The effect of inpatient stress testing on subsequent emergency department visits, readmissions, and costs.
Patients with low-risk chest pain are frequently readmitted for evaluation of recurrent chest pain. It is unknown whether stress testing during the first admission for chest pain is a cost-effective means of reducing readmissions. Using a hospital administrative database, we conducted a retrospective cohort study of patients aged ≥18 years admitted under "observation status" to Baystate Medical Center between January 2007 and July 2009 for chest pain without acute coronary syndrome. We compared subsequent emergency department (ED) visits, readmissions, and costs within 1 year for patients who had a stress test at index admission to those who did not, adjusting for age, gender, race, insurance, and comorbidities. The cohort included 3315 patients. Most (n = 2376, 71.7%) had a stress test during the index admission. Within 1 year, 256 (7.7%) patients returned to the ED at least once with chest pain. Of these, 112 (43.8%) were admitted during their first return visit. In the multivariable model, return visits for chest pain were negatively associated with previous stress testing (odds ratio [OR]: 0.6, 95% confidence interval [CI]: 0.5 to 0.9). Once in the ED, however, the risk of admission did not vary by stress test during index admission (OR: 0.8, 95% CI: 0.4 to 1.4). Overall costs, including index admission and follow-up visits for chest pain, were higher for patients with stress testing at index admission. Inpatient stress testing reduced subsequent resource utilization in terms of ED visits and resultant readmissions, but the savings were not enough to offset the cost of initial testing.


High-level transgene expression mediated by the piggyBac transposon enhances transgenic therapeutic effects in cervical cancer xenografts.
The piggyBac (PB) transposon is a recently identified, active and flexible transgene vector, combining the advantages of non-viral gene delivery with genomic integration and persistent transgene expression. In this study, we utilized the PB transposon to carry the herpes simplex thymidine kinase (HSV-tk) and red fluorescent protein (mRFP1) reporter genes into the HeLa cervical cancer cell line or tumor xenografts of cervical cancer. Our data showed that HSV-tk and mRFP1 were expressed in HeLa cells and tumor xenografts three weeks after intratumoral injection. The mRNA and protein levels of HSV-tk and mRFP1 were increased by using the PB transposon vector. Our system also demonstrated that sensitivity of transfected HeLa cells to the pro-drug ganciclovir (GCV) was enhanced in vitro and in vivo. Furthermore, our data indicated that the enhanced transgenic therapeutic effect was strongly associated with high-level transgene expression mediated by the PB transposon. Our results suggest that applying the PB transposon in HSV-tk gene delivery and GCV treatment is a promising gene therapy strategy in the treatment of cervical cancer.


Insulin Detemir Is Transported From Blood to Cerebrospinal Fluid and Has Prolonged Central Anorectic Action Relative to NPH Insulin.
Insulin detemir (DET) reduces glycemia comparably to other long-acting insulin formulations but causes less weight gain. Insulin signaling in the brain is catabolic, reducing food intake. We hypothesized that DET reduces weight gain, relative to other insulins, owing to increased transport into the central nervous system and/or increased catabolic action within the brain. Transport of DET and NPH insulin into the cerebrospinal fluid (CSF) was compared over several hours and after the administration of different doses peripherally in rats. DET and NPH had comparable saturable, receptor-mediated transport into the CSF. CSF insulin remained elevated significantly longer after intraperitoneal DET than after NPH. When administered acutely into the 3rd cerebral ventricle, both DET and NPH insulin reduced food intake and body weight at 24 h, and both food intake and body weight remained lower after DET than after NPH after 48 h. In direct comparison with another long-acting insulin, insulin glargine (GLAR), DET led to more prolonged increases in CSF insulin despite a shorter plasma half-life in both rats and mice. Additionally, peripheral DET administration reduced weight gain and increased CSF insulin compared with saline or GLAR in mice. Overall, these data support the hypothesis that DET has distinct effects on energy balance through enhanced and prolonged centrally mediated reduction of food intake.


Bile acid levels are increased in the liver of patients with steatohepatitis.
The pathogenesis of steatohepatitis remains largely unknown; however, bile acids may play a role as potential mediators of liver damage. The aim of this study was to characterize bile acid profiles in liver tissue of patients with steatohepatitis. Bile acid composition was determined by gas-liquid chromatography in liver tissue from patients with nonalcoholic steatohepatitis (NASH; n=15), patients with alcoholic steatohepatitis (ASH; n=14), and controls (n=8). Liver biopsies were graded for steatosis, inflammation, and fibrosis. Bile acids were moderately increased in liver tissue of steatohepatitis patients compared with controls (P<0.05). Deoxycholic, chenodeoxycholic, and cholic acids were elevated by 92, 64, and 43%, respectively, in patients with steatohepatitis (P<0.05). Cholic acid was the prevailing bile acid in NASH patients and in controls. More hydrophobic bile acid species were elevated in ASH patients compared with controls (P<0.05). Significant correlations were found in NASH patients between hepatic chenodeoxycholic acid and fibrosis, and between cholic acid and trihydroxy/dihydroxy bile acids and inflammation (P<0.05). In patients with ASH, cholic acid and trihydroxy/dihydroxy bile acids were correlated with steatosis (P<0.01). This study shows a distinct pattern of bile acids in the liver of patients with steatohepatitis. Further, the association between bile acids and histological liver injury suggests an association of specific bile acids and disease progression, possibly through bile acid-induced liver injury.


Whole Grain Intake and Glycaemic Control in Healthy Subjects: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
There is growing evidence from both observational and intervention studies that Whole Grain (WG) cereals exert beneficial effects on human health, especially on the metabolic profile. The aim of this study was to perform a meta-analysis of randomised controlled trials (RCT) to assess the acute and medium/long-term effect of WG foods on glycaemic control and insulin sensitivity in healthy individuals. A search for all the published RCT on the effect of WG food intake on glycaemic and insulin response was performed up to December 2016. Effect size consisted of mean difference (MD) and 95% CI between the outcomes of intervention and the control groups using the generic inverse-variance random effects model. The meta-analysis of the 14 studies testing the acute effects of WG foods showed significant reductions of the post-prandial values of the glucose iAUC (0-120 min) by -29.71 mmol min/L (95% CI: -43.57, -15.85 mmol min/L), the insulin iAUC (0-120 min) by -2.01 nmol min/L (95% CI: -2.88, -1.14 nmol min/L), and the maximal glucose and insulin response. In 16 medium- and long-term RCTs, effects of WG foods on fasting glucose and insulin and homeostatic model assessment-insulin resistance values were not significant. The consumption of WG foods is able to improve acutely the postprandial glucose and insulin homeostasis compared to similar refined foods in healthy subjects. Further research is needed to better understand the long-term effects and the biological mechanisms.


Traversal of a polarized epithelium by pathogenic Neisseriae: facilitation by type IV pili and maintenance of epithelial barrier function.
Gonococci (GC) and meningococci (MC) are gram-negative bacterial pathogens that infect human mucosal epithelia. We would like to understand the functions of specific bacterial components at each stage of mucosal colonization: adhesion, cell invasion, and traversal into subepithelial tissues. As no animal model of mucosal colonization by GC or MC is available, increasingly sophisticated in vitro approaches have been used to address these issues. We adapted the polarized T84 human epithelial cell system to study GC and MC colonization. Epithelial barrier function was monitored by permeability to soluble tracers and with electrical resistance measurements. Polarized cells were used to assay bacterial traversal of the monolayers, and cells grown on plastic were used to assay adhesion and cell invasion. All pathogenic Neisseriae examined traversed the monolayers. The traversal times were species specific and identical to times established previously in organ culture studies. In contrast to experiments with some enteric pathogens, transmigration by GC and MC was not accompanied by disruption of the epithelial barrier. GC mutants lacking type IV pili were compromised in adhesion, invasion, and traversal of T84 cells. Experiments with polarized T84 cells mimic key features of organ culture infections and reveal additional aspects of neisserial infection. Epithelial barrier function can be retained during bacterial traversal. Experiments with a nonpiliated GC mutant and its wild-type parent indicated an unexpected role for pili in cell invasion. Our results are consistent with the hypothesis that bacterial adhesion, invasion, or both are rate-limiting for traversal across the epithelium.


An occult invasive cervical cancer found after a simple hysterectomy: a 10-year experience in a single institution.
The aim of this study was to identify patients who are at risk of a recurrence and those needing adjuvant treatment by risk grouping in invasive cervical cancer after a simple hysterectomy (SH). During 2000-2009, 26 patients who underwent SH and were finally diagnosed with stages higher than IA1 were reviewed retrospectively. The American Joint Committee on Cancer (AJCC) pathologic staging system was adopted. Based on the pathologic findings, the criteria for risk scoring was set: 1 for depth of invasion (DOI) is between 3-5 mm, and 2 for DOI greater than 5 mm; 1 for longest diameter (LD) is between 0.7-20 mm, and 2 for LD greater than 20 mm; 1 for lymphovascular space invasion positive; and 3 each for parametrium, resection margin, and lymph node positive. The final score was calculated by summing up the risk scores. The receiver operation characteristic curve was created to confirm the best cutoff value. All patients were stage IA2 to IB2, of which the number of patients in stages IA2, IB1, and IB2 were 1, 24, and 1, respectively. Eleven patients did not receive any further treatment. Of the remaining 15 patients, 11 received radiation therapy, 3 underwent concurrent chemoradiation therapy, and 1 received chemotherapy alone. No patient underwent a radical parametrectomy. During a median follow-up of 67 months (range, 9-122 months), 3 patients (11.5%) showed a recurrence. Patient whose score was 1 to 3, 4 to 5, and 6 or higher was classified into low-risk, intermediate-risk, and high-risk groups, respectively. All patients in the low-risk group did not recur without any adjuvant treatment (sensitivity, 100%; specificity 34.8-65.2%). Adjuvant treatment can be omitted in low-risk group patients with invasive cervical cancer detected after SH.


