Human anti-p68 autoantibodies recognize a common epitope of U1 RNA containing small nuclear ribonucleoprotein and influenza B virus.
Autoantibodies from patients with systemic rheumatic diseases were used to map antigenic sites on the 68-kD autoantigen (p68) associated with (U1)RNA-containing small nuclear ribonucleoprotein (snRNP) particles. With truncated recombinant fusion proteins and synthetic peptides, a subset of anti-p68 autoantibodies was found to recognize the amino acid sequence motif Glu-Arg-Lys-Arg-Arg (ERKRR). To investigate the possible involvement of epitopes shared by microbial antigens and host self-components in initiation of autoimmunity (molecular mimicry), a sequence data bank was screened for proteins containing an amino acid motif identical or related to ERKRR. The identical motif was found on the M1 matrix protein of influenza B viruses, and affinity-purified human anti-ERKRR autoantibodies recognized this epitope also in the viral amino acid sequence context. The common epitope recognized by human autoantibodies suggests that influenza B virus infection may play a role in initiation of the anti-p68 and anti-(U1)RNP autoimmune response.


Overexpression of microRNA-129-5p in glioblastoma inhibits cell proliferation, migration, and colony-forming ability by targeting ZFP36L1.
Glioblastoma multiforme (GBM) is a highly invasive cancer with a high recurrence rate. The prognosis of GBM patients remains poor, even after standard surgical resection combined with chemoradiotherapy. Thus, there is an urgent need for new therapeutic targets in GBM. In recent years, microRNAs have received considerable attention due to their important role in tumor development and progression. In this study, we investigated the role of miR-129-5p and miR-129-5p/ZFP36L1 axis in GBM tumorigenesis. Analysis of GSE103228 microarray data from the GEO database showed that miR-129-5p was significantly downregulated in GBM vs. normal brain tissues. Quantitative reverse transcription PCR analysis of miR-129-5p expression in seven GBM cell lines (LN229, A172, U87, T98G, U251, H4, and LN118) vs. normal human astrocytes (NHA) showed miR-129-5p was significantly downregulated in GBM cells. Overexpression of miR-129-5p in LN229 and A172 cells significantly suppressed cell proliferation, migration, invasion, and colony-forming ability. Target Scan analysis identified ZFP36L1 as the target of miR-129-5p. UALCAN dataset analysis found that ZFP36L1 was significantly upregulated in GBM vs. normal brain tissues, and high ZFP36L1 expression was positively associated with poor survival of GBM patients. Western blot analysis demonstrated that ZFP36L1 was significantly upregulated in seven GBM cell lines vs. NHA. Overexpression of miR-129-5p in LN229 and A172 cells significantly inhibited ZFP36L1 mRNA and protein expression, while overexpression of ZFP36L1 in LN229 and A172 cells reversed miR-129-5p-mediated inhibition on GBM tumorigenesis. Our results revealed an important role of miR-129-5p in the negative regulation of ZFP36L1 expression in GBM, suggesting new candidates for targeted therapy in GBM patients.


Interleukin 4 inhibits the proliferation but not the differentiation of activated human B cells in response to interleukin 2.
The combined effect of IL-4 and IL-2 on proliferation of anti-IgM antibody or Staphylococcus aureus strain Cowan I (SAC)-preactivated B cells was investigated. It was observed that in most cases, rIL-2 used at optimal concentration induced higher levels of tritiated thymidine ([3H]TdR) uptake than rIL-4 used at optimal concentration. When rIL-4 and rIL-2 were added together, it was repeatedly found that B cell proliferation induced by rIL-2 was significantly reduced and was, in most cases, comparable with the proliferation induced by rIL-4 alone. Cell cycle studies demonstrated that rIL-4 significantly reduced the number of cells entering S and G2/M phases of the cell cycle upon rIL-2 stimulation. B cell blasts preincubated for 24 or 48 h with rIL-4 displayed a reduced proliferation in response to rIL-2. In contrast, preculture of resting B cells with rIL-4 did not impair their subsequent proliferation in response to rIL-2 plus insolubilized anti-IgM antibody. This suggests that rIL-4 can only exert its inhibitory effect once B cells have received an activation signal. The differentiative activity of rIL-2 measured on B cell blasts preactivated for 2 d with SAC was not altered by rIL-4, which suggests that rIL-4 did not exert its inhibitory activity on rIL-2-induced B cell proliferation by enhancing rIL-2-mediated differentiation. Delayed addition of a neutralizing anti-IL-4 antiserum demonstrated that a period of contact of at least 24 h between IL-4 and B cell blasts was necessary for the development of the antagonistic effect of IL-4 on IL-2-mediated growth of activated B cells. These data demonstrate that IL-4 antagonizes the B cell growth-promoting effect of IL-2 without affecting the differentiation of preactivated B cells in response to IL-2.


Information and communication technology based prompting for treatment compliance for people with serious mental illness.
Non-compliance is a significant problem among people with serious mental disorders, presenting a challenge for mental health professionals. Prompts such as telephone calls, visits, and a posted referral letter to patients are currently used to encourage patient attendance at clinics and/or compliance with medication. More recently, the use of information and communication technology (ICT)-based prompting methods have increased. Methods include mobile text message (SMS - short message service), e-mail or use of any other electronic device with the stated purpose of encouraging compliance. To investigate the effects of ICT-based prompting to support treatment compliance in people with serious mental illness compared with standard care. We searched the Cochrane Schizophrenia Group's Trials Register (31(st) May 2011 and 9(th) July 2012) which is based on regular searches of CINAHL, BIOSIS, AMED, EMBASE, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. Also, we inspected references of all identified studies for further trials and contacted authors of trials for additional information. Relevant randomised controlled trials involving adults with serious mental illness, comparing any ICT-based prompt or combination of prompts by automatic or semi-automatic system compared with standard care. Review authors reliably assessed trial quality and extracted data. We calculated risk ratio (RR) with 95% confidence intervals (CI) using a fixed-effect model. For continuous outcomes, we estimated the mean difference (MD) between groups, again with 95% confidence intervals. A 'Summary of findings' table using GRADE was created, and we assessed included studies for risk of bias. The search identified 35 references, with 25 studies, but we could only include two studies with a total of 358 participants. The studies had a moderate risk of bias, and therefore risk overestimating any positive effects of ICT-based prompting. Both included studies compared semi-automatised ICT-based prompting intervention with standard care groups in mental health outpatient care. The interventions were SMS-message and an electronic assistant device. One included study reported our primary outcome, compliance.There was not any clear evidence that ICT-based prompts increase improvement in compliance (stop taking medication within six months n = 320, RR 1.11 CI 0.96 to 1.29, moderate quality evidence). There was some low quality evidence that ICT-based prompts have small effects for: mental state (average change in specific symptom scores within three months n = 251, MD -0.30 CI -0.53 to -0.07; severity of illness within three months n = 251, MD -0.10 CI -0.13 to -0.07 and six months n = 251, MD -0.10 CI -0.13 to -0.07; average change in depressive scores within six months n = 251, RR 0.00 CI -0.28 to 0.28; global symptoms within three months n = 251, MD -0.10 CI -0.38 to -0.07; negative symptoms within three months n = 251, MD -0.10 CI -0.38 to 0.18 and six months n = 251, MD -0.30 CI -0.58 to 0.02, low quality evidence). Level of insight improved more among people receiving ICT-based prompt compared with those in the control group at six months (n = 251, MD -0.10 CI -0.13 to -0.07). ICT-based prompts also increased quality of life (average change in quality of life within six months n = 251, RR 0.50 CI 0.19 to 0.81, moderate quality evidence).Based on the existing data, there is no evidence that either intervention is less acceptable than the other (n = 347, 2 RCTs, RR 1.46 CI 0.70 to 3.05, low quality evidence). Included studies did not report outcomes of service utilisation, behaviour, costs or adverse events. The evidence base on the effects of ICT-based prompts is still inconclusive. Data to clarify ICT-based prompting effects are awaited from an ongoing trial, but further well-conducted trials considering the different ICT-based prompts are warranted.


Comparison of intensive light-emitting diode and intensive compact fluorescent phototherapy in non-hemolytic jaundice.
In severe and rapidly increasing jaundice, the use of intensive phototherapy provides greater effectiveness and a faster decrement in bilirubin levels compared to conventional phototherapy. The aim of this study was to compare the effectiveness of two types of intensive phototherapy: intensive compact fluorescent tube (CFT) and intensive light-emitting diode (LED) phototherapy. Forty-three infants over 35 weeks of gestation with severe non-hemolytic hyperbilirubinemia were enrolled in the prospective study. All infants received multidirectional (circular-shaped) intensive phototherapy. Of these, 20 infants received CFT while 23 infants received LED phototherapy. Bilirubin levels and body temperatures were measured periodically, and the rates of bilirubin decrement were calculated. Mean serum bilirubin level of the 43 infants was 20.5±1.5 mg/dl at the beginning of the therapy and mean duration of phototherapy was 20.6±1.1 hours. The rate of mean bilirubin decline was 47.2% and the decrease was more prominent in the first four hours (0.84 ± 0.41 mg/dl/h). The rates of bilirubin decrement were comparable between the LED and CFT groups. Slightly elevated mean body temperature (37.1ºC) was determined in the CFT group (p<0.05). Intensive phototherapy units with both LED and CFT were effective, showing a decline of half the initial value of bilirubin during the study period in infants with non-hemolytic jaundice. This study shows that intensive phototherapy with either CFT or LED can provide rapid decrease in bilirubin levels in the first few hours. This rapid decline is important in cases that have high risk of bilirubin encephalopathy.


Rapid assessment of postural instability in Parkinson's disease (RAPID): a pilot study.
The Fahn's pull (or retropulsion) test is an item in the motor section of the Unified Parkinson's Disease Rating Scale, which is used almost exclusively to classify postural instability in Parkinson's disease (PD). However, the test is hard to standardize and is often performed incorrectly, making it hard to interpret. Moreover, it may not be safe to administer in patients who experience pain in the shoulders, neck, trunk and/or lower extremities. Identifying and grading postural instability in PD without requiring a physical challenge would not only be useful for the clinician but would assist patients and caregivers in its recognition. We propose the use of the rapid assessment of postural instability in Parkinson's disease (RAPID) questionnaire as a non-physical assessment tool. We determined the associations between the pull test and items on a risk-assessment questionnaire that consisted of three parts: activities of daily living, fear of falling, and frequency of falling. Significant correlations were found between the pull test and the predictor variables, which ranged between 0.51 and 0.56 whilst the correlations amongst the predictor variables ranged between 0.58 and 0.70. The three parts of the questionnaire, when used in combination, produced a 96% sensitivity in the classification of postural instability. The RAPID questionnaire can be used as an adjunct to the pull test or solely if the pull test is contraindicated. It may also be possible to administer the questionnaire via the telephone or Internet. It is hoped that the rapid identification of postural instability would lead to fewer falls.


