On the assessment of photostability of sunscreens exposed to UVA irradiation: from glass plates to pig/human skin, which is best?
Photostability of suncare products is a great area of interest since several sunscreens on the market are photounstable, and this is primarily a problem concerning the UVA region (320-400 nm). Here we report a comparative study on the photostability assessment of two commercial sunscreens with same SPF, spread onto glass plates or onto full thickness pig ear skin or human/pig SCE membranes, and exposed to 183 kJ/m(2) UVA. Absorbance spectra and lipid peroxidation (measured by TBARS production) were determined. The results indicate: (a) sunscreen performance consequent to UVA exposure is independent of whether it is spread onto a non-biological and chemically inert substrate such as glass, or on biological substrates such as skin/SCE membranes; (b) despite the same SPF, sunscreen performance and photostability can be very different; (c) the data on human SCE membranes are similar to those on pig SCE membranes, indicating the suitability of the latter as a model for human skin. However, since the results obtained using skin membranes, akin to the more realistic conditions of use in vivo, do not substantially differ from those obtained on glass plates, the method proposed here using the latter may be applied for rapid, inexpensive, efficacy screening of photostability of sunscreens. Photostability testing should be a mandatory requirement for safer sunscreen protection products, since the results clearly show that some are still far from perfect.


Evidence-Based Nonpharmacologic Strategies for Comprehensive Pain Care: The Consortium Pain Task Force White Paper.
Medical pain management is in crisis; from the pervasiveness of pain to inadequate pain treatment, from the escalation of prescription opioids to an epidemic in addiction, diversion and overdose deaths. The rising costs of pain care and managing adverse effects of that care have prompted action from state and federal agencies including the DOD, VHA, NIH, FDA and CDC. There is pressure for pain medicine to shift away from reliance on opioids, ineffective procedures and surgeries toward comprehensive pain management that includes evidence-based nonpharmacologic options. This White Paper details the historical context and magnitude of the current pain problem including individual, social and economic impacts as well as the challenges of pain management for patients and a healthcare workforce engaging prevalent strategies not entirely based in current evidence. Detailed here is the evidence-base for nonpharmacologic therapies effective in postsurgical pain with opioid sparing, acute non-surgical pain, cancer pain and chronic pain. Therapies reviewed include acupuncture therapy, massage therapy, osteopathic and chiropractic manipulation, meditative movement therapies Tai chi and yoga, mind body behavioral interventions, dietary components and self-care/self-efficacy strategies. Transforming the system of pain care to a responsive comprehensive model necessitates that options for treatment and collaborative care must be evidence-based and include effective nonpharmacologic strategies that have the advantage of reduced risks of adverse events and addiction liability. The evidence demands a call to action to increase awareness of effective nonpharmacologic treatments for pain, to train healthcare practitioners and administrators in the evidence base of effective nonpharmacologic practice, to advocate for policy initiatives that remedy system and reimbursement barriers to evidence-informed comprehensive pain care, and to promote ongoing research and dissemination of the role of effective nonpharmacologic treatments in pain, focused on the short- and long-term therapeutic and economic impact of comprehensive care practices.


Identification and translational validation of novel mammaglobin-A CD8 T cell epitopes.
Mammaglobin-A (MAM-A) is a secretory protein that is overexpressed in 80 % of human breast cancers. Its near-universal expression in breast cancer as well as its exquisite tissue specificity makes it an attractive target for a breast cancer prevention vaccine, and we recently initiated a phase 1 clinical trial of a MAM-A DNA vaccine. Previously, we have identified multiple MAM-A CD8 T cell epitopes using a reverse immunology candidate epitope approach based on predicted binding, but to date no attempt has been made to identify epitopes using an unbiased approach. In this study, we used human T cells primed in vitro with autologous dendritic cells expressing MAM-A to systematically identify MAM-A CD8 T cell epitopes. Using this unbiased approach, we identified three novel HLA-A2-restricted MAM-A epitopes. CD8 T cells specific for these epitopes are able to recognize and lyse human breast cancer cells in a MAM-A-specific, HLA-A2-dependent fashion. HLA-A2(+)/MAM-A(+) breast cancer patients have an increased prevalence of CD8 T cells specific for these novel MAM-A epitopes, and vaccination with a MAM-A DNA vaccine significantly increases the number of these CD8 T cells. The identification and translational validation of novel MAM-A epitopes has important implications for the ongoing clinical development of vaccine strategies targeting MAM-A. The novel MAM-A epitopes represent attractive targets for epitope-based vaccination strategies, and can also be used to monitor immune responses. Taken together these studies provide additional support for MAM-A as an important therapeutic target for the prevention and treatment of breast cancer.


Contemporary rates and correlates of statin use and adherence in nondiabetic adults with cardiovascular risk factors: The KP CHAMP study.
Statin therapy is highly efficacious in the prevention of fatal and nonfatal atherosclerotic events in persons at increased cardiovascular risk. However, its long-term effectiveness in practice depends on a high level of medication adherence by patients. We identified nondiabetic adults with cardiovascular risk factors between 2008 and 2010 within a large integrated health care delivery system in Northern California. Through 2013, we examined the use and adherence of newly initiated statin therapy based on data from dispensed prescriptions from outpatient pharmacy databases. Among 209,704 eligible adults, 68,085 (32.5%) initiated statin therapy during the follow-up period, with 90.4% receiving low-potency statins. At 12 and 24 months after initiating statins, 84.3% and 80.2%, respectively, were actively receiving statin therapy, but only 42% and 30%, respectively, had no gaps in treatment during those time periods. There was also minimal switching between statins or use of other lipid-lowering therapies for augmentation during follow-up. Age≥50 years, Asian/Pacific Islander race, Hispanic ethnicity, prior myocardial infarction, prior ischemic stroke, hypertension, and baseline low-density lipoprotein cholesterol>100 mg/dL were associated with higher adjusted odds, whereas female gender, black race, current smoking, dementia were associated with lower adjusted odds, of active statin treatment at 12 months after initiation. There remain opportunities for improving prevention in patients at risk for cardiovascular events. Our study identified certain patient subgroups that may benefit from interventions to enhance medication adherence, particularly by minimizing treatment gaps and discontinuation of statin therapy within the first year of treatment.


Natural histories of chronic obstructive pulmonary disease.
Concepts relating to the natural history of chronic obstructive pulmonary disease (COPD) arise most importantly from the classic study of Fletcher and colleagues (The Natural History of Chronic Bronchitis and Emphysema, Oxford University Press, New York, 1976). This study, which evaluated working English men over 8 years, was used to construct a proposed life-long natural history. Although this is a classic study that has greatly advanced understanding of COPD, it has a number of limitations. Its duration is relatively short compared with the duration of COPD, so it is more cross-sectional than longitudinal. It was unable to distinguish among varied "natural histories." It assessed primarily the FEV(1), and the natural history of other features of COPD is largely undescribed. With advances in understanding the clinical features of COPD and with the development of evaluating new tools to assess patients with COPD, longitudinal studies evaluating COPD in novel ways and for longer durations are needed.


Natural antibodies in sera from Japanese individuals infected with HTLV-I do not recognize HTLV-III.
Seventy-one sera from Japanese individuals infected with human T cell leukemia virus type I (HTLV-I) were examined for the presence of antibodies to HTLV-III by an enzyme-linked immunosorbent assay (ELISA) and by a strip radioimmunoassay based on the Western blot technique. The sera were from 23 healthy carriers and from 48 patients, including 18 with smoldering adult T cell leukemia (ATL), 13 with chronic ATL, and 17 with acute ATL. All people tested lived in the southwestern part of Japan, a known endemic area for HTLV-I infection. Antibodies against HTLV-I were detected in all sera both by indirect immunofluorescent methods and strip radioimmunoassay using cell lysates. Six sera were reactive in the ELISA assay for HTLV-III. But these sera did not react specifically to HTLV-III-related proteins (p15, p24, gp41) when analyzed by strip radioimmunoassay. Our data suggest that coincidental infection of HTLV-I and HTLV-III is quite rare in Japan.


Network Analysis Prioritizes DEWAX and ICE1 as the Candidate Genes for Major eQTL Hotspots in Seed Germination of Arabidopsis thaliana.
Seed germination is characterized by a constant change of gene expression across different time points. These changes are related to specific processes, which eventually determine the onset of seed germination. To get a better understanding on the regulation of gene expression during seed germination, we performed a quantitative trait locus mapping of gene expression (eQTL) at four important seed germination stages (primary dormant, after-ripened, six-hour after imbibition, and radicle protrusion stage) using Arabidopsis thaliana Bay x Sha recombinant inbred lines (RILs). The mapping displayed the distinctness of the eQTL landscape for each stage. We found several eQTL hotspots across stages associated with the regulation of expression of a large number of genes. Interestingly, an eQTL hotspot on chromosome five collocates with hotspots for phenotypic and metabolic QTL in the same population. Finally, we constructed a gene co-expression network to prioritize the regulatory genes for two major eQTL hotspots. The network analysis prioritizes transcription factors DEWAX and ICE1 as the most likely regulatory genes for the hotspot. Together, we have revealed that the genetic regulation of gene expression is dynamic along the course of seed germination.


[Evaluation of the immune system in Down's syndrome patients].
The authors carry out a study to evaluate the immunoglobulin and complement factor levels and the populations and subpopulations of mononuclear cells enumerated by monoclonal antibodies, in Down's syndrome (DS) patients. The IgG, IgA and IgM immunoglobulins were significantly increased, and presented an age-dependence. The complement factors, C3 and C4 were normal. We enumerated T lymphocyte subsets in these patients using OKT3, OKT4, OKT6, OKT8, OKIa1 and OKM1 monoclonal antibodies. The percentages of total T cells (T3 + cells) and of helper T lymphocytes (T4 + cells), were significantly decreased (DS: 49 +/- 11%; p less than 0,05) (DS: 20 +/- 7%; p less than 0,001); nevertheless in the subpopulations of suppressor/cytotoxic T lymphocytes, we found an increase (T8 + cells) (DS: 34 +/- 12%; p less than 0,01). In the remainder of the populations studied, B lymphocytes, monocytes, null-cells and common thymocytes no apparent alterations were detected. The study has shown an imbalance between populations of helper induced and cytotoxic /suppressor T lymphocytes in these patients. It appears that the unbalances in population and subpopulation studies could be due to an alteration of the Thymus. This is suggested by the increased susceptibility to polytopic infections, high risk of malignancies and high frequency of autoantibodies.