Mucosal Immunity Related to FOXP3+ Regulatory T Cells, Th17 Cells and Cytokines in Pediatric Inflammatory Bowel Disease.
We aimed to investigate mucosal immunity related to forkhead box P3 (FOXP3+) regulatory T (Treg) cells, T helper 17 (Th17) cells and cytokines in pediatric inflammatory bowel disease (IBD). Mucosal tissues from terminal ileum and colon and serum samples were collected from twelve children with IBD and seven control children. Immunohistochemical staining was done using anti-human FOXP3 and anti-RORγt antibodies. Serum levels of cytokines were analyzed using a multiplex assay covering interleukin (IL)-1β, IL-4, IL-6, IL-10, IL-17A/F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, interferon (IFN)-γ, soluble CD40L, and tumor necrosis factor-α. FOXP3+ Treg cells in the lamina propria (LP) of terminal ileum of patients with Crohn's disease were significantly (P < 0.05) higher than those in the healthy controls. RORγt+ T cells of terminal ileum tended to be higher in Crohn's disease than those in the control. In the multiplex assay, serum concentrations (pg/mL) of IL-4 (9.6 ± 1.5 vs. 12.7 ± 3.0), IL-21 (14.9 ± 1.5 vs. 26.4 ± 9.1), IL-33 (14.3 ± 0.9 vs. 19.1 ± 5.3), and IFN-γ (15.2 ± 5.9 vs. 50.2 ± 42.4) were significantly lower in Crohn's disease than those in the control group. However, serum concentration of IL-6 (119.1 ± 79.6 vs. 52.9 ± 39.1) was higher in Crohn's disease than that in the control. Serum concentrations of IL-17A (64.2 ± 17.2 vs. 28.3 ± 10.0) and IL-22 (37.5 ± 8.8 vs. 27.2 ± 3.7) were significantly higher in ulcerative colitis than those in Crohn's disease. Mucosal immunity analysis showed increased FOXP3+ T reg cells in the LP with Crohn's disease while Th17 cell polarizing and signature cytokines were decreased in the serum samples of Crohn's disease but increased in ulcerative colitis.


Comparison of retention of monolithic zirconia crowns with alumina airborne-particle abraded and nonabraded intaglio using three different cements: A clinical simulation.
The necessity of roughening the intaglio surface of zirconia crowns to achieve adequate retention is unclear. The purpose of this clinical simulation study was to evaluate the retention of airborne-particle-abraded and nonabraded monolithic zirconia crowns using 3 different cement types. Extracted human molars were used and prepared with a 10-degree taper. Impressions were made of the prepared teeth with a polyvinyl siloxane (PVS) material, and dies were made with Type 4 gypsum. Each die was scanned with a NobelProcera 1G Scanner, and the standard tessellation language (STL) files were transferred electronically to the Nobel Biocare production site, where a bar was added virtually on top of each crown and parameters were set for milling. Seventy-two Procera zirconia crowns were generated, of which half were airborne-particle abraded on the intaglio surface with 50-µm alumina particles at 400 to 500 kPa for 15 seconds. The other 36 received no intaglio treatment other than cleaning. Both groups of 36 crowns were divided into 3 subgroups of 12 specimens. The area of each preparation was calculated using a computer-aided design software program. The specimens were distributed to attain similar mean surface areas among the cementation groups. The crowns were cemented onto the specimen with a controlled force of 196 N. The 3 cements used were self-adhesive, modified resin RelyX Unicem Aplicap, resin-modified glass ionomer RelyX Luting, and a composite resin, Panavia F2.0 with ED Primer A & B. All specimens were thermocycled (5 °C to 55 °C) for 5000 cycles and then removed axially with a universal testing machine (Instron Model 5585H) at a crosshead speed of 0.5 mm/min. The removal force was recorded, and stress of dislodgement was calculated for each crown. A 2-way analysis of variance was used for statistical analyses. The type of failure was analyzed with the chi-squared test of association for independent samples (α=.05 for all tests). The mean dislodging force for crowns with airborne-particle abraded intaglio was 5.4 MPa, which was statistically greater than the mean of 3.2 MPa for nonabraded specimens (P<.001). No significant differences related to the dislodging stresses were detected among the 3 cements (P=.109). The mode of failure was similar whether abraded or not, with 50% of specimens retaining cement in the crown after separation. Alumina airborne-particle abrasion of the intaglio of zirconia to create surface roughness is beneficial in retaining the crowns, regardless of the cement type. The nonabraded crowns demonstrated significantly lower retentive stress with crown removal. The principal mode of failure was similar whether the zirconia intaglio was airborne-particle abraded or not. The most common mode of failure (>50% of specimens) was at least three-fourths of the cement remaining within the crown.


The principals of surgical oncology: diagnosis and staging.
The surgical treatment of neoplasms is one of the most common procedures performed in small animal practice. The proper approach to surgical oncology requires a knowledge of tumor types and their biologic behavior, different treatment modalities, and prognosis. A thorough physical examination is required to determine the presence and extent of a tumor, evaluate regional lymph nodes, and identify comorbid or paraneoplastic conditions that may influence anesthetic and surgical management. Various imaging modalities can be used for clinical staging to determine the location, size, and extent of a local tumor, as well as the presence of regional and distant metastasis. Biopsy of the tumor is often necessary to identify tumor type. Fine-needle aspiration, needle-core biopsy, incisional biopsy, or excisional biopsy may be used. The results of clinical staging tests and tumor biopsy are then used to ascertain treatment options and prognosis.


Surgical outcomes and natural history of intramedullary spinal cord cavernous malformations: a single-center series and meta-analysis of individual patient data: Clinic article.
Information pertaining to the natural history of intramedullary spinal cord cavernous malformations (ISCCMs) and patient outcomes after surgery is scarce. To evaluate factors associated with favorable outcomes for patients with surgically and conservatively managed ISCCMs, the authors performed a systematic review and metaanalysis of the literature. In addition, they included their single-center series of ISCCMs. The authors searched MEDLINE, EMBASE, CINAHL, Google Scholar, and The Cochrane Library for studies published through June 2013 that reported cases of ISCCMs. Data from all eligible studies were used to examine the epidemiology, clinical features, and neurological outcomes of patients with surgically managed and conservatively treated ISCCMs. To evaluate several variables as predictors of favorable neurological outcomes, the authors conducted a meta-analysis of individual patient data and performed univariate and multivariate logistic regression analyses. Variables included patient age, patient sex, lesion spinal level, lesion size, cerebral cavernomas, family history of cavernous malformations, clinical course, presenting symptoms, treatment strategy (operative or conservative), symptom duration, surgical approach, spinal location, and extent of resection. In addition, they performed a meta-analysis to determine a pooled estimate of the annual hemorrhage rate of ISCCMs. Eligibility criteria were met by 40 studies, totaling 632 patients, including the authors' institutional series of 24 patients. Mean patient age was 39.1 years (range 2-80 years), and the male-to-female ratio was 1.1:1. Spinal levels of cavernomas were cervical (38%), cervicothoracic (2.4%), thoracic (55.2%), thoracolumbar (0.6%), lumbar (2.1%), and conus medullaris (1.7%). Average cavernoma size was 9.2 mm. Associated cerebral cavernomas occurred in 16.5% of patients, and a family history of cavernous malformation was found for 11.9% of evaluated patients. Clinical course was acute with stepwise progression for 45.4% of patients and slowly progressive for 54.6%. Symptoms were motor (60.5%), sensory (57.8%), pain (33.8%), bladder and/or bowel (23.6%), respiratory distress (0.5%), or absent (asymptomatic; 0.9%). The calculated pooled annual rate of hemorrhage was 2.1% (95% CI 1.3%-3.3%). Most (89.9%) patients underwent resection, and 10.1% underwent conservative management (observation). Outcomes were better for those who underwent resection than for those who underwent conservative management (OR 2.79, 95% CI 1.46-5.33, p = 0.002). A positive correlation with improved neurological outcomes was found for resection within 3 months of symptom onset (OR 2.11, 95% CI 1.31-3.41, p = 0.002), hemilaminectomy approach (OR 3.20, 95% CI 1.16-8.86, p = 0.03), and gross-total resection (OR 3.61, 95% CI 1.24-10.52, p = 0.02). Better outcomes were predicted by an acute clinical course (OR 1.72, 95% CI 1.10-2.68, p = 0.02) and motor symptoms (OR 1.76, 95% CI 1.08-2.86, p = 0.02); poor neurological recovery was predicted by sensory symptoms (OR 0.58, 95% CI 0.35-0.98, p = 0.04). Rates of neurological improvement after resection were no higher for patients with superficial ISCCMs than for those with deep-seated ISCCMs (OR 1.36, 95% CI 0.71-2.60, p = 0.36). Intramedullary spinal cord cavernous malformations tend to be clinically progressive. The authors' findings support an operative management plan for patients with a symptomatic ISCCM. Surgical goals include gross-total resection through a more minimally invasive hemilaminectomy approach within 3 months of presentation.


How Telemedicine Can Improve the Quality of Care for Patients with Alzheimer's Disease and Related Dementias? A Narrative Review.
Background and Objectives: Dementia affects more than 55 million patients worldwide, with a significant societal, economic, and psychological impact. However, many patients with Alzheimer's disease (AD) and other related dementias have limited access to effective and individualized treatment. Care provision for dementia is often unequal, fragmented, and inefficient. The COVID-19 pandemic accelerated telemedicine use, which holds promising potential for addressing this important gap. In this narrative review, we aim to analyze and discuss how telemedicine can improve the quality of healthcare for AD and related dementias in a structured manner, based on the seven dimensions of healthcare quality defined by the World Health Organization (WHO), 2018: effectiveness, safety, people-centeredness, timeliness, equitability, integrated care, and efficiency. Materials and Methods: MEDLINE and Scopus databases were searched for peer-reviewed articles investigating the role of telemedicine in the quality of care for patients with dementia. A narrative synthesis was based on the seven WHO dimensions. Results: Most studies indicate that telemedicine is a valuable tool for AD and related dementias: it can improve effectiveness (better access to specialized care, accurate diagnosis, evidence-based treatment, avoidance of preventable hospitalizations), timeliness (reduction of waiting times and unnecessary transportation), patient-centeredness (personalized care for needs and values), safety (appropriate treatment, reduction of infection risk),integrated care (interdisciplinary approach through several dementia-related services), efficiency (mainly cost-effectiveness) and equitability (overcoming geographical barriers, cultural diversities). However, digital illiteracy, legal and organizational issues, as well as limited awareness, are significant potential barriers. Conclusions: Telemedicine may significantly improve all aspects of the quality of care for patients with dementia. However, future longitudinal studies with control groups including participants of a wide educational level spectrum will aid in our deeper understanding of the real impact of telemedicine in quality care for this population.


Clindamycin versus metronidazole in the treatment of bacterial vaginosis.
One hundred forty-three women with complaints of vaginitis were assigned to receive either 500 mg of metronidazole twice daily for 7 days or clindamycin 300 mg twice daily for 7 days. There was no significant difference in the failure rate between patients treated with clindamycin (6.1%) and those treated with metronidazole (4%). Adverse reactions were infrequent and mild in both treatment groups. Three patients who received clindamycin developed non-bloody diarrhea, which was mild and did not necessitate discontinuing therapy. We conclude that clindamycin may be a safe and effective alternative to metronidazole for treating women with bacterial vaginosis.