Actin synthesis and polymerization in the liver of fed and fasted rats bearing a Walker 256 carcinoma.
The effect of tumor growth on the amount, state of polymerization, and synthesis of liver actin was investigated in fed and fasted rats bearing a Walker 256 carcinoma. The increase in liver size in the tumor-bearing animal was accompanied by a rise in the total amount of actin and protein, although the amounts present per g liver fell in both cases. Soluble actin increased in both concentration and total amount in the tumor-bearing animals. While the ratio of total actin to total protein in liver was unaltered by tumor growth, the ratio of soluble actin to total actin was increased. The incorporation of [3H]leucine into liver actin relative to that into liver protein, in vivo, was not affected by tumor growth, but the radioactivity incorporated into soluble actin relative to total actin in the livers of the tumor-bearing rats was increased. Liver polysome preparations from tumor-bearing rats showed an increased ability to synthesize actin and total protein, whereas polysomes from skeletal muscle of tumor-bearing rats exhibited a decreased synthesis of actin and total protein. These results suggest that, in the liver of the tumor-bearing rat, while there is an increase in actin synthesis in parallel with a net increase in protein synthesis, there is a decrease in the polymerization of action. In livers of both control and tumor-bearing rats, the consumption of a meal was accompanied by a decrease in soluble actin relative to total actin and an increase in the synthesis of action relative to total protein.


Development and testing of a scale to measure trust in the public healthcare system.
Trust is an important factor in improving the performance of the healthcare system. This study aimed to develop a validated scale to measure trust in the public healthcare system. We adopted a sequential exploratory mixed study design, with developmental and testing phases. In the developmental phase, the construct of "healthcare system trust" was conceptualised and items were generated on the basis of information from a review of the literature on trust, in-depth interviews and a review of other scales. Exploratory factor analysis was employed for item reduction. In the testing phase, the reliability and validity measures were established. The face validity, content validity and construct validity of the scale were assessed. The final scale was a Likert-type scale with 23 items, 16 of which measured trust in the healthcare providers and 7, in healthcare institutions. The scale is a valid and reliable tool for measuring trust in the public healthcare system.


Nontraditional serum lipid variables and recurrent stroke risk.
Expert consensus guidelines recommend low-density lipoprotein cholesterol as the primary serum lipid target for recurrent stroke risk reduction. However, mounting evidence suggests that other lipid parameters might be additional therapeutic targets or at least also predict cardiovascular risk. Little is known about the effects of nontraditional lipid variables on recurrent stroke risk. We analyzed the Vitamin Intervention for Stroke Prevention study database comprising 3680 recent (<120 days) noncardioembolic stroke patients followed up for 2 years. Independent associations of baseline serum lipid variables with recurrent ischemic stroke (primary outcome) and the composite end point of ischemic stroke/coronary heart disease/vascular death (secondary outcomes) were assessed. Of all variables evaluated, only triglycerides/high-density lipoprotein cholesterol (HDL-C) ratio was consistently and independently related to both outcomes: compared with the lowest quintile, the highest triglycerides/HDL-C ratio quintile was associated with stroke (adjusted hazard ratio, 1.56; 95% confidence interval, 1.05-2.32) and stroke/coronary heart disease/vascular death (1.39; 1.05-1.83), including adjustment for lipid modifier use. Compared with the lowest quintile, the highest total cholesterol/HDL-C ratio quintile was associated with stroke/coronary heart disease/vascular death (1.45; 1.03-2.03). Low-density lipoprotein cholesterol/HDL-C ratio, non-HDL-C, elevated triglycerides alone, and low HDL-C alone were not independently linked to either outcome. Of various nontraditional lipid variables, elevated baseline triglycerides/HDL-C and total cholesterol/HDL-C ratios predict future vascular risk after a stroke, but only elevated triglycerides/HDL-C ratio is related to risk of recurrent stroke. Future studies should assess the role of triglycerides/HDL-C as a potential therapeutic target for global vascular risk reduction after stroke.


Attenuation of cell mechanosensitivity in colon cancer cells during in vitro metastasis.
Human colon carcinoma (HCT-8) cells show a stable transition from low to high metastatic state when cultured on appropriately soft substrates (21 kPa). Initially epithelial (E) in nature, the HCT-8 cells become rounded (R) after seven days of culture on soft substrate. R cells show a number of metastatic hallmarks [1]. Here, we use gradient stiffness substrates, a bio-MEMS force sensor, and Coulter counter assays to study mechanosensitivity and adhesion of E and R cells. We find that HCT-8 cells lose mechanosensitivity as they undergo E-to-R transition. HCT-8 R cells' stiffness, spread area, proliferation and migration become insensitive to substrate stiffness in contrast to their epithelial counterpart. They are softer, proliferative and migratory on all substrates. R cells show negligible cell-cell homotypic adhesion, as well as non-specific cell-substrate adhesion. Consequently they show the same spread area on all substrates in contrast to E cells. Taken together, these results indicate that R cells acquire autonomy and anchorage independence, and are thus potentially more invasive than E cells. To the best of our knowledge, this is the first report of quantitative data relating changes in cancer cell adhesion and stiffness during the expression of an in vitro metastasis-like phenotype.


Determining 3D flow fields via multi-camera light field imaging.
In the field of fluid mechanics, the resolution of computational schemes has outpaced experimental methods and widened the gap between predicted and observed phenomena in fluid flows. Thus, a need exists for an accessible method capable of resolving three-dimensional (3D) data sets for a range of problems. We present a novel technique for performing quantitative 3D imaging of many types of flow fields. The 3D technique enables investigation of complicated velocity fields and bubbly flows. Measurements of these types present a variety of challenges to the instrument. For instance, optically dense bubbly multiphase flows cannot be readily imaged by traditional, non-invasive flow measurement techniques due to the bubbles occluding optical access to the interior regions of the volume of interest. By using Light Field Imaging we are able to reparameterize images captured by an array of cameras to reconstruct a 3D volumetric map for every time instance, despite partial occlusions in the volume. The technique makes use of an algorithm known as synthetic aperture (SA) refocusing, whereby a 3D focal stack is generated by combining images from several cameras post-capture (1). Light Field Imaging allows for the capture of angular as well as spatial information about the light rays, and hence enables 3D scene reconstruction. Quantitative information can then be extracted from the 3D reconstructions using a variety of processing algorithms. In particular, we have developed measurement methods based on Light Field Imaging for performing 3D particle image velocimetry (PIV), extracting bubbles in a 3D field and tracking the boundary of a flickering flame. We present the fundamentals of the Light Field Imaging methodology in the context of our setup for performing 3DPIV of the airflow passing over a set of synthetic vocal folds, and show representative results from application of the technique to a bubble-entraining plunging jet.


Mannose-binding lectin does not explain the course and outcome of pregnancy in rheumatoid arthritis.
Rheumatoid arthritis (RA) improves during pregnancy and flares after delivery. It has been hypothesized that high levels of the complement factor mannose-binding lectin (MBL) are associated with a favourable disease course of RA by facilitating the clearance of pathogenic immunoglobulin G (IgG) lacking galactose sugar moieties. During pregnancy, increased galactosylation of IgG and simultaneously increased MBL levels can be observed, with the latter being strictly related to maternal MBL genotypes. Therefore, increased MBL levels in concert with increased IgG galactosylation may be associated with pregnancy-induced improvement of RA. The objective of this study was to investigate whether MBL genotypes are associated with changes in RA disease activity and with changes in IgG galactosylation during pregnancy and in the postpartum period. We also studied the association between MBL genotypes and pregnancy outcomes in RA. Serum from 216 patients with RA and 31 healthy controls participating in the Pregnancy-induced Amelioration of Rheumatoid Arthritis (PARA) Study was collected before, during and after pregnancy. IgG galactosylation was determined by performing matrix-assisted laser desorption/ionization time of flight mass spectrometry. Disease activity was determined using the internationally recognized Disease Activity Score 28 (DAS28). MBL genotypes were determined. The pregnancy outcome measures studied were gestational age, birth weight, miscarriage and hypertensive disorders. No association was found between the MBL genotype groups and changes in RA disease activity (P = 0.89) or changes in IgG galactosylation (patients, P = 0.75, and controls, P = 0.54) during pregnancy and in the postpartum period. Furthermore, MBL genotype groups were not related to the studied pregnancy outcome measures. This study does not provide evidence for a role for MBL in the improvement of RA during pregnancy or for a role for MBL in pregnancy outcome.


Fat Mass Lowers the Response to Tumor Necrosis Factor-α Blockers in Patients with Ankylosing Spondylitis.
Our main objective was to assess the relationship between body composition (BC) and response to tumor necrosis factor-α (TNF-α) blocker treatment in patients with ankylosing spondylitis (AS). Our secondary objective was to evaluate the change of BC after treatment, accounting for sex and age. All included patients fulfilled the modified New York criteria for AS and were naive to TNF-α blocker. They were followed for at least 6 months after the start of etanercept or adalimumab. The Ankylosing Spondylitis Disease Activity Score containing C-reactive protein (ASDAS-CRP) and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) were reported. BC was assessed by whole body dual-energy X-ray absorptiometry. Body fat percentage (BF%), fat mass index (FMI), and fat free mass index (FFMI) were reported as absolute values and as percentiles. Forty-one patients were included (61% men). The median followup was 14.3 months (interquartile range 8.4-19.4). After multivariate regression analysis, more fat at baseline (BF%, FMI, or FMI percentile) was significantly related with a lower chance of achieving a clinically important improvement of the ASDAS-CRP or BASDAI after treatment. The body composition did not change significantly after treatment, but there was a trend toward muscle recovery in men (FFMI change from 34.0th to 37.4th percentile). Higher body fat content at baseline was independently associated with a worse response to treatment with TNF-α blockers, measured by ASDAS-CRP and BASDAI change, and might contribute to the lower response rates in female patients. Also, there is a trend toward muscle mass recovery in male patients after treatment.


