Risk factors associated with dehydration in older people living in nursing homes: Scoping review.
Dehydration in the older people is a prevalent problem that is often associated with physiological changes, physical limitations and environmental conditions. The scoping review was carried out to identify risk factors associated with dehydration in older people living in nursing homes. The revised scoping methodology framework of Arksey and O'Malley (2005) was applied. Study selection was carried out in accordance with Davis et al. (2009) and focused on the inclusion criteria (people over 65 years old and living in nursing homes). Risk factors were classified using the geriatric assessment. An electronic database search was performed in PubMed, Scopus and CINAHL. The literature search was carried out between October 2016 and January 2017. Thematic reporting was performed and study findings were validated through interdisciplinary meetings of experts. The quality of the papers consulted was also evaluated using the Newcastle-Ottawa Scale adapted for cross-sectional, cohort and case-control studies. In all, 16 papers were analysed, all of which were observational studies. The risk of bias ranged from very low (n = 1), to medium (n = 13) and high (n = 2). The risk factors were classified in line with the different components of the geriatric assessment. In the socio-demographic characteristics age and gender were identified. In the clinical component, infections, renal and cardiovascular diseases and end-of-life situations were the most common factors highlighted in the papers analysed. With reference to the functional component, its limitation was associated with dehydration, while for factors of mental origin, it was related to dementia and behavioural disorders. Finally, the factors relating to the social component were institutionalisation, requiring a skilled level of care and it being winter. The most commonly repeated factors highlighted in the review were age, gender, infections, end of life and dementia, with it being important to highlight the large number of factors in the clinical component. Even so, the great majority of the factors were unmodifiable conditions associated typically associated with the physiology of ageing.


Primary Cardioprotection Reduces Mortality in Lymphoma Patients with Increased Risk of Anthracycline Cardiotoxicity, Treated by R-CHOP Regimen.
Advances in anti-lymphoma therapy prolong overall survival, making late adverse effects, like doxorubicin-related cardiotoxicity, an even more important clinical issue. The effectiveness of cardioprotective strategies with close monitoring, angiotensin-converting enzyme inhibitors and/or β-blockers as well as liposomal doxorubicin are still unconfirmed in clinical practice. This study evaluated the role of a primary cardioprotection strategy in preventing cardiovascular mortality and heart failure occurrence in non-Hodgkin lymphoma (NHL) patients with a high risk of anthracycline cardiotoxicity. Thirty-five NHL patients were subjected prospectively to ramipril and/or bisoprolol at NHL diagnosis, before implementing doxorubicin-containing regimens. Additionally, patients with a diagnosis of asymptomatic/mild heart failure received the liposomal form of doxorubicin. The clinical outcome and frequency of all serious cardiac events were compared with the results in a historical cohort of 62 high-risk cases treated without primary cardioprotection. NHL patients with a primary cardioprotection strategy did not experience cardiovascular deaths in contrast to the retrospective control group where cardiovascular mortality was 14.5% at 3 years (p < 0.05). Primary cardioprotection also decreased the frequency of new cardiotoxicity-related clinical symptoms (2.8 vs. 24.1%; p < 0.05) and prevented the occurrence of cardiac systolic dysfunction (0 vs. 8.5%, respectively; p < 0.05). Although the study was not planned to detect any survival benefit, it demonstrated a trend towards increased response rates (complete response 82 vs. 67%; p not significant) and prolonged survival (projected 5-year overall survival 74 vs. 60%; p < 0.05) for patients treated with primary cardioprotection. A primary personalized cardioprotection strategy decreases the number of cardiac deaths and may potentially prolong overall survival in NHL patients with increased risk of anthracycline cardiotoxicity.


The Burden and Epidemiology of Eustachian Tube Dysfunction in Adults.
Objectives Pediatric eustachian tube dysfunction (ETD), otitis media with effusion (OME), and tympanic membrane retraction (TMR) have been well studied, but no large analyses have described the associated burden beyond childhood. The potential impact and feasibility of prospective trials designed to optimize management of affected adults are thus unclear. Our objectives were therefore (1) to determine the national visit burden associated with ETD/OME/TMR beyond childhood and (2) to examine risk factors specific to adults, highlighting differences in comparison with children. Study Design Cross-sectional analysis of a national database. Setting Ambulatory visits in the United States. Methods Epidemiologic analysis of the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey (2005-2012) included data from 761,291 observations representing 9,369,388,092 visits. Chi-square test with Bonferroni adjustment for multiple comparisons was utilized for hypothesis testing. Results Visits related to ETD/OME/TMR exceeded 2 million per annum in patients 0 to 20 years of age (mean 2,625,965; range 2,239,288-3,329,858). Among those >20 years old, visits also exceeded 2 million (mean, 2,025,050; range, 1,550,669-2,353,799). Characteristics differed according to age: whereas ETD/OME/TMR affected more males <20 years, females were more frequently diagnosed in the older age group ( P < .0001). Patients >20 to 40 years of age were the most likely to visit the emergency department ( P = .0022). There were no statistically significant differences per season or region. The related diagnoses of cholesteatoma and chronic otitis media prompted additional visits. Conclusions ETD/OME/TMR is associated with a visit burden for adults that extends beyond childhood. Among adults, there may also be age-related differences in patient characteristics.


Antigen receptor-regulated exocytosis in cytotoxic T lymphocytes.
We demonstrate here that T cell receptor for antigen (TCR)-triggered exocytosis in cytotoxic T lymphocytes (CTL) is not constitutive and is regulated through crosslinking of the TCR by antigen or monoclonal anti-TCR antibodies. Morphological and biochemical data using three different biochemical markers of granules and Percoll gradient fractionation analysis are presented, suggesting that TCR-triggered exocytosis is accompanied by the loss of granules from CTL and appearance of intragranular proteins and enzymatic activities in the incubation medium. The strict requirement for crosslinking of the TCR in exocytosis triggering could be bypassed by protein kinase C activators (phorbol esters or bryostatin I and II) acting in synergy with Ca2+ ionophores. It is shown that external Ca2+ is obligatory for both the TCR-triggered and for the PMA/A23187-triggered exocytosis, since Ca2+ chelators and divalent cations that compete with Ca2+ for A23187 can inhibit exocytosis of granules. These data suggest that Ca2+ from intracellular stores is not sufficient to support exocytosis in CTL. Ca2+ channel blockers and calmodulin antagonists significantly inhibited TCR-triggered exocytosis without affecting the basal level of secretion. The described results are consistent with a model in which exocytosis of granules in CTL is triggered by the crosslinking of TCR, transmembrane protein kinase C activation, and external Ca2+ translocation through CTL plasma membrane Ca2+ channels and modulation of activity of Ca2+, calmodulin-dependent enzymes, and cytoskeletal proteins.


Essential medicines for emergency care in Africa.
Essential medicines lists (EMLs) are efficient means to ensure access to safe and effective medications. The WHO has led this initiative, generating a biannual EML since 1977. Nearly all countries have implemented national EMLs based on the WHO EML. Although EMLs have given careful consideration to many public health priorities, they have yet to comprehensively address the importance of medicines for treating acute illness and injury. We undertook a multistep consensus process to establish an EML for emergency care in Africa. After a review of existing literature and international EMLs, we generated a candidate list for emergency care. This list was reviewed by expert clinicians who ranked the medicines for overall inclusion and strength of recommendation. These medications and recommendations were then evaluated by an expert group. Medications that reached consensus in both the online survey and expert review were included in a draft emergency care EML, which underwent a final inperson consensus process. The final emergency care EML included 213 medicines, 25 of which are not in the 2017 WHO EML, but were deemed essential for clinical practice by regional emergency providers. The final EML has associated recommendations of desirable or essential and is subdivided by facility level. Thirty-nine medicines were recommended for basic facilities, an additional 96 for intermediate facilities (eg, district hospitals) and an additional 78 for advanced facilities (eg, tertiary centres). The 25 novel medications not currently on the WHO EML should be considered by planners when making rational formularies for developing emergency care systems. It is our hope that these resource-stratified lists will allow for easier implementation and will be a useful tool for practical expansion of emergency care delivery in Africa.


A Slow-Release Substrate Stimulates Groundwater Microbial Communities for Long-Term in Situ Cr(VI) Reduction.
Cr(VI) is a widespread environmental contaminant that is highly toxic and soluble. Previous work indicated that a one-time amendment of polylactate hydrogen-release compound (HRC) reduced groundwater Cr(VI) concentrations for >3.5 years at a contaminated aquifer; however, microbial communities responsible for Cr(VI) reduction are poorly understood. In this study, we hypothesized that HRC amendment would significantly change the composition and structure of groundwater microbial communities, and that the abundance of key functional genes involved in HRC degradation and electron acceptor reduction would increase long-term in response to this slowly degrading, complex substrate. To test these hypotheses, groundwater microbial communities were monitored after HRC amendment for >1 year using a comprehensive functional gene microarray. The results showed that the overall functional composition and structure of groundwater microbial communities underwent sequential shifts after HRC amendment. Particularly, the abundance of functional genes involved in acetate oxidation, denitrification, dissimilatory nitrate reduction, metal reduction, and sulfate reduction significantly increased. The overall community dynamics was significantly correlated with changes in groundwater concentrations of microbial biomass, acetate, NO3-, Cr(VI), Fe(II) and SO4(2-). Our results suggest that HRC amendment primarily stimulated key functional processes associated with HRC degradation and reduction of multiple electron acceptors in the aquifer toward long-term Cr(VI) reduction.


