Genetic dissection of the murine lupus susceptibility locus Sle2: contributions to increased peritoneal B-1a cells and lupus nephritis map to different loci.
Lupus pathogenesis in the NZM2410 mouse model results from the expression of multiple interacting susceptibility loci. Sle2 on chromosome 4 was significantly linked to glomerulonephritis in a linkage analysis of a NZM2410 x B6 cross. Yet, Sle2 expression alone on a C57BL/6 background did not result in any clinical manifestation, but in an abnormal B cell development, including the accumulation of B-1a cells in the peritoneal cavity and spleen. Analysis of B6.Sle2 congenic recombinants showed that at least three independent loci, New Zealand White-derived Sle2a and Sle2b, and New Zealand Black-derived Sle2c, contribute to an elevated number of B-1a cells, with Sle2c contribution being the strongest of the three. To determine the contribution of these three Sle2 loci to lupus pathogenesis, we used a mapping by genetic interaction strategy, in which we bred them to B6.Sle1.Sle3 mice. We then compared the phenotypes of these triple congenic mice with that of previously characterized B6.Sle1.Sle2.Sle3, which express the entire Sle2 interval in combination with Sle1 and Sle3. Sle2a and Sle2b, but not Sle2c, contributed significantly to lupus pathogenesis in terms of survival rate, lymphocytic expansion, and kidney pathology. These results show that the Sle2 locus contains several loci affecting B cell development, with only the two NZW-derived loci having the least effect of B-1a cell accumulation significantly contributing to lupus pathogenesis.


Sexual function improvement in association with serum leptin level elevation in patients with premature ejaculation following sertraline treatment: a preliminary observation.
The objective of our work was to evaluate the effect of sertraline hydrochloride on serum levels of leptin and sexual function in patients with premature ejaculation (PE). A total of 124 patients with a history of PE at least 6 months, aged 20-50 years, were treated with sertraline hydrochloride. One hundred and four age-matched normal males without a history of PE were included control subjects and were untreated. Before and after the 8 week experiment, sexual performance parameters including the intravaginal ejaculation latency time (IELT) and the Chinese premature ejaculation index (CIPE) were collected from both PE patients and control subjects through a questionnaire survey and analyzed. Serum levels of leptin were measured. Correlations of serum leptin with Body Mass Index (BMI) were analyzed. Before sertraline treatment, serum levels of leptin were significantly higher (32.9 vs 8.8 μg/L, p<0.001) but IELT and CIPE score were significantly lower (54 vs 590, p <0.001; 8.7 vs 22.3, p <0.0001) in PE patients than control subjects. After 8 weeks of treatment with sertraline, serum levels of leptinl in PE patients were decreased markedly to 8.0 μg/L, which was not significantly different from the levels in control subjects (p >0.05); and IELT and CIPE score in PE patients were increased to the values similar to those in control subjects. The sensitivity and specificity values were 87.5% and 96.3% for leptin as a diagnosis target. These observations suggest sertraline as a selective serotonin reuptake inhibitor may offer an effective option for treating premature ejaculation.


Differential changes in steroid hormones before competition in bonobos and chimpanzees.
A large body of research has demonstrated that variation in competitive behavior across species and individuals is linked to variation in physiology. In particular, rapid changes in testosterone and cortisol during competition differ according to an individual's or species' psychological and behavioral responses to competition. This suggests that among pairs of species in which there are behavioral differences in competition, there should also be differences in the endocrine shifts surrounding competition. We tested this hypothesis by presenting humans' closest living relatives, chimpanzees (Pan troglodytes) and bonobos (Pan paniscus), with a dyadic food competition and measuring their salivary testosterone and cortisol levels. Given that chimpanzees and bonobos differ markedly in their food-sharing behavior, we predicted that they would differ in their rapid endocrine shifts. We found that in both species, males showed an anticipatory decrease (relative to baseline) in steroids when placed with a partner in a situation in which the two individuals shared food, and an anticipatory increase when placed with a partner in a situation in which the dominant individual obtained more food. The species differed, however, in terms of which hormone was affected; in bonobo males the shifts occurred in cortisol, whereas in chimpanzee males the shifts occurred in testosterone. Thus, in anticipation of an identical competition, bonobo and chimpanzee males showed differential endocrine shifts, perhaps due to differences in perception of the situation, that is, viewing the event either as a stressor or a dominance contest. In turn, common selection pressures in human evolution may have acted on the psychology and the endocrinology of our competitive behavior.


Acupuncture in patients suffering from allergic asthma: is it worth additional costs?
Acupuncture is increasingly used in patients with allergic asthma, but there is a lack of evidence on the cost-benefit relationship of this treatment. The aim of this study was to assess economic aspects of additional acupuncture treatment in patients with allergic bronchial asthma compared to patients receiving routine care alone. DESIGN, SUBJECTS, INTERVENTION, OUTCOME MEASURES: In a randomized controlled trial, patients with allergic bronchial asthma were either allocated to a group receiving acupuncture immediately or a waiting-list control group. Both groups were free to use routine care treatment. The resource consumption, costs, and health-related quality of life were evaluated at baseline, and after 3 and 6 months by using statutory health insurance information and standardized questionnaires. Main economic outcome parameters were direct and indirect cost differences during the study period and the incremental cost-effectiveness ratio (ICER) of acupuncture treatment. Three hundred and six (306) patients (159 acupuncture; 147 controls) were included (mean age 46.5±13.11 years, female 57.2%) and were comparable at baseline. Acupuncture treatment was associated with significantly higher costs compared to control patients (overall costs: €860.76 [95% confidence interval (CI) 705.04-1016.47] versus €518.80 [95% CI 356.66-680.93]; p=0.003; asthma-related costs: €517.52 [95% CI 485.63-549.40] versus €144.87 [95% CI 111.70-178.05]; p<0.001). These additional costs seem essentially driven by acupuncture costs themselves (€378.40 [95% CI 367.10-389.69]). However, acupuncture was associated with superior effectiveness in terms of quality-adjusted life years (QALYs). Resulting ICER lay between €23,231 (overall) and €25,315 (diagnosis-specific) per additional QALY. When using German acupuncture prices of year 2012, the ICER would improve to €12.810 (overall) versus €14,911 (diagnosis-specific) per QALY gained. Treating patients who have allergic bronchial asthma with acupuncture in addition to routine care resulted in additional costs and better effects in terms of patients' quality of life. Acupuncture therefore seems to be a useful and cost-effective add-on treatment.


Chinese herbal medicine for oesophageal cancer.
Oesophageal cancer is the seventh leading cause of cancer death worldwide. Traditional Chinese herbal medicine is sometimes used as an adjunct to radiotherapy or chemotherapy for this type of cancer. This review was first published in 2007 and updated in 2009; this 2016 update is the latest version of the review. To assess the efficacy and possible adverse effects of the addition of Chinese herbal medicine to treatment with radiotherapy or chemotherapy for oesophageal cancer. We searched the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Trials Register, the Cochrane Library, MEDLINE, EMBASE, Allied and Complementary Medicine Database (AMED), China National Knowledge Infrastructure (CNKI), VIP database, Wanfang database and the Chinese Cochrane Centre Controlled Trials Register up to 1 October, 2015. We also searched databases of ongoing trials, the Internet and reference lists. Randomised controlled trials (RCTs) comparing the use of radiotherapy or chemotherapy with and without the addition of Chinese herbal medicine. At least two review authors independently extracted data and assessed trial quality. We tried to contact the 142 study authors by telephone, and finally included nine studies with 490 participants. All included studies were conducted in China, and allocated advanced oesophageal cancer patients to radiotherapy or chemotherapy groups, with and without additional Chinese herbal medicine. Quality of life, short-term therapeutic effects, TCM symptoms and adverse events caused by radiotherapy or chemotherapy were reported in these studies. Overall, we considered the trials to be at unclear or high risk of bias.The quality of life measure was conducted before and after the intervention; our analysis showed a beneficial effect, both in number of participants experiencing an improvement (risk ratio (RR) 2.20, 95% confidence interval (CI) 1.42 to 3.39; 5 RCTs, 233 participants, change of performance status score ≥ 10) and number of participants experiencing a deterioration (RR 0.41, 95% CI 0.27 to 0.62; 6 RCTs, 287 participants, change of performance status score ≤ 10). We judged this to have low quality evidence, downgrading quality of evidence for risk of bias and imprecision, and upgrading quality of evidence for the large effect.For short-term therapeutic effects, the results suggest that traditional Chinese medicine (TCM) has a positive impact on improvement (complete response + partial response) (RR 1.17, 95% CI 1.02 to 1.35; 8 RCTs, 450 participants), moderate quality evidence and downgrading for risk of bias. There was no significant difference for progressive disease (RR 0.73, 95% CI 0.52 to 1.01; 8 RCTs, 450 participants), low quality evidence and downgrading for risk of bias and imprecision. Three studies assessed this outcome after four weeks or three months' follow-up, the remaining studies gave no detailed information for this outcome. TCM symptoms, which was similar to short-term therapeutic effects evaluated with TCM clinical criteria, was diagnosed in two studies of 88 people at the end of the intervention. The results suggest that TCM has a positive impact on both total effectiveness (RR 1.84, 95% CI 1.20 to 2.81) and ineffectiveness (RR 0.22, 95% CI 0.05 to 0.93); we judged the studies to have very low quality evidence, downgrading for risk of bias and imprecision.Nine studies reported a series of adverse events caused by radiotherapy or chemotherapy at the end of the intervention, including mucositis, radiation oesophagitis, arrest of bone marrow, gastrointestinal reactions, renal and hepatic impairment, white blood cell descent, neurotoxicity, cardiac toxicity and anaemia. For those containing multiple studies, we conducted a pooled analysis. As a result, TCM showed a significant effect on radiation oesophagitis (RR 0.66, 95% CI 0.47 to 0.94; 2 RCTs, 90 participants), gastrointestinal reactions (RR 0.54, 95% CI 0.36 to 0.81; 4 RCTs, 268 participants) and white blood cell descent (RR 0.60, 95% CI 0.44 to 0.83; 4 RCTs, 224 participants). The quality of evidence was low or very low, downgrading for risk of bias and imprecision. We currently find no evidence to determine whether TCM is an effective treatment for oesophageal cancer. The effect of TCM on short-term therapeutic effects is uncertain. TCM probably has positive effects on quality of life and on some adverse events caused by radiotherapy or chemotherapy in advanced oesophageal cancer patients undergoing radiotherapy or chemotherapy. The results of the review need to be interpreted cautiously owing to overall low quality evidence. Future trials should be large and correctly designed to detect important clinical effects and minimise risk of bias.


