Promoter trans-activation of protooncogenes c-fos and c-myc, but not c-Ha-ras, by products of adenovirus early region 1A.
The E1A (early region 1A) oncogene products of adenovirus type 2 trans-activate the other early viral transcription units, as well as some cellular promoters. Using a short-term cotransfection assay in murine NIH 3T3 fibroblasts, we show that c-fos and c-myc promoter activities are stimulated by the E1A proteins, whereas c-Ha-ras transcription is not affected. The product of E1A 13S mRNA is responsible for the trans-activation, whereas the 12S mRNA product has no effect. Analysis of the c-fos promoter sequences required for the E1A stimulation shows that responsive sequences are located between positions -402 and -240 upstream of the transcription initiation site. This same region also contains the c-fos serum-responsive element. Furthermore, transcription of the endogenous c-fos gene in HeLa cells is increased after E1A transfection.


Fluoxetine for stroke recovery: Meta-analysis of randomized controlled trials.
To determine whether fluoxetine, at any dose, given within the first year after stroke to patients who did not have to have mood disorders at randomization reduced disability, dependency, neurological deficits and fatigue; improved motor function, mood, and cognition at the end of treatment and follow-up, with the same number or fewer adverse effects. Searches (from 2012) in July 2018 included databases, trials registers, reference lists, and contact with experts. Co-primary outcomes were dependence and disability. Dichotomous data were synthesized using risk ratios (RR) and continuous data using standardized mean differences (SMD). Quality was appraised using Cochrane risk of bias methods. Sensitivity analyses explored influence of study quality. The searches identified 3414 references of which 499 full texts were assessed for eligibility. Six new completed RCTs (n = 3710) were eligible, and were added to the seven trials identified in a 2012 Cochrane review (total: 13 trials, n = 4145). There was no difference in the proportion independent (3 trials, n = 3249, 36.6% fluoxetine vs. 36.7% control; RR 1.00, 95% confidence interval 0.91 to 1.09, p = 0.99, I2 = 78%) nor in disability (7 trials n = 3404, SMD 0.05, -0.02 to 0.12 p = 0.15, I2 = 81%) at end of treatment. Fluoxetine was associated with better neurological scores and less depression. Among the four (n = 3283) high-quality RCTs, the only difference between groups was lower depression scores with fluoxetine. This class I evidence demonstrates that fluoxetine does not reduce disability and dependency after stroke but improves depression.


[Pharmacology and clinical aspects of benzodiazepines].
The widespread use of benzodiazepines has led the authors to review the pharmacological and clinical aspects of these substances. On a molecular level, the benzodiazepines have an effect on receptors in relation with the GABA system. Presently, endogenous ligand(s) to these receptors have not yet been fully demonstrated. The main benzodiazepines are also compared for their kinetics which is function of absorption, metabolisation and various factors such as binding to the receptor, age, hepatic and renal disorders. These pharmacological studies have clinical implications. The authors finally make a brief review of the clinical indications of the benzodiazepines.


The Development of a Melt-Extruded Shellac Carrier for the Targeted Delivery of Probiotics to the Colon.
Hot melt extrusion (HME) is considered an efficient technique in developing solid molecular dispersions, and has been demonstrated to provide sustained, modified and targeted drug delivery resulting in improved bioavailability. However, most commercial enteric or pH-responsive polymers are relatively difficult to process or have high Glass Transition Temperature (Tg) values, making their use with temperature-sensitive drugs, probiotics or biologics not viable. Shellac is a natural thermoplastic, and after a review of current literature on the pharmaceutical HME process, a possible gap in the knowledge of the use of shellac to produce dosage forms by means of HME was identified. This work explores the possibility of SSB® 55 pharmaceutical-grade shellac as a melt-extrudable encapsulation polymer to entrap freeze-dried probiotic powder and to determine bacterial cell viability post-processing. Well-defined strands were produced from the physical mixture of shellac and Biocare® Bifidobacterium Probiotic. FTIR clarified that there are no significant interactions between the probiotic and polymer. All of the samples demonstrated less than 5% degradation over 24 h at pH of both 1.2 and 6.8. At pH 7.4, both loaded samples gave a similar dissolution trend with complete degradation achieved after 10-11 h. Following five-month storage, 57.8% reduction in viability was observed.


[Expert significance of evaluating volatile non-metal combustion products in analysis of blood from subjects dead in fire].
Qualitative and quantitative composition and time course of formation of toxic substances during burning of polymers have been studied for two polymers, P-53-P and STBO. The most toxic gaseous products of nitrogen combustion are listed: hydrogen cyanide, nitrites, acid nitriles, aldehydes, aromatic carbohydrates, alkanes, and carbon oxide. Two expert conclusions are presented, including analysis of blood and viscera from subjects who died during fire. The following toxic substances were detected: carbon oxide, hydrogen cyanide, nitrites, acrylonitrile, acetonitrile, benzene, and methane in one case and the same products except carbon oxide in the other. The author considers that the list of tested toxic substances should be extended, particularly in cases with negative results of blood testing for carbon oxide and carboxyhemoglobin.


Effect of electroacupuncture on function and quality of life in Parkinson's disease: a case report.
A 56-year-old man diagnosed in 2003 as having Hoehn & Yahr stage III Parkinson's disease (PD) came to our clinic in 2012 with slurred speech, right-sided bradykinesia, erectile dysfunction, rigidity, emotional instability and depression. His PD showed progressive signs with postural instability, moderate bilateral signs, and he rated 80% on the Schwab & England Activities of Daily Living Scale. A modified protocol of electroacupuncture was administered for a period of 5 weeks, six times per week, with each session lasting for 30 min. Assessments were based on the Berg Balance Scale (BBS) and Parkinson's Disease Questionnaire-39 (PDQ-39) items, a disease-specific measure of subjective health status. He showed improvement on the BBS, suggesting improved functional status. His quality of life showed improvement particularly on the 'activities of daily living', 'cognition' and 'communication' dimensions of the PDQ-39. Acupuncture treatments in animal experiments have generated valuable mechanistic insights that could be relevant to PD, for example, demonstrating its neuroprotective potential from stimulation of various neuroprotective agents. The literature also suggests acupuncture may play a role in the improvement of motor function and quality of life in PD. Acupuncture is tolerated well by individuals with PD and should be considered as an integrative approach for their symptomatic management.


Attention increases the temporal precision of conscious perception: verifying the Neural-ST Model.
What role does attention play in ensuring the temporal precision of visual perception? Behavioural studies have investigated feature selection and binding in time using fleeting sequences of stimuli in the Rapid Serial Visual Presentation (RSVP) paradigm, and found that temporal accuracy is reduced when attentional control is diminished. To reduce the efficacy of attentional deployment, these studies have employed the Attentional Blink (AB) phenomenon. In this article, we use electroencephalography (EEG) to directly investigate the temporal dynamics of conscious perception. Specifically, employing a combination of experimental analysis and neural network modelling, we test the hypothesis that the availability of attention reduces temporal jitter in the latency between a target's visual onset and its consolidation into working memory. We perform time-frequency analysis on data from an AB study to compare the EEG trials underlying the P3 ERPs (Event-related Potential) evoked by targets seen outside vs. inside the AB time window. We find visual differences in phase-sorted ERPimages and statistical differences in the variance of the P3 phase distributions. These results argue for increased variation in the latency of conscious perception during the AB. This experimental analysis is complemented by a theoretical exploration of temporal attention and target processing. Using activation traces from the Neural-ST(2) model, we generate virtual ERPs and virtual ERPimages. These are compared to their human counterparts to propose an explanation of how target consolidation in the context of the AB influences the temporal variability of selective attention. The AB provides us with a suitable phenomenon with which to investigate the interplay between attention and perception. The combination of experimental and theoretical elucidation in this article contributes to converging evidence for the notion that the AB reflects a reduction in the temporal acuity of selective attention and the timeliness of perception.


[Various approaches to designing the functionally active determinants as illustrated by the influenza virus A(H3N2) hemagglutinin].
Hexapeptide Lys-Gly-Pro-Asp-Ser-Gly analogous to the immunodominant fragment 141-146 of the epitope A of the influenza virus A(H3N2) hemagglutinin is synthesized. Conjugated with thyroglobulin and hemocyanine, the hexapeptide induced formation of highly specific antibodies with heterolytic properties in CBA mice. Antihexapeptide antibodies interact not only with the homologous antigen but also with hemagglutinin and influenza virus. Choice of the hexapeptide sequence is discussed.


Risk of childhood asthma is associated with CpG-site polymorphisms, regional DNA methylation and mRNA levels at the GSDMB/ORMDL3 locus.
Single-nucleotide polymorphisms (SNPs) in GSDMB (Gasdermin B) and ORMDL3 (ORMDL sphingolipid biosynthesis regulator 3) are strongly associated with childhood asthma, but the molecular alterations contributing to disease remain unknown. We investigated the effects of asthma-associated SNPs on DNA methylation and mRNA levels of GSDMB and ORMDL3. Genetic association between GSDMB/ORMDL3 and physician-diagnosed childhood asthma was confirmed in the Swedish birth-cohort BAMSE. CpG-site SNPs (rs7216389 and rs4065275) showed differences in DNA methylation depending on carrier status of the risk alleles, and were significantly associated with methylation levels in two CpG sites in the 5' UTR (untranslated region) of ORMDL3. In the Swedish Search study, we found significant differences in DNA methylation between asthmatics and controls in five CpG sites; after adjusting for lymphocyte and neutrophil cell counts, three remained significant: one in IKZF3 [IKAROS family zinc finger 3 (Aiolos); cg16293631] and two in the CpG island (CGI) of ORMDL3 (cg02305874 and cg16638648). Also, cg16293631 and cg02305874 correlated with mRNA levels of ORMDL3. The association between methylation and asthma was independent of the genotype in rs7216389, rs4065275 and rs12603332. Both SNPs and CpG sites showed significant associations with ORMDL3 mRNA levels. SNPs influenced expression independently of methylation, and the residual association between methylation and expression was not mediated by these SNPs. We found a differentially methylated region in the CGI shore of ORMDL3 with six CpG sites less methylated in CD8(+) T-cells. In summary, this study supports that there are differences in DNA methylation at this locus between asthmatics and controls; and both SNPs and CpG sites are independently associated with ORMDL3 expression.