CHLOROPLAST RIBOSOME ASSOCIATED Supports Translation under Stress and Interacts with the Ribosomal 30S Subunit.
Chloroplast ribosomes, which originated from cyanobacteria, comprise a large subunit (50S) and a small subunit (30S) containing ribosomal RNAs (rRNAs) and various ribosomal proteins. Genes for many chloroplast ribosomal proteins, as well as proteins with auxiliary roles in ribosome biogenesis or functioning, reside in the nucleus. Here, we identified Arabidopsis (Arabidopsis thaliana) CHLOROPLAST RIBOSOME ASSOCIATED (CRASS), a member of the latter class of proteins, based on the tight coexpression of its mRNA with transcripts for nucleus-encoded chloroplast ribosomal proteins. CRASS was acquired during the evolution of embryophytes and is localized to the chloroplast stroma. Loss of CRASS results in minor defects in development, photosynthetic efficiency, and chloroplast translation activity under controlled growth conditions, but these phenotypes are greatly exacerbated under stress conditions induced by the translational inhibitors lincomycin and chloramphenicol or by cold treatment. The CRASS protein comigrates with chloroplast ribosomal particles and coimmunoprecipitates with the 16S rRNA and several chloroplast ribosomal proteins, particularly the plastid ribosomal proteins of the 30S subunit (PRPS1 and PRPS5). The association of CRASS with PRPS1 and PRPS5 is independent of rRNA and is not detectable in yeast two-hybrid experiments, implying that either CRASS interacts indirectly with PRPS1 and PRPS5 via another component of the small ribosomal subunit or that it recognizes structural features of the multiprotein/rRNA particle. CRASS plays a role in the biogenesis and/or stability of the chloroplast ribosome that becomes critical under certain stressful conditions when ribosomal activity is compromised.


Consensus statement on the care of the hyperglycaemic/diabetic patient during and in the immediate follow-up of acute coronary syndrome.
The Diabetes and Cardiovascular Disease study group of the Société francophone du diabète (SFD, French Society of Diabetes) in collaboration with the Société française de cardiologie (SFC, French Society of Cardiology) have devised a consensus statement on the care of the hyperglycaemic/diabetic patient during and in the immediate follow-up of acute coronary syndrome (ACS); in particular, it includes the different phases of ACS [the intensive care unit (ICU) period, the post-ICU period and the short-term follow-up period after discharge, including cardiac rehabilitation] and also embraces all of the various diagnostic and therapeutic issues with a view to optimizing the collaboration between cardiologists and diabetologists. As regards diagnosis, subjects with HbA(1c) greater or equal to 6.5% on admission may be considered diabetic while, in those with no known diabetes and HbA(1c) less than 6.5%, it is recommended that an OGTT be performed 7 to 28 days after ACS. During hospitalization in the ICU, continuous insulin treatment should be initiated in all patients when admission blood glucose levels are greater or equal to 180 mg/dL (10.0 mmol/L) and, in those with previously known diabetes, when preprandial glucose levels are greater or equal to 140 mg/dL (7.77 mmol/L) during follow-up. The recommended blood glucose target is 140-180 mg/dL (7.7-10 mmol/L) for most patients. Following the ICU period, insulin treatment is not mandatory for every patient, and other antidiabetic treatments may be considered, with the choice of optimal treatment depending on the metabolic profile of the patient. Patients should be referred to a diabetologist before discharge from hospital in cases of unknown diabetes diagnosed during ACS hospitalization, of HbA(1c) greater or equal to 8% at the time of admission, or newly introduced insulin therapy or severe/repeated hypoglycaemia. Referral to a diabetologist after hospital discharge is recommended if diabetes is diagnosed by the OGTT, or during cardiac rehabilitation in cases of uncontrolled diabetes (HbA(1c) ≥ 8%) or severe/repeated hypoglycaemia.


Outside looking in: nanotube transistor intracellular sensors.
Nanowire-based field-effect transistors, including devices with planar and three-dimensional configurations, are being actively explored as detectors for extra- and intracellular recording due to their small size and high sensitivities. Here we report the synthesis, fabrication, and characterization of a new needle-shaped nanoprobe based on an active silicon nanotube transistor, ANTT, that enables high-resolution intracellular recording. In the ANTT probe, the source/drain contacts to the silicon nanotube are fabricated on one end, passivated from external solution, and then time-dependent changes in potential can be recorded from the opposite nanotube end via the solution filling the tube. Measurements of conductance versus water-gate potential in aqueous solution show that the ANTT probe is selectively gated by potential changes within the nanotube, thus demonstrating the basic operating principle of the ANTT device. Studies interfacing the ANTT probe with spontaneously beating cardiomyocytes yielded stable intracellular action potentials similar to those reported by other electrophysiological techniques. In addition, the straightforward fabrication of ANTT devices was exploited to prepare multiple ANTT structures at the end of single probes, which enabled multiplexed recording of intracellular action potentials from single cells and multiplexed arrays of single ANTT device probes. These studies open up unique opportunities for multisite recordings from individual cells through cellular networks.


Structure determination of BA0150, a putative polysaccharide deacetylase from Bacillus anthracis.
Polysaccharide deacetylases are bacterial enzymes that catalyze the deacetylation of acetylated sugars on the membranes of Gram-positive bacteria, allowing them to be unrecognized by host immune systems. Inhibition of these enzymes would disrupt such pathogenic defensive mechanisms and therefore offers a promising route for the development of novel antibiotic therapeutics. Here, the first X-ray crystal structure of BA0150, a putative polysaccharide deacetylase from Bacillus anthracis, is reported to 2.0 Å resolution. The overall structure maintains the conserved (α/β)8 fold that is characteristic of this family of enzymes. The lack of a catalytic metal ion and a distinctive metal-binding site, however, suggest that this enzyme is not a functional polysaccharide deacetylase.


Validation of the 8th Edition of the UICC/AJCC Staging System for Nasopharyngeal Carcinoma From Endemic Areas in the Intensity-Modulated Radiotherapy Era.
Background: In this study, we evaluated the 8th edition of the Union for International Cancer Control (UICC)/AJCC staging system for nasopharyngeal carcinoma (NPC) in an endemic area, with the aim of validating its applicability and providing further information for future refinements. Methods: A total of 1,790 patients with newly diagnosed, non-distant metastatic, histologically proven NPC treated with intensity-modulated radiotherapy (IMRT) were retrospectively reviewed. The performance of various staging systems was compared using the Akaike information criterion (AIC) and Harrell's concordance index (c-index). Results: For N (node) category, the survival curves of different groups according to the 8th edition were well-separated, and the prognostic model predicted outcomes fairly well. The 8th edition had higher AIC and c-index values for all end points than the 7th edition. However, probably due to the improved locoregional control provided by IMRT, the survival curves for T2 and T3 almost overlapped, without significant differences in locoregional failure-free survival (P=.606) and disease-free survival (P=.735). Due to the difficultly of differentiating T2 and T3, the AIC and c-index values were similar for the T categories of the 7th and 8th editions. Similarly, the overall survival and disease-free survival curves for stage II and III disease were not clearly separated for either the 8th or 7th editions. Conclusions: The 8th edition of the UICC/AJCC staging system for NPC enables more accurate prediction of treatment outcomes. However, several limitations need to be addressed in future editions, and it would be reasonable to further optimize the T category classification.


Costs of repair of abdominal aortic aneurysm with different devices in a multicenter randomized trial.
Prior analysis in the Open vs Endovascular Repair Veterans Affairs (VA) Cooperative Study (CSP #498) demonstrated that survival, quality of life, and total health care costs are not significantly different between the open and endovascular methods of repair of abdominal aortic aneurysm. The device is a major cost of this method of repair, and the objective of this study was to evaluate the costs of the device, abdominal aortic aneurysm repair, and total health care costs when different endograft systems are selected for the endovascular repair (EVR). Within each selected system, EVR costs are compared with open repair costs. The study randomized 881 patients to open (n = 437) or EVR (n = 444). Device selection was recorded before randomization; therefore, open repair controls were matched to each device cohort. Data were excluded for two low-volume devices, implanted in only 13 individuals, leaving 423 control and 431 endovascular patients: 166 Zenith (Cook Medical, Bloomington, Ind), 177 Excluder (W. L. Gore & Associates, Flagstaff, Ariz), and 88 AneuRx (Medtronic, Minneapolis, Minn). Mean device, hospitalization, and total health care costs from randomization to 2 years were compared. Health care utilization data were obtained from patients and national VA and Medicare data sources. VA costs were determined using methods previously developed by the VA Health Economics Resource Center. Non-VA costs were obtained from Medicare claims data and billing data from the patient's health care providers. Implant costs were 38% of initial hospitalization costs. Mean device (range, $13,600-$14,400), initial hospitalization (range, $34,800-$38,900), and total health care costs at 2 years in the endovascular (range, $72,400-$78,200) and open repair groups (range, $75,600-$82,100) were not significantly different among device systems. Differences between endovascular and corresponding open repair cohorts showed lower mean costs for EVR (range, $3200-$8300), but these were not statistically different. The implant costs of endovascular aneurysm repair are substantial. When evaluating total health care system expenditures, there is large individual variability in costs, and there is no significant difference at 2 years among systems or when an individual system is compared with open repair.


Comparative analysis of collagen type II-specific immune responses during development of collagen-induced arthritis in two B10 mouse strains.
Immune responses against collagen type II (CII) are crucial for the development of collagen-induced arthritis (CIA). The aim of the present study was to evaluate and compare the CII-directed T cell and antibody specificity at different time points in the course of CIA using two mouse strains on the B10 genetic background - B10.Q, expressing Aq MHC class II molecules, and B10.DR4.Ncf1*/*, expressing human rheumatoid arthritis-associated MHC II DR4 molecules (DRA*0101/DRB*0401). B10.Q and B10.DR4.Ncf1*/* mice were immunized with CII emulsified in adjuvant and development of CIA was assessed. T cells from draining lymph nodes were restimulated in vitro with CII peptides and interferon-gamma (IFN-γ) levels in culture supernatants were evaluated by ELISA. CII-specific antibody levels in serum samples were measured by ELISA. At four different CIA time points we analyzed T cell specificity to the immunodominant CII epitope 259-273 (CII259-273) and several posttranslationally modified forms of CII259-273 as well as antibody responses to three B cell immunodominant epitopes on CII (C1, U1, J1). Our data show that CII-specific T and B cell responses increase dramatically after disease onset in both strains and are sustained during the disease course. Concerning anti-CII antibody fine specificity, during all investigated stages of CIA the B10.Q mice responded predominantly to the C1 epitope, whereas the B10.DR4.Ncf1*/* mice also recognized the U1 epitope. In the established disease phase, T cell reactivity toward the galactosylated CII259-273 peptide was similar between the DR4- and the Aq-expressing strains whereas the response to the non-modified CII peptide was dramatically enhanced in the DR4 mice compared with the B10.Q. In addition, we show that the difference in the transgenic DR4-restricted T cell specificity to CII259-273 is not dependent on the degree of glycosylation of the collagen used for immunization. The present study provides important evaluation of CII-specific immune responses at different phases during CIA development as well as a comparative analysis between two CIA mouse models. We indicate significant differences in CII T cell and antibody specificities between the two strains and highlight a need for improved humanized B10.DR4 mouse model for rheumatoid arthritis.


