Early experience of COVID-19 vaccination in adults with systemic rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance Vaccine Survey.
We describe the early experiences of adults with systemic rheumatic disease who received the COVID-19 vaccine. From 2 April to 30 April 2021, we conducted an online, international survey of adults with systemic rheumatic disease who received COVID-19 vaccination. We collected patient-reported data on clinician communication, beliefs and intent about discontinuing disease-modifying antirheumatic drugs (DMARDs) around the time of vaccination, and patient-reported adverse events after vaccination. We analysed 2860 adults with systemic rheumatic diseases who received COVID-19 vaccination (mean age 55.3 years, 86.7% female, 86.3% white). Types of COVID-19 vaccines were Pfizer-BioNTech (53.2%), Oxford/AstraZeneca (22.6%), Moderna (21.3%), Janssen/Johnson & Johnson (1.7%) and others (1.2%). The most common rheumatic disease was rheumatoid arthritis (42.3%), and 81.2% of respondents were on a DMARD. The majority (81.9%) reported communicating with clinicians about vaccination. Most (66.9%) were willing to temporarily discontinue DMARDs to improve vaccine efficacy, although many (44.3%) were concerned about rheumatic disease flares. After vaccination, the most reported patient-reported adverse events were fatigue/somnolence (33.4%), headache (27.7%), muscle/joint pains (22.8%) and fever/chills (19.9%). Rheumatic disease flares that required medication changes occurred in 4.6%. Among adults with systemic rheumatic disease who received COVID-19 vaccination, patient-reported adverse events were typical of those reported in the general population. Most patients were willing to temporarily discontinue DMARDs to improve vaccine efficacy. The relatively low frequency of rheumatic disease flare requiring medications was reassuring.


Monitoring the Health Status of Mice with Bleomycin-induced Lung Injury by Using Body Condition Scoring.
Well-defined, humane endpoints aid in monitoring animal health status during disease development. Body condition scoring (BCS) is a method for assessing health status in mouse studies where wasting and death are potential endpoints. Whether BCS is useful in monitoring animals with bleomycin-induced lung injury has not been reported. Body weight (BW) is a common humane endpoint for this model, but because the lungs increase in weight as BW decreases, the animal's true physical condition could be masked when using BW as the sole endpoint criterion. Therefore, our goal here was to assess the usefulness of BCS in monitoring health status in a mouse model of lung injury. Lung injury was caused by acute instil- lation of the fibrogenic antibiotic bleomycin into the lungs through the trachea. Male C57BL/6 mice received bleomycin (0.075 U) dissolved in saline or saline alone. Bleomycin instillation led to a doubling of lung weight and decreases in both BW and BCS, compared with saline instillation. The changes in BW and BCS were significantly correlated with lung weight. When the adjusted BW was used (corrected for the increase in lung weight), the correlation was unchanged, suggesting that the increase in lung weight did not significantly mask the decrease in BW. Bleomycin instillation caused decreases in both soleus and visceral epididymal fat masses. The change in BCS was significantly correlated with both soleus and VEF mass, suggesting that BCS is reflective of the systemic loss of muscle and fat mass. Our findings suggest that BW and BCS are significantly correlated to lung injury in the bleomycin model of lung fibrosis and that BCS is an appropriate alternative humane endpoint in this mouse model.


Mammary gland specific expression of Brk/PTK6 promotes delayed involution and tumor formation associated with activation of p38 MAPK.
Protein tyrosine kinases (PTKs) are frequently overexpressed and/or activated in human malignancies, and regulate cancer cell proliferation, cellular survival, and migration. As such, they have become promising molecular targets for new therapies. The non-receptor PTK termed breast tumor kinase (Brk/PTK6) is overexpressed in approximately 86% of human breast tumors. The role of Brk in breast pathology is unclear. We expressed a WAP-driven Brk/PTK6 transgene in FVB/n mice, and analyzed mammary glands from wild-type (wt) and transgenic mice after forced weaning. Western blotting and immunohistochemistry (IHC) studies were conducted to visualize markers of mammary gland involution, cell proliferation and apoptosis, as well as Brk, STAT3, and activated p38 mitogen-activated protein kinase (MAPK) in mammary tissues and tumors from WAP-Brk mice. Human (HMEC) or mouse (HC11) mammary epithelial cells were stably or transiently transfected with Brk cDNA to assay p38 MAPK signaling and cell survival in suspension or in response to chemotherapeutic agents. Brk-transgenic dams exhibited delayed mammary gland involution and aged mice developed infrequent tumors with reduced latency relative to wt mice. Consistent with delayed involution, mammary glands of transgenic animals displayed decreased STAT3 phosphorylation, a marker of early-stage involution. Notably, p38 MAPK, a pro-survival signaling mediator downstream of Brk, was activated in mammary glands of Brk transgenic relative to wt mice. Brk-dependent signaling to p38 MAPK was recapitulated by Brk overexpression in the HC11 murine mammary epithelial cell (MEC) line and human MEC, while Brk knock-down in breast cancer cells blocked EGF-stimulated p38 signaling. Additionally, human or mouse MECs expressing Brk exhibited increased anchorage-independent survival and resistance to doxorubicin. Finally, breast tumor biopsies were subjected to IHC analysis for co-expression of Brk and phospho-p38 MAPK; ductal and lobular carcinomas expressing Brk were significantly more likely to express elevated phospho-p38 MAPK. These studies illustrate that forced expression of Brk/PTK6 in non-transformed mammary epithelial cells mediates p38 MAPK phosphorylation and promotes increased cellular survival, delayed involution, and latent tumor formation. Brk expression in human breast tumors may contribute to progression by inducing p38-driven pro-survival signaling pathways.


Localization of the major heparin-binding site in fibronectin.
We have identified the major site required for the interaction of fibronectin (FN) with heparin. Affinity chromatography was used to test the binding ability of a library of truncated, monomeric forms of fibronectin (deminectins) containing deletions or two point mutations in the heparin-binding domain. This domain consists of type III repeats 12, 13, and 14. Deletions of individual repeats showed that both III13 and III14 are required for complete binding. Small deletions within these repeats localized a major site of heparin interaction to the amino-terminal half of III13. Site-directed mutagenesis of adjacent arginines within this sequence to uncharged residues reduced heparin binding by 98%, identifying these positively charged amino acids as essential for the interaction. A significant role for the flanking alternatively spliced regions and for repeat III12 was not found. We conclude that, while both repeats III13 and III14 participate in heparin binding, there is a major site of interaction in repeat III13 that accounts for nearly all of the activity. The significance of multiple heparin-binding sites within this domain is discussed and a model is proposed to account for how these sites may function in vivo.


Finite state projection based bounds to compare chemical master equation models using single-cell data.
Emerging techniques now allow for precise quantification of distributions of biological molecules in single cells. These rapidly advancing experimental methods have created a need for more rigorous and efficient modeling tools. Here, we derive new bounds on the likelihood that observations of single-cell, single-molecule responses come from a discrete stochastic model, posed in the form of the chemical master equation. These strict upper and lower bounds are based on a finite state projection approach, and they converge monotonically to the exact likelihood value. These bounds allow one to discriminate rigorously between models and with a minimum level of computational effort. In practice, these bounds can be incorporated into stochastic model identification and parameter inference routines, which improve the accuracy and efficiency of endeavors to analyze and predict single-cell behavior. We demonstrate the applicability of our approach using simulated data for three example models as well as for experimental measurements of a time-varying stochastic transcriptional response in yeast.


Genome wide analysis of fertility and production traits in Italian Holstein cattle.
A genome wide scan was performed on a total of 2093 Italian Holstein proven bulls genotyped with 50K single nucleotide polymorphisms (SNPs), with the objective of identifying loci associated with fertility related traits and to test their effects on milk production traits. The analysis was carried out using estimated breeding values for the aggregate fertility index and for each trait contributing to the index: angularity, calving interval, non-return rate at 56 days, days to first service, and 305 day first parity lactation. In addition, two production traits not included in the aggregate fertility index were analysed: fat yield and protein yield. Analyses were carried out using all SNPs treated separately, further the most significant marker on BTA14 associated to milk quality located in the DGAT1 region was treated as fixed effect. Genome wide association analysis identified 61 significant SNPs and 75 significant marker-trait associations. Eight additional SNP associations were detected when SNP located near DGAT1 was included as a fixed effect. As there were no obvious common SNPs between the traits analyzed independently in this study, a network analysis was carried out to identify unforeseen relationships that may link production and fertility traits.


Enhancement of bend sensor properties as applied in a glove for use in neurorehabilitation settings.
Following hand function impairment caused by a neurological disorder, the functional level of the upper extremities has to be assessed in the clinical and rehabilitation settings. Current hand function evaluation tests are somewhat imprecise. Instrumented gloves allow finger motion monitoring during the performance of skilled tasks, such as grasping objects. As a result, they provide an objective tool for evaluating slight changes in the fine motor skills of the hand. Numerous gloves are based on resistive bend sensors, given that this is an easy to handle, low-cost, and reliable sensing element. When bending is not applied homogeneously along such a sensor, as is the case with finger-joint bending, its output response varies with the sensor's longitudinal position. Our goal is to determine the optimal sensor position with respect to the finger-joint in order to enhance the resolution of the sensors embedded in a glove. The validity of the integrated sensors is evaluated and the accuracy values are given.


Postoperative surveillance of small appendiceal carcinoid tumors.
The necessity and frequency of postoperative surveillance for appendiceal carcinoid tumors ≤1 cm are undetermined. A retrospective review was conducted of all patients with appendiceal carcinoid tumors ≤1 cm managed at an academic, tertiary referral center. Clinicopathologic characteristics, treatment, surveillance, recurrence, and survival were assessed and analyzed. Over a 16-year period, 31 patients met the inclusion criteria. Appendicitis (n = 17) and pelvic mass (n = 5) were the most common presentations. Median tumor diameter was 5 mm (range, 1-10 mm). Two patients had mesoappendiceal involvement. No patients had regional lymph node involvement or distant metastasis. Postoperatively, 14 patients (45%) received follow-up recommendations, including ≥1 of the following: imaging (n = 9), medical oncology referral (n = 7), colonoscopy (n = 5), and laboratory studies (n = 5). There were no recurrences or disease-specific deaths during a median follow-up period of 5 years (range, 0-15 years). Appendiceal carcinoids ≤1 cm are unlikely to recur. Therefore, postoperative surveillance may be unnecessary.