The classical Starling resistor model often does not predict inspiratory airflow patterns in the human upper airway.
The upper airway is often modeled as a classical Starling resistor, featuring a constant inspiratory airflow, or plateau, over a range of downstream pressures. However, airflow tracings from clinical sleep studies often show an initial peak before the plateau. To conform to the Starling model, the initial peak must be of small magnitude or dismissed as a transient. We developed a method to simulate fast or slow inspirations through the human upper airway, to test the hypothesis that this initial peak is a transient. Eight subjects [4 obstructive sleep apnea (OSA), 4 controls] slept in an "iron lung" and wore a nasal mask connected to a continuous/bilevel positive airway pressure machine. Downstream pressure was measured using an epiglottic catheter. During non-rapid eye movement (NREM) sleep, subjects were hyperventilated to produce a central apnea, then extrathoracic pressure was decreased slowly (∼2-4 s) or abruptly (<0.5 s) to lower downstream pressure and create inspiratory airflow. Pressure-flow curves were constructed for flow-limited breaths, and slow vs. fast reductions in downstream pressure were compared. All subjects exhibited an initial peak and then a decrease in flow with more negative pressures, demonstrating negative effort dependence (NED). The rate of change in downstream pressure did not affect the peak to plateau airflow ratio: %NED 22 ± 13% (slow) vs. 20 ± 5% (fast), P = not significant. We conclude that the initial peak in inspiratory airflow is not a transient but rather a distinct mechanical property of the upper airway. In contrast to the classical Starling resistor model, the upper airway exhibits marked NED in some subjects.


Social control and workplace drinking norms: a comparison of two organizational cultures.
This article reports on an investigation of the relationship of social control mechanisms at work to drinking practices of 10,000 salaried and hourly employees working in the same U.S. industry, with the same union, but in two different work environments. One work environment reflected an organizational culture that is traditional to U.S. management; the other was based on a nontraditional Japanese transplant model. The research team used a combination of methods including in-home surveys (N = 1,723; 1,378 men) and ethnography (110 semistructured interviews and 200 hours of direct observation inside the plants). Respondents were asked about general and work-related drinking, perceptions of drinking norms, strengths or weaknesses of alcohol-related policies and procedures for policy enforcement. Although overall consumption rates in both populations were similar, significant differences between the two samples existed regarding work-related drinking. The Traditional (i.e., U.S.) model was associated with more permissive norms regarding drinking before or during work shifts (including breaks) and higher workplace drinking rates than the Transplant (i.e., Japanese) model. Analyses revealed that alcohol policies, and the extent to which policies are actually enforced, predicted drinking norms and alcohol availability at work. Drinking norms, in turn, predicted work-related drinking and accounted for differences in alcohol consumption between the two worksites. Analyses of ethnographic data provided descriptive understandings of aspects of the two organizational cultures that disabled mechanisms for social control of drinking in one setting and enabled those mechanisms in the other. These understandings of how social control mechanisms predict work-related drinking practices provide guidelines for alcohol problem prevention in a specific kind of occupational environment. However, our identification of aspects of social control that successfully regulate workplace drinking is applicable to other kinds of occupational settings as well.


Effects of vitamin K2 on cortical and cancellous bone mass, cortical osteocyte and lacunar system, and porosity in sciatic neurectomized rats.
The purpose of the present study was to examine the effects of vitamin K2 on cortical and cancellous bone mass, cortical osteocyte and lacunar system, and porosity in sciatic neurectomized rats. Thirty-four female Sprague-Dawley retired breeder rats were randomized into three groups: age-matched control, sciatic neurectomy (NX), and NX + vitamin K2 administration (menatetrenone, 30 mg/kg/day p.o., three times a week). At the end of the 8-week experiment, bone histomorphometric analysis was performed on cortical and cancellous bone of the tibial diaphysis and proximal metaphysis, respectively, and osteocyte lacunar system and porosity were evaluated on cortical bone of the tibial diaphysis. NX decreased cortical and cancellous bone mass compared with age-matched controls as a result of increased endocortical and trabecular bone erosion and decreased trabecular mineral apposition rate (MAR). Vitamin K2 ameliorated the NX-induced increase in bone erosion, prevented the NX-induced decrease in MAR, and increased bone formation rate (BFR/bone surface) in cancellous bone, resulting in an attenuation of NX-induced cancellous bone loss. However, vitamin K2 did not significantly influence cortical bone mass. NX also decreased osteocyte density and lacunar occupancy and increased porosity in cortical bone compared with age-matched controls. Vitamin K2 ameliorated the NX-induced decrease in lacunar occupancy by viable osteocytes and the NX-induced increase in porosity. The present study showed the efficacy of vitamin K2 for cancellous bone mass and cortical lacunar occupancy by viable osteocytes and porosity in sciatic NX rats.


Yellow nail syndrome: resolution of yellow nails after successful treatment of breast cancer.
Yellow nail syndrome (YNS) is a rare entity of unknown cause in which congenitally hypoplastic lymphatics play a major role in the clinical manifestations of the disease. YNS has been associated with many malignancies and immune disorders. We report a case of new-onset YNS associated with breast cancer and dramatic improvement in the yellow nails with cancer treatment.


Efficacy of several vaccination programmes in commercial layer and broiler breeder hens against experimental challenge with Salmonella enterica serovar Enteritidis.
Two experiments were performed to evaluate the protective effect of various vaccination combinations given at 5 and 9 weeks of age against experimental challenge with Salmonella enterica serovar Enteritidis (SE) phage type 4 at 12 weeks of age. In Experiment 1, groups of commercial layers were vaccinated by one of the following programmes: Group 1, two doses of a SE bacterin (Layermune SE); Group 2, one dose of a live Salmonella enterica serovar Gallinarum vaccine (Cevac SG9R) followed by one dose of the SE bacterin; Group 3, one dose of each of two different multivalent inactivated vaccines containing SE cells (Corymune 4K and Corymune 7K; and Group 4, unvaccinated, challenged controls. In Experiment 2, groups of broiler breeders were vaccinated by the same programmes as Groups 1 and 2 above while Group 3 was an unvaccinated, challenged control group. All vaccination programmes and the challenge induced significant (P < 0.05) seroconversion as measured by enzyme-linked immunosorbent assay. Overall, in both experiments, all vaccination schemes were significantly effective in reducing organ (spleen, liver and caeca) colonization by the challenge strain as well as reducing faecal excretion for at least 3 weeks. Vaccinated layers in Groups 1 and 2 and broiler breeders in Group 2 showed the greatest reduction in organ colonization and the least faecal excretion. In Experiment 1, layers vaccinated with multivalent inactivated vaccines containing a SE component (Group 3) were only moderately protected, indicating that such a vaccination programme may be useful in farms with good husbandry and housing conditions and low environmental infectious pressure by Salmonella.


Effects of Using Websites on Physical Activity and Diet Quality for Adults Living With Chronic Health Conditions: Systematic Review and Meta-Analysis.
Adults with chronic health conditions need support to manage modifiable risk factors such as physical inactivity and poor diet. Disease-specific websites with health information on physical activity and diet quality may be effective in supporting adults in managing their chronic illnesses. The primary aim of this review was to determine whether using websites with health information can lead to improvements in physical activity levels or diet quality in adults with chronic health conditions. Randomized controlled trials evaluating the effectiveness of website use on levels of physical activity or diet quality in adults with chronic health conditions were included. MEDLINE, Embase, CINAHL, and the Physiotherapy Evidence Database were searched from the earliest available record until February 2023. Data for outcomes measuring physical activity levels; diet quality; and, where reported, self-efficacy and quality of life were independently extracted by 2 reviewers. The risk of bias was assessed using the Physiotherapy Evidence Database scale, and the overall certainty of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach. Where values were presented as the same unit of measure, postintervention scores were pooled for meta-analysis to yield an overall mean difference (MD). A standardized MD (SMD) was calculated for the pooled data in which different units for the same outcome were used. Individual trial data were described in cases where the data of trials could not be pooled. A total of 29 trials (N=6418 participants) across 8 different disease groups with intervention periods ranging from 4 weeks to 12 months were included in the analysis. There was moderate-certainty evidence that using websites with health information increased levels of moderate to vigorous physical activity (MD=39 min/wk, 95% CI 18.60-58.47), quality of life (SMD=0.36, 95% CI 0.12-0.59), and self-efficacy (SMD=0.26, 95% CI 0.05-0.48) and high-certainty evidence for reduction in processed meat consumption (MD=1.1 portions/wk, 95% CI 0.70-1.58) when compared with usual care. No differences were detected in other measures of diet quality. There was no increased benefit for website users who were offered additional support. The use of websites for risk factor management has the potential to improve physical activity levels, quality of life, and self-efficacy as well as reduce processed meat consumption for adults living with chronic health conditions when compared with usual care. However, it remains unclear whether using websites leads to meaningful and long-lasting behavior change. PROSPERO CRD42021283168; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=283168.


A Practical and Applicable New Index as an Indicator of Inflammation in the Diagnosis of Erectile Dysfunction: C-reactive Protein-to-Albumin Ratio.
Current evidence suggests that the significant underlying pathophysiological mechanism in erectile dysfunction (ED) is endothelial dysfunction. It is clinically essential to monitor ED because inflammatory processes lead to dysfunctional endothelium and the progression of atherosclerosis. The current retrospective analysis assessed the registers of 90 patients with ED complaints (ED group) and 78 healthy people without ED complaints (control group) who were being managed at the urology units of the surgical outpatient clinic. The international index of erectile function-5 (IIEF-5) evaluated the ED. C-reactive protein (CRP)/albumin ratio (CAR) value was determined by manually dividing serum CRP value by the albumin value in patients whose CRP value was between 0 and 5 mg/l. The average CAR was 0.45 ± 0.37 (ED group) versus 0.22 ± 0.1 in the control group (p=0.0001). IIEF-5 results were negatively correlated with CAR values (r=-0.299; p=0.0001). The strongest cut-off of CAR for predicting ED was 0.025, with 81.8% sensitivity and 75% specificity (p=0.0001). The ED group showed higher levels of CAR and CRP than the control group. CAR can be used as a practical, easy-to-calculate, and cost-effective index in diagnosing ED patients.


Wireframe DNA Origami for the Cellular Delivery of Platinum(II)-Based Drugs.
The DNA origami method has revolutionized the field of DNA nanotechnology since its introduction. These nanostructures, with their customizable shape and size, addressability, nontoxicity, and capacity to carry bioactive molecules, are promising vehicles for therapeutic delivery. Different approaches have been developed for manipulating and folding DNA origami, resulting in compact lattice-based and wireframe designs. Platinum-based complexes, such as cisplatin and phenanthriplatin, have gained attention for their potential in cancer and antiviral treatments. Phenanthriplatin, in particular, has shown significant antitumor properties by binding to DNA at a single site and inhibiting transcription. The present work aims to study wireframe DNA origami nanostructures as possible carriers for platinum compounds in cancer therapy, employing both cisplatin and phenanthriplatin as model compounds. This research explores the assembly, platinum loading capacity, stability, and modulation of cytotoxicity in cancer cell lines. The findings indicate that nanomolar quantities of the ball-like origami nanostructure, obtained in the presence of phenanthriplatin and therefore loaded with that specific drug, reduced cell viability in MCF-7 (cisplatin-resistant breast adenocarcinoma cell line) to 33%, while being ineffective on the other tested cancer cell lines. The overall results provide valuable insights into using wireframe DNA origami as a highly stable possible carrier of Pt species for very long time-release purposes.


