis we suggest that the threshold of alcohol consumption to define nonalcoholic fatty liver disease should not be lower than the amount in our study.


Comparative study of different sources of pertussis toxin (PT) as coating antigens in IgG anti-PT enzyme-linked immunosorbent assays.
In an effort to improve the reliability and reproducibility of serological assays for Bordetella pertussis, a collaborative study was conducted to compare four different sources of pertussis toxin (PT) as coating antigens in the immunoglobulin G (IgG) anti-PT enzyme-linked immunosorbent assay (ELISA). Four sources of PT were used as coating antigens in the IgG anti-PT ELISA in four different testing laboratories (labs A to D) to determine whether the different antigen preparations and different laboratories influenced assay results. A panel of 60 sera consisting of deidentified human specimens from previous vaccination trials of healthy adults and infants and clinical specimens from outbreak settings was tested. In the four laboratories, each sample was tested three times with the four PT antigens according to the standard coating optimization and IgG anti-PT ELISA testing procedures used in that laboratory. Differences among the antigens, as well as intra- and interlaboratory variability, were evaluated. Excellent agreement was observed with the test panel results among the four antigens within each laboratory. Concordance correlation coefficient (r(c)) measurements among the different antigens ranged from 0.99, 0.99 to 1.00, 1.00, and 0.97 to 1.00 for labs A to D, respectively. The comparisons between pairs of laboratories also indicated a high degree of concordance for each PT preparation, with r(c) measurements between 0.90 and 0.98, 0.93 and 0.99, 0.92 and 0.98, and 0.93 and 0.99 for antigens 1 to 4, respectively. Relatively minor differences in results were observed among laboratories or among antigens, suggesting that the four PT antigens are quite similar and could be considered for acceptance in harmonized immunoassays used for serodiagnosis or vaccine evaluation.


Discrimination in the workplace, reported by people with major depressive disorder: a cross-sectional study in 35 countries.
Whereas employment has been shown to be beneficial for people with Major Depressive Disorder (MDD) across different cultures, employers' attitudes have been shown to be negative towards workers with MDD. This may form an important barrier to work participation. Today, little is known about how stigma and discrimination affect work participation of workers with MDD, especially from their own perspective. We aimed to assess, in a working age population including respondents with MDD from 35 countries: (1) if people with MDD anticipate and experience discrimination when trying to find or keep paid employment; (2) if participants in high, middle and lower developed countries differ in these respects; and (3) if discrimination experiences are related to actual employment status (ie, having a paid job or not). Participants in this cross-sectional study (N=834) had a diagnosis of MDD in the previous 12 months. They were interviewed using the Discrimination and Stigma Scale (DISC-12). Analysis of variance and generalised linear mixed models were used to analyse the data. Overall, 62.5% had anticipated and/or experienced discrimination in the work setting. In very high developed countries, almost 60% of respondents had stopped themselves from applying for work, education or training because of anticipated discrimination. Having experienced workplace discrimination was independently related to unemployment. Across different countries and cultures, people with MDD very frequently reported discrimination in the work setting. Effective interventions are needed to enhance work participation in people with MDD, focusing simultaneously on decreasing stigma in the work environment and on decreasing self-discrimination by empowering workers with MDD.


Between-word simplification patterns in the continuous speech of children with speech sound disorders.
This study was designed to identify and describe between-word simplification patterns in the continuous speech of children with speech sound disorders. It was hypothesized that word combinations would reveal phonological changes that were unobserved with single words, possibly accounting for discrepancies between the intelligibility of single-word samples and that of continuous speech. Four boys with developmental speech sound disorders provided samples of single words and continuous speech. Substitutions and deletions with single words formed the basis for determining 2 categories of between-word segment mismatches: observed and novel. Mismatches were attributed to one of 4 types of between-word simplifications reported for typical phonological development: between-word consonant deletion, between-word cluster reduction, between-word consonant sequence reduction, and between-word assimilation. Continuous speech revealed observed and novel patterns. Segment mismatches occurred differentially among potential between-word simplification environments. The most frequently occurring novel pattern involved the deletion of a coda consonant within a between-word consonant sequence. Children with speech sound disorders demonstrated substitutions and deletions between words in continuous speech that may not be predicted on the basis of single-word productions. The identification of potential contexts for such mismatches may serve as a framework for the assessment of continuous speech samples of children with speech sound disorders in health care and school settings.


