Metabolomics-driven nutraceutical evaluation of diverse green tea cultivars.
Green tea has various health promotion effects. Although there are numerous tea cultivars, little is known about the differences in their nutraceutical properties. Metabolic profiling techniques can provide information on the relationship between the metabolome and factors such as phenotype or quality. Here, we performed metabolomic analyses to explore the relationship between the metabolome and health-promoting attributes (bioactivity) of diverse Japanese green tea cultivars. We investigated the ability of leaf extracts from 43 Japanese green tea cultivars to inhibit thrombin-induced phosphorylation of myosin regulatory light chain (MRLC) in human umbilical vein endothelial cells (HUVECs). This thrombin-induced phosphorylation is a potential hallmark of vascular endothelial dysfunction. Among the tested cultivars, Cha Chuukanbohon Nou-6 (Nou-6) and Sunrouge (SR) strongly inhibited MRLC phosphorylation. To evaluate the bioactivity of green tea cultivars using a metabolomics approach, the metabolite profiles of all tea extracts were determined by high-performance liquid chromatography-mass spectrometry (LC-MS). Multivariate statistical analyses, principal component analysis (PCA) and orthogonal partial least-squares-discriminant analysis (OPLS-DA), revealed differences among green tea cultivars with respect to their ability to inhibit MRLC phosphorylation. In the SR cultivar, polyphenols were associated with its unique metabolic profile and its bioactivity. In addition, using partial least-squares (PLS) regression analysis, we succeeded in constructing a reliable bioactivity-prediction model to predict the inhibitory effect of tea cultivars based on their metabolome. This model was based on certain identified metabolites that were associated with bioactivity. When added to an extract from the non-bioactive cultivar Yabukita, several metabolites enriched in SR were able to transform the extract into a bioactive extract. Our findings suggest that metabolic profiling is a useful approach for nutraceutical evaluation of the health promotion effects of diverse tea cultivars. This may propose a novel strategy for functional food design.


Chemical defense mechanisms on the Great Barrier Reef, Australia.
Seventy-three percent of all exposed common coral reef invertebrates, from four phyla (42 species) tested, are toxic to fish. This represents the first evidence of the high incidence to toxicity in the marine tropics among several phyletic groups comprising dominant species. Most of the remaining exposed species have structural defense mechanisms against predation by fish. Of cryptic invertebrates, 25 percent are toxic to fish. The relation between toxicity, fish feeding behavior, community structure, and evolutionary theory is discussed.


Epigenetics in atherosclerosis: a clinical perspective.
Significant progress has been made in understanding in the pathogenesis of atherosclerosis. Nevertheless, atherosclerosis remains a great threat to human health worldwide. Epigenetic mechanisms, which involve DNA methylation, histone modification, and microRNA, have significantly enhanced our understanding of the pathological process of atherosclerosis. More importantly, epigenetic processes (in contrast to genetic alterations) are reversible and thus provide a potential therapeutic target in atherosclerosis treatment. Both in vitro and in vivo studies using drugs targeting enzymes involved in epigenetic modifications have shown considerable promise in atherosclerosis treatment. This review aims to present an overview of current epigenetic mechanisms involved in the pathogenesis of atherosclerosis, and discuss points in these processes where therapeutic interventions likely bear fruition.


Tracking Magnetic Rotating Objects by Bipolar Electrochemiluminescence.
There has been a very rapid development of original systems that can be remotely controlled or addressed by playing with chemical and physical concepts. Here, we present the synergetic combination of external magnetic and electric fields to promote, in a double contactless mode, the rotational motion and the concomitant generation of light emission at the level of a gold-coated iron wire. The latter can be moved by rotating magnetic fields. Simultaneously, an electric field induces its remote polarization, which triggers the local generation of electrochemiluminescence (ECL) by bipolar electrochemistry. During rotation, the motion is tracked by changes in ECL intensity as a function of the orientation of the conducting wire in the electric field. The ECL behavior of the rotating bipolar wire is rationalized by considering the angular dependence of the polarization. Unlike previously reported systems, the rotation induces enhanced ECL emission due to the convective flow produced by the motion. This demonstrates that ECL emission can be coupled to magnetically controlled rotating bipolar objects. Such dual magnetically and electrically addressable dynamic systems open exciting prospects for integrating new functions such as imaging and sensing capabilities.


Engineering bacterial cytochrome P450 (P450) BM3 into a prototype with human P450 enzyme activity using indigo formation.
Human cytochrome P450 (P450) enzymes metabolize a variety of endogenous and xenobiotic compounds, including steroids, drugs, and environmental chemicals. In this study, we examine the possibility that bacterial P450 BM3 (CYP102A1) mutants with indole oxidation activity have the catalytic activities of human P450 enzymes. Error-prone polymerase chain reaction was carried out on the heme domain-coding region of the wild-type gene to generate a CYP102A1 DNA library. The library was transformed into Escherichia coli for expression of the P450 mutants. A colorimetric colony-based method was adopted for primary screening of the mutants. When the P450 activities were measured at the whole-cell level, some of the blue colonies, but not the white colonies, possessed apparent oxidation activity toward coumarin and 7-ethoxycoumarin, which are typical human P450 substrates that produce fluorescent products. Coumarin is oxidized by the CYP102A1 mutants to produce two metabolites, 7-hydroxycoumarin and 3-hydroxycoumarin. In addition, 7-ethoxycoumarin is simultaneously oxidized to 7-hydroxycoumarin by O-deethylation reaction and to 3-hydroxy,7-ethoxycoumarin by 3-hydroxylation reactions. Highly active mutants are also able to metabolize several other human P450 substrates, including phenacetin, ethoxyresorufin, and chlorzoxazone. These results indicate that indigo formation provides a simple assay for identifying CYP102A1 mutants with a greater potential for human P450 activity. Furthermore, our computational findings suggest a correlation between the stabilization of the binding site and the catalytic efficiency of CYP102A1 mutants toward coumarin: the more stable the structure in the binding site, the lower the energy barrier and the higher the catalytic efficiency.


[Chromosomal aberrations in lymphocytes of patients with systemic lupus erythematosus during cytostatic therapy].
To study cytogenetics of peripheral blood lymphocytes in patients with systemic lupus erythematosus (SLE) in the course of therapy with a selective immunodepressant sandimmun and universal cytostatic cyclophosphamide. 30 women with lupus-nephritis and nephrotic syndrome received sandimmun in a dose 2.5-7 mg/kg plus 10-20 mg prednisolone for a month with gradual lowering of sandimmun dose to 2.5-5 mg/kg and prednisolone to 0-10 mg/day. 10 patients with lupus-nephritis were given cyclophosphamide in a dose 1000 mg as a single intravenous drip once a month for 6 months in combination with 30-40 mg prednisolone for a month with the dose reduction to 20 mg/day. Sandimmun and cyclophosphamide effects on mutagenesis were studied in 72-120-h PHA-stimulated lymphocyte cultures. Chromosomal aberrations (CA) were assessed according to A.F. Zakharov's classification and proposals of International workshop in Melburn (1993). Sandimmun therapy on day 14 did not increase CA frequency but led to appearance of "premature chromosome condensation phenomenon" (PCC). PCC diminished after one month of sandimmun therapy and disappeared after 3-6 months. Cyclophosphamide provoked a rise in the incidence of both chromatide aberrations and CA. Sandimmun does not increase CA incidence in lymphocytes. On the contrary, it promoted the fall in this incidence while syclophosphamide stimulated CA and chromatide aberrations. This trend was observed till the end of cyclophosphamide administration.


The Effect of Rotator Cuff Repair on Natural History: A Systematic Review of Intermediate to Long-Term Outcomes.
Rotator cuff disease can have a progressive natural history of increasing tear size and worsening function. It remains unknown whether rotator cuff repair alters this natural history. A systematic review of the intermediate to long-term (minimum 5-year) results of operative rotator cuff repair and no repair of rotator cuff injuries was performed to compare (1) patient-based outcomes, (2) future surgical intervention, (3) future tear progression or recurrence, and (4) tear size. The no-repair group included both conservative treatment and surgical treatment without repair. After the application of selection criteria, 29 studies with 1,583 patients remained. Meta-regression was conducted to adjust for baseline age, sex, tear size, and duration of follow-up. Comparison of the repair and no-repair groups revealed no significant differences in terms of age (p = 0.36), sex (p = 0.88), study level of evidence (p = 0.86), or Coleman methodology score (p = 0.8). The duration of follow-up was significantly longer for the no-repair group (p = 0.004), whereas baseline tear size was significantly larger in the repair group (p = 0.014). The percentage of patients requiring additional surgery was significantly higher in the no-repair group after adjustment for age, sex, duration of follow-up, and tear size (9.5% higher in estimated means between groups [95% confidence interval, 2.1% to 17%]; p = 0.012). The likelihood of a recurrent defect (repair group) or extension of the prior tear (no-repair group) was not different between groups after adjustment for age, sex, duration of follow-up, and tear size (p = 0.4). There were no differences between the repair and no-repair groups in terms of the Constant score after adjustment for age, sex, duration of follow-up, and tear size (p = 0.31). The final tear size was significantly larger in the no-repair group than the repair group (967 mm2 higher in estimated means between groups [95% confidence interval, 771 to 1,164 mm2]; p < 0.001). At intermediate to long-term follow-up, rotator cuff repair was associated with decreased final tear size and decreased need for future surgery after adjusting for age, sex, duration of follow-up, and tear size. The likelihood of a recurrent defect after rotator cuff repair did not differ from that of tear extension after nonoperative treatment. Thus, rotator cuff repair may not alter natural history. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Identification of the first recurrent PAR1 deletion in Léri-Weill dyschondrosteosis and idiopathic short stature reveals the presence of a novel SHOX enhancer.
SHOX, located in the pseudoautosomal region 1 (PAR1) of the sexual chromosomes, encodes a transcription factor implicated in human growth. Defects in SHOX or its enhancers have been observed in ∼60% of Leri-Weill dyschondrosteosis (LWD) patients, a skeletal dysplasia characterised by short stature and/or the characteristic Madelung deformity, and in 2-5% of idiopathic short stature (ISS). To identify the molecular defect in the remaining genetically undiagnosed LWD and ISS patients, this study screened previously unanalysed PAR1 regions in 124 LWD and 576 ISS probands. PAR1 screening was undertaken by multiplex ligation dependent probe amplification (MLPA). Copy number alterations were subsequently confirmed and delimited by locus-specific custom-designed MLPA, array comparative genomic hybridisation (CGH) and breakpoint junction PCR/sequencing. A recurrent PAR1 deletion downstream of SHOX spanning 47543 bp with identical breakpoints was identified in 19 LWD (15.3%) and 11 ISS (1.9%) probands, from 30 unrelated families. Eight evolutionarily conserved regions (ECRs 1-8) identified within the deleted sequence were evaluated for SHOX regulatory activity by means of chromosome conformation capture (3C) in chicken embryo limbs and luciferase reporter assays in human U2OS osteosarcoma cells. The 3C assay indicated potential SHOX regulatory activity by ECR1, which was subsequently confirmed to act as a SHOX enhancer, operating in an orientation and position independent manner, in human U2OS cells. This study has identified the first recurrent PAR1 deletion in LWD and ISS, which results in the loss of a previously uncharacterised SHOX enhancer. The loss of this enhancer may decrease SHOX transcription, resulting in LWD or ISS due to SHOX haploinsufficiency.