Human female genital tract infection by the obligate intracellular bacterium Chlamydia trachomatis elicits robust Type 2 immunity.
While Chlamydia trachomatis infections are frequently asymptomatic, mechanisms that regulate host response to this intracellular Gram-negative bacterium remain undefined. This investigation thus used peripheral blood mononuclear cells and endometrial tissue from women with or without Chlamydia genital tract infection to better define this response. Initial genome-wide microarray analysis revealed highly elevated expression of matrix metalloproteinase 10 and other molecules characteristic of Type 2 immunity (e.g., fibrosis and wound repair) in Chlamydia-infected tissue. This result was corroborated in flow cytometry and immunohistochemistry studies that showed extant upper genital tract Chlamydia infection was associated with increased co-expression of CD200 receptor and CD206 (markers of alternative macrophage activation) by endometrial macrophages as well as increased expression of GATA-3 (the transcription factor regulating TH2 differentiation) by endometrial CD4(+) T cells. Also among women with genital tract Chlamydia infection, peripheral CD3(+) CD4(+) and CD3(+) CD4(-) cells that proliferated in response to ex vivo stimulation with inactivated chlamydial antigen secreted significantly more interleukin (IL)-4 than tumor necrosis factor, interferon-γ, or IL-17; findings that repeated in T cells isolated from these same women 1 and 4 months after infection had been eradicated. Our results thus newly reveal that genital infection by an obligate intracellular bacterium induces polarization towards Type 2 immunity, including Chlamydia-specific TH2 development. Based on these findings, we now speculate that Type 2 immunity was selected by evolution as the host response to C. trachomatis in the human female genital tract to control infection and minimize immunopathological damage to vital reproductive structures.


Reevaluation of genetic variants previously associated with arrhythmogenic right ventricular cardiomyopathy integrating population-based cohorts and proteomics data.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is one of the most common causes of sudden cardiac death in young people. Patients diagnosed with ARVC may experience increased likelihood of development of anxiety and depression, emphasizing the need for accurate diagnosis. To assist future genetic diagnosis and avoidance of misdiagnosis, we evaluated the reported monogenic disease-causing variants in ARVD/C Genetic Variants Database, Human Gene Mutation Database, and ClinVar. Within the aforementioned databases, 630 monogenic disease-causing variants from 18 genes were identified. In the genome Aggregation Database, 226 of these were identified; 68 of which were found at greater than expected prevalence. Furthermore, 37/226 genetic variants were identified amongst the 409 000 UK biobank participants, 23 were not associated with ARVC. Among the 14 remaining variants, 13 were previously found with greater than expected prevalence for a monogenic variant. Nevertheless, they were associated with serious cardiac phenotypes, suggesting that these 13 variants may be disease-modifiers of ARVC, rather than monogenic disease-causing. In summary, more than 10% of variants previously reported to cause ARVC were found unlikely to be associated with highly penetrant monogenic forms of ARVC. Notably, all variants in OBSCN and MYBPC3 were found, making these unlikely to be monogenic causes of ARVC.


The automated clinical microbiology laboratory: fact or fantasy?
Automated chemistry laboratories dependent on robotic processes are the standard in both academic and large community hospital settings. Diagnostic microbiology manufacturers are betting that robotics will be used for specimen processing, plate reading, and organism identification in the near future. These systems are highly complex and have large footprints and hefty price tags. However, they are touted as being more efficient, rapid, and accurate than standard processes. Certain features, such as image collection, are highly innovative. Hospital administrators may be swayed to institute these new systems because of the promise of the need for fewer skilled workers, higher throughput, and greater efficiency. They also may be swayed by the fact that workers with the requisite clinical microbiology skills are becoming more difficult to find, and this technology should allow fewer skilled workers to handle larger numbers of cultures. In this Point-Counterpoint, Nate Ledeboer, Medical Director, Clinical Microbiology and Molecular Diagnostics, Dynacare Laboratories, and Froedtert Hospital, Milwaukee, WI, will explain why he believes that this approach will become widespread, while Steve Dallas of the University of Texas Health Science Center San Antonio explains why he thinks that this automation may not become widely used.


Genome specialization and decay of the strangles pathogen, Streptococcus equi, is driven by persistent infection.
Strangles, the most frequently diagnosed infectious disease of horses worldwide, is caused by Streptococcus equi. Despite its prevalence, the global diversity and mechanisms underlying the evolution of S. equi as a host-restricted pathogen remain poorly understood. Here, we define the global population structure of this important pathogen and reveal a population replacement in the late 19th or early 20th Century. Our data reveal a dynamic genome that continues to mutate and decay, but also to amplify and acquire genes despite the organism having lost its natural competence and become host-restricted. The lifestyle of S. equi within the horse is defined by short-term acute disease, strangles, followed by long-term infection. Population analysis reveals evidence of convergent evolution in isolates from post-acute disease samples as a result of niche adaptation to persistent infection within a host. Mutations that lead to metabolic streamlining and the loss of virulence determinants are more frequently found in persistent isolates, suggesting that the pathogenic potential of S. equi reduces as a consequence of long-term residency within the horse post-acute disease. An example of this is the deletion of the equibactin siderophore locus that is associated with iron acquisition, which occurs exclusively in persistent isolates, and renders S. equi significantly less able to cause acute disease in the natural host. We identify several loci that may similarly be required for the full virulence of S. equi, directing future research toward the development of new vaccines against this host-restricted pathogen.


Synaptic processes and immune-related pathways implicated in Tourette syndrome.
Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS.


Photochemical cycling of iron mediated by dicarboxylates: special effect of malonate.
Photochemical redox cycling of iron coupled with oxidation of malonate (Mal) ligand has been investigated under conditions that are representative of atmospheric waters. Malonate exhibited significantly different characteristics from oxalate and other dicarboxylates (or monocarboxylates). Both strong chelating ability with Fe(III) and strong molar absorptivities, but much low efficiency of Fe(II) formation (Phi(Fe(II)) = 0.0022 +/- 0.0009, 300-366 nm) were observed for Fe(III)-Mal complexes (FMCs). Fe(III) speciation calculation indicated that Mal is capable of mediating the proportion between two photoactive species of Fe(III)-OH complexes and FMCs by changing the Mal concentration. Spin-trapping electron spin resonance (ESR) experiments proved the formation of both the (.)CH(2)COOH and (.)OH radicals at lower total Mal concentration ([Mal](T)), but only (.)CH(2)COOH at higher concentrations of malonate, providing strong evidence for competition between malonate and OH(-) and subsequent different photoreaction pathways. Once FMCs dominate the Fe(III) speciation, both photoproduction and photocatalyzed oxidation of Fe(II) will be greatly decelerated. There exists an induction period for both formation and decay of Fe(II) until Fe(III)(OH)(2+) species become the prevailing Fe(III) forms over FMCs as Mal ligand is depleted. A quenching mechanism of Mal in the Fe(II) photoproduction is proposed. The present study is meaningful to advance our understanding of iron cycling in acidified carbon-rich atmospheric waters.


Coactivation of renal sympathetic neurons and somatic motor neurons by chemical stimulation of the midbrain ventral tegmental area.
We examined whether neurons in the midbrain ventral tegmental area (VTA) play a role in generating central command responsible for autonomic control of the cardiovascular system in anesthetized rats and unanesthetized, decerebrated rats with muscle paralysis. Small volumes (60 nl) of an N-methyl-D-aspartate receptor agonist (L-homocysteic acid) and a GABAergic receptor antagonist (bicuculline) were injected into the VTA and substantia nigra (SN). In anesthetized rats, L-homocysteic acid into the VTA induced short-lasting increases in renal sympathetic nerve activity (RSNA; 66 ± 21%), mean arterial pressure (MAP; 5 ± 2 mmHg), and heart rate (HR; 7 ± 2 beats/min), whereas bicuculline into the VTA produced long-lasting increases in RSNA (130 ± 45%), MAP (26 ± 2 mmHg), and HR (66 ± 6 beats/min). Bicuculline into the VTA increased blood flow and vascular conductance of the hindlimb triceps surae muscle, suggesting skeletal muscle vasodilatation. However, neither drug injected into the SN affected all variables. Renal sympathetic nerve and cardiovascular responses to chemical stimulation of the VTA were not essentially affected by decerebration at the premammillary-precollicular level, indicating that the ascending projection to the forebrain from the VTA was not responsible for evoking the sympathetic and cardiovascular responses. Furthermore, bicuculline into the VTA in decerebrate rats produced long-lasting rhythmic bursts of RSNA and tibial motor nerve discharge, which occurred in good synchrony. It is likely that the activation of neurons in the VTA is capable of eliciting synchronized stimulation of the renal sympathetic and tibial motor nerves without any muscular feedback signal.


