Radiological and functional outcome in unstable, osteoporotic trochanteric fractures stabilized with dynamic helical hip system.
A dynamic hip screw (DHS) remains the implant of choice for stabilization of trochanteric fractures because of its favourable results and low rate of non-union or hardware failure, but complication rates of the DHS are higher in unstable and osteoporotic trochanteric fractures. The proponents of the dynamic helical hip system (DHHS) report that it has the potential to decrease the cut-out rates in such fractures as helical blade allows compaction in osteoporotic femoral head which in itself improves anchorage. The purpose of the present study was to evaluate the radiological and functional outcome of DHHS in unstable and osteoporotic trochanteric fractures. This was a prospective observational study. The mean age of the 51 patients (24 men and 27 women) was 72.8 years. Fractures were type AO31A2.2 in 28 patients and AO31A2.3 in 23 patients. According to DEXA scans, 41 patients had osteoporosis and 10 patients had osteopenia. Osteoporosis was grade 3 in 36 patients and grade 2 in 15 patients according to Singh's index. The mean follow-up was 1.84 years. The average sliding of the lag screw was 3.6 mm (range 2-10 mm). The mean operative time was 54.74 (range 48-65) min. The average tip-apex distance was 20.24 mm (range 12-28 mm). All but one fractures united. The average time to union was 13.14 (range 11-24) weeks. There were four mechanical complications namely late helical blade migration (n = 1), late medialization of shaft (n = 2) and varus collapse with cut through (n = 1). No patient was noted to have a plate pull-out. The average Harris hip score was 92.87 (range 76-97). The use of a DHHS for stabilization of unstable(AO31A2), osteoporotic trochanteric fractures in the elderly patients was associated with reliable rates of union and functional outcome and a decreased incidence of screw cut-out and side plate pull-out.


Failing securely: The processes and support which underpin English nurse mentors' assessment decisions regarding under-performing students.
This study was undertaken in response to concerns that mentors who assessed practical competence were reluctant to fail student nurses which generated doubts about the fitness to practise of some registered nurses. Limited evidence was available about the experiences of mentors who had failed underperforming students and what had helped them to do this. To investigate what enabled some mentors to fail underperforming students when it was recognised that many were hesitant to do so. An ethically approved, grounded theory approach was used to explore thirty-one nurses' experiences of failing student nurses in practical assessments in England. Participants were recruited using theoretical sampling techniques. Semi-structured interviews were conducted. Analysis was undertaken using iterative, constant comparative techniques and reflexive processes. The theoretical framework which emerged had strong resonance with professionals. Five categories emerged from the findings: (1) Braving the assessment vortex; (2) Identifying the 'gist' of underperformance; (3) Tempering Reproach; (4) Standing up to scrutiny; and (5) Drawing on an interpersonal network. These categories together revealed that mentors needed to feel secure to fail a student nurse in a practical assessment and that they used a three stage decision making process to ascertain if this was the case. Many of the components which helped mentors to feel secure were informal in nature and functioned on goodwill and local arrangements rather than on timely, formal, organisational systems. The mentor's partner/spouse and practice education facilitator or link lecturer were identified as the key people who provided essential emotional support during this challenging experience. This study contributes to understanding of the combined supportive elements required for robust practical assessment. It presents a new explanatory framework about how mentors formulate the decision to fail a student nurse and the supportive structures which are necessary for this to occur.


Antibodies against serotonin have no diagnostic relevance in patients with fibromyalgia syndrome.
To determine the prevalence and potential diagnostic relevance of autoantibodies against serotonin, thromboplastin, and ganglioside Gm1 in patients with fibromyalgia syndrome (FM). Sera from 203 patients with FM and 64 pain-free control subjects were analyzed with enzyme immunoassays. Clinical and psychometric data of the patients were analyzed for the presence or absence of autoantibodies. Compared with control subjects patients with FM had a significantly higher prevalence of autoantibodies against serotonin (20% vs 5%; p = 0.003) and thromboplastin (43% vs 9%; p < 0.001), but not against ganglioside Gm1 (15% vs 9%; p = 0.301). Differences in autoantibody prevalence between controls and FM patients were not related to age or sex. No association was found between autoantibody pattern and clinical or psychometric data, e.g., pain, depression, pain related anxiety, and activities of daily living. There is an elevated prevalence of antibodies against serotonin and thromboplastin in patients with FM. The pathophysiological significance of this finding is unknown. Calculation of positive predictive values of antiserotonin antibodies shows that measurement of these antibodies has no diagnostic relevance.


Evaluation of the national clinical sentinel surveillance system for sexually transmitted infections in South Africa: Analysis of provincial and district-level data.
Globally, >1 million new cases of curable sexually transmitted infections (STIs) are estimated to occur daily, an alarming rate that has prevailed for over a decade. Modelled STI prevalence estimates for South Africa (SA) are among the highest globally. Robust STI surveillance systems have implications for policy and planning, antimicrobial stewardship and prevention strategies, and are critical in stemming the tide of STIs. To evaluate the STI clinical sentinel surveillance system (STI CSSS) in SA, to describe the population incidence of four designated STI syndromes in males and females ≥15 years, and to provide recommendations for strengthening the STI CSSS. This was a retrospective analysis of the STI CSSS in SA. Distribution of the primary healthcare facilities designated as STI CSSS sites was described, taking into account provincial population distribution and headcount coverage of STI CSSS facilities. Reporting compliance was evaluated to determine completion of data reporting. Further analysis was undertaken for those provinces that had good reporting compliance over a 12-month period. Population-level and demographic STI syndrome incidence were estimated from CSSS data using case reports of male urethritis syndrome (MUS) as a proxy for data extrapolation. Reporting compliance exceeded 70% for seven of the nine provinces. STI syndromes with the highest incidence were MUS and vaginal discharge syndrome (VDS). The 20 - 24 years age group had the highest STI incidence, at least double the incidence estimated in the other two age groups. Overall STI incidence in females was higher than among males in all provinces, except Limpopo and Western Cape. The 15 - 19 years age group had the most prominent gender disparity, with the national STI incidence in females 70% higher than in males. District-level analysis revealed high regional STI incidence even in provinces with lower overall incidence. The STI CSSS is pivotal to epidemiological monitoring and proactive management of STIs, especially in view of the high HIV prevalence in SA. CSSS processes and facility selection should be reviewed and revised to be representative and responsive to the current STI needs of the country, with biennial analysis and reporting to support evidence-based policy development and targeted implementation.


Novel electrochemiluminescence aptasensor based on AuNPs-ABEI encapsulated TiO2 nanorod for the detection of acetamiprid residues in vegetables.
Gold nanoparticles (AuNPs)@N-(4-aminobutyl)-N-ethylisoluminol (ABEI)@Titanium dioxide nanorods (TiO2NRs) were used as sensing materials to produce a unique encapsulated nanostructure aptasensor for the detection of acetamiprid residues in this work. ABEI, an analog of luminol, was extensively used as an electrochemiluminescence (ECL) reagent. The ECL mechanism of ABEI- hydrogen peroxide (H2O2) system had connections to a number of oxygen-centered free radicals. TiO2NRs improved ECL response with high electron transfer and a specific surface area. AuNPs were easy to biolabel and could catalyze H2O2 to enhance ECL signal. AuNPs were wrapped around TiO2NRs by utilizing the reduction property of ABEI to form wrapped modified nanomaterials. The sulfhydryl-modified aptamer bound to the nanomaterial by forming gold-sulfur (Au-S) bonds. The aptamer selectively bound to its target with the addition of acetamiprid, which caused a considerable decrease in ECL intensity and enabled quantitative detection of acetamiprid. The aptasensor showed good stability, repeatability and specificity with a broad detection range (1×10-2-1×103 nM) and a lower limit of detection (3 pM) for acetamiprid residues in vegetables. Overall, this aptasensor presents a simple and highly sensitive method for ECL detecting acetamiprid, with potential applications in vegetable safety monitoring.


Hyperinsulinaemia increases vascular resistance and endothelin-1 expression in the equine digit.
Insulin leads to overexpression of endothelin-1 (ET-1) in the endothelium of insulin-resistant rodents. If this is also the case in equine laminar tissue, this could explain the predisposition of insulin-resistant horses to laminitis. To investigate the effect of hyperinsulinaemia on metabolism and vascular resistance of the isolated equine digit in a model of extracorporeal perfusion. Randomised, controlled study with interventional group, with blinded evaluation of histology results. After exsanguination, equine digits (n = 11) and autologous blood were collected at an abattoir. One digit served as a hyperinsulinaemic pilot limb, 5 digits were assigned to the hyperinsulinaemic perfusion (IP) group and 5 to the control perfusion (CP) group. Digits were perfused for 10 h at a defined perfusion rate of 12 ml/min/kg. After the first hour of perfusion (equilibration period), insulin was added to the reservoir of the IP digits. Perfusion pressure, glucose consumption, lactate and lactate dehydrogenase were monitored. Vascular resistance was calculated as perfusion pressure (in millimetres of mercury) in relation to the flow rate (in millilitres per minute). After perfusion, histology samples of the dorsal hoof wall (haematoxylin & eosin or periodic acid-Schiff) were evaluated. Immunohistology with a polyclonal rabbit-derived anti-endothelin antibody was used for detection of ET-1. In the IP group, the mean insulin concentration in the plasma of the perfusate was 142 ± 81 μiu/ml, while insulin concentration was <3 μiu/ml in the CP group. Mean vascular resistance was significantly higher (P<0.01) in the IP group (2.04 ± 1.13 mmHg/ml/min) than in the CP group (1.31 ± 0.55 mmHg/ml/min). Histology of the IP group samples showed significantly more vessels with an open lumen, increased width of the secondary epidermal lamellae and formation of oedema. In the lamellar vessels (veins and arteries) and nerve fibres, ET-1 expression was much more prominent in the IP group than in the CP group samples. Short-term hyperinsulinaemia leads to increased vascular resistance in the equine digit and increased expression of ET-1 in the laminar tissue.


