Life under lockdown and social restrictions - the experiences of people living with dementia and their carers during the COVID-19 pandemic in England.
The impact of COVID-19 restrictions on people living with dementia and their carers is an emerging focus of recent research determining how we can best support this population. People living with dementia have faced service curtailment, increased risk for COVID-19, as well as potential heightened deterioration. This study reports the experiences of people living with dementia and their family carers during the early months of the COVID-19 pandemic in England and the impact on them. We recruited and remotely interviewed 30 people living with dementia in their own homes and 31 family carers, via video or telephone call in mid-2020. Data were transcribed and analysed using thematic analysis. People living with dementia often had a basic understanding of COVID-19 restrictions but could have difficulty translating this into personalised risk-appraisal of their own actions. Managing COVID-19 risks facing people living with dementia at home was largely done by family carers, exemplified by changes to living arrangements, which could strain or sustain caring relationships. Well-established familial caring relationships contributed to the wellbeing of the person living with dementia and their carer, as well as keeping to simple routines that included leaving the home for exercise and stimulation. People living with dementia reported some negative psychological and cognitive effects due to the imposed restrictions, such as increased apathy, irritability, or anxiety, which were fuelled by lack of social engagement. Structuring routine (remote) social interactions where possible could increase social engagement and improve wellbeing for people living with dementia, especially those with limited familial support in a post-COVID-19 context. As some care relationships had been restructured to manage COVID-19 risks, additional carer strain may emerge as a result of the impact on the independence of the person living with dementia and come to the attention of professionals in health and care services. People living with dementia and their carers highlighted the importance of maintaining or adapting routines which may be useful learning for professionals, although additional support may be necessary for those who are impacted by more severe or worsening symptoms of dementia.


Questioning causal involvement of telomeres in aging.
Multiple studies have demonstrated that telomere length predicts mortality and that telomeres shorten with age. Although rarely acknowledged these associations do not dictate causality. I review telomerase knockout and overexpression studies and find little support that telomeres cause aging. In addition, the causality hypothesis assumes that there is a critical telomere length at which senescence is induced. This generates the prediction that variance in telomere length decreases with age. In contrast, using meta-analysis of human data, I find no such decline. Inferring the causal involvement of telomeres in aging from current knowledge is therefore speculative and could hinder scientific progress.


Transmembrane domain 6 of the human serotonin transporter contributes to an aqueously accessible binding pocket for serotonin and the psychostimulant 3,4-methylene dioxymethamphetamine.
The plasma membrane serotonin (5-HT) transporter (SERT, SLC6A4) clears 5-HT after release at nerve termini and is targeted by both antidepressant medications and psychostimulants (e.g. MDMA, cocaine). Homology modeling of human SERT (hSERT), based on high resolution structures of the microbial SLC6 family member LeuT(Aa), along with biochemical studies of wild type and mutant transporters, predicts transmembrane (TM) domains 1, 3, 6, and 8 comprise the 5-HT-binding pocket. We utilized the substituted cysteine accessibility method along with surface and site-specific biotinylation to probe TM6 for aqueous accessibility and differential interactions with 5-HT and psychostimulants. Our results are consistent with TM6 being composed of an aqueous-accessible, alpha-helical extracellular domain (TM6a) that is separated by a central, unwound section from a cytoplasmically localized domain (TM6b) with limited aqueous accessibility. The substitution G338C appears to lock hSERT in an outward-facing conformation that, although accessible to aminoethylmethanethiosulfonate-biotin, 5-HT, and citalopram, is incapable of inward 5-HT transport. Transport of 5-HT by G338C can be partially restored by the TM1 mutation Y95F. With regard to methanethiosulfonate (MTS) inactivation of uptake, TM6a Cys mutants demonstrate Na(+)-dependent [2-(trimethylammonium)ethyl]-MTS sensitivity. Studies with the centrally located substitution S336C reveal features of a common binding pocket for 5-HT and 3,4-methylenedioxymethamphetamine (MDMA). Interestingly, the substitution I333C reveals an MDMA-induced conformation not observed with 5-HT. In the context of prior studies on TM1, our findings document shared and unique features of TM6 contributing to hSERT aqueous accessibility, ligand recognition, and conformational dynamics.


Informed consent to research in persons with schizophrenia spectrum disorders.
This manuscript describes the responses and correlates of outpatients with schizophrenia spectrum disorders to a tool designed to measure comprehension before obtaining informed consent for research participation. We used the Evaluation to Sign Consent form to document comprehension in 100 outpatients as part of their consent to participate in an ongoing study of an exercise intervention. The findings suggest that using this form is a feasible and acceptable approach to documenting comprehension of research procedures prior to obtaining informed consent. Age 49 years and older and the receipt of intramuscular antipsychotic medication predicted the need for additional assistance to complete the Evaluation to Sign Consent form successfully (chi(2) = 8.29, P = 0.016). Nurse researchers should consider documenting comprehension with this tool owing to its availability, time efficiency and utility.


Mutations of myelodysplastic syndromes (MDS): An update.
The plethora of knowledge gained on myelodysplastic syndromes (MDS), a heterogeneous pre-malignant disorder of hematopoietic stem cells, through sequencing of several pathway genes has unveiled molecular pathogenesis and its progression to AML. Evolution of phenotypic classification and risk-stratification based on peripheral cytopenias and blast count has moved to five-tier risk-groups solely concerning chromosomal aberrations. Increased frequency of complex abnormalities, which is associated with genetic instability, defines the subgroup of worst prognosis in MDS. However, the independent effect of monosomal karyotype remains controversial. Recent discoveries on mutations in RNA-splicing machinery (SF3B1, SRSF2, ZRSR2, U2AF1, U2AF2); DNA methylation (TET2, DNMT3A, IDH1/2); chromatin modification (ASXL1, EZH2); transcription factor (TP53, RUNX1); signal transduction/kinases (FLT3, JAK2); RAS pathway (KRAS, NRAS, CBL, NF1, PTPN11); cohesin complex (STAG2, CTCF, SMC1A, RAD21); DNA repair (ATM, BRCC3, DLRE1C, FANCL); and other pathway genes have given insights into the independent effects and interaction of co-occurrence of mutations on disease-phenotype. RNA-splicing and DNA methylation mutations appeared to occur early and are reported as 'founder' mutations in over 50% MDS patients. TET2 mutation, through altered DNA methylation, has been found to have independent prognostic response to hypomethylating agents. Moreover, presence of DNMT3A, TET2 and ASXL1 mutations in normal elderly individuals forms the basis of understanding that accumulation of somatic mutations may not cause direct disease-development; however, cooperation with other mutations in the genes that are frequently mutated in myeloid and other hematopoietic cancers might result in clonal expansion through self-renewal and/or proliferation of hematopoietic stem cells. Identification of small molecules as inhibitors of epigenetic mutations has opened avenues for tailoring targeted drug development. The recommendations of a Clinical Advisory Committee is being considered by WHO for a revised classification of risk-groups of MDS, which is likely to be published in mid 2016, based on the new developments and discoveries of gene mutations.


A randomised controlled trial of a tailored multifaceted strategy to promote implementation of a clinical guideline on induced abortion care.
To evaluate the effectiveness and efficiency of a tailored multifaceted strategy, delivered by a national clinical effectiveness programme, to implement a guideline on induced abortion. Cluster randomised controlled trial. All 26 hospital gynaecology units in Scotland providing induced abortion care. Following the identification of barriers to guideline implementation, intervention units received a package comprising audit and feedback, unit educational meetings, dissemination of structured case records and promotion of a patient information booklet. Control units received printed guideline summaries alone. Compliance with five key guideline recommendations (primary outcomes) and compliance with other recommendations, patient satisfaction and costs of the implementation strategy (secondary outcomes). No effect was observed for any key recommendation: appointment with a gynaecologist within five days of referral (odds ratio 0.89; 95% confidence interval 0.50 to 1.58); ascertainment of cervical cytology history (0.93; 0.36 to 2.40); antibiotic prophylaxis or screening for lower genital tract infection (1.70; 0.71 to 5.99); use of misoprostol as an alternative to gemeprost (1.00; 0.27 to 1.77); and offer of contraceptive supplies at discharge (1.11; 0.48 to 2.53). Median pre-intervention compliance was near optimal for antibiotic prophylaxis and misoprostol use. No intervention benefit was observed for any secondary outcome. The intervention costs an average of pound 2607 per gynaecology unit. The tailored multifaceted strategy was ineffective. This was possibly attributable to high pre-intervention compliance and the limited impact of the strategy on factors outside the perceived control of clinical staff.


Interactions of pro-apoptotic BH3 proteins with anti-apoptotic Bcl-2 family proteins measured in live MCF-7 cells using FLIM FRET.
Increased interactions between pro-apoptotic BH3-only proteins and anti-apoptotic Bcl-2 family proteins at mitochondria result in tumor initiation, progression and resistance to traditional chemotherapy. Drugs that mimic the BH3 region are expected to release BH3-only proteins from anti-apoptotic proteins, inducing apoptosis in some cancer cells and sensitizing others to chemotherapy. Recently, we applied fluorescence lifetime imaging microscopy and fluorescence resonance energy transfer to measure protein:protein interactions for the Bcl-2 family of proteins in live MCF-7 cells using fluorescent fusion proteins. While the BH3-proteins bound to Bcl-XL and Bcl-2, the BH3 mimetic ABT-737 inhibited binding of only Bad and tBid, but not Bim. We have extended our studies by investigating ABT-263, a clinical drug based on ABT-737. We show that the inhibitory effects and pattern of the two drugs are comparable for both Bcl-XL and Bcl-2. Furthermore, we show that mutation of a conserved residue in the BH3 region in Bad and tBid disrupted their interactions with Bcl-XL and Bcl-2, while the corresponding BimEL mutant showed no decrease in binding to these anti-apoptotic proteins. Therefore, in MCF-7 cells, Bim has unique binding properties compared with other BH3-only proteins that resist displacement from Bcl-XL and Bcl-2 by BH3 mimetics.


Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1).
To evaluate the efficacy and safety of different doses and regimens of filgotinib, an oral Janus kinase 1 inhibitor, as add-on treatment to methotrexate (MTX) in patients with active rheumatoid arthritis (RA) and inadequate response to MTX. In this 24-week phase IIb study, patients with moderate-to-severe active RA receiving a stable dose of MTX were randomised (1:1:1:1:1:1:1) to receive placebo or 50, 100 or 200 mg filgotinib, administered once daily or twice daily. Primary end point was the percentage of patients achieving a week 12 American College of Rheumatology (ACR)20 response. Overall, 594 patients were randomised and treated. At week 12, significantly more patients receiving filgotinib 100 mg once daily or 200 mg daily (both regimens) achieved an ACR20 response versus placebo. For other key end points at week 12 (ACR50, ACR-N, Disease Activity Score based on 28 joints and C reactive protein value, Clinical Disease Activity Index, Simplified Disease Activity Index and Health Assessment Questionnaire-Disability Index), differences in favour of 100 or 200 mg filgotinib daily were seen versus placebo; responses were maintained or improved through to week 24. Rapid onset of action and dose-dependent responses were observed for most efficacy end points and were associated with an increased haemoglobin concentration. No significant differences between once-daily and twice-daily regimens were seen. Treatment-emergent adverse event rates were similar in placebo and filgotinib groups. Serious infections occurred in one and five patients in the placebo and filgotinib groups, respectively. No tuberculosis or opportunistic infections were reported. Filgotinib as add-on to MTX improved the signs and symptoms of active RA over 24 weeks and was associated with a rapid onset of action. Filgotinib was generally well tolerated. NCT01888874.


Dodecylphosphocholine micelles as a membrane-like environment: new results from NMR relaxation and paramagnetic relaxation enhancement analysis.
To further examine to what extent a dodecyl-phosphocholine (DPC) micelle mimics a phosphatidylcholine bilayer environment, we performed 13C, 2H, and 31P NMR relaxation measurements. Our data show that the dynamic behavior of DPC phosphocholine groups at low temperature (12 degrees C) corresponds to that of a phosphatidylcholine interface at high temperature (51 degrees C). In the presence of helical peptides, a PMP1 fragment, or an annexin fragment, the DPC local dynamics are not affected whereas the DPC aggregation number is increased to match an appropriate area/volume ratio for accommodating the bound peptides. We also show that quantitative measurements of paramagnetic relaxation enhancements induced by small amounts of spin-labeled phospholipids on peptide proton signals provide a meaningful insight on the location of both PMP1 and annexin fragments in DPC micelles. The paramagnetic contributions to the relaxation were extracted from intra-residue cross-peaks of NOESY spectra for both peptides. The location of each peptide in the micelles was found consistent with the corresponding relaxation data. As illustrated by the study of the PMP1 fragment, paramagnetic relaxation data also allow us to supply the missing medium-range NOEs and therefore to complete a standard conformational analysis of peptides in micelles.


Blood transfusion. An independent risk factor for postinjury multiple organ failure.
To determine if blood transfusion is a consistent risk factor for postinjury multiple organ failure (MOF), independent of other shock indexes. A 55-month inception cohort study ending on August 30, 1995. Data characterizing postinjury MOF were prospectively collected. Multiple logistic regression analysis was performed on 5 sets of data. Set 1 included admission data (age, sex, comorbidity, injury mechanism, Glasgow Coma Scale, Injury Severity Score, and systolic blood pressure determined in the emergency department) plus the amount of blood transfused within the first 12 hours. In the subsequent 4 data sets, other indexes of shock (early base deficit, early lactate level, late base deficit, and late lactate level) were sequentially added. Additionally, the same multiple logistic regression analyses were performed with early MOF and late MOF as the outcome variables. Denver General Hospital, Denver, Colo, is a regional level I trauma center. Five hundred thirteen consecutive trauma patients admitted to the trauma intensive care unit with an Injury Severity Score greater than 15 who were older than 16 years and who survived longer than 48 hours. None. The relationship of blood transfusions and other shock indexes with the outcome variable, MOF. A dose-response relationship between early blood transfusion and the later development of MOF was identified. Despite the inclusion of other indexes of shock, blood transfusion was identified as an independent risk factor in 13 of the 15 multiple logistic regression models tested; the odds ratios were high, especially in the early MOF models. Blood transfusion is an early consistent risk factor for postinjury MOF, independent of other indexes of shock.


Mortality of middle aged white South African gold miners.
A cohort of 3971 white miners in South Africa, born between 1 January 1916 and 31 December 1930 who were alive on 1 January 1970 and currently working in the East Rand-Central Rand-West Rand mining areas, was followed up for nine years, when the 3426 survivors were aged from 48 to 62. Fifteen (0.4%) had been lost to view and 530 had died (13.4% of the 3956 whose vital status was determined). Based on the occupational histories of a 30% sample of the cohort it was known that the vast majority were gold miners. An estimated 93% had worked more than 85% of their mining service in gold mines. Standardised mortality ratios were calculated as the ratios of the deaths observed in the cohort to those expected on the basis of concurrent mortality in the reference population--the total white male population in the Republic of South Africa. There was little sign of a "healthy worker effect"; of several possible reasons, one is that the white miner in South Africa had adopted certain unhealthy life styles, another is that the reference population was otherwise inappropriate. The SMR for all causes of death (117.6) was raised because of excess mortality due to the following causes: lung cancer (161.2), chronic respiratory diseases (165.6), and acute and chronic nephritis (381.0). A case-referent analysis was carried out on those miners in the cohort who had spent at least 85% of their service in gold mines. For lung cancer, smoking was the main contributory factor towards disease. For chronic respiratory diseases bronchitis, emphysema, asthma, pneumoconiosis, and pulmonary heart disease), smoking was also the main risk factor, but there was an association wih cumulative dust exposure. Raised blood pressure, smoking, and adiposity were associated with ischaemic heart disease as was the duration of service underground. Study of comprehensive medical histories in all 530 deaths, including necropsy in most cases, showed that none was directly due to pneumoconiosis or to tuberculosis.


Risperidone-induced topological alterations of anatomical brain network in first-episode drug-naive schizophrenia patients: a longitudinal diffusion tensor imaging study.
It remains unclear whether the topological deficits of the white matter network documented in cross-sectional studies of chronic schizophrenia patients are due to chronic illness or to other factors such as antipsychotic treatment effects. To answer this question, we evaluated the white matter network in medication-naive first-episode schizophrenia patients (FESP) before and after a course of treatment. We performed a longitudinal diffusion tensor imaging study in 42 drug-naive FESP at baseline and then after 8 weeks of risperidone monotherapy, and compared them with 38 healthy volunteers. Graph theory was utilized to calculate the topological characteristics of brain anatomical network. Patients' clinical state was evaluated using the Positive and Negative Syndrome Scale (PANSS) before and after treatment. Pretreatment, patients had relatively intact overall topological organizations, and deficient nodal topological properties primarily in prefrontal gyrus and limbic system components such as the bilateral anterior and posterior cingulate. Treatment with risperidone normalized topological parameters in the limbic system, and the enhancement positively correlated with the reduction in PANSS-positive symptoms. Prefrontal topological impairments persisted following treatment and negative symptoms did not improve. During the early phase of antipsychotic medication treatment there are region-specific alterations in white matter topological measures. Limbic white matter topological dysfunction improves with positive symptom reduction. Prefrontal deficits and negative symptoms are unresponsive to medication intervention, and prefrontal deficits are potential trait biomarkers and targets for negative symptom treatment development.


Cerebrovascular disease and functional outcome after coronary artery bypass surgery.
A series of patients undergoing coronary artery bypass surgery was studied prospectively to see if angiographic evidence of cerebrovascular disease proved predictive of the incidence of neuropsychological deficit 8 days or 8 weeks after surgery. In 47 patients, intravenous digital subtraction angiography was carried out preoperatively to assess the presence and severity of atheromatous changes in the carotid arteries; 51% had evidence of vessel wall disease and 17% had stenosis of at least one carotid artery in the neck, although only one patient had severe narrowing. Overall, 77% of these 47 patients showed a neuropsychological deficit as defined by a significantly reduced score in at least two of 10 tests administered 8 days after surgery. Eight weeks after surgery 36% still showed a deficit. The incidence of neuropsychological deficit was not significantly greater among those patients with angiographically visible carotid artery disease. The mechanism of surgery-related cognitive impairment is briefly discussed in the light of these findings.


The identification of the inhibitory gamma-subunits of the type 6 retinal cyclic guanosine monophosphate phosphodiesterase in non-retinal tissues: differential processing of mRNA transcripts.
Here, we report that mouse lung expresses gamma-subunit (PDEgamma) transcripts of the rod and cone photoreceptor cGMP phosphodiesterase genes (Pde6g and Pde6h, respectively). Moreover, a major 14-kDa protein (p14) in lung membranes was immunostained with antibodies that react with both rod and cone PDEgamma. We show that p14 is, in fact, a mixture of rod and cone PDEgamma, based on three additional lines of evidence. First, p14 was also immunostained with antibodies specific for the cone PDEgamma isoform. Second, the expression of p14 immunostained with antibodies recognizing both rod and cone PDEgamma was substantially reduced in lung membranes from Pde6g-/- mice. In contrast, the fraction of p14 stained with cone PDEgamma-specific antibodies was not altered in the Pde6g-/- mice. Third, the absence of the Pde6g transcript was correlated with reduced levels of p14 in Pde6g-/- mice. We have also found that mouse lung contains a small Pde6h transcript that has a 41-bp deletion resulting in a frame change, derived by differential mRNA processing of exon 3 of Pde6h. BLAST searches also revealed a rat ovary EST that has the same 41-bp deletion causing the same frame change. However, the premature in-frame stop codon seen in the short Pde6h transcript is absent and the regular stop codon is out of frame leading to a predicted ORF extension into the 3' UTR. These findings show that rod and cone PDEgamma isoforms are expressed in lung and seem to have a critical role in regulating p42/p44 mitogen-activated protein kinase signaling.