Maternal depression and comorbidity: predicting early parenting, attachment security, and toddler social-emotional problems and competencies.
To examine relations between maternal depression (in pure and comorbid forms) and mother-infant interactions, infant attachment, and toddler social-emotional problems and competencies. A second objective was to explore sex differences. Sixty-nine mother-infant dyads were followed from pregnancy to 30 months postpartum. Depression was measured at multiple times with self-report and interview assessments. Play was assessed at 4 months and attachment status at 14 months postpartum. At 30 months, mothers completed the Child Behavior Checklist and Infant-Toddler Social and Emotional Assessment. Lifetime maternal depression predicted less optimal mother-infant interactions and insecure infant attachment. However, this "depression effect" was accounted for by mothers with comorbid diagnoses, who had less optimal interactions, and infants with higher rates of insecurity than either mothers with depression only or mothers with no psychopathology. Prenatal and postpartum depressive symptoms were associated with problem behaviors and lower competencies for boys. In contrast, quality of early interactions predicted problem behaviors in girls. It is important to examine the context of maternal depression with respect to additional psychopathology and environmental risks. Maternal depression in the presence of other psychopathology confers risk to the mother-child dyad. Consistent with previous work, risk pathways appear to differ for boys and girls. Early identification and prevention efforts are warranted.


Ameliorative Effects of Probiotic Lactobacillus paracasei NL41 on Insulin Sensitivity, Oxidative Stress, and Beta-Cell Function in a Type 2 Diabetes Mellitus Rat Model.
The present study aims to assess the antidiabetic effect of Lactobacillus paracasei strain NL41 and its potential mechanisms in rats with type 2 diabetes mellitus (T2DM) induced by a high-fat diet and low-dose streptozotocin administration (HFD/STZ). Eighteen Sprague-Dawley (SD) rats are randomly assigned to three groups: one control, one HFD/STZ model, and one HFD/STZ-Lactobacillus protection group with administration of strain NL41 for 12 weeks. Blood is collected for biochemical parameters analysis and tissue samples for histological analysis. Treatment with strain NL41 results in excellent blood glucose regulation and significantly decreases insulin resistance, and HbA1c, glucagon, and leptin levels, accompanied by remarkable improvement of dyslipidemia and oxidative stress status in the animals. Islets of Langerhans, liver, and kidney are significantly protected in the NL41-treated rats compared to the HFD/STZ-T2DM model rats. Histochemistry shows that strain NL41 inhibits beta-cell loss and alpha-cell expansion, indicating pancreatic islets as the targeted tissues for the primary ameliorative effect of the probiotic strain on HFD/STZ-T2DM rats. Crosstalk between the gut-liver and liver-pancreas endocrine axes is discussed. Probiotic strain NL41 prevents HFD/STZ-T2DM by decreasing insulin resistance and oxidative stress status, and protecting beta-cell function.


Role of sex and migration in adaptation to sink environments.
Understanding the effects of sex and migration on adaptation to novel environments remains a key problem in evolutionary biology. Using a single-cell alga Chlamydomonas reinhardtii, we investigated how sex and migration affected rates of evolutionary rescue in a sink environment, and subsequent changes in fitness following evolutionary rescue. We show that sex and migration affect both the rate of evolutionary rescue and subsequent adaptation. However, their combined effects change as the populations adapt to a sink habitat. Both sex and migration independently increased rates of evolutionary rescue, but the effect of sex on subsequent fitness improvements, following initial rescue, changed with migration, as sex was beneficial in the absence of migration but constraining adaptation when combined with migration. These results suggest that sex and migration are beneficial during the initial stages of adaptation, but can become detrimental as the population adapts to its environment.


Cost-effectiveness of Preoperative Staphylococcus aureus Screening and Decolonization in Cochlear Implantation.
Infection following cochlear implantation is medically and economically devastating. The cost-effectiveness (CE) of colonization screening and decolonization for infection prophylaxis in cochlear implantation has not been examined. An analytic observational study of data collected from purchasing records and the literature. Costs of Staphylococcus aureus colonization screening and decolonization were acquired from purchasing records and the literature. Infection rates after cochlear implantation and average total costs for evaluation and treatment were obtained from a review of the literature. A break-even analysis was performed to determine the required absolute risk reduction (ARR) in infection rate to make colonization screening or decolonization CE. Nasal screening ($144.07) is CE if the initial infection rate (1.7%) had an ARR of 0.60%. Decolonization with 2% intranasal mupirocin ointment ($5.09) was CE (ARR, 0.02%). A combined decolonization technique (2% intranasal mupirocin ointment, chlorhexidine wipes, chlorhexidine shower, and prophylactic vancomycin: $37.57) was CE (ARR, 0.16%). Varying infection rate as high as 15% demonstrated that CE did not change by maintaining an ARR of 0.16%. CE of the most expensive decolonization protocol was enhanced as the cost of infection treatment increased, with an ARR of 0.03% at $125,000. Prophylactic S aureus decolonization techniques can be CE for preventing infection following cochlear implantation. Decolonization with mupirocin is economically justified if it prevents at least 1 infection out of 5000 implants. S aureus colonization screening needed high reductions in infection rate to be CE.


Discovering how the amygdala shapes human behavior: From lesion studies to neuromodulation.
Case studies of patients with amygdala damage or those receiving direct amygdala stimulation have informed our understanding of the amygdala's role in emotion and cognition. These foundational studies illustrate how the human amygdala influences our present behavior and prioritizes memories of our past in service of future experiences. This broad influence makes the amygdala a novel target for clinical neuromodulation.


Evolution of the organizer and the chordate body plan.
The discovery of the organizer by Spemann and Mangold in 1924 raised two kinds of questions: those about the means of patterning the chordate body axis and those about the mechanisms of cell determination by induction. Some researchers, stressing the second, have suggested over the years that the organizer is poorly named and doesn't really organize because inducers act permissively, because they are not unique to the organizer, and because multipotent responsive cells develop complex local differentiations under artificial conditions. Furthermore, with the discovery of meso-endoderm induction in 1969, the possibility arose that this earlier induction generates as much organization as, or more than, does the organizer itself. Evidence is summarized in this article that the organizer does fulfill its title with regard to pattern formation: it adds greatly to embryonic organization by providing information about time, place, scale, and orientation for development by nearby members of the large multipotent competence groups surrounding the organizer. Embryos having smaller or larger organizers due to experimental intervention develop defective axial organization. Without an organizer the embryo develops no body axis and none of the four chordate characters: the notochord, gill slits, dorsal hollow nerve chord, and post-anal tail. For normal axis formation, the organizer's tripartite organization is needed. Each part differs in inducers, morphogenesis, and self-differentiation. The organizer is a trait of development of all members of the chordate phylum. In comparison to hemichordates, which constitute a phylum with some similarities to chordates, the chordamesoderm part is unique to the chordate organizer (the trunk-tail organizer). Its convergent extension displaces the gastrula posterior pole from alignment with the animal-vegetal axis and generates a new anteroposterior axis orthogonal to this old one. Once it has extended to full length, its signaling modifies the dorsoventral dimension. This addition to the organizer is seen as a major event in chordate evolution, bringing body organization beyond that achieved by oocyte organization and meso-endoderm induction in other groups.


Utility and effectiveness of computerised motion sensitivity screening tests in rural onchocercal community survey.
Non-invasive tool of community diagnosis for onchocercal endemicity needs to be identified and ascertained for their utility and effectivity in order to facilitate the control of onchocerciacis in sub-Saharan Africa To determine the utility and effectiveness of the Wu-Jones Motion Sensitivity Screening Test (MSST) in detecting optic nerve diseases in onchocercal-endemic rural Africa. MSST was applied to sampled subjects in the selected communities of Raja in Sudan; Bushenyi in Uganda; Morogoro in Tanzania; and of Ikom, Olamaboro and Gashaka in Nigeria. Basically, six points within the central field of vision were repeatedly tested at 1/3 meter from the screen of a laptop computer in a room darkened. Motion sensitivity was expressed as a percentage of motion detected in the individual eye and this was averaged for the community. A total of 3,858 eyes of 2,072 patients were examined. Seventy-six percent of the subjects completed the test, at an average test time of 120.4 (66.7) seconds. The overall mean motion sensitivity of all eyes tested was 88.49 (17.49%). At a cut-off point of 50%, 6.4% of all subjects tested were subnormal, while at 70% cutoff, 13.3% were subnormal. The highest proportion of 50% cutoff sub-normality was recorded at Morogoro at 12.7%. Motion Sensitivity Screening Test was widely accepted and easily administered to the rural and largely illiterate subjects studied. Our data suggest that the proportion of severe field defects by MSST in a community, with cutoff at 33%, best correlates with optic nerve disease prevalence, while proportion of defect from a higher cut-off level at about 50%, best correlates with overall ocular morbidity.