Polymorphism of alpha 1-antitrypsin in North American species of Canis.
alpha 1-Antitrypsin (A1AT) is a major protease inhibitor present in all mammalian sera that have thus far been investigated. A1AT is also highly polymorphic and is therefore a useful genetic marker. Previously reported A1AT polymorphism in domestic dogs consisted of two alleles designated as PiM and PiS which exhibited frequencies of 0.72 and 0.28, respectively, in a group of randomly collected mongrel dogs. North American species of Canis, which included gray wolves (n = 29), Mexican wolves (n = 20), coyotes (n = 24), wolf-dog crosses (n = 9), and red wolves (n = 27) were tested for A1AT polymorphism. A1AT phenotypes were determined by isoelectric focusing, followed by direct immunoblotting using a specific antiserum. A1AT concentrations were determined by radial immunodiffusion. Concentrations of A1AT were similar to those found in domestic dogs (2.26 +/- 0.3, +/- SD mg/ml, +/- SD) and tended to be higher in females than in males, possibly indicating that A1AT may be hormonally influenced in females. Three phenotypic band patterns were observed (M, MS, S). The allele frequencies for domestic dogs and gray wolves were very similar, 0.72 and 0.67 for PiM and 0.28 and 0.33 for PiS, respectively. The Mexican wolves had a significantly lower frequency of PiS = 0.10. Coyotes and red wolves were all found to be monomorphic for the PiS allele and were indistinguishable from each other in that respect.


Preincisional subcutaneous infiltration of ketamine suppresses postoperative pain after circumcision surgery.
N-methyl-D-aspartate and other glutamate receptors have been shown to present on the peripheral axons of primary afferents, and peripheral injection of N-methyl-D-aspartate-receptor antagonists can suppress hyperalgesia and allodynia. Thus, this study examined postoperative analgesic and adverse effects of local ketamine administered postoperatively. Ketamine (0.3%, 3 mL) or saline was subcutaneously infiltrated before incision in a double-blind manner using a sample population of 40 patients undergoing circumcision surgery, equally and randomly assigned to 2 groups based on the treatment. The saline-infiltrated patients also received 9-mg intramuscular ketamine into the upper arm to control for any related systemic analgesic effects. The patients were followed up for 24 hours to determine postoperative analgesia and identify adverse effects. In the ketamine-infiltrated patients, the time interval until first analgesic demand (166 vs. 80 min) was longer and the incidence of pain-free status (pain score=0) during movement (45% vs. 10%) and erection (40% vs. 0%) was significantly higher than for the saline-treated analogs (P<0.05). The dose of ketorolac use and pain score during erection were significant lower in group ketamine patients. No significant differences were noted with respect to the incidence of adverse effects comparing the 2 groups. We conclude that preincisional subcutaneous ketamine infiltration can suppress postoperative pain after the circumcision surgery.


[Appropriateness criteria for the treatment of atrial fibrillation with dronedarone: practical issues. An Italian cardiologists' expert opinion].
Antiarrhythmic agents are among the therapeutic options available for the treatment of atrial fibrillation when a rhythm control strategy is required. Although their efficacy seems to be generally comparable to that of nonpharmacological interventions, the use of these agents remains controversial. In particular, among this class of drugs, the use of dronedarone in clinical practice is a matter of debate. In this paper, the authors aimed to address these issues, involving a team of expert cardiologists who discussed about the potential use of dronedarone in different clinical scenarios. The RAND/UCLA appropriateness method was used to develop appropriateness measures for the optimal management of patients treated with dronedarone, by combining the best available scientific evidence with the collective judgment of experts. To this purpose, a group of experts was identified and asked to rate the benefit-to-harm ratio of 52 clinical scenarios. Each indication was classified as "appropriate", "uncertain" or "inappropriate" in accordance with the panelists' median score. The classification of each scenario has led to the development of several recommendations for clinical practice. The use of dronedarone for the management of paroxysmal and persistent atrial fibrillation has evolved over time: this antiarrhythmic drug appears to be useful not only in monitoring symptoms, but also in reducing hospitalization and mortality rates in patients with atrial fibrillation.


Risk index proposal to predict atrial fibrillation after cardiac surgery.
Atrial fibrillation (AF) is a common complication following cardiac surgery and is associated with an increased patient morbidity and mortality. The objective of this study was to develop a risk index proposal to predict AF after cardiac surgery. A prospective observational study in that 452 patients were selected to assess the incidence and risk factors associated with postoperative AF. Only patients following cardiac surgery were selected. Continuous cardiac monitor and daily electrocardiogram were assessed. The most associated in a multivariable logistic model were selected for the risk index. The average incidence of AF was 22.1%. The most associated factors with AF were: patients older than 75 years of age, mitral valve disease, no use of a beta blocker, withdrawal of a beta-blocker and a positive fluid balance. The absence risk factor determined 4.6% chance to postoperative AF, and for one, two and three or more risk factors, the chance was 16.6%, 25.9% and 46.3%, respectively. In a multivariable logistic model was possible to develop a risk index proposal to predict postoperative AF with a major risk of 46.3% in the presence of three or more risk factors.


Synergistic effects of VO(x)-Pt probed by the oxidation of propane on VO(x)/Pt(111).
VO(x)/Pt(111), which was grown layer-by-layer and exhibited a well-defined structure, was used as a model catalytic surface to study the intrinsic catalytic activity of Pt, as well as the effect of VO(x) additive, for the oxidation of propane. A special sample system was designed to ensure a reliable analysis of the trace amount of model catalytic reaction products. The results show that the catalytic activities for the oxidation of C3H8 on the Pt(111) surface as adding VO(x) are suppressed apparently at temperatures below 400 K, but enhanced significantly at temperatures above 400 K. Maximum reaction rates are achieved at a VO(x) coverage of about 0.3 ML at the test temperatures of 423 and 473 K. The infrared reflection-absorption spectroscopy (IRAS) results show that the redox property of the VO(x)-Pt is much better than that of the bulklike VO(x). This is confirmed by CO poisoning tests, in that the oxidation of VO(x)/Pt(111) is significantly suppressed by the coadsorbed CO. The kinetic data demonstrate that there are at least two catalytically active sites, metallic Pt and VO(x)-Pt interface, for the activation and oxidation of C3H8. The promotion effects of VO(x) on Pt for the oxidation of C3H8 can be attributed to the synergy between VO(x) and Pt.


Anatomic concepts for brow lift procedures.
Brow lifting became a component of the facialplasty procedure 45 years ago, and the original brow-lifting technique incorporating a coronal incision approach is still practiced by many surgeons today. Over the past 15 years, however, the endoscope-assisted procedure and the limited incision, nonendoscopic techniques have evolved as alternate procedures for brow lifting. The level of artistry in performing any brow lift technique is raised when the surgeon acquires knowledge of upper facial anatomy and integrates that knowledge into a working concept of the aging process of the upper face. This article presents one surgeon's concepts of the process that culminate in the typical appearance of the aged upper face. The same understanding of upper facial anatomy that can be called upon to explain the steps in this aging process can also be applied to the technical steps of any foreheadplasty procedure. Those anatomic structures that play a role in this process are examined here. The typical appearance of the aged upper face is the product of muscle action and gravitational forces acting on the unique anatomy of the human face. Interestingly, the appearance of the typical aged upper face exhibits much the same characteristics as one might observe in the face of an individual experiencing the emotions of sadness or grief. It is an inappropriate facial expression of sadness or grief that most often motivates the patient to schedule a consultation with the plastic surgeon. Any of the brow lift procedures used in current clinical practice can provide a successful cosmetic result in selected patients if the procedure incorporates technical steps based on sound anatomic principles.


Onsite provision of specialized contraceptive services: does Title X funding enhance access?
This article presents the extent to which providers enrolled in California's Family Planning, Access, Care, and Treatment (Family PACT) program offer contraceptive methods onsite, thus eliminating one important access barrier. Family PACT has a diverse provider network, including public-sector providers receiving Title X funding, public-sector providers not receiving Title X funding, and private-sector providers. We explored whether Title X funding enhances providers' ability to offer contraceptive methods that require specialized skills onsite. Data were derived from 1,072 survey responses to a 2010 provider-capacity survey matched by unique identifier to administrative claims data. A significantly greater proportion of Title X-funded providers compared to non-Title X public and private providers offered onsite services for the following studied methods: intrauterine contraceptives (90% Title X, 51% public non-Title X, 38% private); contraceptive implants (58% Title X, 19% public non-Title X, 7% private); vasectomy (8% Title X, 4% public non-Title X, 1% private); and fertility-awareness methods (69% Title X, 55% public non-Title X, 49% private) (all p<0.0001). The association between onsite provision and Title X funding remained after stratifying individually by clinic specialty, facility capacity to provide reproductive health services (based on staffing), and rural/urban location. Extra funding for publicly funded family-planning programs, through mechanisms such as Title X, appears to be associated with increased onsite access to a wide range of contraceptive services, including those that require special skills and training.


The pull of the past: when do habits persist despite conflict with motives?
To identify the factors that disrupt and maintain habit performance, two field experiments tested the conditions under which people eat out of habit, leading them to resist motivational influences. Habitual popcorn eaters at a cinema were minimally influenced by their hunger or how much they liked the food, and they ate equal amounts of stale and fresh popcorn. Yet, mechanisms of automaticity influenced habit performance: Participants ate out of habit, regardless of freshness, only when currently in the context associated with past performance (i.e., a cinema; Study 1) and only when eating in a way that allowed them to automatically execute the response cued by that context (i.e., eating with their dominant hand; Study 2). Across all conditions, participants with weaker cinema-popcorn-eating habits ate because of motivations such as liking for the popcorn. The findings reveal how habits resist conflicting motives and provide insight into promising mechanisms of habit change.


The proto-oncogene Cot kinase participates in CD3/CD28 induction of NF-kappaB acting through the NF-kappaB-inducing kinase and IkappaB kinases.
The proto-oncogene Cot/Tpl-2 encodes a MAP3K-related serine-threonine kinase. Expression of wild type Cot activates the IkappaB kinases (IKK) leading to induction of NF-kappaB. Conversely, expression of kinase-deficient Cot inhibits CD3/CD28 but not TNF alpha induction of NF-kappaB. These findings suggest the selective involvement of Cot/Tpl-2 or a closely related kinase in the CD3/CD28 costimulatory pathway leading to induced nuclear expression of NF-kappaB. In contrast, a kinase-deficient mutant of the NF-kappaB-inducing kinase (NIK) inhibits both CD3/CD28 and TNF alpha signaling, indicating that these pathways converge at or prior to the action of NIK. Consistent with such a sequential function of these two kinases, Cot physically assembles with and phosphorylates NIK in vivo.