Priorities in the implementation of partner services for HIV/STIs in high-income nations: a narrative review of evidence and recommendations.
Partner notification (PN) remains a crucial prevention tool to reduce sexually transmitted infection (STI) transmission and prevent STI-related morbidity. Although there have been a variety of different approaches taken to facilitate the notification, testing and management of sexual contacts of STIs and HIV, there is an increasing acknowledgement that these interventions are unscalable and have relatively little impact on disease transmission. At the same time, an expanding body of evidence supports a shift in the emphasis of STI outreach-related work from an exclusive focus on PN to an approach that incorporates epidemiologic data collection, case management, and PN, an approach that is sometimes called partner services (PS). In this review, we appraise the current evidence base for different PN interventions for STIs in high-income nations, make recommendations for best practices, present a schema for how public health programs might prioritise PS for different programs, and identify priority research questions related to PN.


Cell specific ingrowth hydrogels.
Extracellular mimetic hydrogels formed from peptide crosslinkers and polyethylene glycol monomers permit cell-controlled invasion. The use of matrix metalloproteinase specific peptides might further allow for selective control of different cell-type invasion. In this study, the invasion of fibroblasts and vascular smooth muscle cells (VSMC) into hydrogels polymerised with either a peptide generally permissive for matrix metalloproteinase (MMP) degradation or peptides preferentially cleaved by MMP-14 or MMP-9 enzymes were compared. The two cell-types invaded the MMP permissive hydrogel equally. However, invasion of VSMC into MMP-14 selective peptide crosslinked hydrogels was diametrically opposite in nature to that of fibroblasts whereby VSMC showed a two-fold increase into these hydrogels relative to that observed in permissive hydrogels whilst fibroblasts had a relative two-fold decrease (p < 0.01). These findings are suggestive that invasion and growth of different cell-types in engineered synthetic extracellular matrix mimics may be controlled selectively by the choice of protease specific peptide crosslinker and this could have general utility in tissue regenerative and engineering approaches.


Tailored anti-TNF therapy during pregnancy in patients with IBD: maternal and fetal safety.
Antitumour necrosis factor (TNF) during pregnancy in patients with IBD is related to high fetal anti-TNF levels. We evaluated maternal and child safety on discontinuing anti-TNF in the second trimester of pregnancy. Two groups of women with IBD were prospectively followed-up during pregnancy: women in sustained remission stopped anti-TNF before week 25 (stop group) and the remaining group continued anti-TNF beyond week 30 (continue group). Maternal, birth and 1-year child outcomes were compared with children of non-IBD women. Overall, 106 patients with 83 completed pregnancies were included. Relapse rate after week 22 did not differ between the stop (n=51) and continue (n=32) groups (5 (9.8%) versus 5 (15.6%), p=0.14). There was no difference in allergic reactions (p=1.00) or loss of response (p=1.00) postpartum between the two groups. Birth outcomes were comparable. Infants from both groups had lower birth weight (p=0.001), shorter gestational term (p=0.0001), were more often delivered via caesarean section (p=0.0001) and were less often breastfed (p=0.0001) compared with infants from non-IBD controls. Growth, infection rate, allergies, eczema and adverse reactions to vaccines were comparable across the stop and the continue groups as well as the children of anti-TNF-exposed and non-IBD women at 1 year. To limit anti-TNF exposure in utero, anti-TNF can be stopped safely in the second trimester in women with IBD in sustained remission. In patients not in sustained remission, anti-TNF may be continued without clear additional risks to the fetus. We observed excellent 1-year child outcomes compared with children from non-IBD controls.


Dynamic Functional Stiffness Index of the Ankle Joint During Daily Living.
Exploring ankle joint physiologic functional stiffness is crucial for improving the design of prosthetic feet that aim to mimic normal gait. We hypothesized that ankle joint stiffness would vary among the different activities of daily living and that the magnitude of the stiffness would indicate the degree of energy storage element sufficiency in terms of harvesting and returning energy. We examined sagittal plane ankle moment versus flexion angle curves from 12 healthy subjects during the daily activities. The slopes of these curves were assessed to find the calculated stiffness during the peak energy return and harvest phases. For the energy return and harvest phases, stiffness varied from 0.016 to 0.283 Nm/kg° and 0.025 and 0.858 Nm/kg°, respectively. The optimum stiffness during the energy return phase was 0.111 ± 0.117 Nm/kg° and during the energy harvest phase was 0.234 ± 0.327 Nm/kg°. Ankle joint stiffness varied significantly during the activities of daily living, indicating that an energy storage unit with a constant stiffness would not be sufficient in providing energy regenerative gait during all activities. The present study was directed toward the development of a complete data set to determine the torque-angle properties of the ankle joint to facilitate a better design process.


Interventions to improve adherence to first-line antibiotics in respiratory tract infections. The impact depends on the intensity of the intervention.
Many interventions aimed at improving the quality of antibiotic prescribing have been investigated, but more knowledge is needed regarding the impact of different intensity interventions. To compare the effect of two interventions, a basic intervention (BI) and intensive intervention (II), aimed to improve the adherence to recommendations on first-line antibiotics in patients with respiratory tract infections (RTIs). General practitioners (GPs) from different regions of Spain were offered two different interventions on antibiotic prescribing. They registered all patients with RTIs during 15 days before (2008) and after (2009) the intervention. GPs in Catalonia were exposed to BI including prescriber feedback, clinical guidelines and training sessions focused on appropriate antibiotic prescribing. The other group of GPs was exposed to an II, which besides BI, also included training and access to point-of-care tests in practice. The GPs registered 15 073 RTIs before the intervention and 12 760 RTIs after. The antibiotic prescribing rate reduced from 27.7% to 19.8%. Prescribing of first-choice antibiotics increased after the intervention in both groups. In the group of GPs following the BI, first-line antibiotics accounted for 23.8% of antibiotics before the intervention and 29.4% after (increase 5.6%, 95% confidence interval (CI): 1.2-10%), while in the group of GPs following the II these figures were 26.2% and 48.6% (increase 22.4%, 95% CI: 18.8-26%), respectively. Multifaceted interventions targeting GPs can improve adherence to recommendations for first-line antibiotic prescribing in patients with RTI, with intensive interventions that include point-of-care testing being more effective.


A 3-D "Super Surface" Combining Modern Intraocular Lens Formulas to Generate a "Super Formula" and Maximize Accuracy.
Cataract surgery is the most common eye surgery. Calculating the most accurate power of the intraocular lens (IOL) is a critical factor in optimizing patient outcomes. To develop a graphical method for displaying IOL calculation formulas in 3 dimensions, and to describe a method that uses the most accurate and current information on IOL formulas, adjustments, and lens design to create one "super surface" and develop an IOL "super formula." A numerical computing environment was used to create 3-D surfaces of IOL formulas: Hoffer Q, Holladay I, Holladay I with Koch adjustment, Haigis, and SRK/T. The surfaces were then analyzed to determine where the IOL powers calculated by each formula differed by more than 0.5, 1.0, and 1.5 diopters (D) from each of the other formulas. Next, based on the current literature and empirical knowledge, a super surface was rendered that incorporated the ideal portions from 4 of the 5 formulas to generate a super formula. Last, IOL power values of a set of 100 eyes from consecutive patients at an eye institute were calculated using the 5 formulas and super formula. The study was performed from December 11, 2014, to April 20, 2015. Analysis was conducted from February 18 to May 6, 2015. Intraocular lens power value in diopters and the magnitude of disparity between an existing individual IOL formula and our super formula. In the 100 eyes tested, the super formula localized to the correct portion of the super surface 100% of the time and thus chose the most appropriate IOL power value. The individual formulas deviated from the optimal super formula IOL power values by more than 0.5 D 30% of the time in Hoffer Q, 16% in Holladay I, 22% in Holladay I with Koch adjustment, 48% in Haigis, and 24% in SRK/T. A novel method was developed to represent IOL formulas in 3 dimensions. An IOL super formula was formulated that incorporates the ideal segments from each of the existing formulas and uses the ideal IOL formula for an individual eye. The expectation is that this method will broaden the conceptual understanding of IOL calculations, improve clinical outcomes for patients, and stimulate further progress in IOL formula research.


Exploring stress-induced cognitive impairment in middle aged, centrally obese adults.
Extensive research has shown that psychosocial stress can induce cognitive impairment. However, few studies have explored impairment following acute stress exposure in individuals with central obesity. Central obesity co-occurs with glucocorticoid excess and can lead to elevated cortisol responses to stress. It is not clear whether centrally obese individuals exhibit greater cognitive impairment following acute stress. Cortisol responses to stress versus no-stress control were compared in 66 high- and low waist to hip ratio (WHR) middle-aged adults (mean age of 46 ± 7.17 years). Cognitive performance post exposure was assessed using Cambridge Automated Neuropsychological Test Battery. It was hypothesised that high WHR would exhibit greater cortisol in response to stress exposure and would show poorer cognitive performance. Males, particularly of high WHR, tended to secrete greater cortisol during stress exposure. Exposure to stress and increasing WHR were specifically associated with poorer performance on declarative memory tasks (spatial recognition memory and paired associates learning). These data tentatively suggest a reduction in cognitive performance in those with central obesity following exposure to acute stress. Further research is needed to elucidate the effects of stress on cognition in this population.


Measurement of cortisol in saliva: a comparison of measurement error within and between international academic-research laboratories.
Hundreds of scientific publications are produced annually that involve the measurement of cortisol in saliva. Intra- and inter-laboratory variation in salivary cortisol results has the potential to contribute to cross-study inconsistencies in findings, and the perception that salivary cortisol results are unreliable. This study rigorously estimates sources of measurement variability in the assay of salivary cortisol within and between established international academic-based laboratories that specialize in saliva analyses. One hundred young adults (Mean age: 23.10 years; 62 females) donated 2 mL of whole saliva by passive drool. Each sample was split into multiple- 100 µL aliquots and immediately frozen. One aliquot of each of the 100 participants' saliva was transported to academic laboratories (N = 9) in the United States, Canada, UK, and Germany and assayed for cortisol by the same commercially available immunoassay. 1.76% of the variance in salivary cortisol levels was attributable to differences between duplicate assays of the same sample within laboratories, 7.93% of the variance was associated with differences between laboratories, and 90.31% to differences between samples. In established-qualified laboratories, measurement error of salivary cortisol is minimal, and inter-laboratory differences in measurement are unlikely to have a major influence on the determined values.