Pancreatic metastases: CT and MRI findings.
The pancreas is an unusual but occasionally favored site for metastases in patients with advanced malignancy. The pivotal role of computed tomography (CT) and magnetic resonance imaging (MRI) examination in detecting the pancreatic mass and providing guidance to obtain a definitive tissue diagnosis is emphasized in this study. Eleven patients with pancreatic metastases, 4 women and 7 men with a mean age of 62.45 years, were examined in a period of 5 years. All patients underwent CT examination and 3 patients were further evaluated by MRI. The primary malignancy was lung carcinoma in 7 patients, breast carcinoma in 3 patients and renal cell carcinoma in 1 patient. The pancreatic metastases were detected during initial staging in 4 cases and during follow-up in 7 cases. The type of metastases was solitary in 7 patients, multiple in 3 patients and diffuse in 1 patient, with rim or homogeneous enhancement. Seven patients had metastases to other organs. CT-guided biopsy was performed in 5 patients. Disparity in prognosis and management of patients with secondary pancreatic tumors makes detection and characterization of metastases to the pancreas an important goal of CT and MRI evaluation.


Updates in the management of inflammatory bowel disease during pregnancy.
The best pregnancy outcomes for women with inflammatory bowel disease (IBD) occur when their disease is in remission at conception and remains in remission throughout pregnancy. Active IBD can lead to adverse pregnancy outcomes, including spontaneous abortion, pre-term birth and low birthweight. The majority of women with IBD who are taking maintenance medication will require medication throughout the pregnancy to prevent disease relapse. Most IBD medications are considered safe in pregnancy and breastfeeding, except for methotrexate. Pre-conception counselling should be arranged with the patient's IBD specialist and should include discussions regarding the importance of optimising disease control before and during pregnancy as well as the medication management plan for pregnancy. Patients with IBD should be reassured that their fertility is normal when the disease is quiescent, with the exception of women who have had pelvic surgery. IBD activity should be carefully monitored during pregnancy using non-invasive techniques, and disease flares during pregnancy should be treated promptly with escalation of therapy in consultation with the patient's IBD specialist. Mode of delivery should be determined by obstetric need; however, caesarean delivery is preferred for women with a history of ileal pouch anal anastomosis surgery or active perianal Crohn's disease.


Data-driven control for relative degree systems via iterative learning.
Iterative learning control (ILC) is a kind of effective data-driven method that is developed based on online and/or offline input/output data. The main purpose of this paper is to supply a unified 2-D analysis approach for both continuous-time and discrete-time ILC systems with relative degree. It is shown that the 2-D Roesser system framework can be established for general ILC systems regardless of relative degree, under which convergence conditions can be provided to guarantee both asymptotic stability and monotonic convergence of the ILC processes. In particular, conditions for the monotonic convergence of ILC can be given in terms of linear matrix inequalities, and formulas for the updating law can be derived simultaneously. Simulation results are presented to illustrate the effectiveness of ILC determined through the 2-D design approach in dealing with the higher order relative degree problem of ILC systems, as well as the robustness of such ILC against uncertainties.


Spatial and temporal patterns of imported malaria cases and local transmission in Trinidad.
Over a 30-year period (1968-1997) 213 malaria cases in Trinidad were investigated by the Trinidad and Tobago Ministry of Health. Using a global positional system and a geographic information system, we mapped the precise location of all reported malaria cases, and associated them with breeding habitats of anopheline vectors. The majority of the cases (138, 63%) were individual imported cases around the big port cities. Plasmodium falciparum was the most common parasite, and Africa the most common source of imported cases. Two clusters of cases occurred: an introduced P. vivax outbreak associated with Anopheles aquasalis in 1990-1991, and an autochtonous focus of P. malariae associated with An. bellator and An. homunculus in 1994-1995. Application of a space-time statistic showed a significant clustering of P. malariae cases, and, to a lesser extent of P. vivax cases, but not of P. falciparum cases. Based on potential for occurrence of local transmission, we are developing risk maps to determine surveillance priorities, outbreak potential, and necessary degree and spatial range of control activities following case detections.


Residual HIV-1 DNA Flap-independent nuclear import of cPPT/CTS double mutant viruses does not support spreading infection.
The human immunodeficiency virus type 1 (HIV-1) central DNA Flap is generated during reverse transcription as a result of (+) strand initiation at the central polypurine tract (cPPT) and termination after a ca. 100 bp strand displacement at the central termination sequence (CTS). The central DNA Flap is a determinant of HIV-1 nuclear import, however, neither cPPT nor CTS mutations entirely abolish nuclear import and infection. Therefore, to determine whether or not the DNA Flap is essential for HIV-1 nuclear import, we generated double mutant (DM) viruses, combining cPPT and CTS mutations to abolish DNA Flap formation. The combination of cPPT and CTS mutations reduced the proportion of viruses forming the central DNA Flap at the end of reverse transcription and further decreased virus infectivity in one-cycle titration assays. The most affected DM viruses were unable to establish a spreading infection in the highly permissive MT4 cell line, nor in human primary peripheral blood mononuclear cells (PBMCs), indicating that the DNA Flap is required for virus replication. Surprisingly, we found that DM viruses still maintained residual nuclear import levels, amounting to 5-15% of wild-type virus, as assessed by viral DNA circle quantification. Alu-PCR quantification of integrated viral genome also indicated 5-10% residual integration levels compared to wild-type virus. This work establishes that the central DNA Flap is required for HIV-1 spreading infection but points to a residual DNA Flap independent nuclear import, whose functional significance remains unclear since it is not sufficient to support viral replication.


[Estimate of the validity of a new method for the isolation of rabies virus].
No population-based studies have been conducted to show the potential for the use of virological diagnosis of the rabies virus. The objective of the present study was to estimate accuracy parameters for the isolation of the rabies virus in McCoy cells as an alternative method and to compare this with the use of murine neuroblastoma (N2A) cells, which is considered to be a reference method. An evaluation was performed on 120 bats collected at random in the Atlantic Forest of the State of São Paulo. The immunofluorescence reaction was utilized for the detection of the rabies virus isolated from the brain of these bats and the presence of the virus was tested in the two cell culture systems. Two data sets were constructed with the results and the analysis was performed using the computer methods for diagnosis tests (CMDT) software by means of the two-graph receiver operating characteristic (TG-ROC) technique to determine sensitivity and specificity parameters, as well as other indicators such as efficacy, positive predictive value, negative predictive value and likelihood ratio. N2A cells presented 90% sensitivity and specificity, while McCoy cells presented 95% sensitivity and specificity. These values were based on cut-off points optimized for each cell type. The study showed that McCoy cells allowed the obtaining of accuracy estimates that were better than for N2A. The McCoy cell method is therefore an effective method for the isolation of the rabies virus.


Effect of Arginine on the Aggregation of Protein in Freeze-Dried Formulations Containing Sugars and Polyol: II. BSA Reconstitution and Aggregation.
The current paper continues our study on the ability of L-arginine to prevent/reduce the aggregation of proteins that results from the various stresses during the lyophilisation and/or storage of lyophilized protein-based products. The first part of our study, i.e. formulation development, was devoted to the rational design and optimization of an L-arginine containing lyophilized formulation which can resist the natural tendency of L-arginine to absorb atmosphere moisture. Mannitol and trehalose were chosen among other excipients to be included in the protein-based formulation, as mannitol in a combination with L-arginine has been shown to reduce moisture sorption while trehalose provides a degree of lyoprotection. In the present study, a number of formulations, which comprised bovine serum albumin (BSA) with and without L-arginine, and with five different ratios of trehalose-to-mannitol (from 30:70 to 80:20) were lyophilised and assessed. The internal structures and the moisture sorption/retention of the lyophilized formulations were characterised. To study the effect of L-arginine on BSA solid-phase stability, the lyophilized powder was exposed to accelerated storage conditions (high moisture (75% RH) and temperature (22 or 45 °C)) for up to 24 h. The lyophilized BSA formulations were then reconstituted and solution-state protein aggregation assessed by turbidimetry at 360 nm and fluorescence spectroscopy using the thioflavin T assay. It was demonstrated that L-arginine can be used in protein-based freeze-dried formulations to significantly reduce the aggregation of protein during the manufacturing, storage and subsequent reconstitution. The results also revealed the importance of a sufficient amount of mannitol in the arginine-containing formulations.


Comparison of the major structural core proteins of tick-borne and Culicoides-borne orbiviruses.
Comparison of sequence data for Broadhaven (BRD) virus, a tick-borne orbivirus, and bluetongue virus (BTV), the type species of the genus, indicated that RNA segments 2 and 7 of BRD virus encode the two structural core proteins, VP2 and VP7, respectively. Segment 2 is 2792 nucleotides in length with a coding capacity for a protein (VP2) of 908 amino acids and a net charge of +8.5 at neutral pH. Segment 7 is 1174 nucleotides in length with a coding capacity for a protein (VP7) of 356 amino acids and a net charge of +11.5 at neutral pH. Comparison of the two sequences with BTV serotype 10 revealed amino acid identity of 35% between the product of segment 2 and BTV VP3, and 21% between the product of segment 7 and BTV VP7. The core proteins therefore show evidence of significant evolutionary divergence compared with that shown between different insect-borne orbiviruses. In particular, the amino terminus of BRD virus VP7 differed markedly from the equivalent region in VP7 of BTV and African horse sickness virus. This region is thought to interact with the outer capsid layer of insect-borne orbiviruses.


PHOSPHATE STARVATION RESPONSE transcription factors enable arbuscular mycorrhiza symbiosis.
Arbuscular mycorrhiza (AM) is a widespread symbiosis between roots of the majority of land plants and Glomeromycotina fungi. AM is important for ecosystem health and functioning as the fungi critically support plant performance by providing essential mineral nutrients, particularly the poorly accessible phosphate, in exchange for organic carbon. AM fungi colonize the inside of roots and this is promoted at low but inhibited at high plant phosphate status, while the mechanistic basis for this phosphate-dependence remained obscure. Here we demonstrate that a major transcriptional regulator of phosphate starvation responses in rice PHOSPHATE STARVATION RESPONSE 2 (PHR2) regulates AM. Root colonization of phr2 mutants is drastically reduced, and PHR2 is required for root colonization, mycorrhizal phosphate uptake, and yield increase in field soil. PHR2 promotes AM by targeting genes required for pre-contact signaling, root colonization, and AM function. Thus, this important symbiosis is directly wired to the PHR2-controlled plant phosphate starvation response.