Development of a clinical tool for rating the body function categories of the ICF generic-30/rehabilitation set in Japanese rehabilitation practice and examination of its interrater reliability.
The International Classification of Functioning, Disability, and Health (ICF) Generic-30 (Rehabilitation) Set is a tool used to assess the functioning of a clinical population in rehabilitation. The ICF Generic-30 consists of nine ICF categories from the component "body functions" and 21 from the component "activities and participation". This study aimed to develop a rating reference guide for the nine body function categories of the ICF Generic-30 Set using a predefined, structured process and to examine the interrater reliability of the ratings using the rating reference guide. The development of the first version of the rating reference guide involved the following steps: (1) a trial of rating patients by several raters; (2) cognitive interviews with each rater to analyze the thought process involved in each rating; (3) the drafting of the rating reference guide by a multidisciplinary panel; and (4) a review by ICF specialists to confirm consistency with the ICF. Subsequently, we conducted a first field test to gain insight into the use of the guide in practice. The reference guide was modified based on the raters' feedback in the field test, and an inter-rater reliability test was conducted thereafter. Interrater agreement was evaluated using weighted kappa statistics with linear weights. The first version of the rating reference guide was successfully developed and tested. The weighted kappa coefficient in the field testing ranged from 0.25 to 0.92. The interrater reliability testing of the rating reference guide modified based on the field test results yielded an improved weighted kappa coefficient ranging from 0.53 to 0.78. Relative improvements in the weighted kappa coefficients were observed in seven out of the nine categories. Consequently, seven out of nine categories were found to have a weighted kappa coefficient of 0.61 or higher. In this study, we developed and modified a rating reference guide for the body function categories of the ICF Generic-30 Set. The interrater reliability test using the final version of the rating reference guide showed moderate to substantial interrater agreement, which encouraged the use of the ICF in rehabilitation practice.


Modeling leaf CO2 assimilation and Photosystem II photochemistry from chlorophyll fluorescence and the photochemical reflectance index.
We present a simple model to assess the quantum yield of photochemistry (ΦP ) and CO2 assimilation rate from two parameters that are detectable by remote sensing: chlorophyll (chl) fluorescence and the photochemical reflectance index (PRI). ΦP is expressed as a simple function of the chl fluorescence yield (ΦF ) and nonphotochemical quenching (NPQ): ΦP = 1-bΦF (1 + NPQ). Because NPQ is known to be related with PRI, ΦP can be remotely assessed from solar-induced fluorescence and the PRI. The CO2 assimilation rate can be assessed from the estimated ΦP value with either the maximum carboxylation rate (Vcmax ), the intercellular CO2 concentration (Ci ), or parameters of the stomatal conductance model. The model was applied to experimental data obtained for Chenopodium album leaves under various environmental conditions and was able to successfully predict ΦF values and the CO2 assimilation rate. The present model will improve the accuracy of assessments of gas exchange rates and primary productivity by remote sensing.


Genetic Determinants of 25-Hydroxyvitamin D Concentrations and Their Relevance to Public Health.
Twin studies suggest a considerable genetic contribution to the variability in 25-hydroxyvitamin D (25(OH)D) concentrations, reporting heritability estimates up to 80% in some studies. While genome-wide association studies (GWAS) suggest notably lower rates (13−16%), they have identified many independent variants that associate with serum 25(OH)D concentrations. These discoveries have provided some novel insight into the metabolic pathway, and in this review we outline findings from GWAS studies to date with a particular focus on 35 variants which have provided replicating evidence for an association with 25(OH)D across independent large-scale analyses. Some of the 25(OH)D associating variants are linked directly to the vitamin D metabolic pathway, while others may reflect differences in storage capacity, lipid metabolism, and pathways reflecting skin properties. By constructing a genetic score including these 25(OH)D associated variants we show that genetic differences in 25(OH)D concentrations persist across the seasons, and the odds of having low concentrations (<50 nmol/L) are about halved for individuals in the highest 20% of vitamin D genetic score compared to the lowest quintile, an impact which may have notable influences on retaining adequate levels. We also discuss recent studies on personalized approaches to vitamin D supplementation and show how Mendelian randomization studies can help inform public health strategies to reduce adverse health impacts of vitamin D deficiency.


Morphine Re-arranges Chromatin Spatial Architecture of Primate Cortical Neurons.
The expression of linear DNA sequence is precisely regulated by the three-dimensional (3D) architecture of chromatin. Morphine-induced aberrant gene networks of neurons have been extensively investigated; however, how morphine impacts the 3D genomic architecture of neurons is still unknown. Here, we applied digestion-ligation-only high-throughput chromosome conformation capture (DLO Hi-C) technology to investigate the effects of morphine on the 3D chromatin architecture of primate cortical neurons. After receiving continuous morphine administration for 90 days on rhesus monkeys, we discovered that morphine re-arranged chromosome territories, with a total of 391 segmented compartments being switched. Morphine altered over half of the detected topologically associated domains (TADs), most of which exhibited a variety of shifts, followed by separating and fusing types. Analysis of the looping events at kilobase-scale resolution revealed that morphine increased not only the number but also the length of differential loops. Moreover, all identified differentially expressed genes from the RNA sequencing data were mapped to the specific TAD boundaries or differential loops, and were further validated to be changed. Collectively, an altered 3D genomic architecture of cortical neurons may regulate the gene networks associated with morphine effects. Our finding provides critical hubs connecting chromosome spatial organization and gene networks associated with the morphine effects in humans.


Added value of ultrasound re-evaluation for patients with equivocal CT findings of acute appendicitis: a preliminary study.
To prospectively estimate the additional diagnostic value of ultrasound (US) re-evaluation for patients with equivocal computed tomography (CT) findings of acute appendicitis. Between April 2011 and October 2011, 869 consecutive patients with suspected appendicitis who were referred for CT were included. The likelihood of appendicitis was prospectively categorized into five categories. US re-evaluation was recommended for patients in the 'equivocal appendix' and 'probably not appendicitis' groups. The overall negative appendectomy rate during the study period was compared with the rate of the previous year, and negative appendectomy rates of the US and non-US evaluation groups were also compared. Among 869 patients, 71 (8.2 %) had equivocal appendicitis findings and 63 (7.2 %) were diagnosed as probably not appendicitis. The sensitivity and specificity of CT combined with US re-evaluation group (100 % and 98.1 %, respectively) exceeded those of the CT alone group (93 % and 99 %; equivocal group considered as negative appendicitis, 100 % and 89.9 %; as positive, respectively, P < 0.0001). After adding US re-evaluation, the overall negative appendectomy rate in our institution decreased from 3.4 to 2.3 %. For patients with equivocal CT findings of acute appendicitis, US re-evaluation can improve diagnostic accuracy and decrease the rate of negative appendectomies. • Misdiagnosis of appendicitis still occurs, especially in patients with equivocal radiological findings. • The sensitivity and specificity of CT followed by US exceeded those of CT alone. • After US re-evaluation, the negative appendectomy rate decreased from 3.4 to 2.3 %. • US re-evaluation in equivocal cases helps diagnostic confidence and further management.


Effects of a Supplement Containing a Cranberry Extract on Recurrent Urinary Tract Infections and Intestinal Microbiota: A Prospective, Uncontrolled Exploratory Study.
Aim: Cranberries (Vaccinium macrocarpon) are traditionally used in prevention of urinary tract infections (UTIs). The authors' aim was to evaluate effects of a supplement containing cranberry extract, pumpkin seed extract, vitamin C, and vitamin B2 on recurrent uncomplicated UTIs in women and their intestinal microbiota. Methods: A prospective, uncontrolled exploratory study was conducted in women with recurrent uncomplicated UTIs. The primary exploratory outcome was the number of UTIs in a 6-month prospective observation period compared with a 6-month retrospective period. Further outcomes included number of antibiotics, quality of life (SF-36), intestinal microbiota (assessed by 16S rRNA amplicon sequencing), and evaluation questions. Parameters were assessed at baseline and after 1, 2, and 7 months (start of intake of cranberry supplement after 1 month for 6 months). p-Values were calculated with the pairwise Wilcoxon signed-rank test for α diversity and permutational multivariate analysis of variance. Results: Twenty-three women (aged 52.7 ± 12.4 years) were included in the study. Participants reported 2.2 ± 0.8 UTIs (at baseline) in the previous 6 months. After 6 months of cranberry intake, participants reported a significant decrease to 0.5 ± 0.9 UTIs (p < 0.001). Number of antibiotic therapies was also significantly (p < 0.001) reduced by 68% during 6 months of cranberry intake (0.14 ± 0.35) when compared with 6 months retrospectively (1.14 ± 0.71). The SF-36 physical component score increased from 44.9 ± 5.5 at baseline to 45.7 ± 4.6 at 7 months (p = 0.16). The SF-36 mental component score decreased slightly from the baseline value of 46.5 ± 6.5 to 46.2 ± 6.4 at 7 months (p = 0.74). No significant intragroup mean changes at genus, family, or species level for α and β diversity within the intestinal microbiota were found. In the evaluation questions, participants rated the cranberry extract positively and considered it beneficial. The supplement intake was safe. Conclusions: This study shows that women with recurrent uncomplicated UTIs benefit from cranberry intake. Future larger clinical studies with further investigation of the mechanisms of action are required to determine the effects of cranberries on participants with uncomplicated UTIs.