A ternary complex comprising transportin1, Rab8 and the ciliary targeting signal directs proteins to ciliary membranes.
The sensory functions of cilia are dependent on the enrichment of cilium-resident proteins. Although it is known that ciliary targeting signals (CTSs) specifically target ciliary proteins to cilia, it is still unclear how CTSs facilitate the entry and retention of cilium-resident proteins at the molecular level. We found that non-ciliary membrane reporters can passively diffuse into cilia through the lateral transport pathway, and the translocation of membrane reporters through the ciliary diffusion barrier is facilitated by importin binding motifs and domains. Screening known CTSs of ciliary membrane residents uncovered that fibrocystin, photoreceptor retinol dehydrogenase, rhodopsin and retinitis pigmentosa 2 interact with transportin1 (TNPO1) through previously identified CTSs. We further discovered that a new ternary complex, comprising TNPO1, Rab8 and a CTS, can assemble or disassemble under the guanine nucleotide exchange activity of Rab8. Our study suggests a new mechanism in which the TNPO1-Rab8-CTS complex mediates selective entry into and retention of cargos within cilia.


Engineered Pseudomonas putida simultaneously catabolizes five major components of corn stover lignocellulose: Glucose, xylose, arabinose, p-coumaric acid, and acetic acid.
Valorization of all major lignocellulose components, including lignin, cellulose, and hemicellulose is critical for an economically viable bioeconomy. In most biochemical conversion approaches, the standard process separately upgrades sugar hydrolysates and lignin. Here, we present a new process concept based on an engineered microbe that could enable simultaneous upgrading of all lignocellulose streams, which has the ultimate potential to reduce capital cost and enable new metabolic engineering strategies. Pseudomonas putida is a robust microorganism capable of natively catabolizing aromatics, organic acids, and D-glucose. We engineered this strain to utilize D-xylose by tuning expression of a heterologous D-xylose transporter, catabolic genes xylAB, and pentose phosphate pathway (PPP) genes tal-tkt. We further engineered L-arabinose utilization via the PPP or an oxidative pathway. This resulted in a growth rate on xylose and arabinose of 0.32 h-1 and 0.38 h-1, respectively. Using the oxidative L-arabinose pathway with the PPP xylose pathway enabled D-glucose, D-xylose, and L-arabinose co-utilization in minimal medium using model compounds as well as real corn stover hydrolysate, with a maximum hydrolysate sugar consumption rate of 3.3 g/L/h. After modifying catabolite repression, our engineered P. putida simultaneously co-utilized five representative compounds from cellulose (D-glucose), hemicellulose (D-xylose, L-arabinose, and acetic acid), and lignin-related compounds (p-coumarate), demonstrating the feasibility of simultaneously upgrading total lignocellulosic biomass to value-added chemicals.


Does Exposure to Counterstereotypical Role Models Influence Girls' and Women's Gender Stereotypes and Career Choices? A Review of Social Psychological Research.
Gender roles are formed in early childhood and continue to influence behavior through adolescence and adulthood, including the choice of academic majors and careers. In many countries, men are underrepresented in communal roles in health care, elementary education, and domestic functions (HEED fields, Croft et al., 2015), whereas women are underrepresented in the science, technology, engineering, and mathematical (STEM) fields (Beede et al., 2011) and top leadership positions (Leopold et al., 2016). Theories focusing on the development of gender roles suggest that across the lifespan people perceive certain roles to be more or less appropriate for their gender (e.g., Gender Schema Theory, Martin and Halverson, 1981; Social Role Theory, Eagly and Wood, 2011). Specifically, researchers have postulated that observing same-sex role models triggers learning processes whereby observers internalize gender-stereotypical knowledge of roles and act accordingly, which results in gender-congruent aspirations and behavior. It seems reasonable that if observing men and women in gender congruent roles fosters gender-congruent aspirations and behavior, then frequently observing gender-incongruent role models (e.g., male kindergarten teachers or female scientists and leaders) should reduce gender stereotyping and promote gender-counterstereotypical aspirations and behavior. In many countries, governments and societal decision-makers have formed initiatives based on the idea that exposure to gender-counterstereotypical role models influences aspirations and career choices among children, adolescents, and young adults. The present review gives an overview of research-based interventions involving observing or interacting with counterstereotypical role models, particularly focusing on outcomes for girls and women. Extending earlier reviews, we summarize laboratory-based and field-based studies and then critically discuss and integrate the findings in order to provide an overall picture of how counterstereotypical role models shape observers' occupational aspirations and academic choices in childhood, adolescence, and young adulthood. We conclude by outlining suggestions for future research and briefly discussing implications for future interventions.


International working group identifies need for newborn screening for mucopolysaccharidosis type I but states that existing hurdles must be overcome.
Mucopolysaccharidosis type I is a lysosomal storage disorder that can result in significant disease burden, disability and premature death, if left untreated. The aim of this review was to elaborate on the diagnosis of mucopolysaccharidosis type I and the pros and cons of newborn screening. An international working group was established to discuss ways to improve the early diagnosis of mucopolysaccharidosis type I. It consisted of 13 experts in paediatrics, rare diseases and inherited metabolic diseases from Europe and the Middle East. It is becoming increasingly clearer that the delay between symptom onset and clinical diagnosis is considerable for mucopolysaccharidosis type I and other rare lysosomal storage disorders, despite numerous awareness campaigns since therapies became available. Diagnosis currently depends on recognising the signs and symptoms of the disease. The practice of newborn screening, which is being explored by pilot programmes around the world, enables early diagnosis and consequently early treatment. However, these studies have highlighted numerous new problems and pitfalls that must be faced before newborn screening becomes generally available. Newborn screening for mucopolysaccharidosis type I offers the potential for early diagnosis and early pre-symptomatic treatment, but existing hurdles need to be overcome.


Transcriptional analysis of the major surface array gene of Caulobacter crescentus.
The major component of the paracrystalline surface array of Caulobacter crescentus CB15 and one of the most abundant cellular proteins is a protein designated 130K. We have determined the DNA sequence of the 5' portion of the 130K gene, including the N-terminal one-third of the protein coding region, and analyzed the transcription of the gene. The site of transcription initiation was determined by S1 mapping of Caulobacter RNA. Although the DNA sequence upstream from the transcription start site showed significant homology to the consensus promoter sequences of Escherichia coli, S1 analysis of RNA from E. coli carrying the 130K gene on a plasmid indicated that the 130K promoter was not transcribed by E. coli RNA polymerase in vivo. Quantitative S1 analysis of RNA isolated from synchronously growing Caulobacter cells suggested that this promoter was not under developmental regulation; the amount of 130K transcript varied no more than 1.5-fold during the cell cycle. The length of the 130K mRNA was determined to be 3.3 kilobases by Northern (RNA blot) analysis, indicating that the 130K mRNA is not part of a polycistron. The amino acid sequence predicted from the DNA sequence agreed well with the N-terminal amino acid sequence determined by sequencing of the 130K protein. The 130K protein appears to be synthesized without an N-terminal leader sequence, but the N-terminal 20 amino acids are relatively hydrophobic and may function like a signal sequence during transmembrane translocation.


Interaction between the G20210A mutation of the prothrombin gene and oral contraceptive use in deep vein thrombosis.
Single-point mutations in the gene coding for prothrombin (factor II:A20210) or factor V (factor V:A1691) are associated with an increased risk of venous thromboembolism. The use of oral contraceptives is also a strong and independent risk factor for the disease, and the interaction between factor V:A1691 and oral contraceptives greatly increases the risk. No information is available about the interaction between oral contraceptives and mutant prothrombin. We investigated 148 women with a first, objectively confirmed episode of deep vein thrombosis and 277 healthy women as controls. Fourteen patients (9.4%) were carriers of factor II:A20210, 24 (16.2%) of factor V:A1691, and 4 (2.7%) of both defects. Among controls, the prevalence was 2.5% for either factor II:A20210 or factor V:A1691, and there was no carrier of both the mutations. The relative risk of thrombosis was 6-fold for factor II:A20210 and 9-fold for factor V:A1691. The most prevalent circumstantial risk factor in patients and the only one observed in controls was oral contraceptive use, which per se conferred a 6-fold increased risk of thrombosis. The risk increased to 16.3 and 20.0 when women with factor II:A20210 or factor V:A1691 who used oral contraceptives were compared with noncarriers and nonusers. These figures indicate a multiplicative interaction between the genetic risk factors and oral contraceptives. No difference in the type of oral contraceptives was observed between patients and controls, those of third generation being the most frequently used (73% and 80%). We conclude that carriers of the prothrombin mutation who use oral contraceptives have a markedly increased risk of deep vein thrombosis, much higher than the risk conferred by either factor alone.


Impact of a neuro-intensive care service for newborns.
Advances in treating the injured neonatal brain have given rise to neuro-intensive care services for newborns. This study assessed the impact of one such service in a cohort of newborns treated with therapeutic hypothermia. Our newborn neuro-intensive care service was started in November 2012. From January 2008 to October 2016, a cohort of 158 newborns was treated with therapeutic hypothermia, 29 before and 129 after the inception of the service. This study compared the outcomes of newborns treated by the service with those of newborns treated before. Multivariate regression analysis associating length-of-stay and treatment pre- or post-service was adjusted for five-minute Apgar score, time-to-target temperature, seizures, and mortality. The neuro-intensive care service was also associated with a decrease in mortality (17% before service to 5.4% with the service, p = 0.03), though this association is likely multifactorial and reflects the application of therapeutic hypothermia to a wider variety of patients. However, the service was independently associated with decreased length-of-stay (mean 22 pre-service to 13 days with the service, p < 0.0005.)CONCLUSIONS:The service educated referring hospitals in recognizing therapeutic hypothermia candidates, which increased the number of treated newborns, and created a number of procedures to streamline the delivery of treatment. While the increasing number and variety of patients treated could spuriously reduce length-of-stay, length-of-stay was still significantly reduced after adjustment, providing evidence that neuro-intensive care services for newborns can improve hospital outcomes.