Elevated Matrix Metalloproteinase Levels in Bronchi Infected with Periodontopathogenic Bacteria.
To determine whether bronchial colonisations/infections with periodontopathogenic bacteria are associated with elevated inflammatory markers such as MMPs, interleukins and Tumor necrosis factor alpha in the bronchial fluid. Periodontal status was assessed in consecutive outpatients planned for elective bronchoscopies, and PCR for periodontopathogenic bacteria was performed from a protected specimen brush sample taken from the bronchial mucosa. Additionally, MMPs, interleukins and Tumor necrosis factor alpha were measured in the bronchial fluid. Out of the four species assessed, one species was found in 13 of 91 (14%) patients, and two in 12 (13%), three in 13 (14%) and all four in 1 (1%) patient, respectively. In multiple linear regression models the presence of Treponema denticola showed a consistent pattern of positive effects in bronchial fluid (Bonferroni adjusted p-values) on the levels of MMP9 (p adj.: 0.028) and MMP12 (p adj.: 0.029). Active smoking was independently associated with increased levels of aMMP8 (p adj.: 0.005) and MMP9 (p adj.: 0.009). Levels of IL-1 ß, IL-8 and Tumor necrosis factor alpha measured in the bronchial fluid were not affected by the presence of periodontopathogenic bacteria. Bronchial colonisation/infection with Treponema denticola and smoking are independently associated with elevated MMPs (MMP9/MMP12 and MMP8/MMP9, respectively) in the bronchial fluid.


A Randomized Phase II Trial of Epigenetic Priming with Guadecitabine and Carboplatin in Platinum-resistant, Recurrent Ovarian Cancer.
Platinum resistance in ovarian cancer is associated with epigenetic modifications. Hypomethylating agents (HMA) have been studied as carboplatin resensitizing agents in ovarian cancer. This randomized phase II trial compared guadecitabine, a second-generation HMA, and carboplatin (G+C) against second-line chemotherapy in women with measurable or detectable platinum-resistant ovarian cancer. Patients received either G+C (guadecitabine 30 mg/m2 s.c. once-daily for 5 days and carboplatin) or treatment of choice (TC; topotecan, pegylated liposomal doxorubicin, paclitaxel, or gemcitabine) in 28-day cycles until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were RECIST v1.1 and CA-125 response rate, 6-month PFS, and overall survival (OS). Of 100 patients treated, 51 received G+C and 49 received TC, of which 27 crossed over to G+C. The study did not meet its primary endpoint as the median PFS was not statistically different between arms (16.3 weeks vs. 9.1 weeks in the G+C and TC groups, respectively; P = 0.07). However, the 6-month PFS rate was significantly higher in the G+C group (37% vs. 11% in TC group; P = 0.003). The incidence of grade 3 or higher toxicity was similar in G+C and TC groups (51% and 49%, respectively), with neutropenia and leukopenia being more frequent in the G+C group. Although this trial did not show superiority for PFS of G+C versus TC, the 6-month PFS increased in G+C treated patients. Further refinement of this strategy should focus on identification of predictive markers for patient selection.


Paeoniflorin inhibits systemic inflammation and improves survival in experimental sepsis.
The present study was carried out to investigate the effects of paeoniflorin in cultured RAW264.7 cell line as well as in an experimental model of sepsis induced by cecal ligation and puncture, and intraperitoneal injection (i.p.) of lipopolysaccharide in rats. Results showed that paeoniflorin concentration-dependently down-regulated the levels of TNF-alpha, IL-6 and high-mobility group-box 1 protein in lipopolysaccharide-induced RAW264.7 cell, inhibited the IkappaB kinase pathway and modulated NF-kappaB. Intravenous injection (i.v.) of paeoniflorin alone or in combination with imipenem reduced i.p. of lipopolysaccharide or cecal ligation and puncture-induced lethality in rats. In addition, serum levels of TNF-alpha, IL-6, high-mobility group-box 1 protein, triggering receptor expressed on myeloid cells and endotoxin were down-regulated; by contrast, serum levels of IL-10 were up-regulated. Amelioration of hemodynamics, decrease of enzyme levels, decrease of myeloperoxidase in lung, liver, and small intestine were also found after paeoniflorin injection. These data indicate that the anti-sepsis effect of paeoniflorin was mediated by decreasing local and systemic levels of a wide spectrum of inflammatory mediators. This work provides the first evidence that paeoniflorin has the capacity to inactivate inflammatory response in sepsis and the anti-inflammatory mechanism of paeoniflorin may inhibit activation of the NF-kappaB pathway by inhibiting IkappaB kinase activity.


Acceptability of mHealth Technology for Self-Monitoring Eating and Activity among Rural Men.
To examine rural men's use and perceptions of mobile and wireless devices to self-monitor eating and physical activity (mHealth). Men in this 3-week pilot study used FitBit One® to log daily food intake and monitor activity. A companion application (app) allowed activity monitoring of fellow participants. Health-related text messages were received 1-3 times daily. A purposive sample of 12 rural men (ages 40-67) was recruited by community leaders. (1) baseline heart rate, blood pressure, and BMI, (2) FitBit One® usage, (3) investigator-generated surveys on acceptability of mHealth, and (4) focus group on experience with mHealth. Men were overweight (n = 3) or obese (n = 9) and 9 of 12 were hypertensive. Nine of twelve wore FitBit One® all 21 days. Eleven of 12 men logged food, with 9 of 12 doing this at least 15 of 21 days. Self-monitoring and daily text messaging increased awareness of energy intake and output. Companion app's food log needed targeting for rural foods. Rotating seasons (occupational, religious, recreational) and weak cellular signals created contextual barriers to self-monitoring eating and activity. FitBit One® and text messaging were perceived as useful among the rural men, while the companion apps require adaptation to reflect dietary norms.


NK cells limit therapeutic vaccine-induced CD8+T cell immunity in a PD-L1-dependent manner.
A better understanding of mechanisms that regulate CD8+T cell responses to therapeutic vaccines is needed to develop approaches to enhance vaccine efficacy for chronic viral infections and cancers. We show here that NK cell depletion enhanced antigen-specific T cell responses to chimp adenoviral vector (ChAdOx) vaccination in a mouse model of chronic HBV infection (CHB). Probing the mechanism underlying this negative regulation, we observed that CHB drove parallel up-regulation of programmed cell death ligand 1 (PD-L1) on liver-resident NK cells and programmed cell death 1 (PD-1) on intrahepatic T cells. PD-L1-expressing liver-resident NK cells suppressed PD-1hiCD8+T cells enriched within the HBV-specific response to therapeutic vaccination. Cytokine activation of NK cells also induced PD-L1, and combining cytokine activation with PD-L1 blockade resulted in conversion of NK cells into efficient helpers that boosted HBV-specific CD8+T cell responses to therapeutic vaccination in mice and to chronic infection in humans. Our findings delineate an immunotherapeutic combination that can boost the response to therapeutic vaccination in CHB and highlight the broader importance of PD-L1-dependent regulation of T cells by cytokine-activated NK cells.


Lipopolysaccharide Binding Protein and Oxidative Stress in a Multiple Sclerosis Model.
Recent findings in experimental autoimmune encephalomyelitis (EAE) suggest that altering certain bacterial populations present in the gut may lead to a proinflammatory condition, that could result in the development of multiple sclerosis (MS). Also, Reactive Oxygen Species seem to be involved in the course of MS. In this study, it has been aimed to relate all these variables starting from an analysis of the lipopolysaccharide (LPS) and LPS-binding protein (LBP) with the determination of parameters related to oxidative stress in the blood, brain and spinal cord. For this purpose, samples obtained from EAE rats and relapsing-remitting (RRMS) MS patients were used. In addition, EAE rats were treated with Natalizumab, N-acetyl-cysteine and dimethyl fumarate. Natalizumab was also employed in RRMS. The results of this study revealed an improvement in the clinical symptoms of the EAE and MS with the treatments, as well as a reduction in the oxidative stress parameters and in LBP. Correlations between the clinical variables of the disease, i.e. oxidative damage and LBP, were established. Although the conclusions of this research are indeed relevant, further investigation would be necessary to establish the intrinsic mechanisms of the MS-oxidative stress-microbiota relationship.


Stable Aqueous Dispersions of Hydrophobically Modified Titanium Dioxide Pigments through Polyanion Adsorption: Synthesis, Characterization, and Application in Coatings.
Polyanion dispersants stabilize aqueous dispersions of hydrophilic (native) inorganic oxide particles, including pigments currently used in paints, which are used at an annual scale of 3 million metric tons. While obtaining stable aqueous dispersions of hydrophobically modified particles has been desired for the promise of improved film performance and water barrier properties, it has until now required either prohibitively complex polyanions, which represent a departure from conventional dispersants, or multistep syntheses based on hybrid-material constructs. Here, we demonstrate the aqueous dispersion of alkylsilane-capped inorganic oxide pigments with conventional polycarboxylate dispersants, such as carboxymethylcellulose (CMC) and polyacrylate, as well as a commercial anionic copolymer. Contact-angle measurements demonstrate that the hydrophobically modified pigments retain significant hydrophobic character even after adsorbing polyanion dispersants. CMC adsorption isotherms demonstrate 92% greater polyanion loading on trimethylsilyl modified hydrophobic particles relative to native oxide at pH 8. However, consistent with prior literature, hydrophobically modified silica particles adsorb polyanions very weakly under these conditions. These data suggest that Lewis acidic heteroatoms such as Al(3+) sites on the pigment surface are necessary for polyanion adsorption. The adsorbed polyanions increase the dispersion stability and zeta potential of the particles. Based on particle sedimentation under centrifugal force, the hydrophobically modified pigments possess greater dispersion stability with polyanions than the corresponding native hydroxylated particles. The polyanions also assist in the aqueous wetting of the hydrophobic particles, facilitating the transition from a dry powder into an aqueous dispersion of primary particles using less agitation than the native hydroxylated pigment. The application of aqueous dispersions of hydrophobically modified oxide particles to waterborne coatings leads to films that display lower water uptake at high relative humidities and greater hydrophilic stain resistances. This improved film performance with hydrophobically modified pigments is the result of better association between latex polymer and pigment in the dry film.