Regulation of mouse spermatogonial stem cell differentiation by STAT3 signaling.
Homeostasis of many tissues is maintained by self-renewal and differentiation of stem cells. Spermatogenesis is one such system relying on the activity of spermatogonial stem cells (SSCs). Several key regulators of SSC self-renewal have been identified, yet knowledge of molecules that control SSC differentiation is undefined. In this study, we found that transient impairment of STAT3 signaling enhances SSC self-renewal in vitro without affecting general spermatogonial proliferation, indicating an alteration in the balance of SSC fate decisions that inhibited differentiation. Confirming this observation, short hairpin RNA-mediated stable reduction of STAT3 expression in cultured SSCs abolished their ability to differentiate beyond the undifferentiated spermatogonial stage following transplantation into recipient testes. Collectively, these results demonstrate that STAT3 promotes the differentiation of SSCs. In contrast, STAT3 plays a central role in maintaining self-renewal of mouse embryonic stem cells, and STAT signaling is essential for self-renewal of male germline stem cells in Drosophila.


A pH-responsive bi-MIL-88B MOF coated with folic acid-conjugated chitosan as a promising nanocarrier for targeted drug delivery of 5-Fluorouracil.
Cancer has remained one of the leading causes of death worldwide, with a lack of effective treatment. The intrinsic shortcomings of conventional therapeutics regarding tumor specificity and non-specific toxicity prompt us to look for alternative therapeutics to mitigate these limitations. In this regard, we developed multifunctional bimetallic (FeCo) bi-MIL-88B-FC MOFs modified with folic acid-conjugated chitosan (FC) as drug delivery systems (DDS) for targeted delivery of 5-Fluorouracil (5-FU). The bi-MIL-88B nanocarriers were characterized through various techniques, including powder X-ray diffraction, scanning electron microscopy, energy-dispersive X-ray, thermogravimetric analysis, and Fourier transform infrared spectroscopy. Interestingly, 5-FU@bi-MIL-88B-FC showed slower release of 5-FU due to a gated effect phenomenon endowed by FC surface coating compared to un-modified 5-FU@bi-MIL-88B. The pH-responsive drug release was observed, with 58% of the loaded 5-FU released in cancer cells mimicking pH (5.2) compared to only 24.9% released under physiological pH (5.4). The in vitro cytotoxicity and cellular internalization experiments revealed the superiority of 5-FU@bi-MIL-88B-FC as a highly potent targeted DDS against folate receptor (FR) positive SW480 cancer cells. Moreover, due to the presence of Fe and Co in the structure, bi-MIL-88B exhibited peroxidase-like activity for chemodynamic therapy. Based on the results, 5-FU@bi-MIL-88B-FC could serve as promising candidate for smart DDS by sustained drug release and selective targeting.


Structure of the human gene (COX6A2) for the heart/muscle isoform of cytochrome c oxidase subunit VIa and its chromosomal location in humans, mice, and cattle.
We have mapped the gene for the heart/muscle isoform of cytochrome c oxidase (COX) subunit VIa in three mammalian species and isolated the human COX6AH gene (HGMW-approved symbol COX6A2). The bovine gene was mapped by somatic cell hybrid mapping panels to bovine chromosome BTA 25 with 94-95% concordance. The mouse gene (Cox6ah) was mapped using an interspecific backcross panel from the cross (C57BL/6J x Mus spretus)F1 x Mus spretus probed with the mouse COX VIa-H cDNA. Cox6ah was located on distal chromosome 7, between D7Mit8 and D7Mit13. From the regions of known gene conservation among these three species, we predicted that human COX6AH would be located on chromosome 16p. We hybridized a human x rodent mapping panel of somatic cell hybrids with the human cDNA to confirm this assignment. These data taken together indicated that the human COX6AH gene is located on the short arm of chromosome 16 and facilitated the isolation of the human gene from a chromosome 16-enriched library. The human COX6AH gene spans about 1 kb and contains three exons and two small introns. The sequences of the proximal 5' flanking regions of COX6AH genes are highly conserved between human, bovine, and rodent.


Clinical relevance of three subtypes of primary sinonasal lymphoma characterized by immunophenotypic analysis.
The purpose of this study was to investigate the clinical relevance of subtypes categorized by immunophenotypic analysis in primary sinonasal lymphomas. Eighty patients with localized non-Hodgkin's lymphoma involving the nasal cavity and/or paranasal sinuses were divided into three subtypes on the basis of their immunohistochemical findings: (A) B-cell lymphoma (n = 19), (B) T-cell lymphoma (n = 27), and (C) natural killer (NK)/T-cell lymphoma (n = 34). The clinicopathologic profiles, immunophenotypic data, patterns of treatment failure, and survival data among the three patient groups were retrospectively compared. The nasal cavity was the predominant site of involvement in T-cell and NK/T-cell lymphoma, whereas sinus involvement without nasal disease was common in B-cell lymphoma. Systemic B symptoms were frequently observed in NK/T-cell lymphoma. Almost all patients with NK/T-cell lymphoma showed a strong association with the Epstein-Barr virus by in situ hybridization studies. Sixty-five patients (81%) patients achieved complete remission after initial treatment, but 36 (55%) of these subsequently experienced treatment failure. Although there were no significant differences in locoregional failure rates among the patients of the three groups, distant failure was far more common in B-cell or NK/T-cell lymphoma than in T-cell lymphoma (p =.005). Most B-cell lymphoma cases showed a predilection for sites of systemic failure in the nodal and extranodal sites below the diaphragm, such as the paraaortic lymph nodes or the gastrointestinal (GI) tract, whereas patients with NK/T-cell lymphoma showed an increased risk of systemic dissemination to the skin, testes, or GI tract, including the development of hemophagocytic syndrome. The 5-year actuarial and disease-free survival rates for all patients were 57% and 51%, respectively. Of the three subtypes of primary sinonasal lymphomas, T-cell lymphoma seemed to carry the most favorable prognosis and NK/T-cell lymphoma the worst. (The 5-year actuarial survival rate was 57% for B-cell lymphoma, 80% for T-cell lymphoma, 37% for NK/T-cell lymphoma; p =.02, log-rank.) By univariate and multivariate analyses, immunophenotype was identified as the most important prognostic factor. Our data indicate that the three subtypes of primary sinonasal lymphomas classified by immunohistochemical studies exhibit different clinical profiles, different patterns of failure, and different treatment outcomes. Given these observations, it is concluded that the recognition of these distinct subsets, diagnosed on the basis of immunophenotypic study, is very important and clinically relevant in predicting their potential behavior and prognosis.


Nurses' report of in-hospital pediatric pain assessment: examining challenges and perspectives.
Pain is a symptom pediatric nurses commonly encounter in the hospital setting. Untreated pain can lead to adverse physiologic and psychological effects. This study examines in-hospital pain assessment methods nurses report using and assesses challenges, difficulties, and barriers nurses report to assessing pain in hospitalized children. Cross-sectional study of 82 pediatric nurses from all pediatric departments of a tertiary hospital in Israel. A self-report questionnaire was developed to examine how nurses assess children's in-hospital pain and barriers to in-hospital pain assessment. Nearly all nurses (90%) reported having enough knowledge to assess children's pain in the hospital, relying on child's self-report (86%) and being familiar with commonly used validated pain scales (90%). However, a majority (75%) reported not using pain scales recently and only half (58%) reported using an alternative method involving the child. Most nurses (86%) reported relying on their own overall impression of the child's pain and only a third (34%) reported involving the parents in their pain assessments. Nurses included comments stressing the importance of pain assessments and their frustration with the current validated measures available. This study adds to a growing body of literature demonstrating a gap between recommended pediatric pain assessment guidelines and reported practice, with nurses showing a resistance to relying on single-item or unidimensional measures to assess and evaluate the rich and complex pain experience. A multidimensional approach involving child self-report, parent report, and nurses' own overall impression based on clinical assessment skills of pain is discussed.


A Multicenter Randomized Trial Evaluating the Insulin-Only Configuration of the Bionic Pancreas in Adults with Type 1 Diabetes.
Objective: To evaluate the insulin-only configuration of the iLet® bionic pancreas (BP) using insulin aspart or insulin lispro in adults with type 1 diabetes (T1D). Methods: In this multicenter, randomized, controlled trial, 161 adults with T1D (18-79 years old, baseline HbA1c 5.5%-13.1%, 32% using multiple daily injections, 27% using a pump without automation, 5% using a pump with predictive low glucose suspend, and 36% using a hybrid closed loop system before the study) were randomly assigned 2:1 to use the BP (N = 107) with insulin aspart or insulin lispro (BP group) or a standard-of-care (SC) control group (N = 54) using their usual insulin delivery plus continuous glucose monitoring (CGM). The primary outcome was HbA1c at 13 weeks. Results: Mean HbA1c decreased from 7.6% ± 1.2% at baseline to 7.1% ± 0.6% at 13 weeks with BP versus 7.6% ± 1.2% to 7.5% ± 0.9% with SC (adjusted difference = -0.5%, 95% confidence interval -0.6% to -0.3%, P < 0.001). Over 13 weeks, mean time in range 70-180 mg/dL (TIR) increased by 11% (2.6 h/d) and mean CGM glucose was reduced by 16 mg/dL with BP compared with SC (P < 0.001). Improvement in these metrics was seen during the first day of BP use and by the end of the first week reached levels that remained relatively stable through 13 weeks. Analyses of time >180 mg/dL, time >250 mg/dL, and standard deviation of CGM glucose all favored the BP group (P < 0.001). The CGM-measured hypoglycemia was low at baseline (median time <54 mg/dL of 0.21% [3 min/d] for the BP group and 0.11% [1.6 min/d] for the SC group) and not significantly different between groups over the 13 weeks (P = 0.51 for time <70 mg/dL and 0.33 for time <54 mg/dL). There were 7 (6.5% of 107 participants) severe hypoglycemic events in the BP group and 2 events in the SC group (1.9% of 54 participants, P = 0.40). Conclusions: In adults with T1D, use of the BP with insulin aspart or insulin lispro improved HbA1c, TIR, and hyperglycemic metrics without increasing CGM-measured hypoglycemia compared with standard of care. Clinical Trial Registry: clinicaltrials.gov; NCT04200313.