Thoraco-abdominal coordination and performance during uphill running at altitude.
Running races on mountain trails at moderate-high altitude with large elevation changes throughout has become increasingly popular. During exercise at altitude, ventilatory demands increase due to the combined effects of exercise and hypoxia. To investigate the relationships between thoraco-abdominal coordination, ventilatory pattern, oxygen saturation (SpO2), and endurance performance in runners during high-intensity uphill exercise. Fifteen participants (13 males, mean age 42±9 yrs) ran a "Vertical Kilometer," i.e., an uphill run involving a climb of approximately 1000 m with a slope greater than 30%. The athletes were equipped with a portable respiratory inductive plethysmography system, a finger pulse oximeter and a global positioning unit (GPS). The ventilatory pattern (ventilation (VE), tidal volume (VT), respiratory rate (RR), and VE/VT ratio), thoraco-abdominal coordination, which is represented by the phase angle (PhA), and SpO2 were evaluated at rest and during the run. Before and after the run, we assessed respiratory function, respiratory muscle strength and the occurrence of interstitial pulmonary edema by thoracic ultrasound. Two subjects were excluded from the respiratory inductive plethysmography analysis due to motion artifacts. A quadratic relationship between the slope and the PhA was observed (r = 0.995, p = 0.036). When the slope increased above 30%, the PhA increased, indicating a reduction in thoraco-abdominal coordination. The reduced thoraco-abdominal coordination was significantly related to reduced breathing efficiency (i.e., an increased VE/VT ratio; r = 0.961, p = 0.038) and SpO2 (r = -0.697, p<0.001). Lower SpO2 values were associated with lower speeds at 20%≥slope≤40% (r = 0.335, p<0.001 for horizontal and r = 0.36, p<0.001 for vertical). The reduced thoraco-abdominal coordination and consequent reduction in SpO2 were associated with interstitial pulmonary edema. Reductions in thoraco-abdominal coordination are associated with a less efficient ventilatory pattern and lower SpO2 during uphill running. This fact could have a negative effect on performance.


Effect of maternal lipopolysaccharide administration on the development of dopaminergic receptors and transporter in the rat offspring.
Epidemiological evidence supports that maternal infection during gestation are notable risk factors for developmental mental illnesses including schizophrenia and autism. In prenatal lipopolysaccharide (LPS) model of immune activation in rats, the offspring exhibit significant impairments in behaviors mediated by central dopamine (DA) system. This study aimed to examine the temporal and regional pattern of postnatal DA development in the male offspring of pregnant Sprague-Dawley rats administered with 100 µg/kg LPS or saline at gestational days 15/16. Using ligand autoradiography, D1 and D2 dopamine receptors (D1R, D2R) and dopamine transporter (DAT) binding levels were measured in the prefrontal cortex (PFC) and sub cortical regions (dorsal striatum and nucleus accumbens core and shell) at pre pubertal (P35) and post pubertal ages (P60). We found a significant decrease in D2R ligand [(3)H] YM-90151-2 binding in the medial PFC (mPFC) in prenatal LPS-treated animals at P35 and P60 compared to respective saline groups. The decrease in D2R levels was not observed in the striatum or accumbens of maternal LPS-treated animals. No significant changes were observed in [(3)H] SCH23390 binding to D1R. However, the level of [(125)I] RTI-121 binding to DAT was selectively reduced in the nucleus accumbens core and shell at P35 in the prenatal LPS group. Immunohistochemical analysis showed that number of D2R immunopositive cells in infralimbic/prelimbic (IL/PL) part of mPFC was significantly reduced in the LPS group at P60. Prenatal LPS treatment did not significantly affect either the total number of mature neurons or parvalbumin (PV)-immunopositive interneurons in this region. However the number of PV and D2R co-labeled neurons was significantly reduced in the IL/PL subregion of PFC of LPS treated animals. Our data suggests D2R deficit in the PFC and PV interneurons may be relevant to understanding mechanisms of cortical dysfunctions described in prenatal infection animal models as well as schizophrenia.


Factors affecting childhood immunization in Lao People's Democratic Republic: a cross-sectional study from nationwide, population-based, multistage cluster sampling.
Vaccines are one of the most important achievements in public health, and a major contributor to this success is the Expanded Programme on Immunization (EPI). The effective vaccination series of the EPI should be used by its target population. Various factors influence the utilization of the EPI vaccination series. In Lao People's Democratic Republic (Lao PDR), immunization coverage was lower than the regional average. This study evaluates risk factors affecting immunization underutilization among children five to nine years of age. It is a cross-sectional study from nationwide, population-based, multistage cluster sampling. The children who have received 'standard six' antigens and those who have been partially immunized are compared. In a bivariate analysis, household occupation, maternal age, means of transportation, time to the nearest health facilities, the child's birthplace, birth attended by medical staff, and notification of vaccination date by medical staff, village authority, or megaphone were associated with vaccination status. The final multivariate logistic regression model revealed that maternal age and notification of vaccination date by the village authority increased the odds of full vaccination, while notification of vaccination date by megaphone had decreased those odds. Further detailed qualitative research may be needed to discover how maternal sociodemographic factors influence the utilization of these services. Future research needs to target younger children and must include health care provider factors related to vaccination services.


Occurrence of CYP1B1 Mutations in Juvenile Open-Angle Glaucoma With Advanced Visual Field Loss.
Juvenile open-angle glaucoma (JOAG) is a severe neurodegenerative eye disorder in which most of the genetic contribution remains unexplained. To assess the prevalence of pathogenic CYP1B1 sequence variants in an Australian cohort of patients with JOAG and severe visual field loss. For this cohort study, we recruited 160 patients with JOAG classified as advanced (n = 118) and nonadvanced (n = 42) through the Australian and New Zealand Registry of Advanced Glaucoma from January 1, 2007, through April 1, 2014. Eighty individuals with no evidence of glaucoma served as a control group. We defined JOAG as diagnosis before age 40 years and advanced JOAG as visual field loss in 2 of the 4 central fixation squares on a reliable visual field test result. We performed direct sequencing of the entire coding region of CYP1B1. Data analysis was performed in October 2014. Identification and characterization of CYP1B1 sequence variants. We identified 7 different pathogenic variants among 8 of 118 patients with advanced JOAG (6.8%) but none among the patients with nonadvanced JOAG. Three patients were homozygous or compound heterozygous for CYP1B1 pathogenic variants, which provided a likely basis for their disease. Five patients were heterozygous. The allele frequency among the patients with advanced JOAG (11 in 236 [4.7%]) was higher than among our controls (1 in 160 [0.6%]; P = .02; odds ratio, 7.8 [95% CI, 0.02-1.0]) or among the control population from the Exome Aggregation Consortium database (2946 of 122 960 [2.4%]; P = .02; odds ratio, 2.0 [95% CI, 0.3-0.9]). Individuals with CYP1B1 pathogenic variants, whether heterozygous or homozygous, had worse mean (SD) deviation on visual fields (-24.5 [5.1] [95% CI, -31.8 to -17.2] vs -15.6 [10.0] [95% CI, -17.1 to -13.6] dB; F1,126 = 5.90; P = .02; partial ηp2 = 0.05) and were younger at diagnosis (mean [SD] age, 23.1 [8.4] [95% CI, 17.2-29.1] vs 31.5 [8.0] [95% CI, 30.1-33.0] years; F1,122 = 7.18; P = .008; ηp2 = 0.06) than patients without CYP1B1 pathogenic variants. Patients with advanced JOAG based on visual field loss had enrichment of CYP1B1 pathogenic variants and a more severe phenotype compared with unaffected controls and patients with nonadvanced JOAG.


Mitochondrial Open Reading Frame of the 12S rRNA Type-c: Potential Therapeutic Candidate in Retinal Diseases.
Mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c) is the most unearthed peptide encoded by mitochondrial DNA (mtDNA). It is an important regulator of the nuclear genome during times of stress because it promotes an adaptive stress response to maintain cellular homeostasis. Identifying MOTS-c specific binding partners may aid in deciphering the complex web of mitochondrial and nuclear-encoded signals. Mitochondrial damage and dysfunction have been linked to aging and the accelerated cell death associated with many types of retinal degenerations. Furthermore, research on MOTS-c ability to revive oxidatively stressed RPE cells has revealed a significant protective role for the molecule. Evidence suggests that senescent cells play a role in the development of age-related retinal disorders. This review examines the links between MOTS-c, mitochondria, and age-related diseases of the retina. Moreover, the untapped potential of MOTS-c as a treatment for glaucoma, diabetic retinopathy, and age-related macular degeneration is reviewed.


MEDLINE SDI services: how do they compare?
Selective dissemination of information (SDI) services regularly alert users to new information on their chosen topics. This type of service can increase a user's ability to keep current and may have a positive impact on efficiency and productivity. Currently, there are many venues available where users can establish, store, and automatically run MEDLINE searches. To describe, evaluate, and compare SDI services for MEDLINE. The following SDI services were selected for this study: PubMed Cubby, BioMail, JADE, PubCrawler, OVID, and ScienceDirect. Identical searches were established in four of the six selected SDI services and were run on a weekly basis over a period of two months. Eight search strategies were used in each system to test performance under various search conditions. The PubMed Cubby system was used as the baseline against which the other systems were compared. Other aspects were evaluated in all six services and include ease of use, frequency of results, ability to use MeSH, ability to access and edit existing search strategies, and ability to download to a bibliographic management program. Not all MEDLINE SDI services retrieve identical results, even when identical search strategies are used. This study also showed that the services vary in terms of features and functions offered.


NUCLEAR FACTOR Y, Subunit A (NF-YA) Proteins Positively Regulate Flowering and Act Through FLOWERING LOCUS T.
Photoperiod dependent flowering is one of several mechanisms used by plants to initiate the developmental transition from vegetative growth to reproductive growth. The NUCLEAR FACTOR Y (NF-Y) transcription factors are heterotrimeric complexes composed of NF-YA and histone-fold domain (HFD) containing NF-YB/NF-YC, that initiate photoperiod-dependent flowering by cooperatively interacting with CONSTANS (CO) to drive the expression of FLOWERING LOCUS T (FT). This involves NF-Y and CO binding at distal CCAAT and proximal "CORE" elements, respectively, in the FT promoter. While this is well established for the HFD subunits, there remains some question over the potential role of NF-YA as either positive or negative regulators of this process. Here we provide strong support, in the form of genetic and biochemical analyses, that NF-YA, in complex with NF-YB/NF-YC proteins, can directly bind the distal CCAAT box in the FT promoter and are positive regulators of flowering in an FT-dependent manner.