EAACI position statement on asthma exacerbations and severe asthma.
Asthma exacerbations and severe asthma are linked with high morbidity, significant mortality and high treatment costs. Recurrent asthma exacerbations cause a decline in lung function and, in childhood, are linked to development of persistent asthma. This position paper, from the European Academy of Allergy and Clinical Immunology, highlights the shortcomings of current treatment guidelines for patients suffering from frequent asthma exacerbations and those with difficult-to-treat asthma and severe treatment-resistant asthma. It reviews current evidence that supports a call for increased awareness of (i) the seriousness of asthma exacerbations and (ii) the need for novel treatment strategies in specific forms of severe treatment-resistant asthma. There is strong evidence linking asthma exacerbations with viral airway infection and underlying deficiencies in innate immunity and evidence of a synergism between viral infection and allergic mechanisms in increasing risk of exacerbations. Nonadherence to prescribed medication has been identified as a common clinical problem amongst adults and children with difficult-to-control asthma. Appropriate diagnosis, assessment of adherence and other potentially modifiable factors (such as passive or active smoking, ongoing allergen exposure, psychosocial factors) have to be a priority in clinical assessment of all patients with difficult-to-control asthma. Further studies with improved designs and new diagnostic tools are needed to properly characterize (i) the pathophysiology and risk of asthma exacerbations, and (ii) the clinical and pathophysiological heterogeneity of severe asthma.


Measurement of the production and lepton charge asymmetry of [Formula: see text] bosons in Pb+Pb collisions at [Formula: see text] with the ATLAS detector.
A measurement of [Formula: see text] boson production in lead-lead collisions at [Formula: see text] is presented. It is based on the analysis of data collected with the ATLAS detector at the LHC in 2011 corresponding to an integrated luminosity of 0.14 [Formula: see text] and 0.15 [Formula: see text] in the muon and electron decay channels, respectively. The differential production yields and lepton charge asymmetry are each measured as a function of the average number of participating nucleons [Formula: see text] and absolute pseudorapidity of the charged lepton. The results are compared to predictions based on next-to-leading-order QCD calculations. These measurements are, in principle, sensitive to possible nuclear modifications to the parton distribution functions and also provide information on scaling of [Formula: see text] boson production in multi-nucleon systems.


A construct with fluorescent indicators for conditional expression of miRNA.
Transgenic RNAi holds promise as a simple, low-cost, and fast method for reverse genetics in mammals. It may be particularly useful for producing animal models for hypomorphic gene function. Inducible RNAi that permits spatially and temporally controllable gene silencing in vivo will enhance the power of transgenic RNAi approach. Furthermore, because microRNA (miRNA) targeting specific genes can be expressed simultaneously with protein coding genes, incorporation of fluorescent marker proteins can simplify the screening and analysis of transgenic RNAi animals. We sought to optimally express a miRNA simultaneously with a fluorescent marker. We compared two construct designs. One expressed a red fluorescent protein (RFP) and a miRNA placed in its 3' untranslated region (UTR). The other expressed the same RFP and miRNA, but the precursor miRNA (pre-miRNA) coding sequence was placed in an intron that was inserted into the 3'-UTR. We found that the two constructs expressed comparable levels of miRNA. However, the intron-containing construct expressed a significantly higher level of RFP than the intron-less construct. Further experiments indicate that the 3'-UTR intron enhances RFP expression by its intrinsic gene-expression-enhancing activity and by eliminating the inhibitory effect of the pre-miRNA on the expression of RFP. Based on these findings, we incorporated the intron-embedded pre-miRNA design into a conditional expression construct that employed the Cre-loxP system. This construct initially expressed EGFP gene, which was flanked by loxP sites. After exposure to Cre recombinase, the transgene stopped EGFP expression and began expression of RFP and a miRNA, which silenced the expression of specific cellular genes. We have designed and tested a conditional miRNA-expression construct and showed that this construct expresses both the marker genes strongly and can silence the target gene efficiently upon Cre-mediated induction of the miRNA expression. This construct can be used to increase the efficiency of making cell lines or transgenic animals that stably express miRNA targeting specific genes.


Determination of homocysteine in human saliva by liquid chromatography and electrospray ionization quadrupole time-of-flight mass spectrometry: profiles in healthy adults.
Homocysteine (Hcys) is a non-essential amino acid associated with a range of diseased and abnormal metabolic conditions. Hcys concentration in saliva is routinely determined by enzyme assays, which are broadly specific, but can be expensive and suffer from cross-reactivity. Total Hcys (tHcys) concentrations in eight healthy adults were determined to establish the inter-day variation during resting, normal and intensive physical activity, using the more sensitive analytical techniques of liquid chromatography and tandem mass spectrometry without prior derivatization. Saliva (~ 1.5 mL) was collected over four days; early morning (EA), normal activity (NA) and during physical activity (PA). Samples were processed by disulphide reduction, acetonitrile precipitation and then centrifugation-filtration. Extracts were chromatographically resolved and analysed on a quadrupole time- of-flight (QToF) mass spectrometer. The protonated [M+H]+, m/z 136.101 and product ([M+H]+- HCOOH) m/z 90.103 ions were then monitored against an internal standard (13CHcys) and external set of calibration standards. Mean tHcys concentration for the whole group, including exercise was 6.6 ± 8.0 (range 0.2 - 29.6 nmol/mL). Overall, concentration of tHcys was greater in males than the females but not significantly (p > 0.05). The mean EA concentration was significantly (p < 0.05) greater than NA for both males (p = 0340) and females (p = 0.0045). There were large within-subject variations (coefficient of variation; CV%; 24% to 103%). The limits of detection (LOD) and quantification (LOQ) were 0.07 and 0.22 nmol/mL, respectively. The procedure potentially provides a convenient means of analyzing salivary Hcys as a diagnostic disease marker.


Is there a role for prostanoid-mediated inhibition of IL-6 trans-signalling in the management of pulmonary arterial hypertension?
Inflammation has been highlighted as a key factor in pulmonary arterial hypertension (PAH) development, particularly interleukin-6 (IL-6). IL-6 activates JAK-STAT signalling to induce transcription of pro-inflammatory and pro-angiogenic genes, enabling PAH progression, as well as the transcription of suppressor of cytokine signalling 3 (SOCS3) which limits IL-6 signalling. Current PAH therapies include prostanoid drugs which induce vasodilation via stimulating intracellular 3',5'-cyclic adenosine monophosphate (cAMP) levels. cAMP can also inhibit IL-6-mediated endothelial dysfunction via the induction of SOCS3. Thus, we propose that an important mechanism by which cAMP-mobilising prostanoid drugs limit PAH is by inhibiting IL-6-mediated pulmonary inflammation and remodelling via SOCS3 inhibition of IL-6 signalling. Further clarification may result in effective strategies with which to target the IL-6/JAK-STAT signalling pathway in PAH.


A manyfold increase in sister chromatid exchanges in Bloom's syndrome lymphocytes.
Dividing cells from persons with Bloom's syndrome, an autosomal recessive disorder of growth, exhibit increased numbers of chromatid breaks and rearrangements. A highly characteristic feature of the chromosome instability in this syndrome is the tendency for exchanges to occur between chromatids of homologous chromosomes at homologous sites. In the present experiments, a cytogenetic technique by which the sister chromatids of a metaphase chromosome are stained differentially has been used to demonstrate a striking and possibly specific, but hitherto unrecognized, increase in the frequency with which sister chromatids also exchange segments. The cells were grown in bromodeoxyuridine and stained with 33258 Hoechst and Giemsa. Whereas phytohemagglutinin-stimulated lymphocytes from normal controls had a mean of 6.9 sister chromatid exchanges per metaphase (range 1-14), those from persons with Bloom's syndrome had a mean of 89.0 (range 45-162). Normal frequencies of sister chromatid exchanges were found in cells heterozygous for the Bloom's syndrome gene, and also in cells either homozygous or heterozygous for the genes of the Louis-Bar (ataxia telangiectasia) syndrome and Fanconi's anemia, two other rare disorders characterized by chromosome instability. In a differentially stained chromatid interchange configuration discovered during the study, it was possible to determine the new distribution of both sister and non-sister-but-homologous chromatids that had resulted from numerous exchanges. By following shifts in the pattern of staining from chromatid to chromatid, visual evidence was obtained that the quadriradial configurations long recognized as characteristic of Bloom's syndrome represent exchanges between homologous chromosomes, apparently at homologous points. We postulate that the increase in the frequency of exchanges between nonsister-but-homologous chromatids and those between sister chromatids in Bloom's syndrome represents aspects of one and the same disturbance. A study of this phenomenon in relation to the clinical features of Bloom's syndrome may be helpful eventually in understanding the biological significance of chromatid exchange in somatic cells.


Development and evaluation of a youth mental health community awareness campaign - The Compass Strategy.
Early detection and treatment of mental disorders in adolescents and young adults can lead to better health outcomes. Mental health literacy is a key to early recognition and help seeking. Whilst a number of population health initiatives have attempted to improve mental health literacy, none to date have specifically targeted young people nor have they applied the rigorous standards of population health models now accepted as best practice in other health areas. This paper describes the outcomes from the application of a health promotion model to the development, implementation and evaluation of a community awareness campaign designed to improve mental health literacy and early help seeking amongst young people. The Compass Strategy was implemented in the western metropolitan Melbourne and Barwon regions of Victoria, Australia. The Precede-Proceed Model guided the population assessment, campaign strategy development and evaluation. The campaign included the use of multimedia, a website, and an information telephone service. Multiple levels of evaluation were conducted. This included a cross-sectional telephone survey of mental health literacy undertaken before and after 14 months of the campaign using a quasi-experimental design. Randomly selected independent samples of 600 young people aged 12-25 years from the experimental region and another 600 from a comparison region were interviewed at each time point. A series of binary logistic regression analyses were used to measure the association between a range of campaign outcome variables and the predictor variables of region and time. The program was judged to have an impact on the following variables, as indicated by significant region-by-time interaction effects (p < 0.05): awareness of mental health campaigns, self-identified depression, help for depression sought in the previous year, correct estimate of prevalence of mental health problems, increased awareness of suicide risk, and a reduction in perceived barriers to help seeking. These effects may be underestimated because media distribution error resulted in a small amount of print material "leaking" into the comparison region. We believe this is the first study to apply the rigorous standards of a health promotion model including the use of a control region to a mental health population intervention. The program achieved many of its aims despite the relatively short duration and moderate intensity of the campaign.