Photonic microwave bandpass filter with improved dynamic range.
A technique to improve the dynamic range of a photonic microwave bandpass filter is proposed and experimentally demonstrated. The filter is implemented based on phase modulation to intensity modulation conversion using fiber Bragg gratings (FBGs) serving as frequency discriminators, with the optical carriers located at the left or right slopes of the FBGs, to generate positive or negative tap coefficients. The dynamic range of the photonic microwave bandpass filter is increased by reducing the optical-carrier-induced shot noise and relative intensity noise at the photodetector, which is realized by placing the optical carriers at the lower slopes of the FBG reflection spectra. A photonic microwave bandpass filter with an improvement in dynamic range of about 10 dB is demonstrated.


Direct visualisation of internalization of the adenosine A3 receptor and localization with arrestin3 using a fluorescent agonist.
Fluorescence based probes provide a novel way to study the dynamic internalization process of G protein-coupled receptors (GPCRs). Recent advances in the rational design of fluorescent ligands for GPCRs have been used here to generate new fluorescent agonists containing tripeptide linkers for the adenosine A3 receptor. The fluorescent agonist BY630-X-(D)-A-(D)-A-G-ABEA was found to be a highly potent agonist at the adenosine A3 receptor in both reporter gene (pEC50 = 8.48 ± 0.09) and internalization assays (pEC50 = 7.47 ± 0.11). Confocal imaging studies showed that BY630-X-(D)-A-(D)-A-G-ABEA was internalized with A3 linked to yellow fluorescent protein, which was blocked by the competitive antagonist MRS1220. Internalization of untagged adenosine A3 could also be visualized with BY630-X-(D)-A-(D)-A-G-ABEA treatment. Further, BY630-X-(D)-A-(D)-A-G-ABEA stimulated the formation of receptor-arrestin3 complexes and was found to localize with these intracellular complexes. This highly potent agonist with excellent imaging properties should be a valuable tool to study receptor internalization. This article is part of the Special Issue entitled 'Fluorescent Tools in Neuropharmacology'.


A comparison study of KOOS-PS and KOOS function and sport scores.
The KOOS-PS represents a shortened version of the Knee Injury and Osteoarthritis Outcome Score (KOOS) Function and Sport scales. Previous investigations have not evaluated the KOOS-PS against performance measures or self-report measures composed of items that assess a broad spectrum of ability levels. The purpose of this study was to compare the construct validity of the KOOS Function and Sport subscales with a shorter version of the measure (KOOS-PS). Using a cross-sectional, observational design, consecutive consenting patients diagnosed with knee osteoarthritis were recruited at an assessment center visit to determine need for conservative or surgical management. Participants completed the Lower Extremity Functional Scale (LEFS), KOOS, Timed "Up & Go" Test, and Six-Minute Walk Test. A single function-sport score (KOOS FunSportsum) and the KOOS-PS were abstracted from the KOOS. Pearson correlation coefficients were compared between the reference standards' scores (performance measures and LEFS) and KOOS scores. KOOS-PSraw scores were compared with KOOS-PSRasch scores. Three hundred seventy-seven patients with a mean age of 64.4 years (SD=10.5) participated. The correlation between performance reference standard and KOOS-PSRasch scores was significantly lower than with KOOS FunSportsum scores (mean difference in r=.08 [95% confidence interval=.03, .11], z=4.45, P1<.001). A similar finding was observed with the LEFS comparison. The study sample did not consist of many patients with mild or severe functional status limitations. For patients with knee osteoarthritis, the KOOS-PS appears too restricted in item content to provide a comprehensive estimate of lower extremity functional status level relative to the KOOS Function and Sport subscales. Pursuit of a computer-adapted test may be a productive direction for future inquiry.


Efficient Multiterminal Spectrum Splitting via a Nanowire Array Solar Cell.
Nanowire-based solar cells opened a new avenue for increasing conversion efficiency and rationalizing material use by growing different III-V materials on silicon substrates. Here, we propose a multiterminal nanowire solar cell design with a theoretical conversion efficiency of 48.3% utilizing an efficient lateral spectrum splitting between three different III-V material nanowire arrays grown on a flat silicon substrate. This allows choosing an ideal material combination to achieve the proper spectrum splitting as well as fabrication feasibility. The high efficiency is possible due to an enhanced absorption cross-section of standing nanowires and optimization of the geometric parameters. Furthermore, we propose a multiterminal contacting scheme that can be fabricated with a technology close to standard CMOS. As an alternative we also consider a single power source with a module level voltage matching. These new concepts open avenues for next-generation solar cells for terrestrial and space applications.


Abnormal development of the cerebral cortex and cerebellum in the setting of lamin B2 deficiency.
Nuclear lamins are components of the nuclear lamina, a structural scaffolding for the cell nucleus. Defects in lamins A and C cause an array of human diseases, including muscular dystrophy, lipodystrophy, and progeria, but no diseases have been linked to the loss of lamins B1 or B2. To explore the functional relevance of lamin B2, we generated lamin B2-deficient mice and found that they have severe brain abnormalities resembling lissencephaly, with abnormal layering of neurons in the cerebral cortex and cerebellum. This neuronal layering abnormality is due to defective neuronal migration, a process that is dependent on the organized movement of the nucleus within the cell. These studies establish an essential function for lamin B2 in neuronal migration and brain development.


Nonsteroidal anti-inflammatory drug use among persons with chronic kidney disease in the United States.
Because avoidance of nonsteroidal anti-inflammatory drugs (NSAIDs) is recommended for most individuals with chronic kidney disease (CKD), we sought to characterize patterns of NSAID use among persons with CKD in the United States. A total of 12,065 adult (aged 20 years or older) participants in the cross-sectional National Health and Nutrition Examination Survey (1999-2004) responded to a questionnaire regarding their use of over-the-counter and prescription NSAIDs. NSAIDs (excluding aspirin and acetaminophen) were defined by self-report. CKD was categorized as no CKD, mild CKD (stages 1 and 2; urinary albumin-creatinine ratio of ≥ 30 mg/g) and moderate to severe CKD (stages 3 and 4; estimated glomerular filtration rate of 15-59 mL/min/1.73 m(2)). Adjusted prevalence was calculated using multivariable logistic regression with appropriate population-based weighting. Current use (nearly every day for 30 days or longer) of any NSAID was reported by 2.5%, 2.5%, and 5.0% of the US population with no, mild, and moderate to severe CKD, respectively; nearly all of the NSAIDs used were available over-the-counter. Among those with moderate to severe CKD who were currently using NSAIDs, 10.2% had a current NSAID prescription and 66.1% had used NSAIDs for 1 year or longer. Among those with CKD, disease awareness was not associated with reduced current NSAID use: (3.8% vs 3.9%, aware vs unaware; P=.979). Physicians and other health care clinicians should be aware of use of NSAIDs among those with CKD in the United States and evaluate NSAID use in their CKD patients.


Enzyme histochemical study of germanium dioxide-induced mitochondrial myopathy in rats.
The purpose of this study were 1) to determine the earliest pathological changes of germanium dioxide (GeO2)-induced myopathy; 2) to determine the pathomechanism of GeO2-induced myopathy; and 3) to determine the minimal dose of GeO2 to induce myopathy in rats. One hundred and twenty five male and female Sprague-Dawley rats, each weighing about 150 gm, were divided into seven groups according to daily doses of GeO2. Within each group, histopathological studies were done at 4, 8, 16, and 24 weeks of GeO2 administration. Characteristic mitochondrial myopathy was induced in the groups treated daily with 10 mg/kg of GeO2 or more. In conclusion, the results were as follows: 1) The earliest pathological change on electron microscope was the abnormalities of mitochondrial shape, size and increased number of mitochondria; 2) The earliest pathological change on light microscope was the presence of ragged red fibers which showed enhanced subsarcolemmal succinate dehydrogenase and cytochrome c oxidase reactivity; 3) GeO2 seemed to affect the mitochondrial oxidative metabolism of muscle fibers; 4) GeO2 could induce mitochondrial myopathy with 10 mg/kg of GeO2 for 4 weeks or less duration in rats.


An assessment tool for predicting fracture risk in postmenopausal women.
Due to the magnitude of the morbidity and mortality associated with untreated osteoporosis, it is essential that high-risk individuals be identified so that they can receive appropriate evaluation and treatment. The objective of this investigation was to develop a simple clinical assessment tool based on a small number of risk factors that could be used by women or their clinicians to assess their risk of fractures. Using data from the Study of Osteoporotic Fractures (SOF), a total of 7782 women age 65 years and older with bone mineral density (BMD) measurements and baseline risk factors were included in the analysis. A model with and without BMD T-scores was developed by identifying variables that could be easily assessed in either clinical practice or by self-administration. The assessment tool, called the FRACTURE Index, is comprised of a set of seven variables that include age; BMD T-score, fracture after age 50 years, maternal hip fracture after age 50, weight less than or equal to 125 pounds (57 kg), smoking status, and use of arms to stand up from a chair. The FRACTURE Index was shown to be predictive of hip fracture, as well as vertebral and nonvertebral fractures. In addition, this index was validated using the EPIDOS fracture study. The FRACTURE Index can be used either with or without BMD testing by older postmenopausal women or their clinicians to assess the 5-year risk of hip and other osteoporotic fractures, and could be useful in helping to determine the need for further evaluation and treatment of these women.


Morphological Integration of the Modern Human Mandible during Ontogeny.
Craniofacial integration is prevalent in anatomical modernity research. Little investigation has been done on mandibular integration. Integration patterns were quantified in a longitudinal modern human sample of mandibles. This integration pattern is one of modularization between the alveolar and muscle attachment regions, but with age-specific differences. The ascending ramus and nonalveolar portions of the corpus remain integrated throughout ontogeny. The alveolar region is dynamic, becoming modularized according to the needs of the mandible at a particular developmental stage. Early in ontogeny, this modularity reflects the need for space for the developing dentition; later, modularity is more reflective of mastication. The overall pattern of modern human mandibular integration follows the integration pattern seen in other mammals, including chimpanzees. Given the differences in craniofacial integration patterns between humans and chimpanzees, but the similarities in mandibular integration, it is likely that the mandible has played the more passive role in hominin skull evolution.


