Mode of birth and women's psychological and physical wellbeing in the postnatal period.
Physical and psychological problems after childbirth are common, and may have a significant negative and long-term impact on women's wellbeing and daily functioning. The method of birth may be a particularly important factor influencing women's health and wellbeing following birth, however, population-wide evidence is limited. This study uses data from 5,332 women who responded to a national survey of women's experiences of maternity care in England. We examined women's postnatal wellbeing in the first three months after birth, and whether these varied by mode of birth. This is a secondary analysis of survey data using a random sample of women selected from birth registration. We used multinomial logistic regression models to examine the association between women's self-reported psychological symptoms, health problems and mode of birth. Women who had forceps-assisted vaginal births and unplanned caesarean section births reported the poorest health and wellbeing, while those of women who had unassisted vaginal births and planned caesarean section births were less affected by the birth process. Most women's physical and emotional health appeared to improve with time, however, those who had a forceps-assisted vaginal birth were more likely to report ongoing posttraumatic-type symptoms several months after the birth. Mode of birth was associated with differences in outcomes at three months. By comparison to women who had unassisted vaginal births, the risk of reduced postnatal health and wellbeing was higher amongst the women who had forceps-assisted vaginal births but not amongst women who had ventouse-assisted vaginal births. This would suggest that it is important to differentiate the different types of instrumental birth in outcome studies. Of concern was the higher rate of posttraumatic-type symptoms among women who had forceps-assisted vaginal births relative to the other modes of birth. Women who have forceps-assisted births should be monitored carefully by health professionals in the postnatal period, and in the months after childbirth, when they could be offered the opportunity to discuss their labour and birth.


Effects of estradiol and progesterone on voltage-gated calcium and potassium conductances in rat CA1 hippocampal neurons.
In this study we recorded voltage gated Ca and K conductances with patch electrodes in hippocampal slices from female rats, which were ovariectomized (OVX) 1 week before the experiment. One experimental group was primed with estradiol at day 3 and 4 after OVX and received progesterone 4 hr before the start of the experiment. The second group was treated with estradiol at day 3 and 4, but received vehicle at the day of the experiment. The third group was not treated with hormones (only vehicle injections). We observed that the amplitude of both sustained and transient Ca currents were significantly enhanced in CA1 pyramidal neurons recorded in tissue from estradiol primed rats receiving progesterone when compared to the nontreated OVX controls; without estradiol priming Ca current amplitudes were small. Current amplitudes in tissue from rats treated with estradiol only, were at intermediate values. The voltage for half-maximal steady state inactivation of the transient Ca current was at a less negative value for the estradiol/progesterone treated group in comparison to the OVX controls. Input resistances of the cells, and voltage or kinetic properties of the currents as recorded under these conditions were comparable for the three groups. Characteristics of two voltage gated K conductances, that is, the transient IA and the delayed rectifier, displayed no consistent differences for the three experimental groups. We conclude that long-term modulation of estradiol and progesterone levels alters the Ca but not the K currents that were tested in CA1 pyramidal neurons. These alterations may be linked to steroid-induced morphological changes in dendrites of CA1 pyramidal cells.


Length of stay: an appropriate quality measure?
Although demographic and clinical information are known to affect hospital length of stay (LOS), we hypothesized that LOS after traumatic injury would be significantly influenced by nonclinical factors. Retrospective database analysis. Trauma patients treated at hospitals participating in data submission to the National Trauma Data Bank. The National Trauma Data Bank was queried for all patients older than 18 years with an LOS longer than 48 hours and complete demographic information including age, sex, and race/ethnicity; nonclinical factors including payment type (commercial, Medicaid, Medicare, uninsured, and other) and discharge destination (home, rehabilitation facility, nursing home, and other); and clinical information (body region injured, Injury Severity Score, and Revised Trauma Score). Statistical analysis was performed using generalized linear modeling adjusted for multiple comparisons. Length of stay greater than the mean. We obtained 313 144 medical records. Mean LOS was 9.6 days. Discharge destination had the greatest effect on LOS. Mean LOS for patients with Medicaid (11.3 days) was significantly longer than for patients with commercial insurance and uninsured patients (each 9.3 days) and patients with Medicare (8.8 days). Length of stay was longer for patients discharged to a nursing home (14.2 days) or rehabilitation facility (11.5 days) compared with those discharged to any other facility (9.6 days). In multivariate analysis, factors significantly associated with extended LOS included age, sex, race/ethnicity, insurance status, discharge destination, and Revised Trauma Score. Nonclinical factors significantly influence LOS. If LOS is used as a quality measure for injured patients, adjustment for these factors is necessary.


Detection of the initial site of Toxoplasma gondii reactivation in brain tissue.
Detection of the initial site of Toxoplasma gondii reactivation in brain tissue is difficult because the number of latent cysts is small and reactivation is a transient event. To detect the early stage of reactivation in mouse brain tissue, we constructed a cyst-forming strain of T. gondii in the tachyzoite stage, specifically expressing red fluorescence. The PLK strain of T. gondii was stably transfected with a red fluorescent protein gene, DsRed Express, under the control of a tachyzoite-specific SAG-1 promoter and the resulting parasite was designated as PLK/RED. Tachyzoites of PLK/RED growing in Vero cells showed red fluorescence. When C57BL/6J mice were i.p. infected with tachyzoites of PLK/RED, red fluorescent tachyzoites were detected in their brains at the fourth day p.i. However, red fluorescent tachyzoites were not detected in BALB/c mice latently infected with PLK/RED, although non-fluorescent cysts were detected in their brains. After treatment of latently infected mice with dexamethasone for 1 month, the mice showed neurological symptoms. In mice with symptoms, red fluorescent tachyzoites were again detected in their brains and in other organs. To detect the initial site of reactivation, BALB/c mice latently infected with the strain were treated with dexamethasone for 3 weeks, and brains were excised before any symptoms appeared. Excised brains were examined for red fluorescence-positive sites. By a histological study of red fluorescent-positive sites, we detected a cyst containing red fluorescent zoites, which still had a PAS stain-positive cyst wall. A few red fluorescent zoites breaking away from the cyst were also observed. The stage-specific expression of fluorescent protein facilitates detection of a rare transient event and makes it possible to detect the initial site of reactivation.


Pharmacogenetic considerations for HIV treatment in different ethnicities: an update.
Variations in the human genome sequence sometimes play an important role in pharmacokinetics and/or pharmacodynamics. Previous studies have demonstrated a high degree of variation both between and within different ethnic populations. Areas covered: This review sought to summarize key SNPs in CYP2B6, CYP3A enzymes, CYP2C enzymes, UGT2 enzymes, ABCB1, ABCC2, SLCO1B1, NR1I2, and NR1I3 that have previously been associated with variability in antiretroviral pharmacokinetics. Additionally, the impact of ethnicity in these pharmacogenetics studies is discussed, and variation in findings between different ethnic groups is reviewed. A literature search of relevant published work was conducted between April 2017 and September 2017 utilizing the following databases: PubMed, Google Scholar, Web of Science, and Ensembl. Keywords used included drug name, rs (SNP identifier) number, and known effect (if applicable). This report highlights the variation observed between different ethnic populations and subsequently the importance of stratification within pharmacogenetic studies. Expert opinion: Utilization of these findings in future pharmacogenetics studies would aid in the understanding of the extent and impact of genetic variants in different populations and the consequences this has for achieving sustained virological response to antiretroviral therapy.


Incidence of asthma among workers exposed to sulphur dioxide and other irritant gases.
The aim of the present study was to investigate whether repeated peak exposure (gassings) to sulphur dioxide (SO2) and other irritant gases increases the risk of new-onset asthma. A questionnaire was sent to 4,112 sulphite workers, of whom 1,919 completed the questionnaire and 396 completed the short-form questionnaire, which was sent out as a last reminder. A sample of 130 nonrespondents completed a telephone interview using the short-form questionnaire. The incidence of adult-onset, physician-diagnosed asthma during employment duration was analysed in relation to exposure to SO2 and gassings giving rise to respiratory symptoms. Incidence rates, as well as incidence rate ratios with 95% confidence interval (CI), were calculated. Further Cox regression models were used allowing assessment of hazard ratios (HR) stratified for sex and adjusted for atopy, smoking habits and age. The incidence rate for asthma among sulphite mill workers reporting gassings of SO2 was 6.2 out of 1,000 person-yrs, compared with 1.9 out of 1,000 person-yrs among subjects unexposed to SO2 and any gassings (HR (95% CI) 4.0 (2.1-7.7)). Among males reporting gassings to SO2, the HR (95% CI) for asthma was 5.8 (2.6-13) compared with unexposed males. In conclusion, repeated peak exposure to sulphur dioxide increased the incidence of asthma during work in sulphite pulp mills, which supports the hypothesis of irritant-induced asthma.


Prediction of survival in diffuse large B-cell lymphoma based on the expression of 2 genes reflecting tumor and microenvironment.
Several gene-expression signatures predict survival in diffuse large B-cell lymphoma (DLBCL), but the lack of practical methods for genome-scale analysis has limited translation to clinical practice. We built and validated a simple model using one gene expressed by tumor cells and another expressed by host immune cells, assessing added prognostic value to the clinical International Prognostic Index (IPI). LIM domain only 2 (LMO2) was validated as an independent predictor of survival and the "germinal center B cell-like" subtype. Expression of tumor necrosis factor receptor superfamily member 9 (TNFRSF9) from the DLBCL microenvironment was the best gene in bivariate combination with LMO2. Study of TNFRSF9 tissue expression in 95 patients with DLBCL showed expression limited to infiltrating T cells. A model integrating these 2 genes was independent of "cell-of-origin" classification, "stromal signatures," IPI, and added to the predictive power of the IPI. A composite score integrating these genes with IPI performed well in 3 independent cohorts of 545 DLBCL patients, as well as in a simple assay of routine formalin-fixed specimens from a new validation cohort of 147 patients with DLBCL. We conclude that the measurement of a single gene expressed by tumor cells (LMO2) and a single gene expressed by the immune microenvironment (TNFRSF9) powerfully predicts overall survival in patients with DLBCL.