The effects of resting and exercise serum from children with cystic fibrosis on C2C12 myoblast proliferation in vitro.
Chronic systemic inflammation is a clinical symptom in children with cystic fibrosis (CF), but the effects on skeletal muscle development are unknown. The aims of this study were to determine (1) the effects of systemic factors from children with CF and healthy controls on myoblast proliferation, and (2) whether exercise serum can have an effect on proliferation in vitro. Eleven children with CF and 11 biological age-matched controls completed two 30-min bouts of cycling at an intensity set at 50% peak mechanical power. Serum samples were collected before exercise (REST), immediately following exercise (EX), and after 60 min of recovery (REC). Serum samples prepared in group-specific pools were used for cell culture experiments. C2C12 myoblasts were incubated in 5% serum and media for 1 h and then immediately harvested for protein and mRNA analysis, or incubated in growth media for 2 days to examine proliferation. C2C12 myoblasts treated with CF serum displayed greater proliferation phenotype than myoblasts treated with control serum. Proliferation did not change with EX or REC serum from children with CF compared to CF REST serum, while proliferation was increased with EX and REC serum from control compared to control REST serum. These findings suggest that systemic factors from children with CF at rest and after exercise can alter myoblast proliferation responses when compared to systemic factors from healthy children, which may have implications on skeletal muscle development.


Giant Inguinal Herniae Managed by Primary Repair: A Case Series.
Giant inguinal hernia are usually found in developing countries due to delay in seeking medical attention. The management of such hernias may sometimes require procedures to increase the intra-peritoneal capacity prior to the repair of the giant hernia. Otherwise patients may develop abdominal compartment syndrome leading to various unwanted complications. Primary repair of giant hernias are possible in some cases without having significant post-operative complications. In this present case series, we have managed a total of four patients of giant inguinal hernia by primary repair without much post-operative complications.


Salimesophilobacter vulgaris gen. nov., sp. nov., an anaerobic bacterium isolated from paper-mill wastewater.
A novel anaerobic, heterotrophic bacterium, designated strain Zn2(T), was isolated from the wastewater of a paper mill in Zhejiang, China. Cells were gram-type-positive rods, 0.5-0.8 µm wide and 2-4 µm long, and were motile by a lateral flagellum. The ranges of temperature and pH for growth were 10-50 °C and pH 6.0-9.5. Optimal growth occurred at 35 °C and pH 7.3-7.5. The strain did not require NaCl for growth, but its inclusion in the medium improved growth (optimum concentration 6 %). Substrates utilized as sole carbon sources were peptone, tryptone, Casamino acids, D-xylose, salicin, glycerol, formate, acetate and propionate. The main products of carbohydrate fermentation were acetate, formate, propionate and lactate. Elemental sulfur, thiosulfate and Fe(III) were used as electron acceptors, but sulfate, sulfite, nitrate, nitrite and Mn(IV) were not. Growth was inhibited by the addition of 10 µg ampicillin, penicillin, tetracycline or chloramphenicol ml(-1). iso-C15 : 0, C14 : 0, C16 : 0, C16 : 1 cis9 and C18 : 1 cis9 were the major fatty acids. Strain Zn2(T) did not contain any detectable menaquinones or ubiquinones. The main polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylserine, two unknown phospholipids and four unknown glycolipids. The genomic DNA G+C content was 37 mol%, as determined by HPLC. 16S rRNA gene sequence analysis revealed that strain Zn2(T) was a member of family Clostridiaceae, and was most closely related to the type strains of Geosporobacter subterraneus, Thermotalea metallivorans and Caminicella sporogenes, showing 91.2, 90.3 and 91.1 % sequence similarity, respectively. On the basis of its phenotypic and genotypic properties, strain Zn2(T) is suggested to represent a novel species of a new genus, for which the name Salimesophilobacter vulgaris gen. nov., sp. nov. is proposed. The type strain of Salimesophilobacter vulgaris is Zn2(T) ( = DSM 24770(T) = JCM 17796(T)).


SEVEN IN ABSENTIA Ubiquitin Ligases Positively Regulate Defense Against Verticillium dahliae in Gossypium hirsutum.
Ubiquitination is a post-translational regulatory mechanism that controls a variety of biological processes in plants. The E3 ligases confer specificity by recognizing target proteins for ubiquitination. Here, we identified SEVEN IN ABSENTIA (SINA) ubiquitin ligases, which belong to the RING-type E3 ligase family, in upland cotton (Gossypium hirsutum). Twenty-four GhSINAs were characterized, and the expression levels of GhSINA7, GhSINA8, and GhSINA9 were upregulated at 24 h after inoculation with Verticillium dahliae. In vitro ubiquitination assays indicated that the three GhSINAs possessed E3 ubiquitin ligase activities. Transient expression in Nicotiana benthamiana leaves showed that they localized to the nucleus. And yeast two-hybrid (Y2H) screening revealed that they could interact with each other. The ectopic overexpression of GhSINA7, GhSINA8, and GhSINA9 independently in Arabidopsis thaliana resulted in increased tolerance to V. dahliae, while individual knockdowns of GhSINA7, GhSINA8, and GhSINA9 compromised cotton resistance to the pathogen. Thus, GhSINA7, GhSINA8, and GhSINA9 act as positive regulators of defense responses against V. dahliae in cotton plants.


Inhibition of vagal vasodilatation by a selective neuropeptide Y Y2 receptor agonist in the bronchial circulation of anaesthetised dogs.
Neuropeptide Y (NPY) is both co-stored and co-released with noradrenaline from sympathetic nerve terminals. In the cardiovascular system, NPY acts on two main receptor subtypes. At postjunctional, or Y1 receptors, NPY can cause both direct vasoconstriction and the potentiation of various constrictor agents. NPY acting at the presynaptic, or Y2 receptor, inhibits the release of neurotransmitter from autonomic nerves. In the present paper, we have used both sympathetic stimulation and the selective NPY Y2 receptor agonist, N-acetyl [Leu28,Leu31] NPY24-36, to examine the role of NPY in the inhibition of vagally mediated vasodilatation in the bronchial circulation of the anaesthetised dog. Stimulation of the cardiac end of the cervical vagus nerve at 1 Hz for 15 s (1 ms, 70 V) increased bronchial vascular conductance by 45%. This increase in flow was abolished by atropine. Sympathetic stimulation for 2.5 min at 16 Hz (1 ms, 20 V) produced a significant (P < 0.05) and prolonged (9 min) inhibition of the subsequent parasympathetically evoked vasodilatation. Similarly, the NPY Y2 receptor agonist, N-acetyl [Leu28,Leu31] NPY24-36, produced a significant (P < 0.05) and prolonged (15 min) inhibition of parasympathetically evoked vasodilatation. When vagus was stimulated at 2.5 Hz for 30 s (1 ms, 70 V), an atropine-resistant, but capsaicin-sensitive vasodilatation was observed. Neither sympathetic stimulation nor the NPY Y2 receptor agonist could be demonstrated to inhibit this vasodilatation. These results suggest that NPY can inhibit cholinergic parasympathetic vasodilatation in the bronchial circulation by an action on NPY Y2 receptors.


Umbilical cord milking in preterm infants: a systematic review and meta-analysis.
To conduct a systematic review and meta-analysis of the efficacy and safety of umbilical cord milking in preterm infants. Randomised controlled trials comparing umbilical cord milking with delayed cord clamping/immediate cord clamping in preterm infants were identified by searching databases, clinical trial registries and reference list of relevant studies in November 2019. Fixed effects model was used to pool the data on various clinically relevant outcomes. Mortality and morbidities in preterm neonates. Nineteen studies (2014 preterm infants) were included. Five studies (n=922) compared cord milking with delayed cord clamping, whereas 14 studies (n=1092) compared milking with immediate cord clamping. Cord milking, as opposed to delayed cord clamping, significantly increased the risk of intraventricular haemorrhage (grade III or more) (risk ratio (RR): 1.95 (95% CI 1.01 to 3.76), p=0.05). When compared with immediate cord clamping, cord milking reduced the need for packed RBC transfusions (RR:0.56 (95% CI 0.43 to 0.73), p<0.001). There was limited information on long-term neurodevelopmental outcomes. The grade of evidence was moderate or low for the various outcomes analysed. Umbilical cord milking, when compared with delayed cord clamping, significantly increased the risk of severe intraventricular haemorrhage in preterm infants, especially at lower gestational ages. Cord milking, when compared with immediate cord clamping, reduced the need for packed RBC transfusions but did not improve clinical outcomes. Hence, cord milking cannot be considered as placental transfusion strategy in preterm infants based on the currently available evidence.


Acute bacterial endocarditis with postpartum aortic valve replacement.
A case of acute bacterial endocarditis with aortic valve abscess, aortic insufficiency, and congestive heart failure at 32 weeks' gestation is described. Prompt valve replacement is indicated due to the risks of embolism to the coronary arteries and brain, and to the high mortality of such patients with medical management only. The infant was delivered prematurely to avoid the intraoperative risks to the fetus of cardiac surgery. General rather than regional anesthesia was chosen because venous pooling from a regional block would necessitate preoperative fluid loading and vasopressor therapy, which would be stressful for an already failing heart. In the presence of severe congestive heart failure, the patient underwent cesarean section and delivered a health 2020-g male infant; 36 hours later the aortic valve was successfully replaced with a no. 21 Byork-Shiley prosthesis. The infecting organism was Streptococcus viridans.


Experimental measurement of binding energy, selectivity, and allostery using fluctuation theorems.
Thermodynamic bulk measurements of binding reactions rely on the validity of the law of mass action and the assumption of a dilute solution. Yet, important biological systems such as allosteric ligand-receptor binding, macromolecular crowding, or misfolded molecules may not follow these assumptions and may require a particular reaction model. Here we introduce a fluctuation theorem for ligand binding and an experimental approach using single-molecule force spectroscopy to determine binding energies, selectivity, and allostery of nucleic acids and peptides in a model-independent fashion. A similar approach could be used for proteins. This work extends the use of fluctuation theorems beyond unimolecular folding reactions, bridging the thermodynamics of small systems and the basic laws of chemical equilibrium.


Survival and outcome of total elbow arthroplasty for distal humeral fracture at long term follow-up.
Background Total elbow arthroplasty is an accepted procedure for the treatment of acute comminuted distal humeral fractures in elderly. Few long-term outcomes are available. The purpose of this study was to examine long-term clinical and radiological outcomes of prosthesis performed (January 2002-June 2015) for complex intra- fractures of the distal humerus (AO/C) in patients older than 65 years with low functional demands. Materials and Methods Further inclusion criteria were: the availability of a clinical and radiological follow-up of minimum 5 years and pattern of closed fracture. Demographic data and characteristics of patients were collected. All patients were clinically and radiographically assessed after 2 and 5 years from surgery. Results Twelve patients were included with complete available data. The mean follow-up was 7.6 years. Five patients reported a worsening of the elbow functionality through the follow-ups. Five subjects had complications. There were no cases of revision surgery. The quality of fixation showed a progressive worsening with increase of radiolucency both on humeral and ulnar side. The recorded MEPS showed no correlation with the grade of periprosthetic osteolysis. Polyethylene bushing wear was scored of grade 2 in one subject who had showed type 4 Morrey radiolucency. Discussion and Conclusions Total elbow arthroplasty is an effective and reliable procedure for comminuted fractures of the distal humerus in elderly, although the incidence of complications can not be considered as negligible. For the majority of these patients, a well-performed implant will give them a well-functioning elbow for their remaining life.