The Continuing Burden of Advanced HIV Disease Over 10 Years of Increasing Antiretroviral Therapy Coverage in South Africa.
Antiretroviral treatment (ART) has been massively scaled up to decrease human immunodeficiency virus (HIV)-related morbidity, mortality, and HIV transmission. However, despite documented increases in ART coverage, morbidity and mortality have remained substantial. This study describes trends in the numbers and characteristics of patients with very advanced HIV disease in the Western Cape, South Africa. Annual cross-sectional snapshots of CD4 distributions were described over 10 years, derived from a province-wide cohort of all HIV patients receiving CD4 cell count testing in the public sector. Patients with a first CD4 count <50 cells/µL in each year were characterized with respect to prior CD4 and viral load testing, ART access, and retention in ART care. Patients attending HIV care for the first time initially constituted the largest group of those with CD4 count <50 cells/µL, dropping proportionally over the decade from 60.9% to 26.7%. By contrast, the proportion who were ART experienced increased from 14.3% to 56.7%. In patients with CD4 counts <50 cells/µL in 2016, 51.8% were ART experienced, of whom 76% could be confirmed to be off ART or had recent viremia. More than half who were ART experienced with a CD4 count <50 cells/µL in 2016 were men, compared to approximately one-third of all patients on ART in the same year. Ongoing HIV-associated morbidity now results largely from treatment-experienced patients not being in continuous care or not being fully virologically suppressed. Innovative interventions to retain ART patients in effective care are an essential priority for the ongoing HIV response.


The posology of oseltamivir in infants with influenza infection using a population pharmacokinetic approach.
Infants are at increased risk for morbidity and mortality due to influenza. Until recently, few data were available with which to optimize oseltamivir dosing in this high-risk population. Here, data for 133 infants were pooled from two prospective pharmacokinetic/pharmacodynamic safety studies to develop a population pharmacokinetic model. A three-compartment model with allometric scaling of all clearance and volume parameters described the disposition of oseltamivir and its carboxylate metabolite (OC). Weight dependence, OC clearance, and volume of distribution increased linearly with age. Analyses showed no association between OC exposure and viral clearance, the development of resistance (phenotypic/genotypic), normalization of body temperature, or safety endpoints. Pharmacokinetic bridging showed that a 3 mg/kg dose yielded acceptable OC exposure and good tolerability while minimizing the risk of underexposure and resistance/treatment failure. These pharmacological analyses formed the basis of the US Food and Drug Administration's recent approval of oseltamivir treatment for infants with influenza aged as young as 2 weeks.


Correlation of histology with biomarker status after photodynamic therapy in Barrett esophagus.
Currently, histology is used as the endpoint to define success with photodynamic therapy (PDT) in patients with high-grade dysplasia (HGD). Recurrences despite 'successful' ablation are common. The role of biomarkers in assessing response to PDT remains undefined. The objectives of the current study were 1) to assess biomarkers in a prospective cohort of patients with HGD/mucosal cancer before and after PDT and 2) to correlate biomarker status after PDT with histology. Patients who underwent PDT for HGD/mucosal cancer were studied prospectively. All patients underwent esophagogastroduodenoscopy, 4-quadrant biopsies every centimeter, endoscopic mucosal resection of visible nodules, and endoscopic ultrasound. Cytology samples were obtained by using standard cytology brushes. Biomarkers were assessed by using fluorescence in situ hybridization (FISH). The biomarkers that were assessed included loss of 9p21 (site of the p16 gene) and 17p13.1 (site of the p53 gene) loci; gains of the 8q24(c-myc), 17q (HER2-neu), and 20q13 loci; and multiple gains. Patients received PDT 48 hours after the administration of sodium porfimer. Demographic and clinical variables were collected prospectively. Patients were followed with endoscopy and repeat cytology for biomarkers. The McNemar test was used to compare biomarker proportions before and after PDT. Thirty-one patients were studied. The median patient age was 66 years (interquartile range [IQR], 56-73 years), and 28 patients (88%) were men. The mean Barrett segment length was 5 cm (standard error of the mean, 0.5 cm). Post-PDT biomarkers were obtained after a median duration of 9 months (IQR, 3-12 months). There was a statistically significant decrease in the proportion of several biomarkers assessed after PDT. Six patients without HGD after PDT still had positive FISH results for 1 or more biomarkers: of these, 2 patients (33%) developed recurrent HGD. In this initial study, histologic downgrading of dysplasia after PDT was associated with the loss of biomarkers that have been associated with progression of neoplasia in Barrett esophagus. Patients with persistently positive biomarkers appeared to be at a higher risk of recurrent HGD. These findings should be confirmed in a larger study.


Disseminated intravascular coagulation in burn injury.
Disseminated intravascular coagulation (DIC) is a complex and multifaceted disorder characterized by the activation of coagulation and fibrinolytic pathways, consumption of coagulation factors, and depletion of coagulation regulatory proteins. The introduction into the circulation of cellular debris characterized by strong thromboplastic activity due to tissue factor exposition or release (in or from burned tissues), which can thereby activate extrinsic pathway of coagulation system and trigger massive thrombin generation when present in sufficient concentration, represents the most plausible biological explanation to support the development of intravascular coagulation in patients with burn injury. Severe burns left untreated might also lead to an immunological and inflammatory response (activation of the complement cascade), which can amplify fibrinolysis and blood clotting. Overall, the real prevalence of DIC in patients with burns is as yet unclear. Postmortem, retrospective, and even longitudinal investigations are in fact biased by several factors, such as the objective difficulty to establish whether DIC might have occurred as a primary complication of burns or rather as a consequence of other superimposed pathologies (e.g., sepsis, multiple organ failure), the different diagnostic criteria for assessing DIC, and the heterogeneity of the patient samples studied. Nevertheless, the current scientific evidence is consistent with the hypothesis that biochemical changes suggestive for DIC (hypercoagulability, hypo- and hyperfibrinolysis) are commonplace in patients with burn trauma, and their severity increases exponentially with the severity of injury. Overt DIC seems to occur especially in critically ill burn patients or in those with severe burns (up to third degree) and large involvement of body surface area, in whom an appropriate therapy might be effective to prevent the otherwise fulminant course. Although early prophylaxis with antithrombin concentrates holds promises, especially in the acute phase of thermal injury, larger clinical trials are needed to confirm the benefit of this therapeutic approach.


Are colorectal cancer patients at risk for COVID-19 infection during the postoperative period? The Covid-GRECCAR study.
During the COVID-19 pandemic, cancer patients have been regarded as having a high risk of severe events if they are infected with SARS-CoV-2, particularly those under medical or surgical treatment. The aim of this study was to assess the posttreatment risk of infection by SARS-CoV-2 in a population of patients operated on for colorectal cancer 3 months before the COVID-19 outbreak and who after hospitalization returned to an environment where the virus was circulating. This French, multicenter cohort study included consecutive patients undergoing elective surgery for colorectal cancer between January 1 and March 31, 2020, at 19 GRECCAR hospitals. The outcome was the rate of COVID-19 infection in this group of patients who were followed until June 15, 2020. This study included 448 patients, 262 male (58.5%) and 186 female (41.5%), who underwent surgery for colon cancer (n = 290, 64.7%), rectal cancer (n = 155, 34.6%), or anal cancer (n = 3, 0.7%). The median age was 68 years (19-95). Comorbidities were present in nearly half of the patients, 52% were at least overweight, and the median BMI was 25 (12-42). At the end of the study, 448 were alive. Six patients (1.3%) developed COVID-19 infection; among them, 3 were hospitalized in the conventional ward, and none of them died. The results are reassuring, with only a 1.3% infection rate and no deaths related to COVID-19. We believe that we can operate on colorectal cancer patients without additional mortality from COVID-19, applying all measures aimed at reducing the risk of infection.


Coop-Seq Analysis Demonstrates that Sox2 Evokes Latent Specificities in the DNA Recognition by Pax6.
Sox2 and Pax6 co-regulate genes in neural lineages and the lens by forming a ternary complex likely facilitated allosterically through DNA. We used the quantitative and scalable cooperativity-by-sequencing (Coop-seq) approach to interrogate Sox2/Pax6 dimerization on a DNA library where five positions of the Pax6 half-site were randomized yielding 1024 cooperativity factors. Consensus positions normally required for the high-affinity DNA binding by Pax6 need to be mutated for effective dimerization with Sox2. Out of the five randomized bases, a 5' thymidine is present in most of the top ranking elements. However, this thymidine maps to a region outside of the Pax half site and is not expected to directly interact with Pax6 in known binding modes suggesting structural reconfigurations. Re-analysis of ChIP-seq data identified several genomic regions where the cooperativity promoting sequence pattern is co-bound by Sox2 and Pax6. A highly conserved Sox2/Pax6 bound site near the Sprouty2 locus was verified to promote cooperative dimerization designating Sprouty2 as a potential target reliant on Sox2/Pax6 cooperativity in several neural cell types. Collectively, the functional interplay of Sox2 and Pax6 demands the relaxation of high-affinity binding sites and is enabled by alternative DNA sequences. We conclude that this binding mode evolved to warrant that a subset of target genes is only regulated in the presence of suitable partner factors.


Cerebellar and vestibular nuclear synapses in the inferior olive have distinct release kinetics and neurotransmitters.
The inferior olive (IO) is composed of electrically-coupled neurons that make climbing fiber synapses onto Purkinje cells. Neurons in different IO subnuclei are inhibited by synapses with wide ranging release kinetics. Inhibition can be exclusively synchronous, asynchronous, or a mixture of both. Whether the same boutons, neurons or sources provide these kinetically distinct types of inhibition was not known. We find that in mice the deep cerebellar nuclei (DCN) and vestibular nuclei (VN) are two major sources of inhibition to the IO that are specialized to provide inhibitory input with distinct kinetics. DCN to IO synapses lack fast synaptotagmin isoforms, release neurotransmitter asynchronously, and are exclusively GABAergic. VN to IO synapses contain fast synaptotagmin isoforms, release neurotransmitter synchronously, and are mediated by combined GABAergic and glycinergic transmission. These findings indicate that VN and DCN inhibitory inputs to the IO are suited to control different aspects of IO activity.