Emotion categorization of body expressions in narrative scenarios.
Humans can recognize emotions expressed through body motion with high accuracy even when the stimuli are impoverished. However, most of the research on body motion has relied on exaggerated displays of emotions. In this paper we present two experiments where we investigated whether emotional body expressions could be recognized when they were recorded during natural narration. Our actors were free to use their entire body, face, and voice to express emotions, but our resulting visual stimuli used only the upper body motion trajectories in the form of animated stick figures. Observers were asked to perform an emotion recognition task on short motion sequences using a large and balanced set of emotions (amusement, joy, pride, relief, surprise, anger, disgust, fear, sadness, shame, and neutral). Even with only upper body motion available, our results show recognition accuracy significantly above chance level and high consistency rates among observers. In our first experiment, that used more classic emotion induction setup, all emotions were well recognized. In the second study that employed narrations, four basic emotion categories (joy, anger, fear, and sadness), three non-basic emotion categories (amusement, pride, and shame) and the "neutral" category were recognized above chance. Interestingly, especially in the second experiment, observers showed a bias toward anger when recognizing the motion sequences for emotions. We discovered that similarities between motion sequences across the emotions along such properties as mean motion speed, number of peaks in the motion trajectory and mean motion span can explain a large percent of the variation in observers' responses. Overall, our results show that upper body motion is informative for emotion recognition in narrative scenarios.


Pharmacokinetics, toxicities, and efficacies of sodium stibogluconate formulations after intravenous administration in animals.
The pharmacokinetics and toxicities of free sodium stibogluconate (SSG) and two vesicular formulations of this drug (a nonionic surfactant vesicular formulation of SSG [SSG-NIV] and SSG-NIV-dextran) were determined after treatment with a single intravenous dose in healthy dogs and were related to their antileishmanial efficacies in mice. Analysis of the curves of the concentrations in plasma after intravenous administration of SSG and SSG-NIV in dogs showed that both formulations produced similar antimony (Sb) pharmacokinetics. In contrast, treatment with SSG-NIV-dextran significantly modified the pharmacokinetics of the drug. The elimination half-life was four times longer (280 min) than that observed after administration of SSG (71 min) (P = 0.01), and the volume of distribution at steady state (V(SS)) was also increased (V(SS) for SSG, 0.21 liters/kg; V(SS) for SSG-NIV-dextran, 0.34 liters/kg [P = 0.02]), thus indicating that drug encapsulation favors the distribution of Sb into organs and increases its residence time in tissues. This would explain the superior antileishmanial efficacy of this formulation compared to those of the free drug in mice. No signs of toxicity were found in dogs after SSG and SSG-NIV administration. However, SSG-NIV-dextran treatment was associated with short-term toxicity, demonstrated by the development of chills and diarrhea, which cleared by 24 h postdosing, and hepatic dysfunction at 24 h postdosing (P < 0.05). The levels of all the biochemical parameters had returned to normal at 1 month postdosing. No signs of toxicity were observed in mice treated with all three formulations.


Cancer mortality in a population exposed to nephrite processing.
Although asbestos has been recognised as a strong carcinogen, many asbestos minerals exist in concrete masses, and the health risks of these materials remain inconclusive. Nephrite jade is a concrete mass of amphibole that consists of asbestiform and non-asbestiform particles. The objective of the study was to explore the carcinogenetic effect of nephrite. We examined cancer mortality between 1979 and 2011 in Fengtian, where nephrite was mass produced from 1970 to 1980, and calculated standardised mortality ratios (SMRs). We observed significantly elevated mortality risks for cancer of the hypopharynx (SMR 2.31; 95% CI 1.37 to 3.65), larynx (SMR 2.51; 95% CI 1.55 to 3.83), oesophagus (SMR 2.04; 95% CI 1.62 to 2.54) and stomach (SMR 1.38; 95% CI 1.17 to 1.63). This study analysed the lengths, widths, structures, chemical compositions, aerodynamic diameters and distributions of elongated mineral particles (EMPs) in airways. The majority of the EMPs (68%) were short (<5 μm) and thin (<0.5 µm), and possessed asbestiform structures. The median aerodynamic diameter of the EMPs was 1.2 μm. The total deposition proportion in airways was 51.3%. The major deposition sites were the head airway (37.5%), followed by the alveolar region (10.6%) and the tracheobronchial region (3.2%). The results have shown an association between EMPs and increased risk of respiratory and digestive cancers. Further research is needed that includes information on smoking habits and exposure to asbestos.


3D aggregation of cells in packed microgel media.
In both natural and applied contexts, investigating cell self-assembly and aggregation within controlled 3D environments leads to improved understanding of how structured cell assemblies emerge, what determines their shapes and sizes, and whether their structural features are stable. However, the inherent limits of using solid scaffolding or liquid spheroid culture for this purpose restrict experimental freedom in studies of cell self-assembly. Here we investigate multi-cellular self-assembly using a 3D culture medium made from packed microgels as a bridge between the extremes of solid scaffolds and liquid culture. We find that cells dispersed at different volume fractions in this microgel-based 3D culture media aggregate into clusters of different sizes and shapes, forming large system-spanning networks at the highest cell densities. We find that the transitions between different states of assembly can be controlled by the level of cell-cell cohesion and by the yield stress of the packed microgel environment. Measurements of aggregate fractal dimension show that those with increased cell-cell cohesion are less sphere-like and more irregularly shaped, indicating that cell stickiness inhibits rearrangements in aggregates, in analogy to the assembly of colloids with strong cohesive bonds. Thus, the effective surface tension often expected to emerge from increased cell cohesion is suppressed in this type of cell self-assembly.


CT in the early diagnosis of herpes simplex encephalitis.
Herpes simplex is the most common cause of sporadic viral encephalitis. The recent development of specific antiviral chemotherapeutic agents offers new optimism for patients with this disorder if therapy is begun on or before the fifth day of the disease. Eight patients with herpes simplex encephalitis were studied by CT, and a characteristic but not pathognomonic pattern was observed. In each case a low density lesion was noted in the medial portion of the temporal lobe with extension into the Island of Reil. Sparing of the lenticular nucleus was observed in all cases. Mass effect and streaky linear enhancement after contrast administration was also seen. Unfortunately, the findings may be subtle or absent before the fifth day of disease, and thus CT scans must be examined with a high index of suspicion if the correct diagnosis is to be made at a time when therapy may prove useful. Hemorrhagic areas are rarely observed on CT in this disorder despite the frequent occurrence on pathologic studies. The full extent of involvement may not be appreciated on scans obtained during the first 10 days of the disease.


Hybrid optical processor for pattern recognition and classification using a generalized set of pattern functions.
A pattern recognition and classification system has been studied which computes the inner products of an input pattern with a generalized set of pattern functions. The system utilizes a filter whose impulse response consists of an amplitude superposition of a set of generalized pattern functions in phase-coded form and has a space-bandwidth product the same as that of a matched filter for one pattern function. Each pattern function in the general set may correspond to a different variation (e.g., scale or rotation) of the object to be detected. Because the amplitude superposition of the phase-coded pattern functions takes place in the digital computer, and the filter is created as a computer-generated hologram, the biasing problem of conventional, multiple exposure (intensity superposition) holograms is significantly reduced. This makes it possible to encode many more pattern functions than was previously possible using multiple exposure techniques. Furthermore, the use of computer-generated holograms eliminates the need to generate a transparency for each pattern function and complex phase code. To facilitate real-time operation a hybrid system was constructed consisting of a liquid crystal light valve for incoherent-to-coherent image conversion, a TV camera and image digitizer for image analysis, and a laser scanner to produce the computer-generated holograms. Both the TV camera/digitizer and the laser scanner systems were interfaced to a digital computer for automatic operation. Experimental results using the hybrid system are presented for pattern recognition of rotated and scaled objects and pattern classification. In the second half of the paper we provide an analysis on the SNR of the processor employing the coded-phase technique, on the diffraction efficiencies of computer-generated filters (amplitude superposition) vs conventional filters (intensity superposition), and on the number of pattern functions required for a certain recognition task.


Analysis of cause-specific mortality in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study.
Expectations that reestablishing and maintaining sinus rhythm in patients with atrial fibrillation might improve survival were disproved in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. This report describes the cause-specific modes of death in the AFFIRM treatment groups. All deaths in patients enrolled in AFFIRM underwent blinded review by the AFFIRM Events Committee, and a mode of death was assigned. In AFFIRM, 2033 patients were randomized to a rhythm-control strategy and 2027 patients to a rate-control strategy. During a mean follow-up of 3.5 years, there were 356 deaths in the rhythm-control patients and 310 deaths in the rate-control patients (P=0.07). In the rhythm-control group, 129 patients (9%) died of a cardiac cause, and in the rate-control group, 130 patients (10%) died (P=0.95). Both groups had similar rates of arrhythmic and nonarrhythmic cardiac deaths. The numbers of vascular deaths were similar in the 2 groups: 35 (3%) in the rhythm-control group and 37 (3%) in the rate-control group (P=0.82). There were no differences in the rates of ischemic stroke and central nervous system hemorrhage. In the rhythm-control group, there were 169 noncardiovascular deaths (47.5% of the total number of deaths), whereas in the rate-control arm, there were 113 noncardiovascular deaths (36.5% of the total number of deaths) (P=0.0008). Differences in noncardiovascular death rates were due to pulmonary and cancer-related deaths. Management of atrial fibrillation with a rhythm-control strategy conferred no advantage over a rate-control strategy in cardiac or vascular mortality and may be associated with an increased noncardiovascular death rate.


Effects of duty-cycled passive acoustic recordings on detecting the presence of beaked whales in the northwest Atlantic.
This study investigated the effects of using duty-cycled passive acoustic recordings to monitor the daily presence of beaked whale species at three locations in the northwest Atlantic. Continuous acoustic records were subsampled to simulate duty cycles of 50%, 25%, and 10% and cycle period durations from 10 to 60 min. Short, frequent listening periods were most effective for assessing the daily presence of beaked whales. Furthermore, subsampling at low duty cycles led to consistently greater underestimation of Mesoplodon species than either Cuvier's beaked whales or northern bottlenose whales, leading to a potential bias in estimation of relative species occurrence.