Dental hygienist attendance and its covariates in an ageing Swedish cohort.
Delegation of tasks between professional groups is important to make health-care services accessible and effective for ageing people. Focussing on a Swedish 1942 birth cohort and guided by Andersen's Behavioral Model, this study assessed dental hygienist attendance from age 50 to age 70 and identified covariates at the population-averaged and person-specific levels. In 1992, a census of 50-yr-old subjects was invited to participate in a questionnaire survey. Of the 6,346 respondents, 3,585 completed follow-ups in 1997, 2002, 2007, and 2012. Multiple logistic regression analysis was conducted using a marginal model and a random intercept model. Cochran's Q test revealed that significantly more respondents confirmed dental hygienist attendance in 2012 than in 1992 (57.2% in 2012 vs. 26.0% in 1992). Population-averaged ORs for dental hygienist attendance across time were 3.5 at age 70 yr compared with age 50 yr (baseline); 2.0 if being a regular rather than an irregular dental attendee; and 0.7 if being of non-native origin compared with native origin. The corresponding person-specific ORs were 8.9, 3.2, and 0.5. Consistent with Andersen's Behavioral Model, predisposing, enabling, and need-related factors were associated with dental hygienist attendance at population-averaged and person-specific levels. This has implications for promoting dental hygienist attendance among ageing people.


Clinicians' views of factors of importance for improving the rate of VBAC (vaginal birth after caesarean section): a study from countries with low VBAC rates.
Caesarean section (CS) rates are increasing worldwide and the most common reason is repeat CS following previous CS. For most women a vaginal birth after a previous CS (VBAC) is a safe option. However, the rate of VBAC differs in an international perspective. Obtaining deeper knowledge of clinicians' views on VBAC can help in understanding the factors of importance for increasing VBAC rates. Focus group interviews with clinicians and women in three countries with high VBAC rates (Finland, Sweden and the Netherlands) and three countries with low VBAC rates (Ireland, Italy and Germany) are part of "OptiBIRTH", an ongoing research project. The study reported here aims to explore the views of clinicians from countries with low VBAC rates on factors of importance for improving VBAC rates. Focus group interviews were held in Ireland, Italy and Germany. In total 71 clinicians participated in nine focus group interviews. Five central questions about VBAC were used and interviews were analysed using content analysis. The analysis was performed in each country in the native language and then translated into English. All data were then analysed together and final categories were validated in each country. The findings are presented in four main categories with several sub-categories: 1) "prameters for VBAC", including the importance of the obstetric history, present obstetric factors, a positive attitude among those who are centrally involved, early follow-up after CS and antenatal classes; 2) "organisational support and resources for women undergoing a VBAC", meaning a successful VBAC requires clinical expertise and resources during labour; 3) "fear as a key inhibitor of successful VBAC", including understanding women's fear of childbirth, clinicians' fear of VBAC and the ways that clinicians' fear can be transferred to women; and 4) "shared decision making - rapport, knowledge and confidence", meaning ensuring consistent, realistic and unbiased information and developing trust within the clinician-woman relationship. The findings indicate that increasing the VBAC rate depends on organisational factors, the care offered during pregnancy and childbirth, the decision-making process and the strategies employed to reduce fear in all involved.


Two nucleoside transporters in Lactococcus lactis with different substrate specificities.
In an alternative to biosynthesis of nucleotides, most organisms are capable of exploiting exogenous nucleotide sources. In order to do so, the nucleotide precursors must pass the membrane, which requires the presence of transporters. Normally, phosphorylated compounds are not subject to transport, and the utilization of nucleotides is dependent on exogenous phosphatases. The composition of transporters with specificity for purine and pyrimidine nucleosides and nucleobases is subject to variation. The ability of Lactococcus lactis to transport different nucleosides across the cell membrane was characterized at both genetic and physiological level, using mutagenesis and by measuring the growth and uptake of nucleosides in the different mutants supplemented with different nucleosides. Two high affinity transporters were identified: BmpA-NupABC was shown to be an ABC transporter with the ability to actively transport all common nucleosides, whereas UriP was shown to be responsible for the uptake of only uridine and deoxyuridine. Interestingly, the four genes encoding the ABC transporter were found at different positions on the chromosome. The bmpA gene was separated from the nupABC operon by 60 kb. Moreover, bmpA was subject to regulation by purine availability, whereas the nupABC operon was constitutively expressed.


Effectiveness of infection prevention and control interventions, excluding personal protective equipment, to prevent nosocomial transmission of SARS-CoV-2: a systematic review and call for action.
Many infection prevention and control (IPC) interventions have been adopted by hospitals to limit nosocomial transmission of SARS-CoV-2. The aim of this systematic review is to identify evidence on the effectiveness of these interventions. We conducted a literature search of five databases (OVID MEDLINE, Embase, CENTRAL, COVID-19 Portfolio (pre-print), Web of Science). SWIFT ActiveScreener software was used to screen English titles and abstracts published between 1st January 2020 and 6th April 2021. Intervention studies, defined by Cochrane Effective Practice and Organisation of Care, that evaluated IPC interventions with an outcome of SARS-CoV-2 infection in either patients or healthcare workers were included. Personal protective equipment (PPE) was excluded as this intervention had been previously reviewed. Risks of bias were assessed using the Cochrane tool for randomised trials (RoB2) and non-randomized studies of interventions (ROBINS-I). From 23,156 screened articles, we identified seven articles that met the inclusion criteria, all of which evaluated interventions to prevent infections in healthcare workers and the majority of which were focused on effectiveness of prophylaxes. Due to heterogeneity in interventions, we did not conduct a meta-analysis. All agents used for prophylaxes have little to no evidence of effectiveness against SARS-CoV-2 infections. We did not find any studies evaluating the effectiveness of interventions including but not limited to screening, isolation and improved ventilation. There is limited evidence from interventional studies, excluding PPE, evaluating IPC measures for SARS-CoV-2. This review calls for urgent action to implement such studies to inform policies to protect our most vulnerable populations and healthcare workers.


The time trade-off method: results from a general population study.
An important consideration when establishing priorities in health care is the likely effects that alternative allocations of resources will have on health-related quality-of-life (HRQoL). This paper reports on a large-scale national study that elicited the relative valuations attached by the general public to different states of health (defined in HRQoL terms). Health state valuations were derived using the time trade-off (TTO) method. The data from 3395 respondents were highly consistent, suggesting that it is feasible to use the TTO method to elicit valuations from the general public. The paper shows that valuations for severe health states appear to be affected by the age and the sex of the respondent; those aged 18-59 have higher valuations than those aged 60 or over and men have higher valuations than women. These results contradict those reported elsewhere and suggest that the small samples used in other studies may be concealing real differences that exist between population sub-groups. This has important implications for public policy decisions.


Toxic carriers in pepper sprays may cause corneal erosion.
We describe four patients who developed corneal erosion after an exposure to a pepper spray containing toxic carriers. Two of these patients were exposed to a pepper gas containing 5% oleoresin capsicum (OC) as an irritant and 92% trichlorethylene or unknown amount of dichloromethane as a carrier. One patient was exposed to a mock (containing 92% trichlorethylene as a carrier) training pepper gas without OC. The fourth patient was exposed to an unidentified Russian pepper gas spray. Two of the patients were examined by in vivo confocal microscopy to demonstrate the depth and quality of the stromal damage. To test the toxicity of the commercial tear spray, it was analyzed and test sprayed on a soft contact lens and into a plastic cup. Visual acuity was measured and the eyes were examined with a slit-lamp up to 5 months. Physical damage to a soft contact lens was visually acquired. All patients showed a long-lasting, deep corneal and conjuctival erosion, which resolved partly with medical therapy during the following weeks/months. Confocal microscopy revealed corneal nerve damage, and keratocyte activation reaching two-thirds of stroma for one patient. The spray caused serious damage to both the soft contact lens and the plastic cup. The safety of the commercially available pepper sprays should be assessed before marketing, and a list of acceptable ingredients created. The sprays should also have instructions on the use of the compound as well as on the first aid measures after the exposure. Solvents known to be toxic should not be used.


Silibinin inhibits HIV-1 infection by reducing cellular activation and proliferation.
Purified silymarin-derived natural products from the milk thistle plant (Silybum marianum) block hepatitis C virus (HCV) infection and inhibit T cell proliferation in vitro. An intravenous formulation of silibinin (SIL), a major component of silymarin, displays anti-HCV effects in humans and also inhibits T-cell proliferation in vitro. We show that SIL inhibited replication of HIV-1 in TZM-bl cells, PBMCs, and CEM cells in vitro. SIL suppression of HIV-1 coincided with dose-dependent reductions in actively proliferating CD19+, CD4+, and CD8+ cells, resulting in fewer CD4+ T cells expressing the HIV-1 co-receptors CXCR4 and CCR5. SIL inhibition of T-cell growth was not due to cytotoxicity measured by cell cycle arrest, apoptosis, or necrosis. SIL also blocked induction of the activation markers CD38, HLA-DR, Ki67, and CCR5 on CD4+ T cells. The data suggest that SIL attenuated cellular functions involved in T-cell activation, proliferation, and HIV-1 infection. Silymarin-derived compounds provide cytoprotection by suppressing virus infection, immune activation, and inflammation, and as such may be relevant for both HIV mono-infected and HIV/HCV co-infected subjects.


Poly(N-methylvinylamine)-Based Copolymers for Improved Gene Transfection.
Poly(N-methylvinylamines) with secondary amines can form complexes with plasmid DNA (pDNA) and provide transfection efficiency in HeLa cells in the same order as linear polyethyleneimine but with higher cell viability. Chemical modifications of poly(N-methylvinylamine) backbones are performed to further improve transfection efficiency while maintaining low degree of cytotoxicity. In a first type of polymer, primary amino groups are incorporated via a copolymerization strategy. In a second one, primary amino and imidazole groups are incorporated also via a copolymerization strategy. In a third one, secondary amino groups are substituted with methylguanidine functions through a postpolymerization reaction. Thus, novel polymers of various molecular masses are synthesized, characterized, and their interaction with pDNA studied. Then, their transfection efficiency and cytotoxicity are tested in HeLa cells. Two polymethylvinylamine-based copolymers, one containing 20% of imidazole moieties and another one composed of 12% of guanidinyl units allow remarkable transfection efficiency of HeLa, pulmonary (16HBE), skeletal muscle (C2C12), and dendritic (DC2.4) cells. Overall, this work thus identifies new promising DNA carriers and chemical modifications that improve the transfection efficiency while maintaining low degree of cytotoxicity.