[Epilepsy treatment by vagal stimulation].
Vagal nerve stimulation is the latest therapeutic modality for the treatment of epilepsy. It consists of a lead implanted in the left vagal nerve which is connected to a subcutaneous stimulator implanted in the left axillary or pectorial region. The stimulator is programmed to intermittently stimulate the vagal nerve throughout the day and a magnet also allows the patient to control the stimulation from the outside. This treatment has been used in patients with intractable partial seizures who are not candidates for epilepsy surgery. The results reported have varied but in general the procedure appears promising with at least 50% of the implanted having over 50% improvement in their seizure frequency and many having complete control without significant side effects. Further review of the results are still needed to fully determine the true value of this treatment and to identify the subgroups of patients which will benefit the most.


Metastatic Cutaneous Squamous Cell Carcinoma in Liver Successfully Treated With Partial Hepatectomy and Adjuvant Irinotecan Chemotherapy.
The management of distant metastatic cutaneous squamous cell carcinoma (cSCC) relies mainly on chemotherapies and radiotherapy. Management of patients with cSCC with surgically resectable distant metastatic lesions is not clear. A 59-year-old male had 4×10 cm-sized cSCC on the perianal skin with inguinal lymph node metastasis. Surgical resection was performed followed by radiation and adjuvant carboplatin and farmorubicin combination therapy. Six months later, 25 mm-sized solitary metastatic nodule arose on the liver. Base on his favorable overall condition fulfilling the criteria of tumor resectability for the treatment of tumors in liver and having good performance status, laparoscopic partial hepatectomy and six courses of adjuvant irinotecan therapy were performed. The surgical margin was negative and the patient has maintained complete remission for over 3 years. The clinical course of the present case suggests that surgical approaches should also be considered as candidate additional therapy for resectable distant metastatic cSCC.


Advanced musculoskeletal physiotherapists are effective and safe in managing patients with acute low back pain presenting to emergency departments.
Objective The aim of this study was to compare emergency department (ED) key performance indicators for patients presenting with low back pain and seen by an advanced musculoskeletal physiotherapist (AMP) with those seen by other non-AMP clinicians (ED doctors and nurse practitioners). Methods A retrospective audit (October 2012-September 2013) was performed of data from three metropolitan public hospital EDs to compare patients with low back pain seen by AMP and non-AMP clinicians. Outcome measures included ED length of stay, ED wait time, admission rates and re-presentation to the ED. Results One thousand and eighty-nine patients with low back pain were seen during AMP service hours (360 in the AMP group, 729 in the non-AMP group). Patients seen by the AMP had a significantly shorter ED wait time (median 13 vs 32min; P<0.001) and ED length of stay (median 141 vs 175min; P<0.001). Significantly fewer patients seen by the AMP were admitted (P<0.001), and this difference remained after accounting for the difference in triage code between the groups. Conclusions Improved ED metrics were demonstrated in patients with low back pain when managed by an AMP compared with patients seen by doctors and nurse practitioners. What is known about the topic? There is a growing body of literature regarding the role of AMPs in the Australian healthcare system in providing clinical services for patients with musculoskeletal conditions, including settings such as the ED. AMPs have proven to be safe and cost-effective, achieving high patient satisfaction and improved patient outcomes. However, there is little to no information regarding their effect on ED metrics, such as ED length of stay, wait time and admission rates for patients presenting to the ED with low back pain. What does this paper add? This paper demonstrates improved ED metrics for patients presenting to the ED with low back pain when seen by an AMP compared with patients seen by doctors and nurse practitioners. The specific improved metrics for these patients were decreased admission rates, decreased ED length of stay and decreased wait time. What are the implications for clinicians? This paper provides evidence that the AMPs effectively discharge patients admitted to the ED in a timely manner, without evidence of increased readmissions, compared with their medical and nursing colleagues. Support for the role of the AMP within the ED setting is strengthened by these results.


HPRT-related hyperuricemia with a novel p.V35M mutation in HPRT1 presenting familial juvenile gout.
Unlike complete deficiency of hypoxanthine phosphoribosyltransferase (HPRT) (i.e., Lesch-Nyhan syndrome), partial HPRT deficiency causes HPRT-related hyperuricemia without neurological symptoms. Herein, we describe a 22-year-old man without neurological symptoms that presented gout, hyperuricemia (serum urate level, 12.2 mg/dL), multiple renal microcalculi, and a family history of juvenile gout that was exhibited by his brother and grandfather. Genetic testing revealed a novel missense mutation, c.103G>A (p.V35M), in the HPRT1 gene, and biochemical testing (conducted using the patient's erythrocytes) showed that the patient retained only 12.4% HPRT enzymatic activity compared to that exhibited by a healthy control subject. We thus diagnosed the patient with HPRT-related hyperuricemia caused by partial HPRT deficiency. After his serum urate level was controlled via treatment with febuxostat, his gout did not recur. Thus, this study emphasizes that HPRT deficiency should be considered as a potential cause of familial juvenile gout, even in the absence of neurological symptoms.


Major amputations: clinical patterns and predictors.
The major amputation rate is approximately 200 to 500/million/yr and occurs in patients presenting with an acute onset of critical leg ischemia (CLI) rather than in patients who steadily progress through increasingly severe claudication to rest pain and ulcers. Diabetics, who form only 2% to 5% of the population, form 40% to 45% of all amputees. Although it is widely believed that a below-knee (BK) to above-knee (AK) amputation ratio of 2.5 is the minimum acceptable for units providing a lower limb amputation service, the ratio is in fact usually very much below the recommended figure. The data suggest that primary healing of BK amputations ranges from 30% to 92% and the reamputation rate from 4% to 30%. If a popliteal pulse is palpable, then there is only a 10% failure rate, and bleeding during the operation does not seem to predict healing. Of the 30% of BK amputees whose wounds do not heal primarily, about half will need a higher major amputation, but once a BK major amputation has healed, only 4% of such patients ever need a higher amputation. A total of 90% of AK major amputations heal, 70% primarily. Two to three times as many BK amputees achieve full mobility than AK amputees, and there has not been any dramatic change in 20 years. The fate of the amputee 2 years after a successful BK amputation will be that 15% will have been converted to an AK amputation, another 15% will have had a contralateral major amputation, and 30% will be dead.


Why do frontal lobe symptoms predominate in vascular dementia with lacunes?
We studied 30 necropsy cases of vascular dementia with a lacunar state. Manifestations included dementia, lack of volition, emotional lability, small-stepped gait, dysarthria, urinary incontinence, grasp reflex, pyramidal signs, paraplegia in flexion, and akinetic mutism. Pathologically, there was diffuse incomplete softening of white matter in all cases. Both lacunes and diffuse softening were found predominantly in the frontal lobes. The prominent clinical features were therefore frontal lobe symptoms, with good correlation between the symptoms and the distribution of pathologic lesions.


β-Secretase BACE1 Is Required for Normal Cochlear Function.
Cleavage of amyloid precursor protein (APP) by β-secretase BACE1 initiates the production and accumulation of neurotoxic amyloid-β peptides, which is widely considered an essential pathogenic mechanism in Alzheimer's disease (AD). Here, we report that BACE1 is essential for normal auditory function. Compared with wild-type littermates, BACE1-/- mice of either sex exhibit significant hearing deficits, as indicated by increased thresholds and reduced amplitudes in auditory brainstem responses (ABRs) and decreased distortion product otoacoustic emissions (DPOAEs). Immunohistochemistry revealed aberrant synaptic organization in the cochlea and hypomyelination of auditory nerve fibers as predominant neuropathological substrates of hearing loss in BACE1-/- mice. In particular, we found that fibers of spiral ganglion neurons (SGN) close to the organ of Corti are disorganized and abnormally swollen. BACE1 deficiency also engenders organization defects in the postsynaptic compartment of SGN fibers with ectopic overexpression of PSD95 far outside the synaptic region. During postnatal development, auditory fiber myelination in BACE1-/- mice lags behind dramatically and remains incomplete into adulthood. We relate the marked hypomyelination to the impaired processing of Neuregulin-1 when BACE1 is absent. To determine whether the cochlea of adult wild-type mice is susceptible to AD treatment-like suppression of BACE1, we administered the established BACE1 inhibitor NB-360 for 6 weeks. The drug suppressed BACE1 activity in the brain, but did not impair hearing performance and, upon neuropathological examination, did not produce the characteristic cochlear abnormalities of BACE1-/- mice. Together, these data strongly suggest that the hearing loss of BACE1 knock-out mice represents a developmental phenotype.SIGNIFICANCE STATEMENT Given its crucial role in the pathogenesis of Alzheimer's disease (AD), BACE1 is a prime pharmacological target for AD prevention and therapy. However, the safe and long-term administration of BACE1-inhibitors as envisioned in AD requires a comprehensive understanding of the various physiological functions of BACE1. Here, we report that BACE1 is essential for the processing of auditory signals in the inner ear, as BACE1-deficient mice exhibit significant hearing loss. We relate this deficit to impaired myelination and aberrant synapse formation in the cochlea, which manifest during postnatal development. By contrast, prolonged pharmacological suppression of BACE1 activity in adult wild-type mice did not reproduce the hearing deficit or the cochlear abnormalities of BACE1 null mice.


Modulation of T cell response by Phellinus linteus.
Phellinus linteus, a species of mushroom, has been shown to contribute to health benefits, such as anti-inflammatory activity and immunomodulatory efficacy. The aim of this study was to analyze the most effective constituents of P. linteus fermented broths, polysaccharides, and to evaluate their immunoregulatory effects on T cells. Four fermented broths (PL1-4) and the dialyzate medium (MD) were prepared from P. linteus mycelia, and the polysaccharide contents of each were analyzed. The P. linteus samples were tested for biological activity in the regulation of T cell activation. In T cells, the production of mitogen-induced interleukin (IL)-2 and cell cycle progression were dose-responsively inhibited by PL3 and MD, primarily through cell-cycle arrest in S phase. PL3 broth, which contained large quantities of polysaccharides, significantly decreased the ratio of interferon-gamma (IFN-γ) to interleukin 4 (IL-4) in T cells. Thus, P. linteus fermented broths produced additive effects on the regulation of the Th1/Th2 balance and show promise for the development of immunomodulatory therapeutics.