[Knowledge, attitude and reservations of medical students about organ transplantation: results of a survey during the first year of study].
Establish a list of first year medical students' attitudes, doubts, and knowledge in the fields of organ transplantation and donation. Anonymized questionnaire handed out to students during class lectures. 183 questionnaires were distributed and 117 returned (participation: 64%). The average age of the students was 21.6 +/- 2.7 years (range 18 to 38 years); the sample included 71 women (60.7%) and 48 men (39.3%). Only 2 students (2%) were not interested in the subject of organ donation. The students knew very little of the legal aspects of organ donation and 1/4 of them thought there was even a Federal law regarding organ transplantation. When asked if they knew whether a law existed in the Canton of Berne, 44% replied yes, but only 24 (20%) knew that this is contradictory. There was no gender difference in the answers to these question. From 57 students (48%) 246 individual comments on doubts and concerns were analyzed. In this respect, the students mainly questioned whether the donor was truly dead when donation took place (n = 48), if illegal transplantation could be eliminated (n = 44) and if transplantation was truly necessary (n = 43). Some also mentioned religious/ethical doubts (n = 42). In regard to organ donation by a living individual, 27 students were concerned about the health of this donor. 20 students had doubts regarding the pressure possibly applied by family members and friends and as many voiced doubts in regard to premature diagnosis of brain death of potential donors. Only 2 students were concerned about the post-mortem presentation. 45 students (48%) indicated discomfort with the donation of certain organs. They ranked the kidney as the first organ to donate, followed by the pancreas, heart, cornea, intestine, lung and liver. The interest in organ donation and transplantation is already strong in fist year medical students in the pre-clinical stage. However, differences from lay public are not readably detectable at this stage of medical training. Adequate information could influence future physicians in their mediatory role.


Congener-specific polychlorinated biphenyls and the prevalence of diabetes in the Saku Control Obesity Program (SCOP).
The prevalence of diabetes is increasing globally. In addition to established risk factors for diabetes, such as diet, inactivity, overweight and obesity, the involvement of persistent organic pollutants, including dioxins and polychlorinated biphenyls (PCBs), has also been suggested to be a possible, but controversial, cause of this epidemic. The present study investigated the association between blood PCB congener levels and the prevalence of diabetes among middle-aged, overweight and obese Japanese participants in the Saku Control Obesity Program. One hundred seventeen participants had their congener-specific PCB levels measured in addition to undergoing routine blood analyses at the time of a medical checkup. Prevalent diabetes was defined according to two methods: definite diabetes was defined as people with an HbA1c level ≥ 6.9% or who were taking medication for diabetes, and all diabetes was defined as people with an HbA1c level ≥ 6.5%, a fasting plasma glucose level ≥ 126 mg/dL, or a history of doctor-diagnosed diabetes. A multiple logistic regression analysis was performed to analyze the association between the PCB levels and the prevalence of diabetes, with adjustments for sex, age, body mass index and total lipids. As a result, PCB 146 and 180 were positively associated and PCB 163/164 and 170 were negatively associated with the prevalence of definite diabetes. The significance of the association of PCB 180 and 163/164 with the prevalence of diabetes persisted regardless of the definition of diabetes or adjustments for total lipids, suggesting the possibility that these parameters may modify the risk of diabetes.


Assessment of Cancer Survivors' Experiences of Using a Publicly Available Physical Activity Mobile Application.
Regular participation in physical activity (PA) is associated with improved physical and psychosocial outcomes in cancer survivors. However, PA levels are low during and after cancer treatment. Interventions to promote PA in this population are needed. PA mobile apps are popular and have potential to increase PA participation, but little is known about how appropriate or relevant they are for cancer survivors. This study aims to (1) assess recruitment, study uptake, and engagement for a publicly available PA mobile app (GAINFitness) intervention in cancer survivors; (2) assess cancer survivors' attitudes towards the app; (3) understand how the app could be adapted to better meet the needs of cancer survivors; and (4) to determine the potential for change in PA participation and psychosocial outcomes over a 6-week period of using the app. The present study was a one-arm, pre-post design. Cancer survivors (N=11) aged 33 to 62 years with a mean (SD) age of 45 (9.4), and 82% (9/11) female, were recruited (via community/online convenience sampling to use the app for 6 weeks). Engagement with the app was measured using self-reported frequency and duration of usage. Qualitative semi-structured telephone interviews were conducted after the 6-week study period and were analyzed using thematic analysis. PA, well-being, fatigue, quality of life (QOL), sleep quality, and anxiety and depression were self-reported at baseline and at a 6-week follow-up using the Godin Leisure Time Exercise Questionnaire (GLTEQ), the Functional Assessment of Cancer Therapy-General (FACT-G), the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Questionnaire, the Health and Quality of Life Outcomes (EQ5D) Questionnaire, the Pittsburgh Sleep Quality Index (PSQI), and the Hospital Anxiety and Depression Scale (HADS), respectively. Of the people who responded to the study advertisement, 73% (16/22) agreed to participate and 100% (11/11) of the participants who started the study completed all baseline and follow-up outcome measures and the telephone interview. On average, participants used the app twice a week for 25 minutes per session. Four themes were identified from the qualitative interviews surrounding the suitability of the app for cancer survivors and how it could be adapted: (1) barriers to PA, (2) receiving advice about PA from reliable sources, (3) tailoring the application to one's lifestyle, and (4) receiving social support from others. Pre-post comparison showed significant increases in strenuous PA, improvements in sleep quality, and reductions in mild PA. There were no significant changes in moderate PA or other psychosocial outcomes. All participants engaged with the app and qualitative interviews highlighted that the app was well-received. A generic PA mobile app could bring about positive improvements in PA participation and psychosocial outcomes among cancer survivors. However, a targeted PA app aimed specifically towards cancer survivors may increase the relevance and suitability of the app for this population.


Image-guided core-needle or surgical biopsy for neuroblastoma diagnosis in children: A systematic review and meta-analysis from the International Society of Pediatric Surgical Oncology (IPSO).
Image-guided core-needle biopsy (IGCNB) is a widely used and valuable clinical tool for tissue diagnosis of pediatric neuroblastoma. However, open surgical biopsy remains common practice even if children undergo more invasive and painful procedures. This review aims to determine the diagnostic accuracy and safety of IGCNBs in pediatric patients with neuroblastoma. We conducted a systematic review of peer-reviewed original articles published between 1980 and 2023, by searching "pediatric oncology," "biopsy," "interventional radiology," and "neuroblastoma." Exclusion criteria were patients older than 18 years, studies concerning non-neurogenic tumors, case reports, and language other than English. Both the systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A total of 533 abstracts articles were analyzed. Of these, eight retrospective studies met inclusion criteria (490 infants, 270 surgical biopsies [SB], 220 image-guided biopsies). Tissue adequacy for primary diagnosis (SB: n = 265, 98%; IGCNB: n = 199, 90%; p = .1) and biological characterization (SB: n = 186, 95%; IGCNB: n = 109, 89%; p = .15) was similar with both biopsy techniques, while intraoperative transfusion rate (SB: n = 51, 22%; IGCNB: n = 12, 6%; p = .0002) and complications (%) (SB: n = 58, 21%; IGCNB: n = 14, 6%; p = .005) were higher with surgical biopsy. Length of stay was similar in both groups; however, no additional data about concurrent diagnostic or treatment procedures were available in the analyzed studies. IGCNB is a safe and effective strategic approach for diagnostic workup of NB and should be considered in preferance to SB wherever possible.


Development of stereopsis depends upon contrast sensitivity and spatial tuning.
Various binocular functions such as disparity vergence, and stereopsis develop rapidly during the third to fifth month of life. This time frame coincides with the rapid postnatal development of visual acuity, contrast sensitivity and possibly the tuning of spatial channels. Recent studies of adult stereopsis reveal that small disparities near the stereo threshold are processed within spatial channels tuned above 2.5 cycles/deg. Sensitivity to these higher spatial frequencies develops during the 3-5 months of life. Adult studies also reveal that larger disparities are processed by spatial channels tuned to lower spatial frequencies. Tuning of these low spatial frequency channels may not be present until 3 months of age. Lack of spatial tuning prior to 3 months is predicted to be associated with a lack of disparity tuning as well as an inability to ignore false disparities in ambiguous or redundant stimuli such as random dot stereograms. These observations suggest that refractive anomalies such as anisometropia that limit high frequency spatial resolution and binocular integration can present a major obstacle to the postnatal development of binocular vision.


Reversal of experimental acute cerebral vasospasm by angiotensin converting enzyme inhibition.
We tested the hypothesis that cerebral arteriospasm developing after rupture of a subarachnoid aneurysm may be due to the vasoconstrictor effect of locally generated angiotensin II. Ten dogs had subarachnoid hemorrhage simulated by intracisternal introduction of 2 ml autologous blood, and were followed by cineangiography. Thirty minutes later, when acute arteriospasm was established, seven dogs received injection of the angiotensin converting enzyme inhibitor teprotide and 3 control dogs received normal saline. Repeat angiography at 30 and 90 minutes after injection, showed total or partial release of spasm in the experimental dogs and no change or further intensification of spasm in the control animals. We concluded that angiotensin converting enzyme inhibition may be a potentially useful approach for the reversal or prevention of cerebral arteriospasm after subarachnoid hemorrhage.


[Resource competition in maize/soybean intercropping system].
The soil water storage, growth development, biomass and yield in maize/soybean intercropping system under different separation methods were measured to analyze the resource competition of the intercropping crops. The treatments included no shoot or root separation (T1), shoot and root separation (T2), only root separation (T3), and only shoot separation (T4). Results indicated that compared to others, the average soil moisture content in the 0-120 cm soil layer decreased by 3.1%-12.9% in maize line, and by 2.8%-12.5% in soybean line for T1. Compared to T1, maize growth stage in T2, T3 and T4 came late, and the plant height, leaf area and cumulative total biomass, yield and yield components all decreased, while the trends found for soybean were the opposite. In summary, the changes of crop growth and yield in the maize/soybean intercropping system were driven by the interactions of above- and below-ground parts, and the below-ground part played a more important role.