Cardiovascular Magnetic Resonance in Acute ST-Segment-Elevation Myocardial Infarction: Recent Advances, Controversies, and Future Directions.
Although mortality after ST-segment elevation myocardial infarction (MI) is on the decline, the number of patients developing heart failure as a result of MI is on the rise. Apart from timely reperfusion by primary percutaneous coronary intervention, there is currently no established therapy for reducing MI size. Thus, new cardioprotective therapies are required to improve clinical outcomes after ST-segment-elevation MI. Cardiovascular magnetic resonance has emerged as an important imaging modality for assessing the efficacy of novel therapies for reducing MI size and preventing subsequent adverse left ventricular remodeling. The recent availability of multiparametric mapping cardiovascular magnetic resonance imaging has provided new insights into the pathophysiology underlying myocardial edema, microvascular obstruction, intramyocardial hemorrhage, and changes in the remote myocardial interstitial space after ST-segment-elevation MI. In this article, we provide an overview of the recent advances in cardiovascular magnetic resonance imaging in reperfused patients with ST-segment-elevation MI, discuss the controversies surrounding its use, and explore future applications of cardiovascular magnetic resonance in this setting.


Predicting the risk of gastrointestinal bleeding due to nonsteroidal antiinflammatory drugs: NSAID electronic assessment of risk.
To validate that, using patient demographics and other risk factors readily obtained from computerized databases, one can predict a priori the risk for developing a nonsteroidal antiinflammatory drug (NSAID) associated gastrointestinal (GI) bleed prior to exposing patients to therapy. We conducted a retrospective cohort analysis using computer-stored information from a large group-model health maintenance organization. All patients who received one or more prescriptions for a single NSAID over a 9 month period were eligible. Historical and risk factor data was obtained for age, sex, prior GI bleeds, use of GI medications, prednisone use, and use of disease modifying antirheumatic drugs (DMARD). We tested a model (eSCORE) that is based on a previous risk stratification method. The primary outcome was a hospital admission for a GI bleed (GI event). A total of 303,211 NSAID patient-users met eligibility requirements. Serious GI events occurred in 302 patients, for a rate of 0.68% (0.68 events per 100 patient-years' exposure). All the risk factors except DMARD use were associated with a significant increase in the GI event rate. Higher eSCORE points were associated with increased GI event rates. The study supports the concept that the rate of GI events can be predicted by a defined set of easily assessed patient criteria using the eSCORE. Stratification of patients by risk score can guide the physician to appropriate therapeutic options, with the potential of protecting patients at greatest risk for a GI event.


Parasitoid wasp uses a venom cocktail injected into the brain to manipulate the behavior and metabolism of its cockroach prey.
Unlike other venomous predators, the parasitoid wasp Ampulex compressa incapacitates its prey, the cockroach Periplaneta americana, to provide a fresh food supply for its offspring. We first established that the wasp larval development, from egg laying to pupation, lasts about 8 days during which the cockroach must remain alive but immobile. To this end, the wasp injects a cocktail of neurotoxins to manipulate the behavior of the cockroach. The cocktail is injected directly into the head ganglia using biosensors located on the stinger. The head sting induces first 30 min of intense grooming followed by hypokinesia during which the cockroach is unable to generate an escape response. In addition, stung cockroaches survive longer, lose less water, and consume less oxygen. Dopamine contained in the venom appears to be responsible for inducing grooming behavior. For the hypokinesia, our hypothesis is that the injected venom affects neurons located in the head ganglia, which send descending tonic input to bioaminergic neurons. These, in turn, control the thoracic premotor circuitry for locomotion. We show that the activity of identified octopaminergic neurons from the thoracic ganglia is altered in stung animals. The alteration in the octopaminergic neurons' activity could be one of the mechanisms by which the venom modulates the escape circuit in the cockroach's central nervous system and metabolism in the peripheral system.


Transcriptome sequencing, microarray, and proteomic analyses reveal cellular and metabolic impact of hepatitis C virus infection in vitro.
Hepatitis C virus (HCV) is a major cause of liver disease but the full impact of HCV infection on the hepatocyte is poorly understood. RNA sequencing (RNA-Seq) is a novel method to analyze the full transcriptional activity of a cell or tissue, thus allowing new insight into the impact of HCV infection. We conducted the first full-genome RNA-Seq analysis in a host cell to analyze infected and noninfected cells, and compared this to microarray and proteomic analyses. The combined power of the triple approach revealed that HCV infection affects a number of previously unreported canonical pathways and biological functions, including pregnane X receptor/retinoic acid receptor activation as a potential host antiviral response, and integrin-linked kinase signaling as an entry factor. This approach also identified several mechanisms implicated in HCV pathogenesis, including an increase in reactive oxygen species. HCV infection had a broad effect on cellular metabolism, leading to increases in cellular cholesterol and free fatty acid levels, associated with a profound and specific decrease in cellular glucose levels. RNA-Seq technology, especially when combined with established methods, demonstrated that HCV infection has potentially wide-ranging effects on cellular gene and protein expression. This in vitro study indicates a substantial metabolic impact of HCV infection and highlights new mechanisms of virus-host interaction which may be highly relevant to pathogenesis in vivo.


Single, Repeated, and Maintenance Ketamine Infusions for Treatment-Resistant Depression: A Randomized Controlled Trial.
Subanesthetic ketamine doses have been shown to have rapid yet transient antidepressant effects in patients with treatment-resistant depression, which may be prolonged by repeated administration. The purpose of this study was to evaluate the antidepressant effects of a single ketamine infusion, a series of repeated ketamine infusions, and prolongation of response with maintenance infusions. Forty-one participants with treatment-resistant depression completed a single-site randomized double-blind crossover comparison of single infusions of ketamine and midazolam (an active placebo control). After relapse of depressive symptoms, participants received a course of six open-label ketamine infusions administered thrice weekly over 2 weeks. Responders, classified as those participants who had a ≥50% decrease in their scores on the Montgomery-Åsberg Depression Rating Scale (MADRS), received four additional infusions administered once weekly (maintenance phase). Compared with midazolam, a single ketamine infusion elicited a significantly greater reduction in depressive symptoms at the primary efficacy endpoint (24 hours postinfusion). Linear mixed models revealed cumulative antidepressant effects with repeated infusions and doubling of the antidepressant response rate. Fifty-nine percent of participants met response criteria after repeated infusions, with a median of three infusions required before achieving response. Participants had no further change in MADRS scores during weekly maintenance infusions. Repeated ketamine infusions have cumulative and sustained antidepressant effects. Reductions in depressive symptoms were maintained among responders through once-weekly infusions. These findings provide novel data on efficacious administration strategies for ketamine in patients with treatment-resistant depression. Future studies should further expand on optimizing administration to better translate the use of ketamine into clinical settings.


Dietary N-acetylcysteine supplementation alleviates liver injury in lipopolysaccharide-challenged piglets.
The present study was carried out to determine whether N-acetylcysteine (NAC) could modulate liver injury in a lipopolysaccharide (LPS)-challenged piglet model. For this purpose, eighteen piglets were randomly assigned to the control, LPS or NAC group. Piglets in the control and LPS groups were fed a basal diet, whereas those in the NAC group were fed the basal diet supplemented with 500 mg/kg NAC. On days 10, 13 and 20 of the trial, the LPS- and NAC-treated piglets were intraperitoneally administered LPS (100 μg/kg body weight), while the control group was administered the same volume of saline. On day 20 of the trial, blood samples were obtained 3 h after LPS or saline injection. On day 21, the piglets were killed to collect liver samples. Dietary NAC supplementation attenuated LPS-induced liver histomorphological abnormalities. Compared with the control group, in the LPS-challenged piglets, the activities of alanine aminotransferase and aspartate aminotransferase and the concentrations of H2O2, TNF-α, IL-6 and PGE2 were dramatically increased in the plasma and the activity of superoxide dismutase in the plasma and that of glutathione peroxidase in the liver were significantly decreased. The LPS challenge also increased the concentration of AMP and the ratio of AMP:ATP, but decreased adenylate energy charges and the levels of ATP and ADP. These adverse effects of the LPS challenge were ameliorated by NAC supplementation. Moreover, NAC inhibited the LPS-induced increases in the abundance of liver heat shock protein 70 and NF-κB proteins. In conclusion, these results suggest that dietary NAC supplementation alleviates LPS-induced liver injury by reducing the secretion of pro-inflammatory cytokines, increasing the antioxidative capacity and improving energy metabolism.


Kinetics of glucose transport in rat muscle: effects of insulin and contractions.
The effects of insulin and prior muscle contractions, respectively, on 3-O-methylglucose (3-O-MG) transport in skeletal muscle were studied in the perfused rat hindquarter. Initial rates of entry of 3-O-MG in red gastrocnemius, soleus, and white gastrocnemius muscles as a function of perfusate 3-O-MG concentration exhibited Michaelis-Menten kinetics. Uptake by simple diffusion could not be detected. The maximum 3-O-MG transport velocity (Vmax) was increased more by maximum isometric contractions (10- to 40-fold, depending on fiber type) than by insulin (20,000 microU/ml; 3- to 20-fold) in both red and white muscles. The effects of both contractions and insulin were greater in red than in white muscles. In red but not in white muscles, maximum increases in Vmax elicited by contractions and by insulin were additive. Both insulin and contractions decreased the half-saturating substrate concentration for glucose transport (apparent Km) in all three muscles, in fast-twitch fibers from 70 to approximately 7 mM and in slow-twitch fibers from 12 to 7 mM. After contractions, reversal of contraction-induced glucose transport was monoexponential in red fibers, with a half-time of 7 and 15 min in slow- and fast-twitch fibers, respectively. In white muscle, Vmax continued to increase after contractions, reached a plateau after 10 min, and had only decreased 45% after 70 min. In contrast to the prevailing opinion, in all fiber types, reversal of contraction-induced glucose transport took place in the absence of muscle glycogen repletion.


Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells.
Human respiratory syncytial virus (hRSV) is the leading cause of bronchiolitis and pneumonia in young children worldwide. The recurrent hRSV outbreaks and reinfections are the cause of a significant public health burden and associate with an inefficient antiviral immunity, even after disease resolution. Although several mouse- and human cell-based studies have shown that hRSV infection prevents naïve T-cell activation by antigen-presenting cells, the mechanism underlying such inhibition remains unknown. Here, we show that the hRSV nucleoprotein (N) could be at least partially responsible for inhibiting T-cell activation during infection by this virus. Early after infection, the N protein was expressed on the surface of epithelial and dendritic cells, after interacting with trans-Golgi and lysosomal compartments. Further, experiments on supported lipid bilayers loaded with peptide-MHC (pMHC) complexes showed that surface-anchored N protein prevented immunological synapse assembly by naive CD4(+) T cells and, to a lesser extent, by antigen-experienced T-cell blasts. Synapse assembly inhibition was in part due to reduced T-cell receptor (TCR) signaling and pMHC clustering at the T-cell-bilayer interface, suggesting that N protein interferes with pMHC-TCR interactions. Moreover, N protein colocalized with the TCR independently of pMHC, consistent with a possible interaction with TCR complex components. Based on these data, we conclude that hRSV N protein expression at the surface of infected cells inhibits T-cell activation. Our study defines this protein as a major virulence factor that contributes to impairing acquired immunity and enhances susceptibility to reinfection by hRSV.


Interactions between Schwann and olfactory ensheathing cells with a starch/polycaprolactone scaffold aimed at spinal cord injury repair.
Spinal cord injury (SCI) represents a major world health problem. Therefore it is urgent to develop novel strategies that can specifically target it. We have previously shown that the implantation of starch-based scaffolds (SPCL) aimed for spine stabilization on SCI animals leads to motor skills improvements. Therefore, we hypothesize that the combination of these scaffolds with relevant cell populations for SCI repair will, most likely, lead to further improvements. Therefore, in this work, the ability of SPCL scaffolds to support the 3D culture of olfactory ensheathing cells (OECs) and Schwann cells (SCs) was studied and characterized. The results demonstrate for the first time that SPCL scaffolds were able to support the growth and migration of OECs and SCs. Moreover, the results indicate that two weeks of in vitro culture is the ideal time to reach a high number of transplantable cells. Future work will focus on the spine stabilization of SCI animals using SPCL scaffolds loaded with OECs or SCs for SCI regeneration.


Antihyperlipidemic and Antioxidant Activities of Edible Tunisian Ficus carica L. Fruits in High Fat Diet-Induced Hyperlipidemic Rats.
The phenolic constituents of the aqueous-ethanolic extract of Tunisian Ficus carica (F. carica) fruit (FE) and its antihyperlipidemic and antioxidant activities in high-fat diet-induced hyperlipidemic rats (HFD) were evaluated. The obtained results demonstrated that the FE improved the lipid profile by decreasing the total cholesterol, triglyceride, low-density lipoprotein cholesterol and increasing high-density lipoprotein cholesterol levels. It also reduced the content of thiobarbituric acid-reactive substances and increased the antioxidant enzymes in liver, heart and kidney in HFD-fed rats. These antihyperlipidemic effects and in vivo antioxidative effects correlated with the in vitro phenolic content scavenging ability. Thus, the major phenolic compounds were identified using reversed-phase ultra-high-performance liquid chromatography (RP-UHPLC) coupled with two detection systems: diode-array detection (DAD) and quadrupole time-of-flight (QTOF) mass spectrometry (MS). Therefore, in the negative ionization mode, 28 phenolic compounds, including hydroxybenzoic acids, hydroxycinnamic acids, flavanoids and hydroxycoumarins were characterized. Dihydroxybenzoic acid di-pentoside, the flavonol quercetin 3-O-rutinoside and the flavone assigned as apigenin 8-C-glucoside were the main representative compounds in 'Tounsi' fruits. This work was complemented by the detection of seven other phenolic compounds in the positive ionization mode, including anthocyanins and furanocoumarins. Overall, these results have shown that the FE has a significant hypocholesterolemic effect and antioxidant activity in HFD-fed rats. This beneficial effect may be partly due to these phenolic constituents, especially vitexin, dihydroxybenzoic acid di-pentoside as well as rutin.


J-deconvolution using maximum entropy reconstruction applied to 13C-13C solid-state cross-polarization magic-angle-spinning NMR of proteins.
Scalar couplings between 13C spins can impair both resolution and sensitivity in 13C-labeled preparations. It is demonstrated that deconvolution of magic-angle-spinning NMR data with maximum entropy (MaxEnt) reconstruction allows the removal of splittings due to J-couplings without expenses in sensitivity. A combination of MaxEnt reconstruction in t2 with selective pulses in t1 produces fully J-resolved data in both dimensions. The possibility to obtain J-resolved 13C-13C data without compromising the sensitivity is particularly important for solid-state NMR of "difficult" biological samples, like membrane proteins, where sacrifices in signal-to-noise are fatal. The method is demonstrated using preparations of alpha-spectrin SH3 domain (62 residues) as small test system and of outermembrane protein G as example of a membrane protein with higher molecular weight (281 residues). Both preparations were obtained using [2-13C]-glycerol as the carbon source during the bacterial growth.


Partial factorial trials: comparing methods for statistical analysis and economic evaluation.
Partial factorial trials compare two or more pairs of treatments on overlapping patient groups, randomising some (but not all) patients to more than one comparison. The aims of this research were to compare different methods for conducting and analysing economic evaluations on partial factorial trials and assess the implications of considering factors simultaneously rather than drawing independent conclusions about each comparison. We estimated total costs and quality-adjusted life years (QALYs) within 10 years of surgery for 2252 patients in the Knee Arthroplasty Trial who were randomised to one or more comparisons of different surgical types. We compared three analytical methods: an "at-the-margins" analysis including all patients randomised to each comparison (assuming no interaction); an "inside-the-table" analysis that included interactions but focused on those patients randomised to two comparisons; and a Bayesian vetted bootstrap, which used results from patients randomised to one comparison as priors when estimating outcomes for patients randomised to two comparisons. Outcomes comprised incremental costs, QALYs and net benefits. Qualitative interactions were observed for costs, QALYs and net benefits. Bayesian bootstrapping generally produced smaller standard errors than inside-the-table analysis and gave conclusions that were consistent with at-the-margins analysis, while allowing for these interactions. By contrast, inside-the-table gave different conclusions about which intervention had the highest net benefits compared with other analyses. All analyses of partial factorial trials should explore interactions and assess whether results are sensitive to assumptions about interactions, either as a primary analysis or as a sensitivity analysis. For partial factorial trials closely mirroring routine clinical practice, at-the-margins analysis may provide a reasonable estimate of average costs and benefits for the whole trial population, even in the presence of interactions. However, such conclusions will be misleading if there are large interactions or if the proportion of patients allocated to different treatments differs markedly from what occurs in clinical practice. The Bayesian bootstrap provides an alternative to at-the-margins analysis for analysing clinical or economic endpoints from partial factorial trials, which allows for interactions while making use of the whole sample. The same techniques could be applied to analyses of clinical endpoints. ISRCTN, ISRCTN45837371 . Registered on 25 April 2003.


Lab-on-a-chip methods for point-of-care measurements of salivary biomarkers of periodontitis.
Salivary secretions contain a variety of molecules that reflect important pathophysiological activities. Quantitative changes of specific salivary biomarkers could have significance in the diagnosis and management of both oral and systemic diseases. Modern point-of-care technologies with enhanced detection capabilities are needed to implement a significant advancement in salivary diagnostics. One such promising technology is the recently described lab-on-a-chip (LOC) assay system, in which assays are performed on chemically sensitized beads populated into etched silicon wafers with embedded fluid handling and optical detection capabilities. Using this LOC system, complex assays can be performed with small sample volumes, short analysis times, and markedly reduced reagent costs. This report describes the use of LOC methodologies to assess the levels of interleukin-1beta (IL-1beta), C-reactive protein (CRP), and matrix metalloproteinase-8 (MMP-8) in whole saliva, and the potential use of these biomarkers for diagnosing and categorizing the severity and extent of periodontitis. This study demonstrates that the results achieved by the LOC approach are in agreement with those acquired with standard enzyme-linked immunosorbent assay (ELISA), with significant IL-1beta and MMP-8 elevations in whole saliva of periodontitis patients. Furthermore, because of the superior detection capacities associated with the LOC approach, unlike those with ELISA, significant differences in CRP levels between periodontitis patients and normal subjects are observed. Finally, principal component analysis (PCA) is performed to yield an efficient method to discriminate between periodontally healthy and unhealthy patients, thus increasing the diagnostic value of these biomarkers for periodontitis when examined with the integrated LOC sensor system.


OXTR overexpression leads to abnormal mammary gland development in mice.
Oxytocin receptor (OXTR) is a G-protein coupled receptor and known for regulation of maternal and social behaviors. Null mutation (Oxtr-/-) leads to defects in lactation due to impaired milk ejection and maternal nurturing. Overexpression of OXTR has never been studied. To define the functions of OXTR overexpression, a transgenic mouse model that overexpresses mouse Oxtr under β-actin promoter was developed (++Oxtr). ++Oxtr mice displayed advanced development and maturation of mammary gland, including ductal distention, enhanced secretory differentiation and early milk production at non-pregnancy and early pregnancy. However, ++Oxtr dams failed to produce adequate amount of milk and led to lethality of newborns due to early involution of mammary gland in lactation. Mammary gland transplantation results indicated the abnormal mammary gland development was mainly from hormonal changes in ++Oxtr mice but not from OXTR overexpression in mammary gland. Elevated OXTR expression increased prolactin-induced phosphorylation and nuclear localization of STAT5 (p-STAT5), decreased progesterone level, leading to early milk production in non-pregnant and early pregnant females, whereas low prolactin and STAT5 activation in lactation led to insufficient milk production. Progesterone treatment reversed the OXTR-induced accelerated mammary gland development by inhibition of prolactin/p-STAT5 pathway. Prolactin administration rescued lactation deficiency through STAT5 activation. Progesterone plays a negative role in OXTR regulated prolactin/p-STAT5 pathways. The study provides evidence that OXTR overexpression induces abnormal mammary gland development through progesterone and prolactin-regulated p-STAT5 pathway.