Effect of prism adaptation on left dichotic listening deficit in neglect patients: glasses to hear better?
Unilateral neglect is a disabling syndrome frequently observed following right hemisphere brain damage. Symptoms range from visuo-motor impairments through to deficient visuo-spatial imagery, but impairment can also affect the auditory modality. A short period of adaptation to a rightward prismatic shift of the visual field is known to improve a wide range of hemispatial neglect symptoms, including visuo-manual tasks, mental imagery, postural imbalance, visuo-verbal measures and number bisection. The aim of the present study was to assess whether the beneficial effects of prism adaptation may generalize to auditory manifestations of neglect. Auditory extinction, whose clinical manifestations are independent of the sensory modalities engaged in visuo-manual adaptation, was examined in neglect patients before and after prism adaptation. Two separate groups of neglect patients (all of whom exhibited left auditory extinction) underwent prism adaptation: one group (n = 6) received a classical prism treatment ('Prism' group), the other group (n = 6) was submitted to the same procedure, but wore neutral glasses creating no optical shift (placebo 'Control' group). Auditory extinction was assessed by means of a dichotic listening task performed three times: prior to prism exposure (pre-test), upon prism removal (0 h post-test) and 2 h later (2 h post-test). The total number of correct responses, the lateralization index (detection asymmetry between the two ears) and the number of left-right fusion errors were analysed. Our results demonstrate that prism adaptation can improve left auditory extinction, thus revealing transfer of benefit to a sensory modality that is orthogonal to the visual, proprioceptive and motor modalities directly implicated in the visuo-motor adaptive process. The observed benefit was specific to the detection asymmetry between the two ears and did not affect the total number of responses. This indicates a specific effect of prism adaptation on lateralized processes rather than on general arousal. Our results suggest that the effects of prism adaptation can extend to unexposed sensory systems. The bottom-up approach of visuo-motor adaptation appears to interact with higher order brain functions related to multisensory integration and can have beneficial effects on sensory processing in different modalities. These findings should stimulate the development of therapeutic approaches aimed at bypassing the affected sensory processing modality by adapting other sensory modalities.


Cytotoxicity of denture base resins.
This in vitro study examined the effect of eluate from heat-activated, chemically activated, and microwave-activated denture base resins on cell viability of primary cultures of human gingival fibroblasts. Eluates corresponding to 24, 48, 72, and 96 hours of resin disk immersion were prepared. Fibroblasts were plated at a density of 3 x 10(4) cells in 96-well plates and exposed to a medium containing eluate. After 24 hours, the cytotoxic effect was determined by cellular mitochondrial function. The effect of eluates was compared to control cultures containing culture medium without eluate. Results indicated that at all time periods tested, all three resins leached materials that were cytotoxic to the fibroblasts. Eluate from chemically activated resin disks was more cytotoxic than eluate from heat-activated and microwave-activated disks. In general, cytotoxicity appeared to diminish as disk immersion time was increased. The greatest cytotoxic effect on cell viability was observed with eluates recovered after 24 hours of disk immersion, and the least cytotoxic effect was observed with eluates recovered after 96 hours of immersion.


Regional atmospheric cooling and wetting effect of permafrost thaw-induced boreal forest loss.
In the sporadic permafrost zone of North America, thaw-induced boreal forest loss is leading to permafrost-free wetland expansion. These land cover changes alter landscape-scale surface properties with potentially large, however, still unknown impacts on regional climates. In this study, we combine nested eddy covariance flux tower measurements with satellite remote sensing to characterize the impacts of boreal forest loss on albedo, eco-physiological and aerodynamic surface properties, and turbulent energy fluxes of a lowland boreal forest region in the Northwest Territories, Canada. Planetary boundary layer modelling is used to estimate the potential forest loss impact on regional air temperature and atmospheric moisture. We show that thaw-induced conversion of forests to wetlands increases albedo: and bulk surface conductance for water vapour and decreases aerodynamic surface temperature. At the same time, heat transfer efficiency is reduced. These shifts in land surface properties increase latent at the expense of sensible heat fluxes, thus, drastically reducing Bowen ratios. Due to the lower albedo of forests and their masking effect of highly reflective snow, available energy is lower in wetlands, especially in late winter. Modelling results demonstrate that a conversion of a present-day boreal forest-wetland to a hypothetical homogeneous wetland landscape could induce a near-surface cooling effect on regional air temperatures of up to 3-4 °C in late winter and 1-2 °C in summer. An atmospheric wetting effect in summer is indicated by a maximum increase in water vapour mixing ratios of 2 mmol mol-1 . At the same time, maximum boundary layer heights are reduced by about a third of the original height. In fall, simulated air temperature and atmospheric moisture between the two scenarios do not differ. Therefore, permafrost thaw-induced boreal forest loss may modify regional precipitation patterns and slow down regional warming trends.