Will the Foot Strike Pattern Change at Different Running Speeds with or without Wearing Shoes?
Runners strike their feet with three different patterns during running: forefoot, midfoot, and rearfoot. This study aimed to investigate whether runners maintain consistent patterns while running speed and foot condition change. The foot strike patterns of runners when running on a treadmill at paces ranging from slow to fast were recorded from twenty healthy male regular runners, with and without shoes, in random order. A high-speed camera was used to observe the strike patterns, which were then categorized by an experienced physical therapist. Linear-log and Pearson chi-square analysis with a significance level of α = 0.05 was performed to examine the correlation between foot strike pattern, running speed, and shoe conditions. The results suggest that runners strike with different patterns when running with and without shoes (χ2 = 99.07, p < 0.01); runners preferred to adopt heel strike regardless of running speeds when running with shoes. While running barefoot, only 23.8% of landing strikes were rearfoot, and the strike pattern distribution did not change significantly with the running speed (χ2 = 2.26, p = 0.89). In summary, the foot strike preference of runners is correlated with the foot condition (barefoot or shod) rather than running speed. For runners who intend to change their strike patterns for any reason, we recommend that they consider adjusting their footwear, which may naturally help with the foot strike adjustment. Future studies should attempt to use advanced techniques to observe further foot biomechanics in order to discover if changing strike pattern is directly correlated with lower limb injuries.


Differential effects of epidermal growth factor, transforming growth factor, and insulin on DNA and protein synthesis and morphology in serum-free cultures of AKR-2B cells.
The effects of epidermal growth factor (EGF), insulin, and a transforming growth factor from fetal bovine serum on protein synthesis, DNA synthesis, and morphology in confluent cultures of AKR-2B mouse cells have been examined. The cells were plated and grown to confluence in serum-containing medium, and then the medium was changed to MCDB 402 containing no undefined supplements for 2 days before the addition of the polypeptides to be tested. Under these conditions, all of the factors listed above stimulated rapid increases in protein synthesis. When added to cultures singly, however, only EGF stimulated significant DNA synthesis. The effect of EGF on DNA synthesis was highly synergistic with insulin. Fetal serum transforming growth factor activity, which stimulated multiple rounds of cell replication in soft agar in serum-containing medium, did not stimulate DNA synthesis in serum-free monolayer cultures of these cells when added alone or in combination with EGF or insulin. Fetal serum transforming growth factor did, however, stimulate a rapid change in the morphology of these cells from flat, nonoverlapping cells to bipolar, multilayered cultures when added to the serum-free medium.


Generation of a Library of Carbohydrate-Active Enzymes for Plant Biomass Deconstruction.
In nature, the deconstruction of plant carbohydrates is carried out by carbohydrate-active enzymes (CAZymes). A high-throughput (HTP) strategy was used to isolate and clone 1476 genes obtained from a diverse library of recombinant CAZymes covering a variety of sequence-based families, enzyme classes, and source organisms. All genes were successfully isolated by either PCR (61%) or gene synthesis (GS) (39%) and were subsequently cloned into Escherichia coli expression vectors. Most proteins (79%) were obtained at a good yield during recombinant expression. A significantly lower number (p < 0.01) of proteins from eukaryotic (57.7%) and archaeal (53.3%) origin were soluble compared to bacteria (79.7%). Genes obtained by GS gave a significantly lower number (p = 0.04) of soluble proteins while the green fluorescent protein tag improved protein solubility (p = 0.05). Finally, a relationship between the amino acid composition and protein solubility was observed. Thus, a lower percentage of non-polar and higher percentage of negatively charged amino acids in a protein may be a good predictor for higher protein solubility in E. coli. The HTP approach presented here is a powerful tool for producing recombinant CAZymes that can be used for future studies of plant cell wall degradation. Successful production and expression of soluble recombinant proteins at a high rate opens new possibilities for the high-throughput production of targets from limitless sources.


Dictyostelium discoideum as a model host for meningococcal pathogenesis.
The aim of the present study was to evaluate the possibility of studying meningococcal virulence in a new model organism, Dictyostelium discoideum, a haploid social soil amoeba that is an established host model for several human pathogens, leading to the discovery of novel virulence mechanisms. A number of virulent and hyper-virulent N. meningitidis strains, including isogenic encapsulated, unencapsulated, and lipooligosaccharide (LOS) outer core-defective derivatives, were used to test the ability of D. discoideum to internalize and grow in the presence of bacteria. Intracellular survival of the internalized bacteria was also monitored. Meningococci were internalized and killed by D. discoideum cells. The presence of a capsule did not affect the internalization, but, as in human cells, it increased the resistance of the internalized bacteria. Although both encapsulated and unencapsulated meningococci supported the growth and development of D. discoideum on an agar surface, in liquid medium the encapsulated strains were toxic to the slime mould cells. Toxicity inversely correlated with meningococcal survival in the assay medium that was not favorable to bacterial replication, suggesting that it may be due to some toxic compound released after bacterial autolysis. Intriguingly, unencapsulated isogenic strains efficiently supported Dictyostelium growth in suspension, opening the possibility that the toxicity may be associated with the capsular polysaccharide. These results suggest that several meningococcal virulence determinants, such as the capsular polysaccharide, may be remarkably effective also in Dictyostelium cells, stimulating the use of this model host to search for novel meningococcal virulence determinants.


Predictors of serious, preventable, and costly medical complications in a population of adult spinal deformity patients.
In 2008, the Centers for Medicare and Medicaid Services (CMS) established a list of hospital-acquired conditions (HACs) with significant deleterious effects on both patients and providers. Adult spinal deformity (ASD) surgery is complex and highly invasive, and as such may result in significant morbidity including these HACs. Identify predictors for developing the most common HACs among adult spinal deformity (ASD) patients undergoing corrective surgery. Retrospective analysis. One thousand one hundred and seventy-one ASD patients. HACs, Health-Related Quality of Life scores(HRQLs), Reoperation, Integrated Health State (IHS) METHODS: ASD pts undergoing surgery (>18 years, scoliosis ≥20°, SVA ≥5 cm, PT ≥25° and/or TK >60°) with complete data at BL and up to 2 years post-op were included. Patients were stratified by presence of >1 HAC, defined as at least one superficial/deep SSI, UTI, DVT, or PE within a 30-day post-op window. Random forest analysis generated 5,000 Conditional Inference Trees to compute a variable importance table for top predictors of HACs. An area-under-the-curve (AUC) methodology compared normalized HRQL scores between groups to determine an IHS with 2-year follow-up. Total of 1,171 pts (59.8 years, 76.2%F, 28.1kg/m2) underwent corrective ASD surgery, with 1,053 pts in the non-HAC group and 118 in the HAC group. Of these pts, 25.4% had UTI, 15.4% DVT, 19.2% superficial SSI, 20.8% deep SSI, and 19.2% PE. HAC pts were on average older (63.5 vs 59.3, p=.004) and more often frail (51.3 vs 39.7%, p=.021) than non-HAC pts. Postop LOS and reoperation were most associated with HAC groups: [1] LOS >7 days [2] reoperation. Patient-related predictors of HACs were [3] age >50 yerr, [4] frailty, and [13] BMI >31. Procedure-related predictors of HACs were [5] operative-time >405 minutes, [6] levels fused >9, EBL >1450 mL, and [11] decompression. BL radiographic predictors were [7] PT >20°, [9] PI-LL>6°, [10] TL Cobb angle >15°, [12] SVA C7-S1 >29 mm. No differences were observed between groups with regards to IHS ODI (0.73 vs 0.74, p=.863), SRS (1.3 vs1.3, p=.374), NRS Back (0.6 vs 0.6, p=.158). HAC had higher rates of reoperation than non-HAC (0.08 vs 0.01, p=.066), and any HAC within 30-days of index was a significant predictor of reoperation (OR: 2.448 [1.94-3.09], p<.001). In a population of ASD patients, HACs were associated with length of stay, reoperation, age, and frailty. Radiographic parameters such as pelvic tilt >20°, PI-LL >6°, & SVA >29 mm also increased odds of HACs, and should raise postoperative awareness for HAC development.


Regulation of meristem organization and cell division by TSO1, an Arabidopsis gene with cysteine-rich repeats.
In higher plants, meristem organization and cell division regulation are two fundamentally important and intimately related biological processes. Identifying and isolating regulatory genes in these processes is essential for understanding higher plant growth and development. We describe the molecular isolation and analyses of an Arabidopsis gene, TSO1, which regulates both of these processes. We previously showed that tso1 mutants displayed defects in cell division of floral meristem cells including partially formed cell walls, increased DNA content, and multinucleated cells (Liu, Z., Running, M. P. and Meyerowitz, E. M. (1997). Development 124, 665-672). Here, we characterize a second defect of tso1 in influorescence meristem development and show that the enlarged influorescence in tso1 mutants results from repeated division of one inflorescence meristem into two or more influorescence meristems. Using a map-based approach, we isolated the TSO1 gene and found that TSO1 encodes a protein with cysteine-rich repeats bearing similarity to Drosophila Enhancer of zeste and its plant homologs. In situ TSO1 mRNA expression pattern and the nuclear localization of TSO1-GFP are consistent with a regulatory role of TSO1 in floral meristem cell division and in influorescence meristem organization.


Understanding the type 2 diabetes mellitus and cardiovascular disease risk paradox.
Patients with diabetes have approximately a 2-fold increase in the risk for coronary heart disease, stroke, and death from vascular causes compared with patients who do not have diabetes. Interventions targeted at modifiable risk factors, such as smoking cessation and management of hypertension and dyslipidemia, reduce the risk of cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (T2DM). Paradoxically, large randomized studies have failed to conclusively show that intensively lowering glucose reduces CVD event rates in patients with T2DM, despite pathophysiologic and epidemiologic evidence suggesting that hyperglycemia contributes to CVD. Although initiation of intensive glycemic control early in the disease course may be associated with a reduction in the long-term risk of cardiovascular (CV) events, this approach in those with long-standing or complicated T2DM is not of clear benefit and may even be harmful in some. Failure to mitigate risk with antihyperglycemic therapy and the potential for some treatments to increase CVD risk underlies a treatment paradox. New glucose-lowering therapies are now subject to close scrutiny for CV safety before and after drug approval. Results from the first trials designed to meet the recent CV regulatory requirements have shown no increased risk of major adverse CV events but also no CV benefit from dipeptidyl peptidase-4 inhibitor therapy, as well as a potentially increased risk of hospitalization for heart failure. Conclusive evidence of CV risk reduction with glucose-lowering therapy is still lacking and scrutiny of additional agents is necessary. Type 2 diabetes mellitus is a heterogeneous disease, for which patient-centered, individualized care, and goal-setting is appropriate. Interventions that focus on the management of CV risk factors and glucose lowering with medications that are not cardiotoxic represent an optimal and attainable treatment approach.