An Official American Thoracic Society Clinical Practice Guideline: Pediatric Chronic Home Invasive Ventilation.
Children with chronic invasive ventilator dependence living at home are a diverse group of children with special health care needs. Medical oversight, equipment management, and community resources vary widely. There are no clinical practice guidelines available to health care professionals for the safe hospital discharge and home management of these complex children. To develop evidence-based clinical practice guidelines for the hospital discharge and home/community management of children requiring chronic invasive ventilation. The Pediatric Assembly of the American Thoracic Society assembled an interdisciplinary workgroup with expertise in the care of children requiring chronic invasive ventilation. The experts developed four questions of clinical importance and used an evidence-based strategy to identify relevant medical evidence. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to formulate and grade recommendations. Clinical practice recommendations for the management of children with chronic ventilator dependence at home are provided, and the evidence supporting each recommendation is discussed. Collaborative generalist and subspecialist comanagement is the Medical Home model most likely to be successful for the care of children requiring chronic invasive ventilation. Standardized hospital discharge criteria are suggested. An awake, trained caregiver should be present at all times, and at least two family caregivers should be trained specifically for the child's care. Standardized equipment for monitoring, emergency preparedness, and airway clearance are outlined. The recommendations presented are based on the current evidence and expert opinion and will require an update as new evidence and/or technologies become available.


Tensile forces drive a reversible fibroblast-to-myofibroblast transition during tissue growth in engineered clefts.
Myofibroblasts orchestrate wound healing processes, and if they remain activated, they drive disease progression such as fibrosis and cancer. Besides growth factor signaling, the local extracellular matrix (ECM) and its mechanical properties are central regulators of these processes. It remains unknown whether transforming growth factor-β (TGF-β) and tensile forces work synergistically in up-regulating the transition of fibroblasts into myofibroblasts and whether myofibroblasts undergo apoptosis or become deactivated by other means once tissue homeostasis is reached. We used three-dimensional microtissues grown in vitro from fibroblasts in macroscopically engineered clefts for several weeks and found that fibroblasts transitioned into myofibroblasts at the highly tensed growth front as the microtissue progressively closed the cleft, in analogy to closing a wound site. Proliferation was up-regulated at the growth front, and new highly stretched fibronectin fibers were deposited, as revealed by fibronectin fluorescence resonance energy transfer probes. As the tissue was growing, the ECM underneath matured into a collagen-rich tissue containing mostly fibroblasts instead of myofibroblasts, and the fibronectin fibers were under reduced tension. This correlated with a progressive rounding of cells from the growth front inward, with decreased α-smooth muscle actin expression, YAP nuclear translocation, and cell proliferation. Together, this suggests that the myofibroblast phenotype is stabilized at the growth front by tensile forces, even in the absence of endogenously supplemented TGF-β, and reverts into a quiescent fibroblast phenotype already 10 μm behind the growth front, thus giving rise to a myofibroblast-to-fibroblast transition. This is the hallmark of reaching prohealing homeostasis.


Validity tests of the mixing-length theory of deep convection.
The construction of solar or stellar models is hindered by the difficulty of computing, with sufficient accuracy, the convective fluxes in unstable regions. Although the mixing-length theory of convection has been used for more than three decades, its validity has neither been tested by experiment nor verified by computation. This report presents the results of a three-dimensional numerical simulation of deep and efficient convection that support two conclusions: (i) the basic picture proposed by the mixing-length theory is physically valid-the vertical correlation of the motion of fluid elements is proportional to the pressure scale height; and (ii) some dynamical variables, including the convective flux, can be approximately computed from the structure of the stratification with mixing-length approximations.


Impact of multimorbidity on disability and quality of life in the Spanish older population.
Population aging is closely related to high prevalence of chronic conditions in developed countries. In this context, health care policies aim to increase life span cost-effectively while maintaining quality of life and functional ability. There is still, however, a need for further understanding of how chronic conditions affect these health aspects. The aim of this paper is to assess the individual and combined impact of chronic physical and mental conditions on quality of life and disability in Spain, and secondly to show gender trends. Cross-sectional data were collected from the COURAGE study. A total of 3,625 participants over 50 years old from Spain were included. Crude and adjusted multiple linear regressions were conducted to detect associations between individual chronic conditions and disability, and between chronic conditions and quality of life. Separate models were used to assess the influence of the number of diseases on the same variables. Additional analogous regressions were performed for males and females. All chronic conditions except hypertension were statistically associated with poor results in quality of life and disability. Depression, anxiety and stroke were found to have the greatest impact on outcomes. The number of chronic conditions was associated with substantially lower quality of life [β for 4+ diseases: -18.10 (-20.95,-15.25)] and greater disability [β for 4+ diseases: 27.64 (24.99,30.29]. In general, women suffered from higher rates of multimorbidity and poorer results in quality of life and disability. Chronic conditions impact greatly on quality of life and disability in the older Spanish population, especially when co-occurring diseases are added. Multimorbidity considerations should be a priority in the development of future health policies focused on quality of life and disability. Further studies would benefit from an expanded selection of diseases. Policies should also deal with gender idiosyncrasy in certain cases.


Treatment in the pediatric emergency department is evidence based: a retrospective analysis.
Our goal was to quantify the evidence that is available to the physicians of a pediatric emergency department (PED) in making treatment decisions. Further, we wished to ascertain what percentage of evidence for treatment provided in the PED comes from pediatric studies. We conducted a retrospective chart review of randomly selected patients seen in the PED between January 1 and December 31, 2002. The principal investigator identified a primary diagnosis and primary intervention for each chart. A thorough literature search was then undertaken with respect to the primary intervention. If a randomized control trial (RCT) or a systematic review was found, the intervention was classified as level I evidence. If no RCT was found, the intervention was assessed by an expert committee who determined its appropriateness based on face validity (RCTs were unanimously judged to be both unnecessary and, if a placebo would have been involved, unethical). These interventions were classified as level II evidence. Interventions that did not fall into either above category were classified as level III evidence. Two hundred and sixty-two patient charts were reviewed. Of these, 35.9% did not receive a primary intervention. Of the 168 interventions assessed, 80.4% were evidence-based (level I), 7.1% had face validity (level II) and 12.5% had no supporting evidence (level III). Of the evidence-based interventions, 83.7% were supported by studies with mostly pediatric patients. Our study demonstrates that a substantial proportion of PED treatment decisions are evidence-based, with most based on studies in pediatric patients. Also, a large number of patients seen in the PED receive no intervention.


Efficacy of Auralgan for treating ear pain in children with acute otitis media.
To determine the efficacy of Auralgan otic solution (combination product of antipyrine, benzocaine, and glycerin) compared with an olive oil placebo in the management of moderate to severe ear pain in children with acute otitis media (AOM). Children 5 years or older who presented with ear pain and eardrum findings indicative of AOM were randomly assigned to treatment with Auralgan or olive oil drops instilled into the external auditory canal(s) of the affected ear(s). All children were also treated with 15 mg/kg of acetaminophen in a single dose. Ear pain was assessed by means of 2 visual analog seales-a linear scale and a color scale-at study entry and 10, 20, and 30 minutes later (T0, T10, T20, and T30, respectively). Results of the measurements on the 2 scales were evaluated independently and were averaged to determine an ear pain score. A baseline ear pain score of at least 3 points was required for study entry. Four outcome measures regarding ear pain score at T10, T20, and T30 were used: (1) proportion of subjects who showed 50% reduction, (2) proportion of subjects who showed 25% reduction, (3) proportion of subjects who showed a 1 or more point reduction, and (4) mean score over time. Primary care center and emergency department of a children's hospital. Fifty-four children aged 5 to 19 years with ear pain and AOM. The Auralgan and placebo groups were comparable regarding age, sex, race, laterality of AOM, and T0 ear pain score. By each of the 4 measures used, the response to treatment consistently favored the Auralgan group, but only at T30 were any differences statistically significant. In children with AOM-associated ear pain who are treated with acetaminophen, topically applied Auralgan appears likely to provide additional relief in varying degree within 30 minutes.


Anti-ulcerogenic effect of banana powder (Musa sapientum var. paradisiaca) and its effect on mucosal resistance.
Orally administered banana pulp powder (Musa sapientum var. paradisiaca) was shown to have significant anti-ulcerogenic activity in rats subjected to aspirin, indomethacin, phenylbutazone, prednisolone and cysteamine and in guinea-pigs subjected to histamine. Banana powder not only increased mucosal thickness but also significantly increased [3H]thymidine incorporation into mucosal DNA. Relative to untreated control sections, histological studies showed that banana treatment increased staining by alcian blue in the apical cells with staining noted in the deeper layers of the mucosal glands. Banana-treated and control sections were also stained for DNA by the Feulgen reaction. The banana-treated sections showed a greater aggregation and intensity of pink spots when compared to controls. The present study suggests that banana powder treatment not only strengthens mucosal resistance against ulcerogens but also promotes healing by inducing cellular proliferation.


Implementation of earlier antibiotic administration in patients with severe sepsis and septic shock in Japan: a descriptive analysis of a prospective observational study.
Time to antibiotic administration is a key element in sepsis care; however, it is difficult to implement sepsis care bundles. Additionally, sepsis is different from other emergent conditions including acute coronary syndrome, stroke, or trauma. We aimed to describe the association between time to antibiotic administration and outcomes in patients with severe sepsis and septic shock in Japan. This prospective observational study enrolled 1184 adult patients diagnosed with severe sepsis based on the Sepsis-2 criteria and admitted to 59 intensive care units (ICUs) in Japan between January 1, 2016, and March 31, 2017, as the sepsis cohort of the Focused Outcomes Research in Emergency Care in Acute Respiratory Distress Syndrome, Sepsis and Trauma (FORECAST) study. We compared the characteristics and in-hospital mortality of patients administered with antibiotics at varying durations after sepsis recognition, i.e., 0-60, 61-120, 121-180, 181-240, 241-360, and 361-1440 min, and estimated the impact of antibiotic timing on risk-adjusted in-hospital mortality using the generalized estimating equation model (GEE) with an exchangeable, within-group correlation matrix, with "hospital" as the grouping variable. Data from 1124 patients in 54 hospitals were used for analyses. Of these, 30.5% and 73.9% received antibiotics within 1 h and 3 h, respectively. Overall, the median time to antibiotic administration was 102 min [interquartile range (IQR), 55-189]. Compared with patients diagnosed in the emergency department [90 min (IQR, 48-164 min)], time to antibiotic administration was shortest in patients diagnosed in ICUs [60 min (39-180 min)] and longest in patients transferred from wards [120 min (62-226)]. Overall crude mortality was 23.4%, where patients in the 0-60 min group had the highest mortality (28.0%) and a risk-adjusted mortality rate [28.7% (95% CI 23.3-34.1%)], whereas those in the 61-120 min group had the lowest mortality (20.2%) and risk-adjusted mortality rates [21.6% (95% CI 16.5-26.6%)]. Differences in mortality were noted only between the 0-60 min and 61-120 min groups. We could not find any association between earlier antibiotic administration and reduction in in-hospital mortality in patients with severe sepsis.