Placenta-Derived Cells for Acute Brain Injury.
Acute brain injury resulting from ischemic/hemorrhagic or traumatic damage is one of the leading causes of mortality and disability worldwide and is a significant burden to society. Neuroprotective options to counteract brain damage are very limited in stroke and traumatic brain injury (TBI). Given the multifaceted nature of acute brain injury and damage progression, several therapeutic targets may need to be addressed simultaneously to interfere with the evolution of the injury and improve the patient's outcome. Stem cells are ideal candidates since they act on various mechanisms of protection and repair, improving structural and functional outcomes after experimental stroke or TBI. Stem cells isolated from placenta offer advantages due to their early embryonic origin, ease of procurement, and ethical acceptance. We analyzed the evidence for the beneficial effects of placenta-derived stem cells in acute brain injury, with the focus on experimental studies of TBI and stroke, the engineering strategies pursued to foster cell potential, and characterization of the bioactive molecules secreted by placental cells, known as their secretome, as an alternative cell-free strategy. Results from the clinical application of placenta-derived stem cells for acute brain injury and ongoing clinical trials are summarily discussed.


Interpretation bias and anxiety in childhood: stability, specificity and longitudinal associations.
Biases in the interpretation of ambiguous material are central to cognitive models of anxiety; however, understanding of the association between interpretation and anxiety in childhood is limited. To address this, a prospective investigation of the stability and specificity of anxious cognitions and anxiety and the relationship between these factors was conducted. Sixty-five children (10-11 years) from a community sample completed measures of self-reported anxiety, depression, and conduct problems, and responded to ambiguous stories at three time points over one-year. Individual differences in biases in interpretation of ambiguity (specifically "anticipated distress" and "threat interpretation") were stable over time. Furthermore, anticipated distress and threat interpretation were specifically associated with anxiety symptoms. Distress anticipation predicted change in anxiety symptoms over time. In contrast, anxiety scores predicted change in threat interpretation over time. The results suggest that different cognitive constructs may show different longitudinal links with anxiety. These preliminary findings extend research and theory on anxious cognitions and their link with anxiety in children, and suggest that these cognitive processes may be valuable targets for assessment and intervention.


Minimal impact of an iron-fortified lipid-based nutrient supplement on Hb and iron status: a randomised controlled trial in malnourished HIV-positive African adults starting antiretroviral therapy.
Anaemia, redistribution of Fe, malnutrition and heightened systemic inflammation during HIV infection confer an increased risk of morbidity and mortality in HIV patients. We analysed information on Fe status and inflammation from a randomised, double blind, controlled phase-III clinical trial in Lusaka, Zambia and Mwanza, Tanzania. Malnourished patients (n 1815) were recruited at referral to antiretroviral therapy (ART) into a two-stage nutritional rehabilitation programme, randomised to receive a lipid-based nutrient supplement with or without added micronutrients. Fe was included in the intervention arm during the second stage, given from 2 to 6 weeks post-ART. Hb, serum C-reactive protein (CRP), serum ferritin and soluble transferrin receptor (sTfR) were measured at recruitment and 6 weeks post-ART. Multivariable linear regression models were used to assess the impact of the intervention, and the effect of reducing inflammation from recruitment to week 6 on Hb and Fe status. There was no effect of the intervention on Hb, serum ferritin, sTfR or serum CRP. A one-log decrease of serum CRP from recruitment to week 6 was associated with a 1.81 g/l increase in Hb (95% CI 0.85, 2.76; P< 0.001), and a 0.11 log decrease in serum ferritin (95% CI - 0.22, 0.03; P= 0.012) from recruitment to week 6. There was no association between the change in serum CRP and the change in sTfR over the same time period (P= 0.78). In malnourished, HIV-infected adults receiving dietary Fe, a reduction in inflammation in the early ART treatment period appears to be a precondition for recovery from anaemia.


Occupation and mesothelioma in Sweden: updated incidence in men and women in the 27 years after the asbestos ban.
We updated the Swedish component of the Nordic Occupational Cancer (NOCCA) Study through 2009 in order to investigate the incidence of mesothelioma of the peritoneum and pleura in both genders, and explored occupational exposures that may be associated with mesothelioma. The Swedish component of the NOCCA Study includes 6.78 million individuals. Data from this cohort were linked to the population-based Swedish Cancer Registry and Swedish Total Population Registry for three periods between 1961 and 2009, and then further linked to the Swedish NOCCA job-exposure matrix, which includes 25 carcinogenic substances and the corresponding exposure levels for 280 occupations. Multivariate analysis was used to calculate standardized incidence ratios (SIRs) for mesothelioma of the peritoneum and pleura by gender, occupational category, carcinogenic substance, and for multiple occupational exposures simultaneously. A total of 3,716 incident mesotheliomas were recorded (21.1% in women). We found a significantly increased risk of mesothelioma in 24 occupations, as well as clear differences between the genders. Among men, increased risks of mesothelioma of the pleura were observed in male-dominated occupations, with the greatest elevation of risk among plumbers (SIR, 4.99; 95% confidence interval, 4.20 to 5.90). Among women, increased risks were observed in sewing workers, canning workers, packers, cleaners, and postal workers. In multivariate analysis controlling for multiple occupational exposures, significant associations were only observed between asbestos exposure and mesothelioma. Asbestos exposure was associated with mesothelioma incidence in our study. The asbestos ban of 1982 has yet to show any clear effect on the occurrence of mesothelioma in this cohort. Among women, the occupations of canning workers and cleaners showed increased risks of mesothelioma of the pleura without evidence of asbestos exposure.


Do different styles of antismoking ads influence the types of smokers who call quitlines?
This study examined the relationship between television antismoking advertisements and the proportion of smokers who call a smokers' quitline who are ready to quit or have high confidence in quitting. The primary data of interest came from completed intake interviews of smokers. Using a generalized linear model, we modeled the proportion of Quitline callers who are ready to quit and/or have high confidence in quitting. The primary explanatory variable was monthly target audience rating points (TARPs) for antismoking advertisements, a measure of broadcast media exposure, obtained from the state's media buyer. The proportions of callers ready to quit and with high confidence in quitting were negatively associated with total TARPs. This result, over all ad types, was driven by why to quit-graphic ads. These results suggest that why to quit-graphic ads influence smokers who are less ready to quit or have lower confidence they can quit, likely new quitters, to call the Quitline.


FKBPL is a critical antiangiogenic regulator of developmental and pathological angiogenesis.
The antitumor effects of FK506-binding protein like (FKBPL) and its extracellular role in angiogenesis are well characterized; however, its role in physiological/developmental angiogenesis and the effect of FKBPL ablation has not been evaluated. This is important as effects of some angiogenic proteins are dosage dependent. Here we evaluate the regulation of FKBPL secretion under angiogenic stimuli, as well as the effect of FKBPL ablation in angiogenesis using mouse and zebrafish models. FKBPL is secreted maximally by human microvascular endothelial cells and fibroblasts, and this was specifically downregulated by proangiogenic hypoxic signals, but not by the angiogenic cytokines, VEGF or IL8. FKBPL's critical role in angiogenesis was supported by our inability to generate an Fkbpl knockout mouse, with embryonic lethality occurring before E8.5. However, whilst Fkbpl heterozygotic embryos showed some vasculature irregularities, the mice developed normally. In murine angiogenesis models, including the ex vivo aortic ring assay, in vivo sponge assay, and tumor growth assay, Fkbpl(+/-) mice exhibited increased sprouting, enhanced vessel recruitment, and faster tumor growth, respectively, supporting the antiangiogenic function of FKBPL. In zebrafish, knockdown of zFkbpl using morpholinos disrupted the vasculature, and the phenotype was rescued with hFKBPL. Interestingly, this vessel disruption was ineffective when zcd44 was knocked-down, supporting the dependency of zFkbpl on zCd44 in zebrafish. FKBPL is an important regulator of angiogenesis, having an essential role in murine and zebrafish blood vessel development. Mouse models of angiogenesis demonstrated a proangiogenic phenotype in Fkbpl heterozygotes.


Evaluation of zeolite for control of odorants emissions from simulated poultry manure storage.
Poultry operations are associated with emissions of aerial ammonia (NH3), volatile organic compounds (VOCs), and odor, and the magnitude of emissions is influenced by manure management practices. As a manure treatment additive, zeolites have been shown to have the potential to control NH3. Because of their properties it is also expected that zeolites could effectively adsorb VOCs and odor. The effectiveness of zeolite in controlling odor and VOCs was qualitatively evaluated in this controlled laboratory study involving simulated poultry manure storage. In the first two trials, zeolite was topically applied on nearly fresh laying hen manure at the rates of 0, 2.5, 5, and 10% (by weight). In the third trial, zeolite was topically applied at 5% with each addition of fresh manure into the storage vessel. Headspace samples from the emission vessels were collected with solid phase microextraction (SPME) and analyzed on a multidimensional-gas chromatograph-mass spectrometry-olfactometry (MDGC-MS-O) system for identification and prioritization of poultry manure odorants. Acetic acid, butanoic acid, isovaleric acid, indole, and skatole were consistently controlled in the headspace, with the reduction rate being proportional to the zeolite application rate. Dimethyl trisulfide and phenol were consistently generated, and with a few exceptions, the rate of generation was proportional to the application rate. Average reduction of the odor caused by all odorants evaluated with SPME-GC-O was 67% (+/-12%) and 51% (+/-26%) for the two topical applications, respectively, while no significant reduction of VOCs and odor was detected for the layered application.


Computerized analysis of occlusal contacts in bruxism patients treated with occlusal splint therapy.
Occlusal splints are commonly used to prevent tooth wear caused by bruxism. However, the effects of splints on occlusion are still unclear. Although it is rarely alluded in literature, splints can provoke severe occlusal alterations and other complications. This study was aimed to identify differences in the responses of individuals with bruxism and healthy individuals to a full-arch maxillary stabilization splint in terms of occlusal changes. Occlusal contacts in 20 (5 male, 15 female) bruxism patients and 20 (5 male, 15 female) controls with normal occlusion were evaluated before and after occlusal splint therapy. T-Scan III, a computerized occlusal analysis system, was used to simultaneously measure occlusion and disclusion times as well as left-right and anterior-posterior contact distributions before splint therapy and 3 months after therapy. Wilcoxon and Mann-Whitney U tests were used for statistical analyses (α=.05). No differences were found in the posterior contact of bruxism patients before and after stabilization splint treatment. However, differences in posterior contact were observed between bruxists and normal individuals prior to treatment, and this difference disappeared following treatment. The results of this study showed the use of a stabilization splint may not have an effect on occlusion. However, the area of posterior occlusal contact among bruxists was found to be greater than that of normal individuals. According to this study, the clinical use of splints may be harmless.