Steering without navigation equipment: the lamentable state of Australian health policy reform.
Commentary on health policy reform in Australia often commences with an unstated logical error: Australians' health is good, therefore the Australian Health System is good. This possibly explains the disconnect between the options discussed, the areas needing reform and the generally self-congratulatory tone of the discussion: a good system needs (relatively) minor improvement. This paper comments on some issues of particular concern to Australian health policy makers and some areas needing urgent reform. The two sets of issues do not overlap. It is suggested that there are two fundamental reasons for this. The first is the failure to develop governance structures which promote the identification and resolution of problems according to their importance. The second and related failure is the failure to equip the health services industry with satisfactory navigation equipment - independent research capacity, independent reporting and evaluation - on a scale commensurate with the needs of the country's largest industry. These two failures together deprive the health system - as a system - of the chief driver of progress in every successful industry in the 20th Century. Concluding comment is made on the National Health and Hospitals Reform Commission (NHHRC). This continued the tradition of largely evidence free argument and decision making. It failed to identify and properly analyse major system failures, the reasons for them and the form of governance which would maximise the likelihood of future error leaning. The NHHRC itself failed to error learn from past policy failures, a key lesson from which is that a major - and possibly the major - obstacle to reform, is government itself. The Commission virtually ignored the issue of governance. The endorsement of a monopolised system, driven by benevolent managers will miss the major lesson of history which is illustrated by Australia's own failures.


Fabrication of pristine Mn2O3 and Ag-Mn2O3 composite thin films by AACVD for photoelectrochemical water splitting.
Pristine Mn2O3 and Ag-Mn2O3 composite thin films have been developed on fluorine doped tin oxide (FTO) coated glass substrates at 450 °C by aerosol assisted chemical vapor deposition (AACVD) using a methanol solution of a 1 : 2 mixture of acetatoargentate(i), Ag(CH3COO), and a newly synthesized manganese complex, [Mn(dmae)2(TFA)4] (1) (dmae = N,N-dimethylaminoethanolate, TFA = trifluoroacetate). The phase purity and stoichiometric composition of the films were investigated by X-ray diffraction (XRD) and Raman spectroscopy techniques. Energy dispersive X-ray (EDX) and X-ray photoelectron spectroscopy (XPS) analyses revealed a Ag to Mn ratio of 1 : 2 and further confirmed the uniform dispersion of Ag nanoparticles into the Mn2O3 structure. Optical studies showed a direct band gap of 2.0 eV for the pristine Mn2O3 film that was lowered to 1.8 eV for Ag-Mn2O3 due to the plasmonic interaction of Ag with Mn2O3. The Ag-Mn2O3 composite film displayed enhanced photocatalytic activity in photoelectrochemical (PEC) water splitting and yielded a photocurrent of 3 mA cm(-2) at 0.7 V versus Ag/AgCl which was 1.6 times higher than a pristine Mn2O3 film alone, under AM 1.5 G illumination (100 mW cm(-2)). The high PEC efficiency is mainly due to the plasmonic effect of Ag nanoparticles, which enhances the visible light absorption, efficient electron-hole separation and high carrier mobility of the Ag-Mn2O3 photoelectrode. The charge carrier density of Ag-Mn2O3 is two times higher than the pristine Mn2O3 as calculated by the Mott-Schottky plot. Based on the PEC studies a mechanism is proposed to elucidate the high activity of Ag-Mn2O3 in PEC water splitting.


Disturbances of the alimentary tract motility and hypermotilinemia in the patients with diabetes mellitus.
Lower esophageal sphincter pressure (LESP), gastric emptying, small bowel transit time and plasma motilin levels were measured in diabetics and normal subjects in order to investigate the disturbances of the alimentary tract motility and the participation of motilin in these motility disorders. Hypermotilinemia was observed in all diabetics with or without autonomic neuropathy. Low response of LESP to tetragastrin found in diabetics with autonomic neuropathy could not be explained by motilin. Gastric emptying was highly correlated with fasting plasma motilin levels and a significantly accelerated gastric emptying observed in diabetics without complications or diabetics with diarrhea was considered to be due to hypermotilinemia. On the contrary, no significant correlation was observed between small bowel transit time and plasma motilin levels, suggesting no participation of endogenous motilin in the regulation of small bowel transit.


Who might benefit from early aspirin after coronary artery surgery?
A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether early administration of aspirin might optimize vein graft patency. More than 250 papers were found using the reported search, of which 4 new papers in addition to the previous 7 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Early postoperative aspirin administered within 6 h following coronary artery bypass grafting (CABG) has been shown to be optimal for prevention of vein graft occlusion. Early aspirin has significant benefit in reducing vein graft occlusion, mortality, myocardial infarction, stroke, renal failure and bowel infarction. The efficacy of early postoperative aspirin on vein graft patency diminishes the later it is administered. It has optimal benefit at 6 h, some benefit at 24 h and no benefit after 48 h post CABG. ACC/AHA, EACTS and ACCP have issued guidelines recommending administration of early aspirin or an alternative (clopidogrel, ticlopidine and indobufen) at 6 h or soon after bleeding has settled as the standard of care for optimization of vein graft patency. The ACCP guideline has also suggested that optimal prevention of cardiovascular complication should have higher value than prevention of postoperative bleeding. Several randomized, controlled studies, including a meta-analysis, have shown that early administration of aspirin following CABG is not associated with increased blood loss or transfusion requirement. Postoperative bleeding has been identified as a significant reason for non administration of early aspirin in a prospective study. It is essential to define/quantify the postoperative blood loss that precludes administration of early aspirin. This will enhance prompt administration in some cases and guide judgement, especially in patients with high-risk factors for vein graft thrombosis. Administration at 6 h is the optimal time to give aspirin as long as bleeding has settled.


[Neurofibromatosis and multiple nonossifying bone fibromas].
Three patients with a combination of neurofibromatosis and multiple non-ossifying fibromas are presented. All patients possessed multiple osteolytic lesions with sclerotic margins, resembling non-ossifying fibromas. Two patients showed similar lesions in additional localizations. In two patients, non-ossifying fibroma was histologically verified. The simultaneous occurrence of neurofibromatosis and multiple non-ossifying fibromas can possibly be put down to a generalized mesodermal dysplasia. However, the definite explanation is unknown.


Radial and translational motions of a gas bubble in a Gaussian standing wave field.
Acoustic waves with a finite beam width are widely used in acoustic manipulation and cavitation applications. In view of this, radial oscillation and translational motion of a gas bubble in a Gaussian standing wave field are studied in this work. Dynamic differential equations for the bubble are derived with the axial and transverse motions coupled with each other. A comprehensive numerical study is also carried out in the parameter space of the driving frequency, pressure amplitude, initial coordinate, off-axial distance and beam waist. The results demonstrate that the nonlinear radial oscillation can be intensified by a higher pressure amplitude and a smaller off-axial distance. Whether the driving frequency is much lower than the resonance frequency determines not only the final equilibrium position but also the direction of translational motion for the gas bubble. With the widening of the Gaussian standing wave, the radial oscillation will be weakened and the translational motion will be slowed down due to reduction of the pressure gradient regardless of the driving frequency. The results obtained in this study is of interest for an understanding of the bubble dynamics in non-plane acoustic wave fields.


One-step detection of human papilloma viral infection using quantum dot-nucleotide interaction specificity.
Due to the close relationship between carcinogenesis and human papillomavirus (HPV), and since they are transmitted via huge number of asymptomatic carriers, the detection of HPV is really needed to reduce the risk of developing cancer. According to the best of our knowledge, our study provides the very first method for one-step detection of viral infection and if it has initiated the subsequent cancer proliferation. The proposed novel nanosystem consists of magnetic glass particles (MGPs), which were attached with DNA probe on their surface to hybridize with target DNAs. The MGP-probe-DNA hybrid was finally conjugated with CdTe/ZnSe core/shell quantum dots (QDs). The proposed detection system is based on a novel mechanism in which the MGPs separate out the target DNAs from different biological samples using external magnetic field for better and clear detection and the QDs give different fluorescent maxima for different target DNAs due to their ability to interact differently with different nucleotides. Firstly, the method was optimized using HPV genes cloned into synthetic plasmids. Then it was applied directly on the samples from normal and cancerous cells. After that, the real hospital samples of head and neck squamous cell carcinoma (HNSCC) with or without the infection of HPV were also analyzed. Our novel nano-system is proved successful in detecting and distinguishing between the patients suffering by HPV infection with or without subsequent cancer having detection limit estimated as 1.0 x 109 (GEq/mL). The proposed methodology is faster and cost-effective, which can be applied at the clinical level to help the doctors to decide the strategy of medication that may save the life of the patients with an early treatment.


Analytical solution of stochastic resonance in the nonadiabatic regime.
We generalize stochastic resonance to the nonadiabatic limit by treating the double-well potential using two quadratic potentials. We use a singular perturbation method to determine an approximate analytical solution for the probability density function that asymptotically connects local solutions in boundary layers near the two minima with those in the region of the maximum that separates them. The validity of the analytical solution is confirmed numerically. Free from the constraints of the adiabatic limit, the approach allows us to predict the escape rate from one stable basin to another for systems experiencing a more complex periodic forcing.


Influence of protein binding on the myocardial uptake and pharmacodynamics of propafenone.
The relationship between plasma protein binding, myocardial uptake, and cardiac pharmacodynamics of propafenone was studied in an isolated perfused rabbit heart model. Hearts were perfused with buffer which contained varied concentrations of alpha 1-acid glycoprotein (alpha 1AGP). The rate and extent of myocardial uptake was assessed, as was the time course and magnitude of the change in QRS duration. The addition of alpha 1AGP has significant influence on both the rate and extent of myocardial accumulation as well as the resultant changes in QRS duration. The steady-state changes in QRS duration were linearly related to the free perfusate propafenone concentration. At times of disequilibrium, the relationship between free concentration and effect was not evident. However, at all times, a linear relationship between the myocardial concentration of propafenone and the resultant effect was observed. This relationship was not influenced by addition of alpha 1AGP protein to the perfusate; however, the amount of drug which was able to partition into the myocardium was greatly affected. These studies demonstrate that protein binding does influence the partitioning of drug into the myocardium and subsequently modulates the cardiac effect.