Nocardia pseudobrasiliensis infection in a patient with arthritis.
Nocardia pseudobrasiliensis is a new taxon constituting an emerging species of human pathogenic Nocardia, which shares morphological features with N. brasiliensis. However, N. pseudobrasiliensis is more invasive and more easily disseminated, and it exhibits distinctive antibiotic susceptibility. Few clinical cases related to N. pseudobrasiliensis infection have been reported, and N. pseudobrasiliensis hydrarthrosis has not been described. Here, we analyzed the case information, diagnostic process, treatment, and prognosis of a patient with N. pseudobrasiliensis hydrarthrosis who received treatment in Zhejiang Provincial People's Hospital. Magnetic resonance imaging showed joint cavity effusion and soft tissue swelling with high signal on proton density-fat saturated images and low signal on T1-weighted images. Oil microscopy revealed abundant acid-fast-positive filaments in hydrarthrosis puncture fluid. The pathogen was identified as N. pseudobrasiliensis by matrix-assisted laser desorption ionization-time of flight mass spectrometry. In contrast to the 100% ciprofloxacin resistance displayed by N. brasiliensis, this clinical isolate of N. pseudobrasiliensis was completely susceptible. In summary, this is the first report of N. pseudobrasiliensis in joint effusion from a patient with arthritis.


Quantification of residual limb skeletal muscle perfusion with contrast-enhanced ultrasound during application of a focal junctional tourniquet.
Focal junctional tourniquets (JTs) have been developed to control hemorrhage from proximal limb injuries. These devices may permit greater collateral perfusion than circumferential tourniquets. We hypothesized that JTs eliminate large-vessel pulse pressure yet allow a small amount of residual limb perfusion that could be useful for maintaining tissue viability. Ten healthy control subjects were studied. Transthoracic echocardiography, Doppler ultrasound of the femoral artery (FA) and posterior tibial artery, and contrast-enhanced ultrasound (CEU) perfusion imaging of the anterior thigh extensor and calf plantar flexor muscles were performed at baseline and during application of a JT over the common FA. Intramuscular arterial pulsatility index was also measured from CEU intensity variation during the cardiac cycle. FA flow was eliminated by JTs in all subjects; posterior tibial flow was eliminated in all but one. Perfusion measured in the thigh and calf muscles was similar at baseline (0.33 ± 0.29 vs 0.29 ± 0.22 mL/min/g). Application of the JT resulted in a reduction of perfusion (P < .05) that was similar for the thigh and calf (0.08 ± 0.07 and 0.10 ± 0.03 mL/min/g). On CEU, microvascular flux rate was reduced by ≈55%, and functional microvascular blood volume was reduced by ≈35%. Arterial pulsatility index was reduced by ≈90% in the calf. JT inflation did not alter left ventricle dimensions, fractional shortening, cardiac output, or arterial elastance as a measure of total systolic load. Application of a JT eliminates conduit arterial pulse and markedly reduces intramuscular pulse pressure, but thigh and calf skeletal muscle perfusion is maintained at 25% to 35% of basal levels. These data suggest that JTs that are used to control limb hemorrhage allow residual tissue perfusion even when pulse pressure is absent.


A meta-analysis of gender stereotypes and bias in experimental simulations of employment decision making.
Gender bias continues to be a concern in many work settings, leading researchers to identify factors that influence workplace decisions. In this study we examine several of these factors, using an organizing framework of sex distribution within jobs (including male- and female-dominated jobs as well as sex-balanced, or integrated, jobs). We conducted random effects meta-analyses including 136 independent effect sizes from experimental studies (N = 22,348) and examined the effects of decision-maker gender, amount and content of information available to the decision maker, type of evaluation, and motivation to make careful decisions on gender bias in organizational decisions. We also examined study characteristics such as type of participant, publication year, and study design. Our findings revealed that men were preferred for male-dominated jobs (i.e., gender-role congruity bias), whereas no strong preference for either gender was found for female-dominated or integrated jobs. Second, male raters exhibited greater gender-role congruity bias than did female raters for male-dominated jobs. Third, gender-role congruity bias did not consistently decrease when decision makers were provided with additional information about those they were rating, but gender-role congruity bias was reduced when information clearly indicated high competence of those being evaluated. Fourth, gender-role congruity bias did not differ between decisions that required comparisons among ratees and decisions made about individual ratees. Fifth, decision makers who were motivated to make careful decisions tended to exhibit less gender-role congruity bias for male-dominated jobs. Finally, for male-dominated jobs, experienced professionals showed smaller gender-role congruity bias than did undergraduates or working adults.


[Chagas disease in the Netherlands: an estimate of the number of patients].
A total of 8-10 million persons are infected worldwide with Trypanosoma cruzi, the causative parasite of Chagas disease, most of whom are inhabitants of Latin America. Due to the increased migration of peoples, Chagas disease has been on the uprise outside Latin America, including in Europe. The course of Chagas, also called American trypanosomiasis, runs in 2 phases: an acute phase lasting approximately 2 months, and a chronic phase in which symptoms may appear years after infection. Without treatment, the patient will remain infected for life. The acute phase is usually asymptomatic; in the chronic phase of American trypanosomiasis, severe gastro-intestinal and cardiac abnormalities may develop, finally with fatal course. In the Netherlands, the number of immigrants who would serologically test positive for American trypanosomiasis is estimated to be between 726 and 2929. Healthcare providers in the Netherlands may encounter patients who have Chagas disease more and more frequently. The screening of pregnant women and blood donors at risk for American trypanosomiasis should be considered.


Impact of in-hospital revascularization on survival in patients with non-ST-elevation acute coronary syndrome and congestive heart failure.
Patients with non-ST-elevation acute coronary syndrome complicated by congestive heart failure (CHF) have a poor prognosis. The aims of this study were to describe the use of revascularization in non-ST-elevation acute coronary syndrome and CHF and to analyze its impact on survival. In the Global Registry of Acute Coronary Events, 29 844 patients with non-ST-elevation acute coronary syndrome were enrolled at 120 hospitals in 14 countries between April 1999 and June 2007; 4953 had CHF at presentation. One fifth of the patients with CHF underwent revascularization versus 35% of those without CHF (P<0.001). Among CHF patients, revascularized patients had lower-risk baseline clinical characteristics than nonrevascularized patients and were more likely to receive evidence-based cardiac medications. Hospital rates were not affected by revascularization (adjusted hazard ratio 0.97, 95% confidence interval 0.72 to 1.33, P=0.87). Death from discharge to 6-month follow-up was lower in patients who underwent revascularization than in those who did not (odds ratio 0.51, 95% confidence interval 0.35 to 0.74, P<0.001). This difference persisted after adjustment for GRACE risk score variables, country, and propensity for revascularization (odds ratio 0.58, 95% confidence interval 0.40 to 0.85, P=0.005). When revascularization as a time-varying covariate was taken into account in an adjusted Cox regression, the rate of death was again lower in patients undergoing revascularization (hazard ratio 0.64, 95% confidence interval 0.45 to 0.93, P=0.02). This observational study suggests a low use of in-hospital revascularization in non-ST-elevation acute coronary syndrome patients with CHF. The consistent reduction in postdischarge death in revascularized patients suggests that broader application of revascularization in this high-risk group may be beneficial.


Recovery of children following hospitalisation for complicated severe acute malnutrition.
Nutritional recovery and hospital readmission following inpatient management of complicated severe acute malnutrition (SAM) are poorly characterised. We aimed to ascertain patterns and factors associated with hospital readmission, nutritional recovery and morbidity, in children discharged from hospital following management of complicated SAM in Zambia and Zimbabwe over 52-weeks posthospitalization. Multivariable Fine-Gray subdistribution hazard models, with death and loss to follow-up as competing risks, were used to identify factors associated with hospital readmission; negative binomial regression to assess time to hospitalisation and ordinal logistic regression to model factors associated with nutritional recovery. A total of 649 children (53% male, median age 18.2 months) were discharged to continue community nutritional rehabilitation. All-cause hospital readmission was 15.4% (95% CI 12.7, 18.6) over 52 weeks. Independent risk factors for time to readmission were cerebral palsy (adjusted subhazard ratio (aSHR): 2.96, 95% CI 1.56, 5.61) and nonoedematous SAM (aSHR: 1.64, 95%CI 1.03, 2.64). Unit increases in height-for-age Z-score (HAZ) (aSHR: 0.82, 95% CI 0.71, 0.95) and enrolment in Zambia (aSHR: 0.52, 95% CI 0.28, 0.97) were associated with reduced subhazard of time to readmission. Young age, SAM at discharge, nonoedematous SAM and cerebral palsy were associated with poor nutritional recovery throughout follow-up. Collectively, nonoedematous SAM, ongoing SAM at discharge, cerebral palsy and low HAZ are independent risk factors for readmission and poor nutritional recovery following complicated SAM. Children with these high-risk features should be prioritised for additional convalescent care to improve long-term outcomes.


One-Step Approach to Identifying Gestational Diabetes Mellitus: Association With Perinatal Outcomes.
To compare perinatal outcomes before and after a clinical guideline change from a two-step to a one-step approach to screening for gestational diabetes mellitus (GDM). We conducted a before-after cohort study of women with singleton live birth deliveries within Kaiser Permanente Washington, a mixed-model health plan in Washington state. We used Kaiser Permanente Washington electronic health data and linked birth certificates. We compared outcomes before (January 2009-March 2011) and after (April 2012-December 2014) the guideline change among women who received prenatal care from health care providers internal to Kaiser Permanente Washington (n=4,977 before, n=6,337 after). We made the same comparison among women who received prenatal care from external health care providers (not exposed to the guideline change; n=3,386 before, n=4,454 after) to control for time trends unrelated to the guideline change. Adjusted relative risks and 95% CIs were estimated using Poisson generalized estimating equations. After the guideline change, receipt of the one-step approach became widespread among women cared for by Kaiser Permanente Washington internal providers (87%), and use of insulin increased 3.7-fold from 1.2% to 4.4%. Among women cared for by Kaiser Permanente Washington internal providers, GDM increased from 6.9% to 11.4%, induction of labor from 25.2% to 28.6%, neonatal hypoglycemia from 1.3% to 2.0%, and outpatient nonstress testing from 134.6 to 157.0 test days per 100 women. After accounting for background trends in outcomes (based on the women cared for by external providers), the guideline change was associated with increased incidence of GDM (relative risk [RR] 1.41, 95% CI 1.17-1.69), labor induction (RR 1.20, 95% CI 1.09-1.32), neonatal hypoglycemia (RR 1.77, 95% CI 1.14-2.75), and nonstress testing (RR 1.12, 95% CI 1.02-1.24% per 100 women). There was no association with other outcomes including cesarean delivery or macrosomia. Adopting the one-step approach was associated with a 41% increase in the diagnosis of GDM without improved maternal or neonatal outcomes.