Stability of large segmental duplications in the yeast genome.
The high level of gene redundancy that characterizes eukaryotic genomes results in part from segmental duplications. Spontaneous duplications of large chromosomal segments have been experimentally demonstrated in yeast. However, the dynamics of inheritance of such structures and their eventual fixation in populations remain largely unsolved. We analyzed the stability of a vast panel of large segmental duplications in Saccharomyces cerevisiae (from 41 kb for the smallest to 268 kb for the largest). We monitored the stability of three different types of interchromosomal duplications as well as that of three intrachromosomal direct tandem duplications. In the absence of any selective advantage associated with the presence of the duplication, we show that a duplicated segment internally translocated within a natural chromosome is stably inherited both mitotically and meiotically. By contrast, large duplications carried by a supernumerary chromosome are highly unstable. Duplications translocated into subtelomeric regions are lost at variable rates depending on the location of the insertion sites. Direct tandem duplications are lost by unequal crossing over, both mitotically and meiotically, at a frequency proportional to their sizes. These results show that most of the duplicated structures present an intrinsic level of instability. However, translocation within another chromosome significantly stabilizes a duplicated segment, increasing its chance to get fixed in a population even in the absence of any immediate selective advantage conferred by the duplicated genes.


Assembly of Influenza Hemagglutinin Fusion Peptides in a Phospholipid Bilayer by Coarse-grained Computer Simulations.
Membrane fusion is critical to eukaryotic cellular function and crucial to the entry of enveloped viruses such as influenza and human immunodeficiency virus. Influenza viral entry in the host cell is mediated by a 20-23 amino acid long sequence, called the fusion peptide (FP). Recently, possible structures for the fusion peptide (ranging from an inverted V shaped α-helical structure to an α-helical hairpin, or to a complete α-helix) and their implication in the membrane fusion initiation have been proposed. Despite the large number of studies devoted to the structure of the FP, the mechanism of action of this peptide remains unclear with several mechanisms having been suggested, including the induction of local disorder, promoting membrane curvature, and/or altering local membrane composition. In recent years, several research groups have employed atomistic and/or coarse-grained molecular dynamics (MD) simulations to investigate the matter. In all previous works, the behavior of a single FP monomer was studied, while in this manuscript, we use a simplified model of a tripeptide (TP) monomer of FP (TFP) instead of a single FP monomer because each Influenza Hemagglutinin contains three FP molecules in the biological system. In this manuscript we report findings targeted at understanding the fusogenic properties and the collective behavior of these trimers of FP peptides on a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine model membrane. Here we show how the TFP monomers self-assemble into differently sized oligomers in the presence of the membrane. We measure the perturbation to the structure of the phospholipid membrane caused by the presence of these TFP oligomers. Our work (i) shows how self-assembly of TFP in the presence of the membrane induces non negligible deformation to the membrane and (ii) could be a useful starting point to stimulate discussion and further work targeted to fusion pore formation.


Beyond executive functions, creativity skills benefit academic outcomes: Insights from Montessori education.
Studies have shown scholastic, creative, and social benefits of Montessori education, benefits that were hypothesized to result from better executive functioning on the part of those so educated. As these previous studies have not reported consistent outcomes supporting this idea, we therefore evaluated scholastic development in a cross-sectional study of kindergarten and elementary school-age students, with an emphasis on the three core executive measures of cognitive flexibility, working memory update, and selective attention (inhibition). Two hundred and one (201) children underwent a complete assessment: half of the participants were from Montessori settings, while the other half were controls from traditional schools. The results confirmed that Montessori participants outperformed peers from traditional schools both in academic outcomes and in creativity skills across age groups and in self-reported well-being at school at kindergarten age. No differences were found in global executive functions, except working memory. Moreover, a multiple mediations model revealed a significant impact of creative skills on academic outcomes influenced by the school experience. These results shed light on the possibly overestimated contribution of executive functions as the main contributor to scholastic success of Montessori students and call for further investigation. Here, we propose that Montessori school-age children benefit instead from a more balanced development stemming from self-directed creative execution.


The complex distribution of arterial system mechanical properties, pulsatile hemodynamics, and vascular stresses emerges from three simple adaptive rules.
Arterial mechanical properties, pulsatile hemodynamic variables, and mechanical vascular stresses vary significantly throughout the systemic arterial system. Although the fundamental principles governing pulsatile hemodynamics in elastic arteries are widely accepted, a set of rules governing stress-induced adaptation of mechanical properties can only be indirectly inferred from experimental studies. Previously reported mathematical models have assumed mechanical properties adapt to achieve an assumed target stress "set point." Simultaneous prediction of the mechanical properties, hemodynamics, and stresses, however, requires that equilibrium stresses are not assumed a priori. Therefore, the purpose of this work was to use a "balance point" approach to identify the simplest set of universal adaptation rules that simultaneously predict observed mechanical properties, hemodynamics, and stresses throughout the human systemic arterial system. First, we employed a classical systemic arterial system model with 121 arterial segments and removed all parameter values except vessel lengths and peripheral resistances. We then assumed vessel radii increase with endothelial shear stress, wall thicknesses increase with circumferential wall stress, and material stiffnesses decrease with circumferential wall stress. Parameters characterizing adaptive responses were assumed to be identical in all arterial segments. Iteratively predicting local mechanical properties, hemodynamics, and stresses reproduced five trends observed when traversing away from the aortic root towards the periphery: decrease in lumen radii, wall thicknesses, and pulsatile flows and increase in wall stiffnesses and pulsatile pressures. The extraordinary complexity of the systemic arterial system can thus arise from independent adaptation of vessels to local stresses characterized by three simple adaptive rules.


How many psychiatric patients in prison?
The paper compares the prevalence of psychiatric morbidity amongst sentenced prisoners and in the general population. Major psychosis was no more common in the majority of studies of criminal populations. Although prisoners have a higher level of neurotic symptomatology, this was mainly found to be secondary to imprisonment itself. Long term imprisonment was not found to be a precipitant of severe psychiatric morbidity or intellectual deterioration, and prisoners adopt elaborate coping mechanisms which may themselves be protective. However, there is a higher prevalence of mentally handicapped and epileptic prisoners, and doctors in the Prison Medical Service have to cope with frequent, serious behavioural problems. Prisons appear to be a particularly important area for future psychiatric research.


Induction chemotherapy with docetaxel, cisplatin, fluorouracil, and leucovorin for squamous cell carcinoma of the head and neck: a phase I/II trial.
A phase I/II trial of docetaxel, cisplatin, fluorouracil (5-FU), and leucovorin (TPFL5) induction chemotherapy for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Twenty-three previously untreated patients with stage III or IV SCCHN and Eastern Cooperative Oncology Group functional status less than or equal to 2 were treated with TPFL5. Postchemotherapy home support included intravenous fluids, prophylactic antibiotics, and granulocyte colony-stimulating factor (G-CSF). Docetaxel dose was escalated to determine the maximum-tolerated dose (MTD). Fifteen patients were treated with three cycles of TPFL5 at MTD. Patients who achieved either a partial response (PR) or complete response (CR) to three cycles of TPFL5 then received definitive twice-daily radiation therapy. Toxicity and clinical and pathologic response to TPFL5 were assessed. Twenty-three patients received a total of 69 cycles of TPFL5. The MTD was determined to be docetaxel 60 mg/m2. Dose-limiting toxicity (DLT) was neutropenia. Additional significant toxicities at MTD were nausea, mucositis, diarrhea, peripheral neuropathy, and sodium-wasting nephropathy. The overall response rate to TPFL5 was 100%, which included 14 of 23 (61%) clinical CRs and nine of 23 (39%) clinical PRs. Primary-site clinical and pathologic CR rates were 19 of 22 (86%) CRs and 20 of 22 (91%) CRs, respectively. Eight patients had less than a CR in the neck to chemotherapy and, therefore, had postradiation neck dissections, four of which were positive for residual tumor. TPFL5 is a tolerable induction regimen in patients with good performance status. The DLT is neutropenia with significant mucositis, diarrhea, peripheral neuropathy, and sodium-wasting nephropathy. The high response rates to TPFL5 justify further evaluation of this combination of agents in the context of formal clinical trials.


Fibrinogenolysis and thrombin generation after reduced dose bolus or conventional rt-PA for pulmonary embolism. The Coagulation Project Investigators of the Bolus Alteplase Pulmonary Embolism Group.
The aim of this study was to compare the effects on fibrinogenolysis and thrombin generation of two recombinant tissue-type plasminogen activator (rt-PA) regimens in patients with pulmonary embolism entering a randomised, controlled study with a 1:2 allocation ratio to rt-PA, 100 mg over 2 h (Group A) or rt-PA, 0.6 mg/kg, maximum dose 50 mg, over 15 min (Group B). In both groups the heparin infusion was stopped 2-4 h before starting thrombolytic treatment and resumed accordingly to the activated partial thromboplastin time (aPTT) or thrombin clotting time (TcT). Seventeen patients in Group A and 30 patients in Group B were evaluated before starting thrombolytic treatment and 2, 6 and 24 h after its end for the following parameters: aPTT, TcT, fibrinogen, fibrinogen degradation products (FDP), plasmin-alpha 2 antiplasmin (PAP) and thrombin-antithrombin III (TAT) complexes. The two groups had similar coagulation parameters at baseline. Two h after starting rt-PA, the aPTT was more prolonged in Group A than in Group B patients (P = 0.01). Patients in Group B showed less reduction in plasma fibrinogen levels at all study times after rt-PA treatment (P = 0.008). The increase in plasma FDP (P = 0.037) and PAP (P = 0.001) levels was lower at 2 and 6 h samples in Group B compared with Group A. TcT was prolonged (P = 0.003) and TAT increased (P = 0.001) during treatment without differences between the two groups. AUC0-24 of fibrinogen, FDP and PAP levels confirmed the statistically significant differences (P = 0.04) between the two groups over the entire 24 h period of the study. Three patients in Group A (17.6%) and three (10.0%) in Group B suffered major or other important bleeding. Our results indicate that the administration of weight-adjusted reduced-dose rt-PA bolus produces less impairment of blood coagulation than the FDA approved regimen.