Mechanism of RNA recombination in carmo- and tombusviruses: evidence for template switching by the RNA-dependent RNA polymerase in vitro.
RNA recombination occurs frequently during replication of tombusviruses and carmoviruses, which are related small plus-sense RNA viruses of plants. The most common recombinants generated by these viruses are either defective interfering (DI) RNAs or chimeric satellite RNAs, which are thought to be generated by template switching of the viral RNA-dependent RNA polymerase (RdRp) during the viral replication process. To test if RNA recombination is mediated by the viral RdRp, we used either a purified recombinant RdRp of Turnip crinkle carmovirus or a partially purified RdRp preparation of Cucumber necrosis tombusvirus. We demonstrated that these RdRp preparations generated RNA recombinants in vitro. The RdRp-driven template switching events occurred between either identical templates or two different RNA templates. The template containing a replication enhancer recombined more efficiently than templates containing artificial sequences. We also observed that AU-rich sequences promote recombination more efficiently than GC-rich sequences. Cloning and sequencing of the generated recombinants revealed that the junction sites were located frequently at the ends of the templates (end-to-end template switching). We also found several recombinants that were generated by template switching involving internal positions in the RNA templates. In contrast, RNA ligation-based RNA recombination was not detected in vitro. Demonstration of the ability of carmo- and tombusvirus RdRps to switch RNA templates in vitro supports the copy-choice models of RNA recombination and DI RNA formation for these viruses.


Inhibition of cardiotrophin‑1 overexpression is involved in the anti‑fibrotic effect of Astrogaloside IV.
Astragaloside IV (AsIV), one of the major active ingredients in Astragalus membranaceus, has demonstrated remarkable antifibrotic effects via its antioxidative activity. Cardiac fibrosis is an important pathological mechanism during cardiac remodelling associated with heart failure. In the present study, the mechanism underlying the antifibrotic effect of AsIV upon isoprenaline (ISO) stimulation was investigated. AsIV significantly improved cardiac fibrosis in vivo and dose‑dependently inhibited ISO‑induced CF proliferation in vitro. The ISO‑triggered elevation in reactive oxygen species (ROS) levels was remarkably inhibited by AsIV, as well as ROS scavenger N‑acetylcysteine (NAC), and not affected by cardiotrophin‑1 (CT‑1) knockdown. In addition, AsIV effectively reversed ISO‑induced upregulation of CT‑1 expression, which was blunted by pretreatment with NAC. Cardiac fibroblast (CF) proliferation and collagen Ι overexpression induced by ISO stimulation were effectively abrogated by AsIV, NAC, and CT‑1 small interfering RNA transfection. Taken together, these results demonstrated that AsIV was able to effectively inhibit ISO‑induced CF proliferation and collagen production through negative regulation of ROS‑mediated CT‑1 upregulation.


Dynamic patterns in mood among newly diagnosed patients with major depressive episode or panic disorder and normal controls.
The purpose of this pilot study was to compare the dynamic patterns of hourly mood variation among newly diagnosed primary care patients with major depressive disorder or panic disorder with patterns in patients with neither disorder. Five adult patients with major depressive episode, 5 with panic disorder, and 5 with neither disorder were asked to complete hourly self-assessments of anxiety and depression (using 100-mm visual analog scales) for each hour they were awake during a 30-day period. Time series were analyzed using ARIMA (autoregression, integration, moving average) modeling (to assess periodicity), Lyapunov exponents (to assess sensitivity to initial conditions indicative of chaotic patterns), and correlation dimension saturation (to assess whether an attractor is limiting change). The study was conducted from March to June 2003. Controls displayed circadian rhythms with underlying chaotic variability. Depressed patients did not display circadian rhythm, but did show chaotic dynamics. Panic disorder patients showed circadian rhythms, but 2 of the 4 patients completing the self-assessments displayed nonchaotic underlying patterns. Patients with major depressive disorder or panic disorder may differ from controls and from each other in their patterns of mood variability. There is a need for more research on the dynamics of mood among patients with mental disorders.


Impact of Job Status on Accessibility of Cancer Screening.
Cancer is a leading cause of death worldwide with approximately 75,000 cancer deaths in Korea alone in 2013. Cancer screening is an important method of prevention; however, only 63.4% of Koreans sought cancer screening in 2012 even though it was widely offered at no cost. We focused on part time workers because they often experience job instability and relative discrimination. Therefore, we investigated the correlation between job status and cancer screening. Data from the 2013 Korea National Health and Nutrition Examination Survey (KNHANES) were used for selection of individuals who participated in the national cancer screening program. A total of 1,326 wage earners were selected for our study. The association between cancer screening and part time job status was examined using logistic regression models. Of the 1,326 individuals selected for the study, 869 (64.5%) had participated in the cancer screening program; among these, 421 (48.4%) were part time workers and 448 (51.6%) were full time workers. Lower prevalence of cancer screening was observed for part time workers compared to full time workers (odds ratio, 0.72; confidence interval, 0.53 to 1.00; p=0.0495). Factors including age, marital status, private insurance, chronic disease, smoking, and residential area emerged as showed significant association with participation in screening programs. We found that part time workers had difficulty participating in prevention programs. Change in the workplace environment as well as development of positive social programs targeted to part time workers is necessary in order to encourage participation of part time workers in prevention programs.


Speckle contrast diffuse correlation tomography of cerebral blood flow in perinatal disease model of neonatal piglets.
We adapted and tested an innovative noncontact speckle contrast diffuse correlation tomography (scDCT) system for 3D imaging of cerebral blood flow (CBF) variations in perinatal disease models utilizing neonatal piglets, which closely resemble human neonates. CBF variations were concurrently measured by the scDCT and an established diffuse correlation spectroscopy (DCS) during global ischemia, intraventricular hemorrhage, and asphyxia; significant correlations were observed. Moreover, CBF variations associated reasonably with vital pathophysiological changes. In contrast to DCS measurements of mixed signals from local scalp, skull and brain, scDCT generates 3D images of CBF distributions at prescribed depths within the head, thus enabling specific determination of regional cerebral ischemia. With further optimization and validation in animals and human neonates, scDCT has the potential to be a noninvasive imaging tool for both basic neuroscience research in laboratories and clinical applications in neonatal intensive care units.


Post-translational modifications involved in the biosynthesis of thiopeptide antibiotics.
Thiopeptide antibiotics are a class of typical ribosomally synthesized and post-translationally modified peptides (RiPPs) with complex chemical structures that are difficult to construct via chemical synthesis. To date, more than 100 thiopeptides have been discovered, and most of these compounds exhibit remarkable biological activities, such as antibacterial, antitumor and immunosuppressive activities. Therefore, studies of the biosynthesis of thiopeptides can contribute to the development of new drug leads and facilitate the understanding of the complex post-translational modifications (PTMs) of peptides and/or proteins. Since the biosynthetic gene clusters of thiopeptides were first discovered in 2009, several research studies regarding the biochemistry and enzymology of thiopeptide biosyntheses have been reported, indicating that their characteristic framework is constructed via a cascade of common PTMs and that additional specific PTMs diversify the molecules. In this review, we primarily summarize recent advances in understanding the biosynthesis of thiopeptide antibiotics and propose some potential applications based on our insights into the biosynthetic logic and machinery.


High Peak Estradiol/Mature Oocyte Ratio Predicts Lower Clinical Pregnancy, Ongoing Pregnancy, and Live Birth Rates in GnRH Antagonist Intracytoplasmic Sperm Injection Cycles.
To define the relationship between peak estradiol (E2)/mature oocyte ratio and pregnancy outcomes in gonadotropin-releasing hormone (GnRH) antagonist intracytoplasmic sperm injection (ICSI) cycles. Retrospective cohort study in the setting of an academic reproductive medicine practice. Records from 162 fresh, autologous, GnRH antagonist ICSI cycles performed between 2009 and 2012 .were analyzed. The main outcome measures were rates of clinical pregnancy (CPR), ongoing pregnancy (OPR), and live birth (LBR). For the primary analysis, 4 groups were created based on peak E2/mature oocyte ratio (group 1: <200, group 2: 200-300, group 3: 300-400, and group 4: >400 pg/mL/oocyte). After adjusting for age, basal FSH, and the number of mature oocytes, a significantly lower OPR was seen in group 4 as compared to group I (OR 0.15, 95% CI 0.03-0.86; p=0.032) and group 3 (OR 0.17, 95% CI 0.03-0.98; p=0.048), respectively. The adjusted LBR was also significantly lower in group 4 as compared to group 1 (OR 0.15, 95% CI 0.03-0.83; p=0.030). In a secondary analysis, 3 ranges of peak E2/ mature oocyte ratio (<200, 200-400, and >400 pg/ mL/oocyte) were compared between low, normal, and high responders (<6, 6-15, and >15 mature oocytes, respectively). Clinical pregnancy rate, OPR, and LBR were all lower in normal responders when the E2/oocyte ratio exceeded 400 pg/mL/oocyte as compared to <200 pg/mL/oocyte and 200-300 pg/mL/oocyte (CPR 1% vs. 16% and 32%, respectively, p=0.017; OPR 0 vs. 15% and 27%, respectively, p=0.011; and LBR 0 vs. 13% and 26%, respectively, p=0.018). Very elevated peak E2/mature oocyte ratio is associated with a lower CPR, OPR, and LBR in fresh, autologous, GnRH antagonist ICSI cycles.


Downregulation of FKBP14 by RNA interference inhibits the proliferation, adhesion and invasion of gastric cancer cells.
FK506 binding protein (FBBP) 14 belongs to the family of FKBPs. Altered expression of FKBPs are observed in several malignancies. The present study aimed to explore the expression and biological function of FKBP14 in gastric cancer. FKBP14 expression levels in 40 gastric cancer samples and matched control samples were evaluated using quantitative polymerase chain reaction. Cell proliferation was evaluated using Cell Counting kit-8 assay. A cell adhesion and a Transwell assay were performed to detect cell adhesion and invasion. Protein expression was determined using western blot analysis. It was found that FKBP14 expression in gastric cancer tissues was elevated compared with normal tissues. Silencing of FKBP14 expression in the gastric cancer MKN-45 and AGS cell lines, which have a higher expression level of FKBP14 compared with four other gastric cancer cell lines, significantly inhibited cellular proliferation, adhesion and invasion. In addition, the protein levels of proliferating cell nuclear antigen, matrix metalloproteinase 2 and the epithelial-mesenchymal-transition (EMT) markers β-catenin, Snail1 and Twist were repressed in gastric cancer cells with FKBP14 silenced. In conclusion, FKBP14 may act as an oncogene by suppressing cellular proliferation, adhesion and invasion and EMT in gastric carcinogenesis. FKBP14 may be a diagnosis marker and potential therapeutic target in gastric cancer.