Benefits of induced sputum for the evaluation of therapeutic efficacy in patients with bronchial asthma.
Airway inflammation is a major factor in the pathogenesis of asthma. Inducing sputum by hypertonic saline is a noninvasive method of assessment of the airway inflammation in asthmatic patients. To investigate sputum induction as a method for assessing airway inflammation and to evaluate the effect of inhaled beclomethasone dipropionate (BDP) in asthmatic patients, we examined the bronchial hyperresponsibility (BHR), pulmonary function and differential cell counts in induced sputum of the patients before and after BDP therapy. In asthmatic patients, the percentage of eosinophils in induced sputum was significantly higher than that in non-asthmatic subjects. Ten patients with atopic asthma (four men and six women; mean [+/- SD] age, 30.5 +/- 12.4 years) participated. Their mean percentage of eosinophils (% eosinophils) in induced sputum fell from 22.9 +/- 7.2% to 13.9 +/- 8.3% (p < 0.05) by 3 months of BDP treatment. The percentage of eosinophils in induced sputum before BDP treatment was significantly correlated with the ratio of the forced expiratory volume in one second to the forced vital capacity (FEV1%) at baseline (r = -0.75, p < 0.05), but not with log Dmin at baseline (p = 0.18). The change in FEV1% between at baseline and post-treatment correlated significantly with the change in the sputum eosinophil percentage (r = -0.79, p < 0.01). In addition, there was a significant correlation between the change of log Dmin and the change of the sputum eosinophil percentage (r = -0.64, p < 0.05). In conclusion, analysis of induced sputum is a safe, noninvasive, repeatable and useful method to assess the clinical condition of bronchial inflammation in patients with bronchial asthma.


Third Annual Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs) Report: Preimplant Characteristics and Outcomes.
The influence of ventricular assist device (VAD) use in the care of children with end-stage heart failure is growing rapidly through increasing numbers, new devices, expanding indications, and improving outcomes. Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs), a National Institutes of Health-sponsored United States database, provides a platform to understand this emerging population. Between September 19, 2012, and December 31, 2017, 30 hospitals implanted 508 devices in 423 patients aged younger than 19 years. This past year was one of evolution for the database as its management was transitioned to The Society of Thoracic Surgery; therefore, this report does not include data from institutions not under contract by August 1, 2018. Of the 423 patients, the diagnosis was cardiomyopathy in 261 (62%), myocarditis in 48 (11%), other in 28 (7%), and congenital heart disease (CHD) in 86 (20%), with 52 of these patients having single-ventricle physiology. The two most common support strategies included left VAD in 342 (81%) and biventricular assist device in 64 (15%). Positive outcome (alive on device or bridge to transplantation/recovery) was 80% at 6 months (overall mortality of 20%). The patient cohort for implantable continuous-flow (IC) pumps (n = 197; age at implant, 13.4 ± 3.8 years; 19% Interagency Registry for Mechanically Assisted Circulatory Support [Intermacs] profile 1, 21% intubated at implant, and 12% with CHD) was significantly different from the paracorporeal continuous-flow (PC) pump cohort (n = 79; age, 3.9 ± 5.2 years; 49% Intermacs profile 1, 86% intubated at implant, and 38% with CHD) and the paracorporeal pulsatile (PP) pump cohort (n = 121; age, 3.3 ± 3.9 years; 41% Intermacs profile 1, 77% intubated at implant, and 21% with CHD). Consistent with their cohort composition, device type positive outcomes at 6 months were PC, 63%; PP, 77%; and IC, 92%. Parametric hazard modeling showed an early hazard for death was associated with Intermacs profile 1, biventricular assist device, percutaneous devices, PC devices, small-volume institutions, low age, and low weight, whereas a constant hazard was associated with intubation and liver dysfunction at time of implant. IC VADs are the most common VAD type placed in children. The positive outcomes for the IC VADs exceed 90% at 6 months, which may represent our field's maturation in both patient selection and timing of implantation. The PP/PC devices are currently limited to supporting our most challenging patients, those weighing less than 20 kg and those with CHD. The introduction of new devices and our communities' commitment to shared learning and improvement will lead to more pediatric lives saved by VAD support and will also focus on improving the quality of life of children supported with VADs.


Identifying barriers and opportunities for a circular phosphorus economy in the Baltic Sea region.
Phosphorus (P) is one of the essential elements needed for global food security. However, the phosphate life cycle is currently predominantly linear, from P-rock mining to fertiliser production, agriculture, and food consumption, with the P excess ending up in soil and runoff. Eutrophication coupled with limited global commercial phosphorus reserves call for increased efforts toward creating a circular economy for P in many populated drainage basins such as the Baltic Sea region. To identify barriers and opportunities for such a transition, we employ an analytical framework that merges an innovation systems perspective with elements from the socio-technical transitions literature. Combining a literature review with key informant interviews, we find that lack of appropriate policy steering and insufficient knowledge on the performance of technologies for reuse remain key obstacles for closing the P loop. There are, however, structural opportunities presented by the new EU Fertilising Products Regulation that are likely to level the playing field between conventional and waste-derived fertilisers and thereby improve the market opportunities for recovered P. However, the system currently appears to be moving towards a narrow focus on a few new technologies for P recovery and reuse which could lead to new lock-ins. Solutions need to address users' acceptability of the technologies and waste-derived products while the vision of a circular economy needs to be better articulated through government interventions to capture environmental externalities of phosphate mining. The paper further highlights knowledge gaps and proposes recommendations for policy and research related to the circular economy of P.


These are not the k-mers you are looking for: efficient online k-mer counting using a probabilistic data structure.
K-mer abundance analysis is widely used for many purposes in nucleotide sequence analysis, including data preprocessing for de novo assembly, repeat detection, and sequencing coverage estimation. We present the khmer software package for fast and memory efficient online counting of k-mers in sequencing data sets. Unlike previous methods based on data structures such as hash tables, suffix arrays, and trie structures, khmer relies entirely on a simple probabilistic data structure, a Count-Min Sketch. The Count-Min Sketch permits online updating and retrieval of k-mer counts in memory which is necessary to support online k-mer analysis algorithms. On sparse data sets this data structure is considerably more memory efficient than any exact data structure. In exchange, the use of a Count-Min Sketch introduces a systematic overcount for k-mers; moreover, only the counts, and not the k-mers, are stored. Here we analyze the speed, the memory usage, and the miscount rate of khmer for generating k-mer frequency distributions and retrieving k-mer counts for individual k-mers. We also compare the performance of khmer to several other k-mer counting packages, including Tallymer, Jellyfish, BFCounter, DSK, KMC, Turtle and KAnalyze. Finally, we examine the effectiveness of profiling sequencing error, k-mer abundance trimming, and digital normalization of reads in the context of high khmer false positive rates. khmer is implemented in C++ wrapped in a Python interface, offers a tested and robust API, and is freely available under the BSD license at github.com/ged-lab/khmer.


NIH Conference. Herpes simplex virus infection: biology, treatment, and prevention.
Herpes simplex viruses cause common mucocutaneous infections, but many aspects of their epidemiology and transmission are incompletely defined. Although the incidence of oral herpes remains relatively unchanged, the incidence of genital herpes is increasing significantly. Definitive diagnosis of herpes remains dependent on virus isolation, but techniques involving direct examination of clinical specimens are increasingly sensitive and may simplify and speed diagnosis. With the advent of acyclovir, effective therapy and suppression of infection are feasible for immunodeficient and selected normal patients. Unanswered questions remain regarding the long-term safety of acyclovir and the potential for emergence of clinically significant drug resistance. No effective vaccines are yet available for herpes virus infections. Promising strategies for vaccine development include preparation of immunogenic proteins, engineering of specially attenuated live virus strains, and incorporation of selected herpes genes into live vaccinia virus vectors.


Transforming Education Research Through Open Video Data Sharing.
Open data sharing promises to accelerate the pace of discovery in the developmental and learning sciences, but significant technical, policy, and cultural barriers have limited its adoption. As a result, most research on learning and development remains shrouded in a culture of isolation. Data sharing is the rare exception (Gilmore, 2016). Many researchers who study teaching and learning in classroom, laboratory, museum, and home contexts use video as a primary source of raw research data. Unlike other measures, video captures the complexity, richness, and diversity of behavior. Moreover, because video is self-documenting, it presents significant potential for reuse. However, the potential for reuse goes largely unrealized because videos are rarely shared. Research videos contain information about participants' identities making the materials challenging to share. The large size of video files, diversity of formats, and incompatible software tools pose technical challenges. The Databrary (databrary.org) digital library enables researchers who study learning and development to store, share, stream, and annotate videos. In this article, we describe how Databrary has overcome barriers to sharing research videos and associated data and metadata. Databrary has developed solutions for respecting participants' privacy; for storing, streaming, and sharing videos; and for managing videos and associated metadata. The Databrary experience suggests ways that videos and other identifiable data collected in the context of educational research might be shared. Open data sharing enabled by Databrary can serve as a catalyst for a truly multidisciplinary science of learning.


Methane emission by camelids.
Methane emissions from ruminant livestock have been intensively studied in order to reduce contribution to the greenhouse effect. Ruminants were found to produce more enteric methane than other mammalian herbivores. As camelids share some features of their digestive anatomy and physiology with ruminants, it has been proposed that they produce similar amounts of methane per unit of body mass. This is of special relevance for countrywide greenhouse gas budgets of countries that harbor large populations of camelids like Australia. However, hardly any quantitative methane emission measurements have been performed in camelids. In order to fill this gap, we carried out respiration chamber measurements with three camelid species (Vicugna pacos, Lama glama, Camelus bactrianus; n = 16 in total), all kept on a diet consisting of food produced from alfalfa only. The camelids produced less methane expressed on the basis of body mass (0.32±0.11 L kg⁻¹ d⁻¹) when compared to literature data on domestic ruminants fed on roughage diets (0.58±0.16 L kg⁻¹ d⁻¹). However, there was no significant difference between the two suborders when methane emission was expressed on the basis of digestible neutral detergent fiber intake (92.7±33.9 L kg⁻¹ in camelids vs. 86.2±12.1 L kg⁻¹ in ruminants). This implies that the pathways of methanogenesis forming part of the microbial digestion of fiber in the foregut are similar between the groups, and that the lower methane emission of camelids can be explained by their generally lower relative food intake. Our results suggest that the methane emission of Australia's feral camels corresponds only to 1 to 2% of the methane amount produced by the countries' domestic ruminants and that calculations of greenhouse gas budgets of countries with large camelid populations based on equations developed for ruminants are generally overestimating the actual levels.