Molecular mechanisms underlying WOX1 activation during apoptotic and stress responses.
Human WWOX gene encodes a putative tumor suppressor WW domain-containing oxidoreductase WOX1 (also known as WWOX or FOR). A high frequency of loss of heterozygosity (LOH) of this gene has been shown in prostate, lung, breast and other cancers. In addition, numerous aberrant WWOX mRNA transcripts have been found in cancer cells. WOX1 is a proapoptotic protein. In response to stress or apoptotic stimuli, WOX1 became phosphorylated at Tyr33, which enabled its complex formation with activated p53 and JNK1. The p53/WOX1 complex translocated to the mitochondria and further to the nuclei to mediate apoptosis. WOX1 mutants, which were inactivated for nuclear translocation or Tyr33 phosphorylation, failed to induce apoptosis, indicating that activation of WOX1 via Tyr33 phosphorylation, followed by nuclear translocation, is essential for inducing cell death. WOX1 induced apoptosis synergistically with p53. In contrast, transiently activated JNK1 induced anti-apoptotic response, and this protective activity inhibited WOX1-induced apoptosis. Taken together, WOX1 is involved in stress and apoptotic responses, and is likely to regulate the activation of both p53 and JNK1.


Loss of GPR3 reduces the amyloid plaque burden and improves memory in Alzheimer's disease mouse models.
The orphan G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR) GPR3 regulates activity of the γ-secretase complex in the absence of an effect on Notch proteolysis, providing a potential therapeutic target for Alzheimer's disease (AD). However, given the vast resources required to develop and evaluate any new therapy for AD and the multiple failures involved in translational research, demonstration of the pathophysiological relevance of research findings in multiple disease-relevant models is necessary before initiating costly drug development programs. We evaluated the physiological consequences of loss of Gpr3 in four AD transgenic mouse models, including two that contain the humanized murine Aβ sequence and express similar amyloid precursor protein (APP) levels as wild-type mice, thereby reducing potential artificial phenotypes. Our findings reveal that genetic deletion of Gpr3 reduced amyloid pathology in all of the AD mouse models and alleviated cognitive deficits in APP/PS1 mice. Additional three-dimensional visualization and analysis of the amyloid plaque burden provided accurate information on the amyloid load, distribution, and volume in the structurally intact adult mouse brain. Analysis of 10 different regions in healthy human postmortem brain tissue indicated that GPR3 expression was stable during aging. However, two cohorts of human AD postmortem brain tissue samples showed a correlation between elevated GPR3 and AD progression. Collectively, these studies provide evidence that GPR3 mediates the amyloidogenic proteolysis of APP in four AD transgenic mouse models as well as the physiological processing of APP in wild-type mice, suggesting that GPR3 may be a potential therapeutic target for AD drug development.


Early activation of quorum sensing in Pseudomonas aeruginosa reveals the architecture of a complex regulon.
Quorum-sensing regulation of gene expression in Pseudomonas aeruginosa is complex. Two interconnected acyl-homoserine lactone (acyl-HSL) signal-receptor pairs, 3-oxo-dodecanoyl-HSL-LasR and butanoyl-HSL-RhlR, regulate more than 300 genes. The induction of most of the genes is delayed during growth of P. aeruginosa in complex medium, cannot be advanced by addition of exogenous signal, and requires additional regulatory components. Many of these late genes can be induced by addition of signals early by using specific media conditions. While several factors super-regulate the quorum receptors, others may co-regulate target promoters or may affect expression posttranscriptionally. To better understand the contributions of super-regulation and co-regulation to quorum-sensing gene expression, and to better understand the general structure of the quorum sensing network, we ectopically expressed the two receptors (in the presence of their cognate signals) and another component that affects quorum sensing, the stationary phase sigma factor RpoS, early in growth. We determined the effect on target gene expression by microarray and real-time PCR analysis. Our results show that many target genes (e.g. lasB and hcnABC) are directly responsive to receptor protein levels. Most genes (e.g. lasA, lecA, and phnAB), however, are not significantly affected, although at least some of these genes are directly regulated by quorum sensing. The majority of promoters advanced by RhlR appeared to be regulated directly, which allowed us to build a RhlR consensus sequence. The direct responsiveness of many quorum sensing target genes to receptor protein levels early in growth confirms the role of super-regulation in quorum sensing gene expression. The observation that the induction of most target genes is not affected by signal or receptor protein levels indicates that either target promoters are co-regulated by other transcription factors, or that expression is controlled posttranscriptionally. This architecture permits the integration of multiple signaling pathways resulting in quorum responses that require a "quorum" but are otherwise highly adaptable and receptive to environmental conditions.


CD6+ T cell depleted allogeneic bone marrow transplantation from genotypically HLA nonidentical related donors.
The widespread use of allogeneic bone marrow transplantation (BMT) is limited by the availability of suitable donors. Recent attempts to expand the donor pool by employing HLA matched unrelated marrow have been partially successful. However, severe graft-versus-host disease (GVHD) and graft failure remain obstacles and contribute to the substantial morbidity and mortality associated with matched unrelated BMT. The use of genotypically nonidentical related or unrelated donor marrow could have wider application if problems associated with GVHD could be overcome. Based upon the low incidence of GVHD in recipients of HLA-matched related donor marrow depleted of T cells with T12, an anti-CD6 monoclonal antibody, we applied this approach to 27 adult recipients of HLA mismatched related bone marrow. Ten patients received marrow mismatched at 2 HLA loci, 13 received 1 antigen mismatched marrow, and 4 received phenotypically identical marrow from a non-sibling. Immediately prior to admission, patients were treated with total lymphoid irradiation (750-1050 cGy) to suppress host derived. T lymphocytes capable of mediating graft rejection. The ablative regimen consisted of cyclophosphamide (60 mg/kg x 2 days) followed by total body irradiation (1400 cGy in 7 fractions over 4 days). Patients then received marrow depleted of T cells with T12 (CD6) plus complement. No immune suppressive medications were administered to prevent GVHD. Twenty-four of 27 patients displayed stable hematologic engraftment, achieving an absolute neutrophil count of 0.5 x 10(9)/L at a median of 19 days post-BMT. Degree of HLA disparity did not influence engraftment. Among engrafting patients, grades 2-4 acute GVHD occurred in 40% and grade 3-4 GVHD in 8%. Chronic GVHD developed in 5 patients. Patients mismatched at 2 loci were more likely to develop GVHD than those mismatched at 0-1 loci (logrank, p = .04). Disease relapse has occurred in only 3 patients receiving mismatched marrow. Estimated overall survival for mismatched patients is 56% at 2 years and is independent of HLA disparity. Among the patients transplanted for chronic myelogenous in stable phase or acute leukemia in first remission, estimated event free survival is 69% at 2 years compared to 20% for patients with more advanced disease. Our results suggest that transplantation of mismatched related marrow using modalities designed to reduce GVHD without immune suppressive medication (CD6 depletion) is feasible and should prompt wider investigation into the extended families of patients in the search for potential marrow donors. This approach also merits investigation in recipients of matched unrelated marrow as a potential means of reducing transplant-related toxicity.


Improved Multiscale Entropy Technique with Nearest-Neighbor Moving-Average Kernel for Nonlinear and Nonstationary Short-Time Biomedical Signal Analysis.
Analysis of biomedical signals can yield invaluable information for prognosis, diagnosis, therapy evaluation, risk assessment, and disease prevention which is often recorded as short time series data that challenges existing complexity classification algorithms such as Shannon entropy (SE) and other techniques. The purpose of this study was to improve previously developed multiscale entropy (MSE) technique by incorporating nearest-neighbor moving-average kernel, which can be used for analysis of nonlinear and non-stationary short time series physiological data. The approach was tested for robustness with respect to noise analysis using simulated sinusoidal and ECG waveforms. Feasibility of MSE to discriminate between normal sinus rhythm (NSR) and atrial fibrillation (AF) was tested on a single-lead ECG. In addition, the MSE algorithm was applied to identify pivot points of rotors that were induced in ex vivo isolated rabbit hearts. The improved MSE technique robustly estimated the complexity of the signal compared to that of SE with various noises, discriminated NSR and AF on single-lead ECG, and precisely identified the pivot points of ex vivo rotors by providing better contrast between the rotor core and the peripheral region. The improved MSE technique can provide efficient complexity analysis of variety of nonlinear and nonstationary short-time biomedical signals.


Angiotensin-converting enzyme inhibiting ability of ethanol extracts, steviol glycosides and protein hydrolysates from stevia leaves.
Efficient treatment of hypertension is vital. The inhibition of angiotensin-converting enzyme activity has been one of the major strategies for treating hypertension. The ethanol extract of stevia leaves, steviol glycosides (with 95% purity; natural sweeteners widely used in the food industry) isolated from the ethanol extract and stevia leaf protein hydrolysates inhibited 26.60%, 59.56% and 74.38% of angiotensin-converting enzyme activities, respectively. Their effect was dose-dependent, which can be beneficial for avoiding hypertension or hypotension just by the proper control of the amount of their intake, and it was found to be superior to that of pharmaceutical drugs. A sensory test indicated that the application of the mixtures of steviol glycosides and stevia protein hydrolysates to decaffeinated coffee or tea as well as a formulated peanut protein drink was found to be well accepted, and an animal test showed that they had a significantly antihypertensive effect in spontaneously hypertensive rats. Steviol glycosides and stevia leaf protein hydrolysates can be good ingredients for making functional or healthy food products or beverages targeted for the prevention or treatment of hypertension.


Hand blink reflex in virtual reality: The role of vision and proprioception in modulating defensive responses.
Our research focused on the role of vision and proprioception in modulating a defensive reflex (hand blink reflex, HBR) whose magnitude is enhanced when the threatened hand is inside the peripersonal space of the face. We capitalized on virtual reality, which allows dissociating vision and proprioception by presenting a virtual limb in congruent/incongruent positions with respect to the participants' limb. In experiment 1, participants placed their own stimulated hand in far/near positions with respect to their face (postural manipulation task), while observing a virtual empty scenario. Vision was not informative, but the HBR was significantly enhanced in near compared with far position, suggesting that proprioception is sufficient for the HBR modulation to occur. In experiment 2, participants did not perform the postural manipulation but they (passively) observed the avatar's virtual limb performing it. Proprioceptive signals were not informative, but the HBR was significantly enhanced when the observed virtual limb was near to the face, suggesting that visual information plays a role in modulating the HBR. In experiment 3, both participants and avatar performed the postural manipulation, either congruently (both of them far/near) or incongruently (one of them far, the other near). The HBR modulation was present only in congruent conditions. In incongruent conditions, the conflict between vision and proprioception confounded the system, abolishing the difference between far and near positions. Taken together, these findings promote the view that observing a virtual limb modulates the HBR, providing also new evidence on the role of vision and proprioception in modulating this subcortical reflex.