A nonsynonymous SNP in ATG16L1 predisposes to ileal Crohn's disease and is independent of CARD15 and IBD5.
A genome-wide association scan of nonsynonymous DNA polymorphisms identified association of a threonine-to-alanine substitution (T300A) in the autophagy-related 16-like gene ATG16L1 with Crohn's disease. We investigated this association in independent U.K. cohorts of Crohn's disease and ulcerative colitis. The T300A variant (rs2241880) was genotyped in an independent sample of 727 Crohn's disease and 877 ulcerative colitis cases, and in 579 controls. We then performed an extension analysis combining these data with the U.K. data from the initial study to give a total of 1236 U.K. Crohn's disease cases and 1235 controls to estimate disease risk and test for interaction with the CARD15 and IBD5 risk loci and for association with disease subtypes. The association of T300A was replicated in the independent sample of 727 Crohn's disease cases (P = .001), and was strongly associated in the extended analysis of 1236 Crohn's cases (P = 2.4 x 10(-6)). The 300A/A genotype conferred a 1.65-fold risk of Crohn's disease, with a 2.2-fold risk of ileal disease. Analysis of the interaction of ATG16L1 with CARD15 and IBD5 indicated that all 3 loci contribute independently to disease risk. Homozygosity for the risk allele at all 3 loci conferred a combined risk of 20.4 (95% confidence interval: 8.71, 47.7) for Crohn's disease. The ATG16L1 risk genotype showed a modest but significant association with ulcerative colitis (P = .026). The association of ATG16L1 with Crohn's disease and possibly with ulcerative colitis supports a role for autophagy in the pathogenesis of inflammatory bowel disease.


Multi-scale processes in metapopulations: contributions of stage structure, rescue effect, and correlated extinctions.
Metapopulations function and persist through a combination of processes acting at a variety of spatial scales. Although the contributions of stage structure, spatially correlated processes, and the rescue effect to metapopulation dynamics have been investigated in isolation, there is no empirical demonstration of all of these processes shaping dynamics in a single system. Dispersal and settlement differ according to the life stage involved; therefore, stage-specific population size may outperform total population size when predicting colonization-extinction dynamics. Synchrony in patch dynamics can lead to accelerated metapopulation extinction, although empirical evidence of the interplay between correlated colonization events and correlated extinctions is lacking. Likewise, few empirical examples exist that provide compelling evidence of migration acting to reduce extinction risk (the rescue effect). We parameterized a hierarchy of metapopulation models to investigate these predictions using a seven-year study of a naturally occurring water vole (Arvicola amphibius) metapopulation. Specifically, we demonstrated the importance of local stage structure in predicting both colonization and extinction events using juvenile and adult population sizes, respectively. Using a novel approach for quantifying correlation in extinction events, we compared the scale of synchrony in colonization and extinction. Strikingly, the scale of dispersal acting to synchronize colonization was an order of magnitude larger than that of correlated extinctions (halving distance of the effect: 12.40 km and 0.89 km, respectively). Additionally, we found compelling evidence for the existence of a nontrivial rescue effect. Here we provide a novel empirical demonstration of a variety of metapopulation processes operating at multiple spatial scales, further emphasizing the need to consider stage structure and local synchrony in the dynamics of spatially dependent, stage-structured (meta) populations.


Functional and biochemical characterization of a secreted I-J(+) suppressor factor that binds to immunoglobulin.
A secreted product of a T cell leukemic cell line, LH-8, was examined for its biochemical and biological properties. The factor that we have termed Immunoglobulin-Binding T cell Suppressor Factor (IgB-TsF) was shown to be suppressive for the in vitro and in vivo humoral response to a variety (but not all) antigens tested. The cell surface phenotype of the LH-8.1 subclone was M.Ig(-), Thy-1(+), L3T4(-), Lyt-2(+), FcR(-), MAC-1(-), and H-2b(+). In addition, both the cell surface and secreted factor, IgB-TsF, of LH-8.1 expressed determinants that were recognized by anti-I-Jb mAbs but not by an anti-I-Jd monoclonal. The same factor also retained an affinity for the Fc portion of approximately 30% of randomly selected, purified mAbs. This binding could be abolished if the Fab or F(ab')2 fragments of these mAb were used, but was found to be unrelated to isotype of the respective mAbs. Using subclones that expressed quantitative differences in their ability to exert suppression as sources of biosynthetically labeled IgB-TsF, we have shown the suppressor activity correlated with a single, 28 kD protein. Furthermore, comparisons of these same subclones that differ in their suppressor activity, do not show any direct correlation of this biological activity with the expression of the previously described T cell receptor genes. It also suggests that at least some suppressor cell subsets may use the same or related family of T cell receptor genes for their recognitive stage of activation as helper and cytotoxic T cell subsets, but not for their effector stage of immunologic suppression.


Validity and feasibility of a satellite imagery-based method for rapid estimation of displaced populations.
Estimating the size of forcibly displaced populations is key to documenting their plight and allocating sufficient resources to their assistance, but is often not done, particularly during the acute phase of displacement, due to methodological challenges and inaccessibility. In this study, we explored the potential use of very high resolution satellite imagery to remotely estimate forcibly displaced populations. Our method consisted of multiplying (i) manual counts of assumed residential structures on a satellite image and (ii) estimates of the mean number of people per structure (structure occupancy) obtained from publicly available reports. We computed population estimates for 11 sites in Bangladesh, Chad, Democratic Republic of Congo, Ethiopia, Haiti, Kenya and Mozambique (six refugee camps, three internally displaced persons' camps and two urban neighbourhoods with a mixture of residents and displaced) ranging in population from 1,969 to 90,547, and compared these to "gold standard" reference population figures from census or other robust methods. Structure counts by independent analysts were reasonably consistent. Between one and 11 occupancy reports were available per site and most of these reported people per household rather than per structure. The imagery-based method had a precision relative to reference population figures of <10% in four sites and 10-30% in three sites, but severely over-estimated the population in an Ethiopian camp with implausible occupancy data and two post-earthquake Haiti sites featuring dense and complex residential layout. For each site, estimates were produced in 2-5 working person-days. In settings with clearly distinguishable individual structures, the remote, imagery-based method had reasonable accuracy for the purposes of rapid estimation, was simple and quick to implement, and would likely perform better in more current application. However, it may have insurmountable limitations in settings featuring connected buildings or shelters, a complex pattern of roofs and multi-level buildings. Based on these results, we discuss possible ways forward for the method's development.


Calcium channel gating and modulation by transmitters depend on cellular compartmentalization.
Voltage-gated Ca2+ channels participate in dendritic integration, yet functional properties of Ca2+ channels and mechanisms of their modulation by neurotransmitters in dendrites are unknown. Here we report how pharmacologically identified Ca2+ channels behave in different neural compartments. Whole-cell and cell-attached patch-clamp recordings were made on both cell bodies and electrically isolated dendrites of sympathetic neurons. We found not only that Ca2+ channel populations differentially contribute to somatic and dendritic currents but also that families of Ca2+ channels display gating properties and neurotransmitter modulation that depend on channel compartmentalization. By comparison with their somatic counterparts, dendritic N-type Ca2+ currents were hypersensitive to neurotransmitters and G proteins. Single-channel analysis showed that dendrites express a unique N-type channel that has enhanced interaction with Gbetagamma. Thus Ca2+ channels in dendrites seem to be specialized elements with unique regulatory mechanisms.


A systematic review of elderly suicide prevention programs.
Suicide rates are highest among the elderly, yet research on suicide prevention in old age remains a much-neglected area. We carried out a systematic review to examine the results of interventions aimed at suicidal elderly persons and to identify successful strategies and areas needing further exploration. Searches through various electronic databases yielded 19 studies with an empirical evaluation of a suicide prevention or intervention program designed especially for adults aged 60 years and older. Most studies were centered on the reduction of risk factors (depression screening and treatment, and decreasing isolation), but when gender was considered, programs were mostly efficient for women. The empirical evaluations of programs attending to the needs of high-risk older adults seemed positive; most studies showed a reduction in the level of suicidal ideation of patients or in the suicide rate of the participating communities. However, not all studies used measures of suicidality to evaluate the outcome of the intervention, and rarely did they aim at improving protective factors. Innovative strategies should improve resilience and positive aging, engage family and community gatekeepers, use telecommunications to reach vulnerable older adult, and evaluate the effects of means restriction and physicians education on elderly suicide.


Human trophoblast cells express CD4 and are permissive for productive infection with HIV-1.
The European collaborative study of HIV-infected pregnant women in Europe now indicates a 13% risk of fetal HIV infection (originally thought to be about 30%, and possibly higher in some countries). Several reports suggest trans-placental passage. However, the detailed mechanisms associated with such vertical transmission have not yet been clarified. We have examined the possibility that HIV enters placental tissue from maternal blood via binding to CD4 and Fc receptors (FcR) at the trophoblast level, allowing intraplacental infection. Here we report the detection of several FcR with distinct localization in the placental villus as well as CD4 surface expression on human trophoblast cells. In addition, we show that trophoblastic cells interact specifically with the gp120/gp160 viral envelope protein. By their tissue localization, these receptors could be responsible for the entry of HIV into the fetal placental cells. Furthermore, purified placental cells can be directly infected by HIV in vitro, and the infection is inhibited by soluble CD4. This suggests a crucial role of the CD4 receptor but an additional way of entry cannot be excluded. Such an in vitro model may be suitable for further studies concerning placental HIV transmission and its prevention.