Binding of anticonvulsant drugs to cytochrome P-450: correlation with evidence of induction of hepatic microsomal enzymes.
Mephenytoin, diphenylhydantoin, pheneturide, and phenobarbital produced a concentration-dependent inhibition in the binding of hexobarbital to cytochrome P-450 at the type 1 site, while sulthiame slightly potentiated, and ethosuximide did not affect the binding characteristic of hexobarbital. Diphenylhydantoin, phenobarbital, and pheneturide have previously been shown to enhance the urinary excretion of D-glucaric acid (DGA), while sulthiame inhibited the potentiation of DGA excretion caused by these drugs, and ethosuximide produced no change. The results suggest a close relationship between the ability of these drugs to induce hepatic microsomal drug-metabolizing enzyme systems (as indicated by enhancement of DGA excretion) and binding behaviour at the type 1 site.


In situ formed copper nanoparticles templated by TdT-mediated DNA for enhanced SPR sensor-based DNA assay.
For the efficient surface plasmon resonance (SPR)-based DNA assay researching, signal amplification tactics were absolutely necessary. In this work, a sensitive SPR-DNA sensor was developed by employing in situ synthesis of copper nanoparticles (CuNPs) templated by poly-T sequences DNA from terminal deoxynucleotidyl transferase (TdT)-mediated extension, and synergistically with nano-effect deposition as the mass relay. The objective of this strategy was manifold: firstly, tDNA hybridized with the optimal designed probes to active the TdT-mediated DNA extension onto the surface of SPR chip, resulted a long poly-T sequences ssDNA chain in dsDNA terminal onto surface of gold chip and characterized by SPR signal amplitudes. Secondly, copper ion (Cu2+) adsorbed into the skeleton of poly-T sequences DNA, with the aid of ascorbic acid (VC) to achieve the Cu2+ reduction, copper nanostructures (CuNPs) was synchronously generated onto the single nucleotide chain anchoring in dsDNA derivatives and the formation was featured by transmission electron micrographs (TEM) and electrochemistry. Lastly, dsDNA-complexed CuNPs (CuNPs@dsDNA) triggered the final signal amplification via real-time conversion of the additive catechol violet (CV) into oligomer or chelation precipitation by CuNPs-tagged reporters. With the proposed setups, a precise and replicable DNA sensing platform for specific target oligo was obtained with a detection limit down to 3.21 femtomolar, demonstrating a beneficial overlapping exploitation of nanomaterials and biochemical reaction as unique SPR infrastructure. Such triple-amplification strategic setups, the possibility of various methods abutment and biocompatibility weight reactor was amassed and adapted to more biological detection field.


The dynamics of niche evolution upon abrupt environmental change.
Abrupt environmental changes are of particular interest to understand how species can quickly evolve at the boundary of their current niche. In particular the "sliding niche" model, wherein a niche shifts globally toward the new condition, has been used in understanding and modeling this process. Here, we investigate the dynamics of relative fitness change in four evolutionary replicates of Escherichia coli populations exposed to an extreme pH shift. We analyzed these changes at generations 500, 1000, and 2000 to determine whether niche global deformations fully capture the temporal dynamics of niche evolution. Strikingly, this analysis reveals that fitness variations can indeed be attributed to simple and global deformation of an underlying simple niche template. Analysis from two experimental replicates displays a transient increase in niche width, consistent with recent theory considering plasticity evolution in the context of an abrupt environmental change. We term this scenario the "sidestep niche model."


Duloxetine in Reducing Catheter-Related Bladder Discomfort: A Prospective, Randomized, Double-Blind, Placebo-Controlled Study.
The excessive desire to void with discomfort in the supra-pubic region, which is experienced postoperatively by patients who underwent urinary catheterization, is known as catheter-related bladder discomfort. In this study, we evaluated duloxetine, a selective serotonin and norepinephrine reuptake inhibitor, in preventing catheter-related bladder discomfort. Around 64 adults (18-60 years), of either sex, with American Society of American Society of Anesthesiologists (ASA) physical status I and II, scheduled to undergo elective gastrointestinal carcinoma surgeries under general anesthesia were analyzed in the final assessment of 2 comparative groups C and D of 32 patients each. Group D received 1 ranitidine tablet of 150 mg and 1 duloxetine tablet of 60 mg, while group C patients received 2 tablets of ranitidine of 75 mg 2 hours prior to induction. A 16 F Foley catheter was used to catheterize bladder intra-operatively, and 10 mL of distilled water was used to fill the balloon. At 0, 1, 2, and 6 hours, the catheter-related bladder discomfort was evaluated, and categorized into none, mild, moderate, and severe. The study drug's adverse effects, if any, were reported. At all-time intervals, group D had lower incidence and severity of catheterrelated bladder discomfort than group C (P < .05). Compared to group C, patients in group D had a higher incidence of nausea, dizziness, and vomiting; nevertheless, the difference was statistically insignificant (P > .05). Duloxetine of 60 mg given orally 2 hours before induction decreases the incidence and severity of catheter-related bladder discomfort.


Predicting protein complexes from PPI data: a core-attachment approach.
Protein complexes play a critical role in many biological processes. Identifying the component proteins in a protein complex is an important step in understanding the complex as well as the related biological activities. This paper addresses the problem of predicting protein complexes from the protein-protein interaction (PPI) network of one species using a computational approach. Most of the previous methods rely on the assumption that proteins within the same complex would have relatively more interactions. This translates into dense subgraphs in the PPI network. However, the existing software tools have limited success. Recently, Gavin et al. (2006) provided a detailed study on the organization of protein complexes and suggested that a complex consists of two parts: a core and an attachment. Based on this core-attachment concept, we developed a novel approach to identify complexes from the PPI network by identifying their cores and attachments separately. We evaluated the effectiveness of our proposed approach using three different datasets and compared the quality of our predicted complexes with three existing tools. The evaluation results show that we can predict many more complexes and with higher accuracy than these tools with an improvement of over 30%. To verify the cores we identified in each complex, we compared our cores with the mediators produced by Andreopoulos et al. (2007), which were claimed to be the cores, based on the benchmark result produced by Gavin et al. (2006). We found that the cores we produced are of much higher quality ranging from 10- to 30-fold more correctly predicted cores and with better accuracy. (http://alse.cs.hku.hk/complexes/).


Calcium flow-independent actions of calcium channel blockers in toad urinary bladder.
A role for transmembrane calcium movement in vasopressin stimulation of its target cell has been postulated based on studies with calcium entry blockers such as verapamil. We examined the effect of three sets of structurally different calcium blockers--D600 (an analogue of verapamil), diltiazem, and nifedipine--on water flow in toad bladder. D600 (200 microM), diltiazem (200 microM), and nifedipine (60 microM) inhibited vasopressin-induced water flow but enhanced adenosine 3',5'-cyclic monophosphate (cAMP)-induced water flow, suggesting that the drugs inhibit cAMP generation in response to vasopressin but enhance the response to exogenous cAMP by inhibiting phosphodiesterase activity. In the case of vasopressin stimulation, inhibition of cAMP generation appears to be the overriding effect. This was confirmed by measurements of cAMP content and the protein kinase ratio (-cAMP/+cAMP), which were significantly lower in bladders receiving both D600 and vasopressin than in those receiving vasopressin alone. Furthermore the drugs inhibited activation of adenylate cyclase by vasopressin in cell homogenates and inhibited phosphodiesterase in both homogenates and membrane-free supernatants. Thus these "calcium channel blockers" can directly alter cAMP metabolism in settings where movement of calcium should be irrelevant. The close correlation between the biochemical and transport effects of these agents suggests that their effect on water flow may occur by a direct effect on cellular enzymes or the membranes in which they reside and not by altering local calcium concentrations.


Wy'east: An Innovative, Culturally Responsive Postbaccalaureate Pathway for American Indians and Alaska Natives.
American Indians and Alaska Natives (AIANs) face significant health disparities that are exacerbated by limited access to high-quality, culturally congruent health care providers. There are no premedical postbaccalaureate programs focused on AIAN students. The Northwest Native American Center of Excellence designed the Wy'east Pathway in 2018 to increase the number of AIANs matriculating to U.S. medical schools by supporting those on the cusp of matriculation. Wy'east scholars undertake 10 months of structured programming to augment their academic preparation, improve their Medical College Admission Test (MCAT) scores, and enhance their confidence and cultural identity. Cultural events and mentorship opportunities with AIAN faculty, staff, and cultural liaisons are threaded throughout the pathway curriculum to foster cultural resilience, mentorship, and community. Scholars earn conditional acceptance to Oregon Health and Science University (OHSU) School of Medicine if they complete Wy'east and meet the following criteria: pass all examinations in the primary curricular threads, obtain a qualifying MCAT score, and meet professionalism standards. All 14 scholars who successfully completed Wy'east and met criteria in the first 2 cohorts (academic years 2018-2019 and 2019-2020) earned conditional acceptance to OHSU School of Medicine. Ten of the 14 scholars (71.4%) matriculated to OHSU School of Medicine, 2 (14.3%) matriculated to other medical schools, and 2 (14.3%) chose to pursue other health care fields. Wy'east scholars rated the foundational science of medicine and population health and epidemiology threads higher in terms of making them feel better prepared for medical school (mean = 4.71 and 4.83, respectively) than the academic skills and wellness thread (mean = 3.43). Over the next 5 years, Wy'east will grow incrementally to offer a total of 18 conditional acceptance spots per cohort across 3 medical schools. Longitudinal tracking of Wy'east scholars' medical training and career outcomes will be conducted.


Gymnosperm B-sister genes may be involved in ovule/seed development and, in some species, in the growth of fleshy fruit-like structures.
The evolution of seeds together with the mechanisms related to their dispersal into the environment represented a turning point in the evolution of plants. Seeds are produced by gymnosperms and angiosperms but only the latter have an ovary to be transformed into a fruit. Yet some gymnosperms produce fleshy structures attractive to animals, thus behaving like fruits from a functional point of view. The aim of this work is to increase our knowledge of possible mechanisms common to the development of both gymnosperm and angiosperm fruits. B-sister genes from two gymnosperms (Ginkgo biloba and Taxus baccata) were isolated and studied. The Ginkgo gene was also functionally characterized by ectopically expressing it in tobacco. In Ginkgo the fleshy structure derives from the outer seed integument and the B-sister gene is involved in its growth. In Taxus the fleshy structure is formed de novo as an outgrowth of the ovule peduncle, and the B-sister gene is not involved in this growth. In transgenic tobacco the Ginkgo gene has a positive role in tissue growth and confirms its importance in ovule/seed development. This study suggests that B-sister genes have a main function in ovule/seed development and a subsidiary role in the formation of fleshy fruit-like structures when the latter have an ovular origin, as occurs in Ginkgo. Thus, the 'fruit function' of B-sister genes is quite old, already being present in Gymnosperms as ancient as Ginkgoales, and is also present in Angiosperms where a B-sister gene has been shown to be involved in the formation of the Arabidopsis fruit.