Unlinked total elbow arthroplasty.
For more than 60 years, total elbow arthroplasty (TEA) has been successfully used to treat a variety of elbow conditions. Although first designed to treat older patients with rheumatoid arthritis, the indications have expanded to include younger, higher-demand patients with a broad range of elbow pathology. Two groups of TEA currently exist. The first group includes linked or semiconstrained elbows with a mechanical connection between the humeral and ulnar components that prevents disassociation. These implants do not rely on muscular or ligamentous tissues for stability. The second group includes unlinked implants that have no physical connection between the humeral and ulnar components. They rely on bearing surface architecture as well as soft-tissue integrity for elbow stability. Critical to the success of unlinked implants is a thorough preoperative evaluation of elbow stability, including bone stock, collateral ligament integrity, and periarticular muscle function. Unlinked implants should apply less strain to the bone-cement-implant interfaces, which may theoretically decrease rates of bearing wear and aseptic loosening. For this reason, some surgeons prefer unlinked implants for younger, higher-demand patients. To date, unlinked implants have not been clinically shown to improve survivorship compared with linked devices. No prospective randomized trials comparing linked and unlinked TEAs are currently available. Historically, unlinked implants have had higher revision rates, mostly caused by instability and early design flaws. More recent series have shown no significant differences in outcomes compared with linked devices. Unlinked TEA provides reliable pain relief and improved range of motion for patients with a variety of elbow disorders. Diligent patient selection and careful surgical technique are of utmost importance when considering an unlinked TEA as a treatment option. The recent development of convertible implants now allows surgeons to make intraoperative decisions regarding elbow stability and convert to a linked implant without revising the stems.


[Necrotizing inflammation of the vulva--a symptom of Richter intestinal wall hernia].
Parietal hernias, often also known as Littre's hernia and Richter's hernia, are a special kind of inguinal hernias. In this type of hernia, part of the abdominal (intestinal) wall is strangulated in "calotte form" in the hernial orifice; as a result, parietal hernias often cause only mild complaints and are surgically treated only in the late stage of enterocutaneous faecal fistula. In contrast to incarcerated inguinal hernias resulting in diffuse faecal peritonitis via infarction and necrosis, parietal hernia of the Richter type is locally restricted in extension because of the narrow hernial orifice, as far as the extension into the abdominal cavity is concerned; intestinal patency is usually maintained. The possibility of the existence of a perforated parietal hernia should always be considered in necrotising inflammations in the inguinal and vulvar regions, even if abdominal signs and symptoms are absent.


Adolescent gambling: understanding the role of stress and coping.
The central variables of stress, coping, and gambling severity were examined along three lines of inquiry. The first addressed whether adolescents with gambling problems reported a greater number of minor or major stressful (i.e., negative) life events relative to others. The second examined whether more with gambling problems employed less-effective coping styles, such as those characterized as less task- or solution-focused, and more emotion- or avoidance-focused coping. Finally, the third question explored whether adolescents' coping styles mediated the association between stress and gambling severity. Ranging from 11 to 20 years of age, 2,156 high-school students completed instruments assessing gambling involvement, gambling severity, stressful life events, and coping styles. Results indicated that, overall, adolescents with gambling-related problems reported more negative life events relative to social gamblers and non-gamblers. When negative life events were further separated into major and minor events, results revealed that problem gamblers reported more major negative life events but not more minor negative life events relative to others. Results indicated that adolescents with gambling-related problems used less task-focused coping, and more avoidance-focused coping. Males, but not females, who experience gambling-related problems reported using more emotion-focused coping strategies. Finally, emotion-oriented coping was found to mediate the relationship between negative life events and gambling severity. Implications and directions for future research are discussed.


Keratitis Due to Achromobacter xylosoxidans in a Contact Lens User.
Ocular infections due to Achromobacter xylosoxidans are extremely uncommon; their diagnosis is a challenge and the optimal treatment remains controversial. We present a case of A. xylosoxidans in a contact lens user and a review of the literature to facilitate diagnostic suspicion and empirical therapeutic management. Review of the literature in PubMed and MEDLINE. We also document a case diagnosed in our department in January 2016. Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain. According to the literature, clinical manifestations and antibiotic sensitivity of A. xylosoxidans varied greatly. Our patient with no history of keratopathy presented three risk factors that made the diagnosis suspicious. The infection was resolved with topical moxifloxacin and fluorometholone. A. xylosoxidans is an uncommon cause of infection, but must be suspected in atypical keratitis, reported contact with warm or still waters, use of contact lenses, or previous corneal damage. In these cases, microbiological studies and antibiotic sensitivity testing are particularly important.


Success Bias and Inflation Bias After Planning and Communicating Emotional Support.
This study investigates the potential for cancer patients' supporters to experience cognitive biases after communicating emotional support messages. A success bias was predicted, such that those who planned their messages would rate those messages as more effective in comparison with those who did not plan their messages (H1a-H1c). An inflation bias was also predicted, such that supporters would rate their messages as more effective than cancer patients who also rated the messages (H2a-H2c). One hundred laboratory participants were randomly assigned to a planning or distraction task before recording an emotional support message for a friend who had hypothetically been diagnosed with cancer. Laboratory participants rated their own messages in terms of relational assurances, problem-solving utility, and emotional awareness. Subsequently, cancer patients viewed and rated the laboratory participants' messages on the same characteristics. Participants who planned their messages rated their messages significantly higher than those who did not plan their messages in terms of relational assurance and problem-solving utility but not emotional awareness. Irrespective of planning or distraction condition, participants also rated their messages significantly higher on all three dependent variables than did cancer patients. Supporters should be aware of the propensity to overrate their supportive abilities and guard against the assumption that planning messages results in more effective support messages.


Clinical management of tendinopathy: A systematic review of systematic reviews evaluating the effectiveness of tendinopathy treatments.
While the pathoetiology is disputed, a wide array of treatments is available to treat tendinopathy. The most common treatments found in the literature include therapeutic modalities, exercise protocols, and surgical interventions; however, their effectiveness remains ambiguous. The purpose of this study was to perform a systematic review of systematic reviews to determine the ability of therapeutic interventions to improve pain and dysfunction in patients with tendinopathy regardless of type or location. Five databases were searched for systematic reviews containing only randomized control trials to determine the effectiveness of treatments for tendinopathies based on pain and patient-reported outcomes. Systematic reviews were assessed via the Assessment of Multiple Systematic Reviews (AMSTAR) for methodological quality. From the database search, 3,295 articles were found, 107 passed the initial inclusion criteria. After further review, 25 systematic reviews were included in the final qualitative analysis. The AMSTAR scores were relatively high (8.8 ± 1.0) across the 25 systematic reviews. Eccentric exercises were the most common and consistently effective treatment for tendinopathy across systematic reviews. Low-level laser therapy and extracorporeal shockwave therapy demonstrated moderate effectiveness, while platelet-rich plasma injections demonstrated inconclusive evidence on their ability to decrease tendinopathy-related pain and improve function. Corticosteroids also showed some effectiveness for short-term pain, but for the long-term use deemed ineffective and at times contraindicated. Regarding surgical options, minimally invasive procedures were more effective compared to open surgical interventions. When treating tendinopathy regardless of location, eccentric exercises were the best treatment option to improve tendinopathy-related pain and improve self-reported function.


Making Decisions About Stopping Medicines for Well-Controlled Juvenile Idiopathic Arthritis: A Mixed-Methods Study of Patients and Caregivers.
Improved treatments for juvenile idiopathic arthritis (JIA) have increased remission rates. We conducted this study to investigate how patients and caregivers make decisions about stopping medications when JIA is inactive. We performed a mixed-methods study of caregivers and patients affected by JIA, recruited through social media and flyers, and selected by purposive sampling. Participants discussed their experiences with JIA, medications, and decision-making through recorded telephone interviews. Of 44 interviewees, 20 were patients (50% ages <18 years), and 24 were caregivers (50% caring for children ages ≤10 years). We evaluated characteristics associated with high levels of reported concerns about JIA or medicines using Fisher's exact testing. Decisions about stopping medicines were informed by competing risks between disease activity and treatment. Participants who expressed more concerns about JIA were more likely to report disease-related complications (P = 0.002) and more motivated to continue treatment. However, participants expressing more concern about medicines were more likely to report treatment-related complications (P = 0.04) and felt more compelled to stop treatment. Additionally, participants considered how JIA or treatments facilitated or interfered with their sense of normalcy and safety, expressed feelings of guilt and regret about previous or potential adverse events, and reflected on uncertainty and unpredictability of future harms. Decision-making was also informed by trust in rheumatologists and other information sources (e.g., family and online support groups). When deciding whether to stop medicines whenever JIA is inactive, patients and caregivers weigh competing risks between disease activity and treatment. Based on our results, we suggest specific approaches for clinicians to perform shared decision-making regarding stopping medicines for JIA.


Appraising the relevance of DNA copy number loss and gain in prostate cancer using whole genome DNA sequence data.
A variety of models have been proposed to explain regions of recurrent somatic copy number alteration (SCNA) in human cancer. Our study employs Whole Genome DNA Sequence (WGS) data from tumor samples (n = 103) to comprehensively assess the role of the Knudson two hit genetic model in SCNA generation in prostate cancer. 64 recurrent regions of loss and gain were detected, of which 28 were novel, including regions of loss with more than 15% frequency at Chr4p15.2-p15.1 (15.53%), Chr6q27 (16.50%) and Chr18q12.3 (17.48%). Comprehensive mutation screens of genes, lincRNA encoding sequences, control regions and conserved domains within SCNAs demonstrated that a two-hit genetic model was supported in only a minor proportion of recurrent SCNA losses examined (15/40). We found that recurrent breakpoints and regions of inversion often occur within Knudson model SCNAs, leading to the identification of ZNF292 as a target gene for the deletion at 6q14.3-q15 and NKX3.1 as a two-hit target at 8p21.3-p21.2. The importance of alterations of lincRNA sequences was illustrated by the identification of a novel mutational hotspot at the KCCAT42, FENDRR, CAT1886 and STCAT2 loci at the 16q23.1-q24.3 loss. Our data confirm that the burden of SCNAs is predictive of biochemical recurrence, define nine individual regions that are associated with relapse, and highlight the possible importance of ion channel and G-protein coupled-receptor (GPCR) pathways in cancer development. We concluded that a two-hit genetic model accounts for about one third of SCNA indicating that mechanisms, such haploinsufficiency and epigenetic inactivation, account for the remaining SCNA losses.