Inverted (hobnail) high-grade prostatic intraepithelial neoplasia and invasive inverted pattern.
High-grade prostatic intraepithelial neoplasia (HGPIN) is considered to be an important precursor for prostatic adenocarcinoma. The present study aimed to investigate the histological features of the uncommon inverted (hobnail) pattern of HGPIN in transrectal ultrasonographic (TRUS) prostatic needle biopsies from 13 cases. These 13 diagnosed cases of inverted HGPIN were identified out of a total of 2,034 TRUS biopsies (0.63%), obtained from patients suspected to have prostate cancer. The hobnail pattern is comprised of secretory cell nuclei, which are histologically localized at the luminal surface of the prostate gland, rather than the periphery, and exhibit reverse polarity. Histological examinations were performed and the results demonstrated that 5 of the 13 cases exhibited pure inverted histology, while HGPIN was observed to be histologically associated with other patterns in the remaining 8 patients. In addition, an association with adenocarcinoma was identified in 7 of the 13 cases. All 7 carcinomas accompanied by inverted HGPIN were conventional acinar adenocarcinoma cases; of note, for these 7 cases, the Gleason score was 7 for each. One acinar adenocarcinoma case accompanying inverted HGPIN demonstrated hobnail characteristics in large areas of the invasive component. It was observed that nuclei were proliferated in the invasive cribriform glands, which was comparable to that of inverted HGPIN, and were located on the cytoplasmic luminal surface; a similar morphology was also observed in individual glands. In conclusion, the results of the present study suggested that the hobnail HGPIN pattern may be of diagnostic importance due to its high association with adenocarcinoma and the high Gleason scores in the accompanying carcinomas.


Multisensory numerosity judgments for visual and tactile stimuli.
To date, numerosity judgments have been studied only under conditions of unimodal stimulus presentation. It is therefore unclear whether the same limitations on correctly reporting the number of unimodal visual or tactile stimuli presented in a display might be expected under conditions in which participants have to count stimuli presented simultaneously in two or more different sensory modalities. In Experiment 1, we investigated numerosity judgments using both unimodal and bimodal displays consisting of one to six vibrotactile stimuli (presented over the body surface) and one to six visual stimuli (seen on the body via mirror reflection). Participants had to count the number of stimuli regardless of their modality of presentation. Bimodal numerosity judgments were significantly less accurate than predicted on the basis of an independent modality-specific resources account, thus showing that numerosity judgments might rely on a unitary amodal system instead. The results of a second experiment demonstrated that divided attention costs could not account for the poor performance in the bimodal conditions of Experiment 1. We discuss these results in relation to current theories of cross-modal integration and to the cognitive resources and/or common higher order spatial representations possibly accessed by both visual and tactile stimuli.


Qualitative study on the price of drugs for multiple sclerosis: Gaming the system.
To describe pricing decisions, justifications, and attitudes among current and former biotech industry executives for companies that manufacture multiple sclerosis disease-modifying therapies. Four leaders in biotech who have been directly involved in multiple sclerosis disease-modifying therapy pricing or marketing volunteered to participate in 30-minute semistructured interviews conducted via telephone. An expert in qualitative methods moderated and analyzed the interviews alongside the principal investigator. Brief, preinterview online surveys were also administered to provide additional context and insight for discussion. Interviews were audio-recorded and professionally transcribed. Participants consistently stated that initial price decisions were dictated by the price of existing competitors in the market. Revenue maximization and corporate growth were drivers of price escalations in the absence of continued market penetration. Lower revenue predictions outside the United States also informed pricing strategies. The growing complexity and clout of drug distribution and supply channels were also cited as contributing factors. Although decisions to raise prices were motivated by the need to attract investment for future innovation, recouping drug-specific research and development costs as a justification was not strongly endorsed as having a significant influence on pricing decisions. Contrary to prevailing narratives that underscore drug development costs, findings from our interviews suggest that the existing price ecosystem, overall corporate growth, international pricing disparities, and supply chain-related distortions may play a more central role in drug pricing decision.


Barriers to evidence based practice in primary care: a review of the literature.
People with health problems deserve a service that is based on best available evidence and is possible within obtainable resources. No credible health professional could deny that sound evidence should be an integral part of clinical decision making. The demand for up to date information to inform care and treatment highlights the crucial role of research and development in the modern health service. However, within primary care, practitioners have not always been able to underpin their actions with robust research findings. In addition, the research activities within primary care are limited to a small number of 'enthusiasts'. This paper aims to analyse the literature surrounding this area, highlighting the significance of United Kingdom (UK) government reports on primary care, primary care research activities and the pursuit of evidence based practice in primary care. It shows that primary care research has been the 'poor relation' in terms of research funding and this has resulted is a dearth of high quality research results to underpin practice.


Establishment of induced pluripotent stem cells from centenarians for neurodegenerative disease research.
Induced pluripotent stem cell (iPSC) technology can be used to model human disorders, create cell-based models of human diseases, including neurodegenerative diseases, and in establishing therapeutic strategies. To detect subtle cellular abnormalities associated with common late-onset disease in iPSCs, valid control iPSCs derived from healthy donors free of serious late-onset diseases are necessary. Here, we report the generation of iPSCs from fibroblasts obtained immediately postmortem from centenarian donors (106- and 109-years-old) who were extremely healthy until an advanced age. The iPSCs were generated using a conventional method involving OCT4, SOX2, KLF4, and c-MYC, and then differentiated into neuronal cells using a neurosphere method. The expression of molecules that play critical roles in late-onset neurodegenerative diseases by neurons differentiated from the centenarian-iPSCs was compared to that of neurons differentiated from iPSCs derived from familial Alzheimer's disease and familial Parkinson's disease (PARK4: triplication of the α synuclein gene) patients. The results indicated that our series of iPSCs would be useful in neurodegeneration research. The iPSCs we describe, which were derived from donors with exceptional longevity who were presumed to have no serious disease risk factors, would be useful in longevity research and as valid super-controls for use in studies of various late-onset diseases.


Stimulation of oral fibroblast chemokine receptors identifies CCR3 and CCR4 as potential wound healing targets.
The focus of this study was to determine which chemokine receptors are present on oral fibroblasts and whether these receptors influence proliferation, migration, and/or the release of wound healing mediators. This information may provide insight into the superior wound healing characteristics of the oral mucosa. The gingiva fibroblasts expressed 12 different chemokine receptors (CCR3, CCR4, CCR6, CCR9, CCR10, CXCR1, CXCR2, CXCR4, CXCR5, CXCR7, CX3CR1, and XCR1), as analyzed by flow cytometry. Fourteen corresponding chemokines (CCL5, CCL15, CCL20, CCL22, CCL25, CCL27, CCL28, CXCL1, CXCL8, CXCL11, CXCL12, CXCL13, CX3CL1, and XCL1) were used to study the activation of these receptors on gingiva fibroblasts. Twelve of these fourteen chemokines stimulated gingiva fibroblast migration (all except for CXCL8 and CXCL12). Five of the chemokines stimulated proliferation (CCL5/CCR3, CCL15/CCR3, CCL22/CCR4, CCL28/CCR3/CCR10, and XCL1/XCR1). Furthermore, CCL28/CCR3/CCR10 and CCL22/CCR4 stimulation increased IL-6 secretion and CCL28/CCR3/CCR10 together with CCL27/CCR10 upregulated HGF secretion. Moreover, TIMP-1 secretion was reduced by CCL15/CCR3. In conclusion, this in-vitro study identifies chemokine receptor-ligand pairs which may be used in future targeted wound healing strategies. In particular, we identified the chemokine receptors CCR3 and CCR4, and the mucosa specific chemokine CCL28, as having an predominant role in oral wound healing by increasing human gingiva fibroblast proliferation, migration, and the secretion of IL-6 and HGF and reducing the secretion of TIMP-1.


The C-terminal basic tail of RhoG assists the guanine nucleotide exchange factor trio in binding to phospholipids.
The multidomain protein Trio regulates among others neuronal outgrowth and axonal guidance in vertebrates and invertebrates. Trio contains two Dbl-homology/pleckstrin homology (DH/PH) tandem domains that activate several RhoGTPases. Here, we present the x-ray structure of the N-terminal DH/PH, hereafter TrioN, refined to 1.7-A resolution. We show that the relative orientations of the DH and PH domains of TrioN and free Dbs are similar. However, this relative orientation is dissimilar to Dbs in the Dbs/Cdc42 structure. In vitro nucleotide exchange experiments catalyzed by TrioN show that RhoG is approximately 3x more efficiently exchanged than Rac and support the conclusion that RhoG is likely the downstream target of TrioN. Residues 54 and 69, which are not conserved between the two GTPases, are responsible for this specificity. Dot-blot assay reveals that the TrioN-PH domain does not detectably bind phosphatidylinositol 3,4-bisphosphate, PtdIns(3,4)P(2), or other phospholipids. This finding is supported by our three-dimensional structure and affinity binding experiments. Interestingly, the presence of RhoG but not Rac or a C-terminal-truncated RhoG mutant allows TrioN to bind PtdIns(3,4)P(2) with a micromolar affinity constant. We conclude the variable C-terminal basic tail of RhoG specifically assists the recruitment of the TrioN-PH domain to specific membrane-bound phospholipids. Our data suggest a role for the phosphoinositide 3-kinase, PI 3-kinase, in modulating the Trio/RhoG signaling pathway.


Effects of systematic clinical supervision on psychiatric nurses' sense of coherence, creativity, work-related strain, job satisfaction and view of the effects from clinical supervision: a pre-post test design.
There are few investigations of the type and the outcome of interventions aimed at supporting nurses caring for psychiatric patients. Therefore a prepost-test design study was used in which 22 psychiatric nurses, on a general psychiatric ward were examined before, during and after one year of systematic clinical supervision combined with supervised documented, planned, individualized care. The methods used were the Sense of Coherence scale (SOC), the Creative Climate Questionnaire (CCQ), the Work-Related Strain Inventory and 34 statements from the Satisfaction with Nursing Care and Work Questionnaire (SNCW). In addition 14 statements were developed to evaluate the nurses' view of the effects from clinical supervision. The baseline values for the CCQ indicated a stagnant organization and a high score in the conflict dimension indicated personal and emotional tensions within the organization. The intervention led to a significantly increased creative and innovative climate in the dimensions for trust, idea time and reduced conflicts. However, the organizational climate remained stagnant. The nurses' view of the effects from clinical supervision also increased significantly. There were no significant changes in the nurses' SNCW, WRSI or SOC score. The result of the correlation analysis indicated that a strong sense of coherence was related to low work-related strain but not to unsatisfactory working conditions/milieu. The results gave some support to the idea that systematic clinical supervision and supervised nursing care plans constitute one type of support strategy that improves creativity and the organizational climate. It may, not, however, buffer for interpersonal problems. Further research is required to explore the need for effects of various support systems depending on the circumstances in the organization.