Care relationships at stake? Home healthcare professionals' experiences with digital medicine dispensers - a qualitative study.
Although digital technologies can mitigate the burdens of home healthcare services caused by an ageing population that lives at home longer with complex health problems, research on the impacts and consequences of digitalised remote communication between patients and caregivers is lacking. The present study explores how home healthcare professionals had experienced the introduction of digital medicine dispensers and their influence on patient-caregiver relationships. The multi-case study comprised semi-structured interviews with 21 healthcare professionals whose home healthcare service involved using the digital medicine dispensers. The constant comparative method was used for data analyses. Altogether, interviewed healthcare professionals reported three main technology-related impacts upon their patient-caregiver relationships. First, national and local pressure to increase efficiency had troubled their relationships with patients who suspected that municipalities have sought to lower costs by reducing and digitalising services. Participants reported having to consider such worries when introducing technologies into their services. Second, participants reported a shift towards empowering patients. Digital technology can empower patients who value their independence, whereas safety is more important for other patients. Healthcare professionals needed to ensure that replacing care tasks with technology implies safe and improved care. Third, the safety and quality of digital healthcare services continues to depend upon surveillance and control mechanisms that compensate for less face-to-face monitoring. Participants did not consider the possibility that surveillance exposes information about patients' everyday lives to be problematic, but to constitute opportunities for adjusting services to meet patients' needs. Technologies such as digital medicine dispensers can improve the efficiency of healthcare services and enhance patients' independence when introduced in a way that empowers patients as well as safeguards trust and service quality. Conversely, the patient-caregiver relationship can suffer if the technology does not meet patients' needs and fails to offer safe and trustworthy services. Upon introducing technology, home healthcare professionals therefore need to carefully consider the benefits and possible disadvantages of the technology. Ethical implications for both individuals and societies need to be further discussed.


Presynaptic inhibition of gamma-aminobutyric acidB-mediated synaptic current by adenosine recorded in vitro in midbrain dopamine neurons.
Adenosine receptor antagonists such as caffeine cause dopamine-dependent behavioral arousal and hyperlocomotion in rodents. In the present study, we used the whole-cell recording technique in the rat brain slice to investigate effects of adenosine on dopamine neurons and their synaptic inputs in the substantia nigra zona compacta and ventral tegmental area. Adenosine was most potent for inhibiting the amplitude of the inhibitory postsynaptic current (IPSC) mediated by gamma-aminobutyric acid (GABA)B receptors (EC50 = 47 +/- 3 microM) compared with inhibition of the GABAA-mediated IPSC (117 +/- 51 microM) and the excitatory amino acid-mediated excitatory postsynaptic current (119 +/- 36 microM). Adenosine failed to inhibit current evoked by exogenous GABA or baclofen, suggesting that adenosine acted presynaptically to reduce GABA release from nerve terminals. Adenosine inhibited the GABAB-mediated IPSC by acting at the adenosine A1 receptor, because its effect was blocked by the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (100 nM), as well as by the methylxanthines caffeine (1 mM) and theophylline (300 microM). The rank-order of potency of adenosine agonists [N6-cyclohexyladenosine > R-(-)-N6-(2-phenylisopropyl)-adenosine = N6- cyclohexyladenosine > 5'-N-ethylcarboxamidoadenosine > 2-chloroadenosine] also was consistent with activation of the adenosine A1 receptor, whereas the selective adenosine A2A agonist CGS 21680 [2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido adenosine] had no effect on the GABAB IPSC. None of the adenosine agonists or antagonists affected holding current or membrane conductance.(ABSTRACT TRUNCATED AT 250 WORDS)


Vibration modulated subaperture stitching interferometry.
A novel subaperture stitching interferometry is developed to measure the surface deformation of the lens by utilizing the mechanical vibration induced from a motorized stage. The interferograms of different subapertures are acquired on the fly while the tested optics is rotating against its symmetrical axis. The measurement throughput and the subaperture positioning accuracy are improved simultaneously by adopting both the synchronous rotational scanning mechanism and the non-uniform phase shifting algorithm. The experimental measurement shows the stitched phase RMS error of 0.0037 waves proving the feasibility of the proposed phase acquisition method.


In silico insights into the symbiotic nitrogen fixation in Sinorhizobium meliloti via metabolic reconstruction.
Sinorhizobium meliloti is a soil bacterium, known for its capability to establish symbiotic nitrogen fixation (SNF) with leguminous plants such as alfalfa. S. meliloti 1021 is the most extensively studied strain to understand the mechanism of SNF and further to study the legume-microbe interaction. In order to provide insight into the metabolic characteristics underlying the SNF mechanism of S. meliloti 1021, there is an increasing demand to reconstruct a metabolic network for the stage of SNF in S. meliloti 1021. Through an iterative reconstruction process, a metabolic network during the stage of SNF in S. meliloti 1021 was presented, named as iHZ565, which accounts for 565 genes, 503 internal reactions, and 522 metabolites. Subjected to a novelly defined objective function, the in silico predicted flux distribution was highly consistent with the in vivo evidences reported previously, which proves the robustness of the model. Based on the model, refinement of genome annotation of S. meliloti 1021 was performed and 15 genes were re-annotated properly. There were 19.8% (112) of the 565 metabolic genes included in iHZ565 predicted to be essential for efficient SNF in bacteroids under the in silico microaerobic and nutrient sharing condition. As the first metabolic network during the stage of SNF in S. meliloti 1021, the manually curated model iHZ565 provides an overview of the major metabolic properties of the SNF bioprocess in S. meliloti 1021. The predicted SNF-required essential genes will facilitate understanding of the key functions in SNF and help identify key genes and design experiments for further validation. The model iHZ565 can be used as a knowledge-based framework for better understanding the symbiotic relationship between rhizobia and legumes, ultimately, uncovering the mechanism of nitrogen fixation in bacteroids and providing new strategies to efficiently improve biological nitrogen fixation.


Sexual function and depressive symptoms among male North American medical students.
The role of sexuality as an association of medical student well-being has not been extensively studied. We explored the relationship between depressive symptoms, sexuality, and sexual dysfunction in male North American medical students. North American medical students were invited to participate in an Internet-based survey. The Center for Epidemiological Studies Depression Scale (CES-D) was utilized to screen for depressive symptoms. Subjects completed an ethnodemographic survey, a sexuality survey, and instruments for the quantification of anxiety, sexuality, and psychosocial function. Descriptive statistics, odds ratios (ORs), and logistic regression were used to analyze our data. There were 844 male subjects with complete data on the CES-D and the Spielberger State-Trait Anxiety Index. Depressive symptoms (CES-D ≥ 16) were present in 37% of respondents and were more common in subjects with greater levels of anxiety. Subjects who were in sexual relationships and/or had frequent sexual activity were less likely to be depressed compared to other subjects. Erectile dysfunction (ED) was associated with significantly greater likelihood of depressive symptoms (OR 2.90 and 9.27 for depressive symptoms in men with mild or moderate/severe ED relative to men without ED, P < 0.01). After adjusting for ethnodemographic and sexual history factors, ED remained significantly positively associated with depressive symptoms (OR 2.87 and 6.59 for depressive symptoms in men with mild or moderate/severe ED relative to men without ED after adjustment, P ≤ 0.01). Inclusion of data related to psychosocial/relationship factors in the multivariate model eliminated the significant association between ED and depressive symptoms (OR 1.59 and 2.29 for depressive symptoms in men with mild or moderate/severe ED relative to men without ED after adjustment with the Self-Esteem and Relationship quality instrument, P > 0.05), suggesting that psychosocial factors were more strongly associated with depressive symptoms than erectile function. Healthy sexuality and relationships may be protective against depressive symptoms in medical students. Attention to these factors may enhance medical student well-being.


Hair cycle-dependent expression of corticotropin-releasing factor (CRF) and CRF receptors in murine skin.
We demonstrate the presence and hair cycle-dependent expression of corticotropin-releasing factor (CRF) and CRF receptors (CRF-R) in C57BL/6 mouse skin. To correlate this with a physiological, developmentally controlled tissue remodeling process, we have analyzed CRF and CRF-R expression during defined stages of the murine hair cycle with its rhythmic changes between growth (anagen), regression (catagen), and resting (telogen). Using reversed-phase HPLC combined with two independent anti-CRF radioimmunoassays, we have identified CRF in murine skin. Maximal CRF levels were found in anagen III-IV skin, and minimal values were detected in catagen and telogen skin. By immunofluorescence, maximal CRF immunoreactivity (CRF-IR) was seen in the basal epidermis, nerve bundles of skin, the outer root sheath and matrix region of anagen IV-VI follicles, and in defined sections of their perifollicular neural network, whereas catagen and telogen skin displayed minimal CRF-IR. Using quantitative autoradiography and 125I-CRF as a tracer, high-affinity binding sites for CRF were detected in murine skin. The highest density of specific binding sites was detected in the panniculus carnosus, the epidermis, and the hair follicle. CRF-R type 1 (CRF-R1) IR was detected by immunohistology mainly in the outer root sheath, hair matrix, and dermal papilla of anagen VI follicles, as well as in the inner and outer root sheaths of early catagen follicles. CRF-R1 expression was also hair cycle dependent. Therefore, in normal murine skin, the CRF-CRF-R signaling system may operate as an additional neuroendocrine pathway regulating skin functions, possibly in the context of cutaneous stress responses.


Protein misfolding induces hypoxic preconditioning via a subset of the unfolded protein response machinery.
Prolonged cellular hypoxia results in energy failure and ultimately cell death. However, less-severe hypoxia can induce a cytoprotective response termed hypoxic preconditioning (HP). The unfolded protein response pathway (UPR) has been known for some time to respond to hypoxia and regulate hypoxic sensitivity; however, the role of the UPR, if any, in HP essentially has been unexplored. We have shown previously that a sublethal hypoxic exposure of the nematode Caenorhabditis elegans induces a protein chaperone component of the UPR (L. L. Anderson, X. Mao, B. A. Scott, and C. M. Crowder, Science 323:630-633, 2009). Here, we show that HP induces the UPR and that the pharmacological induction of misfolded proteins is itself sufficient to stimulate a delayed protective response to hypoxic injury that requires the UPR pathway proteins IRE-1, XBP-1, and ATF-6. HP also required IRE-1 but not XBP-1 or ATF-6; instead, GCN-2, which is known to suppress translation and induce an adaptive transcriptional response under conditions of UPR activation or amino acid deprivation, was required for HP. The phosphorylation of the translation factor eIF2α, an established mechanism of GCN-2-mediated translational suppression, was not necessary for HP. These data suggest a model where hypoxia-induced misfolded proteins trigger the activation of IRE-1, which along with GCN-2 controls an adaptive response that is essential to HP.