Effects of relative humidity on the broadband extinction performance of bioaerosol.
Bioaerosol, a significant constituent of the atmosphere, exhibits excellent broadband extinction performance and has attracted increasing attentions in the fields of atmospheric science, environmental science and electromagnetic field, et al. Relative humidity of the atmosphere has obvious diurnal and seasonal variation characteristics, and the frequent variation of relative humidity has a significant impact on bioaerosol in the atmosphere. However, the influence of relative humidity on broadband extinction performance of bioaerosol is unclear. Herein, we present the humidity growth model of bioaerosol. And the variation law of broadband extinction performance of bioaerosol in different humidity conditions was obtained by simulation. The simulation results and experimental data from an aerosol chamber experiment show that as the relative humidity values above 70%, the broadband extinction performance of bioaerosol will be increased with humidity. As the relative humidity increases from 70% to 90%, the extinction performance of AN0913 spores increase about 30% in visible and mid-infrared bands, about 20% in ultraviolet and far-infrared bands. And the extinction performance of AO0907 spores increase about 23% in the all four bands.


The silent majority: The typical Canadian sex worker may not be who we think.
Most sex worker population studies measure population at discrete points in time and very few studies have been done in industrialized democracies. The purpose of this study is to consider how time affects the population dynamics of contact sex workers in Canada using publicly available internet advertising data collected over multiple years. 3.6 million web pages were collected from advertising sites used by contact sex workers between November, 2014 and December, 2016 inclusive. Contacts were extracted from ads and used to identify advertisers. First names were used to estimate the number of workers represented by an advertiser. Counts of advertisers and names were adjusted for missing data and overcounting. Two approaches for correcting overcounts are compared. Population estimates were generated weekly, monthly and for the two year period. The length of time advertisers were active was also estimated. Estimates are also compared with related research. Canadian sex workers typically advertised individually or in small collectives (median name count 1, IQR 1-2, average 1.8, SD 4.4). Advertisers were active for a mean of 73.3 days (SD 151.8, median 14, IQR 1-58). Advertisers were at least 83.5% female. Respectively the scaled weekly, monthly, and biannual estimates for female sex workers represented 0.2%, 0.3% and 2% of the 2016 Canadian female 20-49 population. White advertisers were the most predominant ethnic group (53%). Sex work in Canada is a more pervasive phenomenon than indicated by spot estimates and the length of the data collection period is an important variable. Non-random samples used in qualitative research in Canada likely do not reflect the larger sex worker population represented in advertising. The overall brevity of advertising activity suggests that workers typically exercise agency, reflecting the findings of other Canadian research.


9(10)-alkoxystearic acids lengthen the circadian period of a fatty acid auxotroph of Neurospora crassa.
9- and 10-Alkoxystearic acids with alkoxy groups of varying size were synthesized by solvomercuration of methyl oleate. These "knobbed" fatty acids were used to supplement a Neurospora strain carrying the cel mutation, which confers a partial fatty acid deficiency. Supplemental unsaturated or short-chain fatty acids are known to lengthen dramatically the circadian period of spore formation (conidiation) in cel strains. A similar dramatic lengthening was obtained with the alkoxy supplements. The change in period, however, did not correlate positively with the size of the knob. Smaller knobbed analogs gave somewhat greater period lengthening and were removed from the medium faster. It may be that the knobbed analogs cause period lengthening by an indirect effect on Neurospora membranes rather than, or in addition to, a direct perturbation.


Alternate complement pathway induction of aggregation and release of 5-hydroxytryptamine and adenosine diphosphate by rabbit platelets.
The present studies investigated patterns of rabbit platelet aggregation and release of 5-hydroxytryptamine (5HT) utilizing nine variables: three different types of challenge, soluble antigen and antibody (AG-AB), zymosan (Z), an agent known to activate the alternate complement pathway (ACP), and Z preincubated in lightly heparinized plasma so as to become coated with complement (ZC); three different types of platelet-rich plasma (PRP), lightly heparinized PRP in which both complement pathways are active, ethylene glycol tetraacetic acid-PRP (EGTA-PRP) in which only the ACP is active, and ethylene diamine tetraacetic acid PRP (EDTA-PRP), which inhibits both complement pathways; three different types of inhibitors, cobra venom factor (CoF), which causes activation of C3 proactivator (C3PA) to C3 activator (C3A) and fluid phase decomplementation of C3 and C5 through C9, adenosine monophosphate (AMP), a specific antagonist of ADP, and tosyl arginine methyl ester (TAME), an inhibitor thought to act not only on the first component of complement, but also on a platelet membrane site of mediating complement-induced platelet injury as well as on C3PAse. In heparinized PRP, both AG-AB and Z produced biphasic aggregation and prompt and extensive 5HT release. A brief lag period noted with both AG-AB and Z challenge was not observed with ZC challenge, indicating that this lag period represented time required for generation of the necessary complement-dependent membrane-injuring activity. Prior decomplementation by CoF entirely prevented both aggregation and release by either AG-AB or Z but by ZC, indicating first that fluid-phase ACP activation did not produce platelet injury, and second that ZC had on its surface an activity capable of producing immediate biphasic aggregation and prompt 5HT release without the further participation of later acting complement components. Both AMP and TAME eliminated the second phase of aggregation and diminished or eliminated 5HT release with all three challenges, suggesting that both inhibitors might be operative on similar or identical platelet membrane receptors mediating complement-dependent platelet injury. In EGTA-PRP, AG-AB and Z produced delayed monophasic aggregation and delayed and diminished 5HT release, whereas ZC produced immediate although monophasic aggregation but delayed and diminished 5HT release. This suggested that all three challenges were capable of producing ACP-mediated platelet injury.


Nanopore gates via reversible crosslinking of polymer brushes: a theoretical study.
Polymer-brush-modified nanopores are synthetic structures inspired by the gated transport exhibited by their biological counterparts. This work theoretically analyzes how the reversible crosslinking of a polymer network by soluble species can be used to control transport through nanochannels and pores. The study was performed with a molecular theory that allows inhomogeneities in the three spatial dimensions and explicitly takes into account the size, shape and conformations of all molecular species, considers the intermolecular interactions between the polymers and the soluble crosslinkers and includes the presence of a translocating particle inside the pore. It is shown than increasing the concentration of the soluble crosslinkers in bulk solution leads to a gradual increase of its number within the pore until a critical bulk concentration is reached. At the critical concentration, the number of crosslinkers inside the pore increases abruptly. For long chains, this sudden transition triggers the collapse of the polymer brush to the center of the nanopore. The resulting structure increases the free-energy barrier that a translocating particle has to surmount to go across the pore and modifies the route of translocation from the axis of the pore to its walls. On the other hand, for short polymer chains the crosslinkers trigger the collapse of the brush to the pore walls, which reduces the translocation barrier.


Increased lipolysis and decreased leptin production by human omental as compared with subcutaneous preadipocytes.
Site differences in adipose tissue function may have implications for insulin-resistant conditions. In mature adipose tissue, subcutaneous adipocytes have higher leptin secretion, similar tumor necrosis factor (TNF)-alpha secretion, and lower catecholamine-stimulated lipolysis as compared with omental adipocytes. In this study, lipolysis and leptin and TNF-alpha secretion were compared between human omental and subcutaneous preadipocytes. After 16 days of incubation in a minimal differentiation medium, leptin mRNA and secretion were found to be two to eight times higher in subcutaneous than omental preadipocytes (P < 0.05). On the other hand, norepinephrine-induced lipolysis was about two times higher in the omental than in the subcutaneous preadipocytes, whereas basal lipolysis did not differ between the two regions. TNF-alpha secretion was marginally but significantly higher in the omental than in the subcutaneous preadipocytes. Preadipocyte differentiation was equal in both regions and was augmented to the same extent by different thiazolidinediones (rosiglitazone, pioglitazone, or troglitazone) in the two depots. In the presence of rosiglitazone, leptin secretion remained about three times higher and norepinephrine-induced lipolysis about six times lower in subcutaneous as compared with omental preadipocytes (P < 0.05), whereas TNF-alpha secretion and basal lipolysis were similar in preadipocytes from the two regions. These findings remained unaltered even if rosiglitazone was removed from the medium. However, leptin mRNA showed no regional differences in rosiglitazone-treated cells. Thus, regional differences in adipocyte leptin secretion as well as in norepinephrine-induced lipolysis are marked and present during different stages of preadipocyte differentiation and seem to be determined by intrinsic (i.e., primary) factors.


Circular RNA ciRS-7 correlates with advance disease and poor prognosis, and its down-regulation inhibits cells proliferation while induces cells apoptosis in non-small cell lung cancer.
This study aimed to assess the association of circular RNA (circRNA) ciRS-7 expression with clinicopathological characteristics and prognosis of non-small cell lung cancer (NSCLC) patients, and to investigate its effect on cells proliferation as well as apoptosis in NSCLC. 132 patients with primary NSCLC who received surgical resection were recruited in this retrospective study. All patients' tumor tissue and paired adjacent tissue were collected for circRNA ciRS-7 expression detection by RT-qPCR. Disease-free survival (DFS) and overall survival (OS) were calculated. CCK-8 and Annexin-V/propidium iodide (AV/PI) assays were performed to detect cells proliferation and apoptosis in A549 cells after circRNA ciRS-7 inhibition plasmid transfection. CircRNA ciRS-7 expression in tumor tissue was elevated compared to paired adjacent tissue, and positively correlated with tumor size, lymph node metastasis and tumor node metastasis (TNM) stages. K-M curves illustrated that circRNA ciRS-7 high expression was correlated with both shorter DFS and OS, and multivariate Cox's proportional hazards regression analysis showed that circRNA ciRS-7 high expression was an independent factor for predicting unfavorable DFS and OS. Cells methods revealed that circRNA ciRS-7 expression was elevated in NSCLC cell lines (A549, PC9, NCI-H1299 and NCI-H1650) compared to normal lung epithelial cells (DEAS-2B), and the inhibition of circRNA ciRS-7 expression reduced cells proliferation and promoted cells apoptosis in A549 cells. CircRNA ciRS-7 overexpression is associated with advanced disease and poor prognosis in NSCLC patients, and the down-regulation of circRNA ciRS-7 inhibits tumor cells proliferation as well as improves cells apoptosis.