Effect of marination in lemon juice on beef tenderization and in vitro gastric digestibility.
There is limited knowledge regarding digestion and absorption of nutrients after cooked marinated meat is ingested. Most of the previous studies on food gastric digestion have focused on chemical digestion and did not reflect upon physical digestion driven by peristalsis. In the present study, we examined the effects of marinating beef in lemon juice on gastric digestibility using a human gastric digestion simulator (GDS) that mimics peristaltic motion called antral contraction waves. Beef thigh slices were marinated in 100% lemon juice for 1 h and then grilled; an image of a stained tissue sample revealed that muscle tissue contraction (i.e. that usually occurs upon cooking) was suppressed. The measurement of physical properties using a rheometer and texture analyzer showed that the meat marinated in lemon juice had a soft texture. In vitro digestion experiments using the GDS revealed that the extent of both physical digestion driven by peristalsis and chemical digestion catalyzed by digestive enzymes was enhanced by the lemon juice marinade. The results of the present study suggest that marinating beef in lemon juice affects nutrient digestibility. An integrated evaluation of tissue structure, physical properties and GDS digestion to analyze meat digestion would enhance our understanding of the effects of seasoning and cooking methods on meat. © 2023 Society of Chemical Industry.


Mineralocorticoid Excess or Glucocorticoid Insufficiency: Renal and Metabolic Phenotypes in a Rat Hsd11b2 Knockout Model.
Obesity and hypertension are 2 major health issues of the 21st century. The syndrome of apparent mineralocorticoid excess is caused by deficiency of 11β-hydroxysteroid dehydrogenase type 2 (Hsd11b2), which normally inactivates glucocorticoids, rendering the mineralocorticoid receptor aldosterone-specific. The metabolic consequences of Hsd11b2 knockout in the rat are investigated in parallel with electrolyte homeostasis. Hsd11b2 was knocked out, by pronuclear microinjection of targeted zinc-finger nuclease mRNAs, and 1 line was characterized for its response to renal and metabolic challenges. Plasma 11-dehydrocorticosterone was below detection thresholds, and Hsd11b2 protein was undetected by Western blot, indicating complete ablation. Homozygotes were 13% smaller than wild-type littermates, and were polydipsic and polyuric. Their kidneys, adrenals, and hearts were significantly enlarged, but mesenteric fat pads and liver were significantly smaller. On a 0.3% Na diet, mean arterial blood pressure was ≈65 mm Hg higher than controls but only 25 mm Hg higher on a 0.03% Na(+) diet. Urinary Na/K ratio of homozygotes was similar to controls on 0.3% Na(+) diet but urinary albumin and calcium were elevated. Corticosterone and aldosterone levels showed normal circadian variation on both a 0.3% and 0.03% Na(+) diet, but plasma renin was suppressed in homozygotes on both diets. Plasma glucose responses to an oral glucose challenge were reduced despite low circulating insulin, indicating much greater sensitivity to insulin in homozygotes. The rat model reveals mechanisms linking electrolyte homeostasis and metabolic control through the restriction of Hsd11b1 substrate availability.


Staged Revision of Infected-hip Arthroplasty Using an Antibiotics-loaded Intra-articular Cement Spacer: Impact on Cemented and Cementless Stem Retention.
Currently, standard management of a peri-prosthetic infection is a two-stage revision precedure. However, removal of well-fixed cement is technically demanding and associated with numerous potential complications. For theses reasons, two-stage revision with preservation of the original femoral stem can be considered and several previous studies have achieved successful results. While most prior studies used cemented stems, the use of cementless stems during arthroplasty has been gradually increasing; this study aims to assess the comparative effectiveness of a two-stage revision of infected hip arthroplasties at preserving cemented and cementless stems. Between December 2001 and February 2017, Inje University Sanggye Paik Hospital treated 45 cases of deep infections following hip arthroplasty with a two stage revisional arthroplasty using antibiotics-loaded cement spacers. This approach was applied in an effort to preserve the previously implanted femoral stem. Of these 45 cases, 20 were followed-up for at least two years and included in this analysis. Perioperative clinical symptoms, radiological findings, function and complications during insertion of an antibiotics-loaded cement spacer were analyzed in this study. Peri-prothetic infections were controlled in 19 of the 20 included cases. Clinical outcomes, as assessed using the Harris hip score, Western Ontario and McMaster University score, also improved. Importantly, similarly improved outcomes were achieved for both cemented and cementless femoral stems. In cases of deep infection following hip arthroplasty, two-stage revision arthroplasty to preserve the previously implanted femoral stem (cemented or cementless) effectively controls infections and preserves joint function.


[Regulation of the cellular action of antidiuretic hormone].
The steps of cell reactions which could modulate the effect of the antidiuretic hormone (ADH) were investigated in experiments on frog urinary bladder. Adrenaline and D2O reduced the interaction between ADH and its receptors. The urinary bladder cells released an inhibitor of ADH changing the reaction of receptors to ADH; adsorption of this inhibitor increased the water permeability after addition of ADH. Increased intracellular concentration of cellular near basolateral membranes produced the increase of water permeability whereas near the apical membranes calcium produced its decrease acting, perhaps, on microtubules. Swelling of the cells caused by ADH didn't change the reaction of these cells to ADH. Nevertheless, the cells swollen in hypotonic solution before the application ADH showed a lesser reaction to ADH. The role of cAMP phosphodiesterase, hyaluronidase, aldosterone, prostaglandins and other physiologically active substances in the action of ADH has been discussed. The data obtained suggest some possible ways and mechanisms of regulation of the cellular action of ADH.


Cyclic adenosine-3',5'-monophosphate alters hydrolysis of phospholipids by mouse embryo palate mesenchyme cells.
The purpose of this study was to determine whether inhibition of release of arachidonic acid from mouse embryo palate mesenchyme (MEPM) cells in response to cAMP is due to a selected or generalized inhibition of hydrolysis of esterified pools of arachidonic acid. The calcium ionophore A23187 proved to be a useful probe of phospholipid hydrolases in MEPM cells, since it stimulated release of radiolabeled fatty acids from phospholipids of prelabeled MEPM cells as a function of the length of exposure, concentration, and concentration of Ca2+ in the medium. Elevation of intracellular levels of cAMP by treatment with (-) isoproterenol resulted in the inhibition of release of radiolabeled arachidonic acid in response to A23187. Analysis by quantitative gas-liquid chromatography revealed the source of the arachidonic acid released in response to the ionophore to be 1,2-diradyl-sn-glycero-3-phosphoethanolamine; elevation of intracellular levels of cAMP inhibited hydrolysis of this substrate, but may have stimulated hydrolysis of 1,2-diradyl-sn-glycero-3-phosphocholine. These findings permit the conclusions that 1) the ionophore stimulates activities of selected phospholipases A in MEPM cells and 2) cAMP modulates certain phospholipases A in MEPM cells in a specific manner.


Familial hemiplegic migraine in the west of Scotland: a clinical and genetic study of seven families.
Clinical and genetic characterisation of families in the west of Scotland with familial hemiplegic migraine. Families with familial hemiplegic migraine were identified via probands attending the regional paediatric neurology and child development centre. All available family members were assessed clinically and genetic linkage studies for the known familial hemiplegic migraine gene locus on chromosome 19 were carried out on three families. Seven unrelated kindreds with familial hemiplegic migraine were identified. Clinical information was obtained on 138 family members, 27 of whom fulfilled the International Headache Society criteria for familial hemiplegic migraine. Whereas the severity, duration, frequency, and temporal progression of acute hemiplegic migrainous attacks showed pronounced variability within and between families, and even in the same individual over time, no true clinical heterogeneity of the condition was apparent. Genetic linkage analysis gave results consistent with linkage to the familial hemiplegic migraine gene locus on chromosome 19p in one family. In the other two families, evidence against linkage was obtained. There was no significant clinical difference between these three families. This study provides characterisation of the clinical features of familial hemiplegic migraine in a British population. Significant variability was found in the frequency and character of migraine attacks within and between families, and no true clinical heterogeneity was identified. On the other hand, further evidence for genetic heterogeneity of the condition was found.


Long-Term Effectiveness and Tolerability of Pain Treatment with Tapentadol Prolonged Release.
The central analgesic tapentadol prolonged release (PR) has proven effective and generally well tolerated in a broad range of chronic pain conditions. Long-term data of its use are still scarce. To evaluate long-term effectiveness, tolerability, and safety of tapentadol PR in patients with severe chronic osteoarthritis (OA) knee pain or low back pain (LBP) who responded to tapentadol in 1 of 4 preceding 12-week phase 3b clinical trials. Open-label, uncontrolled, observational extension study of up to 72 weeks. Fourteen centers in Spain. Protocol approval by the reference ethics committee for all the participating centers. Eligible patients started the extension trial on the tapentadol PR dosage optimized for them in the preceding trial; dose adjustments were permitted throughout the extension. Treatment effectiveness outcomes included changes in pain intensity, sleep, state of health, quality of life, patient and clinician global impression of change, and patients' satisfaction with treatment. Patients with OA knee pain also answered the Western Ontario and McMaster Universities OA index, and patients with LBP with a possible neuropathic pain component completed neuropathic pain-related questionnaires. Eighty-three patients were enrolled: 40 with OA knee pain, 43 with LBP. The full analysis set consisted of 81 patients. Mean pain intensity remained relatively stable over the 72-week extension period with mean increases from baseline of 0.44 (95% confidence interval [CI], -0.1,1.0; Numeric Rating Scale) for all patients, 0.2 (95% CI, -0.5, 0.9) for patients with OA, and 0.68 (95% CI, -0.2, 1.6) for patients with LBP. State of health and quality of life baseline ratings were maintained; overall impression of change was "improved." Most patients (88.9%) reported at least good treatment satisfaction at the end of treatment. Mean daily tapentadol PR doses slightly increased from 313.3 ± 139.5 mg at baseline to 315.7 ± 140.1 mg at end of study. Uptitration was required for 8.4% of the patients, 4.8% had a dose reduction during the trial. Adverse events considered probably/likely or certainly related to tapentadol PR treatment by the investigator were documented for 18.1% of all patients, most commonly constipation (7.2%). Seven patients (8.4%) experienced adverse events leading to premature discontinuation. An open-label design, stable concomitant analgesics (World Health Organization step I), and dose adjustments were allowed during the study. All patients had benefitted from tapentadol PR in preceding trials. Sustained pain relief and quality of life for up to 72 treatment weeks under relatively stable dosing, as well as the good safety profile, indicate the usefulness of tapentadol PR for patients who suffer from severe chronic OA knee pain and LBP with limited risk for tolerance development.