A latent class typology of young women smokers.
Despite aggressive anti-smoking campaigns, smoking rates are increasing among young women, suggesting the need for new approaches to reach this population. Segmenting audiences can facilitate targeting interventions to specific populations, based on association of smoking behaviors with other health behaviors and psychological and social antecedents. Using latent class analysis, we sought to profile patterns of behavioral, attitudinal and cognitive variables related to tobacco use among young women. This study is part of an ongoing Midwestern longitudinal self-report survey of the natural history of cigarette smoking. Participants were 18-25-year-old women smokers (n = 443). Variables included a comprehensive range of demographic characteristics, smoking-related variables and general attitudinal variables. Three distinct classes emerged with the following characteristics: (1) working women who tended to smoke daily but reported high levels of positive affect and life satisfaction (n = 212); (2) light-smoking college students who exercised regularly, began smoking after high school and quit successfully at follow-up 5 years later (n = 86); and (3) heavy smokers who were more likely to have children, report high levels of negative affect and smoke for addictive reasons, for stimulation and to control affect (n = 145). Differences in smoking cessation at a 5-year follow-up were significant across the classes (18.1%, 34.4% and 13.0% had quit for at least 6 months, respectively). The psychosocial and behavioral profiles of these classes can potentially be used to tailor smoking interventions more effectively within this population.


Genetic basis of virulence attenuation revealed by comparative genomic analysis of Mycobacterium tuberculosis strain H37Ra versus H37Rv.
Tuberculosis, caused by Mycobacterium tuberculosis, remains a leading infectious disease despite the availability of chemotherapy and BCG vaccine. The commonly used avirulent M. tuberculosis strain H37Ra was derived from virulent strain H37 in 1935 but the basis of virulence attenuation has remained obscure despite numerous studies. We determined the complete genomic sequence of H37Ra ATCC25177 and compared that with its virulent counterpart H37Rv and a clinical isolate CDC1551. The H37Ra genome is highly similar to that of H37Rv with respect to gene content and order but is 8,445 bp larger as a result of 53 insertions and 21 deletions in H37Ra relative to H37Rv. Variations in repetitive sequences such as IS6110 and PE/PPE/PE-PGRS family genes are responsible for most of the gross genetic changes. A total of 198 single nucleotide variations (SNVs) that are different between H37Ra and H37Rv were identified, yet 119 of them are identical between H37Ra and CDC1551 and 3 are due to H37Rv strain variation, leaving only 76 H37Ra-specific SNVs that affect only 32 genes. The biological impact of missense mutations in protein coding sequences was analyzed in silico while nucleotide variations in potential promoter regions of several important genes were verified by quantitative RT-PCR. Mutations affecting transcription factors and/or global metabolic regulations related to in vitro survival under aging stress, and mutations affecting cell envelope, primary metabolism, in vivo growth as well as variations in the PE/PPE/PE-PGRS family genes, may underlie the basis of virulence attenuation. These findings have implications not only for improved understanding of pathogenesis of M. tuberculosis but also for development of new vaccines and new therapeutic agents.


The SALMFamides: a new family of neuropeptides isolated from an echinoderm.
We have isolated two novel related neuropeptides from the radial nerve cords of the starfishes Asterias rubens and Asterias forbesi. One is an octapeptide with the amino acid sequence Gly-Phe-Asn-Ser-Ala-Leu-Met-Phe-NH2 and the other is a dodecapeptide with the amino acid sequence Ser-Gly-Pro-Tyr-Ser-Phe-Asn-Ser-Gly-Leu-Thr-Phe-NH2. The peptides were purified using high performance liquid chromatography (HPLC) and a radioimmunoassay for the molluscan FMRFamide-related neuropeptide, pQDPFLRFamide. Both peptides share minimal sequence identity with members of the family of FMRFamide-like peptides so we have designated them as founder members of a new family, the SALMFamides. We refer to the octapeptide as SALMFamide 1 (S1) and the dodecapeptide as SALMFamide 2 (S2). S1 and S2 are the first neuropeptides identified in species belonging to the phylum Echinodermata.


Multi-objective property optimisation of a phosphoserine-modified calcium phosphate cement for orthopaedic and dental applications using design of experiments methodology.
Phosphoserine is a ubiquitous molecule found in numerous proteins and, when combined with alpha-tricalcium phosphate (α-TCP) powder, demonstrates the ability to generate an adhesive biomaterial capable of stabilising and repairing bone fractures. Design of Experiments (DoE) approach was able to optimise the composition of phosphoserine-modified calcium phosphate cement (PM-CPC) demonstrating that the liquid:powder ratio (LPR) and quantity of phosphoserine (wt%) significantly influenced the handling, mechanical, and adhesion properties. Subsequently, the DoE optimisation process identified the optimal PM-CPC formulation, exhibiting a compressive strength of 29.2 ± 4.9 MPa and bond/shear strength of 3.6 ± 0.9 MPa after a 24 h setting reaction. Moreover, the optimal PM-CPC composition necessitated a mixing time of 20 s and displayed an initial setting time between 3 and 4 min, thus enabling homogenous mixing and precise delivery within a surgical environment. Notably, the PM-CPC demonstrated a bone-to-bone bond strength of 1.05 ± 0.3 MPa under wet conditions, coupled with a slow degradation rate during the first five days. These findings highlight the ability of PM-CPC to effectively support and stabilise bone fragments during the initial stages of natural bone healing. The developed PM-CPC formulations fulfil the clinical requirements for working and setting times, static mechanical, degradation properties, and injectability, enabling surgeons to stabilise complex bone fractures. This innovative bioinspired adhesive represents a significant advancement in the treatment of challenging bone injuries, offering precise delivery within a surgical environment and the potential to enhance patient outcomes. STATEMENT OF SIGNIFICANCE: This manuscript presents a noteworthy contribution to the field of bone fracture healing and fixation by introducing a novel phosphoserine-modified calcium phosphate cement (PM-CPC) adhesive by incorporating phosphoserine and alpha-TCP. This study demonstrates the fabrication and extensive characterisation of this adhesive biomaterial that holds great promise for stabilising and repairing complex bone fractures. Design of Experiment (DoE) software was used to investigate the correlations between process, property, and structure of the adhesive, resulting in a cost-effective formulation with desirable physical and handling properties. The PM-CPC adhesive exhibited excellent adhesion and cohesion properties in wet-field conditions. This research offers significant potential for clinical translation and contributes to the ongoing advancements in bone tissue engineering.


Adjuvanted Influenza Vaccines Elicits Higher Antibody Responses against the A(H3N2) Subtype than Non-Adjuvanted Vaccines.
vaccination is the best approach to prevent influenza infections so far. Serological studies on the effect of different vaccine types are important to address vaccination campaigns and protect our population. In our study, we compared the serological response against influenza A subtypes using the non-adjuvanted influenza vaccine (NAIV) in adults and the elderly and the adjuvanted influenza vaccine (AIV) in the elderly. We performed a retrospective analysis by hemagglutination inhibition assay (HI) of serum samples right before and 28 days after seasonal influenza vaccination during the 1996-2017 seasons. The AIV presents better performance against the A(H3N2) subtype in the elderly whereas the NAIV induces a better response against A(H1N1)pdm09 in the same group.


Neutrophil to Lymphocyte Ratio: An Emerging Marker of the Relationships between the Immune System and Diseases.
Over the last 10 years, the evaluation of the neutrophil-to-lymphocyte ratio (NLR) as an emerging marker of diseases has become a compelling field of bio-medical research. Although a precise and unique cut-off value has not been yet found, its role as a flag of immune system homeostasis is well established. NLR has a well-known prognostic value and independently correlates with mortality in the general population and in several specific subsets of disease (sepsis, pneumonia, COVID-19, cancer, etc.). Moreover, NLR was recently considered as part of the decision-making processes concerning the admission/recovery of patients with COVID-19 pneumonia. This review aims to provide an overview of the main use of this biomarker, focusing on the pathophysiology and the molecular basis underlying its central role as a reliable mirror of inflammatory status and adaptive immunity.


Public healthcare interests require strict competition enforcement.
Several countries have introduced competition in their health systems in order to maintain the supply of high quality health care in a cost-effective manner. The introduction of competition triggers competition enforcement. Since healthcare is characterized by specific market failures, many favor healthcare-specific competition enforcement in order not only to account for the competition interest, but also for the healthcare interests. The question is whether healthcare systems based on competition can succeed when competition enforcement deviates from standard practice. This paper analyzes whether healthcare-specific competition enforcement is theoretically sound and practically effective. This is exemplified by the Dutch system that is based on regulated competition and thus crucially depends on getting competition enforcement right. Governments are responsible for correcting market failures. Markets are responsible for maximizing the public healthcare interests. By securing sufficient competitive pressure, competition enforcement makes sure they do. When interpreted according to welfare-economics, competition law takes into account both costs and benefits specific market behavior may have for healthcare. Competition agencies and judiciary are not legitimized to deviate from standard evidentiary requirements. Dutch case law shows that healthcare-specific enforcement favors the healthcare undertakings concerned, but to the detriment of public health care. Healthcare-specific competition enforcement is conceptually flawed and counterproductive. In order for healthcare systems based on competition to succeed, competition enforcement should be strict.


ICF and ICD codes provide a standard language of disability in young children.
The aim of this study was to examine the utility of a hierarchical algorithm incorporating codes from the International Classification of Functioning, Disability and Health--ICF (WHO, 2001) and the International Statistical Classification of Diseases-ICD (WHO, 1994) to classify reasons for eligibility of young children in early intervention. The database for this study was a nationally representative enrollment sample of more than 5,500 children in a longitudinal study of early intervention. Reasons for eligibility were reviewed and matched to the closest ICF or ICD codes under one of four major categories (Body Functions/Structures, Activities/Participation, Health Conditions, and Environmental Factors). The average number of reasons for eligibility provided per child was 1.5, resulting in a population summary exceeding 100%. A total of 305 ICF and ICD codes were used with most (77%) of the children having codes in the category of Body Function/Structures. Forty-one percent of the sample had codes of Health Conditions, whereas the proportions with codes in the Activities/Partipication and Environmental Categories were 10 and 5%, respectively. The results demonstrate that ICD and ICF can be jointly used as a common language to document disability characteristics of children in early intervention.