Economic burden, work, and school productivity in individuals with tuberous sclerosis and their families.
Tuberous sclerosis complex (TSC) is a multi-organ autosomal-dominant, genetic disorder with incomplete penetrance. The multiple manifestations of TSC and impacts to numerous organ systems represent significant disease, healthcare, and treatment burden. The economic and employment burden of the disease on individuals and their families is poorly understood. This study assessed the cost of illness and work and school productivity burden associated with TSC in a cross-sectional web-survey sample. Eligible TSC individuals and caregivers were invited through the Tuberous Sclerosis Alliance advocacy group to complete a web-based survey about illness characteristics, treatment, disease burden, direct and indirect healthcare costs, work and school impairment. Data from 609 TSC adults or caregiver respondents with no cognitive impairments were analyzed. TSC adults (>18 years of age) had significantly higher direct out-of-pocket costs for ER visits, expenses for medical tests and procedures, alternative treatments, medications and lifetime cost of surgeries compared to TSC pediatric individuals. Both TSC adults and TSC caregivers reported work and school absenteeism and presenteeism; however, adults reported significantly higher absenteeism and presenteeism and overall activity impairment due to TSC, as might be expected, compared to TSC caregivers. TSC adults had significantly higher absenteeism and presenteeism rates compared to adults with moderate-to-severe plaque psoriasis and muscular sclerosis. TSC results in considerable direct out-of-pocket medical costs and impairment to work productivity, especially for adults. Future studies should include the comparator group and examine direct cost burden in the US using electronic medical records and insurance databases.


High frequency of nonadherence to Clostridium difficile treatment guidelines.
The 2010 Infectious Diseases Society of America/Society for Healthcare Epidemiology of America treatment guidelines for Clostridium difficile infections (CDI) recommend oral metronidazole for mild-to-moderate disease and oral vancomycin for severe disease. Given that disease severity is easily determined by the peripheral white blood cell count and serum creatinine level, a computerized decision support (CDS) pathway to guide treatment is inherently appealing. Because providers often override or ignore the computer-based alerts, the proposed CDS pathway should be justified before implementation. We undertook this study to ascertain the frequency of nonadherence to CDI guidelines. Between October 1, 2007 and September 30, 2008, a total of 229 cases were screened and 78 cases were included in the study, which took place at a 661-bed acute tertiary care teaching hospital. During the year-long study of CDI cases at our tertiary care hospital, 61.5% (48/78) of the patients received an antibiotic regimen that was not recommended by the 2010 guidelines. Among the 35 patients with mild-to-moderate CDI, 85.7% (30/35) received the recommended treatment of oral metronidazole monotherapy; in contrast, among the 43 patients with severe disease, none (0/43) received the recommended treatment of oral vancomycin monotherapy (P < 0.01). Moreover, 17.9% (14/78) of patients received concurrent oral metronidazole and vancomycin, a regimen that is not recommended anywhere in the Infectious Diseases Society of America/Society for Healthcare Epidemiology of America guidelines and which may be associated with a poor outcome. Patients who received combination oral metronidazole and vancomycin were not more likely to have comorbidities or severe CDI compared with those who received a single antibiotic agent. As a result of this study, we plan to educate our providers on the treatment of CDI through a CDS pathway in an effort to increase guideline adherence, decrease inappropriate antibiotic use, and potentially improve patient outcomes.


Changing behavioural pattern of drug users in Hong Kong 1991-1995.
To analyse the temporal changes in demography and drug-taking behaviours of a cohort of drug users in Hong Kong. An analysis of records of clients over a 5-year period. Shek Kwu Chau Treatment and Rehabilitation Centre, a large residential service offering voluntary rehabilitation programmes for male drug users in Hong Kong. The following parameters were analysed for all admissions between 1991 and 1995: duration of drug-taking, route(s) of drug administration, type of drugs abused, practice of injection and needle-sharing, time since last needle-sharing, and expenditure on drugs. A total of 10,353 admissions were recorded in the 5-year period from 1991 to 1995, of whom 2853 (27.6%) were new admissions. The mean age was 36 years. There was a significant increase in new admission in those between the age of 13 and 19. Almost all clients were heroin users. The needle-sharing rates fell from over 20% in 1991 to < 5% in 1995. Needle-sharing was more common in younger clients. The decline in the rate of needle-sharing was especially significant in those between the age of 20 and 39. The proportion of young drug users in the study population in Hong Kong has risen over the 5-year period. The prevalence of high-risk drug-taking behaviours had declined, which might have contributed to the low HIV rates in the community.


Low cost 3D microfluidic chips for multiplex protein detection based on photonic crystal beads.
Point-of-care testing (POCT) devices used in multiplex bioassays are in great demand for clinical, environmental and biomedical applications. Photonic crystal beads (PCBs), as structural color self-coding carriers, can be integrated with microfluidic chips to realize convenient and highly sensitive biomarker detection. Here we developed a three dimensional (3D) microfluidic chip based on PCBs, which is low cost and easy to manufacture for mass production and application. The chip was fabricated with polyethylene terephthalate, polymethyl methacrylate sheets, a Ni square mesh grid and transparent double-sided tape. In practice, the target molecules could be captured by PCBs immobilized with probes in a flow-through manner. It was found that the as-proposed chip needed less washing and its background was effectively reduced in comparison with a flow-over chip. Besides, the limit of detection (LOD) of anti-human alpha fetoprotein (AFP) was calculated to be 18.92 ng mL-1, which could meet the need of clinical detection of AFP. Furthermore, the chip demonstrated the feasibility of simultaneous detection of human immunoglobulin G, carcinoembryonic antigen and AFP, which suggests that it has a broad application prospect in multiplex bioassays.


Intensive Triangulation of Qualitative Research and Quantitative Data to Improve Recruitment to Randomized Trials: The QuinteT Approach.
Randomized controlled trials (RCTs) can provide high quality evidence about the comparative effectiveness of health care interventions, but many RCTs struggle with or fail to complete recruitment. RCTs are built on the principles of the experimental method, but their planning, conduct, and interpretation can depend on complex social, behavioral, and cultural factors that may be best understood through qualitative research. Most qualitative studies undertaken alongside RCTs involve interviews that produce data that are used in a supportive or supplicatory role, but there is potential for qualitative research to be more influential. In this article, we describe the research methods underpinning the "QuinteT" (Qualitative Research Integrated Within Trials) approach to understand and address RCT recruitment difficulties. The QuinteT Recruitment Intervention (QRI) brings together multiple qualitative strategies and quantitative data and uses triangulation to understand recruitment issues rapidly. These nuanced understandings are used to inform the implementation of collaborative actions to improve recruitment.


Safety and effectiveness of adalimumab in Japanese rheumatoid arthritis patients: postmarketing surveillance report of the first 3,000 patients.
This interim analysis of postmarketing surveillance data for adalimumab-treated rheumatoid arthritis (RA) patients summarizes safety and effectiveness during the first 24 weeks of therapy for the first 3,000 patients treated in Japan (June 2008-December 2009). Patient eligibility for antitumor necrosis factor therapy was based on the Japanese College of Rheumatology treatment guidelines and Japanese labeling. All patients were screened for tuberculosis. Approximately 50% of the population was biologic naïve, 66% received concomitant methotrexate (MTX), and 72% received concomitant glucocorticoids. The overall incidence rate of adverse events was 31% (5.5% serious) and that of adverse drug reactions (ADRs) was 27% (4.1% serious). Incidence rates of ADRs and serious ADRs were similar regardless of prior biologic therapy or concomitant MTX use but were significantly higher in patients receiving glucocorticoids compared with those not receiving glucocorticoids. Bacterial/bronchial pneumonia occurred in 1.2% of patients; interstitial pneumonia, 0.6%; Pneumocystis jirovecii pneumonia, 0.3%; tuberculosis, 0.13%; and administration-site reactions, 6.1%. Mean 28-joint Disease Activity Scores decreased significantly after 24 weeks from 5.29 to 3.91. All subgroups showed significant improvement, particularly the biologic-naïve patients receiving concomitant MTX. No new safety concerns were identified. ADR Incidence rates were similar to those of other biologic agents approved for RA.


Phylogenomic analyses confirm a novel invasive North American Corbicula (Bivalvia: Cyrenidae) lineage.
The genus Corbicula consists of estuarine or freshwater clams native to temperate/tropical regions of Asia, Africa, and Australia that collectively encompass both sexual species and clonal (androgenetic) lineages. The latter have become globally invasive in freshwater systems and they represent some of the most successful aquatic invasive lineages. Previous studies have documented four invasive clonal lineages, Forms A, B, C, and Rlc, with varying known distributions. Form A (R in Europe) occurs globally, Form B is found solely in North America, mainly the western United States, Form C (S in Europe) occurs both in European watersheds and in South America, and Rlc is known from Europe. A putative fifth invasive morph, Form D, was recently described in the New World from the Illinois River (Great Lakes watershed), where it occurs in sympatry with Forms A and B. An initial study showed Form D to be conchologically distinct: possessing rust-colored rays and white nacre with purple teeth. However, its genetic distinctiveness using standard molecular markers (mitochondrial cytochrome c oxidase subunit I and nuclear ribosomal 28S RNA) was ambiguous. To resolve this issue, we performed a phylogenomic analysis using 1,699-30,027 nuclear genomic loci collected via the next generation double digested restriction-site associated DNA sequencing method. Our results confirmed Form D to be a distinct invasive New World lineage with a population genomic profile consistent with clonality. A majority (7/9) of the phylogenomic analyses recovered the four New World invasive Corbicula lineages (Forms A, B, C, and D) as members of a clonal clade, sister to the non-clonal Lake Biwa (Japan) endemic, Corbicula sandai. The age of the clonal clade was estimated at 1.49 million years (my; ± 0.401-2.955 my) whereas the estimated ages of the four invasive lineage crown clades ranged from 0.27 to 0.44 my. We recovered very little evidence of nuclear genomic admixture among the four invasive lineages in our study populations. In contrast, 2/6 C. sandai individuals displayed partial nuclear genomic Structure assignments with multiple invasive clonal lineages. These results provide new insights into the origin and maintenance of clonality in this complex system.


Tolfenamic acid in combination with caffeine: absorption during acute migraine.
Tolfenamic acid is an anti-inflammatory analgesic which is used in the treatment of migraine attacks. Because caffeine is used in certain analgesic combinations, its effects on the absorption of tolfenamic acid was studied in a crossover study in migraine patients. Caffeine did not significantly change the absorption of tolfenamic acid during migraine attacks. The extent of absorption following oral administration of tolfenamic acid is decreased during migraine attacks, irrespectively if the volunteers received caffeine or placebo in combination with the drug. The reasons are discussed. It seems obvious that the migraine itself is responsible for the lack of absorption that cannot be counteracted with caffeine. Pain relief within a five-hour testing period was not influenced by concomitant administration of caffeine. It is concluded that tolfenamic acid alone is sufficient in treating migraines.