Clinically significant prostate cancer detection on MRI: A radiomic shape features study.
Prostate multiparametric MRI (mpMRI) is the imaging modality of choice for detecting clinically significant prostate cancer (csPCa). Among various parameters, lesion maximum diameter and volume are currently considered of value to increase diagnostic accuracy. Quantitative radiomics allows for the extraction of more advanced shape features. Our aim was to assess which shape features derived from MRI index lesions correlate with csPCa presence. We retrospectively enrolled 75 consecutive subjects, who underwent mpMRI on a 3 T scanner, divided based on MRI index lesion Gleason Score in a csPCa group (GS > 3 + 4, n = 41) and a non-csPCa one (n = 34). Ten shape features were extracted both from axial T2-weighted and ADC maps images, after lesion tridimensional segmentation. Univariable and multivariable logistic analysis were used to evaluate the relationship between shape features and csPCa. Diagnostic performance was assessed measuring the area under the curve of the receiver operating characteristic (ROC) analysis. Diagnostic accuracy, sensitivity, and specificity were determined using the best cut-off on each ROC. A P value < 0.05 was considered statistically significant. Univariable analysis demonstrated that almost every shape feature was statistically significant between csPCa e non-csPCa groups. However, multivariable analysis revealed that the parameter defined as surface area to volume ratio (SAVR), especially when extracted from ADC maps is the strongest independent predictor of csPCa among tested shape features. The radiomic shape feature SAVR, extracted from ADC maps after index lesion segmentation, appears as a promising tool for csPCa detection.


Efficient Triplet-Triplet Annihilation-Based Upconversion for Nanoparticle Phototargeting.
High-efficiency upconverted light would be a desirable stimulus for triggered drug delivery. Here we present a general strategy to achieve photoreactions based on triplet-triplet annihilation upconversion (TTA-UC) and Förster resonance energy transfer (FRET). We designed PLA-PEG micellar nanoparticles containing in their cores hydrophobic photosensitizer and annihilator molecules which, when stimulated with green light, would undergo TTA-UC. The upconverted energy was then transferred by FRET to a hydrophobic photocleavable group (DEACM), also in the core. The DEACM was bonded to (and thus inactivated) the cell-binding peptide cyclo-(RGDfK), which was bound to the PLA-PEG chain. Cleavage of DEACM by FRET reactivated the PLA-PEG-bound peptide and allowed it to move from the particle core to the surface. TTA-UC followed by FRET allowed photocontrolled binding of cell adhesion with green light LED irradiation at low irradiance for short periods. These are attractive properties in phototriggered systems.


KTP Laser assisted microendoscopic cricopharyngeal myotomy and web excision for dysphagia management.
Cricopharyngeal dysfunction is defined as the delayed or incomplete relaxation of the cricopharyngeal muscle during swallowing. This may cause dysphagia and aspiration, affecting the quality of life. For this condition, injection of botulinum toxin into the cricopharyngeus, dilatation of cricopharynx with bougies and external cricopharyngeal myotomy have been the treatment of choice with varying results. We present in this paper the treatment of this clinical condition by KTP 532 laser a recent advance in the field of Otolaryngology and Head and Neck Surgery. Very few series have been reported in literature so far regarding the use of laser for cricopharyngeal myotomy. This is perhaps the first series of eight cases of KTP laser assisted microendoscopic cricopharyngeal myotomy and web excision reporting the benefit of this treatment by an Indian author in an Indian Journal. KTP laser assisted cricopharyngeal myotomy avoids an external scar; aids precise incision at the cricopharynx by direct visualization, brings optimum results in deglutition and reduces postoperative morbidity and complications. The short hospital stay reduces the overall cost. The use of KTP 532 laser in the treatment of selected cases with cricopharyngeal dysfunction is therefore safe and effective.


Health impacts of parental migration on left-behind children and adolescents: a systematic review and meta-analysis.
Globally, a growing number of children and adolescents are left behind when parents migrate. We investigated the effect of parental migration on the health of left behind-children and adolescents in low-income and middle-income countries (LMICs). For this systematic review and meta-analysis we searched MEDLINE, Embase, CINAHL, the Cochrane Library, Web of Science, PsychINFO, Global Index Medicus, Scopus, and Popline from inception to April 27, 2017, without language restrictions, for observational studies investigating the effects of parental migration on nutrition, mental health, unintentional injuries, infectious disease, substance use, unprotected sex, early pregnancy, and abuse in left-behind children (aged 0-19 years) in LMICs. We excluded studies in which less than 50% of participants were aged 0-19 years, the mean or median age of participants was more than 19 years, fewer than 50% of parents had migrated for more than 6 months, or the mean or median duration of migration was less than 6 months. We screened studies using systematic review software and extracted summary estimates from published reports independently. The main outcomes were risk and prevalence of health outcomes, including nutrition (stunting, wasting, underweight, overweight and obesity, low birthweight, and anaemia), mental health (depressive disorder, anxiety disorder, conduct disorders, self-harm, and suicide), unintentional injuries, substance use, abuse, and infectious disease. We calculated pooled risk ratios (RRs) and standardised mean differences (SMDs) using random-effects models. This study is registered with PROSPERO, number CRD42017064871. Our search identified 10 284 records, of which 111 studies were included for analysis, including a total of 264 967 children (n=106 167 left-behind children and adolescents; n=158 800 children and adolescents of non-migrant parents). 91 studies were done in China and focused on effects of internal labour migration. Compared with children of non-migrants, left-behind children had increased risk of depression and higher depression scores (RR 1·52 [95% CI 1·27-1·82]; SMD 0·16 [0·10-0·21]), anxiety (RR 1·85 [1·36-2·53]; SMD 0·18 [0·11-0·26]), suicidal ideation (RR 1·70 [1·28-2·26]), conduct disorder (SMD 0·16 [0·04-0·28]), substance use (RR 1·24 [1·00-1·52]), wasting (RR 1·13 [1·02-1·24]) and stunting (RR 1·12 [1·00-1·26]). No differences were identified between left-behind children and children of non-migrants for other nutrition outcomes, unintentional injury, abuse, or diarrhoea. No studies reported outcomes for other infectious diseases, self-harm, unprotected sex, or early pregnancy. Study quality varied across the included studies, with 43% of studies at high or unclear risk of bias across five or more domains. Parental migration is detrimental to the health of left-behind children and adolescents, with no evidence of any benefit. Policy makers and health-care professionals need to take action to improve the health of these young people. Wellcome Trust.


Parameters of the protein energy landscapes of several light-harvesting complexes probed via spectral hole growth kinetics measurements.
The parameters of barrier distributions on the protein energy landscape in the excited electronic state of the pigment/protein system have been determined by means of spectral hole burning for the lowest-energy pigments of CP43 core antenna complex and CP29 minor antenna complex of spinach Photosystem II (PS II) as well as of trimeric and monomeric LHCII complexes transiently associated with the pea Photosystem I (PS I) pool. All of these complexes exhibit sixty to several hundred times lower spectral hole burning yields as compared with molecular glassy solids previously probed by means of the hole growth kinetics measurements. Therefore, the entities (groups of atoms), which participate in conformational changes in protein, appear to be significantly larger and heavier than those in molecular glasses. No evidence of a small (∼1 cm(-1)) spectral shift tier of the spectral diffusion dynamics has been observed. Therefore, our data most likely reflect the true barrier distributions of the intact protein and not those related to the interface or surrounding host. Possible applications of the barrier distributions as well as the assignments of low-energy states of CP29 and LHCII are discussed in light of the above results.


Involvement of proapoptotic genes in autophagic cell death induced by irradiation.
Irradiation is widely used in anticancer therapy; however, the efficiency is limited. Most cancer cells have mutations in apoptosis that they can easily escape the apoptosis induced by irradiation. Autophagy has been known as type II programmed cell death that can be activated by irradiation, especially when apoptosis is blocked, but the underlying molecular mechanism is largely unknown. We demonstrated that proapoptotic genes PUMA and Bid are involved in the regulation of autophagic cell death. When wild-type (WT), Bax-/- and PUMA-/- HCT116 cells were exposed to irradiation, we found that, compared with WT, Bax-/- cells showed significantly decreased cell death because of Bax deficiency; however, surprisingly PUMA-/- cells showed significant increase in cell death although the proapoptotic gene PUMA was knocked out. By analyzing apoptosis via Annexin V-fluorescein isothiocyanate (FITC) assay with flow cytometry, both Bax-/- and PUMA-/- cells showed less apoptosis than WT, suggesting the existence of another type of cell death in PUMA-/- cells. Autophagy was then examined in three cell lines by counting the percentage of cells with punctate GFP-LC3. Although all three cell lines showed significantly increased autophagy activity after irradiation, that of PUMA-/- cells was much higher than the other two cell lines, which suggests that PUMA-/- cells may die through autophagy. This was then confirmed by the decreased cell death in PUMA-/- cells when autophagy was blocked by 3-MA. In addition, we also tested the responses of WT and Bid-/- MEFs to irradiation. Bid-/- MEFs but not WT died through autophagy after irradiation. These results imply the involvement of apoptosis-associated genes such as PUMA and Bid in autophagic cell death, which contributes to identifying the molecular mechanism by which autophagy drives cells to death.


Clustering of gene expression profiles: creating initialization-independent clusterings by eliminating unstable genes.
Clustering is an important approach in the analysis of biological data, and often a first step to identify interesting patterns of coexpression in gene expression data. Because of the high complexity and diversity of gene expression data, many genes cannot be easily assigned to a cluster, but even if the dissimilarity of these genes with all other gene groups is large, they will finally be forced to become member of a cluster. In this paper we show how to detect such elements, called unstable elements. We have developed an approach for iterative clustering algorithms in which unstable elements are deleted, making the iterative algorithm less dependent on initial centers. Although the approach is unsupervised, it is less likely that the clusters into which the reduced data set is subdivided contain false positives. This clustering yields a more differentiated approach for biological data, since the cluster analysis is divided into two parts: the pruned data set is divided into highly consistent clusters in an unsupervised way and the removed, unstable elements for which no meaningful cluster exists in unsupervised terms can be given a cluster with the use of biological knowledge and information about the likelihood of cluster membership. We illustrate our framework on both an artificial and real biological data set.