Computational analysis of p63(+) nuclei distribution pattern by graph theoretic approach in an oral pre-cancer (sub-mucous fibrosis).
Oral submucous fibrosis (OSF) is a pre-cancerous condition with features of chronic, inflammatory and progressive sub-epithelial fibrotic disorder of the buccal mucosa. In this study, malignant potentiality of OSF has been assessed by quantification of immunohistochemical expression of epithelial prime regulator-p63 molecule in correlation to its malignant (oral squamous cell carcinoma [OSCC] and normal counterpart [normal oral mucosa [NOM]). Attributes of spatial extent and distribution of p63(+) expression in the epithelium have been investigated. Further, a correlated assessment of histopathological attributes inferred from H&E staining and their mathematical counterparts (molecular pathology of p63) have been proposed. The suggested analytical framework envisaged standardization of the immunohistochemistry evaluation procedure for the molecular marker, using computer-aided image analysis, toward enhancing its prognostic value. In histopathologically confirmed OSF, OSCC and NOM tissue sections, p63(+) nuclei were localized and segmented by identifying regional maxima in plateau-like intensity spatial profiles of nuclei. The clustered nuclei were localized and segmented by identifying concave points in the morphometry and by marker-controlled watersheds. Voronoi tessellations were constructed around nuclei centroids and mean values of spatial-relation metrics such as tessellation area, tessellation perimeter, roundness factor and disorder of the area were extracted. Morphology and extent of expression are characterized by area, diameter, perimeter, compactness, eccentricity and density, fraction of p63(+) expression and expression distance of p63(+) nuclei. Correlative framework between histopathological features characterizing malignant potentiality and their quantitative p63 counterparts was developed. Statistical analyses of mathematical trends were evaluated between different biologically relevant combinations: (i) NOM to oral submucous fibrosis without dysplasia (OSFWT) (ii) NOM to oral submucous fibrosis with dysplasia (OSFWD) (iii) OSFWT-OSFWD (iv) OSFWD-OSCC. Significant histopathogical correlates and their corroborative mathematical features, inferred from p63 staining, were also investigated into. Quantitative assessment and correlative analysis identified mathematical features related to hyperplasia, cellular stratification, differentiation and maturation, shape and size, nuclear crowding and nucleocytoplasmic ratio. It is envisaged that this approach for analyzing the p63 expression and its distribution pattern may help to establish it as a quantitative bio-marker to predict the malignant potentiality and progression. The proposed work would be a value addition to the gold standard by incorporating an observer-independent framework for the associated molecular pathology.


Coping, daily hassles and behavior and emotional problems in adolescents with high-functioning autism/Asperger's Disorder.
Although daily hassles and coping are associated with behavior and emotional problems in non-clinical populations, few studies have investigated these relationships in individuals with high-functioning autism/Asperger's Disorder (HFASD). This study examined the relationships between daily hassles, coping and behavior and emotional problems in adolescents with HFASD. Thirty-one adolescents with HFASD completed questionnaires assessing their coping and behavior and emotional problems, and completed an Ecological Momentary Assessment run via a mobile phone application on their coping and daily hassles. Parents completed questionnaires of the adolescents' daily hassles, coping, and behavior and emotional problems. The disengagement coping style was associated with significantly higher levels of behavior and emotional problems regardless of respondent or methodology, suggesting it may be a valuable target for intervention.


The PedsQL Multidimensional Fatigue Scale in pediatric rheumatology: reliability and validity.
. The PedsQL (Pediatric Quality of Life Inventory) is a modular instrument designed to measure health related quality of life (HRQOL) in children and adolescents ages 2-18 years. The recently developed 18-item PedsQL Multidimensional Fatigue Scale was designed to measure fatigue in pediatric patients and comprises the General Fatigue Scale (6 items), Sleep/Rest Fatigue Scale (6 items), and Cognitive Fatigue Scale (6 items). The PedsQL 4.0 Generic Core Scales were developed as the generic core measure to be integrated with the PedsQL Disease-Specific Modules. The PedsQL 3.0 Rheumatology Module was designed to measure pediatric rheumatology-specific HRQOL. Methods. The PedsQL Multidimensional Fatigue Scale, Generic Core Scales, and Rheumatology Module were administered to 163 children and 154 parents (183 families accrued overall) recruited from a pediatric rheumatology clinic. Results. Internal consistency reliability for the PedsQL Multidimensional Fatigue Scale Total Score (a = 0.95 child, 0.95 parent report), General Fatigue Scale (a = 0.93 child, 0.92 parent), Sleep/Rest Fatigue Scale (a = 0.88 child, 0.90 parent), and Cognitive Fatigue Scale (a = 0.93 child, 0.96 parent) were excellent for group and individual comparisons. The validity of the PedsQL Multidimensional Fatigue Scale was confirmed through hypothesized intercorrelations with dimensions of generic and rheumatology-specific HRQOL. The PedsQL Multidimensional Fatigue Scale distinguished between healthy children and children with rheumatic diseases as a group, and was associated with greater disease severity. Children with fibromyalgia manifested greater fatigue than children with other rheumatic diseases. The results confirm the initial reliability and validity of the PedsQL Multidimensional Fatigue Scale in pediatric rheumatology.


Vitamin D Deficiency and Increased Risk of Bladder Carcinoma: A Meta-Analysis.
Vitamin D status in relation to bladder carcinoma risk was still inconsistent. This study was carried out to evaluate the relationship between vitamin D status and bladder carcinoma risk through a meta-analysis approach. Pubmed, Web of Science, CNKI, and Embase were searched systemically to find eligible studies from the earliest available date to April 16, 2015. The search terms "vitamin D", "25-hydroxyvitamin D", "bladder cancer" or "bladder carcinoma" were used to retrieve relevant studies. The exposure of interest was intake of vitamin D or serum vitamin D levels, and the outcome of interest was bladder carcinoma incidence or mortality. The pooled risk ratio (RR) values and their 95%CIs were calculated through meta-analysis. Seven studies with a total of 62,141 participants met the inclusion criteria and were finally included into the meta-analysis. There was no heterogeneity among those included studies (I2 = 0%, P = 0.53). The pooled RR of bladder carcinoma for the lowest category versus the highest category of vitamin D was 1.34 (95% CI 1.17-1.53, P < 0.0001). Sensitivity analysis by omitting one study by turns showed all the pooled RRs were statistically significant. Meta-analysis of 5 studies reporting outcomes of serum vitamin D levels also showed that the low serum vitamin D level was associated with increased risk of bladder carcinoma (RR = 1.32, 95%CI 1.15-1.52, P = 0.0001). No obvious risk of publication bias was observed. Vitamin D deficiency is associated with increased risk of bladder carcinoma in present study.


Mechanism of the Formation of Electronically Excited Species by Oxidative Metabolic Processes: Role of Reactive Oxygen Species.
It is well known that biological systems, such as microorganisms, plants, and animals, including human beings, form spontaneous electronically excited species through oxidative metabolic processes. Though the mechanism responsible for the formation of electronically excited species is still not clearly understood, several lines of evidence suggest that reactive oxygen species (ROS) are involved in the formation of electronically excited species. This review attempts to describe the role of ROS in the formation of electronically excited species during oxidative metabolic processes. Briefly, the oxidation of biomolecules, such as lipids, proteins, and nucleic acids by ROS initiates a cascade of reactions that leads to the formation of triplet excited carbonyls formed by the decomposition of cyclic (1,2-dioxetane) and linear (tetroxide) high-energy intermediates. When chromophores are in proximity to triplet excited carbonyls, the triplet-singlet and triplet-triplet energy transfers from triplet excited carbonyls to chromophores result in the formation of singlet and triplet excited chromophores, respectively. Alternatively, when molecular oxygen is present, the triplet-singlet energy transfer from triplet excited carbonyls to molecular oxygen initiates the formation of singlet oxygen. Understanding the mechanism of the formation of electronically excited species allows us to use electronically excited species as a marker for oxidative metabolic processes in cells.


Inducible HIV RNA transcription assays to measure HIV persistence: pros and cons of a compromise.
With the increasing number of therapeutic strategies tested in humans to reduce the size of the latent reservoir, the development of a robust, precise and clinical trial scalable assay that measures the frequency of infected cells carrying inducible replication-competent HIV is urgently needed. The size of the pool of cells carrying replication-competent HIV is largely overestimated by DNA assays, as a result of a large proportion of defective viruses, and underestimated by co-culture outgrowth assays. New culture methods that measure the inducible HIV reservoir have been developed during the past few years. In these induction assays, CD4+ T cells from virally suppressed individuals are activated and HIV RNA is measured in cell extracts or cell supernatants. In this review, we summarize the principle and outcomes of these assays and discuss the potential of these methods in the evaluation of HIV eradication strategies.


A Novel Bispecific Antibody against Human CD3 and Ephrin Receptor A10 for Breast Cancer Therapy.
Ephrin receptor A10 (EphA10), a transmembrane receptor that binds to ephrin, is a newly identified breast cancer marker protein that has also been detected in HER2-negative tissue. In this study, we report creation of a novel bispecific antibody (BsAb) binding both EphA10 and CD3, thereby forming a bridge between antigens expressed on both tumor and immune cells and promoting recognition of tumor cells by immune cells and redirection of cytotoxic T cells (CTL). This BsAb (EphA10/CD3) was expressed in supernatants of BsAb gene-transfected cells as monomeric and dimeric molecules. Redirected T-cell lysis was observed when monomeric and dimeric BsAb were added to EphA10-overexpressing tumor cells in vitro. Furthermore, dimeric BsAb (EphA10/CD3) was more cytotoxic than monomeric BsAb, with efficient tumor cell lysis elicited by lower concentrations (≤10(-1) μg/mL) and a lower effector to target (E/T) cell ratio (E/T = 2.5). Dimeric BsAb (EphA10/CD3) also showed significant anti-tumor effects in human xenograft mouse models. Together, these results revealed opportunities to redirect the activity of CTL towards tumor cells that express EphA10 using the BsAb (EphA10/CD3), which could be tested in future clinical trials as a novel and potent therapeutic for breast cancer tumors.