Accuracy and comparison of two rapid multiplex PCR tests for gastroenteritis pathogens: a systematic review and meta-analysis.
The primary aim is to provide a summary of evidence for the diagnostic accuracies of multiplex PCR gastrointestinal (GI) panels-BioFire FilmArray and Luminex xTAG on the detection of gastroenteritis pathogens. The secondary aim is to compare the performance of these GI panels head to head. A comprehensive search up to 1 December 2019 was conducted on PubMed, Embase, Ovid Medline and Web of Science for studies that used FilmArray or Luminex xTAG Gastrointestinal Pathogen Panel (GPP) for diagnosis of acute gastroenteritis. A summary of diagnostic accuracies for the 16 pathogens were calculated by comparing the GI panels to the current gold standards (conventional standard microbiology techniques such as culture or PCR for bacteria, PCR or enzyme immunoassay (EIA) for viruses, microscopy or EIA for parasite). Hierarchical summary receiver operating characteristic (HSROC) curve analysis, pretest and post-test probabilities were used for estimating the pathogen detection performance. A total of 11 studies with 7085 stool samples were eligible for analysis. Multiplex PCRs demonstrated high diagnostic accuracy, with specificity ≧0.98 and area under the ROC curve (AUROC) ≧0.97 for all the pathogens except for Yersinia enterocolitica (AUROC 0.91). The FilmArray panel demonstrated a higher sensitivity than xTAG GPP for most of the pathogens with the exception of Rotavirus A (xTAG GPP and FilmArray were both 0.93). This is the first meta-analysis that is a head-to-head comparison examining the performance of the novel multiplex PCR-based tests Luminex xTAG GPP and FilmArray GI panel in detecting each pathogen. Point estimates calculated from eligible studies showed that both GI panels are highly accurate and may provide important diagnostic information for early identification of gastroenteritis. In addition, although FilmArray has higher sensitivity and post-test probability than xTAG GPP for most of the pathogens, how this will translate to a clinical setting remains unclear.


Role of metallothionein in biliary metal excretion.
We have studied the effect of acute induction of metallothionein on the biliary excretion of a bolus of metal in the rat. Female Sprague-Dawley rats were administered zinc chloride (6.5 mg/kg) or dexamethasone (2 mg/kg), ip in saline daily for 3 d; control animals received saline alone. Zinc causes a 17-fold induction in hepatic metallothionein levels, while dexamethasone caused a 5-fold induction. A bolus of metal chloride, either zinc, mercury, or cadmium, 1 mg/kg iv, was administered, and bile and plasma samples were collected and analyzed for metal content. At 3 h the rats were killed, livers excised, and both metallothionein and the metals associated with metallothionein estimated. Cadmium was excreted into the bile in inverse proportion to the hepatic metallothionein content, while metallothionein content did not appear to bear any relationship to biliary excretion of mercury or zinc. Metallothionein from rats pretreated with zinc contained twice as much zinc per molecule of metallothionein as that found in control rats. Cadmium, which exhibits a very high affinity for metallothionein, replaced this zinc found in association with metallothionein. Conversely, mercury only partially replaced the zinc associated with metallothionein, and a bolus of zinc was completely unable to bind to the already zinc-saturated metallothionein. Consequently, the bolus zinc was found associated with alternative cytosolic proteins, here termed the high-molecular-weight fraction. These findings support the hypothesis that the inhibitory effect of metallothionein on the biliary excretion of metals is dependent on the ability of the metal in question to replace any existing metals associated with metallothionein. Biliary metal excretion was directly proportional to the free metal content, regardless of the metal studied. Consequently, acute induction of metallothionein was inhibitory to biliary cadmium excretion, slightly inhibitory to biliary mercury excretion, and without effect on biliary zinc excretion.


[Dynamics of the biochemical makeup of the blood in cosmonauts during flights].
Prolonged space flights (15 to 63 days) led to changes in the biochemical composition of the blood that were observed both during and after flight. Blood samples were withdrawn inflight, stored in a special device onboard and analyzed on return to Earth. The data obtained in real flights were compared with those from the 30-day simulation flight. In real and simulated flights the urea content showed the most significant changes. Inflight it increased to 40 mg% versus 31 mg% preflight. The urea content grew on the 3rd-5th flight day, reaching maximum on the 15-30th day and decreasing again afterwards. The content of glucose and inorganic phosphorus increased slightly whereas that of acid-soluble and lipid phosphorus remained unaltered. The level of cholesterol decreased. The striking similarity between the changes in blood biochemistries during real and simulated flights suggests that they are induced by factors other than weightlessness.


Role of Protein Phosphatase1 Regulatory Subunit3 in Mediating the Abscisic Acid Response.
Protein phosphatase1 (PP1) plays important roles in eukaryotes, including in plant hormone responses, and functions as a holoenzyme that consists of catalytic and regulatory subunits. Animal genomes encode ∼200 PP1-interacting proteins; by contrast, only a few have been reported in plants. In this study, PP1 Regulatory Subunit3 (PP1R3), a protein that interacts with PP1 in Arabidopsis (Arabidopsis thaliana), was characterized by mass spectrometry. PP1R3 was widely expressed in various plant tissues and PP1R3 colocalized with Type One Protein Phosphatases (TOPPs) in the nucleus and cytoplasm. The pp1r3 mutants were hypersensitive to abscisic acid (ABA), similar to the dominant-negative mutant topp4-1 or the loss-of-function multiple mutants topp1 topp4-3, topp8 topp9, topp6/7/9, topp1/2/4-3/6/7/9, and topp1/4-3/5/6/7/8/9 (topp-7m). About two-thirds of differentially expressed genes in topp-7m showed the same gene expression changes as in pp1r3-2 In response to ABA, the phenotypes of pp1r3 topp1 topp4-3 and pp1r3 topp4-1 were consistent with those of pp1r3, while pp1r3 abi1-1 showed an additive effect of the pp1r3 and abi1-1 (mutation in Abscisic Acid Insensitive1 [ABI1]) single mutants. Moreover, pp1r3 could partially recover the ABA response-related phenotype, gene expression, and plant morphology of topp4-1 PP1R3 inhibited TOPP enzyme activity and facilitated the nuclear localization of TOPP4. By contrast, ABA treatment increased the amounts of TOPP1 and TOPP4 in the cytoplasm. Importantly, nuclear localization of TOPP4 partially restored the ABA-hypersensitive phenotype of topp4-1 Overall, our results suggest that the PP1R3:TOPP holoenzyme functions in parallel with ABI1 in the nucleus to regulate ABA signaling.


Photostimulation of Ventral Tegmental Area-Insular Cortex Dopaminergic Inputs Enhances the Salience to Consolidate Aversive Taste Recognition Memory via D1-Like Receptors.
Taste memory involves storing information through plasticity changes in the neural network of taste, including the insular cortex (IC) and ventral tegmental area (VTA), a critical provider of dopamine. Although a VTA-IC dopaminergic pathway has been demonstrated, its role to consolidate taste recognition memory remains poorly understood. We found that photostimulation of dopaminergic neurons in the VTA or VTA-IC dopaminergic terminals of TH-Cre mice improves the salience to consolidate a subthreshold novel taste stimulus regardless of its hedonic value, without altering their taste palatability. Importantly, the inhibition of the D1-like receptor into the IC impairs the salience to facilitate consolidation of an aversive taste recognition memory. Finally, our results showed that VTA photostimulation improves the salience to consolidate a conditioned taste aversion memory through the D1-like receptor into the IC. It is concluded that the dopamine activity from the VTA into IC is required to increase the salience enabling the consolidation of a taste recognition memory. Notably, the D1-like receptor activity into the IC is required to consolidate both innate and learned aversive taste memories but not appetitive taste memory.


Bin1 directly remodels actin dynamics through its BAR domain.
Endocytic processes are facilitated by both curvature-generating BAR-domain proteins and the coordinated polymerization of actin filaments. Under physiological conditions, the N-BAR protein Bin1 has been shown to sense and curve membranes in a variety of cellular processes. Recent studies have identified Bin1 as a risk factor for Alzheimer's disease, although its possible pathological function in neurodegeneration is currently unknown. Here, we report that Bin1 not only shapes membranes, but is also directly involved in actin binding through its BAR domain. We observed a moderate actin bundling activity by human Bin1 and describe its ability to stabilize actin filaments against depolymerization. Moreover, Bin1 is also involved in stabilizing tau-induced actin bundles, which are neuropathological hallmarks of Alzheimer's disease. We also provide evidence for this effect in vivo, where we observed that downregulation of Bin1 in a Drosophila model of tauopathy significantly reduces the appearance of tau-induced actin inclusions. Together, these findings reveal the ability of Bin1 to modify actin dynamics and provide a possible mechanistic connection between Bin1 and tau-induced pathobiological changes of the actin cytoskeleton.


Mouse spinal cord in cell culture. III. Neuronal chemosensitivity and its relationship to synaptic activity.
1. Mouse spinal cord (SC) cells in dissociated cell cultures showed strong electrophysiologic responses to glutamate, gamma-aminobutyric acid (GABA), and glycine when these were iontophoretically applied to the neurons. 2. The extrapolated reversal potential for the glutamate response was 20-30 mV negative in contrast to the positive extrapolated reversal potential for the SC-SC excitatory postsynaptic potential. The data are interpreted as indicating different ionic mechanisms for the glutamate response and the EPSP. 3. The reversal potentials for the glycine and GABA responses were similar to one another and to the IPSP reversal potential. The time course of the glycine and GABA responses were quite different from each other, however. 4. While some SC cells showed a relatively uniform sensitivity over their surfaces to iontophoretically applied glutamate, discrete regions of higher sensitivity occurred on most cells. 5. Release of excitatory and inhibitory transmitter could be elicited by focal application of glutamate and, in favorable instances, this could be shown to be due to the sensitivity of presynaptic terminals to the applied glutamate. Considerable spatial resolution of regions from which transmitter release could be elicited was achieved by this technique. Some correspondence between glutamate "hot spots" and such release sites was found.