Total mercury and methylmercury concentrations over a gradient of contamination in earthworms living in rice paddy soil.
Mercury (Hg) deposited from emissions or from local contamination, can have serious health effects on humans and wildlife. Traditionally, Hg has been seen as a threat to aquatic wildlife, because of its conversion in suboxic conditions into bioavailable methylmercury (MeHg), but it can also threaten contaminated terrestrial ecosystems. In Asia, rice paddies in particular may be sensitive ecosystems. Earthworms are soil-dwelling organisms that have been used as indicators of Hg bioavailability; however, the MeHg concentrations they accumulate in rice paddy environments are not well known. Earthworm and soil samples were collected from rice paddies at progressive distances from abandoned mercury mines in Guizhou, China, and at control sites without a history of Hg mining. Total Hg (THg) and MeHg concentrations declined in soil and earthworms as distance increased from the mines, but the percentage of THg that was MeHg, and the bioaccumulation factors in earthworms, increased over this gradient. This escalation in methylation and the incursion of MeHg into earthworms may be influenced by more acidic soil conditions and higher organic content further from the mines. In areas where the source of Hg is deposition, especially in water-logged and acidic rice paddy soil, earthworms may biomagnify MeHg more than was previously reported. It is emphasized that rice paddy environments affected by acidifying deposition may be widely dispersed throughout Asia. Environ Toxicol Chem 2017;36:1202-1210. © 2016 SETAC.


Economic effects of ocean acidification: Publication patterns and directions for future research.
Human societies derive economic benefit from marine systems, yet these benefits may be modified as humans drive environmental change. Here, we conducted the first systematic review of literature on the potential economic effects of ocean acidification. We identified that while there is a growing literature discussing this topic, assessments of the direction and magnitude of anticipated economic change remain limited. The few assessments which have been conducted indicate largely negative economic effects of ocean acidification. Insights are, however, limited as the scope of the studies remains restricted. We propose that understanding of this topic will benefit from using standard approaches (e.g. timescales and emissions scenarios) to consider an increasing range of species/habitats and ecosystem services over a range of spatial scales. The resulting understanding could inform decisions such that we maintain, or enhance, economic services obtained from future marine environments.


Stacking of colors in exfoliable plasmonic superlattices.
Color printing with plasmonic resonators can overcome limitations in pigment-based printing approaches. While layering in pigment-based prints results in familiar color mixing effects, the color effects of stacking plasmonic resonator structures have not been investigated. Here, we demonstrate an experimental strategy to fabricate a 3-tiered complex superlattice of nanostructures with multiple sets of building blocks. Laser interference lithography was used to fabricate the nanostructures and a thin-layer of aluminum was deposited to introduce plasmonic colors. Interestingly, the structures exhibited drastic color changes when the layers of structures were sequentially exfoliated. Our theoretical analysis shows that the colors of the superlattice nanostructure were predominantly determined by the plasmonic properties of the two topmost layers. These results suggest the feasibility of the sub-wavelength vertical stacking of multiple plasmonic colors for applications in sensitive tamper-evident seals, dense 3D barcoding, and substrates for plasmonic color laser printing.


Phenol degradation on novel nickel-antimony doped tin dioxide electrode.
Nickel and antimony doped tin dioxide is a novel anodic material for its good performance of electrochemical ozone generation and direct electro-catalytic oxidation. Electro-catalytic oxidation of phenol on this novel nickel-antimony doped tin dioxide electrode is presented here. The morphology and composition of the electrode are characterized. The effects of applied current densities on phenol degradation rate, energy consumption and coulomb efficiency are discussed. In 0.1 M sulfuric acid, after 4 h electrolysis with current density of 25 mA cm(-1), 90% phenol is removed. And with current density of 20 mA cm(-1), the highest energy efficiency of 6.85 g kWh(-1) and the highest coulomb efficiency of 6.87 μg C(-1) are obtained. The effect of current densities on TOC removal is also discussed.


Honokiol, a potential therapeutic agent, induces cell cycle arrest and program cell death in vitro and in vivo in human thyroid cancer cells.
Thyroid cancer is the most common endocrine malignancy, the global incidence rate of which is rapidly rising. Surgery and radioiodine therapies are common and effective treatments only for nonmetastasized primary tumors. Therefore, effective treatment modalities are imperative for patients with radioiodine-resistant thyroid cancer. Honokiol, a biophenolic compound derived from Magnolia spp., has been shown have diverse biological and pharmacological activities, including anti-inflammatory, antioxidative, antiangiogenic, and anticancer properties. In the present study, three human thyroid cancer cell lines, namely anaplastic, follicular, and poorly differentiated thyroid cancer cells, were used to evaluate the chemotherapeutic activity of honokiol. Cell viability, cell cycle, apoptosis, and autophagy induction were determined through flow cytometry and western blot analysis. We found that honokiol treatment can suppress cell growth, induce cell cycle arrest, and enhance the induction of caspase-dependent apoptosis and autophagy in cancer cells. Moreover, honokiol treatment modulated signaling pathways including Akt/mTOR, ERK, JNK, and p38 in the studied cells. In addition, the antitumorigenic activity of honokiol was also confirmed in vitro and in vivo. Our data provide evidence that honokiol has a unique application in chemotherapy for human thyroid cancers.


Plant-Derived Chimeric Virus Particles for the Diagnosis of Primary Sjögren Syndrome.
Plants are ideal for the production of protein-based nanomaterials because they synthesize and assemble complex multimeric proteins that cannot be expressed efficiently using other platforms. Plant viruses can be thought of as self-replicating proteinaceous nanomaterials generally stable and easily produced in high titers. We used Potato virus X (PVX), chimeric virus particles, and Cowpea mosaic virus, empty virus-like particles to display a linear peptide (lipo) derived from human lipocalin, which is immunodominant in Sjögren's syndrome (SjS) and is thus recognized by autoantibodies in SjS patient serum. These virus-derived nanoparticles were thus used to develop a diagnostic assay for SjS based on a direct enzyme linked immunosorbent assay format. We found that PVX-lipo formulations were more sensitive than the chemically synthesized immunodominant peptide and equally specific when used to distinguish between healthy individuals and SjS patients. Our novel assay therefore allows the diagnosis of SjS using a simple, low-invasive serum test, contrasting with the invasive labial biopsy required for current tests. Our results demonstrate that nanomaterials based on plant viruses can be used as diagnostic reagents for SjS, and could also be developed for the diagnosis of other diseases.


Administration of Momordica charantia Enhances the Neuroprotection and Reduces the Side Effects of LiCl in the Treatment of Alzheimer's Disease.
Recently, the use of natural food supplements to reduce the side effects of chemical compounds used for the treatment of various diseases has become popular. Lithium chloride (LiCl) has some protective effects in neurological diseases, including Alzheimer's disease (AD). However, its toxic effects on various systems and some relevant interactions with other drugs limit its broader use in clinical practice. In this study, we investigated the in vitro and in vivo pharmacological functions of LiCl combined with Momordica charantia (MC) in the treatment of AD. The in vitro results show that the order of the neuroprotective effect is MC5, MC3, MC2, and MC5523 under hyperglycemia or tau hyperphosphorylation. Therefore, MC5523 (80 mg/kg; oral gavage) and/or LiCl (141.3 mg/kg; intraperitoneal injection) were applied to ovariectomized (OVX) 3×Tg-AD female and C57BL/6J (B6) male mice that received intracerebroventricular injections of streptozotocin (icv-STZ, 3 mg/kg) for 28 days. We found that the combined treatment not only increased the survival rate by reducing hepatotoxicity but also increased neuroprotection associated with anti-gliosis in the icv-STZ OVX 3×Tg-AD mice. Furthermore, the cotreatment with MC5523 and LiCl prevented memory deficits associated with reduced neuronal loss, gliosis, oligomeric Aβ level, and tau hyperphosphorylation and increased the expression levels of synaptic-related protein and pS9-GSK3β (inactive form) in the icv-STZ B6 mice. Therefore, MC5523 combined with LiCl could be a potential strategy for the treatment of AD.


Distinct behavioural and network correlates of two interneuron types in prefrontal cortex.
Neurons in the prefrontal cortex exhibit diverse behavioural correlates, an observation that has been attributed to cell-type diversity. To link identified neuron types with network and behavioural functions, we recorded from the two largest genetically defined inhibitory interneuron classes, the perisomatically targeting parvalbumin (PV) and the dendritically targeting somatostatin (SOM) neurons in anterior cingulate cortex of mice performing a reward foraging task. Here we show that PV and a subtype of SOM neurons form functionally homogeneous populations showing a double dissociation between both their inhibitory effects and behavioural correlates. Out of several events pertaining to behaviour, a subtype of SOM neurons selectively responded at reward approach, whereas PV neurons responded at reward leaving and encoded preceding stay duration. These behavioural correlates of PV and SOM neurons defined a behavioural epoch and a decision variable important for foraging (whether to stay or to leave), a crucial function attributed to the anterior cingulate cortex. Furthermore, PV neurons could fire in millisecond synchrony, exerting fast and powerful inhibition on principal cell firing, whereas the inhibitory effect of SOM neurons on firing output was weak and more variable, consistent with the idea that they respectively control the outputs of, and inputs to, principal neurons. These results suggest a connection between the circuit-level function of different interneuron types in regulating the flow of information and the behavioural functions served by the cortical circuits. Moreover, these observations bolster the hope that functional response diversity during behaviour can in part be explained by cell-type diversity.


Novel use of glucagon in a closed-loop system for prevention of hypoglycemia in type 1 diabetes.
To minimize hypoglycemia in subjects with type 1 diabetes by automated glucagon delivery in a closed-loop insulin delivery system. Adult subjects with type 1 diabetes underwent one closed-loop study with insulin plus placebo and one study with insulin plus glucagon, given at times of impending hypoglycemia. Seven subjects received glucagon using high-gain parameters, and six subjects received glucagon in a more prolonged manner using low-gain parameters. Blood glucose levels were measured every 10 min and insulin and glucagon infusions were adjusted every 5 min. All subjects received a portion of their usual premeal insulin after meal announcement. Automated glucagon plus insulin delivery, compared with placebo plus insulin, significantly reduced time spent in the hypoglycemic range (15 +/- 6 vs. 40 +/- 10 min/day, P = 0.04). Compared with placebo, high-gain glucagon delivery reduced the frequency of hypoglycemic events (1.0 +/- 0.6 vs. 2.1 +/- 0.6 events/day, P = 0.01) and the need for carbohydrate treatment (1.4 +/- 0.8 vs. 4.0 +/- 1.4 treatments/day, P = 0.01). Glucagon given with low-gain parameters did not significantly reduce hypoglycemic event frequency (P = NS) but did reduce frequency of carbohydrate treatment (P = 0.05). During closed-loop treatment in subjects with type 1 diabetes, high-gain pulses of glucagon decreased the frequency of hypoglycemia. Larger and longer-term studies will be required to assess the effect of ongoing glucagon treatment on overall glycemic control.