The monitoring of progress in apoptosis of liver cells in bile duct-ligated rats.
We aimed to determine the progress of lipid peroxidation and ultrastructural changes established in the rat liver after acute bile duct ligation. Groups A1, B1, C1 and D1 were the controls of groups A2, B2, C2 and D2, which represented the 1st, 3rd, 5th and 8th days after bile duct ligation. Serum bilirubin and malondialdehyde, liver malondialdehyde and reduced glutathione levels, and inducible nitric oxide synthase expression were determined. Liver tissue was examined with light and electron microscopy. Serum bilirubin increased progressively. Serum and liver malondialdehyde and inducible nitric oxide synthase expression reached a peak level at day 3, reduced at the 5th day and continued at a constant rate. Reduced glutathione decreased progressively. Ductal proliferation increased progressively to a plateau at day 5. The marked electron microscopic changes were detected at day 3 (B2) and continued constantly. The first five days after acute bile duct ligation are the most critical.


Involving relatives in ICU patient care: critical care nursing challenges.
To identify the barriers critical care nurses experience to relative involvement in intensive care unit patient care. Previous studies have discussed the experiences of relatives visiting an intensive care unit, the needs of relatives in the intensive care environment, critical care nurse and relative interaction, intensive care unit visiting policies and the benefits of including relatives in patient care. The barriers that critical care nurses experience to relative involvement in patient care have received minimal exploration. Critical care nurses were recruited for a mixed methods study. An explanatory mixed method design was used, with two phases. Phase 1 was Quantitative and Phase 2 was Qualitative. Data collection occurred over five months in 2012-2013. Phase 1 used an online questionnaire (n = 70), and semi-structured interviews (n = 6) were conducted in Phase 2. Phase 1 participants were 70 critical care nurses working in Australian intensive care units and six critical care nurses were recruited from a single Sydney intensive care unit for Phase 2. Through sequential data collection, Phase 1 results formed the development of Phase 2 interview questions. Participants reported various barriers to relative involvement in critically ill patient care. Factors related to the intensive care unit patient, the intensive care unit relative, the critical care nurse and the intensive care environment contributed to difficulties encompassing relative involvement. This study has identified that when considering relative involvement in patient care, critical care nurses take on a paternalistic role. The barriers experienced to relative involvement result in the individual critical care nurse deciding to include or exclude relatives from patient care. Knowledge of the barriers to relative involvement in critically ill patient care may provide a basis for improving discussion on this topic and may assist intensive care units to implement strategies to reduce barriers.


The promise and peril of intensive-site-based ecological research: insights from the Hubbard Brook ecosystem study.
Ecological research is increasingly concentrated at particular locations or sites. This trend reflects a variety of advantages of intensive, site-based research, but also raises important questions about the nature of such spatially delimited research: how well does site based research represent broader areas, and does it constrain scientific discovery? We provide an overview of these issues with a particular focus on one prominent intensive research site: the Hubbard Brook Experimental Forest (HBEF), New Hampshire, USA. Among the key features of intensive sites are: long-term, archived data sets that provide a context for new discoveries and the elucidation of ecological mechanisms; the capacity to constrain inputs and parameters, and to validate models of complex ecological processes; and the intellectual cross-fertilization among disciplines in ecological and environmental sciences. The feasibility of scaling up ecological observations from intensive sites depends upon both the phenomenon of interest and the characteristics of the site. An evaluation of deviation metrics for the HBEF illustrates that, in some respects, including sensitivity and recovery of streams and trees from acid deposition, this site is representative of the Northern Forest region, of which HBEF is a part. However, the mountainous terrain and lack of significant agricultural legacy make the HBEF among the least disturbed sites in the Northern Forest region. Its relatively cool, wet climate contributes to high stream flow compared to other sites. These similarities and differences between the HBEF and the region can profoundly influence ecological patterns and processes and potentially limit the generality of observations at this and other intensive sites. Indeed, the difficulty of scaling up may be greatest for ecological phenomena that are sensitive to historical disturbance and that exhibit the greatest spatiotemporal variation, such as denitrification in soils and the dynamics of bird communities. Our research shows that end member sites for some processes often provide important insights into the behavior of inherently heterogeneous ecological processes. In the current era of rapid environmental and biological change, key ecological responses at intensive sites will reflect both specific local drivers and regional trends.


Agency-based empowerment training enhances sales capacity of female energy entrepreneurs in Kenya.
Globally, women's involvement in clean cooking value chains has been minimal. This is partly because of the multiple challenges faced by women that impede their capacity to effectively engage in the energy sector. To better discern gender-specific differences in involvement in the energy sector, the authors conducted a randomized trial in Kenya to compare sales performance of newly trained male and female improved cookstove entrepreneurs and to test the effects of an agency-based empowerment training on business activity. A total of 257 entrepreneurs completed either a 4-day entrepreneurial training (control) or a 4-day empowerment training (intervention) and were followed for nearly 8 months documenting business activity and sales. The empowerment training led to more than doubling of sales for both genders. In addition, participants in the intervention group were significantly more likely to demonstrate business commitment over time and nearly three times more likely to be higher sellers (relative risk = 2.7, 95% CI [1.4, 5.4]), controlling for gender and rural/urban locale. Women outsold men by a margin of nearly 3 to 1 and were more likely to continue to pursue leads despite limited sales. Nonactive participants (those selling 1 improved cookstove or less) were a larger percentage of the control group (72%) than the intervention group (50%), and more men were nonactive participants (65% of men) compared with women (56% of women).These data show that women can serve as active improved cookstove entrepreneurs in both urban and rural settings and that targeted agency-based empowerment training can significantly increase women's capacity to engage effectively within the improved cookstove value chain.


Users' guides to the medical literature: XXII: how to use articles about clinical decision rules. Evidence-Based Medicine Working Group.
Clinical experience provides clinicians with an intuitive sense of which findings on history, physical examination, and investigation are critical in making an accurate diagnosis, or an accurate assessment of a patient's fate. A clinical decision rule (CDR) is a clinical tool that quantifies the individual contributions that various components of the history, physical examination, and basic laboratory results make toward the diagnosis, prognosis, or likely response to treatment in a patient. Clinical decision rules attempt to formally test, simplify, and increase the accuracy of clinicians' diagnostic and prognostic assessments. Existing CDRs guide clinicians, establish pretest probability, provide screening tests for common problems, and estimate risk. Three steps are involved in the development and testing of a CDR: creation of the rule, testing or validating the rule, and assessing the impact of the rule on clinical behavior. Clinicians evaluating CDRs for possible clinical use should assess the following components: the method of derivation; the validation of the CDR to ensure that its repeated use leads to the same results; and its predictive power. We consider CDRs that have been validated in a new clinical setting to be level 1 CDRs and most appropriate for implementation. Level 1 CDRs have the potential to inform clinical judgment, to change clinical behavior, and to reduce unnecessary costs, while maintaining quality of care and patient satisfaction. JAMA. 2000;284:79-84


Protective role of hydrogen peroxide in oxygen-deprived dopaminergic neurones of the rat substantia nigra.
Hydrogen peroxide (H2O2) is a reactive oxygen species, responsible for cytotoxic damage through the formation of hydroxyl radicals. Dopamine (DA) neurones of the substantia nigra pars compacta (SNc) are highly sensitive to metabolic stress, and they typically respond to energy deprivation with membrane hyperpolarization, mainly through opening of ATP-dependent K+ channels. Accordingly, H2O2 (3 mM) induced a tolbutamide-sensitive outward current in DA neurones. Conversely, in a hypoxic medium, H2O2 reverted membrane hyperpolarization, which is associated with oxygen deprivation in DA neurones, restored their action potential firing, and reduced the hypoxia-mediated outward current in a concentration-dependent manner, between 0.1 and 3 mM (IC50 0.6+/-0.1 mM). Notably, H2O2 did not counteract membrane hyperpolarization associated with hypoglycaemia, moreover, when catalase was inhibited with 3-amino-1,2,4-triazole (3-AT; 30 mM), H2O2 did not reduce hypoxia-mediated outward current. The counteracting action of H2O2 on hypoxia-mediated effects was further confirmed by single-unit extracellular recordings of presumed DA neurones in acute midbrain slices preparations, using a planar multi-electrode array device. Whilst a prolonged period of hypoxia (40 min) caused firing suppression, which did not recover after perfusion in normoxic conditions, the presence of H2O2 (3 mM) during this prolonged hypoxic period rescued most of the neurones from irreversible firing inhibition. Accordingly, morphological studies showed that H2O2 counteracts the cytochrome c release provoked by prolonged hypoxic treatment. Taken together, our data suggest that H2O2 prevents the metabolic stress of DA neurones induced by hypoxia by serving as a supplementary source of molecular oxygen, through its degradation by catalase.


Efficacy of thiopurines and adalimumab in preventing Crohn's disease recurrence in high-risk patients - a POCER study analysis.
Crohn's disease recurs in the majority of patients after intestinal resection. To compare the relative efficacy of thiopurines and anti-TNF therapy in patients at high risk of disease recurrence. As part of a larger study comparing post-operative management strategies, patients at high risk of recurrence (smoker, perforating disease, ≥2nd operation) were treated after resection of all macroscopic disease with 3 months metronidazole together with either azathioprine 2 mg/kg/day or mercaptopurine 1.5 mg/kg/day. Thiopurine-intolerant patients received adalimumab induction then 40 mg fortnightly. Patients underwent colonoscopy at 6 months with endoscopic recurrence assessed blind to treatment. A total of 101 patients [50% male; median (IQR) age 36 (25-46) years] were included. There were no differences in disease history between thiopurine- and adalimumab-treated patients. Fifteen patients withdrew prior to 6 months, five due to symptom recurrence (of whom four were colonoscoped). Endoscopic recurrence (Rutgeerts score i2-i4) occurred in 33 of 73 (45%) thiopurine vs. 6 of 28 (21%) adalimumab-treated patients [intention-to-treat (ITT); P = 0.028] or 24 of 62 (39%) vs. 3 of 24 (13%) respectively [per-protocol analysis (PPA); P = 0.020]. Complete mucosal endoscopic normality (Rutgeerts i0) occurred in 17/73 (23%) vs. 15/28 (54%) (ITT; P = 0.003) and in 27% vs. 63% (PPA; P = 0.002). The most advanced disease (Rutgeerts i3 and i4) occurred in 8% vs. 4% (thiopurine vs. adalimumab). In Crohn's disease patients at high risk of post-operative recurrence adalimumab is superior to thiopurines in preventing early disease recurrence.


Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma.
Alterations of the tumor suppressor Neurofibromatosis type II (NF2) have been reported in about 40% of Malignant pleural mesothelioma (MPM) patients. NF2 (Merlin) deficiency leads to alterations of the Hippo pathway; resulting in activation of the oncogenic Yes Associated Protein-1 (YAP1). Our aim was to investigate the association between these alterations and clinical outcomes. Tissue microarrays composed of MPM tumors derived from 2 independent MPM cohorts were employed for this study. Immunohistochemical expression of Merlin, YAP1 and its target genes, Survivin and connective tissue growth factor (CTGF) were assessed in nuclear and cytoplasmic fractions. Cohort 1 was comprised of 145 patients intended to be treated with chemotherapy (CTX) followed by extrapleural pneumonectomy (EPP), thus both pre- and post-CTX tissues were available. Cohort 2 was comprised of 59 patients treated with EPP followed by intraoperative hyperthermic cisplatin and/or adjuvant CTX and/or radiotherapy. Marker expression was quantified by means of labeling index (%) for nuclear Survivin and by H-score for the other markers. The dichotomized marker expression was tested for the association with overall survival (OS) and freedom from recurrence (FFR). Kaplan-Meier survival curves revealed a significant association between low cytoplasmic Merlin expression in pre-induction CTX tissues of cohort 1 with shorter FFR (p = 0.02) and OS (p = 0.03). The same tendency was observed in the chemotherapy naïve tissues obtained during EPP of cohort 2. Low nuclear Merlin expression in post-CTX tissues (available from cohort 1 only) was associated with shorter FFR (p = 0.04) and OS (p = 0.05). High nuclear Survivin labeling indices in both pre- and post-CTX tissues of cohort 1 was associated with shorter FFR (p = 0.02). In cohort 2, this was associated with both FFR and OS (p = 0.046 and p = 0.002, respectively). In multivariate analysis, low expression of cytoplasmic Merlin remained an independent prognosticator for shorter FFR of cohort 1 [hazard ratio (HR) = 0.5, 95% confidence interval (CI) = 0.3-0.9, p = 0.001] and OS [HR = 0.5, 95% CI = 0.3-1, p = 0.04]. High Survivin labeling index was an independent prognostic factor for shorter FFR in patients from cohort 1 [HR = 3.4, 95% CI = 1.7-6.8, p = 0.006] and shorter OS in patients from cohort 2 [HR = 2.35, 95% CI = 1.27-4.33, p = 0.006]. Our findings uncover the significance of Merlin protein expression and Survivin labeling index as prognosticators for poor clinical outcome in two independent MPM cohorts. If confirmed, these markers may be used to identify subgroups of patients benefitting from additional treatment.


Benthic foraminifera show some resilience to ocean acidification in the northern Gulf of California, Mexico.
Extensive CO2 vents have been discovered in the Wagner Basin, northern Gulf of California, where they create large areas with lowered seawater pH. Such areas are suitable for investigations of long-term biological effects of ocean acidification and effects of CO2 leakage from subsea carbon capture storage. Here, we show responses of benthic foraminifera to seawater pH gradients at 74-207m water depth. Living (rose Bengal stained) benthic foraminifera included Nonionella basispinata, Epistominella bradyana and Bulimina marginata. Studies on foraminifera at CO2 vents in the Mediterranean and off Papua New Guinea have shown dramatic long-term effects of acidified seawater. We found living calcareous benthic foraminifera in low pH conditions in the northern Gulf of California, although there was an impoverished species assemblage and evidence of post-mortem test dissolution.


Molecular mechanisms leading to loss of differentiation and gain of invasiveness in epithelial cells.
It has been realized for some time that the loss of epithelial differentiation in carcinomas, which is accompanied by higher mobility and invasiveness of the tumor cells, is a consequence of reduced intercellular adhesion. A variety of recent reports have indicated that the primary cause for the 'scattering' of the cells in invasive carcinomas is a loss of the integrity of intercellular junctions. Thus, defects in expression or structure of several components of the epithelial adherens junctions (e.g. E-cadherin, alpha-catenin) can occur, and our increased knowledge about the molecules of the junctions allows an explanation of these defects in molecular terms in some of the cases. Furthermore, tyrosine phosphorylation of junctional components (e.g. beta-catenin) appears to play a role in the assembly and disassembly of cell-cell contacts. Some of the effectors of epithelial junction formation are tyrosine protein kinases, e.g. the scatter factor/hepatocyte growth factor receptor c-Met, the FGF receptors and the pp60src kinase. The importance of tyrosine phosphorylation in junctions during tumor development is becoming increasingly evident.


Objectively measured physical activity of young Canadian children using accelerometry.
The objective of the study was to describe objectively measured physical activity (PA) and sedentary time of infants, toddlers, and preschoolers and determine the proportion meeting Canadian age-specific PA guidelines. Ninety children (47 girls, 43 boys; mean age 32 (range, 4-70) months) attending scheduled health supervision visits and in the TARGet Kids! (The Applied Research Group for Kids) cohort wore an Actical accelerometer for 7 days. Participants with 4 or more valid days were included in the analysis. Time, in mean minutes per day (min/day), spent sedentary and in light PA, moderate to vigorous PA (MVPA), and total PA was determined using published cut-points; age groups were compared using ANOVA. Twenty-three percent of children <18 months (n = 28) and 76% of children aged 18-59 months (n = 45) met the guideline of 180 min/day of total PA; 13% of children ≥60 months (n = 17) met the guideline of 60 min/day of MVPA. Children <18 months spent more of their waking time per day engaged in sedentary behaviours (79%; ∼7.3 h) compared with children aged 18-59 months (63%; ∼6.6 h) and children ≥60 months (58%; ∼6.6 h). In conclusion, most children aged 18-59 months met the Canadian PA guidelines for children aged 0-4 years, whereas few younger than 18 months met the same guidelines. Only 13% of children ≥5 years met their age-specific PA guidelines. Further research is needed to develop, test, and implement effective strategies to promote PA and reduce sedentary behaviour in very young children.


The PYRIN Domain-only Protein POP1 Inhibits Inflammasome Assembly and Ameliorates Inflammatory Disease.
In response to infections and tissue damage, ASC-containing inflammasome protein complexes are assembled that promote caspase-1 activation, IL-1β and IL-18 processing and release, pyroptosis, and the release of ASC particles. However, excessive or persistent activation of the inflammasome causes inflammatory diseases. Therefore, a well-balanced inflammasome response is crucial for the maintenance of homeostasis. We show that the PYD-only protein POP1 inhibited ASC-dependent inflammasome assembly by preventing inflammasome nucleation, and consequently interfered with caspase-1 activation, IL-1β and IL-18 release, pyroptosis, and the release of ASC particles. There is no mouse ortholog for POP1, but transgenic expression of human POP1 in monocytes, macrophages, and dendritic cells protected mice from systemic inflammation triggered by molecular PAMPs, inflammasome component NLRP3 mutation, and ASC danger particles. POP1 expression was regulated by TLR and IL-1R signaling, and we propose that POP1 provides a regulatory feedback loop that shuts down excessive inflammatory responses and thereby prevents systemic inflammation.


Wing serial homologues and the diversification of insect outgrowths: insights from the pupae of scarab beetles.
Modification of serially homologous structures is a common avenue towards functional innovation in developmental evolution, yet ancestral affinities among serial homologues may be obscured as structure-specific modifications accumulate over time. We sought to assess the degree of homology to wings of three types of body wall projections commonly observed in scarab beetles: (i) the dorsomedial support structures found on the second and third thoracic segments of pupae, (ii) the abdominal support structures found bilaterally in most abdominal segments of pupae, and (iii) the prothoracic horns which depending on species and sex may be restricted to pupae or also found in adults. We functionally investigated 14 genes within, as well as two genes outside, the canonical wing gene regulatory network to compare and contrast their role in the formation of each of the three presumed wing serial homologues. We found 11 of 14 wing genes to be functionally required for the proper formation of lateral and dorsal support structures, respectively, and nine for the formation of prothoracic horns. At the same time, we document multiple instances of divergence in gene function across our focal structures. Collectively, our results support the hypothesis that dorsal and lateral support structures as well as prothoracic horns share a developmental origin with insect wings. Our findings suggest that the morphological and underlying gene regulatory diversification of wing serial homologues across species, life stages and segments has contributed significantly to the extraordinary diversity of arthropod appendages and outgrowths.


Thymus and aging: morphological, radiological, and functional overview.
Aging is a continuous process that induces many alterations in the cytoarchitecture of different organs and systems both in humans and animals. Moreover, it is associated with increased susceptibility to infectious, autoimmune, and neoplastic processes. The thymus is a primary lymphoid organ responsible for the production of immunocompetent T cells and, with aging, it atrophies and declines in functions. Universality of thymic involution in all species possessing thymus, including human, indicates it as a long-standing evolutionary event. Although it is accepted that many factors contribute to age-associated thymic involution, little is known about the mechanisms involved in the process. The exact time point of the initiation is not well defined. To address the issue, we report the exact age of thymus throughout the review so that readers can have a nicely pictured synoptic view of the process. Focusing our attention on the different stages of the development of the thymus gland (natal, postnatal, adult, and old), we describe chronologically the morphological changes of the gland. We report that the thymic morphology and cell types are evolutionarily preserved in several vertebrate species. This finding is important in understanding the similar problems caused by senescence and other diseases. Another point that we considered very important is to indicate the assessment of the thymus through radiological images to highlight its variability in shape, size, and anatomical conformation.