An improved molecular dynamics algorithm to study thermodiffusion in binary hydrocarbon mixtures.
In multicomponent liquid mixtures, the diffusion flow of chemical species can be induced by temperature gradients, which leads to a separation of the constituent components. This cross effect between temperature and concentration is known as thermodiffusion or the Ludwig-Soret effect. The performance of boundary driven non-equilibrium molecular dynamics along with the enhanced heat exchange (eHEX) algorithm was studied by assessing the thermodiffusion process in n-pentane/n-decane (nC5-nC10) binary mixtures. The eHEX algorithm consists of an extended version of the HEX algorithm with an improved energy conservation property. In addition to this, the transferable potentials for phase equilibria-united atom force field were employed in all molecular dynamics (MD) simulations to precisely model the molecular interactions in the fluid. The Soret coefficients of the n-pentane/n-decane (nC5-nC10) mixture for three different compositions (at 300.15 K and 0.1 MPa) were calculated and compared with the experimental data and other MD results available in the literature. Results of our newly employed MD algorithm showed great agreement with experimental data and a better accuracy compared to other MD procedures.


Plastid proteome assembly without Toc159: photosynthetic protein import and accumulation of N-acetylated plastid precursor proteins.
Import of nuclear-encoded precursor proteins from the cytosol is an essential step in chloroplast biogenesis that is mediated by protein translocon complexes at the inner and outer envelope membrane (TOC). Toc159 is thought to be the main receptor for photosynthetic proteins, but lacking a large-scale systems approach, this hypothesis has only been tested for a handful of photosynthetic and nonphotosynthetic proteins. To assess Toc159 precursor specificity, we quantitatively analyzed the accumulation of plastid proteins in two mutant lines deficient in this receptor. Parallel genome-wide transcript profiling allowed us to discern the consequences of impaired protein import from systemic transcriptional responses that contribute to the loss of photosynthetic capacity. On this basis, we defined putative Toc159-independent and Toc159-dependent precursor proteins. Many photosynthetic proteins accumulate in Toc159-deficient plastids, and, surprisingly, several distinct metabolic pathways are negatively affected by Toc159 depletion. Lack of Toc159 furthermore affects several proteins that accumulate as unprocessed N-acetylated precursor proteins outside of plastids. Together, our data show an unexpected client protein promiscuity of Toc159 that requires a far more differentiated view of Toc159 receptor function and regulation of plastid protein import, in which cytosolic Met removal followed by N-terminal acetylation of precursors emerges as an additional regulatory step.


Clofibrate hypocholesterolemia associated with increased hepatic copper.
Copper metabolism is important in the etiology of ischemic heart disease according to a new hypothesis. Hypercholesterolemic people may be more likely to be malnourished in copper than normocholesterolemic people. Clofibrate was fed to rats as a component of a diet that produces copper deficiency. Rats fed clofibrate had 20 to 29% (P less than 0.003) lower concentration of cholesterol in blood plasma and higher copper in liver (47 to 78%, P less than 0.025) and plasma (19 to 25%, P less than 0.03). The experiments are a successful test of the hypotheses that clofibrate is active in animals malnourished in copper and that the change in cholesterol metabolism induced by clofibrate may be the result of a change in copper metabolism. Clofibrate is a member of a class of cholesterotropic and cuprotropic chemicals.


Combined neurosurgical-orthopedic approach to the correction of radiculopathy and instability in spondylolysis and spondylolisthesis.
The authors give a brief review of the pathologic anatomy, the incidence and distribution, the probable etiologic factors in the development of spondylolysis and spondylisthesis, and a description of the clinical syndrome of this abnormality. It is pointed out that there are two distinct parts to the clinical syndrome: back pain due to instability of the isthmic defect and/or radiculopathy due to direct compression of the lumbar nerve root in its course immediately beneath the osteocartilaginous deformity which is the primary pathologic feature of this disorder. It is suggested that the variable benefits of the several operative procedures advocated for this disorder are largely related to fortuitous removal of some of the osteocartilaginous deformity and/or stabilization of the isthmic defects. Other writers have advocated fusion as a necessary part of any operative intervention for the treatment of spondylolysis. The authors here agree with this viewpoint and in addition, feel that complete and precise removal of the isthmic deformity is an equally imperative part of such surgery. While the principles of isthmic decompression combined with fusion are not innovative, the operative technique described here is innovative, simple, and precise, and has been followed by a high rate of excellent results.


The effect of energy reserves on social foraging: hungry sparrows scrounge more.
Animals often use alternative strategies when they compete for resources, but it is unclear in most cases what factors determine the actual tactic followed by individuals. Although recent models suggest that the internal state of animals may be particularly important in tactic choice, the effects of state variables on the use of alternative behavioural forms have rarely been demonstrated. In this study, using experimental wind exposure to increase overnight energy expenditure, we show that flock-feeding house sparrows (Passer domesticus) with lowered energy reserves increase their use of scrounging (exploiting others' food findings) during their first feed of the day. This result is in accordance with the prediction of a state-dependent model of use of social foraging tactics. We also show that scrounging provides less variable feeding rates and patch finding times than the alternative tactic. These latter results support the theoretical assumption that scrounging is a risk-averse tactic, i.e. it reduces the risk of immediate starvation. As the level of energy reserves predicts the use of social foraging tactics, we propose that selection should favour individuals that monitor the internal state of flock mates and use this information to adjust their own tactic choice.


"Kids Get in Shape with Nature": A Systematic Review Exploring the Impact of Green Spaces on Childhood Obesity.
Green and blue spaces (GABS) are vital components of sustainable and healthy communities. Evidence suggest that GABS positively affect population health and wellbeing. However, few studies examine GABS influence on childhood obesity. This systematic review investigates the impact of GABS on childhood obesity particularly on children's physical activity and eating behavior. The search protocol identified 544 studies from PubMed, Medline, PsycINFO, CINAHL, and Web of Science. A two-tier screening process document using the PRISMA flow diagram identified 16 studies which underwent quality analysis using the National Heart, Lung, and Blood Institute (NHLBI) and Critical Appraisal Skills Programme (CASP) tools. Data were interpreted using thematic analysis and narrative synthesis. Selected studies show varying sociodemographic characteristics of sampled populations located in urban and rural settings. The influence of GABS on children's physical activity and eating behaviour depends on the type, location, proximity, density, facilities, and activity types that interplay with gender, ethnicity, and parent-child relationship. The review demonstrates the significant effect of GABS on children's physical activity and eating behaviour. GABS provide children with safe venues for socialisation and long, intensive, and enjoyable physical activity; and influence children's perceptions on vegetable consumption supporting healthier eating behaviour. These spaces have the potential to eradicate childhood obesity if policy, social, economic, environmental, and organisational considerations are addressed.


In vitro amplification of pathogenic tau conserves disease-specific bioactive characteristics.
The microtubule-associated protein tau (tau) forms hyperphosphorylated aggregates in the brains of tauopathy patients that can be pathologically and biochemically defined as distinct tau strains. Recent studies show that these tau strains exhibit strain-specific biological activities, also referred to as pathogenicities, in the tau spreading models. Currently, the specific pathogenicity of human-derived tau strains cannot be fully recapitulated by synthetic tau preformed fibrils (pffs), which are generated from recombinant tau protein. Reproducing disease-relevant tau pathology in cell and animal models necessitates the use of human brain-derived tau seeds. However, the availability of human-derived tau is extremely limited. Generation of tau variants that can mimic the pathogenicity of human-derived tau seeds would significantly extend the scale of experimental design within the field of tauopathy research. Previous studies have demonstrated that in vitro seeding reactions can amplify the beta-sheet structure of tau protein from a minute quantity of human-derived tau. However, whether the strain-specific pathogenicities of the original, human-derived tau seeds are conserved in the amplified tau strains has yet to be experimentally validated. Here, we used biochemically enriched brain-derived tau seeds from Alzheimer's disease (AD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) patient brains with a modified seeding protocol to template the recruitment of recombinant 2N4R (T40) tau in vitro. We quantitatively interrogated efficacy of the amplification reactions and the pathogenic fidelity of the amplified material to the original tau seeds using recently developed sporadic tau spreading models. Our data suggest that different tau strains can be faithfully amplified in vitro from tau isolated from different tauopathy brains and that the amplified tau variants retain their strain-dependent pathogenic characteristics.


Small-sided games versus interval training in amateur soccer players: effects on the aerobic capacity and the ability to perform intermittent exercises with changes of direction.
The purpose of this study was to compare the effects of small-sided games (SSGs) in soccer versus high-intensity intermittent training (HIT) on a continuous aerobic test (Vameval) and the performance in an intermittent test with changes of direction (CODs; 30-15 intermittent fitness test [30-15(IFT)]). Twenty-two amateur soccer players (mean age ± SD: 26.3 ± 4.7 years) were assigned to 3 different groups for 6 weeks: SSG group (n = 8), HIT group (n = 8), and control group (CG; n = 6). In addition to the usual technical and tactical sessions and competitive games, the SSG group performed 9 sessions of 2 versus 2 and 1 versus 1 SSGs, whereas the HIT group performed 9 sessions of intermittent runs in the form of 30 seconds of effort interspersed with 30 seconds of passive recovery (30s-30s), 15s-15s, and 10s-10s. The HIT and SSG groups showed performance improvements in the Vameval test (5.1 and 6.6%, respectively) and the 30-15(IFT) intermittent test with CODs (5.1 and 5.8%, respectively), whereas there was no change in the performance of the CG. Players from HIT and SSG groups showed similar increase in their performance in the 30-15(IFT) and the Vameval tests during the 6-week training period, especially with an increase significantly different to that in a traditional training as in the CG (p < 0.05). This investigation demonstrates that both SSG and HIT interventions are equally effective in developing the aerobic capacity and the ability to perform intermittent exercises with CODs in male amateur soccer players. Furthermore, these 2 methods of training applied during the 6 weeks induce similar effect on the recovery capacity and on the ability to repeat directional changes of 180°. Coaches will now be able to choose between these two methods according to the objective of the training and to optimize the training.