Gram-Negative Bacterial Infections: Research Priorities, Accomplishments, and Future Directions of the Antibacterial Resistance Leadership Group.
Antimicrobial resistance in pathogenic gram-negative bacteria is one of the most pressing challenges in the field of infectious diseases and is one of 4 key areas of unmet medical need identified by the Antibacterial Resistance Leadership Group (ARLG). The mission of the Gram-Negative Committee is to advance our knowledge of these challenging infections and implement studies to improve patient outcomes. Studies have fallen primarily into 2 broad categories: prospective cohort studies and interventional trials. Among the observational studies, CRACKLE (Consortium on Resistance Against Carbapenems in Klebsiella pneumoniae and Other Enterobacteriaceae) has contributed seminal multicenter data describing risk factors and clinical outcomes of carbapenem-resistant Enterobacteriaceae (CRE) in sentinel US hospitals. Building on this success, CRACKLE II will expand the network to hospitals across the United States and Colombia. Similar protocols have been proposed to include Acinetobacter baumannii and Pseudomonas aeruginosa (SNAP and POP studies). In addition, the CREST study (Carbapenem-Resistant Enterobacteriaceae in Solid Organ Transplant Patients) has provided pivotal data on extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae and CRE carriage among solid organ transplant recipients to inform management of this vulnerable patient population. Two clinical trials to define novel ways of using an existing antibiotic, fosfomycin, to treat ESBL-producing Enterobacteriaceae (one that has completed enrollment and the other in late protocol development) will determine the clinical efficacy of fosfomycin as step-down oral therapy to treat complicated urinary tract infections. Additional clinical studies and trials using immunotherapeutic or newly approved agents are also in the planning stage, with the main goals of generating actionable data that will inform clinical decision making and facilitate development of new treatment options for highly resistant gram-negative bacterial infections.


Pseudomonas syringae pv. actinidiae (PSA) isolates from recent bacterial canker of kiwifruit outbreaks belong to the same genetic lineage.
Intercontinental spread of emerging plant diseases is one of the most serious threats to world agriculture. One emerging disease is bacterial canker of kiwi fruit (Actinidia deliciosa and A. chinensis) caused by Pseudomonas syringae pv. actinidiae (PSA). The disease first occurred in China and Japan in the 1980s and in Korea and Italy in the 1990s. A more severe form of the disease broke out in Italy in 2008 and in additional countries in 2010 and 2011 threatening the viability of the global kiwi fruit industry. To start investigating the source and routes of international transmission of PSA, genomes of strains from China (the country of origin of the genus Actinidia), Japan, Korea, Italy and Portugal have been sequenced. Strains from China, Italy, and Portugal have been found to belong to the same clonal lineage with only 6 single nucleotide polymorphisms (SNPs) in 3,453,192 bp and one genomic island distinguishing the Chinese strains from the European strains. Not more than two SNPs distinguish each of the Italian and Portuguese strains from each other. The Japanese and Korean strains belong to a separate genetic lineage as previously reported. Analysis of additional European isolates and of New Zealand isolates exploiting genome-derived markers showed that these strains belong to the same lineage as the Italian and Chinese strains. Interestingly, the analyzed New Zealand strains are identical to European strains at the tested SNP loci but test positive for the genomic island present in the sequenced Chinese strains and negative for the genomic island present in the European strains. Results are interpreted in regard to the possible direction of movement of the pathogen between countries and suggest a possible Chinese origin of the European and New Zealand outbreaks.


Are hemoglobin A1c point-of-care analyzers fit for purpose? The story continues.
Point-of-care (POC) analyzers are playing an increasingly important role in diabetes management but it is essential that we know the performance of these analyzers in order to make appropriate clinical decisions. Whilst there is a growing body of evidence around the more well-known analyzers, there are many 'new kids on the block' with new features, such as displaying the presence of potential Hb-variants, which do not yet have a proven track record. The study is a comprehensive analytical and usability study of six POC analyzers for HbA1c using Clinical and Laboratory Standards Institute (CLSI) protocols, international quality targets and certified International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) and National Glycohemoglobin Standardization Program (NGSP) Secondary Reference Measurement Procedures (SRMP). The study includes precision (EP-5 and EP-15), trueness (EP-9), linearity (EP-6), sample commutability (fresh, frozen and lyophilized), interference of Hb-variants (fresh and frozen samples). Only two of the six analyzers performed to acceptable levels over the range of performance criteria. Hb-variant interference, imprecision or variability between lot numbers are still poor in four of the analyzers. This unique and comprehensive study shows that out of six POC analyzers studied only two (The Lab 001 and Cobas B101) met international quality criteria (IFCC and NGSP), two (A1Care and Innovastar) were borderline and two (QuikReadgo and Allegro) were unacceptable. It is essential that the scientific and clinical community are equipped with this knowledge in order to make sound decisions on the use of these analyzers.


The diagnostic accuracy of chest ultrasound for CT-detected radiographic consolidation in hospitalised adults with acute respiratory failure: a systematic review.
(1) Summarise chest ultrasound accuracy to diagnose radiological consolidation, referenced to chest CT in patients with acute respiratory failure (ARF). (2) Directly compared ultrasound with chest X-ray. Hospitalised patients. Studies were eligible if adult participants in respiratory failure underwent chest ultrasound to diagnose consolidation referenced to CT. Exclusion: (1) not primary study, (2) not respiratory failure, (3) not chest ultrasound, (4) not consolidation, (5) translation unobtainable, (6) unable to extract data, (7) unable to obtain paper. 4 studies comprising 224 participants met inclusion. As planned, paired forest plots display 95% CIs of sensitivity and specificity for ultrasound and chest X-ray. Sensitivity and specificity from each study are plotted in receiver operator characteristics space. Meta-analysis was planned if studies were sufficiently homogeneous and numerous (≥4). Although this numerical requirement was met, meta-analysis was prevented by heterogeneous units of analysis between studies. All studies were in intensive care, with either a high risk of selection bias or high applicability concerns. Studies had unclear or high risk of bias related to use of ultrasound. Only 1 study clearly performed ultrasound within 24 h of respiratory failure diagnosis. Ultrasound sensitivity ranged from 0.91 (95% CI 0.81 to 0.97) to 1.00 (95% CI 0.95 to 1.00). Specificity ranged from 0.78 (95% CI 0.52 to 0.94) to 1.00 (0.99 to 1.00). In two studies, chest X-ray had lower sensitivity than ultrasound, but there were insufficient patients to compare specificity. Four small studies suggest ultrasound is highly sensitive and specific for consolidation in ARF, but high risk of bias and concerns about applicability in all studies may have inflated diagnostic accuracy. Further robustly designed studies are needed to define the role of ultrasound in this setting. http://www.crd.york.ac.uk/PROSPERO/ (CRD42013006472).


Sustained neuronal activation raises oxidative metabolism to a new steady-state level: evidence from 1H NMR spectroscopy in the human visual cortex.
To date, functional 1H NMR spectroscopy has been utilized to report the time courses of few metabolites, primarily lactate. Benefiting from the sensitivity offered by ultra-high magnetic field (7 T), the concentrations of 17 metabolites were measured in the human visual cortex during two paradigms of visual stimulation lasting 5.3 and 10.6 mins. Significant concentration changes of approximately 0.2 micromol/g were observed for several metabolites: lactate increased by 23%+/-5% (P<0.0005), glutamate increased by 3%+/-1% (P<0.01), whereas aspartate decreased by 15%+/-6% (P<0.05). Glucose concentration also manifested a tendency to decrease during activation periods. The lactate concentration reached the new steady-state level within the first minute of activation and came back to baseline only after the stimulus ended. The changes of the concentration of metabolites implied a rise in oxidative metabolism to a new steady-state level during activation and indicated that amino-acid homeostasis is affected by physiological stimulation, likely because of an increased flux through the malate-aspartate shuttle.


Side Chain Cyclized Aromatic Amino Acids: Great Tools as Local Constraints in Peptide and Peptidomimetic Design.
Constraining the conformation of flexible peptides is a proven strategy to increase potency, selectivity, and metabolic stability. The focus has mostly been on constraining the backbone dihedral angles; however, the correct orientation of the amino acid side chains (χ-space) that constitute the peptide pharmacophore is equally important. Control of χ-space utilizes conformationally constrained amino acids that favor, disfavor, or exclude the gauche (-), the gauche (+), or the trans conformation. In this review we focus on cyclic aromatic amino acids in which the side chain is connected to the peptide backbone to provide control of χ1- and χ2-space. The manifold applications for cyclized analogues of the aromatic amino acids Phe, Tyr, Trp, and His within peptide medicinal chemistry are showcased herein with examples of enzyme inhibitors and ligands for G protein-coupled receptors.


Do non-pharmacological sleep interventions affect anxiety symptoms? A meta-analysis.
Research indicates a bidirectional relationship between sleep and anxiety, with findings suggesting anxiety can precede poor sleep and vice versa. Evidence suggests sleep-related thought processes associated with anxiety are involved in the maintenance of insomnia. Previous meta-analyses provide some evidence to suggest cognitive behavioural therapy for insomnia moderately improves anxiety, yet little research has investigated the effect of other sleep interventions on anxiety symptoms. The aim of this meta-analysis was to review whether non-pharmacological sleep interventions have an impact on anxiety symptoms immediately post-intervention. A systematic search of electronic databases was conducted to identify all randomized control trials (RCTs) investigating non-pharmacological sleep interventions that included anxiety symptoms as an outcome. Forty-three RCTs (n = 5945) met full inclusion criteria and were included in a random-effects meta-analysis model. The combined effect size of non-pharmacological sleep interventions on anxiety symptoms was moderate (Hedges' g = -0.38), indicating a reduction in symptoms. Subgroup analyses found a moderate effect for those with additional physical health difficulties (g = -0.46), a moderate effect for those with additional mental health difficulties (g = -0.47) and a moderate effect for those with elevated levels of anxiety at baseline (g = -0.43). A secondary meta-analysis found a large effect of non-pharmacological sleep interventions on sleep-related thought processes (g = -0.92). These findings indicate non-pharmacological sleep interventions are effective in reducing anxiety and sleep-related thought processes, and these effects may be larger in patients with anxiety. This has clinical implications for considering sleep interventions in the treatment of anxiety.