Combined effects of EPS and HRT enhanced biofouling on a submerged and hybrid PAC-MF membrane bioreactor.
The goal of this study was to quantify and demonstrate the dynamic effects of hydraulic retention time (HRT), organic carbon and various components of extracellular polymeric substances (EPS) produced by microorganisms on the performance of submersed hollow-fiber microfiltration (MF) membrane in a hybrid powdered activated carbon (PAC)-MF membrane bioreactor (MBR). The reactors were operated continuously for 45 days to treat surface (river) water before and after pretreatment using a biofiltration unit. The real-time levels of organic carbon and the major components of EPS including five different carbohydrates (D(+) glucose and D(+) mannose, D(+) galactose, N-acetyl-D-galactosamine and D-galactose, oligosaccharides and L(-) fucose), proteins, and polysaccharides were quantified in the influent water, foulants, and in the bulk phases of different reactors. The presence of PAC extended the filtration cycle and enhanced the organic carbon adsorption and removal more than two fold. Biological filtration improved the filtrate quality and decreased membrane fouling. However, HRT influenced the length of the filtration cycle and had less effect on organic carbon and EPS component removal and/or biodegradation. The abundance of carbohydrates in the foulants on MF surfaces was more than 40 times higher than in the bulk phase, which demonstrates that the accumulation of carbohydrates on membrane surfaces contributed to the increase in transmembrane pressure significantly and PAC was not a potential adsorbent of carbohydrates. The abundance of N-acetyl-d-galactosamine and d-galactose was the highest in the foulants on membranes receiving biofilter-treated river water. Most of the biological fouling compounds were produced inside the reactors due to biodegradation. PAC inside the reactor enhanced the biodegradation of polysaccharides up to 97% and that of proteins by more than 95%. This real-time extensive and novel study demonstrates that the PAC-MF hybrid MBR is a sustainable technology for treating river water.


Does lack of resources impair access to breast and cervical cancer screening in Japan?
To assess the impact of the quantity of resources for breast and cervical cancer screening on the participation rates in screening in clinical settings in municipalities, as well as to clarify whether lack of resources impairs access to cancer screening in Japan. Of the 1,746 municipalities in 2010, 1,443 (82.6%) and 1,469 (84.1%) were included in the analyses for breast and cervical cancer screening, respectively. In order to estimate the effects of the number of mammography units and of gynecologists on the participation rates in breast and cervical cancer screening in clinical settings, multiple regression analyses were performed using the interaction term for urban municipalities. The average participation rate in screening in clinical settings was 6.01% for breast cancer, and was 8.93% for cervical cancer. The marginal effect of the number of mammography units per 1,000 women was significantly positive in urban municipalities (8.20 percent point). The marginal effect of the number of gynecologists per 1,000 women was significantly positive in all municipalities (2.54 percent point) and rural municipalities (3.68 percent point). Lack of mammography units in urban areas and of gynecologists particularly in rural areas impaired access to breast and cervical cancer screening. Strategies are required that quickly improve access for the residents and increase their participation rates in cancer screening.


The assessment of emotional intelligence: a comparison of performance-based and self-report methodologies.
We assessed the patterns of convergent validity for the Mayer-Salovey-Caruso Emotional Intelligence Test (Mayer, Salovey, & Caruso, 2002), a performance-based measure of emotional intelligence (EI) that entails presenting problems thought to have correct responses, and a self-report measure of EI (Schutte et al., 1998). The relations between EI and demographic characteristics of a diverse community sample (N = 223) concurred with previous research. However, the performance-based and self-report scales were not related to one another. Only self-reported EI scores showed a consistent pattern of relations with self-reported coping styles and depressive affect, whereas the performance-based measure demonstrated stronger relations with age, education, and receiving psychotherapy. We discuss implications for the validity of these measures and their utility.


Normal Distribution of CD8+ T-Cell-Derived ELISPOT Counts within Replicates Justifies the Reliance on Parametric Statistics for Identifying Positive Responses.
Accurate assessment of positive ELISPOT responses for low frequencies of antigen-specific T-cells is controversial. In particular, it is still unknown whether ELISPOT counts within replicate wells follow a theoretical distribution function, and thus whether high power parametric statistics can be used to discriminate between positive and negative wells. We studied experimental distributions of spot counts for up to 120 replicate wells of IFN-γ production by CD8+ T-cell responding to EBV LMP2A (426 - 434) peptide in human PBMC. The cells were tested in serial dilutions covering a wide range of average spot counts per condition, from just a few to hundreds of spots per well. Statistical analysis of the data using diagnostic Q-Q plots and the Shapiro-Wilk normality test showed that in the entire dynamic range of ELISPOT spot counts within replicate wells followed a normal distribution. This result implies that the Student t-Test and ANOVA are suited to identify positive responses. We also show experimentally that borderline responses can be reliably detected by involving more replicate wells, plating higher numbers of PBMC, addition of IL-7, or a combination of these. Furthermore, we have experimentally verified that the number of replicates needed for detection of weak responses can be calculated using parametric statistics.


Involvement of dopamine D2 receptors in the suppressive effect of the thyrotropin-releasing hormone analog TA-0910 on alcohol intake in alcohol-preferring rats.
Pharmacological experiments were conducted to determine the neuronal mechanisms involved in the suppressive effects of the thyrotropin-releasing hormone analog TA-0910 on alcohol intake in alcohol-preferring (P) rats. We previously reported that single intraperitoneal injections of TA-0910 dose-dependently reduced alcohol intake in P rats without altering fluid or total calorie intake; however, after several consecutive, once-daily injections, P rats developed tolerance to the suppressive effects of TA-0910 on alcohol intake and cross-tolerance to like effects of the dopamine D2 agonist bromocriptine, but not to like effects of the serotonin uptake inhibitor fluoxetine. In the present study, rats were injected with vehicle or different doses of the D2 antagonist s(-)-eticlopride (0.01 to 0.05 mg/kg) or the D1 antagonist R(+)-SCH23390 (0.1 to 0.5 mg/kg) and 20 min later with TA-0910 (0.75 mg/kg). Alcohol and water intakes were measured at 2, 4, 6, and 24 hr, and food was measured every 24 hr. Both s(-)-eticlopride and R(+)-SCH23390 produced modest reductions in alcohol intake alone; however, only s(-)-eticlopride antagonized the suppressive effect of TA-0910 on alcohol intake. In related experiments, it was confirmed that the dopamine D3 agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin reduced alcohol intake in P rats, and it was found that tolerance to this effect did not develop during or after seven consecutive once-daily injections. Furthermore, this effect of 7-hydroxy-N,N-di-n-propyl-2-aminotetralin was not diminished in rats made tolerant to the effect of TA-0910 on alcohol intake. These data, those of previous studies, and recent preliminary findings support involvement of dopamine D2, but not D1 or D3 receptors in mediating the suppressive effect of TA-0910 on alcohol intake of P rats.


Vegetarian diets and the incidence of cancer in a low-risk population.
Cancer is the second leading cause of death in the United States. Dietary factors account for at least 30% of all cancers in Western countries. As people do not consume individual foods but rather combinations of them, the assessment of dietary patterns may offer valuable information when determining associations between diet and cancer risk. We examined the association between dietary patterns (non-vegetarians, lacto, pesco, vegan, and semi-vegetarian) and the overall cancer incidence among 69,120 participants of the Adventist Health Study-2. Cancer cases were identified by matching to cancer registries. Cox proportional hazard regression analysis was conducted to estimate hazard ratios, with "attained age" as the time variable. A total of 2,939 incident cancer cases were identified. The multivariate HR of overall cancer risk among vegetarians compared with non-vegetarians was statistically significant [HR, 0.92; 95% confidence interval (CI), 0.85-0.99] for both genders combined. Also, a statistically significant association was found between vegetarian diet and cancers of the gastrointestinal tract (HR, 0.76; 95% CI, 0.63-0.90). When analyzing the association of specific vegetarian dietary patterns, vegan diets showed statistically significant protection for overall cancer incidence (HR, 0.84; 95% CI, 0.72-0.99) in both genders combined and for female-specific cancers (HR, 0.66; 95% CI, 0.47-0.92). Lacto-ovo-vegetarians appeared to be associated with decreased risk of cancers of the gastrointestinal system (HR, 0.75; 95% CI, 0.60-0.92). Vegetarian diets seem to confer protection against cancer. Vegan diet seems to confer lower risk for overall and female-specific cancer than other dietary patterns. The lacto-ovo-vegetarian diets seem to confer protection from cancers of the gastrointestinal tract.


Exercise and self-management for people with chronic knee, hip or lower back pain: a cluster randomised controlled trial of clinical and cost-effectiveness. Study protocol.
Chronic musculoskeletal pain and osteoarthritis can significantly limit the functional independence of individuals, and given that 25% of the population experience these problems, the socioeconomic impact is immense. Exercise and self-management have proven benefits for these conditions, but most trials tailor interventions for specific joints. Epidemiological data demonstrates that many older people with degenerative joint problems experience pain and functional difficulty in other joints, seeking further healthcare input when these present. Managing multiple joint presentations simultaneously could potentially reduce the need for repeat visits to healthcare professionals as advice is frequently the same for differing site presentations. This single-blind cluster randomised controlled trial will determine the clinical and cost-effectiveness of an exercise and self-management intervention delivered to people over-50 with either hip, knee or lower back pain, compared to 'standard' GP care. A qualitative analysis will also establish the acceptability of the intervention. 352 people with chronic degenerative musculoskeletal pain of the hip, knee or lower back will be recruited from primary care. GP surgeries will be randomised to either the intervention or control arms. Participants in the intervention arm will receive a 6-week group exercise and self-management programme facilitated by a physiotherapist in primary care. Participants allocated to the control arm will continue under 'standard' GP care. The primary outcome measure is the Dysfunction Index of the Short Musculoskeletal Functional Assessment (SMFA). Individual patient responses will be modelled using a mixed effects linear regression, allowing for the clustering effects. Resource use and related intervention costs will be estimated and broader resource use data will be collected using a version of the Client Service Receipt Inventory adapted for musculoskeletal relevance. In addition, a cost-utility analysis will be undertaken to present an estimate of the incremental cost per QALY. A qualitative analysis investigating the acceptability of the intervention to participants and healthcare professionals will also be undertaken and thematically analysed. Ethical approval was received from South West 4 REC, identification number 11/SW/0053. Study findings will be disseminated via conference and journal presentation; via arthritis charitable organisations; and through local GP consortia.