A critical review of the literature on the uptake of cervical and breast screening in British South Asian women.
To consider the recent evidence which examines factors that are associated with uptake of cervical and breast screening in the British South Asian community and to consider the effectiveness of interventions to improve uptake in this group. A search strategy was developed and key databases were searched to identify primary research studies that examined the uptake of cervical and breast screening in British women of South Asian origin. Studies published prior to 1996 were excluded from the review. Seventy-eight studies were identified and ten were included in the review. Observational studies demonstrated mixed results on the effect of ethnicity on uptake of screening. Controlling for confounders attenuated the effect in all studies and removed its effect entirely in some. Investigation of low uptake in qualitative and quantitative research indicates that South Asian women were more likely to have incorrect addresses and language or cultural barriers to screening than other women. Few interventional studies were identified and all varied in their design. The success of interventions was mixed and the lack of control groups in some studies made it difficult to draw conclusions on their effectiveness. There is a poor uptake of cervical and breast screening by South Asian women compared with the general population in Britain. Evidence is inconclusive as to whether this is due to a residual effect of ethnicity following control for socio-demographic and local health service variables. Currently there is a lack of robust experimental studies on which to base interventions intended to increase uptake in this population.


Expression and protein kinase C-dependent regulation of peptide/H+ co-transport system in the Caco-2 human colon carcinoma cell line.
The characteristics of the transport of the dipeptide glycylsarcosine were studied in the human colon carcinoma cell line Caco-2 grown as a monolayer on impermeable plastic support. Transport of glycylsarcosine in these cells was found to be Na(+)-independent, but was stimulated by an inwardly directed H+ gradient. This H(+)-dependent transport of glycylsarcosine was inhibited by di- and tri-peptides and also by the beta-lactam antibiotic cephalexin, but was unaffected by the amino acids glycine and leucine. The transport system exhibited a Michaelis-Menten constant (Kt) of 1.1 +/- 0.1 mM for glycylsarcosine. The specific activity of the transport system in this cell line was found to be maximal when the cultures were confluent. Treatment of the cells with phorbol esters which activate protein kinase C resulted in a significant inhibition of the transport system. This inhibition was specific and could be blocked if treatment was done in the presence of staurosporine, an inhibitor of protein kinase C. Kinetic analysis revealed that the inhibition was associated with a decrease in the maximal velocity, the Kt remaining unaffected. The phorbol-ester-induced inhibition of the peptide-transport system was not prevented by co-treatment with cycloheximide, an inhibitor of cellular protein synthesis. In addition, there was no change in the intracellular pH following treatment with the phorbol ester, suggesting that the effect was not due to alterations in the transmembrane pH gradient. It is concluded that the peptide/H+ co-transport system, which is known to exist in the normal intestine, is expressed in Caco-2 cells and that the function of the transport system is under the regulatory control of protein kinase C.


Tumor infiltration of the vena cava in nephroblastoma.
Although operative treatment of Wilms' tumors has become more straightforward as a result of advances in preoperative treatment and precise diagnosis, vascular involvement by the tumor can cause serious problems at operation. These problems can be more easily managed if they have been identified pre-operatively and the level of the intravascular tumor thrombus has been defined. In this study we propose a classification of intravascular involvement of Wilms' tumors suggesting the clinical consequences and operative strategy. In our series of 84 patients we treated 7 (8.3%) with preoperatively diagnosed intracaval tumor thrombus using ultrasound as the most sensitive non-invasive diagnostic technique. The surgical therapy depends on the stage; stage III and stage IV should be operated in cooperation with the cardiovascular surgeon in deep hypothermic circular arrest.


Firearms Availability Among High-School Age Youth With Recent Depression or Suicidality.
Limiting firearm access is essential to decreasing teen suicide. Previous efforts have focused on household firearms; however, less is known about firearm access and possession among teens at increased suicide risk. Our objective was to estimate prevalence of firearm possession and access among high school-aged teens with recent depression and/or lifetime history of suicidality (DLHS). We conducted a probability-based, cross-sectional Web survey of 1914 parent-teen dyads between June 24, 2020, and July 22, 2020, with data weighted to generate a nationally representative sample of US teenagers (aged 14-18). Logistic regression analyses examined the difference between teens with and without DLHS for: (1) personal firearm possession, (2) perceived firearm access, and (3) method of firearm attainment. Among high school-aged teens, 22.6% (95% confidence interval [CI], 19.4-25.8) reported DLHS, 11.5% (95% CI, 8.7-14.3) reported personal firearm possession, and 44.2% (95% CI, 40.2-48.2) endorsed firearm access. Teens experiencing DLHS had increased perceived access (adjusted odds ratio, 1.56; 95% CI, 1.07-2.28) compared with non-DLHS peers. There was no association between DLHS and personal firearm possession (adjusted odds ratio, 0.97; 95% CI, 0.47-2.00). Among teens reporting firearm possession, those with DLHS were more likely to have acquired it by buying/trading for it (odds ratio, 5.66; 95% CI, 1.17-27.37) and less likely receiving it as a gift (odds ratio, 0.06; 95% CI, 0.01-0.36). High school-aged teens experiencing DLHS have higher perceived firearm access compared with lower-risk peers. Providers should speak directly to high school-aged teens at increased suicide risk about firearm access, in addition to counseling parents.


Information mining over heterogeneous and high-dimensional time-series data in clinical trials databases.
An effective analysis of clinical trials data involves analyzing different types of data such as heterogeneous and high dimensional time series data. The current time series analysis methods generally assume that the series at hand have sufficient length to apply statistical techniques to them. Other ideal case assumptions are that data are collected in equal length intervals, and while comparing time series, the lengths are usually expected to be equal to each other. However, these assumptions are not valid for many real data sets, especially for the clinical trials data sets. An addition, the data sources are different from each other, the data are heterogeneous, and the sensitivity of the experiments varies by the source. Approaches for mining time series data need to be revisited, keeping the wide range of requirements in mind. In this paper, we propose a novel approach for information mining that involves two major steps: applying a data mining algorithm over homogeneous subsets of data, and identifying common or distinct patterns over the information gathered in the first step. Our approach is implemented specifically for heterogeneous and high dimensional time series clinical trials data. Using this framework, we propose a new way of utilizing frequent itemset mining, as well as clustering and declustering techniques with novel distance metrics for measuring similarity between time series data. By clustering the data, we find groups of analytes (substances in blood) that are most strongly correlated. Most of these relationships already known are verified by the clinical panels, and, in addition, we identify novel groups that need further biomedical analysis. A slight modification to our algorithm results an effective declustering of high dimensional time series data, which is then used for "feature selection." Using industry-sponsored clinical trials data sets, we are able to identify a small set of analytes that effectively models the state of normal health.


Do large-scale hospital- and system-wide interventions improve patient outcomes: a systematic review.
While health care services are beginning to implement system-wide patient safety interventions, evidence on the efficacy of these interventions is sparse. We know that uptake can be variable, but we do not know the factors that affect uptake or how the interventions establish change and, in particular, whether they influence patient outcomes. We conducted a systematic review to identify how organisational and cultural factors mediate or are mediated by hospital-wide interventions, and to assess the effects of those factors on patient outcomes. A systematic review was conducted and reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Database searches were conducted using MEDLINE from 1946, CINAHL from 1991, EMBASE from 1947, Web of Science from 1934, PsycINFO from 1967, and Global Health from 1910 to September 2012. The Lancet, JAMA, BMJ, BMJ Quality and Safety, The New England Journal of Medicine and Implementation Science were also hand searched for relevant studies published over the last 5 years. Eligible studies were required to focus on organisational determinants of hospital- and system-wide interventions, and to provide patient outcome data before and after implementation of the intervention. Empirical, peer-reviewed studies reporting randomised and non-randomised controlled trials, observational, and controlled before and after studies were included in the review. Six studies met the inclusion criteria. Improved outcomes were observed for studies where outcomes were measured at least two years after the intervention. Associations between organisational factors, intervention success and patient outcomes were undetermined: organisational culture and patient outcomes were rarely measured together, and measures for culture and outcome were not standardised. Common findings show the difficulty of introducing large-scale interventions, and that effective leadership and clinical champions, adequate financial and educational resources, and dedicated promotional activities appear to be common factors in successful system-wide change.The protocol has been registered in the international prospective register of systematic reviews, PROSPERO (Registration No. CRD42103003050).


Planum Sphenoidale and Tuberculum Sellae Meningiomas: Operative Nuances of a Modern Surgical Technique with Outcome and Proposal of a New Classification System.
The resection of planum sphenoidale and tuberculum sellae meningiomas is challenging. A universally accepted classification system predicting surgical risk and outcome is still lacking. We report a modern surgical technique specific for planum sphenoidale and tuberculum sellae meningiomas with associated outcome. A new classification system that can guide the surgical approach and may predict surgical risk is proposed. We conducted a retrospective review of the patients who between 2005 and March 2015 underwent a craniotomy or endoscopic surgery for the resection of meningiomas involving the suprasellar region. Operative nuances of a modified frontotemporal craniotomy and orbital osteotomy technique for meningioma removal and reconstruction are described. Twenty-seven patients were found to have tumors arising mainly from the planum sphenoidale or the tuberculum sellae; 25 underwent frontotemporal craniotomy and tumor removal with orbital osteotomy and bilateral optic canal decompression, and 2 patients underwent endonasal transphenoidal resection. The most common presenting symptom was visual disturbance (77%). Vision improved in 90% of those who presented with visual decline, and there was no permanent visual deterioration. Cerebrospinal fluid leak occurred in one of the 25 cranial cases (4%) and in 1 of 2 transphenoidal cases (50%), and in both cases it resolved with treatment. There was no surgical mortality. An orbitotomy and early decompression of the involved optic canal are important for achieving gross total resection, maximizing visual improvement, and avoiding recurrence. The visual outcomes were excellent. A new classification system that can allow the comparison of different series and approaches and indicate cases that are more suitable for an endoscopic transsphenoidal approach is presented.