Clinical and demographic characteristics associated with postural instability in patients with schizophrenia.
As people with schizophrenia grow older, prevention of falls in this older population has become a public health priority. It is therefore critically important to identify risk factors to effectively prevent falls. For this purpose, the degree of postural sway can serve as a convenient index of risk assessment. The objective of this study was to find clinical and demographic characteristics associated with postural instability. Inpatients and outpatients with schizophrenia or related psychosis were recruited at 2 hospitals in Japan. The clinical stabilometric platform, which measured a range of the trunk motion, and extrapyramidal side effects were evaluated between 9 and 11 A.M. Four hundred two subjects were enrolled (age: mean, 55.5 [SD, 14.4] years). A univariate general linear model showed that the use of antipsychotic drugs with a chlorpromazine equivalent of 10 or greater, being overweight, and inpatient treatment setting were associated with a greater degree of the range of postural sway. Another general linear model, including a subgroup of 300 subjects who did not present any extrapyramidal side effects, not only consolidated these findings, but also revealed a great degree of postural sway in older subjects. In addition, quetiapine was found to be associated with a greater range of postural sway among atypical antipsychotics. Schizophrenia patients generally showed a greater degree of postural instability, compared with the reference data of healthy people. These findings highlight truncal instability as a risk factor of falls in patients with schizophrenia, especially when they are overweight, old, and/or receiving antipsychotics with a chlorpromazine equivalent of 10 or greater, including quetiapine.


Expression of IL-4/IL-13 receptors in differentiating human airway epithelial cells.
IL-4 and IL-13 elicit several important responses in airway epithelium including chemokine secretion and mucous secretion that may contribute to airway inflammation, cell migration, and differentiation. These cytokines have overlapping but not identical effector profiles likely due to shared subunits in their receptor complexes. These receptors are variably described in epithelial cells, and the relative expression, localization, and function of these receptors in differentiated and repairing epithelial cells are not clear. We examined IL-4/IL-13 receptor expression and localization in primary airway epithelial cells collected from normal human lungs and grown under conditions yielding both undifferentiated and differentiated cells inclusive of basal, goblet, and ciliated cell phenotypes. Gene expression of the IL-4Rα, IL-2Rγc, IL-13Rα1, and IL-13Rα2 receptor subunits increased with differentiation, but different patterns of localization and protein abundance were seen for each subunit based on both differentiation and the cell subtypes present. Increased expression of receptor subunits observed in more differentiated cells was associated with more substantial functional responses to IL-4 stimulation including increased eotaxin-3 expression and accelerated migration after injury. We demonstrate substantial differences in IL-4/IL-13 receptor subunit expression and responsiveness to IL-4 based on the extent of airway epithelial cell differentiation and suggest that these differences may have functional consequences in airway inflammation.


Successful treatment of juvenile pemphigus foliaceus in a Nigerian Dwarf goat.
CASE DESCRIPTION-A 2-month-old female Nigerian Dwarf goat was evaluated for a generalized crusting dermatitis; signs of depression; and fever of 1 month's duration. CLINICAL FINDINGS-Histologic evaluation of skin biopsy specimens revealed subcorneal pustules and rafts of acantholytic cells. No etiologic agents were detected in the biopsy material, and bacterial culture of skin biopsy specimens yielded no growth of pathological organisms. A diagnosis of pemphigus foliaceus was made. TREATMENT AND OUTCOME-Remission was achieved with a combination of SC administration of dexamethasone and IM administration of gold sodium thiomalate. The goat remained free of clinical signs for at least 26 months after discontinuation of all medications. No clinically apparent adverse effects of treatment were evident. CLINICAL RELEVANCE-This report represents the first description of successful treatment of juvenile pemphigus foliaceus in a goat by use of a novel protocol involving dexamethasone and gold sodium thiomalate.


A novel angiotensin I-converting enzyme mutation (S333W) impairs N-domain enzymatic cleavage of the anti-fibrotic peptide, AcSDKP.
Angiotensin I-converting enzyme (ACE) has two functional N- and C-domain active centers that display differences in the metabolism of biologically-active peptides including the hemoregulatory tetrapeptide, Ac-SDKP, hydrolysed preferentially by the N domain active center. Elevated Ac-SDKP concentrations are associated with reduced tissue fibrosis. We identified a patient of African descent exhibiting unusual blood ACE kinetics with reduced relative hydrolysis of two synthetic ACE substrates (ZPHL/HHL ratio) suggestive of the ACE N domain center inactivation. Inhibition of blood ACE activity by anti-catalytic mAbs and ACE inhibitors and conformational fingerprint of blood ACE suggested overall conformational changes in the ACE molecule and sequencing identified Ser333Trp substitution in the N domain of ACE. In silico analysis demonstrated S333W localized in the S1 pocket of the active site of the N domain with the bulky Trp adversely affecting binding of ACE substrates due to steric hindrance. Expression of mutant ACE (S333W) in CHO cells confirmed altered kinetic properties of mutant ACE and conformational changes in the N domain. Further, the S333W mutant displayed decreased ability (5-fold) to cleave the physiological substrate AcSDKP compared to wild-type ACE. A novel Ser333Trp ACE mutation results in dramatic changes in ACE kinetic properties and lowered clearance of Ac-SDKP. Individuals with this mutation (likely with significantly increased levels of the hemoregulatory tetrapeptide in blood and tissues), may confer protection against fibrosis.


Characterization of acceptance angles of small circular apertures.
We characterize the acceptance angles of small circular apertures for light collection by simulations and experimental measurements. By examining the full width half maximum acceptance angle as a function of the aperture size, we show that the acceptance angle of a circular aperture reaches a minimum of 67 deg before rebounding around the transition between single mode and multimode transmission (approximately 400 nm). This behavior can be explained by the change of mode-coupling efficiency during the transition from single mode to multimode propagation regime. This work in understanding of the behavior of light transmission through subwavelength apertures will guide the design of better aperture based imaging devices where apertures are used as light collection units.


Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products.
The abuse of psychoactive 'bath salts' containing cathinones such as 3,4-methylenedioxypyrovalerone (MDPV) is a growing public health concern, yet little is known about their pharmacology. Here, we evaluated the effects of MDPV and related drugs using molecular, cellular, and whole-animal methods. In vitro transporter assays were performed in rat brain synaptosomes and in cells expressing human transporters, while clearance of endogenous dopamine was measured by fast-scan cyclic voltammetry in mouse striatal slices. Assessments of in vivo neurochemistry, locomotor activity, and cardiovascular parameters were carried out in rats. We found that MDPV blocks uptake of [(3)H]dopamine (IC(50)=4.1 nM) and [(3)H]norepinephrine (IC(50)=26 nM) with high potency but has weak effects on uptake of [(3)H]serotonin (IC(50)=3349 nM). In contrast to other psychoactive cathinones (eg, mephedrone), MDPV is not a transporter substrate. The clearance of endogenous dopamine is inhibited by MDPV and cocaine in a similar manner, but MDPV displays greater potency and efficacy. Consistent with in vitro findings, MDPV (0.1-0.3 mg/kg, intravenous) increases extracellular concentrations of dopamine in the nucleus accumbens. Additionally, MDPV (0.1-3.0 mg/kg, subcutaneous) is at least 10 times more potent than cocaine at producing locomotor activation, tachycardia, and hypertension in rats. Our data show that MDPV is a monoamine transporter blocker with increased potency and selectivity for catecholamines when compared with cocaine. The robust stimulation of dopamine transmission by MDPV predicts serious potential for abuse and may provide a mechanism to explain the adverse effects observed in humans taking high doses of 'bath salts' preparations.


Objectively Measured Physical Activity Levels among Ethnic Minority Children Attending School-Based Afterschool Programs in a High-Poverty Neighborhood.
Ethnic minority children living in high poverty neighborhoods are at high risk of having insufficient physical activity (PA) during school days and, thus, the importance of school as a place to facilitate PA in these underserved children has been largely emphasized. This study examined the levels and patterns of PA in minority children, with particular focus on the relative contributions of regular physical education (PE) and school-based afterschool PA program in promoting moderate- and vigorous-intensity PA (MVPA) during school days. PA data were repeatedly measured using a Polar Active accelerometer across multiple school days (M = 5.3 days per child), from seventy-five ethnic minority children attending a Title I public elementary school in a high-poverty neighborhood in the US. The minutes and percentage of MVPA accumulated during school, PE, and afterschool PA program were compared to the current recommendations (≥30-min of MVPA during school hours; and ≥50% of MVPA during PE or afterschool PA program) as well as by the demographic characteristics including sex, grade, ethnicity, and weight status using a general linear mixed model that accounts for repeated observations. On average, children spent 41.6 mins (SE = 1.8) of MVPA during school hours and of those, 14.1 mins (SE = 0.6) were contributed during PE. The average proportion of time spent in MVPA during PE was 31.3% (SE = 1.3), which was significantly lower than the recommendation (≥50% of MVPA), whereas 54.2% (SE = 1.2) of time in afterschool PA program were spent in MVPA. The percentage of monitoring days meeting current recommendations were 69.5% (SE = 0.03), 20.8% (SE = 0.02), and 59.6% (SE = 0.03) for during school, PE, and afterschool PA program, respectively. Our findings highlighted that school-based afterschool PA, in addition to regular PE classes, could be of great benefit to promote PA in minority children during school days. Further research and practice are still needed to increase MVPA during school hours, particularly during PE classes.


Buckling of an elastic rod embedded on an elastomeric matrix: planar vs. non-planar configurations.
We investigate the buckling of a slender rod embedded in a soft elastomeric matrix through a combination of experiments, numerics and theory. Depending on the control parameters, both planar wavy (2D) or non-planar coiled (3D) configurations are observed in the post-buckling regime. Our analytical and numerical results indicate that the rod buckles into 2D configurations when the compression forces associated to the two lowest critical modes are well separated. In contrast, 3D coiled configurations occur when the two buckling modes are triggered at onset, nearly simultaneously. We show that the separation between these two lowest critical forces can be controlled by tuning the ratio between the stiffness of the matrix and the bending stiffness of the rod, thereby allowing for specific buckling configurations to be target by design.