Information theory applied to the sparse gene ontology annotation network to predict novel gene function.
Despite advances in the gene annotation process, the functions of a large portion of gene products remain insufficiently characterized. In addition, the in silico prediction of novel Gene Ontology (GO) annotations for partially characterized gene functions or processes is highly dependent on reverse genetic or functional genomic approaches. To our knowledge, no prediction method has been demonstrated to be highly accurate for sparsely annotated GO terms (those associated to fewer than 10 genes). We propose a novel approach, information theory-based semantic similarity (ITSS), to automatically predict molecular functions of genes based on existing GO annotations. Using a 10-fold cross-validation, we demonstrate that the ITSS algorithm obtains prediction accuracies (precision 97%, recall 77%) comparable to other machine learning algorithms when compared in similar conditions over densely annotated portions of the GO datasets. This method is able to generate highly accurate predictions in sparsely annotated portions of GO, where previous algorithms have failed. As a result, our technique generates an order of magnitude more functional predictions than previous methods. A 10-fold cross validation demonstrated a precision of 90% at a recall of 36% for the algorithm over sparsely annotated networks of the recent GO annotations (about 1400 GO terms and 11,000 genes in Homo sapiens). To our knowledge, this article presents the first historical rollback validation for the predicted GO annotations, which may represent more realistic conditions than more widely used cross-validation approaches. By manually assessing a random sample of 100 predictions conducted in a historical rollback evaluation, we estimate that a minimum precision of 51% (95% confidence interval: 43-58%) can be achieved for the human GO Annotation file dated 2003. The program is available on request. The 97,732 positive predictions of novel gene annotations from the 2005 GO Annotation dataset and other supplementary information is available at http://phenos.bsd.uchicago.edu/ITSS/. Supplementary data are available at Bioinformatics online.


MAGE genes in the kidney: identification of MAGED2 as upregulated during kidney injury and in stressed tubular cells.
Mutations in Melanoma Antigen-encoding Gene D2 (MAGED2) promote tubular dysfunction, suggesting that MAGE proteins may play a role in kidney pathophysiology. We have characterized the expression and regulation of MAGE genes in normal kidneys and during kidney disease. The expression of MAGE genes and their encoded proteins was explored by systems biology multi-omics (kidney transcriptomics and proteomics) in healthy adult murine kidneys and following induction of experimental acute kidney injury (AKI) by a folic acid overdose. Changes in kidney expression during nephrotoxic AKI were validated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), western blot and immunohistochemistry. Factors regulating gene expression were studied in cultured tubular cells. Five MAGE genes (MAGED1, MAGED2, MAGED3, MAGEH1, MAGEE1) were expressed at the mRNA level in healthy adult mouse kidneys, as assessed by RNA-Seq. Additionally, MAGED2 was significantly upregulated during experimental AKI as assessed by array transcriptomics. Kidney proteomics also identified MAGED2 as upregulated during AKI. The increased kidney expression of MAGED2 mRNA and protein was confirmed by qRT-PCR and western blot, respectively, in murine folic acid- and cisplatin-induced AKI. Immunohistochemistry located MAGED2 to tubular cells in experimental and human kidney injury. Tubular cell stressors [serum deprivation and the inflammatory cytokine tumour necrosis factor-like weak inducer of apoptosis (TWEAK)] upregulated MAGED2 in cultured tubular cells. MAGED2 is upregulated in tubular cells in experimental and human kidney injury and is increased by stressors in cultured tubular cells. This points to a role of MAGED2 in tubular cell injury during kidney disease that should be dissected by carefully designed functional approaches.


Local adaptation, phenotypic differentiation, and hybrid fitness in diverged natural populations of Arabidopsis lyrata.
Selection for local adaptation results in genetic differentiation in ecologically important traits. In a perennial, outcrossing model plant Arabidopsis lyrata, several differentiated phenotypic traits contribute to local adaptation, as demonstrated by fitness advantage of the local population at each site in reciprocal transplant experiments. Here we compared fitness components, hierarchical total fitness and differentiation in putatively ecologically important traits of plants from two diverged parental populations from different continents in the native climate conditions of the populations in Norway and in North Carolina (NC, U.S.A.). Survival and number of fruits per inflorescence indicated local advantage at both sites and aster life-history models provided additional evidence for local adaptation also at the level of hierarchical total fitness. Populations were also differentiated in flowering start date and floral display. We also included reciprocal experimental F(1) and F(2) hybrids to examine the genetic basis of adaptation. Surprisingly, the F(2) hybrids showed heterosis at the study site in Norway, likely because of a combination of beneficial dominance effects from different traits. At the NC site, hybrid fitness was mostly intermediate relative to the parental populations. Local cytoplasmic origin was associated with higher fitness, indicating that cytoplasmic genomes also may contribute to the evolution of local adaptation.


Simultaneous treatment with 1-beta-D-arabinofuranosylcytosine and daunorubicin induces cross-resistance to both drugs due to a combination-specific mechanism in HL60 cells.
We have established a human myelogenous leukemia cell line (HL60/AD) that is 10-fold cross-resistant to both 1-beta-D-arabinofuranosylcytosine (ara-C) and daunorubicin; the cell line was isolated from HL60 by simultaneous treatment with these two agents at low drug concentrations attainable in clinical trials. HL60/AD was found to have multiple resistance mechanisms. With regard to ara-C, HL60/AD cells showed decreased deoxycytidine kinase activity but did not show elevation of cytidine deaminase activity or a decrease in ara-C influx. With regard to daunorubicin, a decrease in topoisomerase II activity was found. A decrease in intracellular accumulation of daunorubicin was also found. P-glycoprotein was not detected, but the multidrug resistance-associated protein was expressed. Furthermore, an increase of total cellular glutathione (GSH) content was found. Interestingly, the resistance of HL60/AD cells not only to daunorubicin but also to ara-C was markedly reversed by treatment with L-buthionine-(S,R)-sulfoximine (BSO), a potent inhibitor of GSH synthesis. After exposure of HL60/AD to ara-C, mitochondrial membrane potential and reactive oxygen intermediates showed no significant change, but a considerable loss of mitochondrial membrane potential and an increase in reactive oxygen intermediate generation were caused by pre-incubation with BSO. Neither elevation of GSH nor reversal of resistance by BSO was found in ara-C-resistant HL60 cells that were selected only with ara-C. These findings suggest that in addition to the summation of the mechanisms of resistance to each agent reported previously, an increased level of GSH plays an important role in the cross-resistance induced in HL60/AD cells by simultaneous exposure to both drugs.


Sauropus androgynus and papaverine do not induce bronchiolitis obliterans in Sprague-Dawley rats.
In August 1995, an outbreak of bronchiolitis obliterans was observed in Taiwan. This progressive respiratory distress disease was associated with consumption of the uncooked vegetable, Sauropus androgynus. The vegetable is reportedly high in papaverine, a chemical that affects vasodilatation. This study determined whether S androgynus and papaverine induce bronchiolitis obliterans in Sprague-Dawley (S/D) rats. The feeding doses were derived from the mean amount (in mg/kg body weight) that humans had eaten. In part A of the experiment, 30 S/D rats were fed various concentrations of S androgynus juice for eight weeks. The rats were divided into six groups, including a normal control and study groups with one time (1X), 10 times (10X, leaf only and mixed leaf and stalk) and 30 times (30X, leaf only and mixed leaf and stalk) concentration. In part B, 33 S/D rats were fed different doses of papaverine for 4 weeks. The rats were also divided into six groups, including normal control, oral feeding subgroups (1X, 10X and 20X) and intraperitoneal injection subgroups (5X and 10X). The degree of inflammation was defined semiquantitatively in the bronchioles and pulmonary vessel adventitia as including grade 0 (no inflammation), grade 1 (minimal), grade 2 (mild), grade 3 (moderate) and grade 4 (severe). There was no evidence of bronchiolitis obliterans in either experiment. The histopathologic findings of the lungs revealed normal or only minimal inflammatory changes in the peribronchial and perivascular adventitia in each group of both studies. The mean degree of inflammatory changes in the study groups was no different from that of control group. We conclude that ingestion of high-dose S anggogynus and papaverine do not induce injuries to the airways, alveoli or pulmonary vessels in the animal model of S/D rats. The species barrier may be one of the possible reasons.


Setting the scene and generating evidence for malaria elimination in Southern Mozambique.
Mozambique has historically been one of the countries with the highest malaria burden in the world. Starting in the 1960s, malaria control efforts were intensified in the southern region of the country, especially in Maputo city and Maputo province, to aid regional initiatives aimed to eliminate malaria in South Africa and eSwatini. Despite significant reductions in malaria prevalence, elimination was never achieved. Following the World Health Organization's renewed vision of a malaria-free-world, and considering the achievements from the past, the Mozambican National Malaria Control Programme (NMCP) embarked on the development and implementation of a strategic plan to accelerate from malaria control to malaria elimination in southern Mozambique. An initial partnership, supported by the Bill and Melinda Gates Foundation and the La Caixa Foundation, led to the creation of the Mozambican Alliance Towards the Elimination of Malaria (MALTEM) and the Malaria Technical and Advisory Committee (MTAC) to promote national ownership and partner coordination to work towards the goal of malaria elimination in local and cross-border initiatives. Surveillance systems to generate epidemiological and entomological intelligence to inform the malaria control strategies were strengthened, and an impact and feasibility assessment of various interventions aimed to interrupt malaria transmission were conducted in Magude district (Maputo Province) through the "Magude Project". The primary aim of this project was to generate evidence to inform malaria elimination strategies for southern Mozambique. The goal of malaria elimination in areas of low transmission intensity is now included in the national malaria strategic plan for 2017-22 and the NMCP and its partners have started to work towards this goal while evidence continues to be generated to move the national elimination agenda forward.