Methyltransferase-like 3 contributes to inflammatory pain by targeting TET1 in YTHDF2-dependent manner.
The methyltransferase-like 3 (Mettl3) is a key component of the large N6-adenosine-methyltransferase complex in mammalian responsible for RNA N6-methyladenosine (m6A) modification, which plays an important role in gene post-transcription modulation. Although RNA m6A is enriched in mammalian neurons, its regulatory function in nociceptive information processing remains elusive. Here, we reported that Complete Freund's Adjuvant (CFA)-induced inflammatory pain significantly decreased global m6A level and m6A writer Mettl3 in the spinal cord. Mimicking this decease by knocking down or conditionally deleting spinal Mettl3 elevated the levels of m6A in ten-eleven translocation methylcytosine dioxygenases 1 (Tet1) mRNA and TET1 protein in the spinal cord, leading to production of pain hypersensitivity. By contrast, overexpressing Mettl3 reversed a loss of m6A in Tet1 mRNA and blocked the CFA-induced increase of TET1 in the spinal cord, resulting in the attenuation of pain behavior. Furthermore, the decreased level of spinal YT521-B homology domain family protein 2 (YTHDF2), an RNA m6A reader, stabilized upregulation of spinal TET1 because of the reduction of Tet1 mRNA decay by the binding to m6A in Tet1 mRNA in the spinal cord after CFA. This study reveals a novel mechanism for downregulated spinal cord METTL3 coordinating with YTHDF2 contributes to the modulation of inflammatory pain through stabilizing upregulation of TET1 in spinal neurons.


Impact of the COVID-19 pandemic on breast and cervical cancer stage at diagnosis in Brazil.
The COVID-19 pandemic has led to the need for health services adjustments, which may have compromised management of other diseases. For cancer patients, delays may significantly impair outcomes in some situations. We aimed to assess the impact of the COVID-19 pandemic in breast and cervical cancer diagnosis and treatment compared to the same period prior to the pandemic. Data were collected from patients attending their first visit to a Brazilian cancer centre from 1 September 2020 to 31 January 2021 and from 1 September 2019 to 31 January 2020. The pandemic started in February 2020 in Brazil and is still ongoing. We considered this period (September/20-January/21) to be representative of the pandemic impact on cancer management. The primary endpoint was breast and cervical cancer stages at diagnosis. A total of 268 breast cancer patients and 44 cervical cancer patients had their first consult in our cancer centre from September/20 to January/21; 457 and 60, respectively, occurred from September/19 to January/20. Patients who attended their first visit during the pandemic (September/20-January/21) presented with more advanced-stage breast cancer (p < 0.001) and cervical cancer (p = 0.328) than those in the period prior to the pandemic (September/19-January/20), although the difference was not statistically significant for cervical cancer. The proportion of cervical cancer patients diagnosed with locally advanced disease (stages III-IVA) was 56.8% (N = 25) in September/20-January/21 compared to 43.3% (N = 26) in September/19-January/20. Similarly, 37.3% (N = 100) of breast cancer patients had stage III disease in September/20-January/21 compared to 23.2% (N = 106) in September/19-January/20. Fewer breast cancer patients (13.7%) were diagnosed due to screening tests during the pandemic than before it (25.5%) (p < 0.001). Breast and cervical cancer patients had more advanced-stage diseases in their first visit to a cancer centre during the COVID-19 pandemic compared to a similar period prior to the pandemic. Efforts should be made not to compromise essential cancer services since this results in long-term negative impacts for oncologic patients.


Estimating fatality rates in occupational light vehicle users using vehicle registration and crash data.
To estimate occupational light vehicle (OLV) fatality numbers using vehicle registration and crash data and compare these with previous estimates based on workers' compensation data. New South Wales (NSW) Roads and Traffic Authority (RTA) vehicle registration and crash data were obtained for 2004. NSW is the only Australian jurisdiction with mandatory work-use registration, which was used as a proxy for work-relatedness. OLV fatality rates based on registration data as the denominator were calculated and comparisons made with published 2003/04 fatalities based on workers' compensation data. Thirty-four NSW RTA OLV-user fatalities were identified, a rate of 4.5 deaths per 100,000 organisationally registered OLV, whereas the Australian Safety and Compensation Council (ASCC), reported 28 OLV deaths Australia-wide. More OLV user fatalities were identified from vehicle registration-based data than those based on workers' compensation estimates and the data are likely to provide an improved estimate of fatalities specific to OLV use. OLV-use is an important cause of traumatic fatalities that would be better identified through the use of vehicle-registration data, which provides a stronger evidence base from which to develop policy responses.


Meal size and number: relationship to dopamine levels in the ventromedial hypothalamic nucleus.
Evidence shows a reciprocal relationship exists between the lateral hypothalamic area (LHA) and the ventromedial hypothalamic nucleus (VMN) in food intake regulation. Since a direct correlation between meal size and LHA-dopamine in Fischer rats was previously reported, we tested the hypothesis that an inverse association may exist between meal size and VMN-dopamine response. This was studied in awake 24-h food-deprived rats who were then allowed to eat freely for 20 min while the VMN-dopamine response was measured by microdialysis every 20 min for 2 h. In a second experiment, only one-half the amount freely eaten was provided during microdialysis. The following were observed. 1) Dopamine concentrations in VMN decreased during eating. 2) The degree and duration of decrease after the meal corresponded to the size of the meal. 3) When the decreased postmeal VMN-dopamine level had returned to baseline and food was available, rats ate once more. The findings show that, in normal rats, eating was associated with decreased dopamine levels in the VMN and was followed by a lag time during which no additional eating occurred. VMN dopamine levels thereby contribute to determining the duration of the intermeal interval and hence, by inference, the meal number.


Older Peoples' Willingness to Delay Social Security Claiming.
We have designed and implemented an experimental module in the 2014 Health and Retirement Study (HRS) to measure older persons' willingness to defer claiming of Social Security benefits. Under the current system' status quo where delaying claiming boosts eventual benefits, we show that 46% of the respondents would delay claiming and work longer. If respondents were instead offered an actuarially fair lump sum payment instead of higher lifelong benefits, about 56% indicate they would delay claiming. Without a work requirement, the average amount needed to induce delayed claiming is only $60,400, while when part-time work is stipulated, the amount is slightly higher, $66,700. This small difference implies a low utility value of leisure foregone, of under 20% of average household income.


Preventable anesthesia mishaps: a study of human factors.
A modified critical-incident analysis technique was used in a retrospective examination of the characteristics of human error and equipment failure in anesthetic practice. The objective was to uncover patterns of frequently occurring incidents that are in need of careful prospective investigation. Forty-seven interviews were conducted with staff and resident anesthesiologists at one urban teaching institution, and descriptions of 359 preventable incidents were obtained. Twenty-three categories of details from these descriptions were subjected to computer-aided analysis for trends and patterns. Most of the preventable incidents involved human error (82 per cent), with breathing-circuit disconnections, inadvertent changes in gas flow, and drug-syringe errors being frequent problems. Overt equipment failures constituted only 14 per cent of the total number of preventable incidents, but equipment design was indictable in many categories of human error, as were inadequate experience and insufficient familiarity with equipment or with the specific surgical procedure. Other factors frequently associated with incidents were inadequate communication among personnel, haste or lack of precaution, and distraction. Results from multi-hospital studies based on the methodology developed could be used for more objective determination of priorities and planning of specific investments for decreasing the risk associated with anesthesia.


Effects of off-the-shelf foot orthoses on plantar foot pressures in patients with early rheumatoid arthritis.
Rheumatoid arthritis (RA) often affects feet with progressive pathologic changes to foot morphology and pressure distribution. Studies in RA suggest that reductions in forefoot peak pressures can reduce pain. We investigated the effects of off-the-shelf foot orthoses on plantar foot pressures in patients with early RA. Thirty-five patients with early RA were recorded walking. Variables measured were forefoot peak plantar pressure (PPPft), forefoot pressure-time integral (PTIft), and hallux and lesser toe and midfoot contact areas. Patients were analyzed while walking barefoot, with shoes, and with shoes and foot orthoses. Measurements were taken at baseline and at 3 and 6 months. There were significantly increased PPPft values between barefoot and shod and between barefoot and orthoses (P < .01). However, there was a significant reduction in PPPft during the 6 months with orthoses compared with shoes only (P < .01). Foot orthoses significantly reduced PTIft over 6 months (P < .01). Results also demonstrated a significant increase in hallux and lesser toe (P < .01) and midfoot (P < .01) contact areas during the 6 months with foot orthoses. In patients with early RA, off-the-shelf foot orthoses cause a significant reduction of 22% in PPPft and 14% in PTIft as soon as insoles are worn compared with shod. Further reductions for orthoses compared with baseline were found by 3 months (15% in PPPft and 14% in PTIft) and 6 months (33% in PPPft and 33% in PTIft). These findings could contribute to reductions in foot pain.


Antioxidant and Anti-Melanogenic Activities of Heat-Treated Licorice (Wongam, Glycyrrhiza glabra × G. uralensis) Extract.
Melanin is a brown or black pigment that protects skin from ultraviolet radiation and reactive oxygen species (ROS). However, overproduction of melanin is associated with lentigines, melasma, freckles and skin cancer. Licorice has shown antioxidant, anti-tumor, anti-platelet, anti-inflammatory and immunomodulatory activities and is used as a natural treatment for skin whitening. We aimed to confirm the potential of Wongam, a new cultivar of licorice developed by the Rural Development Administration (RDA), as a whitening agent in cosmetics. In addition, we verified the effect of heat treatment on the bioactivity of licorice by comparing antioxidant and anti-melanogenic activities of licorice extract before and after heating (130 °C). The heat-treated licorice extract (WH-130) showed higher radical-scavenging activities in the ABTS+ (2,2'-azino-bis-(3-ethylbenzothiazolin-6-sulfonic acid) diammonium salt) and DPPH (2,2-diphenyl-1-picrylhydrazyl) assays. In addition, WH-130 inhibited melanogenesis more effectively due to downregulation of tyrosinase in B16F10 melanoma cells than non-heated licorice extract. Moreover, heat treatment increased total phenolic content. In particular, isoliquiritigenin, an antioxidant and anti-melanogenic compound of licorice, was produced by heat treatment. In conclusion, WH-130, with increased levels of bioactive phenolics such as isoliquiritigenin, has potential for development into a novel skin whitening material with applications in cosmetics.