Temperate pine barrens and tropical rain forests are both rich in undescribed fungi.
Most of fungal biodiversity on Earth remains unknown especially in the unexplored habitats. In this study, we compared fungi associated with grass (Poaceae) roots from two ecosystems: the temperate pine barrens in New Jersey, USA and tropical rain forests in Yunnan, China, using the same sampling, isolation and species identification methods. A total of 426 fungal isolates were obtained from 1600 root segments from 80 grass samples. Based on the internal transcribed spacer (ITS) sequences and morphological characteristics, a total of 85 fungal species (OTUs) belonging in 45 genera, 23 families, 16 orders, and 6 classes were identified, among which the pine barrens had 38 and Yunnan had 56 species, with only 9 species in common. The finding that grass roots in the tropical forests harbor higher fungal species diversity supports that tropical forests are fungal biodiversity hotspots. Sordariomycetes was dominant in both places but more Leotiomycetes were found in the pine barrens than Yunnan, which may play a role in the acidic and oligotrophic pine barrens ecosystem. Equal number of undescribed fungal species were discovered from the two sampled ecosystems, although the tropical Yunnan had more known fungal species. Pine barrens is a unique, unexplored ecosystem. Our finding suggests that sampling plants in such unexplored habitats will uncover novel fungi and that grass roots in pine barrens are one of the major reservoirs of novel fungi with about 47% being undescribed species.


Prevalence and correlates of cigarette smoking among operation Iraqi freedom-era and operation enduring freedom-era women from the Active Component military and Reserve/National Guard.
Tobacco use adversely affects the health and readiness of military personnel. Although rates of cigarette smoking have historically been elevated among men serving in the military, less is known about tobacco use in servicewomen. To examine the prevalence and correlates of tobacco use among women serving in the Active Component (AC) and Reserve/National Guard (RNG) as well as factors associated with starting to smoke during military service. Cross-sectional surveys of 1320 women serving in the AC or RNG were used to examine cigarette use in servicewomen. Associations between self-reported tobacco use history, sociodemographics, military service, and psychosocial factors were investigated using logistic regression analyses. Thirty-six percent of servicewomen had a lifetime history of cigarette use, with 18% reporting current smoking. Thirty-one percent of lifetime smokers initiated smoking during military service. Factors associated with current smoking included pay grade, marital status, use of psychotropic medications, past-year alcohol use, and lifetime illicit drug or illegal prescription medication use. An enlisted pay grade, being white, and a history of deployment were all associated with starting to smoke during military service. Although progress has been made in reducing the gap in tobacco use between military and civilian populations, nearly 1 in 5 servicewomen in our sample smoked cigarettes. Further efforts are needed to address tobacco use in this population. In addition to providing resources to assist smokers with quitting, additional attention should be given to preventing smoking initiation, particularly among deployed female personnel.


Modulation of human peripheral blood lymphocyte Fc gamma receptors by immune complexes: recovery of Fc gamma receptors in the presence of normal human serum.
When normal human peripheral blood lymphocytes (PBL) were incubated at 37 degrees with soluble transferrin anti-transferrin (TAT) complexes a significant reduction in the proportion of PBL bearing receptors for the reacted Fc portion of IgG(Fc gamma R) was found. Following incubation of such complex-treated PBL in normal human serum the proportion of Fc gamma R + PBL, as assessed by rosette formation with chicken erythrocytes (E) presensitized with rabbit antibody (A) was found to be significantly increased. Such serum-mediated recovery of Fc gamma R was not affected by pretreating PBL with cycloheximide. Recovery was found to be species restricted, Ca++ dependent and confined to a serum fraction containing molecules of relatively low molecular weight (less than 90,000 Mr). Following absorption with EA the restorative capacity of human serum was lost. These findings suggest that following modulation of human PBL-Fc gamma R by immune complexes, receptors may be restored to the cell surface from a serum pool of 'fluid-phase' Fc gamma R. The origin and biological significance of serum Fc gamma R is not known but it is conceivable that they play an important role in immunoregulation.


Regional-scale assessment of soil salinity in the Red River Valley using multi-year MODIS EVI and NDVI.
The ability to inventory and map soil salinity at regional scales remains a significant challenge to scientists concerned with the salinization of agricultural soils throughout the world. Previous attempts to use satellite or aerial imagery to assess soil salinity have found limited success in part because of the inability of methods to isolate the effects of soil salinity on vegetative growth from other factors. This study evaluated the use of Moderate Resolution Imaging Spectroradiometer (MODIS) imagery in conjunction with directed soil sampling to assess and map soil salinity at a regional scale (i.e., 10-10(5) km(2)) in a parsimonious manner. Correlations with three soil salinity ground truth datasets differing in scale were made in Kittson County within the Red River Valley (RRV) of North Dakota and Minnesota, an area where soil salinity assessment is a top priority for the Natural Resource Conservation Service (NRCS). Multi-year MODIS imagery was used to mitigate the influence of temporally dynamic factors such as weather, pests, disease, and management influences. The average of the MODIS enhanced vegetation index (EVI) for a 7-yr period exhibited a strong relationship with soil salinity in all three datasets, and outperformed the normalized difference vegetation index (NDVI). One-third to one-half of the spatial variability in soil salinity could be captured by measuring average MODIS EVI and whether the land qualified for the Conservation Reserve Program (a USDA program that sets aside marginally productive land based on conservation principles). The approach has the practical simplicity to allow broad application in areas where limited resources are available for salinity assessment.


Delayed puberty induced by chronic suppression of prolactin release in the female rat.
To study the effect of PRL deficiency on the onset of puberty, PRL release was chronically inhibited by treating immature female rats with the dopaminergic receptor agonist, bromoergocriptine (CB-154). The resulting alterations in the time of puberty onset, and in other associated parameters, such as serum levels of pituitary hormones, ovarian responsiveness to gonadotropins and ovarian hCG receptor content were then evaluated. CB-154 was provided in the drinking water from day 22 onward at the concentration of 20 and 100 micrograms/ml. The treatment resulted in almost complete suppression of serum PRL levels throughout the entire period studied (day 22 to first diestrus). In contrast, serum GH, FSH, and LH levels were not depressed. Likewise, pulsatile release of FSH was not affected and only a subtle alteration in pulsatile LH release was apparent. The onset of puberty, as determined by the age at vaginal opening, and at first diestrus after the first estrus and by the presence of corpora lutea at sacrifice (first diestrus), was markedly delayed in the hypoprolactinemic (HPO) rats. This inhibitory effect of CB-154 was completely prevented by concomitant administration of PRL. Ovarian weight was significantly decreased in HPO rats at the three ages studied (27, 32, and 36 days of age). By day 36, 50% of the control animals had already ovulated, as compared with only 9% of the HPO rats. Microscopic examination of ovaries from HPO rats revealed a retarded follicular development. In vitro ovarian progesterone response to hCG studied at day 32 and 36 of age was reduced in the HPO rats. Uterine growth was also depressed in HPO rats, the ovaries of which, when incubated in vitro, failed to show the prepubertal increase in estrogen response to hCG seen in control rats between day 32 ad 36. Aromatase activity, as measured by the in vitro release of estradiol from ovaries incubated in the presence of an excess of androgen substrate, was depressed in HPO rats. hCG receptor content in the ovaries from HPO rats (counts per min [125]hCG bound per micrograms DNA) was also lower than that of control animals at day 32 and 34 but not at day 36. However, at this later time the hCG receptor content per milligram of ovary was still significantly reduced in HPO rats. The results support the view that PRL plays an important role in the process of ovarian development that leads to the onset of puberty in the female rat and that this effect is, at least in part, exerted through a positive influence of PRL on ovarian LH receptor content.


Familial CJD associated PrP mutants within transmembrane region induced Ctm-PrP retention in ER and triggered apoptosis by ER stress in SH-SY5Y cells.
Genetic prion diseases are linked to point and inserted mutations in the prion protein (PrP) gene that are presumed to favor conversion of the cellular isoform of PrP (PrP(C)) to the pathogenic one (PrP(Sc)). The pathogenic mechanisms and the subcellular sites of the conversion are not completely understood. Here we introduce several PRNP gene mutations (such as, PrP-KDEL, PrP-3AV, PrP-A117V, PrP-G114V, PrP-P102L and PrP-E200K) into the cultured cells in order to explore the pathogenic mechanism of familial prion disease. To address the roles of aberrant retention of PrP in endoplasmic reticulum (ER), the recombinant plasmids expressing full-length human PrP tailed with an ER signal peptide at the COOH-terminal (PrP-KDEL) and PrP with three amino acids exchange in transmembrane region (PrP-3AV) were constructed. In the preparations of transient transfections, 18-kD COOH-terminal proteolytic resistant fragments (Ctm-PrP) were detected in the cells expressing PrP-KDEL and PrP-3AV. Analyses of the cell viabilities in the presences of tunicamycin and brefeldin A revealed that expressions of PrP-KDEL and PrP-3AV sensitized the transfected cells to ER stress stimuli. Western blots and RT-PCR identified the clear alternations of ER stress associated events in the cells expressing PrP-KDEL and PrP-3AV that induced ER mediated apoptosis by CHOP and caspase-12 apoptosis pathway. Moreover, several familial CJD related PrP mutants were transiently introduced into the cultured cells. Only the mutants within the transmembrane region (G114V and A117V) induced the formation of Ctm-PrP and caused the ER stress, while the mutants outside the transmembrane region (P102L and E200K) failed. The data indicate that the retention of PrP in ER through formation of Ctm-PrP results in ER stress and cell apoptosis. The cytopathic activities caused by different familial CJD associated PrP mutants may vary, among them the mutants within the transmembrane region undergo an ER-stress mediated cell apoptosis.


The influence of self-compassion on emotional well-being among early and older adolescent males and females.
Self-compassion has been associated with well-being in adult samples, but has rarely been assessed in adolescents. In this study, 90 students ages 11-18 completed an online survey assessing self-compassion, life satisfaction, perceived stress and positive and negative affect. Findings indicated that older female adolescents had lower self-compassion than either older male adolescents or early adolescents of either gender, and self-compassion was associated significantly with all dimensions of emotional well-being with the exception of positive affect. Additionally, phase of adolescence, but not gender, was found to moderate the relationship between self-compassion and dimensions of well-being; for older adolescents, the inverse relationship between self-compassion and negative affect was stronger. Lastly, the influence of the various components of self-compassion was investigated and discussed.