SdH Oscillations from the Dirac Surface State in the Fermi-Arc Antiferromagnet NdBi.
The recent progress in CuMnAs and Mn3X (X = Sn, Ge, Pt) shows that antiferromagnets (AFMs) provide a promising platform for advanced spintronics device innovations. Most recently, a switchable Fermi-arc is discovered by the ARPES technique in antiferromagnet NdBi, but the knowledge about electron-transport property and the manipulability of the magnetic structure in NdBi is still vacant to date. In this study, SdH oscillations are successfully verified from the Dirac surface states (SSs) with 2-dimensionality and nonzero Berry phase. Particularly, it is observed that the spin-flop transition only appears when the external magnetical field is applied along [001] direction, and features obvious hysteresis for the first time in NdBi, which provides a powerful handle for adjusting the spin texture in NdBi. Crucially, the DFT shows the Dirac cone and the Fermi arc strongly depend on the high-order magnetic structure of NdBi and further reveals the orbital magnetic moment of Nd plays a crucial role in fostering the peculiar SSs, leading to unveil the mystery of the band-splitting effect and to manipulate the electronic transport, high-effectively, in the thin film works in NdBi. It is believed that this study provides important guidance for the development of new antiferromagnet-based spintronics devices based on cutting-edge rare-earth monopnictides.


Equation of state and self-bound droplet in Rabi-coupled Bose mixtures.
Laser induced transitions between internal states of atoms have been playing a fundamental role to manipulate atomic clouds for many decades. In absence of interactions each atom behaves independently and their coherent quantum dynamics is described by the Rabi model. Since the experimental observation of Bose condensation in dilute gases, static and dynamical properties of multicomponent quantum gases have been extensively investigated. Moreover, at very low temperatures quantum fluctuations crucially affect the equation of state of many-body systems. Here we study the effects of quantum fluctuations on a Rabi-coupled two-component Bose gas of interacting alkali atoms. The divergent zero-point energy of gapless and gapped elementary excitations of the uniform system is properly regularized obtaining a meaningful analytical expression for the beyond-mean-field equation of state. In the case of attractive inter-particle interaction we show that the quantum pressure arising from Gaussian fluctuations can prevent the collapse of the mixture with the creation of a self-bound droplet. We characterize the droplet phase and discover an energetic instability above a critical Rabi frequency provoking the evaporation of the droplet. Finally, we suggest an experiment to observe such quantum droplets using Rabi-coupled internal states of K39 atoms.


Comparison of information obtained by operative note abstraction with that recorded on a standardized data collection form.
The Ischemic Optic Neuropathy Decompression Trial compared optic nerve decompression surgery with careful follow-up for treatment of patients with nonarteritic ischemic optic neuropathy. Surgeons submitted a standardized data collection form and operative notes for 123 patients randomized to and undergoing surgery. The purpose of this study was to see whether operative notes have sufficient and reliable data to avoid development of a surgery data collection form in future trials. We abstracted data from Ischemic Optic Neuropathy Decompression Trial patient operative notes, calculated the proportion of completed responses, and compared abstracted responses with those originally recorded on corresponding case report forms. Variables used to identify persons, dates, or eye (left/right) were reported 100% of the time on operative notes and with excellent agreement with those recorded on the case report form (median agreement, 100%; range, 95% to 100%). Categoric variables, used to establish the characteristics of surgical steps, were also reported reliably on operative notes (median agreement, 84%; range, 0 to 100%). Open-ended variables tended to be reported more frequently on operative notes (exact agreement, 57% and 34%, respectively, for complications and postoperative medications). Quantitative variables were infrequently reported but correlated well with values reported on the data collection forms (Pearson correlation coefficients, 0.78, 0.79, 0.94, 0.96). For many variables, disagreements were minor and often were related to interpretation of the operative notes by the abstractor. In our trial, operative note abstraction adequately documented surgery date and surgeon and provided more complete information than the standardized report form with respect to complications but did not provide complete information for other variables.


Restoration of TRAIL-induced apoptosis in resistant human pancreatic cancer cells by a novel FAK inhibitor, PH11.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) emerges as one of the most-promising experimental cancer therapeutic drugs and is currently being tested in clinical trials. However, both intrinsic and acquired resistance of human cancer cells to TRAIL-induced apoptosis poses a huge problem in establishing clinically efficient TRAIL therapies. To assess the regulation of TRAIL-resistance in human pancreatic cancer cells, we studied the TRAIL resistant pancreatic cell line PANC-1. We show that treatment with PH11, a novel Focal Adhesion Kinase (FAK) inhibitor in association with TRAIL rapidly induces apoptosis in TRAIL-resistant PANC-1 cells, but not in normal human fibroblast cells. To explain sensitization, we showed that PH11 restores TRAIL apoptotic pathway in PANC-1 cells through down-regulation of c-FLIP via inhibition of FAK and the phosphatidylinositol-3 kinase (PI3K)/AKT pathways. These findings suggest that this combined treatment may offer an attractive therapeutic strategy for safely and efficiently treating pancreatic cancer.


Clinical review 123: Anabolic therapy for osteoporosis.
All currently available, approved therapies for osteoporosis inhibit bone resorption. By acting at this site in the bone remodeling cycle, estrogens, selective estrogen receptor modulators, calcitonin, and the bisphosphonates all have the capacity to increase bone mineral density and to reduce the risk of new fractures. There can be no doubt that these agents have had an enormous impact on our diagnostic and therapeutic approach to osteoporosis. Despite their great value, the antiresorptives are generally not associated with dramatic increases in bone mass, and their action to reduce fracture risk, although highly significant, is rarely more than 50% of the baseline risk. Another approach is anabolic therapy, in which bone formation is directly stimulated. In this review we will summarize the anabolic agents that have been studied and present a current view of their current standing. Fluoride, GH, insulin-like growth factor I, the statins, and PTH will be reviewed. Although still in development, approaches to combination therapy with antiresorptives and anabolic agents are also promising.


Differences in APOBEC3G expression in CD4+ T helper lymphocyte subtypes modulate HIV-1 infectivity.
The cytidine deaminases APOBEC3G and APOBEC3F exert anti-HIV-1 activity that is countered by the HIV-1 vif protein. Based on potential transcription factor binding sites in their putative promoters, we hypothesized that expression of APOBEC3G and APOBEC3F would vary with T helper lymphocyte differentiation. Naive CD4+ T lymphocytes were differentiated to T helper type 1 (Th1) and 2 (Th2) effector cells by expression of transcription factors Tbet and GATA3, respectively, as well as by cytokine polarization. APOBEC3G and APOBEC3F RNA levels, and APOBEC3G protein levels, were higher in Th1 than in Th2 cells. T cell receptor stimulation further increased APOBEC3G and APOBEC3F expression in Tbet- and control-transduced, but not in GATA3-transduced, cells. Neutralizing anti-interferon-gamma antibodies reduced both basal and T cell receptor-stimulated APOBEC3G and APOBEC3F expression in Tbet- and control-transduced cells. HIV-1 produced from Th1 cells had more virion APOBEC3G, and decreased infectivity, compared to virions produced from Th2 cells. These differences between Th1- and Th2-produced virions were greater for viruses lacking functional vif, but also seen with vif-positive viruses. Over-expression of APOBEC3G in Th2 cells decreased the infectivity of virions produced from Th2 cells, and reduction of APOBEC3G in Th1 cells increased infectivity of virions produced from Th1 cells, consistent with a causal role for APOBEC3G in the infectivity difference. These results indicate that APOBEC3G and APOBEC3F levels vary physiologically during CD4+ T lymphocyte differentiation, that interferon-gamma contributes to this modulation, and that this physiological regulation can cause changes in infectivity of progeny virions, even in the presence of HIV-1 vif.


Pathoecology of Chiribaya parasitism.
The excavations of Chiribaya culture sites in the Osmore drainage of southern Peru focused on the recovery of information about prehistoric disease, including parasitism. The archaeologists excavated human, dog, guinea pig, and llama mummies. These mummies were analyzed for internal and external parasites. The results of the analysis and reconstruction of prehistoric life from the excavations allows us to interpret the pathoecology of the Chiribaya culture.


Student Self-Assessment of Operative Dentistry Experiences: A Time-Dependent Exercise in Self-Directed Learning.
The aim of this study was to evaluate the process of student self-assessment on operative dentistry skills across four years at the University of Louisville School of Dentistry. First, a retrospective analysis of the Class of 2016 students' self-assessment and faculty assessment grade sheets was conducted to determine mean differences and correlations across time. Both preclinical (D2: n=120) and clinical (D3: n=120; D4: n=120) grade sheets were evaluated. Second, 25 students from each of the D1, D2, D3, and D4 classes in 2016 were asked to evaluate dentoform work, and 25 operative calibrated faculty members graded the same two dentoforms. The results of the retrospective analysis were that the D2 students' self-assessment scores were significantly higher than the faculty scores (t-test; p<0.05), and there was a negative correlation of scores (r=-0.503). The D3 students' self-assessment scores were also significantly higher than the faculty scores (t-test; p<0.05), and there was a negative correlation (r=-0.235). The D4 students' self-assessment scores were not significantly different from the faculty scores (t-test; p>0.05), and there was a positive correlation (r=0.408). In the prospective analysis, the D1, D2, and D3 students graded the dentoforms significantly higher (ANOVA; p<0.05) than did the D4 students and faculty members. There was an increasing correlation of scores directly related to experience (D1: r=-0.120; D2: r=0.255; D3: r=0.352; D4: r=0.689). These results support the concept that students' self-assessment is a learned process through experiential and continual encounters across time. The summative goal for all dental schools is to provide students with the skills and knowledge to critically evaluate their work for self-directed learning.


Divergent regulation of human and rat proglucagon gene promoters in vivo.
A single mammalian proglucagon gene is expressed in the brain, islets, and intestinal enteroendocrine cells, which gives rise to a unique profile of proglucagon-derived peptides (PGDPs) in each tissue. The biological importance of glucagon, glucagon-like peptide (GLP)-1, and GLP-2 has engendered considerable interest in the factors regulating the synthesis and secretion of the PGDPs in vivo. Although rat proglucagon gene transcription has been extensively studied, the factors important for control of human proglucagon gene expression have not been examined. We now report that, despite conservation of proximal promoter G1-G4 enhancer-like elements, human proglucagon reporter plasmids containing these elements are transcriptionally inactive in islet cell lines. Remarkably, larger human proglucagon promoter fragments, such as the 1604 hGLU-Luc, are expressed in GLUTag enteroendocrine cells but not in islet cell lines. A total of 5775 bases of human proglucagon promoter were required for expression in islet cell lines. Analysis of human proglucagon promoter expression in transgenic mice demonstrated that approximately 1.6 kb of human proglucagon gene sequences directs expression of a human growth hormone reporter gene to the brain and intestinal enteroendocrine cells but not islet cells in vivo. These findings provide the first evidence demonstrating divergence in the mechanisms utilized for tissue-specific regulation of the human and rodent proglucagon genes.