Shaped graft for aneurysmal bone cyst of upper limb bones.
The optimal treatment of aneurysmal bone cyst remains challenging. The aim of this prospective study was to evaluate the results of using bone grafts shaped to the defects caused by aneurysmal bone cysts of upper limb bones. Fifteen patients (12 males and 3 females) with an average age of 12 years (range 6-16 years) were treated for aneurysmal bone cysts of upper limb bones by intralesional resection, argon beam coagulation and shaped bone graft. The grafts were harvested from 14 patients (11 fibulas and 3 iliac bones) and from the mother of one patient (proximal fibula). Osteosynthesis was required to stabilize the graft in four cases. The modified Enneking's scoring system was used for functional evaluation. One patient developed partial recurrence at 6 months and required reoperation. Superficial wound infection was encountered in one patient. Shortening of the humeral segment was seen in two patients (1 and 1.5 cm) but without angular deformity. After a mean follow-up of 45 months (range 24-68 months), the mean functional score was 97.3%. This technique proved to be reliable in obtaining a well reconstructed and growing bone with no or minimal deformity and good function.


Health, wartime stress, and unit cohesion: evidence from Union Army veterans.
We find that Union Army veterans of the American Civil War who faced greater wartime stress (as measured by higher battlefield mortality rates) experienced higher mortality rates at older ages, but that men who were from more cohesive companies were statistically significantly less likely to be affected by wartime stress. Our results hold for overall mortality, mortality from ischemic heart disease and stroke, and new diagnoses of arteriosclerosis. Our findings represent one of the first long-run health follow-ups of the interaction between stress and social networks in a human population in which both stress and social networks are arguably exogenous.


Ca(2+) modulating α-synuclein membrane transient interactions revealed by solution NMR spectroscopy.
α-Synuclein is involved in Parkinson's disease and its interaction with cell membrane is crucial to its pathological and physiological functions. Membrane properties, such as curvature and lipid composition, have been shown to affect the interactions by various techniques, but ion effects on α-synuclein membrane interactions remain elusive. Ca(2+) dynamic fluctuation in neurons plays important roles in the onset of Parkinson's disease and its influx is considered as one of the reasons to cause cell death. Using solution Nuclear Magnetic Resonance (NMR) spectroscopy, here we show that Ca(2+) can modulate α-synuclein membrane interactions through competitive binding to anionic lipids, resulting in dissociation of α-synuclein from membranes. These results suggest a negative modulatory effect of Ca(2+) on membrane mediated normal function of α-synuclein, which may provide a clue, to their dysfunction in neurodegenerative disease.


Assessing Physical Activity and Sedentary Behavior under Free-Living Conditions: Comparison of Active Style Pro HJA-350IT and ActiGraphTM GT3X.
Various accelerometers have been used in research measuring physical activity (PA) and sedentary behavior (SB). This study compared two triaxial accelerometers-Active style Pro (ASP) and ActiGraph (AG)-in measuring PA and SB during work and nonwork days in free-living conditions. A total of 50 working participants simultaneously wore these two accelerometers on one work day and one nonwork day. The difference and agreement between the ASP and AG were analyzed using paired t-tests, Bland-Altman plots, and intraclass coefficients, respectively. Correction factors were provided by linear regression analysis. The agreement in intraclass coefficients was high among all PA intensities between ASP and AG. SB in the AG vertical axis was approximately 103 min greater than ASP. Regarding moderate-to-vigorous-intensity PA (MVPA), ASP had the greatest amount, followed by AG. There were significant differences in all variables among these devices across all day classifications, except for SB between ASP and AG vector magnitude. The correction factors decreased the differences of SB and MVPA. PA time differed significantly between ASP and AG. However, SB and MVPA differences between these two devices can be decreased using correction factors, which are useful methods for public health researchers.


A hemolytic plaque assay for activated murine T cells.
In an earlier report, it was shown that murine spleen cells cultured with concanavalin A (Con A) released into the culture supernatants helper and suppressor substances for antibody production. The present communication describes the production of rabbit antisera against culture supernates from Con A-activated spleen cells and their use in a plaque assay for mitogen-activated T cells. The plaque assay, utilizing SRBC to which Staphylococcal protein A had been coupled, the developing anti-supernatant antiserum and guinea pig complement, readily detected secreting T cells. The T-cell nature of the plaque-forming cells (PFC) was established principally by the following: (a) the majority of lymphocytes in the centers of plaques were Thy-1-positive by fluroescence; (b) spleen cells depleted of B cells by incubation in plastic dishes coated with rabbit anti-mouse Ig antibody gave greatly enriched PFC responses; (c) anti-Thy-1 and anti-Lyt-2.2 treatment of spleen cells almost completely depleted PFC; (d) T-cell mitogens (Con A and phytohemagglutinin) but not B-cell mitogens (lipopolysaccharides) induced PFC responses; (e) T cells maintained in culture for 10 d with Con A and T-cell growth factor yielded PFC. Kinetic and dose response studies showed that high doses of mitogen induced rapidly appearing T-PFC and the responses peaked at day 1--2 of culture. Lower doses of mitogen-induced PFC required longer periods of incubation for detection, indicating that cell activation and secretion may be different dose-dependent activities of mitogens. Another noteworthy finding was that the antiserum reacted with surface antigens of T-PFC, indicating that secreted products are expressed on the membranes of T cells, offering the possibility of isolating populations of cells with specific secretory potential. Although the precise nature of the T-cell products detected by the antiserum used in this assay are unresolved, 10% of the target-cell-adherent population from spleen cells of BALB/c mice sensitized to L929 cells formed plaques. This suggests that the antiserum has significant activity against the products of cytotoxic T cells, a finding which accords with the activity of anti-Lyt-2.2 serum against mitogen-induced T-PFC. The method clearly offers new possibilities for the analysis of T cells and their products and should provide an important approach to the clonal analysis of lymphokine production.


What a drop can do: dried blood spots as a minimally invasive method for integrating biomarkers into population-based research.
Logistical constraints associated with the collection and analysis of biological samples in community-based settings have been a significant impediment to integrative, multilevel bio-demographic and biobehavioral research. However recent methodological developments have overcome many of these constraints and have also expanded the options for incorporating biomarkers into population-based health research in international as well as domestic contexts. In particular using dried blood spot (DBS) samples-drops of whole blood collected on filter paper from a simple finger prick-provides a minimally invasive method for collecting blood samples in nonclinical settings. After a brief discussion of biomarkers more generally, we review procedures for collecting, handling, and analyzing DBS samples. Advantages of using DBS samples-compared with venipuncture include the relative ease and low cost of sample collection, transport, and storage. Disadvantages include requirements for assay development and validation as well as the relatively small volumes of sample. We present the results of a comprehensive literature review of published protocols for analysis of DBS samples, and we provide more detailed analysis of protocols for 45 analytes likely to be of particular relevance to population-level health research. Our objective is to provide investigators with the information they need to make informed decisions regarding the appropriateness of blood spot methods for their research interests.


Signal Diversity of Receptor for Advanced Glycation End Products.
The receptor for advanced glycation end products (RAGE) is involved in inflammatory pathogenesis. It functions as a receptor to multiple ligands such as AGEs, HMGB1 and S100 proteins, activating multiple intracellular signaling pathways with each ligand binding. The molecular events by which ligand-activated RAGE controls diverse signaling are not well understood, but some progress was made recently. Accumulating evidence revealed that RAGE has multiple binding partners within the cytoplasm and on the plasma membrane. It was first pointed out in 2008 that RAGE's cytoplasmic tail is able to recruit Diaphanous-1 (Dia-1), resulting in the acquisition of increased cellular motility through Rac1/Cdc42 activation. We also observed that within the cytosol, RAGE's cytoplasmic tail behaves similarly to a Toll-like receptor (TLR4)-TIR domain, interacting with TIRAP and MyD88 adaptor molecules that in turn activate multiple downstream signals. Subsequent studies demonstrated the presence of an alternative adaptor molecule, DAP10, on the plasma membrane. The coupling of RAGE with DAP10 is critical for enhancing the RAGE-mediated survival signal. Interestingly, RAGE interaction on the membrane was not restricted to DAP10 alone. The chemotactic G-protein-coupled receptors (GPCRs) formyl peptide receptors1 and 2 (FPR1 and FPR2) also interacted with RAGE on the plasma membrane. Binding interaction between leukotriene B4 receptor 1 (BLT1) and RAGE was also demonstrated. All of the interactions affected the RAGE signal polarity. These findings indicate that functional interactions between RAGE and various molecules within the cytoplasmic area or on the membrane area coordinately regulate multiple ligand-mediated RAGE responses, leading to typical cellular phenotypes in several pathological settings. Here we review RAGE's signaling diversity, to contribute to the understanding of the elaborate functions of RAGE in physiological and pathological contexts.


Population differentiation and hybridisation of Australian snubfin (Orcaella heinsohni) and Indo-Pacific humpback (Sousa chinensis) dolphins in north-western Australia.
Little is known about the Australian snubfin (Orcaella heinsohni) and Indo-Pacific humpback (Sousa chinensis) dolphins ('snubfin' and 'humpback dolphins', hereafter) of north-western Australia. While both species are listed as 'near threatened' by the IUCN, data deficiencies are impeding rigorous assessment of their conservation status across Australia. Understanding the genetic structure of populations, including levels of gene flow among populations, is important for the assessment of conservation status and the effective management of a species. Using nuclear and mitochondrial DNA markers, we assessed population genetic diversity and differentiation between snubfin dolphins from Cygnet (n = 32) and Roebuck Bays (n = 25), and humpback dolphins from the Dampier Archipelago (n = 19) and the North West Cape (n = 18). All sampling locations were separated by geographic distances >200 km. For each species, we found significant genetic differentiation between sampling locations based on 12 (for snubfin dolphins) and 13 (for humpback dolphins) microsatellite loci (FST = 0.05-0.09; P<0.001) and a 422 bp sequence of the mitochondrial control region (FST = 0.50-0.70; P<0.001). The estimated proportion of migrants in a population ranged from 0.01 (95% CI 0.00-0.06) to 0.13 (0.03-0.24). These are the first estimates of genetic diversity and differentiation for snubfin and humpback dolphins in Western Australia, providing valuable information towards the assessment of their conservation status in this rapidly developing region. Our results suggest that north-western Australian snubfin and humpback dolphins may exist as metapopulations of small, largely isolated population fragments, and should be managed accordingly. Management plans should seek to maintain effective population size and gene flow. Additionally, while interactions of a socio-sexual nature between these two species have been observed previously, here we provide strong evidence for the first documented case of hybridisation between a female snubfin dolphin and a male humpback dolphin.