Characterization of T cell epitopes in bovine α-lactalbumin.
Recent studies have indicated that peptides containing T cell epitopes may be used for immunotherapy. While for several cow's milk allergens the T cell epitopes have been described, the T cell epitopes in the major allergen α-lactalbumin (α-LAC) are unknown. Therefore, the aim of this study was to determine the T cell epitopes in α-LAC. Nineteen synthetic peptides spanning α-LAC were obtained. Cow's milk-specific T cell lines (TCLs) of 46 subjects were generated and tested for their specificity for α-LAC. The lines responding to α-LAC were subsequently tested to determine their activation in response to the peptides. More than half of the TCLs generated did not respond to α-LAC or lost their responsiveness during subsequent experiments, which indicates that α-LAC has low immunogenicity. Only 8 TCLs recognized 1 or more peptides. The recognition of the peptides was diverse and no major epitopes could be defined. The immunogenicity of α-LAC is very low compared to other major allergens in cow's milk. Moreover, there seems to be no dominant epitope present in the protein. Therefore, it seems unlikely that peptides of this protein can be used for immunotherapy.


Fusion of protein aggregates facilitates asymmetric damage segregation.
Asymmetric segregation of damaged proteins at cell division generates a cell that retains damage and a clean cell that supports population survival. In cells that divide asymmetrically, such as Saccharomyces cerevisiae, segregation of damaged proteins is achieved by retention and active transport. We have previously shown that in the symmetrically dividing Schizosaccharomyces pombe there is a transition between symmetric and asymmetric segregation of damaged proteins. Yet how this transition and generation of damage-free cells are achieved remained unknown. Here, by combining in vivo imaging of Hsp104-associated aggregates, a form of damage, with mathematical modeling, we find that fusion of protein aggregates facilitates asymmetric segregation. Our model predicts that, after stress, the increased number of aggregates fuse into a single large unit, which is inherited asymmetrically by one daughter cell, whereas the other one is born clean. We experimentally confirmed that fusion increases segregation asymmetry, for a range of stresses, and identified Hsp16 as a fusion factor. Our work shows that fusion of protein aggregates promotes the formation of damage-free cells. Fusion of cellular factors may represent a general mechanism for their asymmetric segregation at division.


Severe jaundice in malignant lymphoma. Report of two autopsy cases.
Two autopsy cases of malignant lymphoma with marked hyperbilirubinemia (18.6 and 36.5 mg/dl at maximum) are presented. Histology revealed the portal area to be enlarged due to lymphoma cell infiltration and cholestasis in the hepatic lobules in both. Of 30 cases of malignant lymphoma treated in our department, hyperbilirubinemia was seen in 7 cases (23%) including these two cases (6.7%) which were severely jaundiced. The occurrence rate of jaundice in malignant lymphoma to all jaundiced diseases showing serum total bilirubin levels of more than 5 mg/dl was 0.7%.


Mucosal immunity and nasal influenza vaccination.
Influenza remains a threat to public health, with immunization being a suitable method of infection prevention and control. Our understanding of the immunological regulations at the mucosa, antigen processing and presentation, and B-cell activation has improved, enabling research and targeted induction of immune responses at the site of antigen delivery. Nasal influenza immunization has distinct features compared with intramuscular vaccines, providing protection at the pathogen's entry site, higher levels of mucosal antibodies, cross-protection and needle-free application. This review summarizes our knowledge about mucosal immunity and the experience from clinical trials on the impact and safety of nasal influenza vaccination.


Characterizing peak exposure of secondhand smoke using a real-time PM2.5 monitor.
Although short-duration elevated exposures (peak exposures) to pollutants may trigger adverse acute effects, epidemiological studies to understand their influence on different health effects are hampered by lack of methods for objectively identifying peaks. Secondhand smoke from cigarettes (SHS) in the residential environment can lead to peak exposures. The aim of this study was to explore whether peaks in continuous PM2.5 data can indicate SHS exposure. A total of 41 children (21 with and 20 without SHS exposure based on self-report) from 28 families in New York City (NY, USA) were recruited. Both personal and residential continuous PM2.5 monitoring were performed for five consecutive days using MicroPEM sensors (RTI International, USA). A threshold detection method based on cumulative distribution function was developed to identify peaks. When children were home, the mean accumulated peak area (APA) for peak exposures was 297 ± 325 hour*µg/m3 for children from smoking families and six times that of the APA from non-smoking families (~50 ± 54 hour*µg/m3 ). Average PM2.5 mass concentrations for SHS exposed and unexposed children were 24 ± 15 µg/m3 and 15 ± 9 µg/m3 , respectively. The average SHS exposure duration represents ~5% of total exposure time, but ~13% of children's total PM2.5 exposure dose, equivalent to an additional 2.6 µg/m3 per day. This study demonstrated the feasibility of peak analysis for quantifying SHS exposure. The developed method can be adopted more widely to support epidemiology studies on impacts of short-term exposures.


Activation of NF-κB in CD8+ dendritic cells Ex Vivo by the γ134.5 null mutant correlates with immunity against herpes simplex virus 1.
The γ(1)34.5 protein of herpes simplex viruses (HSV) is essential for virulence. Accordingly, an HSV mutant lacking γ(1)34.5 is attenuated in vivo. Despite its vaccine potential, the mechanism by which the γ(1)34.5 null mutant triggers protective immunity is unknown. In this report we show that vaccination with the γ(1)34.5 null mutant protects against lethal challenge from wild-type virus via IκB kinase in dendritic cells (DCs), which sense virus-associated molecular patterns. Unlike mock-treated DCs, DCs primed with the γ(1)34.5 null mutant ex vivo mediate resistance to wild-type HSV after adoptive transfer into naïve mice. Furthermore, the γ(1)34.5 null mutant activates IκB kinase, which facilitates p65/RelA phosphorylation and nuclear translocation, resulting in DC maturation. While unable to produce infectious virus in DCs, this mutant virus expresses early and late genes. In its abortive infection, the γ(1)34.5 null mutant induces protective immunity more effectively in CD8(+) DCs than in CD8(-) DCs. This is mirrored by a higher level of interleukin-6 (IL-6) and IL-12 secretion by CD8(+) DCs than CD8(-) DCs. Remarkably, inhibition of p65/RelA phosphorylation or nuclear translocation in CD8(+) DCs disrupts protective immunity. These results suggest that engagement of the γ(1)34.5 null mutant with CD8(+) DCs elicits innate immunity to activate NF-κB, which translates into protective immunity.


Antinucleic acid autoantibody responses of normal human origin: antigen specificity and idiotypic characteristics compared to patients with systemic lupus erythematosus and patients with monoclonal IgM.
One idiotype family 4.6.3 derived from a human hybridoma IgML monoclonal anti-DNA antibody of normal origin is commonly expressed (approximately 85%) in the serum of patients with systemic lupus erythematosus but not in normal controls, where its level appears to fluctuate with clinical disease activity. In contrast, the IgM released by normal cultured lymphocytes in vitro expresses this idiotype family but does not bind DNA. Both idiotype 4.6.3 and anti-DNA antibodies are frequently detectable in the serum of patients with monoclonal IgM but not IgG. Therefore, it is likely that idiotype 4.6.3 reflects the expression of a common germ line immunoglobulin gene family. Some of the IgM molecules encoded by these germ line immunoglobulin genes also bind DNA.


Suramin and disulfonated stilbene derivatives stimulate the Ca2+-induced Ca2+ -release mechanism in A7r5 cells.
We have described previously a novel Ca2+-induced Ca2+-release (CICR) mechanism in permeabilized A7r5 cells (embryonic rat aorta) and 16HBE14o-cells (human bronchial mucosa) cells (J Biol Chem 278:27548-27555, 2003). This CICR mechanism was activated upon the elevation of the free cytosolic calcium concentration [Ca2+]c and was not inhibited by pharmacological inhibitors of the inositol-1,4,5-trisphosphate (IP3) receptor nor of the ryanodine receptor. This CICR mechanism was inhibited by calmodulin (CaM)1234, a Ca2+-insensitive CaM mutant, and by different members of the superfamily of CaM-like Ca2+-binding proteins. Here, we present evidence that the CICR mechanism that is expressed in A7r5 and 16HBE14o-cells is strongly activated by suramin and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS). We found several indications that both activation mechanisms are indeed two different modes of the same release system. Suramin/DIDS-induced Ca2+ release was only detected in cells that displayed the CICR mechanism, and cell types that do not express this type of CICR mechanism did not exhibit suramin/DIDS-induced Ca2+ release. Furthermore, we show that the suramin-stimulated Ca2+ release is regulated by Ca2+ and CaM in a similar way as the previously described CICR mechanism. The pharmacological characterization of the suramin/DIDS-induced Ca2+ release further confirms its properties as a novel CaM-regulated Ca2+-release mechanism. We also investigated the effects of disulfonated stilbene derivatives on IP3-induced Ca2+ release and found, in contrast to the effect on CICR, a strong inhibition by DIDS and 4'-acetoamido-4'-isothiocyanostilbene-2',2'-disulfonic acid.


Hereditary pulmonary alveolar proteinosis: pathogenesis, presentation, diagnosis, and therapy.
We identified a 6-year-old girl with pulmonary alveolar proteinosis (PAP), impaired granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor function, and increased GM-CSF. Increased serum GM-CSF may be useful to identify individuals with PAP caused by GM-CSF receptor dysfunction. We screened 187 patients referred to us for measurement of GM-CSF autoantibodies to diagnose autoimmune PAP. Five were children with PAP and increased serum GM-CSF but without GM-CSF autoantibodies or any disease causing secondary PAP; all were studied with family members, subsequently identified patients, and controls. Eight children (seven female, one male) were identified with PAP caused by recessive CSF2RA mutations. Six presented with progressive dyspnea of insidious onset at 4.8 ± 1.6 years and two were asymptomatic at ages 5 and 8 years. Radiologic and histopathologic manifestations were similar to those of autoimmune PAP. Molecular analysis demonstrated that GM-CSF signaling was absent in six and severely reduced in two patients. The GM-CSF receptor β chain was detected in all patients, whereas the α chain was absent in six and abnormal in two, paralleling the GM-CSF signaling defects. Genetic analysis revealed multiple distinct CSF2RA abnormalities, including missense, duplication, frameshift, and nonsense mutations; exon and gene deletion; and cryptic alternative splicing. All symptomatic patients responded well to whole-lung lavage therapy. CSF2RA mutations cause a genetic form of PAP presenting as insidious, progressive dyspnea in children that can be diagnosed by a combination of characteristic radiologic findings and blood tests and treated successfully by whole-lung lavage.