Effect of previous benign breast biopsy on the interpretive performance of subsequent screening mammography.
Most breast biopsies will be negative for cancer. Benign breast biopsy can cause changes in the breast tissue, but whether such changes affect the interpretive performance of future screening mammography is not known. We prospectively evaluated whether self-reported benign breast biopsy was associated with reduced subsequent screening mammography performance using examination data from the mammography registries of the Breast Cancer Surveillance Consortium from January 2, 1996, through December 31, 2005. A positive interpretation was defined as a recommendation for any additional evaluation. Cancer was defined as any invasive breast cancer or ductal carcinoma in situ diagnosed within 1 year of mammography screening. Measures of mammography performance (sensitivity, specificity, and positive predictive value 1 [PPV1]) were compared both at woman level and breast level in the presence and absence of self-reported benign biopsy history. Referral to biopsy was considered a positive interpretation to calculate positive predictive value 2 (PPV2). Multivariable analysis of a correct interpretation on each performance measure was conducted after adjusting for registry, year of examination, patient characteristics, months since last mammogram, and availability of comparison film. Accuracy of the mammogram interpretation was measured using area under the receiver operating characteristic curve (AUC). All statistical tests were two-sided. A total of 2,007,381 screening mammograms were identified among 799,613 women, of which 14.6% mammograms were associated with self-reported previous breast biopsy. Multivariable adjusted models for mammography performance showed reduced specificity (odds ratio [OR] = 0.74, 95% confidence interval [CI] = 0.73 to 0.75, P < .001), PPV2 (OR = 0.85, 95% CI = 0.79 to 0.92, P < .001), and AUC (AUC 0.892 vs 0.925, P < .001) among women with self-reported benign biopsy. There was no difference in sensitivity or PPV1 in the same adjusted models, although unadjusted differences in both were found. Specificity was lowest among women with documented fine needle aspiration-the least invasive biopsy technique (OR = 0.58, 95% CI = 0.55 to 0.61, P < .001). Repeating the analysis among women with documented biopsy history, unilateral biopsy history, or restricted to invasive cancers did not change the results. Self-reported benign breast biopsy history was associated with statistically significantly reduced mammography performance. The difference in performance was likely because of tissue characteristics rather than the biopsy itself.


An epigenetic clock controls aging.
We are accustomed to treating aging as a set of things that go wrong with the body. But for more than twenty years, there has been accumulating evidence that much of the process takes place under genetic control. We have seen that signaling chemistry can make dramatic differences in life span, and that single molecules can significantly affect longevity. We are frequently confronted with puzzling choices the body makes which benefit neither present health nor fertility nor long-term survival. If we permit ourselves a shift of reference frame and regard aging as a programmed biological function like growth and development, then these observations fall into place and make sense. This perspective suggests that aging proceeds under control of a master clock, or several redundant clocks. If this is so, we may learn to reset the clocks with biochemical interventions and make an old body behave like a young body, including repair of many of the modes of damage that we are accustomed to regard as independent symptoms of the senescent phenotype, and for which we have assumed that the body has no remedy.


Effect of a long-term behavioural weight loss intervention on nephropathy in overweight or obese adults with type 2 diabetes: a secondary analysis of the Look AHEAD randomised clinical trial.
Long-term effects of behavioural weight loss interventions on diabetes complications are unknown. In a secondary analysis of the Look AHEAD (Action for Health in Diabetes) multicentre randomised clinical trial, we assessed whether an intensive lifestyle intervention (ILI) affects the development of nephropathy in people with type 2 diabetes. Overweight or obese people aged 45-76 years with type 2 diabetes were randomly assigned (1:1) to ILI or to a diabetes support and education (DSE) group by a central web-based data management system, stratified by clinical centre and blocked with random block sizes. The ILI was designed to achieve and maintain weight loss through reduced caloric consumption and increased physical activity. The interventions were terminated early because of absence of effect on the primary outcome of cardiovascular disease events in the main Look AHEAD trial. Albuminuria and estimated glomerular filtration rate were prespecified as two of many other outcomes and were assessed from baseline until the interventions ended. They were combined post hoc to define the main outcome for this report, very-high-risk chronic kidney disease (CKD), based on the 2013 Kidney Disease Improving Global Outcomes (KDIGO) classification. Outcomes assessors and laboratory staff were masked to treatment, but participants and interventionists were not masked. Time-to-event data were analysed by intention to treat by the Kaplan-Meier method and proportional hazards models. The Look AHEAD trial is registered with ClinicalTrials.gov, NCT00017953. Of the 5145 participants randomly assigned in the Look AHEAD trial (2570 to ILI and 2575 to DSE), analyses for very-high-risk CKD were done in 2423 (94%) of patients in the ILI group and 2408 (94%) of those in the DSE group. After a median of 8·0 years (IQR 7·9-9·9) of follow-up, the incidence of very-high-risk CKD was lower in the ILI group than in the DSE group, with incidence rates of 0·91 cases per 100 person-years in the DSE group and 0·63 per 100 person-years in the ILI group (difference 0·27 cases per 100 person-years, hazard ratio 0·69, 95% CI 0·55-0·87; p=0·0016). This effect was partly attributable to reductions in bodyweight, HbA1c, and systolic blood pressure. There were no safety concerns regarding kidney-related adverse events. Weight loss should be considered as an adjunct to medical treatments to prevent or delay progression of CKD in overweight or obese people with type 2 diabetes. National Institute of Diabetes and Digestive and Kidney Diseases.


Treatment with anti-CD137 mAbs causes intense accumulations of liver T cells without selective antitumor immunotherapeutic effects in this organ.
Cancer therapy with agonist anti-CD137 mAbs has been shown to induce immune-mediated tumor rejections in mice, and equivalent agents of this kind are currently being tested in cancer patients. Previous reports indicated that CD137 stimulation induced polyclonal infiltrates of T lymphocytes in the liver. This study characterizes the liver infiltrates and the target dependency of the phenomena and addresses the question of whether tumors nested in the liver are a more favorable target for CD137-based immunotherapy. Liver infiltrates were studied with conventional histology and multiple color flow cytometry of total liver leukocytes. CD137(-/-) mice, mice with a single rearrangement of the TCR (OT-1 mice) and Rag(-/-) mice were used to clarify molecular requirements. Mice implanted with MC38 colon carcinomas either subcutaneously or inside the liver were used for comparative studies under treatment with agonist anti-CD137 mAbs. CD137 treatment caused mononuclear inflammation in the portal spaces of the liver, which gave rise to moderate increases in transaminases without signs of cholestasis. Marked increases in the numbers of CD8+ T cells were observed, including CD8+ T lymphocytes co-expressing CD11c. Infiltrates were absent in CD137(-/-) mice and mitigated in mice harboring a single transgenic TCR on their CD8 T cells. Despite the tumor-independent accumulation of T cells in the liver, immunotherapeutic effects were not more prominent against tumors located in this organ. Target-dependent effects of CD137 stimulation lead to liver infiltration with T cells, but lymphocyte enrichment in this organ does not privilege this site for immunotherapeutic effects against transplanted tumors.


bcl2, bax, and nestin in the brains of patients with neurodegeneration and those of normal aging.
This study was conducted by employing specimens from the frontal cortices of Alzheimer, multiple-infarct dementia patients, and those of normal aging (age matched to patients). The objective was to evaluate and compare the bcl2, bax, and nestin patterns in these three groups. Using immunocytochemistry, it was observed that bcl2 and bax active sites were colocalized in 45% of cells in Alzheimer, 52% of cells in multiple infarct, and 30% of cells in normal aging. bcl2 and bax could also be separately located in cells of all three groups. bax cells were most prominent in number in Alzheimer patients and least prominent in normal aging. nestin was found in all three groups but was most prominent in the multiple-infarct patients. Both astrocytes and neurons demonstrated positive nestin sites. The difference in pattern between groups will lead to further understanding of cellular changes in neurodegenerative patients and those of normal aging.


Evaluation and treatment of hyperglycemia in critically ill patients.
The hyperglycemic reaction to stress is part of adaptive metabolic response to critical illness, especially hypoxia, hemorrhage and sepsis. It involves neuro-endocrine and immune pathways leading to the development of insulin resistance and hepatic glucose production by gluconeogenesis and glycogenolysis. Over the last years the concept of stress related hyperglycemia has been replaced by the concept of dysglycemia and its three domains: hyperglycemia, hypoglycemia and glycemic variability. Each of the three domains is independently associated with increased risk of mortality in patients admitted in intensive care unit and non critically ill patients, both medical and surgical. The strongest association with mortality is demonstrated for hypoglycemia, with additive negative effects for hyperglycemia and glycemic variability. The influence of pre-existing diabetes mellitus on the relation of the three domains of dysglycemia with mortality is not clear, suggesting that patients affected by diabetes mellitus may tolerate a larger glucose variability. Advances in continuous glucose monitoring systems and insulin therapy algorithms may reduce the development of glycemic variability and hypoglycemia, but the benefits in clinical practice have not yet been established in clinical trials.


Menopause as a regulatory device for matching the demand for children with its supply: A hypothesis.
Drawing on two assumptions: that menopause is an instrument for the efficient regulation of the duration of a biologically expensive state, and that people have children in order to obtain support from them in old age, we set out a new idea that seeks to explain both the occurrence of menopause and its timing. On the basis of the notion that the purpose of having children is to obtain support in old age, we perceive menopause as an upper limit to the fertile state, when a continued ability to give birth to children would not generate the desired support. The conjecture yields specific testable predictions, and can be assessed against the "reproductive conflict" hypothesis. Being supported by one's offspring is a distinctive feature of humans; in this context, we cannot rely on animal studies in evolutionary biology and related fields to help us to ascertain something that is specific to humans.