Effect of Stress Ulcer Prophylaxis With Proton Pump Inhibitors vs Histamine-2 Receptor Blockers on In-Hospital Mortality Among ICU Patients Receiving Invasive Mechanical Ventilation: The PEPTIC Randomized Clinical Trial.
Proton pump inhibitors (PPIs) or histamine-2 receptor blockers (H2RBs) are often prescribed for patients as stress ulcer prophylaxis drugs in the intensive care unit (ICU). The comparative effect of these drugs on mortality is unknown. To compare in-hospital mortality rates using PPIs vs H2RBs for stress ulcer prophylaxis. Cluster crossover randomized clinical trial conducted at 50 ICUs in 5 countries between August 2016 and January 2019. Patients requiring invasive mechanical ventilation within 24 hours of ICU admission were followed up for 90 days at the hospital. Two stress ulcer prophylaxis strategies were compared (preferential use with PPIs vs preferential use with H2RBs). Each ICU used each strategy sequentially for 6 months in random order; 25 ICUs were randomized to the sequence with use of PPIs and then use of H2RBs and 25 ICUs were randomized to the sequence with use of H2RBs and then use of PPIs (13 436 patients randomized by site to PPIs and 13 392 randomized by site to H2RBs). The primary outcome was all-cause mortality within 90 days during index hospitalization. Secondary outcomes were clinically important upper gastrointestinal bleeding, Clostridioides difficile infection, and ICU and hospital lengths of stay. Among 26 982 patients who were randomized, 154 opted out, and 26 828 were analyzed (mean [SD] age, 58 [17.0] years; 9691 [36.1%] were women). There were 26 771 patients (99.2%) included in the mortality analysis; 2459 of 13 415 patients (18.3%) in the PPI group died at the hospital by day 90 and 2333 of 13 356 patients (17.5%) in the H2RB group died at the hospital by day 90 (risk ratio, 1.05 [95% CI, 1.00 to 1.10]; absolute risk difference, 0.93 percentage points [95% CI, -0.01 to 1.88] percentage points; P = .054). An estimated 4.1% of patients randomized by ICU site to PPIs actually received H2RBs and an estimated 20.1% of patients randomized by ICU site to H2RBs actually received PPIs. Clinically important upper gastrointestinal bleeding occurred in 1.3% of the PPI group and 1.8% of the H2RB group (risk ratio, 0.73 [95% CI, 0.57 to 0.92]; absolute risk difference, -0.51 percentage points [95% CI, -0.90 to -0.12 percentage points]; P = .009). Rates of Clostridioides difficile infection and ICU and hospital lengths of stay were not significantly different by treatment group. One adverse event (an allergic reaction) was reported in 1 patient in the PPI group. Among ICU patients requiring mechanical ventilation, a strategy of stress ulcer prophylaxis with use of proton pump inhibitors vs histamine-2 receptor blockers resulted in hospital mortality rates of 18.3% vs 17.5%, respectively, a difference that did not reach the significance threshold. However, study interpretation may be limited by crossover in the use of the assigned medication. anzctr.org.au Identifier: ACTRN12616000481471.


In vitro shear bond strength of adhesive to normal and fluoridated enamel under various contaminated conditions.
This study examined the shear bond strength of bonding agents to normal or fluoridated enamel following use of weak or strong acids to prepare enamel surfaces and after contamination with a measured amount of saliva at various stages of the bonding procedure. One hundred extracted human third molar teeth were randomly separated into 2 basic groups (normal or fluoridated teeth), then divided into 5 subgroups. Group A specimens were not contaminated. After etching, enamel surfaces were dry and clean. Group B was left with wet surfaces after etching. Group C specimens were contaminated with artificial saliva and then dried. Group D specimens were contaminated with artificial saliva, rinsed, and then dried. In group E, all enamel surfaces were left contaminated with saliva after the etching procedures (with maleic acid or phosphoric acids). Adhesive resins were applied to all enamel surfaces according to the manufacturer's instructions. The specimens were then mounted and tested to determine shear bond strength. If normal enamel surfaces were rinsed and dried immediately after contamination, there was no significant reduction of shear bond strength of adhesive to enamel. Specimens in group E and group C had significantly lower bond strengths than did control specimens (group A). In the fluoridated groups etched with the phosphoric acid, statistically significant reductions in bond strengths were obtained in all contamination groups and in the control group. In the fluoridated specimens, there were no statistically significant differences between any of the contamination groups and the control group when maleic acid was used. Saliva contamination may not be a risk factor for successful bonding between bonding agent and dental tissues for normal or fluoridated enamel surfaces if they are rinsed and dried immediately after contamination. Etching of normal enamel surfaces with phosphoric acid in the presence of contamination may provide higher shear bond strength than etching with maleic acid.


Paradoxical associations between familial affective responsiveness, stress, and amygdala reactivity.
Studies of early life extremes such as trauma, abuse, and neglect highlight the critical importance of quality caregiving in the development of brain circuits supporting emotional behavior and mental health. The impact of normative variability in caregiving on such biobehavioral processes, however, is poorly understood. Here, we provide initial evidence that even subtle variability in normative caregiving maps onto individual differences in threat-related brain function and, potentially, associated psychopathology in adolescence. Specifically, we report that greater familial affective responsiveness is associated with heightened amygdala reactivity to interpersonal threat, particularly in adolescents having experienced relatively low recent stress. These findings extend the literature on the effects of caregiving extremes on brain function to subtle, normative variability but suggest that presumably protective factors may be associated with increased risk-related amygdala reactivity. We consider these paradoxical associations with regard to studies of basic associative threat learning and further consider their relevance for understanding potential effects of caregiving on psychological development. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Adiposity and asthma in adults: a bidirectional Mendelian randomisation analysis of The HUNT Study.
We aimed to investigate the potential causal associations of adiposity with asthma overall, asthma by atopic status or by levels of symptom control in a large adult population and stratified by sex. We also investigated the potential for reverse causation between asthma and risk of adiposity. We performed a bidirectional one-sample Mendelian randomisation (MR) study using the Norwegian Nord-Trøndelag Health Study population including 56 105 adults. 73 and 47 genetic variants were included as instrumental variables for body mass index (BMI) and waist-to-hip ratio (WHR), respectively. Asthma was defined as ever asthma, doctor-diagnosed asthma and doctor-diagnosed active asthma, and was further classified by atopic status or levels of symptom control. Causal OR was calculated with the Wald method. The ORs per 1 SD (4.1 kg/m2) increase in genetically determined BMI were ranged from 1.36 to 1.49 for the three asthma definitions and similar for women and men. The corresponding ORs for non-atopic asthma (range 1.42-1.72) appeared stronger than those for the atopic asthma (range 1.18-1.26), but they were similar for controlled versus partly controlled doctor-diagnosed active asthma (1.43 vs 1.44). There was no clear association between genetically predicted WHR and asthma risk or between genetically predicted asthma and the adiposity markers. Our MR study provided evidence of a causal association of BMI with asthma in adults, particularly with non-atopic asthma. There was no clear evidence of a causal link between WHR and asthma or of reverse causation.


Transcriptional response to hypoxia in human tumors.
The presence of hypoxic regions within solid tumors is associated with a more malignant tumor phenotype and worse prognosis. To obtain a blood supply and protect against cellular damage and death, oxygen-deprived cells in tumors alter gene expression, resulting in resistance to therapy. To investigate the mechanisms by which cancer cells adapt to hypoxia, we looked for novel hypoxia-induced genes. The transcriptional response to hypoxia in human glioblastoma cells was quantified with the use of serial analysis of gene expression. The time course of gene expression in response to hypoxia in a panel of various human tumor cell lines was measured by real-time polymerase chain reaction. Hypoxic regions of human carcinomas were chemically marked with pimonidazole. Immunohistochemistry and in situ hybridization were used to examine gene expression in the tumor's hypoxic regions. From the 24 504 unique transcripts expressed, 10 new hypoxia-regulated genes were detected-all induced, to a greater extent than vascular endothelial growth factor, a hypoxia-induced mitogen that promotes blood vessel growth. These genes also responded to hypoxia in breast and colon cancer cells and were activated by hypoxia-inducible factor 1, a key regulator of hypoxic responses. In tumors, gene expression was limited to hypoxic regions. Induced genes included hexabrachion (an extracellular matrix glycoprotein), stanniocalcin 1 (a calcium homeostasis protein), and an angiopoietin-related gene. We have identified the genes that are transcriptionally activated within hypoxic malignant cells, a crucial first step in understanding the complex interactions driving hypoxia response. Within our catalogue of hypoxia-responsive genes are novel candidates for hypoxia-driven angiogenesis.


LRRK1 is critical in the regulation of B-cell responses and CARMA1-dependent NF-κB activation.
B-cell receptor (BCR) signaling plays a critical role in B-cell activation and humoral immunity. In this study, we discovered a critical function of leucine-rich repeat kinase 1 (LRRK1) in BCR-mediated immune responses. Lrrk1(-/-) mice exhibited altered B1a-cell development and basal immunoglobulin production. In addition, these mice failed to produce IgG3 antibody in response to T cell-independent type 2 antigen due to defects in IgG3 class-switch recombination. Concomitantly, B cells lacking LRRK1 exhibited a profound defect in proliferation and survival upon BCR stimulation, which correlated with impaired BCR-mediated NF-κB activation and reduced expression of NF-κB target genes including Bcl-xL, cyclin D2, and NFATc1/αA. Furthermore, LRRK1 physically interacted and potently synergized with CARMA1 to enhance NF-κB activation. Our results reveal a critical role of LRRK1 in NF-κB signaling in B cells and the humoral immune response.


Estrogen receptor-dependent and independent mechanisms of breast cancer carcinogenesis.
Long term exposure to estrogens is associated with an increased risk of breast cancer. The precise mechanisms responsible for estrogen mediated carcinogenesis are not well understood. The most widely accepted theory holds that estradiol (E(2)), acting through estrogen receptor alpha (ERα), stimulates cell proliferation and initiates mutations arising from replicative errors occurring during pre-mitotic DNA synthesis. The promotional effects of E(2) then support the growth of cells harboring mutations. Over a period of time, sufficient numbers of mutations accumulate to induce neoplastic transformation. Laboratory and epidemiological data also suggest that non-receptor mediated mechanisms resulting from the genotoxic effects of estrogen metabolites are involved in breast cancer development. This manuscript critically reviews existing data implicating both ER-dependent and -independent mechanisms. The weight of evidence supports the possibility that both mechanisms are involved in the carcinogenic process. In addition, estrogen metabolites likely modulate stem cell functionality and cancer progression. The roles of ER dependent and independent actions in the carcinogenic process are pertinent to the consideration of breast cancer preventative agents as anti-estrogens block only receptor mediated pathways whereas the aromatase inhibitors block both.