Pulmonary nocardiosis in the acquired immunodeficiency syndrome. Diagnosis with bronchoalveolar lavage and treatment with non-sulphur containing drugs.
A patient with the acquired immunodeficiency syndrome (AIDS) presented with Pneumocystis carinii pneumonia and pulmonary nocardiosis. The nocardial lesions appeared small and localized on chest radiograph. On two separate occasions, nocardial organisms were absent in transbronchial lung biopsy specimens, but were identified in bronchoalveolar lavage fluid probably because the latter specimen sampled a larger area of lung. The patient was initially treated with trimethoprim-sulfamethoxazole (TMP/SMX) for both infections. When TMP/SMX was discontinued because of an adverse reaction, the nocardiosis promptly exacerbated but was then easily controlled with minocycline and amikacin followed by minocycline and cycloserine. Among patients with AIDS who have sulfamethoxazole hypersensitivity during treatment for nocardiosis, alternative drugs may be efficacious and may be particularly important in this setting because they have a lower incidence of toxicity.


Does trophic status enhance or reduce the thermal tolerance of scleractinian corals? A review, experiment and conceptual framework.
Global warming, and nutrient and sediment runoff from coastal development, both exert increasing pressures on coastal coral reefs. The objective of this study was to resolve the question of whether coastal eutrophication may protect corals from thermal stress by improving their nutritional status, or rather diminish their thermal tolerance through the synergy of dual stressors. A review of previous studies on the topic of combined trophic status and heat exposure on the thermal tolerance of corals reveals a broad range of outcomes, including synergistic, additive and antagonistic effects. We conducted a 90-day long experiment exposing corals to realistic levels of elevated nutrients and sediments, and heat stress. Colonies of two common scleractinian corals (Acropora millepora and Montipora tuberculosa) were kept in coastal seawater, or coastal seawater that was further organically and nutrient enriched (OE), and/or enriched with nitrate. Batches of OE were created daily, facilitating nutrient uptake, plankton succession and organic enrichment as observed in coastal waters. After 10 days of acclimation, 67% of the colonies had their temperature gradually increased from 27° to 31.2°C. After 3-7 weeks of heat stress, colonies of both species had significantly greater reductions in fluorescence yields and lower survival in OE than without addition of OE. Furthermore, photophysiological recovery was incomplete 31-38 days after ending the heat stress only in the OE treatments. Nitrate alone had no measurable effect on survival, bleaching and recovery in either species. Skeletal growth rates were reduced by 45% in heat-stressed A. millepora and by 24% in OE-exposed M. tuberculosa. We propose a conceptual trophic framework that resolves some of the apparently contradictory outcomes revealed by the review. Our study shows that management actions to reduce coastal eutrophication can improve the resistance and resilience of vulnerable coastal coral reefs to warming temperatures.


Effects of hydration on cognitive function of pilots.
The objective of this study was to examine the effect of fluid intake and possible dehydration on cognitive flight performance of pilots. A repeated-measures, counterbalanced, mixed study design was used to examine differences in working memory, spatial orientation, and cognitive flight performance of 40 randomly selected healthy pilots after having high and low fluid intakes. Serial weights were also analyzed to determine differences in cognitive flight performance of the dehydrated (1-3% weight loss) and hydrated study participants. Results showed flight performance and spatial cognition test scores were significantly (p < 0.05) poorer for pilots who had low fluid intakes and experienced dehydration in comparison to the hydrated pilots. These findings indicate fluid intake differences resulting in dehydration may have safety implications because peak cognitive performance among pilots is critical for flight safety.


Open-Source Data and the Study of Homicide.
To date, no discussion has taken place in the social sciences as to the appropriateness of using open-source data to augment, or replace, official data sources in homicide research. The purpose of this article is to examine whether open-source data have the potential to be used as a valid and reliable data source in testing theory and studying homicide. Official and open-source homicide data were collected as a case study in a single jurisdiction over a 1-year period. The data sets were compared to determine whether open-sources could recreate the population of homicides and variable responses collected in official data. Open-source data were able to replicate the population of homicides identified in the official data. Also, for every variable measured, the open-sources captured as much, or more, of the information presented in the official data. Also, variables not available in official data, but potentially useful for testing theory, were identified in open-sources. The results of the case study show that open-source data are potentially as effective as official data in identifying individual- and situational-level characteristics, provide access to variables not found in official homicide data, and offer geographic data that can be used to link macro-level characteristics to homicide events.


Evaluation of wideband frequency responses and non-linear frequency compression for children with mild to moderate high-frequency hearing loss.
To evaluate wideband amplification and non-linear frequency compression (NLFC) as a means to improve speech recognition for children with mild/moderate hearing loss. Randomized within-subject design with repeated measures across test conditions. Eleven children with mild to moderate hearing loss were evaluated with: (1) Phonak BTE without NLFC, (2) Phonak BTE with NLFC, and (3) Oticon BTE with wideband response extending to 8000 Hz. Use of NLFC provided better detection and recognition of high-frequency stimuli (e.g. /sh/ and /s/). No difference in performance between conditions was observed for speech recognition when measured with the University of Western Ontario (UWO) plurals test and the UWO distinctive features difference test. Finally, there were no differences between conditions on the BKB-SIN test. Children with mild to moderate hearing loss have good access to high-frequency phonemes presented at fixed levels (e.g. 50 to 60 dBA) with both wideband and NLFC technology. Similarly, sentence recognition in noise was similar with wideband and NLFC. Adaptive test procedures that probe performance at lower input levels showed small but significant improvements in the detection and recognition of the phonemes /s/ and /sh/ with NLFC condition when compared to the NLFC Off and wideband conditions.


Role of apoptotic processes in platelet biogenesis.
Platelets are anucleate cells that fragment from mature megakaryocytes and play an essential role in thrombosis and hemostasis. Platelets are among the first cell types to be recruited to an injured blood vessel, assisting in endothelial repair. Platelet hyperactivation contributes to the development of atherosclerosis, myocardial infarction, and ischemia of peripheral limbs. A fall in platelet counts, due to a variety of conditions, including disseminated intravascular coagulation, chemotherapy or genetic disorders, may lead, in most severe cases, to death from hemorrhage. This review focuses on the late stages of megakaryocyte differentiation and platelet fragmentation, including associated cytoskeletal changes, and on the importance of apoptotic events for these processes. Studies point to a unique biological system in which programmed cell death may be linked with biogenesis of new cells.


Heat shock protein 70 is a potential virulence factor in murine toxoplasma infection via immunomodulation of host NF-kappa B and nitric oxide.
We propose that the 70-kDa heat shock protein (HSP70) protects virulent Toxoplasma gondii from the effects of the host by immunomodulation. This hypothesis was tested using quercetin and antisense oligonucleotides targeting the start codon of the virulent T. gondii HSP70 gene. Oligonucleotides were transiently transfected into two virulent (RH, ENT) and two avirulent (ME49, C) strains of T. gondii, significantly reducing HSP70 expression in treated parasites. Virulent parasites with reduced HSP70 expression displayed reduced proliferation in vivo, as measured by the number of tachyzoites present in spleens of infected mice. They also exhibited an enhanced rate of conversion from tachyzoites to bradyzoites in vitro. Our results implicate HSP70 as a means by which virulent strains of T. gondii evade host proinflammatory responses: when RAW 264.7 cells were exposed to parasites with reduced HSP70 expression, differential expression of inducible NO synthase (iNOS) and cell NO production were observed between infections with normal and HSP70-deficient T. gondii. iNOS message levels were significantly increased when host cells were infected with HSP70 reduced virulent tachyzoites and HSP70-related inhibition of iNOS transcription resulted in altered host NO production by virulent T. gondii infection. Virulent parasites expressing reduced levels of HSP70 initiated significantly more NF-kappa B activation in host splenocytes than infections with untreated parasites. Neither proliferative ability nor conversion from tachyzoites to bradyzoites was affected by lack of HSP70 in avirulent strains of T. gondii. Furthermore, avirulent T. gondii strains induced high levels of host iNOS expression and NO production, regardless of HSP70 expression in these parasites, and inhibition of HSP70 had no significant effects on translocation of NF-kappa B to the nucleus. Therefore, the 70-kDa parasite stress protein may be part of an important survival strategy by which virulent strains down-regulate host parasiticidal mechanisms.


Cross-Reactivity to Mutated Viral Immune Targets Can Influence CD8+ T Cell Functionality: An Alternative Viral Adaptation Strategy.
Loss of T cell immunogenicity due to mutations in virally encoded epitopes is a well-described adaptation strategy to limit host anti-viral immunity. Another described, but less understood, adaptation strategy involves the selection of mutations within epitopes that retain immune recognition, suggesting a benefit for the virus despite continued immune pressure (termed non-classical adaptation). To understand this adaptation strategy, we utilized a single cell transcriptomic approach to identify features of the HIV-specific CD8+ T cell responses targeting non-adapted (NAE) and adapted (AE) forms of epitopes containing a non-classical adaptation. T cell receptor (TCR) repertoire and transcriptome were obtained from antigen-specific CD8+ T cells of chronic (n=7) and acute (n=4) HIV-infected subjects identified by either HLA class I tetramers or upregulation of activation markers following peptide stimulation. CD8+ T cells were predominantly dual tetramer+, confirming a large proportion of cross-reactive TCR clonotypes capable of recognizing the NAE and AE form. However, single-reactive CD8+ T cells were identified in acute HIV-infected subjects only, providing the potential for the selection of T cell clones over time. The transcriptomic profile of CD8+ T cells was dependent on the autologous virus: subjects whose virus encoded the NAE form of the epitope (and who transitioned to the AE form at a later timepoint) exhibited an 'effective' immune response, as indicated by expression of transcripts associated with polyfunctionality, cytotoxicity and apoptosis (largely driven by the genes GZMB, IFNɣ, CCL3, CCL4 and CCL5). These data suggest that viral adaptation at a single amino acid residue can provide an alternative strategy for viral survival by modulating the transcriptome of CD8+ T cells and potentially selecting for less effective T cell clones from the acute to chronic phase.