Future Oncotargets: Targeting Overexpressed Conserved Protein Targets in Androgen Independent Prostate Cancer Cell Lines.
Targeting evolutionarily conserved proteins in malignant cells and the adapter proteins involved in signalling that generates from such proteins may play a cardinal role in the selection of anti-cancer drugs. Drugs targeting these proteins could be of importance in developing anti-cancer drugs. We inferred that drugs like loperamide and promethazine that act as antagonists of proteins conserved in cancer cells like voltage-gated Calcium channels (Cav), Calmodulin (CaM) and drug efflux (ABCB1) pump may have the potential to be re-purposed as an anti-cancer agent in Prostate Cancer (PCa). Growth and cytotoxic assays were performed by selecting loperamide and promethazine to target Cav, CaM and drug efflux (ABCB1) pumps to elucidate their effects on androgen-independent PC3 and DU145 PCa cell lines. We show that loperamide and promethazine in doses of 80-100μg/ml exert oncocidal effects when tested in DU145 and PC3 cell lines. Diphenhydramine, which shares its targets with promethazine, except the CaM, failed to exhibit oncocidal effects. Anti-cancer effects can be of significance if structural analogues of loperamide and promethazine that specifically target Cav, CaM and ABCB1 drug efflux pumps can be synthesized, or these two drugs could be re-purposed after human trials in PCa.


Whole blood fatty acid composition differs in term versus mildly preterm infants: small versus matched appropriate for gestational age.
To investigate the associations between whole blood fatty acid (FA) profile and restricted intrauterine growth, any small for gestational age (SGA) infant born in our maternity ward through 1 y was matched with two appropriate for gestational age (AGA), of the same GA +/- 0.5 wk, infants, further subdivided into term and preterm. Whole blood was collected at d 4 on a strip and FA % composition assessed by means of gas chromatography. The whole sample consisted of 28 SGA versus 56 AGA born at term and 20 SGA versus 40 AGA born preterm at around 35 wks. Parent FA of the n-6 and n-3 FA families were higher in preterm groups, whereas docosahexaenoic acid was higher in term AGA (median % values, 3.9 versus 3.7 in term SGA, 2.8 in preterm AGA, and 2.5 in preterm SGA, p < 0.001). Term AGA had markedly higher values for the docosahexaenoic acid/alpha-linolenic acid ratio (median value: 91, versus 18 in term SGA, 12 in preterm AGA, and 10 in preterm SGA, p < 0.001). Term SGA had significantly lower levels of total monounsaturated FA and higher levels of eicosapentaenoic acid. Therefore, the 4-d whole blood FA pattern is associated with both GA and birth weight.


Clinicopathological features and prognosis of synchronous and metachronous colorectal cancer: a retrospective cohort study.
To investigate the clinicopathological features and prognosis of synchronous and metachronous multiple primary colorectal cancer. Patients who underwent operation for synchronous and metachronous colorectal cancer at the colorectal surgery department of XX Hospital between January 2000 and December 2021 were included. Perioperative indicators were comprehensively compared and included in the survival analyses. In total, 563 patients with synchronous (n=372) and metachronous (n=191) colorectal cancer were included. Patients with synchronous colorectal cancer were more likely to have a long onset time, positive carcinoembryonic antigen, advanced TNM stage, large tumor, perineural invasion, p53 high expression, and mismatch repair proficient. Compared with metachronous colorectal cancer, patients with synchronous colorectal cancer showed worse 5-year overall survival (68.6%±3.0% vs 81.9%±3.5%, P=0.018) and 5-year disease-free survival (61.2%±3.1% vs 71.0%±3.9%, P=0.022). In the subgroup analysis, segmental resection was an independent risk factor for the long-term outcomes of bilateral synchronous colorectal cancer. Clinicopathological and molecular features were different between synchronous and metachronous colorectal cancer. Patients with synchronous colorectal cancer showed a worse prognosis than those with metachronous colorectal cancer. Bilateral synchronous colorectal cancer requires extended resection to achieve improved long-term outcomes.


Brain iron and ferritin in Parkinson's and Alzheimer's diseases.
Semiquantitative histological evaluation of brain iron and ferritin in Parkinson's (PD) and Alzheimer's disease (DAT) have been performed in paraffin sections of brain regions which included frontal cortex, hippocampus, basal ganglia and brain stem. The results indicate a significant selective increase of Fe3+ and ferritin in substantia nigra zona compacta but not in zona reticulata of Parkinsonian brains, confirming the biochemical estimation of iron. No such changes were observed in the same regions of DAT brains. The increase of iron is evident in astrocytes, macrophages, reactive microglia and non-pigmented neurons, and in damaged areas devoid of pigmented neurons. In substantia nigra of PD and PD/DAT, strong ferritin reactivity was also associated with proliferated microglia. A faint iron staining was seen occasionally in peripheral halo of Lewy bodies. By contrast, in DAT and PD/DAT, strong ferritin immunoreactivity was observed in and around senile plaques and neurofibrillary tangles. The interrelationship between selective increase of iron and ferritin in PD requires further investigation, because both changes could participate in the induction of oxidative stress and neuronal death, due to their ability to promote formation of oxygen radicals.


Polycomb and Trithorax group protein-mediated control of stress responses in plants.
A plant's experience of abiotic or biotic stress can lead to stress memory in order to react faster and more efficiently to subsequent stresses. Molecularly, the memory of a stress can rely on stable inheritance through mitotic and meiotic cell divisions, thus epigenetic inheritance. The key epigenetic regulators are DNA cytosine methyltransferases and the Polycomb group (PcG) and Trithorax group (TrxG) proteins, which control numerous developmental processes. PcG and TrxG proteins act antagonistically on stable gene repression through mediating trimethylation of histone H3 lysine 27 (H3K27me3) and H3K4me3, respectively, and target thousands of genes in plants, including many genes responsive to stress. The role of PcG/TrxG proteins in regulating stress responses and memory, however, is just emerging. While it is well investigated that stress can induce changes of histone modifications at genes regulated by stress, it is largely unclear whether these changes are mitotically and/or meiotically heritable, hence confer somatic and/or transgenerational stress memory. As the literature on the role of DNA methylation in regulating stress responses has recently been extensively summarized, we focus this review on the current knowledge on the role of PcG and TrxG in stress responses and memory.


Longitudinal Impact of Vision Impairment on Concern About Falling in People With Age-Related Macular Degeneration.
To explore the longitudinal impact of central vision loss on concern about falling (CF), over a 12-month period, in people with age-related macular degeneration (AMD). Participants included 60 community-dwelling older people (age, 79.7 ± 6.4 years) with central vision impairment due to AMD. Binocular high-contrast visual acuity, contrast sensitivity, and visual fields were assessed at baseline and at 12 months. CF was assessed at both time points using the Falls Efficacy Scale-International (FES-I). Sensorimotor function (sit to stand, knee extension, postural sway, and walking speed) and neuropsychological function (reaction time, symptoms of anxiety and depression) were also assessed at both time points using validated instruments. Falls data were collected using monthly diaries during the 12 months. CF increased by a small but significant amount over the 12-month follow-up (2.1 units; P = 0.01), with increasing prevalence of high levels of CF (FES-I score ≥ 23), from 48% at baseline to 65% at 12 months. Linear mixed models showed that reduced contrast sensitivity was significantly associated with increased concern about falling (P = 0.004), whereas declines in both visual acuity and contrast sensitivity during the follow-up period were associated with increases in CF over the 12-month follow-up (P = 0.041 and P = 0.054, respectively), independent of age, gender, falls history, or number of comorbidities. Higher levels of CF are common in older people with AMD, and levels increase over time; this increase is associated with declines in both visual acuity and contrast sensitivity. These findings highlight the need for regular assessment of both visual acuity and contrast sensitivity to identify those at greatest risk of developing higher CF. Routine assessment of visual acuity and contrast sensitivity in older people with AMD will assist in identifying those at risk of developing high CF.


Development of an in-house ELISA for detection of antibodies against Enterococcus cecorum in Pekin ducks.
Enterococcus cecorum (EC) is known to cause skeletal lesions in broiler chickens and also systemic infections in Pekin ducks. Despite the importance of the pathogen, there is still a lack of serological diagnostic tools for the detection of EC infections. Here we describe the development of an in-house indirect enzyme-linked immunosorbent assay (ELISA) for the detection of EC-specific antibodies and its application by examination of 67 sera from experimentally infected Pekin ducks, 710 field samples from four Pekin duck breeder flocks previously vaccinated with inactivated vaccines, and 80 samples from commercial Pekin ducks coming from vaccinated parent flocks. All groups that had been experimentally inoculated via the air sac route were positive in the new ELISA, with significantly (P ≤ 0.05) increased mean sample/positive (S/P) ratios of 0.71-2.70 at days 7, 14 and 21 post-infection, while orally inoculated ducks and the EC-free control group remained negative with mean S/P ratios of 0.0-0.15. Antibodies were also detected in each of four vaccinated Pekin duck breeder flocks; 67.8% of the samples were antibody positive. The highest S/P ratios were found between 16 and 26 weeks (median S/P ratios from 0.15 to 1.03), but antibodies were still detected in some serum samples in weeks 61-67 post-hatch. No antibodies were detected in the commercial Pekin ducks. Antibody development in the ducks may be influenced by the composition of the inactivated vaccine. The new ELISA provides a useful tool for investigations of response to EC infections and vaccinations.