Scanning tunneling spectroscopic evidence for granular metallic conductivity in conducting polymeric polyaniline.
Scanning tunneling microscopy (STM) and point-probe electrical conductivity measurements of electrochemically protonated films of the emeraldine-base form of the conducting polymer, polyaniline are reported. The conductivity varies spatially, dependent on the size (L(M) \m=~\ 200 to 300 angstroms) of granular metallic regions which relate directly to the inhomogeneous micromorphology of the electrodeposited films. The normalized conductivity at zero bias is observed to increase with doping, indicating an increase in states at the Fermi level. The STM electronic measurements also show regions of negative differential resistance. Negative differential resistance is observed for all samples, although more frequently on less oxidized samples.


Analysis of the conformational behavior and stability of the SAP and TSAP isomers of lanthanide(III) NB-DOTA-type chelates.
Controlling the water exchange kinetics of macrocyclic Gd(3+) chelates, a key parameter in the design of improved magnetic resonance imaging (MRI) contrast media, may be facilitated by selecting the coordination geometry of the chelate. The water exchange kinetics of the mono- capped twisted square antiprism (TSAP) being much closer to optimal than those of the mono capped square antiprism (SAP) render the TSAP isomer more desirable for high relaxivity applications. Two systems have been developed that allow for selection of the TSAP coordination geometry in 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-type Gd(3+) chelates, both based upon the macrocycle nitrobenzyl cyclen. In this paper we report investigations into the stability and formation of these chelates. Particular focus is given to the production of two regioisomeric chelates during the chelation reaction. These regioisomers are distinguished by having the nitrobenzyl substituent either on a corner or on the side of the macrocyclic ring. The origin of these two regioisomers appears to stem from a conformation of the ligand in solution in which it is hypothesized that pendant arms lie both above and below the plane of the macrocycle. The conformational changes that then result during the formation of the intermediate H(2)GdL(+) chelate give rise to differing positions of the nitrobenzyl substituent depending upon from which face of the macrocycle the Ln(3+) approaches the ligand.


Nurses' knowledge, attitudes and practices related to physical restraint: a cross-sectional study.
To investigate nurses' knowledge, attitudes and practices related to physical restraint in tertiary hospitals and identify the factors that influence physical restraint use. Physical restraint is used to maintain patient safety. Nurses play an important role in the restraint process. It is important to identify their understanding, feelings and approach regarding the use of physical restraint. Physical restraint is widely practiced in hospitals in China. However, it results in a range of serious negative consequences. This article provides a clear description of nurses' knowledge, attitudes and practices related to physical restraint. A cross-sectional survey was conducted. The participants were asked to complete a questionnaire examining their knowledge, attitudes and practices related to physical restraint use. A total of 200 questionnaires were distributed in four tertiary hospitals in Hubei Province, China between August and October 2014. The nurses' responses indicated a good level of knowledge regarding physical restraint use. However, they held some misconceptions. The nurses' attitudes towards physical restraint tended to be neutral. The nurses were well experienced in the use of physical restraint. Nurses who had received on-the-job training performed better than those who had received no training related to knowledge and practices regarding physical restraint use. In-service training is highly recommended for nursing managers to improve nurses' physical restraint related knowledge and practices. Regulations regarding the use of restraints should be established as soon as possible by healthcare administration system. Nurses should be open to evaluate and improve their views and attitudes regarding effective physical restraint use via multidimensional interventions.


Mac-1 (CD11b/CD18) and CD45 mediate the adhesion of hematopoietic progenitor cells to stromal cell elements via recognition of stromal heparan sulfate.
Hematopoiesis is regulated by two sets of signals, those generated by cytokines and those generated when precursor cells interact with bone marrow (BM) stroma. The intimate contact between precursors and stroma appears to be mediated by multiple, different receptor-ligand binding events. To identify receptor-ligand pairs mediating the adhesion of hematopoietic precursor cells to stroma, an in vitro model of hematopoiesis was used. This involved coculturing the BM-derived, interleukin-3 (IL-3)-dependent, multipotential cells, FCDP-mix A4 (A4) with a stromal equivalent embryonic mesenchymal cell line, Swiss 3T3 (3T3). In coculture, A4 cells survive, proliferate, and differentiate in the absence of exogenous IL-3, providing they are attached to the 3T3 cell surface. By using detergent lysates of surface-biotinylated A4 cells, A4 cell molecules that bind to the stroma could be detected by either fluorescein isothiocyanate (FITC)-streptavidin or FITC-antibody staining and flow cytometry. Using this approach the beta 2 integrin, Mac-1, and CD45, a receptor-type tyrosine phosphatase, were identified as molecules on the A4 cell surface that bind 3T3 cells. Various glycosaminoglycans (GAGs), particularly heparin and heparan sulfate, blocked binding of A4 cell surface molecules to the 3T3 cells. The binding of CD45 and Mac-1 to the 3T3 cells was similarly blocked by these GAGs. Removal of heparin-binding molecules from A4 cell lysates diminished binding to the 3T3 cells and digestion of the 3T3 cell surface with heparinase abolished the binding of CD45 and Mac-1. The data suggest that heparan sulfate on the 3T3 cell surface is a ligand for both CD45 and Mac-1, but the two molecules recognize different heparan sulfate structural motifs.


Activation of the 9E3/cCAF chemokine by phorbol esters occurs via multiple signal transduction pathways that converge to MEK1/ERK2 and activate the Elk1 transcription factor.
Using primary fibroblasts in culture, we have investigated the signal transduction mechanisms by which phorbol esters, a class of tumor promoters, activate the 9E3 gene and its chemokine product the chicken chemotactic and angiogenic factor. This gene is highly stimulated by phorbol 12,13-dibutyrate (PDBu) via three pathways: (i) a small contribution through protein kinase C (the commonly recognized pathway for these tumor promoters), (ii) a contribution involving tyrosine kinases, and (iii) a larger contribution via pathways that can be interrupted by dexamethasone. All three of these pathways converge into the mitogen-activated protein kinases, MEK1/ERK2. Using a luciferase reporter system, we show that although both the AP-1 and PDRIIkB (a NFkappaB-like factor in chickens) response elements are capable of activation in these normal cells, regions of the 9E3 promoter containing them are unresponsive to PDBu stimulation. In contrast, we show for the first time that activation by PDBu occurs through a segment of the promoter containing Elk1 response elements; deletion and mutation of these elements abrogates 9E3/chicken chemotactic and angiogenic factor expression. Electrophoretic mobility shift assays and functional studies using PathDetect systems show that stimulation of the cells by phorbol esters leads to activation of the Elk1 transcription factor, which binds to its element in the 9E3 promoter.


Aortoiliac and aortoiliofemoral reconstruction.
In general, aortoiliac and aortoiliofemoral reconstruction when properly selected and properly performed is one of the most gratifying peripheral vascular procedures. The mortality is reasonably low in spite of the fact that the patients operated upon have generalized arteriosclerosis, including coronary artery diseases. The precise procedure selected depends upon many factors having to do with the patient's general condition, body habitus, and artery condition. Although thromboendarterectomy always will have a place, it has been superseded largely by bypass grafts because grafting is an easier operation. As yet, however, bypass grafts have not been shown to have a clear-cut superiority in long-term patency.


Use of uterine artery Doppler ultrasonography to predict pre-eclampsia and intrauterine growth restriction: a systematic review and bivariable meta-analysis.
Alterations in waveforms in the uterine artery are associated with the development of pre-eclampsia and intrauterine growth restriction. We investigated the predictive accuracy of all uterine artery Doppler indices for both conditions in the first and second trimesters. We identified relevant studies through searches of MEDLINE, EMBASE, the Cochrane Library and Medion databases (all records to April 2006) and by checking bibliographies of identified studies and consulting with experts. Four of us independently selected studies, extracted data and assessed study validity. We performed a bivariable meta-analysis of sensitivity and specificity and calculated likelihood ratios. We identified 74 studies of pre-eclampsia (total 79,547 patients) and 61 studies of intrauterine growth restriction (total 41 131 patients). Uterine artery Doppler ultrasonography provided a more accurate prediction when performed in the second trimester than in the first-trimester. Most Doppler indices had poor predictive characteristics, but this varied with patient risk and outcome severity. An increased pulsatility index with notching was the best predictor of pre-eclampsia (positive likelihood ratio 21.0 among high-risk patients and 7.5 among low-risk patients). It was also the best predictor of overall (positive likelihood ratio 9.1) and severe (positive likelihood ratio 14.6) intrauterine growth restriction among low-risk patients. Abnormal uterine artery waveforms are a better predictor of pre-eclampsia than of intrauterine growth restriction. A pulsatility index, alone or combined with notching, is the most predictive Doppler index. These indices should be used in clinical practice. Future research should also concentrate on combining uterine artery Doppler ultrasonography with other tests.


Class-A penicillin binding proteins do not contribute to cell shape but repair cell-wall defects.
Cell shape and cell-envelope integrity of bacteria are determined by the peptidoglycan cell wall. In rod-shaped Escherichia coli, two conserved sets of machinery are essential for cell-wall insertion in the cylindrical part of the cell: the Rod complex and the class-A penicillin-binding proteins (aPBPs). While the Rod complex governs rod-like cell shape, aPBP function is less well understood. aPBPs were previously hypothesized to either work in concert with the Rod complex or to independently repair cell-wall defects. First, we demonstrate through modulation of enzyme levels that aPBPs do not contribute to rod-like cell shape but are required for mechanical stability, supporting their independent activity. By combining measurements of cell-wall stiffness, cell-wall insertion, and PBP1b motion at the single-molecule level, we then present evidence that PBP1b, the major aPBP, contributes to cell-wall integrity by repairing cell wall defects.