Differential involvement of Hedgehog signaling in butterfly wing and eyespot development.
Butterfly eyespots may have evolved from the recruitment of pre-existent gene circuits or regulatory networks into novel locations on the wing. Gene expression data suggests one such circuit, the Hedgehog (Hh) signaling pathway and its target gene engrailed (en), was recruited from a role in patterning the anterior-posterior insect wing axis to a role patterning butterfly eyespots. However, while Junonia coenia expresses hh and en both in the posterior compartment of the wing and in eyespot centers, Bicyclus anynana lacks hh eyespot-specific expression. This suggests that Hh signaling may not be functioning in eyespot development in either species or that it functions in J. coenia but not in B. anynana. In order to test these hypotheses, we performed functional tests of Hh signaling in these species. We investigated the effects of Hh protein sequestration during the larval stage on en expression levels, and on wing size and eyespot size in adults. Hh sequestration led to significantly reduced en expression and to significantly smaller wings and eyespots in both species. But while eyespot size in B. anynana was reduced proportionately to wing size, in J. coenia, eyespots were reduced disproportionately, indicating an independent role of Hh signaling in eyespot development in J. coenia. We conclude that while Hh signaling retains a conserved role in promoting wing growth across nymphalid butterflies, it plays an additional role in eyespot development in some, but not all, lineages of nymphalid butterflies. We discuss our findings in the context of alternative evolutionary scenarios that led to the differential expression of hh and other Hh pathway signaling members across nymphalid species.


Granuloma formation in patients receiving BCG immunotherapy.
Eleven patients with acute myeloblastic leukaemia have received repeated intravenous injections of BCG containing 4-9 X 10(6) live organisms per millilitre. Non-caseating epithelioid granulomas, sometimes with giant-cell formation, have been demonstrated in eight bone marrow aspirates. Seven patients had granulomas in the liver, three in the lung, one in the spleen, one in lymph nodes, and one in a skin biopsy. One patient had a raised serum alkaline phosphatase, but none of the patients had any illness which could be related to the presence of granulomas. Granuloma formation appeared more extensive in four patients who were probably anergic before BCG treatment. Until the significance of this finding becomes clear great care should be taken when giving BCG by the intratumour of intravenous routes to potentially immunoincompetent patients.


Comparison of the acute ultraviolet photoresponse in congenic albino hairless C57BL/6J mice relative to outbred SKH1 hairless mice.
Hairless albino Crl:SKH1-Hr(hr) mice are commonly utilized for studies in which hair or pigmentation would introduce an impediment to observational studies. Being an outbred strain, the SKH1 model suffers from key limitations that are not seen with congenic mouse strains. Inbred and congenic C57BL/6J mice are commonly utilized for modified genetic mouse models. We compare the acute UV-induced photoresponse between outbred SKH1 mice and an immune competent, hairless, albino C57BL/6J congenic mouse line [B6.Cg-Tyr(c-2J) Hr(hr) /J]. Histologically, B6.Cg-Tyr(c-2J) Hr(hr) /J skin is indistinguishable from that of SKH1 mice. The skin of both SKH1 and B6.Cg-Tyr(c-2J) Hr(hr) /J mice exhibited a reduction in hypodermal adipose tissue, the presence of utricles and dermal cystic structures, the presence of dermal granulomas and epidermal thickening. In response to a single 1500 J/m(2) ultraviolet B dose, the oedema and apoptotic responses were equivalent in both mouse strains. However, B6.Cg-Tyr(c-2J) Hr(hr) /J mice exhibited a more robust delayed sunburn reaction, with an increase in epidermal erosion, scab formation and myeloperoxidase activity relative to SKH1 mice. Compared with SKH1 mice, B6.Cg-Tyr(c-2J) Hr(hr) /J also exhibited an aberrant proliferative response to this single UV exposure. Epidermal Ki67 immunopositivity was significantly suppressed in B6.Cg-Tyr(c-2J) Hr(hr) /J mice at 24 h post-UV. A smaller non-significant reduction in Ki67 labelling was observed in SKH1 mice. Finally, at 72 h post-UV, SKH1 mice, but not B6.Cg-Tyr(c-2J) Hr(hr) /J mice, exhibited a significant increase in Ki67 immunolabelling relative to non-irradiated controls. Thus, B6.Cg-Tyr(c-2J) Hr(hr) /J mice are suitable for photobiology experiments.


Voltage- and substrate-dependent interactions between sites in putative re-entrant domains of a Na(+)-coupled phosphate cotransporter.
A common structural feature characterises sodium-coupled inorganic phosphate cotransporters of the SLC34 family (NaPi-IIa/b/c): a pair of inverted regions in the N- and C-terminal halves of the protein. These regions are hypothesised to contain re-entrant domains that associate to allow alternating access of the substrates from either side of the membrane. To investigate if these domains interact during the NaPi-II transport cycle, we introduced novel cysteines at three functionally important sites associated with the predicted re-entrant domains of the flounder NaPi-IIb for the purpose of fluorescent labelling and cross-linking. Single and double mutants were expressed in Xenopus oocytes and their function analysed using electrophysiological and real-time fluorometric assays. The substitution at the cytosolic end of the first re-entrant domain induced a large hyperpolarizing shift in the voltage dependence of steady-state and presteady-state kinetics, whereas the two substitutions at the external face were less critical. By using Cu-phenanthroline to induce disulfide bridge formation, we observed a loss of transport activity that depended on the presence of sodium in the incubation medium. This suggested that external sodium increased the probability of NaPi-IIb occupying a conformation that favours interaction between sites in the re-entrant domains. Furthermore, voltage-dependent fluorescence data supported the hypothesis that a localised interaction between the two domains occurs that depends on the membrane potential and substrate present: we found that the fluorescence intensity reported by a labelled cysteine in one domain was dependent on the side chain substituted at a functionally critical site in the opposed domain.


Genome-wide identification of Epstein-Barr virus-driven promoter methylation profiles of human genes in gastric cancer cells.
Aberrant methylation of tumor-related genes has been reported in Epstein-Barr virus (EBV)-associated gastric cancers. This study sought to profile EBV-driven hypermethylation in EBV-infected cells. The EBV-positive AGS gastric cancer cell line (AGS-EBV) and EBV-negative AGS cells were used in this study. DNA methyltransferase-3b (DNMT3b) activity was assessed by EpiQuick activity assay, and genome-wide DNA methylation profiles were assessed by methyl-DNA immunoprecipitation microarray assay. EBV infection was confirmed in AGS-EBV cells by EBV-encoded RNA in situ hybridization. Expression and activity of DNA methyltransferase-3b (DNMT3b) was significantly increased in AGS-EBV compared to AGS. Ectopic expression of LMP2A (latent membrane protein 2A) in AGS increased activity of DNMT3b. A total of 1065 genes were differentially methylated by EBV infection (fold-changes ≥ 2, P < .05) in AGS-EBV compared to AGS cells. The majority of the differentially methylated genes (83.2%, 886 of 1065 genes) had cytosine-guanine dinucleotide (CpG) hypermethylation in AGS-EBV (fold-changes 2.43∼65.2) versus that found in AGS cells. Gene ontology analysis revealed that hypermethylated genes were enriched in the important cancer pathways (≥ 10 genes each, P ≤ .05) including mitogen-activated protein kinase signaling, cell adhesion molecules, wnt signaling pathway, and so forth. Six novel hypermethylated candidates (IL15RA, REC8, SSTR1, EPHB6, MDGA2, and SCARF2) were further validated. Higher levels of DNA methylation were confirmed for all these genes in AGS-EBV cells by bisulfite genomic sequencing. Furthermore, these candidates were silenced or down-regulated in AGS-EBV cells, but can be restored by demethylation treatment. EBV infection in AGS cells induced aberrant CpG hypermethylation of 886 genes involving in important cancer-related pathways. Induction of promoter methylation by EBV is regulated by up-regulation of DNMT3b through LMP2A.


The quality of reports of medical and public health research from Palestinian institutions: a systematic review.
Over the past decade, there has been an increase in reports of health research from Palestine, but no assessment of their quality. We have assessed the quality of reports of Palestinian health research and factors associated with it. This is a systematic review. We searched Medline and Scopus for reports of original research relevant to human health or healthcare authored by researchers affiliated with Palestinian institutions and published between January 2000 and August 2015 inclusive. We used international guidelines to assess report quality, classifying as adequate those with ≥50% of items completely addressed. Of 2383 reports identified, 497 met our inclusion criteria. Just over half (264; 55%) of these were published after 2010. 354 (71%) of first authors were affiliated with Palestinian institutions; 261 (53%) reports had coauthors from outside Palestine. The majority of the reports in our study were inadequately reported (342; 69%), and none had adequately reported all items. Of 439 observational studies, 11 (2.5%) reports provided adequate descriptions of eligibility criteria and selection procedures; 35 (8%) reported efforts to address potential sources of bias; 50 (11.4%) reported the basis for the study sample size; and funding sources were mentioned in 74 reports (17%). Higher reporting quality was associated with international affiliation of the first author (prevalence ratio (PR) 1.6 (95% CI 1.2 to 2.1)), international collaboration (PR 2.9 (95% CI 1.7 to 5.0)), international funding (PR 1.9 (95% CI1.5 to 2.5)), publication after 2005 (PR 3.9 (95% CI 1.8 to 8.5)) and four or more coauthors (PR 1.5 (95% CI 1.1 to 2.1)). Although the quality of reports of Palestinian research has improved in recent years, it remains well below an acceptable standard. International reporting guidelines should be used to guide research design and improve the quality of reports of research. The systematic review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) registery (registration number: CRD42015027553).