Effectiveness of a TEOAE-based screening program. Can a patient-tracking system effectively be organized using modern information technology and central data management?
It has been shown that detecting and treating children with hearing loss at an early age will improve their speech and language development. The implementation of universal hearing screening programs is therefore one of the major goals in pediatric audiology. One problem of present screening programs is high lost to follow-up rates. The aim of this paper was to evaluate the effectiveness of a patient tracking system based on central data management and data transmission via the internet. The screening program was organized as a TEOAE (transitory evoked otoacoustic emissions)-based three-stage procedure and covered a complete German federal state (Saarland). The measurements of the first stage took place in well-baby nurseries (WBNs) as well as neonatal intensive care units (NICUs). Measurements of the second stage were performed by pediatricians and ENT physicians on an outpatient basis. The third stage comprised diagnostic ABR (auditory brainstem response) measurements performed by pediatric audiologists. Using a central data management system we were able to identify and follow every child not screened or with negative results. The overall coverage in the first stage was 93% of all newborns. A screening result of the second stage could be obtained for 90% of the children. Four out of 3,830 children screened turned out to have a relevant hearing loss and were fitted with hearing aids. A TEOAE-based newborn hearing screening system can be organized effectively. Central data management as well as interdisciplinary organization of the follow-up are important prerequisites for the success of a hearing screening program. A follow-up system as proposed in this paper can also be implemented in AABR (automated auditory brainstem response)-based programs.


The procoagulant molecule plasminogen activator inhibitor-1 is associated with injury severity and shock in patients with and without traumatic brain injury.
Traumatic injury is associated with an increased risk of coagulopathy and venous thrombosis. plasminogen activator inhibitor-1 (PAI-1) is a procoagulant molecule that inhibits tPA/uPA, thrombomodulin, and activated protein C. We hypothesized that elevated PAI-1 levels would be associated with increased Injury Severity Score (ISS) in injured patients with and without traumatic brain injury and that PAI-1 levels would vary with injury type. We retrospectively analyzed demographic, ISS, and hemodynamic data from a prospectively collected database. Patients with traumatic injury requiring intensive care unit admission (n = 268) were classified as multiple injuries, isolated body, or isolated head based on Abbreviated Injury Severity score. Admission PAI-1 levels were quantified using a Luminex analyte platform. Univariate tests for association informed the construction of a multivariate model of the relationship between PAI-1 and ISS. Plasminogen activator inhibitor-1 positively associated with ISS (p < 0.0001) and was highest in patients with ISS greater than 35 (p < 0.0001). Plasminogen activator inhibitor-1 was significantly different between multiple injuries, isolated body, and isolated head patients (p < 0.0001). On univariate analysis, age (p = 0.0011), hypotension (p = 0.0076), and alcohol intoxication (p = 0.0024) were all positively associated with PAI-1 level. Admission international normalized ratio was not associated with PAI-1 level (p = 0.638). After adjusting for age, sex, hypotension, and alcohol intoxication, higher PAI-1 levels were associated with higher ISS (p < 0.0001). Elevated PAI-1 at admission is associated with higher ISS. This association is more pronounced in patients with hypotension. These findings suggest that PAI-1 levels may reflect the burden of endothelial damage and platelet activation after injury. Prognostic, level III.


Transcorneal electrical stimulation for the treatment of retinitis pigmentosa: results from the TESOLAUK trial.
To explore the impact of weekly transcorneal electrical stimulation (TES) over a 6-month period as a treatment for retinitis pigmentosa (RP). A prospective open-label observational trial was carried out assessing weekly TES in participants with RP for a period of 6 months followed by observation for a further 6 months. Clinical examination and investigations were carried out at 3 monthly intervals for a total of 12 months. The primary outcome measure explored safety through a descriptive analysis of adverse effects with secondary outcome measures evaluating structural and functional efficacy. Seven male and seven female participants with RP aged 18-80 years were recruited. TES was well tolerated with no serious adverse events reported. Two participants reported transient foreign body sensation and one participant had discomfort underneath the skin electrode. Following 6 months of TES, best-corrected visual acuity increased by 1.1±1.4 letters in the control arm and 0.93±1.4 letters in the treated arm. Central microperimetry threshold sensitivity rose by 0.02±0.5 decibels (dB) and 0.37±0.4 dB and Goldmann visual field volume by 0.16±0.09 steradians (sr) vs 0.22±0.12 sr for the control and treated eye, respectively. There was no statistical significance seen between eyes following the treatment or observation period. This small open-label clinical trial showed that TES was safe and well tolerated in patients with RP. Visual function measurements at 6 months demonstrated no significant difference between the control and treated eyes. The results justify a larger clinical trial over a longer period of time in order to identify any treatment effect.


Photoacoustic technique for the measurement of absorption line profiles.
A spectrophone utilizing a resonant cylindrical cavity and operated by driving the first azimuthal mode of the cavity has been developed for the study of weak absorption lines of gases at pressures from 100 to 1300 Torr. Presented are the acoustic resonant amplification factor as a function of pressure, and a description of the noise sources inherent in this spectrophone. An example is given of the optical frequency resolution resulting when this spectrophone is used in conjunction with a tunable ring dye laser as a high resolution spectrometer.


An investigation towards real time dose rate monitoring, and fuel rod detection in a First Generation Magnox Storage Pond (FGMSP).
The First Generation Magnox Storage Pond (FGMSP) is located on the Sellafield Nuclear Site, housing legacy spent Magnox nuclear fuel. Some of which has since corroded, forming a layer of Corroded Magnox Sludge (CMS) creating one of the largest decommissioning challenges the UK has faced. In this work the composition, physical properties and potentially high hazard nature of CMS are discussed, as are the gamma emission spectra of spent Magnox fuel rods typical of the ilk stored. We assess the potential use of a RadLine gamma detector to dose rate map this area and provide fuel rod detection. RadLine consists of a small scintillator, fibre optic cable and photon counter. The probe has the unusual advantage of not being electrically active and therefore fully submersible underwater, with the option to deploy hundreds of metres in length. Our experimental method encompasses general purpose Monte Carlo radiation transport code, MCNP, where we describe the modelling of CMS and pond liquor in comprehensive detail, including their radiological spectrum, chemical composition data, and physical properties. This investigation concludes that the maximum energy deposited within the scintillator crystal due to ambient CMS corresponds to a dose rate of 5.65Gy h(-1), thus above this value positive detection of a fuel rod would be anticipated. It is additionally established that the detectable region is within a 20cm range.


Maternal anaemia and maternal, fetal, and neonatal outcomes in a prospective cohort study in India and Pakistan.
To describe the association of maternal anaemia with maternal, fetal, and neonatal outcomes. Prospective cohort study. Rural India and Pakistan. Pregnant women residing in the study catchment area. We performed an analysis of a prospective pregnancy registry in which haemoglobin is commonly obtained as well as maternal, fetal, and neonatal outcomes for 42 days post-delivery. Women 40 years or older who delivered before 20 weeks or had a haemoglobin level of <3.0 g/dl were excluded. Our primary exposure was maternal anaemia, which was categorised in keeping with World Health Organization criteria based on a normal (≥11 g/dl), mild (>10-10.9 g/dl), moderate (7-9.9 g/dl) or severe (<7 g/dl). haemoglobin level. The primary maternal outcome was maternal death, the primary fetal outcome was stillbirth, and the primary neonatal outcome was neonatal mortality <28 days. A total of 92 247 deliveries and 93 107 infants were included, of which 87.8% were born to mothers who were anaemic (mild 37.9%, moderate 49.1%, and severe 0.7%). Maternal mortality (number per 100 000) was not associated with anaemia: normal 124, mild 106, moderate 135, and severe 325 (P = 0.64). Fetal and neonatal mortality was associated with severe anaemia: stillbirth rate (n/1000)-normal 27.7, mild 25.8, moderate 30.1, and severe 90.9; P < 0.0001; 28-day neonatal mortality (n/1000)-normal 24.7, mild 22.9, moderate 28.1, and severe 72.6 (P < 0.0001). Severe maternal anaemia was also associated with low birthweight (<2500 and <1500 g), preterm birth, and postpartum haemorrhage. Severe maternal anaemia is associated with higher risks of poor maternal, fetal, and neonatal outcomes but other degrees of anaemia are not. Interventions directed at preventing severe anaemia in pregnant women should be considered. Severe maternal anaemia is associated with adverse fetal and neonatal outcomes in low/middle-income countries.


Growth and skeletal maturation after pediatric cardiac transplantation.
To examine the effects of cardiac transplantation on skeletal maturation and linear growth, we retrospectively evaluated annual bone age determinations and growth parameters of pediatric cardiac transplant recipients followed at our center. Included in the analysis were records of 86 patients (32 females) who had received a cardiac transplant at our institution between 1984 and 1998. Bone age delay of > or =12 months was apparent in 38.5% at the time of transplantation. At some point in their post-transplant course, 23 patients (29%) had one or more bone age measurements that were > or =36 months delayed with respect to chronological age. Children transplanted before age seven and those with a pretransplantation diagnosis of cardiomyopathy experienced the most significant decrement in skeletal maturation after transplantation. High cyclosporin A levels and low body mass index were the only parameters found to be associated with delayed bone age. Although the majority of children grew at a normal rate after transplantation, height Z scores and height age were adversely affected regardless of the type of heart disease or the age at transplantation. The pathogenesis of both delayed skeletal maturation and growth retardation in this population warrant further investigation.


Failure to detect mismatches between intention and outcome in a simple decision task.
A fundamental assumption of theories of decision-making is that we detect mismatches between intention and outcome, adjust our behavior in the face of error, and adapt to changing circumstances. Is this always the case? We investigated the relation between intention, choice, and introspection. Participants made choices between presented face pairs on the basis of attractiveness, while we covertly manipulated the relationship between choice and outcome that they experienced. Participants failed to notice conspicuous mismatches between their intended choice and the outcome they were presented with, while nevertheless offering introspectively derived reasons for why they chose the way they did. We call this effect choice blindness.