Imprinting effects of UBE3A loss on synaptic gene networks and Wnt signaling pathways.
Ubiquitin E3 ligase 3A (UBE3A) encodes an E3 ubiquitin ligase whose loss from the maternal allele causes the neurodevelopmental disorder Angelman syndrome (AS). Previous studies of UBE3A function have not examined full Ube3a deletion in mouse, the complexity of imprinted gene networks in brain nor the molecular basis of systems-level cognitive dysfunctions in AS. We therefore utilized a systems biology approach to elucidate how UBE3A loss impacts the early postnatal brain in a novel CRISPR/Cas9-engineered rat Angelman model of a complete Ube3a deletion. Strand-specific transcriptome analysis of offspring from maternally or paternally inherited Ube3a deletions revealed the expected parental expression patterns of Ube3a sense and antisense transcripts by postnatal day 2 (P2) in hypothalamus and day 9 (P9) in cortex, compared to wild-type littermates. The dependency of genome-wide effects on parent-of-origin, Ube3a genotype and time (P2 and P9) was investigated through transcriptome (RNA sequencing of cortex and hypothalamus) and methylome (whole-genome bisulfite sequencing of hypothalamus). Weighted gene co-expression and co-methylation network analyses identified co-regulated networks in maternally inherited Ube3a deletion offspring enriched in postnatal developmental processes including Wnt signaling, synaptic regulation, neuronal and glial functions, epigenetic regulation, ubiquitin, circadian entrainment and splicing. Furthermore, we showed that loss of the paternal Ube3a antisense transcript resulted in both unique and overlapping dysregulated gene pathways with maternal loss, predominantly at the level of differential methylation. Together, these results provide a holistic examination of the molecular impacts of UBE3A loss in brain, supporting the existence of interactive epigenetic networks between maternal and paternal transcripts at the Ube3a locus.


Expression of heat shock protein 72 by alveolar macrophages in hypersensitivity pneumonitis.
The current study was done to look at a possible role of heat shock proteins (HSPs) in hypersensitivity pneumonitis (HP). The specific aims were to determine whether there was a difference in the expression of HSP72 in alveolar macrophages (AMs) between mice challenged with HP antigen and saline-treated control mice and between AMs obtained by bronchoalveolar lavage from 18 patients with HP and 11 normal subjects. The expression of HSP72 was studied under basal conditions and under a mild heat shock. HSP72 expression by AMs in response to in vitro stimulation with Saccharopolyspora rectivirgula was lower in AMs of control mice than in those of HP animals. HSP72 was constitutively expressed in AMs of both normal and HP subjects. Densitometric ratios showed that AMs from normal subjects responded to heat shock with a 39 degrees C-to-37 degrees C ratio of 1.72 +/- 0.18 (mean +/- SE), and AMs from HP patients responded with a ratio of 1.16 +/- 0.16 (P = 0.0377). This decreased induction by additional stress of AMs could lead to an altered immunoregulatory activity and account for the inflammation seen in HP.


[Suspected diagnosis of cancer in hospital emergency services].
To measure the frequency, trends and distribution of cancers with suspected diagnosis in the Hospital Emergency Services (HES) in Asturias during 2006-12. To describe the clinical characteristics of these cancers and to determine if they differ from those whose diagnosis is made in other services. Population based descriptive study of cancers registered in the Hospital Tumour Registry of Asturias (Spain), which provided data of patient characteristics, cancer variables (site, histology, stage, metastasis and delay), the hospital and service of diagnosis. Patients with confirmed diagnosis of cancer (non-melanoma of skin excluded) in the study period were included (N=26,020). Differences of cancer cases according to the service that had performed the suspected diagnosis were analyzed. We performed regression analysis of the time between the first symptom and the suspected diagnosis, the definitive diagnosis and treatment, controlling main confounders. Seven point nine percent (n=2,056) of all cancer cases were suspected in a HES (annual minimum of 5.3% and maximum 10.4%, with an upward trend). These patients were mainly men (60.6%), with a mean age of 67.7 years, and with lung (21.0%) and colon cancer (15.5%). The HES ranks 6th place in the list of services which diagnosed cancer. There was more diagnosis of advanced tumours (33.0%) and metastasis (29.5%) in the HES. The HES halved the time between the first symptom and the SD (-63.3 days; p<0.001), and between definitive diagnosis and initiation of treatment (-15.9 days; p<0.001) compared to the other services. The HES contribute significantly to suspected cancer diagnosis, mainly advanced and metastatic tumours in the respiratory and digestive system, whose symptoms escape accidental diagnosis conducted in primary care, and they start abruptly.


Changes in the mechanical environment of stenotic arteries during interaction with stents: computational assessment of parametric stent designs.
Clinical studies have identified factors such as the stent design and the deployment technique that are one cause for the success or failure of angioplasty treatments. In addition, the success rate may also depend on the stenosis type. Hence, for a particular stenotic artery, the optimal intervention can only be identified by studying the influence of factors such as stent type, strut thickness, geometry of the stent cell, and stent-artery radial mismatch with the wall. We propose a methodology that allows a set of stent parameters to be varied, with the aim of evaluating the difference in the mechanical environment within the wall before and after angioplasty with stenting. Novel scalar quantities attempt to characterize the wall changes inform of the contact pressure caused by the stent struts, and the stresses within the individual components of the wall caused by the stent. These quantities are derived numerically and serve as indicators, which allow the determination of the correct size and type of the stent for each individual stenosis. In addition, the luminal change due to angioplasty may be computed as well. The methodology is demonstrated by using a full three-dimensional geometrical model of a postmortem specimen of a human iliac artery with a stenosis using imaging data. To describe the material behavior of the artery, we considered mechanical data of eight different vascular tissues, which formed the stenosis. The constitutive models for the tissue components capture the typical anisotropic, nonlinear and dissipative characteristics under supra-physiological loading conditions. Three-dimensional stent models were parametrized in such a way as to enable new designs to be generated simply with regard to variations in their geometric structure. For the three-dimensional stent-artery interaction we use a contact algorithm based on smooth contact surfaces of at least C-continuity, which prevents numerical problems known from standard facet-based contact algorithm. The proposed methodology has the potential to provide a scientific basis for optimizing treatment procedures and stent geometries and materials, to help stent designers examine new stent designs "virtually," and to assist clinicians in choosing the most suitable stent for a particular stenosis.


Patient satisfaction or acquiescence? Comparing mail and telephone survey results.
Debates about whether to use telephone or mail to survey discharged patients are waged in many hospitals. Findings from a methodological test indicate the two methods result in significant differences in evaluations--differences that health care marketers would be wise to heed. Mail-back questionnaires generate a wider range of responses and minimize the "acquiescence bias" telephone interviews tend to elicit, especially in health care surveys.


Tamoxifen therapy in steroid-resistant Riedels disease.
Riedels thyroiditis is a rare chronic inflammatory disorder characterised by extensive fibrosis of the thyroid gland and sometimes the surrounding tissues. We report a case of Riedels Thyroiditis in a middle aged female presenting with goitre, stridor and dyspnoea. She initially responded to corticosteroid treatment and subsequently to tamoxifen. The rationale for these treatments are discussed.


Inactivation of sestrin 2 induces TGF-beta signaling and partially rescues pulmonary emphysema in a mouse model of COPD.
Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Cigarette smoking has been identified as one of the major risk factors and several predisposing genetic factors have been implicated in the pathogenesis of COPD, including a single nucleotide polymorphism (SNP) in the latent transforming growth factor (TGF)-beta binding protein 4 (Ltbp4)-encoding gene. Consistent with this finding, mice with a null mutation of the short splice variant of Ltbp4 (Ltbp4S) develop pulmonary emphysema that is reminiscent of COPD. Here, we report that the mutational inactivation of the antioxidant protein sestrin 2 (sesn2) partially rescues the emphysema phenotype of Ltbp4S mice and is associated with activation of the TGF-beta and mammalian target of rapamycin (mTOR) signal transduction pathways. The results suggest that sesn2 could be clinically relevant to patients with COPD who might benefit from antagonists of sestrin function.


Advances in the Molecular Genetics of Non-syndromic Syndactyly.
Syndactyly, webbing of adjacent digits with or without bony fusion, is one of the most common hereditary limb malformations. It occurs either as an isolated abnormality or as a component of more than 300 syndromic anomalies. There are currently nine types of phenotypically diverse nonsyndromic syndactyly. Non-syndromic syndactyly is usually inherited as an autosomal dominant trait, although the more severe presenting types and subtypes may show autosomal recessive or X-linked pattern of inheritance. The phenotype appears to be not only caused by a main gene, but also dependant on genetic background and subsequent signaling pathways involved in limb formation. So far, the principal genes identified to be involved in congenital syndactyly are mainly involved in the zone of polarizing activity and sonic hedgehog pathway. This review summarizes the recent progress made in the molecular genetics, including known genes and loci responsible for non-syndromic syndactyly, and the signaling pathways those genetic factors involved in, as well as clinical features and animal models. We hope our review will contribute to the understanding of underlying pathogenesis of this complicated disorder and have implication on genetic counseling.