Proton diffusion along biological membranes.
Biological surfaces are known to be capable of retaining protons and facilitating their lateral diffusion. Since the surface dynamically exchanges protons with the bulk, the proton movement from a source to a target at the surface acquires a complicated pattern of coupled surface and bulk (2D + 3D) diffusion of which the main feature is that the surface acts as a proton-collecting antenna enhancing the proton flux from the bulk. A phenomenological model of this process is reviewed and its applications to recent experiments on lipid bilayers and small unilaminar vesicles are discussed. The model (i) introduces the important notions of the fast and slow regimes of proton exchange between the surface and the bulk, (ii) permits evaluation of the antenna radius and amplification coefficient in both regimes, (iii) explains the observed macroscopically large distances (in the micrometer range; Antonenko and Pohl 1998 FEBS Lett. 429 197) that the proton can travel along lipid membranes embedded into pure aqueous solutions, and (iv) predicts the dependence of the steady-state proton flux and the kinetics of the non-stationary diffusion upon the buffer concentration in buffered solutions. The surface diffusion coefficient for small unilaminar vesicles is calculated from experimental data (Sandén et al 2010 Proc. Natl Acad. Sci. USA 107 4129) to be 1 × 10(-5) cm(2) s(-1). The dependence of the shape of the kinetic curves representing protonation/deprotonation of a lipid-bound pH-sensitive dye attached to a planar bilayer lipid membrane upon the buffer concentration (Serowy et al 2003 Biophys. J. 84 1031) and the effect of changing the membrane composition (Antonenko and Pohl 2008 Eur. Biophys. J. 37 865) are explained.


Vascular ultrasound for the diagnosis of giant cell arteritis: a reliability and agreement study based on a standardised training programme.
To evaluate the impact of a standardised training programme including equipment adjustment for experienced musculoskeletal ultrasonographers without previous experience in vascular ultrasound (US) on the reliability of US in the diagnosis of giant cell arteritis (GCA). In this prospective, non-interventional observational cohort study, patients suspected of GCA were evaluated by US by one of five rheumatologists with long-standing experience in musculoskeletal US (>8 years), trained using a standardised training programme including equipment adjustment. Images of cranial and large vessels were subsequently evaluated first by the performing ultrasonographer and thereafter by a blinded external expert (gold standard). In three Danish centres, 112 patients suspected of GCA were included. According to the external expert, vasculitis changes were seen in 66 patients, in 45 of them with only cranial involvement, in 14 with both cranial and large vessel involvement, while in seven patients isolated large vessel vasculitis was found. The reliability was excellent between the local ultrasonographer and the US expert for the overall GCA diagnosis regarding the diagnosis of cranial and for large vessel GCA, with an interobserver agreement of 95-96%, mean kappa values of 0.88-0.92 (95% CI 0.78 to 0.99). Excellent reliability (mean kappa 0.86-1.00) was also found for the US examination of the individual arteries (temporal, facial, common carotid and axillary). The US training programme resulted in excellent agreement between trainees and an expert in patients suspected of GCA and may thus be applicable for implementation of vascular US in clinical practice.


Comparative Disease Burden in Patients with Rheumatoid Arthritis, Psoriatic Arthritis, or Axial Spondyloarthritis: Data from Two Corrona Registries.
Rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) are three common inflammatory rheumatic diseases that can lead to deformities and joint destruction. Few studies have compared disease burden across patients with these diseases. The objective of this study was to compare disease burden in patients with RA, PsA, or axSpA in routine US clinical practice. This study included adults with RA, PsA, or axSpA enrolled in the Corrona RA and PsA/SpA registries between March 2013 and March 2018. Patient and clinical characteristics at enrollment were compared between patients with RA vs. PsA and RA vs. axSpA using t tests or Wilcoxon rank-sum tests for continuous variables and χ2 or Fisher's exact tests for categorical variables. A total of 11,350 patients with RA, 2003 with PsA, and 495 with axSpA were included. Patients with RA had shorter mean symptom and disease duration (9.4 and 7.6 years, respectively) than those with PsA (11.2 and 8.4 years) or axSpA (16.7 and 9.8 years). Patients with PsA had lower mean physician global assessment (18.6 vs. 27.3), higher patient global assessment (43.2 vs. 36.9), comparable pain (38.9 vs. 39.5), and lower fatigue (41.1 vs. 43.4) scores than those with RA. Patients with axSpA had comparable mean physician global assessment (25.5 vs. 27.3) and higher patient global assessment (50.2 vs. 36.9), pain (46.1 vs. 39.5), and fatigue (48.3 vs. 43.4) scores than those with RA. Disease burden in patients with PsA or axSpA was comparable to or greater than that in patients with RA on the basis of common patient-reported outcome measures but appeared lower when assessed using RA disease activity measures, suggesting that disease-specific approaches to care are needed to optimize disease management. This study was sponsored by Corrona, LLC, and financial support was provided by Novartis. The Rapid Service Fee was funded by Novartis. Plain language summary available for this article.


Associations between body composition and gait-speed decline: results from the Health, Aging, and Body Composition study.
In older adults, every 0.1-m/s slower gait speed is associated with a 12% higher mortality. However, little research has identified risk factors for gait-speed decline. We assessed the association between several measures of body composition and age-related decline in gait speed. Data were from 2306 older adults who were participating in the Health, Aging, and Body Composition cohort and were followed for 4 y (50% women; 38% black). Usual walking speed (m/s) over 20 m was measured in years 2 through 6, and the baseline and changes in several measures of body composition were included in mixed-effects models. Gait speed declined by 0.06 ± 0.00 m/s over the 4-y period. Baseline thigh intermuscular fat predicted the annual gait-speed decline (±SE) in both men and women (-0.01 ± 0.00 and -0.02 ± 0.00 m/s per 0.57 cm(2), respectively; P < 0.01). In men, but not in women, this relation was independent of total body adiposity. In longitudinal analyses, changes in thigh intermuscular fat and total thigh muscle were the only body-composition measures that predicted gait-speed decline in men and women combined. When modeled together, every 5.75-cm(2) increase in thigh intermuscular fat was associated with a 0.01 ± 0.00-m/s decrease in gait speed, whereas every 16.92-cm(2) decrease in thigh muscle was associated with a 0.01 ± 0.00-m/s decrease in gait speed. High and increasing thigh intermuscular fat are important predictors of gait-speed decline, implying that fat infiltration into muscle contributes to a loss of mobility with age. Conversely, a decreasing thigh muscle area is also predictive of a decline in gait speed.


Does knee malalignment mediate the effects of quadriceps strengthening on knee adduction moment, pain, and function in medial knee osteoarthritis? A randomized controlled trial.
To examine whether the effects of 12 weeks of quadriceps strengthening on the knee adduction moment, pain, and function in people with medial knee osteoarthritis (OA) differ in those with and without varus malalignment. A single-blind, randomized controlled trial of 107 community volunteers with medial knee OA was conducted. Participants were stratified according to knee malalignment (more varus or more neutral) and then randomized into either a 12-week supervised home-based quadriceps strengthening group or a control group with no intervention. The primary outcome was the knee adduction moment, measured using 3-dimensional gait analysis. Secondary outcomes included the Western Ontario and McMaster Universities Osteoarthritis Index scores (measuring pain and physical function), step test score, stair climb test score, and maximum quadriceps isometric strength. Analyses of covariance were carried out based on intent-to-treat principles. Quadriceps strengthening did not significantly alter the knee adduction moment in either the more malaligned or the more neutral group (unadjusted knee adduction moment 0.12 and 0.05% Nm/BWxHT, respectively). Function did not improve significantly following quadriceps strengthening in either alignment group, but there was a significant improvement in knee pain in the more neutrally aligned group (P < 0.001). Quadriceps strengthening did not have any significant effect on the knee adduction moment in participants with either more varus or more neutral alignment. The benefits of quadriceps strengthening on pain were more evident in those with more neutral alignment. Knee alignment thus represents a local mechanical factor that can mediate symptomatic outcome from exercise interventions in knee OA.


Dose-response relationship between testosterone and erectile function: evidence for the existence of a critical threshold.
Androgens play an important role in erectile function. However, the dose-response relationship between plasma testosterone levels and penile erection remains unclear. Intact (sham operated) or bilaterally orchiectomized, mature male Sprague-Dawley rats were used. Two weeks after surgery, rats were infused continuously with either vehicle (polyethyleneglycol) or varying doses of testosterone (44, 88, 220, or 440 mug/day) for 14 days using subcutaneous osmotic infusion pumps (study 1). In a separate study, 4 weeks after surgery, rats were infused with a lower range of testosterone doses (11, 22, or 44 mug/day) for 14 days (study 2). In the first study, intact rats had a mean plasma testosterone concentration of 0.56 +/- 0.12 ng/mL ( approximately 1.9 nM), as determined by standard radioimmunoassay. In the second study, a more sensitive enzyme-linked immunoassay was used to measure the lower testosterone levels. Using this assay, intact rats had a mean plasma testosterone concentration of 2.02 +/- 0.59 ng/mL. Intracavernosal pressure measurements indicated that orchiectomy resulted in a significant reduction in erectile function, when compared to intact animals, whereas testosterone infusion restored erectile function to varying degrees. Erectile function was maintained by a wide range of systemic testosterone levels as low as 10%-12% of normal physiological plasma concentrations. Below these concentrations, erectile function was significantly and positively correlated with testosterone plasma levels in a dose-dependent manner. Interestingly, prostate tissue mass was positively correlated to plasma testosterone levels across all concentrations examined. Protein expression of neural nitric oxide synthase (nNOS) and phosphodiesterase type 5 (PDE 5) was reduced in penile tissue from orchiectomized animals and increased in testosterone-infused animals, as assessed by Western blot analyses. We suggest that testosterone at levels approaching one-tenth normal physiological plasma concentration may represent a threshold value, below which erectile function declines in a dose-dependent fashion. However, different androgen-dependent tissues may exhibit varying sensitivities to circulating testosterone with regard to growth and function.