Loss of miR-133a expression associated with poor survival of breast cancer and restoration of miR-133a expression inhibited breast cancer cell growth and invasion.
miRNAs, endogenous oligonucleotide RNAs, play an important role in mammary gland carcinogenesis and tumor progression. Detection of their expression and investigation of their functions could lead to discovery of novel biomarkers for breast cancer. In situ hybridization was used to detect miR-133a expression in formalin-fixed paraffin-embedded breast surgical specimens from 26 benign, 34 pericancerously normal and 90 cancerous tissues. qRT-PCR was performed to assess miR-133a levels in 6 breast cell lines and 10 benign and 18 cancerous fresh breast tissue specimens. Cell viability, migration, and invasion assays were used to determine the role of miR-133a in regulation of breast cancer cell growth, migration, and invasion, respectively. Luciferase assay was performed to assess miR-133a binding to FSCN1 gene. Expression of miR-133a was reduced from normal through benign to cancerous breast tissues. Expression of miR-133a was also low in breast cancer cell lines. The reduced miR-133a expression was associated with lymph nodes metastasis, high clinical stages, and shorter relapse-free survivals of patients with breast cancer. Furthermore, transfection of miR-133a oligonucleotides slightly inhibited growth but significantly decreased migration and invasion capacity of breast cancer cells, compared with negative controls, whereas knockdown of miR-133a expression induced breast cancer cell migration and invasion. In addition, we identified a putative miR-133a binding site in the 3'-untranslated region (UTR) of Fascin1 (FSCN1) gene using an online bioinformatical tool. We found that miR-133a transfection significantly reduced expression of FSCN1 mRNA and protein. The luciferase reporter assay confirmed that FSCN1 was the direct target gene of miR-133a. miR-133a expression was lost in breast cancer tissues, loss of which was associated with lymph nodes metastasis, high clinical stages and shorter relapse-free survivals of patients with breast cancer. Functionally, miR-133a can suppress tumor cell invasion and migration and targeted the expression of FSCN1. Future study will verify whether detection of miR-133a expression can served as a novel biomarker for breast cancer progression and patient prognosis.


Distinct patterns of whole blood transcriptional responses are induced in mice following immunisation with adenoviral and poxviral vector vaccines encoding the same antigen.
Viral vectors, including adenovirus (Ad) and modified vaccinia Ankara (MVA), have gained increasing attention as vaccine platforms in recent years due to their capacity to express antigens from a wide array of pathogens, their rapid induction of humoral and cellular protective immune responses, and their relatively low production costs. In particular, the chimpanzee Ad vector, ChAdOx1, has taken centre stage as a leading COVID-19 vaccine candidate. However, despite mounting data, both clinical and pre-clinical, demonstrating effective induction of adaptive immune responses, the innate immune signals that precede the protective responses that make these vectors attractive vaccine platforms remain poorly understood. In this study, a mouse immunisation model was used to evaluate whole blood gene expression changes 24 h after either a single dose or heterologous prime-boost regimen of an Ad and/or MVA vaccine. We demonstrate through comparative analysis of Ad vectors encoding different antigens that a transgene product-specific gene signature can be discerned from the vector-induced transcriptional response. Expression of genes involved in TLR2 stimulation and γδ T cell and natural killer cell activation were induced after a single dose of Ad, while MVA led to greater expression of type I interferon genes. The order of prime-boost combinations was found to influence the magnitude of the gene expression changes, with MVA/Ad eliciting greater transcriptional perturbation than Ad/MVA. Contrasting the two regimens revealed significant enrichment of epigenetic regulation pathways and augmented expression of MHC class I and II molecules associated with MVA/Ad. These data demonstrate that the order in which vaccines from heterologous prime-boost regimens are administered leads to distinct transcriptional responses and may shape the immune response induced by such combinations. The characterisation of early vaccine-induce responses strengthens our understanding of viral vector vaccine mechanisms of action ahead of their characterisation in human clinical trials and are a valuable resource to inform the pre-clinical design of appropriate vaccine constructs for emerging infectious diseases.


The impact of body vigilance on help-seeking for cancer 'alarm' symptoms: a community-based survey.
The act of detecting bodily changes is a pre-requisite for subsequent responses to symptoms, such as seeking medical help. This is the first study to explore associations between self-reported body vigilance and help-seeking in a community sample currently experiencing cancer 'alarm' symptoms. Using a cross-sectional study design, a 'health survey' was mailed through primary care practices to 4913 UK adults (age ≥50 years, no cancer diagnosis), asking about symptom experiences and medical help-seeking over the previous three months. Body vigilance, cancer worry and current illness were assessed with a small number of self-report items derived from existing measures. The response rate was 42% (N = 2042). Almost half the respondents (936/2042; 46%) experienced at least one cancer alarm symptom. Results from logistic regression analysis revealed that paying more attention to bodily changes was significantly associated with help-seeking for cancer symptoms (OR = 1.44; 1.06-1.97), after controlling for socio-demographics, current illness and cancer worry. Being more sensitive to bodily changes was not significantly associated with help-seeking. Respondents who paid attention to their bodily changes were more likely to seek help for their symptoms. Although the use of a cross-sectional study design and the limited assessment of key variables preclude any firm conclusions, encouraging people to be body vigilant may contribute towards earlier cancer diagnosis. More needs to be understood about the impact this might have on cancer-related anxiety.


Jumping to conclusions, neuropsychological functioning, and delusional beliefs in first episode psychosis.
The "jumping to conclusions" (JTC) data-gathering bias is implicated in the development and maintenance of psychosis but has only recently been studied in first episode psychosis (FEP). In this study, we set out to establish the relationship of JTC in FEP with delusions and neuropsychological functioning. One hundred and eight FEP patients and 101 age-matched controls completed assessments of delusions, general intelligence (IQ), working memory (WM), and JTC (the probabilistic reasoning "beads" task). Half the FEP participants jumped to conclusions on at least 1 task, compared with 25% of controls (OR range 2.1 to 3.9; 95% CI range 1.5 to 8.0, P values ≤ .02). JTC was associated with clinical, but not nonclinical delusion severity, and with neuropsychological functioning, irrespective of clinical status. Both IQ and delusion severity, but not WM, were independently associated with JTC in the FEP group. JTC is present in FEP. The specific association of JTC with clinical delusions supports a state, maintaining role for the bias. The associations of JTC with neuropsychological functioning indicate a separable, trait aspect to the bias, which may confer vulnerability to psychosis. The work has potential to inform emerging interventions targeting reasoning biases in early psychosis.


Early functional alterations in membrane properties and neuronal degeneration are hallmarks of progressive hearing loss in NOD mice.
Presbycusis or age-related hearing loss (ARHL) is the most common sensory deficit in the human population. A substantial component of the etiology stems from pathological changes in sensory and non-sensory cells in the cochlea. Using a non-obese diabetic (NOD) mouse model, we have characterized changes in both hair cells and spiral ganglion neurons that may be relevant for early signs of age-related hearing loss (ARHL). We demonstrate that hair cell loss is preceded by, or in parallel with altered primary auditory neuron functions, and latent neurite retraction at the hair cell-auditory neuron synapse. The results were observed first in afferent inner hair cell synapse of type I neurites, followed by type II neuronal cell-body degeneration. Reduced membrane excitability and loss of postsynaptic densities were some of the inaugural events before any outward manifestation of hair bundle disarray and hair cell loss. We have identified profound alterations in type I neuronal membrane properties, including a reduction in membrane input resistance, prolonged action potential latency, and a decrease in membrane excitability. The resting membrane potential of aging type I neurons in the NOD, ARHL model, was significantly hyperpolarized, and analyses of the underlying membrane conductance showed a significant increase in K+ currents. We propose that attempts to alleviate some forms of ARHL should include early targeted primary latent neural degeneration for effective positive outcomes.


The global and domestic politics of health policy in emerging nations.
In recent years, several emerging nations with burgeoning economies and in transition to democracy have pursued health policy innovations. As these nations have integrated into the world economy through bilateral trade and diplomacy, they have also become increasingly exposed to international pressures and norms and focused on more effective, equitable health care systems. There are several lessons learned from the case studies of Brazil, Ghana, India, China, Vietnam, and Thailand in this special issue on the global and domestic politics of health policy in emerging nations. For the countries examined, although sensitive to international preferences, domestic governments preferred to implement policy on their own and at their own pace. During the policy-making and implementation process, international and domestic actors played different roles in health policy making vis-à-vis other reform actors -- at times the state played an intermediary role. In several countries, civil society also played a central role in designing and implementing policy at all levels of government. International institutions also have a number of mechanisms and strategies in their tool box to influence a country's domestic health governance, and they use them, particularly in the context of an uncertain state or internal discordance within the state.


The role of parenting and goal selection in positive youth development: a person-centered approach.
Using a person-centered approach, we examined the relations between goal selection, various indicators of parenting, and positive development among 510 Grades 9 to 11 participants (68% female) in the 4-H Study of Positive Youth Development (PYD), a longitudinal study involving U.S. adolescents. Goal selection was operationalized by the "Selection" (S) subscale of the Selection, Optimization, and Compensation intentional self-regulation measure. Using Configural Frequency Analysis, we assessed the association between Selection, parenting (warmth, monitoring, and school involvement), and PYD. Results indicated that, while having the combination of consistently high Selection and above-median levels of the parenting variables was the most common path to PYD, having consistently low levels of Selection across grades was also related to positive development at Grade 11, regardless of parenting factors. We interpret these findings based in relation to the PYD and the identity development literatures and discuss implications for applied programs.