DIAMOND (DIgital Alcohol Management ON Demand): a feasibility RCT and embedded process evaluation of a digital health intervention to reduce hazardous and harmful alcohol use recruiting in hospital emergency departments and online.
The harmful use of alcohol is a causal factor in more than 200 disease and injury conditions and leads to over 3 million deaths every year worldwide. Relatively few problem alcohol users access treatment due to stigma and lack of services. Alcohol-specific digital health interventions (DHI) may help them, but trial data comparing DHI with face-to-face treatment are lacking. We conducted a feasibility RCT of an alcohol DHI, testing recruitment, online data-collection and randomisation processes, with an embedded process evaluation. Recruitment ran from October 2015 for 12 months. Participants were adults, drinking at hazardous and harmful levels, recruited from hospital emergency departments (ED) in London or recruited online. Participants were randomised to HeLP-Alcohol, a six module DHI with weekly reminder prompts (phone, email or text message), or to face-to-face treatment as usual (TAU). Participants were invited to take part in qualitative interviews after the trial. The trial website was accessed 1074 times: 420 people completed online eligibility questionnaires; 350 did not meet eligibility criteria, 51 declined to participate, and 19 were recruited and randomised. Follow-up data were collected from three participants (retention 3/19), and four agreed to be interviewed for the process evaluation. The main themes of the interviews were:Participants were not at equipoise. They wanted to try the website and were disappointed to be randomised to face-to-face, so they were less engaged and dropped out.Other reasons for drop out included not accepting that they had a drink problem; problem drinking interfering with their ability to take part in a trial or forgetting appointments; having a busy life and being randomised to TAU made it difficult to attend appointments. This feasibility RCT aimed to test recruitment, randomisation, retention, and data collection methods, but recruited only 19 participants. This illustrates the importance of undertaking feasibility studies prior to fully powered RCTs. From the qualitative interviews we found that potential recruits were not at equipoise for recruitment. An alternative methodology, for example a preference RCT recruiting from multiple locations, needs to be explored in future trials. International Standard Randomized Controlled Trial Number: ISRCTN31789096.


Helpful and Hindering Factors in Psychodrama Field Training: A Longitudinal Mixed Methods Study of Student Development.
Although the literature indicates that students in mental health professions start to form their professional identity and competence in graduate school, there are few studies on the in-training experience of creative arts therapies students. This mixed methods study examined how five first-year students in a psychodrama master's degree program in Israel experienced their field training, with the aim of identifying the factors likely to promote or hinder the development of their professional identity and sense of professional ability. Longitudinal data were collected weekly throughout the 20-week field training experience. The students reported qualitatively on helpful and hindering factors and were assessed quantitatively on questionnaires measuring professional identity, perceived demands-abilities fit, client involvement, and therapy session evaluations. A thematic analysis of the students' reports indicated that a clear and defined setting and structure, observing the instructor as a role model, actively leading parts of the session, and observing fellow students were all helpful factors. The hindering factors included role confusion, issues related to coping with client resistance and disciplinary problems, as well as school end-of-year activities that disrupted the continuity of therapy. The quantitative results indicated that students' professional identity did not significantly change over the year, whereas a U-shaped curve trajectory characterized the changes in demands-abilities fit and other measures. Students began their field training with an overstated sense of ability that soon declined and later increased. These findings provide indications of which helping and hindering factors should be maximized and minimized, to enhance students' field training.


Mapping and confirmation of a major left ventricular mass QTL on rat chromosome 1 by contrasting SHRSP and F344 rats.
An abnormal increase in left ventricular (LV) mass, i.e., LV hypertrophy (LVH), represents an important target organ damage in arterial hypertension and has been associated with poor clinical outcome. Genetic factors are contributing to variation in LV mass in addition to blood pressure and other factors such as dietary salt intake. We set out to map quantitative trait loci (QTL) for LV mass by comparing the spontaneously hypertensive stroke-prone (SHRSP) rat with LVH and normotensive Fischer rats (F344) with contrasting low LV mass. To this end we performed a genome-wide QTL mapping analysis in 232 F2 animals derived from SHRSP and F344 exposed to high-salt (4% in chow) intake for 8 wk. We mapped one major QTL for LV mass on rat chromosome 1 (RNO1) that demonstrated strong linkage (peak logarithm of odds score 8.4) to relative LV weight (RLVW) and accounted for ∼19% of the variance of this phenotype in F2 rats. We therefore generated a consomic SHRSP-1(F344) strain in which RNO1 from F344 was introgressed into the SHRSP background. Consomic and SHRSP animals showed similar blood pressures during conventional intra-arterial measurements, while RLVW was already significantly lower (-17.7%, P<0.05) in SHRSP-1(F344) in response to a normal-salt diet; a similar significant reduction of LV mass was also observed in consomic rats after high-salt intake (P<0.05 vs. SHRSP). Thus, a major QTL on RNO1 was confirmed with significant impact on LV mass in the hypertensive background of SHRSP.


TGFβ loss activates ADAMTS-1-mediated EGF-dependent invasion in a model of esophageal cell invasion.
The TGFβ signaling pathway is essential to epithelial homeostasis and is often inhibited during progression of esophageal squamous cell carcinoma. Recently, an important role for TGFβ signaling has been described in the crosstalk between epithelial and stromal cells regulating squamous tumor cell invasion in mouse models of head-and-neck squamous cell carcinoma (HNSCC). Loss of TGFβ signaling, in either compartment, leads to HNSCC however, the mechanisms involved are not well understood. Using organotypic reconstruct cultures (OTC) to model the interaction between epithelial and stromal cells that occur in dysplastic lesions, we show that loss of TGFβ signaling promotes an invasive phenotype in both fibroblast and epithelial compartments. Employing immortalized esophageal keratinocytes established to reproduce common mutations of esophageal squamous cell carcinoma, we show that treatment of OTC with inhibitors of TGFβ signaling (A83-01 or SB431542) enhances invasion of epithelial cells into a fibroblast-embedded Matrigel/collagen I matrix. Invasion induced by A83-01 is independent of proliferation but relies on protease activity and expression of ADAMTS-1 and can be altered by matrix density. This invasion was associated with increased expression of pro-inflammatory cytokines, IL1 and EGFR ligands HB-EGF and TGFα. Altering EGF signaling prevented or induced epithelial cell invasion in this model. Loss of expression of the TGFβ target gene ROBO1 suggested that chemorepulsion may regulate keratinocyte invasion. Taken together, our data show increased invasion through inhibition of TGFβ signaling altered epithelial-fibroblasts interactions, repressing markers of activated fibroblasts, and altering integrin-fibronectin interactions. These results suggest that inhibition of TGFβ signaling modulates an array of pathways that combined promote multiple aspects of tumor invasion.


Analysis of narwhal tusks reveals lifelong feeding ecology and mercury exposure.
The ability of animals to respond to changes in their environment is critical to their persistence. In the Arctic, climate change and mercury exposure are two of the most important environmental threats for top predators.1-3 Rapid warming is causing precipitous sea-ice loss, with consequences on the distribution, composition, and dietary ecology of species4-7 and, thus, exposure to food-borne mercury.8 Current understanding of global change and pollution impacts on Arctic wildlife relies on single-time-point individual data representing a snapshot in time. These data often lack comprehensive temporal resolution and overlook the cumulative lifelong nature of stressors as well as individual variation. To overcome these challenges, we explore the unique capacity of narwhal tusks to characterize chronological lifetime biogeochemical profiles, allowing for investigations of climate-induced dietary changes and contaminant trends. Using temporal patterns of stable isotopes (δ13C and δ15N) and mercury concentrations in annually deposited dentine growth layer groups in 10 tusks from Northwest Greenland (1962-2010), we show surprising plasticity in narwhal feeding ecology likely resulting from climate-induced changes in sea-ice cover, biological communities, and narwhal migration. Dietary changes consequently impacted mercury exposure primarily through trophic magnification effects. Mercury increased log-linearly over the study period, albeit with an unexpected rise in recent years, likely caused by increased emissions and/or greater bioavailability in a warmer, ice-free Arctic. Our findings are consistent with an emerging pattern in the Arctic of reduced sea-ice leading to changes in the migration, habitat use, food web, and contaminant exposure in Arctic top predators.


Consanguinity and its sociodemographic differentials in Bhimber District, Azad Jammu and Kashmir, Pakistan.
Kashmiri population in the northeast of Pakistan has strong historical, cultural and linguistic affinities with the neighbouring populations of upper Punjab and Potohar region of Pakistan. However, the study of consanguineous unions, which are customarily practised in many populations of Pakistan, revealed marked differences between the Kashmiris and other populations of northern Pakistan with respect to the distribution of marriage types and inbreeding coefficient (F). The current descriptive epidemiological study carried out in Bhimber district of Mirpur division, Azad Jammu and Kashmir, Pakistan, demonstrated that consanguineous marriages were 62% of the total marriages (F=0.0348). First-cousin unions were the predominant type of marriages and constituted 50.13% of total marital unions. The estimates of inbreeding coefficient were higher in the literate subjects, and consanguinity was witnessed to be rising with increasing literacy level. Additionally, consanguinity was observed to be associated with ethnicity, family structure, language, and marriage arrangements. Based upon these data, a distinct sociobiological structure, with increased stratification and higher genomic homozygosity, is expected for this Kashmiri population. In this communication, we present detailed distribution of the types of marital unions and the incidences of consanguinity and inbreeding coefficient (F) across various sociodemographic strata of Bhimber/Mirpuri population. The results of this study would have implication not only for other endogamous populations of Pakistan but also for the sizeable Kashmiri community immigrated to Europe.


Atomic crystal and molecular dynamics simulation structures of human carbonic anhydrase II: insights into the proton transfer mechanism.
Human carbonic anhydrase II (HCA II) is a zinc-metalloenzyme that catalyzes the reversible interconversion of CO2 and HCO3-. The rate-limiting step of this catalysis is the transfer of a proton between the Zn-bound solvent molecule and residue His64. In order to fully characterize the active site structural features implicated in the proton transfer mechanism, the refined X-ray crystal structure of uncomplexed wild type HCA II to 1.05 A resolution with an Rcryst value of 12.0% and an Rfree value of 15.1% has been elucidated. This structure provides strong clues as to the pathway of the intramolecular proton transfer between the Zn-bound solvent and His64. The structure emphasizes the role of the solvent network, the unique positioning of solvent molecule W2, and the significance of the dual conformation of His64 in the active site. The structure is compared with molecular dynamics (MD) simulation calculations of the Zn-bound hydroxyl/His64+ (charged) and the Zn-bound water/His64 (uncharged) HCA II states. A comparison of the crystallographic anisotropic atomic thermal parameters and MD simulation root-mean-square fluctuation values show excellent agreement in the atomic motion observed between the two methods. It is also interesting that the observed active site solvent positions in the crystal structure are also the most probable positions of the solvent during the MD simulations. On the basis of the comparative study of the MD simulation results, the HCA II crystal structure observed is most likely in the Zn-bound water/His64 state. This conclusion is based on the following observations: His64 is mainly (80%) orientated in an inward conformation; electron density omit maps infer that His64 is not charged in an either inward or outward conformation; and the Zn-bound solvent is most likely a water molecule.