Long-Term Risk of Stroke after Transient Ischemic Attack.
In the absence of active management, the stroke risk after a transient ischemic attack (TIA) may be high. Almost 10 years ago, the results of the EXPRESS and SOS-TIA studies called for a more rapid management of TIA patients. The purpose of this study was to investigate the other stroke risks in the longer term, after the implementation of a more active approach to TIA. We also wanted to assess the predictive value of the ABCD2 score in this context. Riksstroke is the national stroke registry in Sweden. Data from Riksstroke's TIA module, and the national cause-of-death register, for the years 2011 and 2012 were used in this study. Stroke occurrence was monitored via Riksstroke. Cox's regression was used for risk evaluation. The predictive value of the ABCD2 score was assessed by calculating the area under the receiver operating characteristics curve. A total of 15,068 TIA episodes occurred in 14,102 patients. The follow-up time varied between 0 and 819 days, with an average of 417 days. The mortality for all TIA patients during the follow-up time was 7.1%. Of the unique patients, 545 had one or more strokes (3.9%), corresponding to 34 events per 1,000 person years. Significant risk factors for stroke were: age, previous TIA, atrial fibrillation (AF), oral anticoagulant (OAC) treatment, hypertension treatment, and the ABCD2 items speech impairment, unilateral weakness, and diabetes mellitus. The ABCD2 score correlated with a subsequent stroke, but its predictive value was low. The risk of stroke is low after the acute phase of a TIA, probably lower than in previous studies. This may be due to better secondary prevention in recent years. Several risk factors predict stroke, notably hypertensive treatment, which may be inadequate; and AF, where OACs may be under-used. It is difficult to identify the role of the ABCD2 score in clinical practice.


Household fuel use and child respiratory ill health in two towns in Mpumalanga, South Africa.
This cross-sectional study examined respiratory health outcomes and associated risk factors in children living in a part of South Africa characterised by high levels of air pollution. A questionnaire was used to collect self-reported respiratory health and risk factor data from the parents/guardians of children between the ages of 9 and 11 years attending primary schools in the study area. Six government schools were selected based on their location, class size and willingness to participate. Univariate and bivariate analyses as well as logistic regression analysis were performed on the data, using a p-value of 0.25 and biological plausibility. The overall prevalence of respiratory ill-health symptoms was 34.1%. The prevalence of respiratory ill-health conditions was significantly elevated among children from households using non-electrical fuels v. electricity for cooking (43.9% v. 31.6%; adjusted p-value 0.005). The same was noted among those using non-electrical fuels for heating (37.8% v. 29.0%). The elevated prevalence of some respiratory health outcomes among schoolchildren, especially in conjunction with domestic fossil fuel burning, is of concern. The data collected in this study may be used to complement or form a basis for future policy regarding indoor or ambient air quality in the area.


A national experiment reveals where a growth mindset improves achievement.
A global priority for the behavioural sciences is to develop cost-effective, scalable interventions that could improve the academic outcomes of adolescents at a population level, but no such interventions have so far been evaluated in a population-generalizable sample. Here we show that a short (less than one hour), online growth mindset intervention-which teaches that intellectual abilities can be developed-improved grades among lower-achieving students and increased overall enrolment to advanced mathematics courses in a nationally representative sample of students in secondary education in the United States. Notably, the study identified school contexts that sustained the effects of the growth mindset intervention: the intervention changed grades when peer norms aligned with the messages of the intervention. Confidence in the conclusions of this study comes from independent data collection and processing, pre-registration of analyses, and corroboration of results by a blinded Bayesian analysis.


[Screening for metabolic syndrome in older patients with severe mental illness].
Diabetes, cardiovascular disease and metabolic syndrome are more prevalent in older patients with severe mental illness (smi) than in healthy older persons in the same age-group as the smi patients. Compared to the general population, smi patients are often in a poorer state of (physical) health and have a shorter life expectancy.
 AIM: To assess the value of screening older smi patients (≥ 60) for metabolic syndrome.
 METHOD: We performed a prospective evaluation of the metabolic screening outcome data relating to 100 older smi patients and 124 healthy older patients and compared the results.
 RESULTS: In our smi patients (average age 69 years; 52% bipolar disorder, 48% schizophrenia) the frequency of metabolic syndrome (43%) was no higher than in healthy older persons (39.5%, p = 0.60). However, in 51% of the smi sample, metabolic screening detected at least one metabolic abnormality in a patient with no previous history for that specific parameter.
 CONCLUSION: By making routine metabolic screening available to a greater number of older smi patients, we should be able to identify substantial numbers of metabolic abnormalities that have been previously overlooked.


Effects and safety of iopanoic acid in cats administered levothyroxine.
The purpose of this study was to evaluate the safety and effect of iopanoic acid in 13 cats with hyperthyroidism induced by daily subcutaneous administration of 25microg/kg levothyroxine for a period of 42 days. On day 28 of levothyroxine administration, cats were randomly allocated to receive treatment twice daily with a placebo (control group; n=4), 50mg iopanoic acid (low dose group; n=5), or 100mg iopanoic acid (high dose group; n=4) for 14 days. Compared to the control group, T(3) concentrations were significantly decreased in both the low dose and high dose groups on days 35 and 42. T(3) concentrations in the low dose and high dose groups at days 35 and 42 were not different from day -8. The effect of iopanoic acid on clinical signs of hyperthyroidism was less apparent. Further clinical studies evaluating the long-term effect in cats with spontaneous hyperthyroidism are warranted.


CAUSES OF MATERNAL DEATH IN THE CALLAO REGION, PERÚ. DESCRIPTIVE STUDY, 2000-2015.
To identify the causes of maternal mor- tality in the Callao Region between 2000 and 2015. Case series study conducted in public and private healthcare institutions in the region of Callao in Perú. Overall, 131 women who met the selection criteria were included as cases of maternal mortality (MM). MM was defined as death of a woman during pregnancy, childbirth or the postpartum period (within the first 42 days after childbirth) in healthcare institutions in Callao. MM clinical-epidemiological records were reviewed. The analysis was performed using percent frequencies and means. Of the causes of MM, 61.1 % were direct and 38.9 % were indirect. The most frequent direct causes were hypertensive disorders of pregnancy, obstetric bleeding and miscarriage. Average time between the onset of discomfort and the decision to ask for assistance was 20 minutes; mean time to arrive at the healthcare institution after making the decision was 20 minutes; and mean delay time between arrival to the institution and provision of care was 7 minutes. Of the total number of maternal deaths, 96.9 % occurred in a healthcare institution. The study showed that the causes of MM are mainly of a direct type, primarily due to hypertensive disorders of pregnancy, obstetric bleeding and miscarriage, while indirect causes of MM were less frequent, consisting mainly of infectious causes..


Asymptomatic bruit, carotid and vertebrobasilar transient ischemic attacks--a clinical and ultrasonic correlation.
One hundred patients with asymptomatic carotid bruit or transient ischemic attack (TIA) underwent continuous-wave Doppler (CWD) and real time ultrasound (RTU) testing of their cervical carotid arteries. After ultrasonic studies, 51 patients also underwent bilateral carotid angiography. There was 95% agreement between CWD and angiography for the diagnosis of a significant (greater than 50%) stenosis. The RTU diagnosis of a normal or occluded vessel was correct in 100% of cases. Seven plaques appreciated on RTU may not have been large enough for detection by angiography. In this small series, ulceration confirmed pathologically was more reliably predicted by RTU than by cerebral angiography. Significant ipsilateral carotid plaques occurred more often in patients with amaurosis fugax than in patients with hemispheric TIAs. Ipsilateral plaque ulceration occurred in 50% of symptomatic carotid bruits, but in only 10% of asymptomatic carotid bruits. Plasma concentrations of total cholesterol were significantly higher in TIA patients with carotid stenosis than in controls.


Cognitive abilities relate to self-reported hearing disability.
In this explorative study, the authors investigated the relationship between auditory and cognitive abilities and self-reported hearing disability. Thirty-two adults with mild to moderate hearing loss completed the Amsterdam Inventory for Auditory Disability and Handicap (AIADH; Kramer, Kapteyn, Festen, & Tobi, 1996) and performed the Text Reception Threshold (TRT; Zekveld, George, Kramer, Goverts, & Houtgast, 2007) test as well as tests of spatial working memory (SWM) and visual sustained attention. Regression analyses examined the predictive value of age, hearing thresholds (pure-tone averages [PTAs]), speech perception in noise (speech reception thresholds in noise [SRTNs]), and the cognitive tests for the 5 AIADH factors. Besides the variance explained by age, PTA, and SRTN, cognitive abilities were related to each hearing factor. The reported difficulties with sound detection and speech perception in quiet were less severe for participants with higher age, lower PTAs, and better TRTs. Fewer sound localization and speech perception in noise problems were reported by participants with better SRTNs and smaller SWM. Fewer sound discrimination difficulties were reported by subjects with better SRTNs and TRTs and smaller SWM. The results suggest a general role of the ability to read partly masked text in subjective hearing. Large working memory was associated with more reported hearing difficulties. This study shows that besides auditory variables and age, cognitive abilities are related to self-reported hearing disability.


Responses of preschool children with and without ADHD to sensory events in daily life.
The purpose of this study was to compare parents' perceptions of the responses of their preschool children, with and without attention deficit hyperactivity disorder (ADHD), to sensory events in daily life in Israel. In addition, the relationship between levels of hyperactivity and sensory deficits was examined. The Sensory Profile Questionnaire (SP) was completed by mothers of forty-eight 4- to 6-year-old children with ADHD, and mothers of 46 children without disabilities. A matched group comparison design was used to identify possible differences in sensory processing. Based on the measure of mothers' perceptions, children with ADHD demonstrated statistically significant differences from children without ADHD in their sensory responsiveness as reflected in 6 out of 9 factor scores (p < .001-.05), and on their sensory processing, modulation, and behavioral and emotional responses, as reflected in 11 out of 14 section scores (p < .001-.05). Scores on the SP yielded statistically significant low to moderate correlations with scores on the hyperactive scale of the Preschool Behavior Questionnaire (r = .28-.66). The findings of the present study suggest that young children with ADHD may be at increased risk of deficits in various sensory processing abilities, over and above the core symptoms of ADHD. Early identification and treatment of sensory processing deficits from a young age may extend our ability to support the successful performance of children with ADHD in meaningful and productive occupations.