Randomized controlled trial of stroke volume optimization during elective major abdominal surgery in patients stratified by aerobic fitness.
The benefits of stroke volume optimization during surgery are unclear, with recent data not replicating the positive effects of earlier studies. This was a randomized controlled trial of standard fluid therapy with or without supplementary blinded intraoperative stroke volume optimization in 220 patients having major elective rectal resection or cystectomy with ileal conduit. All patients were treated using a contemporary enhanced recovery pathway. Interventional fluid challenges used Gelofusine (B Braun, Germany), guided by stoke volume variability measured by LiDCOrapid (LiDCO, UK). Participants were stratified by aerobic fitness (characterized by preoperative cardiopulmonary exercise test), surgical specialty, and intended surgical approach (open or laparoscopic). The primary outcome was the prevalence of moderate or severe complications on day 5 after surgery, defined using the postoperative morbidity survey (POMS) criteria. Patients received ∼13 ml kg(-1) h(-1) of i.v. fluids during surgery. The intervention group received an additional mean (sd) 956 (896) ml Gelofusine. There were no statistically significant differences between groups in any primary or secondary end point. A positive POMS on postoperative day 5 was noted in 54 of 111 control subjects (48.6%) and 55 of 109 participants in the intervention group [50.5%; adjusted odds ratio 0.90 (95% confidence interval 0.52-1.57), P=0.717]. Mean (sd) hospital length of stay was 9.6 (6.8) days in the control group and 11.8 (11.5) days in the intervention group (adjusted difference -2.1 (-4.6 to 0.3) days, P=0.091). There was no statistical interaction between stroke volume optimization and aerobic fitness in terms of rate of complications or length of stay. Algorithm-driven stroke volume optimization is of no benefit when superimposed on a liberal baseline fluid regimen in patients having elective major abdominal surgery, when stratified to minimize differences in fitness and surgical approach between groups. ISRCTN21597243.


An engineered ultra-high affinity Fab-Protein G pair enables a modular antibody platform with multifunctional capability.
Engineered recombinant antibody-based reagents are rapidly supplanting traditionally derived antibodies in many cell biological applications. A particularly powerful aspect of these engineered reagents is that other modules having myriad functions can be attached to them either chemically or through molecular fusions. However, these processes can be cumbersome and do not lend themselves to high throughput applications. Consequently, we have endeavored to develop a platform that can introduce multiple functionalities into a class of Fab-based affinity reagents in a "plug and play" fashion. This platform exploits the ultra-tight binding interaction between affinity matured variants of a Fab scaffold (FabS ) and a domain of an immunoglobulin binding protein, protein G (GA1). GA1 is easily genetically manipulatable facilitating the ability to link these modules together like beads on a string with adjustable spacing to produce multivalent and bi-specific entities. GA1 can also be fused to other proteins or be chemically modified to engage other types of functional components. To demonstrate the utility for the Fab-GA1 platform, we applied it to a detection proximity assay based on the β-lactamase (BL) split enzyme system. We also show the bi-specific capabilities of the module by using it in context of a Bi-specific T-cell engager (BiTE), which is a therapeutic assemblage that induces cell killing by crosslinking T-cells to cancer cells. We show that GA1-Fab modules are easily engineered into potent cell-killing BiTE-like assemblages and have the advantage of interchanging Fabs directed against different cell surface cancer-related targets in a plug and play fashion.


Psychometric properties of the Swedish version of the satisfaction with life scale in a sample of individuals with mental illness.
Health assessment among individuals with mental health problems often involves measures of ill-being (e.g., anxiety, depression). Health is, however, defined as a state of physical, mental and social well-being and not merely the absence of disease (WHO, 1948, 2001). Hence, in order to address mental illness during the 21st century, we need to develop methods for the prevention, identification and treatment of mental illness; but also, for the promotion, identification, and maintenance of well-being. In this context, over three decades of subjective well-being research have resulted in the development of measures of positive aspects of human life, such as the Satisfaction with Life Scale (Diener et al., 1985). Our aim was to investigate the psychometric properties of the Satisfaction with Life Scale in a Swedish population of individuals with mental illness using both Classical Test Theory (CTT) and Item Response Theory (IRT). A total of 264 participants (age mean = 43.46, SD = 13.31) diagnosed with different types of mental illness answered to the Swedish version of the Satisfaction with Life Scale (five items, 7-point scale: 1 = strongly disagree, 7 = strongly agree). We found positive and significant relationships between the five items of the scale (r ranging from 0.37 to 0.75), good reliability (Cronbach's alpha = 0.86), and that the one-factor solution had best goodness of fit (loadings between 0.52-0.88, p < 0.001). Additionally, there were no significant differences in comparative fit indexes regarding gender and occupation status. All items had high discrimination values (between 1.95-3.81), but item 5 ("If I could live my life over, I would change almost nothing"); which had a moderate discrimination value (1.17) and the highest estimated difficulty on response 7 (3.06). Moreover, item 2 ("The conditions of my life are excellent") had less discrimination and redundant difficulty with both item 1 ("In most ways my life is close to my ideal"; 2.03) on response 7 and with item 3 ("I am satisfied with my life"; -1.21) on response 1. The five items together provided good information, with especial good reliability and small standard error within -1.00 up to about 2.00 and the highest amount of test information at 0.00 of the level of life satisfaction within this population. Consistent with previous research, the scale had good reliability and provided good information across most of the latent trait range. In addition, within this population, sociodemographic factors such as gender and occupation status do not influence how individuals respond to the items in the scale. However, the items couldn't measure extreme levels of low/high life satisfaction. We suggest replication of these findings, the test of additional items, and the modification of items 2 and 5 in order to use the scale among individuals with mental illness.


Whole genome linkage disequilibrium maps in cattle.
Bovine whole genome linkage disequilibrium maps were constructed for eight breeds of cattle. These data provide fundamental information concerning bovine genome organization which will allow the design of studies to associate genetic variation with economically important traits and also provides background information concerning the extent of long range linkage disequilibrium in cattle. Linkage disequilibrium was assessed using r2 among all pairs of syntenic markers within eight breeds of cattle from the Bos taurus and Bos indicus subspecies. Bos taurus breeds included Angus, Charolais, Dutch Black and White Dairy, Holstein, Japanese Black and Limousin while Bos indicus breeds included Brahman and Nelore. Approximately 2670 markers spanning the entire bovine autosomal genome were used to estimate pairwise r2 values. We found that the extent of linkage disequilibrium is no more than 0.5 Mb in these eight breeds of cattle. Linkage disequilibrium in cattle has previously been reported to extend several tens of centimorgans. Our results, based on a much larger sample of marker loci and across eight breeds of cattle indicate that in cattle linkage disequilibrium persists over much more limited distances. Our findings suggest that 30,000-50,000 loci will be needed to conduct whole genome association studies in cattle.


Case management or assertive community treatment. What is the difference?
There has been a long-running controversy about the relative benefits of Assertive Community Treatment (ACT) compared to Case Management (CM). Several health care systems have initiated major service overhauls on the basis of published evidence. Yet this evidence has been ambiguous and supports differing interpretations. Research is examined which explores the differences in outcomes reported. It uses a range of approaches, most prominently meta-regression, to test a small range of hypotheses to explain the heterogeneity in outcomes. The main determinant of differences between ACT and CM studies is the local bed management procedures and occupancy practice. Those organizational aspects of ACT which are generally shared by CM teams are associated with reduced hospital care but the stringent staffing proposed for ACT does not affect it. ACT is a specialized form of CM, not a categorically different approach. The benefits of introducing it will depend on the nature of current local practice. Important lessons about the need to focus on treatments rather than structures seem not to have been learnt. Psychiatry's recent excessive focus on service structures may have had unintended consequences for our professional identity.


Smooth muscle myosin: regulation and properties.
The relationship of the biochemical states to the mechanical events in contraction of smooth muscle cross-bridges is reviewed. These studies use direct measurements of the kinetics of Pi and ADP release. The rate of release of Pi from thiophosphorylated cycling cross-bridges held isometric was biphasic with turnovers of 1.8 s-1 and 0.3 s-1, reflecting properties and forces directly acting on cross-bridges through mechanisms such as positive strain and inhibition by high-affinity MgADP binding. Fluorescent transients reporting release of an ADP analogue 3'-deac-edaADP were significantly faster in phasic than in tonic smooth muscles. Thiophosphorylation of myosin regulatory light chains (RLCs) increased and positive strain decreased the release rate around twofold. The rates of ADP release from rigor cross-bridges and the steady-state Pi release from cycling isometric cross-bridges are similar, indicating that the ADP-release step or an isomerization preceding it may limit the ATPase rate. Thus ADP release in phasic and tonic smooth muscles is a regulated step with strain- and dephosphorylation-dependence. High affinity of cross-bridges for ADP and slow ADP release prolong the fraction of the duty cycle occupied by strongly bound AM.ADP state(s) and contribute to the high economy of force that is characteristic of smooth muscle. RLC thiophosphorylation led to structural changes in smooth muscle cross-bridges consistent with our findings that thiophosphorylation and strain modulate product release.


Construction and molecular characterization of a T-cell receptor-like antibody and CAR-T cells specific for minor histocompatibility antigen HA-1H.
The genetic transfer of T-cell receptors (TCRs) directed toward target antigens into T lymphocytes has been used to generate antitumor T cells efficiently without the need for the in vitro induction and expansion of T cells with cognate specificity. Alternatively, T cells have been gene-modified with a TCR-like antibody or chimeric antigen receptor (CAR). We show that immunization of HLA-A2 transgenic mice with tetramerized recombinant HLA-A2 incorporating HA-1 H minor histocompatibility antigen (mHag) peptides and β2-microglobulin (HA-1 H/HLA-A2) generate highly specific antibodies. One single-chain variable region moiety (scFv) antibody, #131, demonstrated high affinity (KD=14.9 nM) for the HA-1 H/HLA-A2 complex. Primary human T cells transduced with #131 scFV coupled to CD28 transmembrane and CD3ζ domains were stained with HA-1 H/HLA-A2 tetramers slightly more intensely than a cytotoxic T lymphocyte (CTL) clone specific for endogenously HLA-A2- and HA-1 H-positive cells. Although #131 scFv CAR-T cells required >100-fold higher antigen density to exert cytotoxicity compared with the cognate CTL clone, they could produce inflammatory cytokines against cells expressing HLA-A2 and HA-1 H transgenes. These data implicate that T cells with high-affinity antigen receptors reduce the ability to lyse targets with low-density peptide/MHC complexes (~100 per cell), while they could respond at cytokine production level.