Copper and zinc tolerance of two tropical microalgae after copper acclimation.
Current toxicity tests with microalgae are often criticized as being overly sensitive to metals because algae are cultured in metal-deficient media. If such bioassays overestimate copper toxicity in surface waters, the relevance of water quality guidelines derived from these tests is questionable. In this study, the effect of acclimation to copper at environmentally relevant concentrations, on the sensitivity of the marine diatom Nitzschia closterium and the freshwater green alga Chlorella sp. to copper and zinc was examined. N. closterium was acclimated in culture medium containing 5 or 25 microg Cu L(-1) for 200 days, while Chlorella sp. was acclimated in medium containing 2 microg Cu L(-1) for 100 days. Changes in algal growth rates and copper and zinc tolerance were monitored using standard growth inhibition toxicity tests in minimal medium over 72 h. Neither of the two acclimated N. closterium cultures had increased zinc or copper tolerance compared with that of the nonacclimated algae, nor were there any changes in control growth rates. Similarly, no changes in copper tolerance or control growth rates were observed for the acclimated Chlorella sp. culture. This was supported by measurements of intracellular and extracellular copper which confirmed that there were no differences in copper accumulation in either acclimated or nonacclimated algae. These results suggest that these algae grown in standard culture media are generally no more sensitive than algae grown in a metal-enriched medium. This supports the continued use of current laboratory bioassays with microalgae, as part of a suite of tests for assessing metal bioavailability, for use in ecological risk assessments and for providing data for the derivation of water quality guidelines.


The European health divide: a matter of financial or social capital?
The 'European east--west health divide' has been documented both for mortality and for self-rated health. The reason for this divide, however, remains to be explained. The aim of this study is, firstly, to investigate whether in 1995-97 differences in self-rated health persisted between countries in central and eastern Europe, the former Soviet Union, and western Europe. A further aim is to try to explain these differences with reference to people's financial status and social capital. This study found substantial differences in self-rated health between countries in western Europe, in central and eastern Europe, and in the former Soviet Union (where self-rated health seems to be poorest in general). There were also substantial differences between areas in terms of economic and social capital, with western Europe doing better in all the analysed circumstances. In economic terms people in the former Soviet Union seemed to be more dissatisfied than those living in central and eastern Europe. When one looks at differences in social capital between the two post-communist areas the picture is more mixed. Economic satisfaction was demonstrated to have a strong and significant effect on people's self-rated health, with a higher satisfaction reducing the odds of 'poor' health. When this factor was controlled for the area, differences in self-rated health were reduced dramatically, for both men and women. Organisational activity (men only), trust in people, and confidence in the legal system also reduced the odds of 'less than good health', but were not as important in explaining the health differences between areas. One can conclude that economic factors as well as some aspects of social capital play a role for area differences in self-rated health. Of these it would appear that economic factors are the more important.


Neurovascular protection of cilostazol in stroke-prone spontaneous hypertensive rats associated with angiogenesis and pericyte proliferation.
Stroke is the major cause of death and decrease in the activities of daily living. This study sought to evaluate the effects of commonly used antiplatelet drugs on spontaneous cerebral infarction in relation to neurovascular protection associated with angiogenesis and pericyte proliferation. Stroke-prone spontaneously hypertensive rats (SHR-SP) were treated with vehicle, aspirin, clopidogrel, or cilostazol from 8 to 10 weeks of age. The interaction of neurovascular components among endothelial cells, pericytes, and astrocytic endfeet were immunohistochemically examined in brain sections. Angiogenesis associated with vascular endothelial growth factor receptor 2 (VEGFR2) and pericyte proliferation were also examined immunohistochemically. The expression and activity of matrix metalloproteinase 9 (MMP-9) were assessed immunohistochemically and by gelatin zymography. Among the antiplatelet drugs, cilostazol preserved the neurovascular unit (NVU) by preventing astrocytic endfeet or pericytes from pathological detachment found in the vehicle and aspirin treatment. Cilostazol also inhibited the expression and activity of MMP-9, which led to protection of the NVU. Furthermore, in the periinfarct area, cilostazol increased VEGFR2 expression, promoting angiogenesis through proliferation of pericytes. The present study showed a strong protection of NVU integrity by cilostazol and the promotion of angiogenesis by stimulating both endothelial VEGFR2 expression and pericyte proliferation. In addition to the antioxidative effect, these pleiotropic effects of cilostazol contribute to reduce spontaneous infarct volume and preserve motor and cognitive function in SHR-SP.


The one and the many: effects of the cell adhesion molecule pathway on neuropsychological function in psychosis.
Genetic studies of single gene variants have been criticized as providing a simplistic characterization of the genetic basis of illness risk that ignores the effects of other variants within the same biological pathways. Of candidate biological pathways for schizophrenia (SZ), the cell adhesion molecule (CAM) pathway has repeatedly been linked to both psychosis and neurocognitive dysfunction. Here we tested, using risk allele scores derived from the Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC-SCZ), whether alleles within the CAM pathway were correlated with poorer neuropsychological function in patients. In total, 424 patients with psychosis were assessed in areas of cognitive ability typically found to be impaired in SZ: intelligence quotient, memory, working memory and attentional control. CAM pathway genes were identified using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Alleles within these genes identified as significantly associated with SZ risk in the PGC-SCZ were then used to calculate a CAM pathway-based polygenic risk allele score for each patient and these scores were tested for association with cognitive ability. Increased CAM pathway polygenic risk scores were significantly associated with poorer performance on measures of memory and attention, explaining 1-3% of variation on these measures. Notably, the most strongly associated single nucleotide polymorphism (SNP) in the CAM pathway (rs9272105 within HLA-DQA1) explained a similar amount of variance in attentional control, but not memory, as the polygenic risk analysis. These data support a role for the CAM pathway in cognitive function, both at the level of individual SNPs and the wider pathway. In so doing these data highlight the value of pathway-based polygenic risk score studies as well as single gene studies for understanding SZ-associated deficits in cognition.


Strengthening health systems at facility-level: feasibility of integrating antiretroviral therapy into primary health care services in lusaka, zambia.
HIV care and treatment services are primarily delivered in vertical antiretroviral (ART) clinics in sub-Saharan Africa but there have been concerns over the impact on existing primary health care services. This paper presents results from a feasibility study of a fully integrated model of HIV and non-HIV outpatient services in two urban Lusaka clinics. INTEGRATION INVOLVED THREE KEY MODIFICATIONS: i) amalgamation of space and patient flow; ii) standardization of medical records and iii) introduction of routine provider initiated testing and counseling (PITC). Assessment of feasibility included monitoring rates of HIV case-finding and referral to care, measuring median waiting and consultation times and assessing adherence to clinical care protocols for HIV and non-HIV outpatients. Qualitative data on patient/provider perceptions was also collected. Provider and patient interviews at both sites indicated broad acceptability of the model and highlighted a perceived reduction in stigma associated with integrated HIV services. Over six months in Clinic 1, PITC was provided to 2760 patients; 1485 (53%) accepted testing, 192 (13%) were HIV positive and 80 (42%) enrolled. Median OPD patient-provider contact time increased 55% (6.9 vs. 10.7 minutes; p<0.001) and decreased 1% for ART patients (27.9 vs. 27.7 minutes; p = 0.94). Median waiting times increased by 36 (p<0.001) and 23 minutes (p<0.001) for ART and OPD patients respectively. In Clinic 2, PITC was offered to 1510 patients, with 882 (58%) accepting testing, 208 (24%) HIV positive and 121 (58%) enrolled. Median OPD patient-provider contact time increased 110% (6.1 vs. 12.8 minutes; p<0.001) and decreased for ART patients by 23% (23 vs. 17.7 minutes; p<0.001). Median waiting times increased by 47 (p<0.001) and 34 minutes (p<0.001) for ART and OPD patients, respectively. Integrating vertical ART and OPD services is feasible in the low-resource and high HIV-prevalence setting of Lusaka, Zambia. Integration enabled shared use of space and staffing that resulted in increased HIV case finding, a reduction in stigma associated with vertical ART services but resulted in an overall increase in patient waiting times. Further research is urgently required to assess long-term clinical outcomes and cost effectiveness in order to evaluate scalability and generalizability.


Complement in paroxysmal nocturnal hemoglobinuria: exploiting our current knowledge to improve the treatment landscape.
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disorder associated with an acquired deficiency in glycophosphatidylinositol-anchor biosynthesis that renders erythrocytes susceptible to complement attack. Intravascular hemolysis via the membrane attack complex is a clinical hallmark of the disease, and C5 blockade is currently the only approved treatment for PNH. However, residual anemia is an emerging observation for many PNH patients receiving anti-C5 treatment. A range of complement-targeted therapeutic approaches, encompassing surface-directed inhibition of C3 convertases, blockade of membrane attack complex assembly or C3 interception using peptidic inhibitors, has yielded promising results and offers leverage for even more effective treatment of PNH. This article discusses recent advances in this rapidly evolving field, integrating critical perspectives from preclinical PNH models and diverse complement modulation strategies with genetic insights and therapy response profiles. It also evaluates the relative efficacy, limitations and benefits afforded by C3 or C5 inhibition in the context of PNH therapeutics.


Single-Molecule FRET Measurements in Additive-Enriched Aqueous Solutions.
The addition of high amounts of chemical denaturants, salts, viscosity enhancers or macro-molecular crowding agents has an impact on the physical properties of buffer solutions. Among others, the (microscopic) viscosity, the refractive index, the dielectric constant, and the ionic strength can be affected. Here, we systematically evaluate the importance of solvent characteristics with respect to single-molecule FRET (smFRET) data. First, we present a confocal based method for the determination of fluorescence quantum yields to facilitate a fast characterization of smFRET-samples at sub-nM-concentrations. As a case study, we analyze smFRET data of structurally rigid, double-stranded DNA-oligonucleotides in aqueous buffer and in buffers with specific amounts of glycerol, guanidine hydrochloride (GdnHCl), and sodium chloride (NaCl) added. We show that the calculation of interdye distances, without taking into account solvent-induced spectral and photophysical changes of the labels, leads to deviations of up to 4 Å from the real interdye distances. Additionally, we demonstrate that electrostatic dye-dye repulsions are negligible for the interdye distance regime considered here (>50 Å). Finally, we use our approach to validate the further compaction of the already unfolded state of phosphoglycerate kinase (PGK) with decreasing denaturant concentrations, a mechanism known as coil-globule transition.