Depression in working adults: comparing the costs and health outcomes of working when ill.
Working through a depressive illness can improve mental health but also carries risks and costs from reduced concentration, fatigue, and poor on-the-job performance. However, evidence-based recommendations for managing work attendance decisions, which benefit individuals and employers, are lacking. Therefore, this study has compared the costs and health outcomes of short-term absenteeism versus working while ill ("presenteeism") amongst employed Australians reporting lifetime major depression. Cohort simulation using state-transition Markov models simulated movement of a hypothetical cohort of workers, reporting lifetime major depression, between health states over one- and five-years according to probabilities derived from a quality epidemiological data source and existing clinical literature. Model outcomes were health service and employment-related costs, and quality-adjusted-life-years (QALYs), captured for absenteeism relative to presenteeism, and stratified by occupation (blue versus white-collar). Per employee with depression, absenteeism produced higher mean costs than presenteeism over one- and five-years ($42,573/5-years for absenteeism, $37,791/5-years for presenteeism). However, overlapping confidence intervals rendered differences non-significant. Employment-related costs (lost productive time, job turnover), and antidepressant medication and service use costs of absenteeism and presenteeism were significantly higher for white-collar workers. Health outcomes differed for absenteeism versus presenteeism amongst white-collar workers only. Costs and health outcomes for absenteeism and presenteeism were not significantly different; service use costs excepted. Significant variation by occupation type was identified. These findings provide the first occupation-specific cost evidence which can be used by clinicians, employees, and employers to review their management of depression-related work attendance, and may suggest encouraging employees to continue working is warranted.


[Adaptability of fine-needle biopsy for preoperative and postoperative studies in femoro-crural vascular reconstruction].
During two years we performed 199 pre- and postoperative angiograms on 99 patients with femoro-crural reconstruction. 133 of these were by FNP. In 4.2% of postoperative FNPs (fully anticoagulated patients), there was significant bleeding from the puncture or the operative scar. It was not necessary to reoperate on any bypasses and there were no late complications. As regards the demonstration of the calf vessels. FNP proved itself superior as a pre- and postoperative method. Because of the rapidity of the method, the small amount of contrast required and the minimal trauma, FNP is the method of choice for pre- and post-operative studies of the calf vessels for femoro-crural reconstructions.


Cutaneous vascular responses to acetylcholine are mediated by a prostanoid-dependent mechanism in man.
Approximately 50% of the forearm vasodilatation to intra-arterial infusions of acetylcholine is mediated by endothelium-derived nitric oxide. These conclusions have been derived from venous occlusion plethysmographic measurements of total forearm blood flow during co-infusions of acetylcholine and NG-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide synthase. Since venous occlusion plethysmography measures total limb blood flow, the relative proportion of the measurement from skin cannot be determined precisely. To determine the effects of acetylcholine on skin specifically, we have used laser Doppler flowmetry to measure vascular responses to local iontophoresis of acetylcholine in the forearm of normal male volunteers. To elucidate the possible mechanisms of cutaneous vasodilatation to acetylcholine, vascular responses were measured before and after systemic inhibition of prostanoid production and nitric oxide synthesis by oral aspirin (600 mg daily for 3 days) and intravenous L-NMMA (3 mg/kg for 60 min), respectively. After aspirin administration, dose-dependent vascular responses to acetylcholine were reduced significantly by approximately 53% (p < 0.005, ANOVA). In contrast, intravenous L-NMMA appeared to have no significant effect on cutaneous vascular responses to acetylcholine. While the role of nitric oxide is uncertain, vasodilatation to acetylcholine in the forearm skin is mediated largely by a prostanoid-dependent mechanism. Assessment of cutaneous vascular responses to iontophoresis of acetylcholine may, therefore, be useful in diseases where abnormal endothelium-dependent prostanoid function has been implicated.


Identification of the varR gene as a transcriptional regulator of virginiamycin S resistance in Streptomyces virginiae.
A gene designated varR (for virginiae antibiotic resistance regulator) was identified in Streptomyces virginiae 89 bp downstream of a varS gene encoding a virginiamycin S (VS)-specific transporter. The deduced varR product showed high homology to repressors of the TetR family with a conserved helix-turn-helix DNA binding motif. Purified recombinant VarR protein was present as a dimer in vitro and showed clear DNA binding activity toward the varS promoter region. This binding was abolished by the presence of VS, suggesting that VarR regulates transcription of varS in a VS-dependent manner. Northern blot analysis revealed that varR was cotranscribed with upstream varS as a 2.4-kb transcript and that VS acted as an inducer of bicistronic transcription. Deletion analysis of the varS promoter region clarified two adjacent VarR binding sites in the varS promoter.


Gait variability patterns are altered in healthy young individuals during the acute reperfusion phase of ischemia-reperfusion.
The role of ischemia reperfusion contributing to functional impairment in lower extremity peripheral arterial disease (PAD) patients has not previously been elucidated. The evaluation of gait variability patterns has proven useful in many pathologic populations. Therefore, the purpose of this study is to isolate and determine the specific effect of the acute reperfusion phase of ischemia-reperfusion on gait variability in young individuals with no vascular disease. Thirty healthy young individuals walked on a treadmill during baseline and the acute reperfusion phase of ischemia-reperfusion conditions while lower extremity joint kinematics were captured. Stride to stride variability was assessed using the largest Lyapunov exponent, approximate entropy, standard deviation, and coefficient of variation. Differences in gait variability between conditions were assessed using dependent t-tests. The largest Lyapunov exponent values and approximate entropy values were significantly higher in the acute reperfusion phase of ischemia-reperfusion condition for the ankle, knee, and the hip. Coefficient of variation was significantly higher at the hip and standard deviation was higher at the knee and the hip during the acute reperfusion phase of ischemia-reperfusion condition. The acute reperfusion phase of the ischemia-reperfusion cycle alters gait variability patterns at the ankle, knee, and the hip in healthy young individuals. Our findings indicate increased noise and irregularity of gait variability patterns post-ischemia. In young healthy individuals who do not have neuromuscular impairments, significant gait alterations are present during walking after a period of interruption of blood flow.


Forum on the Brain and Hearing Aids.
The purpose of this article is to introduce and provide an overview of the 3 articles presented in the invited forum "The Brain and Hearing Aids." The main ideas of the articles presented by the 3 panelists are identified, and a commentary is provided to synthesize the ideas. Benefits from hearing aids and auditory training entail higher-level cortical and cognitive processing involved in categorizing and remembering sound. New approaches to predicting, designing, and evaluating technological and behavioral interventions will need to consider the brain and not just the ears of listeners.


Cloning and characterization of a hemolysin gene from Actinobacillus (Haemophilus) pleuropneumoniae.
Neutralizing antisera to the leukotoxin secreted by Pasteurella haemolytica neutralized the hemolysin of Actinobacillus pleuropneumoniae and recognized a 110-kD antigen in cell-free culture supernatants from this organism. A series of nine overlapping recombinant phage clones carrying the gene for this 110-kD antigen were identified using affinity-purified anti-hemolysin antibody and a DNA probe containing sequences from the P. haemolytica lktCA genes. Eight of the nine clones expressed a 110-kD protein recognized by both anti-leukotoxin and anti-hemolysin antisera. The remaining clone expressed a truncated 80-kD antigen which was also recognized by both antisera. Sequence analysis of a region of the cloned DNA revealed two open reading frames encoding proteins with predicted masses of 18.5 and 102.5 kD. These genes, which we designate appC and appA, respectively, are similar in sequence to the hlyCA genes of Escherichia coli and the lktCA genes of P. haemolytica. Hemolytic activity could be detected in lysates of E. coli harboring plasmids containing the appCa genes.


Social Mind and Long-Lasting Disease: Focus on Affective and Cognitive Theory of Mind in Multiple Sclerosis.
The role of social cognition, including theory of mind (ToM), in affecting quality of life (QoL) along the course of diseases has been reported. This is a considerable aspect in chronic pathologies, such as multiple sclerosis (MS), in which supporting and maintaining QoL is of crucial importance. We aimed to investigate the relation between ToM, clinical variables and neuropsychological profile in a cohort of adults with long lasting disease, such as different clinical MS phenotypes (Relapsing Remitting -RR- versus Progressive -Pr). In particular, our study focuses on (1) how (affective and cognitive) ToM impairment occurs in different phenotypes, (2) whether MS ToM impairment is secondary to or independent from cognitive deficit and (3) whether ToM deficit impacts QoL. 42 adults with MS (18 M: 24 F, 52.38 ± 10.31 mean age, 21.24 ± 10.94 mean disease duration, 26 RR and 16 Pr) and 26 matched healthy controls (HC) (7 M: 19 F, 51.35 ± 12.42 mean age) were screened with a neuropsychological and ToM battery, assessing both affective and cognitive components. We found statistically significant groups differences in cognitive but not affective ToM, with a lower performance in PrMS than those with a RRMS disease course. Also, significant predictive effects of neuropsychological tests on ToM were identified in MS group. Finally, MS people with different level of affective ToM differed significantly in QoL. ToM deficit in moderately disabled people with MS involves cognitive but not affective ToM components with implications on QoL. It also appears to be related to cognitive performance. As neurological and neurocognitive profiles influence mentalizing in MS, ToM evaluation should be considered for inclusion in clinical screening.


How did a lower drink-drive limit affect bar trade and drinking practices? A qualitative study of how alcohol retailers experienced a change in policy.
Reducing the legal drink-drive limit from 0.08% to 0.05% blood alcohol concentration (BAC) can reduce road traffic accidents and deaths if properly enforced. Reduced limits may be opposed by alcohol retail and manufacturing industries on the basis of commercial impact. Our aim was to qualitatively explore how a reduction in the drink-drive limit from 0.08% to 0.05% BAC in Scotland, was experienced by bar owners or managers, including any resultant changes in customer drinking or business practice. This is the first study of this type. Semi-structured interviews were conducted with 16 owners and managers of on-trade premises in Scotland in 2018, approximately three years after the drink-drive limit was reduced. Data were analysed using thematic analysis. Most participants reported no long-term financial impact on their business, but a few, mainly from rural areas, reported some reduction in alcohol sales. Observed drinking changes included fewer people drinking after work or leaving premises earlier on weekdays. Adaptations to businesses included improving the range of no/low-alcohol drinks and food offered. Changes such as these were seen as key to minimising economic impact. Opposition to legislative measures that impact on commercial interests is often strong and receives significant public attention. This study found that Scottish businesses that adapted to the drink-drive limit change reported little long-term economic impact. These findings are of international relevance as potential BAC limit reductions in several other jurisdictions remain the subject of debate, including regarding the impact on business.