Controlled study of metoprolol and propranolol during prolonged administration in patients with essential tremor.
The efficacy of propranolol and metoprolol in the treatment of essential tremor was compared in a double blind crossover placebo-controlled study in 16 patients. Each treatment was given for a period of 4 weeks at two different dosage regimens (150 and 300 mg daily for metoprolol, 120 and 240 mg daily for propranolol). Each dosage regimen lasted for 2 weeks. Tremor assessment was carried out by accelerometry, clinical evaluation, patient's self-rating and a battery of performance tests. At the lower dosage, propranolol was found to be superior to placebo on the basis of performance tests and patient's self-assessment. At the higher dosage, propranolol was superior to placebo on all methods of assessment. By contrast, the tremorolytic effect of metoprolol was not significantly different from that of placebo, irrespective of the dosage or of the method of assessment used. Propranolol (120 mg daily) was better than metoprolol (150 mg daily) on the basis of clinical evaluation and patient's self-assessment. Propranolol (240 mg daily) was superior to metoprolol (300 mg daily) on the basis of patient's self-assessment. Both drugs antagonised standing tachycardia to a similar extent. These results indicate that the effectiveness of metoprolol, previously demonstrated in a single-dose study in the same patients, is not fully maintained during prolonged administration. In the absence of specific contraindications, propranolol represents a better choice in the treatment of patients with essential tremor.


Greater trochanteric pain syndrome: defining the clinical syndrome.
Effective treatment of hip pain improves population health and quality of life. Accurate differential diagnosis is fundamental to effective treatment. The diagnostic criteria for one common hip problem, greater trochanteric pain syndrome (GTPS) have not been well defined. To define the clinical presentation of GTPS. Forty-one people with GTPS, 20 with hip osteoarthritis (OA), and 23 age-matched and sex-matched asymptomatic participants (ASC) were recruited. Inclusion and exclusion criteria ensured mutually exclusive groups. the Harris hip score (HHS), a battery of clinical tests, and single leg stance (SLS). Participants identified the site of reproduced pain. Fisher's exact test, analysis of variance (ANOVA) informed recursive partitioning to develop two classification trees. Maximum walking distance and the ability to manipulate shoes and socks were the only HHS domains to differentiate GTPS from OA (ANOVA: p=0.010 and <0.001); OR (95% CI) of 3.47 (1.09 to 10.93) and 0.06 (0.00 to 0.26), respectively. The lateral hip pain (LHP) classification tree: (dichotomous LHP associated with a flexion abduction external rotation (FABER) test) had a mean (SE) sensitivity and specificity of 0.81 (0.019) and 0.82 (0.044), respectively. A non-specific hip pain classification tree had a mean (SE) sensitivity and specificity of 0.78 (0.058) and 0.28 (0.080). Patients with LHP in the absence of difficulty with manipulating shoes and socks, together with pain on palpation of the greater trochanter and LHP with a FABER test are likely to have GTPS.


Evidence for two types of bipolar depression using a dimensional approach.
Although there is a great heterogeneity of depressive states in bipolar patients, there is only one definition in international classifications for describing them. However, this variety seems particularly important to recognize because of the possible exacerbation of some of these bipolar depressive states by antidepressants. We aimed at assessing whether it is possible to distinguish different forms of bipolar depression using a dimensional approach. We characterized 60 bipolar patients with a Major Depressive Episode (DSM-IV) using a new tool (MAThyS; Multidimensional Assessment of Thymic States), assessing five fundamental dimensions (emotional reactivity, cognitive speed, psychomotor function, motivation, and sensory perception) of mood states. A cluster analysis using the items of the dimensional scale revealed two types of depressive state: group 1 (n = 38), which had a low score, is characterized by an inhibition in all dimensions, whereas group 2 (n = 22) is characterized by an overactivation. The emotional reactivity is the most relevant dimension for discriminating these two types of depression (group 1: hyporeactivity; group 2: hyperreactivity), whereas sadness is not. Bipolar depressive states are not homogeneous. A dimensional approach based on emotional reactivity could be useful for discriminating the different forms of bipolar depression. Bipolar depressions may be classified as hyporeactive or hyperreactive. This classification might have therapeutic implications, because hyperreactive depression should belong to the broad spectrum of mixed states.


Recurrence in the high-order nonlinear Schrödinger equation: A low-dimensional analysis.
We study a three-wave truncation of the high-order nonlinear Schrödinger equation for deep-water waves (also named Dysthe equation). We validate the model by comparing it to numerical simulation; we distinguish the impact of the different fourth-order terms and classify the solutions according to their topology. This allows us to properly define the temporary spectral upshift occurring in the nonlinear stage of Benjamin-Feir instability and provides a tool for studying further generalizations of this model.


Treatment After First-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance in Non-Small-Cell Lung Cancer.
Systemic treatment is the basic treatment approach to advanced-stage non-small-cell lung cancer (NSCLC), and chemotherapy and targeted treatments are commonly employed in these patients. Recently, positive results achieved with immunotherapy have led to a growing number of treatment options and prolonged survival time. Today, specific tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib, and afatinib, which target the epidermal growth factor receptor (EGFR), and the TKI crizotinib, which targets anaplastic lymphoma kinase gene rearrangement, have become the standard treatment among targeted therapies for patients with sensitive molecular anomalies. However, resistance develops against all these agents after a while. Numerous genetic mutations, T790M+ in particular, have been identified as resistance mechanisms against EGFR-TKIs, and researchers are developing specific inhibitors against them. Among those inhibitors, third-generation EGFR-TKIs such as osimertinib and rociletinib have gained prominence due to their high level of effectiveness and low toxicity profile. Besides, systemic chemotherapy and immunotherapy are proper alternatives. A second biopsy during the progression stage and better clarification of the mechanisms causing secondary resistance will enable more successful treatments in the future.


Update on the Risk of Introduction of African Swine Fever by Wild Boar into Disease-Free European Union Countries.
Despite efforts to prevent the appearance and spread of African swine fever (ASF) in the European Union, several Member States are now affected (Lithuania, Poland, Latvia and Estonia). Disease appearance in 2014 was associated with multiple entrances linked to wild boar movement from endemic areas (EFSA Journal, 8, 2015, 1556), but the risk of new introductions remains high (Gallardo et al., Porcine Health Management, 1, and 21) as ASF continues to be active in endemic countries (Russian Federation, Belarus and Ukraine). Since 2014, the number of ASF notifications has increased substantially, particularly in wild boar (WB), in parallel with slow but constant geographical advance of the disease. This situation suggests a real risk of further disease spread into other Member States, posing a great threat to pig production in the EU. Following the principles of the risk-based veterinary surveillance, this article applies a methodology developed by De la Torre et al. (Transboundary and Emerging Diseases, 62, and 272) to assess the relative risk of new introductions of ASF by natural movements of WB according to the current epidemiological situation. This update incorporates the most recent available data and an improved version of the most important risk estimator: an optimized cartographic tool of WB distribution to analyse wild boar suitable habitat. The highest relative risk values were estimated for Slovakia (5) and Romania (5), followed by Finland (4), Czech Republic (3) and Germany (3). Relative risk for Romania and Finland is associated mainly with disease entrance from endemic areas such as the Russian Federation and Ukraine, where the disease is currently spreading; relative risk for Germany and Czech Republic is associated mainly with the potential progress of the disease through the EU, and relative risk for Slovakia is associated with both pathways. WB habitat is the most important risk estimator, whereas WB density is the least significant, suggesting that WB presence is more relevant than density. These results can provide actionable advice for dealing with risk. They can be directly used to inform risk-based national strategies and identify countries that may need to pay greater attention to surveillance or conduct additional evaluations at the subnational level.


Decitabine induces delayed reactive oxygen species (ROS) accumulation in leukemia cells and induces the expression of ROS generating enzymes.
Azanucleoside DNA methyltransferase (DNMT) inhibitors are currently approved by the U.S. Food and Drug Administration for treatment of myelodysplastic syndrome. The relative contributions of DNMT inhibition and other off-target effects to their clinical efficacy remain unclear. Data correlating DNA methylation reversal and clinical response have been conflicting. Consequently, it is necessary to investigate so-called off-target effects and their impact on cell survival and differentiation. Flow cytometry was used for cell cycle, apoptosis, and reactive oxygen species (ROS) accumulation analysis. Gene expression analysis was performed using real-time PCR. DNA methylation was detected by methylation-specific PCR. Mitochondrial membrane potential was analyzed using JC-1 dye staining. Western blotting was used for quantitative protein expression analysis. 5-Aza-2'-deoxycytidine (DAC) induced cell-cycle arrest and apoptosis in leukemia cells. p53 expression was dispensable for DAC-induced apoptosis. DAC induced delayed ROS accumulation in leukemia cells but not in solid tumor cells and p53 expression was dispensable for ROS increase. ROS increase was deoxycytidine kinase dependent, indicating that incorporation of DAC into nuclear DNA is required for ROS generation. ROS accumulation by DAC was caspase-independent and mediated the dissipation of the mitochondrial membrane potential. Concordantly, ROS scavengers diminished DAC-induced apoptosis. DAC induced the expression of different NADPH oxidase isoforms and upregulated Nox4 protein expression in an ATM-dependent manner, indicating the involvement of DNA damage signaling in Nox4 upregulation. These data highlight the importance of mechanisms other than DNA cytosine demethylation in modulating gene expression and suggest investigating the relevance of ROS accumulation to the clinical activity of DAC.


Temporal constraints on visual learning: a computational model.
Given a constant stream of perceptual stimuli, how can the underlying invariances associated with a given input be learned? One approach consists of using generic truths about the spatiotemporal structure of the physical world as constraints on the types of quantities learned. The learning methodology employed here embodies one such truth: that perceptually salient properties (such as stereo disparity) tend to vary smoothly over time. Unfortunately, the units of an artificial neural network tend to encode superficial image properties, such as individual grey-level pixel values, which vary rapidly over time. However, if the states of units are constrained to vary slowly, then the network is forced to learn a smoothly varying function of the training data. We implemented this temporal-smoothness constraint in a backpropagation network which learned stereo disparity from random-dot stereograms. Temporal smoothness was formalized with the use of regularization theory by modifying the standard cost function minimised during training of a network. Temporal smoothness was found to be similar to other techniques for improving generalisation, such as early stopping and weight decay. However, in contrast to these, the theoretical underpinnings of temporal smoothing are intimately related to fundamental characteristics of the physical world. Results are discussed in terms of regularization theory and the physically realistic assumptions upon which temporal smoothing is based.