Ectoparasites of dogs in home environments on the Caribbean slope of Costa Rica.
Reports on ectoparasites on dogs in Central America are scarce. The aim of this study was to identify flea, louse and tick species infesting dogs in home environments on the Caribbean slope of Costa Rica, and determine their frequency and coexistence. Ectoparasites were collected from dogs in 83 rural homes at five study sites. Specimens were identified and separated according to species. Fleas were the most common ectoparasite (G = 22,217, DF = 8, p = 0.004). Ctenocephalides felis and Pulex simulans were found in 83% and 55% of the homes with ectoparasites, respectively. Trichodectes canis (13%), Heterodoxus spiniger (10%), Rhipicephalus sanguineus (18%), Rhipicephalus (Boophilus) microplus (5%) and Amblyomma ovale (8%) were also present. More than one species was collected in most cases (66%), and the most common combination was C. felis and P. simulans (59% of homes with fleas). The high frequency of P. simulans emphasizes the need for adequate identification. This was the first study involving different ectoparasites of dogs in Costa Rica, as well as the first report of T. canis in this country. The relative frequency and coexistence of these ectoparasites in the home environment may have implications for animal and human health.


A 15-year-old boy with Rubinstein-Taybi syndrome associated with severe congenital malalignment of the toenails.
Rubinstein-Taybi syndrome (RTS) is a well-known disorder characterized by growth and mental retardation, typical facial features, short stature, and broad thumbs and toes. Although several cutaneous manifestations are observed in these patients, they are not diagnostic and are usually considered to be coincidental. Congenital malalignment of the great toenails is a very rare disorder that is characterized by lateral deviation of the nail plate along its longitudinal axis. The nail plate grows into the lateral nail fold resulting in pain and infection. It is usually present at birth or begins in early childhood. We report a patient with characteristic manifestations of RTS and congenital malalignment of the great toenails. The association of these two entities has not been reported previously.


In utero Exposure to Maternal Chronic Inflammation Transfers a Pro-Inflammatory Profile to Generation F2 via Sex-Specific Mechanisms.
Generational transfer of maladaptations in offspring have been reported to persist for multiple generations in conditions of chronic inflammation, metabolic and psychological stress. Thus, the current study aimed to expand our understanding of the nature, potential sex specificity, and transgenerational plasticity of inflammatory maladaptations resulting from maternal chronic inflammation. Briefly, F1 and F2 generations of offspring from C57/BL/6 dams exposed to a modified maternal periconception systemic inflammation (MSPI) protocol were profiled in terms of leukocyte and splenocyte counts and cytokine responses, as well as glucocorticoid sensitivity. Overall, F1 male and female LPS groups presented with glucocorticoid hypersensitivity (with elevated corticosterone and increased leukocyte glucocorticoid receptor levels) along with a pro-inflammatory phenotype, which carried over to the F2 generation. The transfer of inflammatory and glucocorticoid responsiveness from F1 to F2 is evident, with heritability of this phenotype in F2. The findings suggest that maternal (F0) perinatal chronic inflammation resulted in glucocorticoid dysregulation and a resultant pro-inflammatory phenotype, which is transferred in the maternal lineage but seems to affect male offspring to a greater extent. Of further interest, upregulation of IL-1β cytokine responses is reported in female offspring only. The cumulative maladaptation reported in F2 offspring when both F1 parents were affected by maternal LPS exposure is suggestive of immune senescence. Given the potential impact of current results and the lack of sex-specific investigations, more research in this context is urgently required.


The emergence of HIV/AIDS in the Americas and beyond.
HIV-1 group M subtype B was the first HIV discovered and is the predominant variant of AIDS virus in most countries outside of sub-Saharan Africa. However, the circumstances of its origin and emergence remain unresolved. Here we propose a geographic sequence and time line for the origin of subtype B and the emergence of pandemic HIV/AIDS out of Africa. Using HIV-1 gene sequences recovered from archival samples from some of the earliest known Haitian AIDS patients, we find that subtype B likely moved from Africa to Haiti in or around 1966 (1962-1970) and then spread there for some years before successfully dispersing elsewhere. A "pandemic" clade, encompassing the vast majority of non-Haitian subtype B infections in the United States and elsewhere around the world, subsequently emerged after a single migration of the virus out of Haiti in or around 1969 (1966-1972). Haiti appears to have the oldest HIV/AIDS epidemic outside sub-Saharan Africa and the most genetically diverse subtype B epidemic, which might present challenges for HIV-1 vaccine design and testing. The emergence of the pandemic variant of subtype B was an important turning point in the history of AIDS, but its spread was likely driven by ecological rather than evolutionary factors. Our results suggest that HIV-1 circulated cryptically in the United States for approximately 12 years before the recognition of AIDS in 1981.


Endobronchial Presentation of Hodgkin Lymphoma Responding to Pembrolizumab: A Case Report.
An endobronchial localization of Hodgkin lymphoma is rare, and few experiences since the 1900s have been reported in the literature. Here we report the first case of a relapsed/refractory Hodgkin lymphoma with a critical vegetative mass at the level of the trachea successfully treated with pembrolizumab.


Flagellin glycans from two pathovars of Pseudomonas syringae contain rhamnose in D and L configurations in different ratios and modified 4-amino-4,6-dideoxyglucose.
Flagellins from Pseudomonas syringae pv. glycinea race 4 and Pseudomonas syringae pv. tabaci 6605 have been found to be glycosylated. Glycosylation of flagellin is essential for bacterial virulence and is also involved in the determination of host specificity. Flagellin glycans from both pathovars were characterized, and common sites of glycosylation were identified on six serine residues (positions 143, 164, 176, 183, 193, and 201). The structure of the glycan at serine 201 (S201) of flagellin from each pathovar was determined by sugar composition analysis, mass spectrometry, and (1)H and (13)C nuclear magnetic resonance spectroscopy. These analyses showed that the S201 glycans from both pathovars were composed of a common unique trisaccharide consisting of two rhamnosyl (Rha) residues and one modified 4-amino-4,6-dideoxyglucosyl (Qui4N) residue, beta-D-Quip4N(3-hydroxy-1-oxobutyl)2Me-(1-->3)-alpha-L-Rhap-(1-->2)-alpha-L-Rhap. Furthermore, mass analysis suggests that the glycans on each of the six serine residues are composed of similar trisaccharide units. Determination of the enantiomeric ratio of Rha from the flagellin proteins showed that flagellin from P. syringae pv. tabaci 6605 consisted solely of L-Rha, whereas P. syringae pv. glycinea race 4 flagellin contained both L-Rha and D-Rha at a molar ratio of about 4:1. Taking these findings together with those from our previous study, we conclude that these flagellin glycan structures may be important for the virulence and host specificity of P. syringae.


Temperature compensation in the oscillatory bray reaction.
The influence of temperature on the oscillatory frequency of the hydrogen peroxide-iodate ion reaction is found to be two-sided: (i) the period length decreases with increasing temperature in most of the instances studied, (ii) or in some cases an opposite change is observed. A temperature-independent period length (temperature compensation) is also discovered experimentally in a rather wide temperature interval at a narrow concentration range of reactants both in a batch configuration and under flow conditions. A simple model was considered to simulate this behavior. Opposing effects of the composite reactions of the model on the calculated period length with changing temperature are shown to be responsible for temperature compensation or overcompensation.


A Revised Diagnostic Classification of Canine Glioma: Towards Validation of the Canine Glioma Patient as a Naturally Occurring Preclinical Model for Human Glioma.
The National Cancer Institute-led multidisciplinary Comparative Brain Tumor Consortium (CBTC) convened a glioma pathology board, comprising both veterinarian and physician neuropathologists, and conducted a comprehensive review of 193 cases of canine glioma. The immediate goal was to improve existing glioma classification methods through creation of a histologic atlas of features, thus yielding greater harmonization of phenotypic characterization. The long-term goal was to support future incorporation of clinical outcomes and genomic data into proposed simplified diagnostic schema, so as to further bridge the worlds of veterinary and physician neuropathology and strengthen validity of the dog as a naturally occurring, translationally relevant animal model of human glioma. All cases were morphologically reclassified according to a new schema devised by the entire board, yielding a majority opinion diagnosis of astrocytoma (43, 22.3%), 19 of which were low-grade and 24 high-grade, and oligodendroglioma (134, 69.4%), 35 of which were low-grade and 99 were high-grade. Sixteen cases (8.3%) could not be classified as oligodendroglioma or astrocytoma based on morphology alone and were designated as undefined gliomas. The simplified classification scheme proposed herein provides a tractable means for future addition of molecular data, and also serves to highlight histologic similarities and differences between human and canine glioma.


Molecular diagnosis of celiac disease: are we there yet?
Celiac disease (CD) is a complex genetic disorder of the small intestine resulting from aberrant cellular responses to gluten peptides. It may affect as much as 1% of the Western population and the only treatment is a lifelong gluten-free diet. Allelic variants of the HLA-DQ locus, coding for the HLA-DQ2 and HLA-DQ8 molecules, contribute to ∼ 40% of CD etiology, whereas other genes, such as MYO9B, CTLA4, IL2, IL21, PARD3 and MAGI2, have only a modest effect. Most of these genes have shown varied association among different populations and an overlap with other autoimmune or inflammatory disorders, indicating that such disorders may share common pathways. In this review, a molecular approach into diagnostics of celiac disease is shown. Genome-wide association studies will allow more genes to be identified, and knowing how risk variants combine will help to predict better the risk for the individual. HLA typing can already be used to identify high-risk individuals.


Effect of IBD sera on expression of inducible and endothelial nitric oxide synthase in human umbilical vein endothelial cells.
To study the expression of endothelial and inducible nitric oxide synthases (eNOS and iNOS) and their role in inflammatory bowel disease (IBD). We examined the effect of sera obtained from patients with active Crohn's disease (CD) and ulcerative colitis (UC) on the function and viability of human umbilical vein endothelial cells (HUVEC). HUVECs were cultured for 0-48 h in the presence of a medium containing pooled serum of healthy controls, or serum from patients with active CD or UC. Expression of eNOS and iNOS was visualized by immunofluorescence, and quantified by the densitometry of Western blots. Proliferation activity was assessed by computerized image analyses of Ki-67 immunoreactive cells, and also tested in the presence of the NOS inhibitor, 10(-4) mol/L L-NAME. Apoptosis and necrosis was examined by the annexin-V-biotin method and by propidium iodide staining, respectively. In HUVEC immediately after exposure to UC, serum eNOS was markedly induced, reaching a peak at 12 h. In contrast, a decrease in eNOS was observed after incubation with CD sera and the eNOS level was minimal at 20 h compared to control (18%+/-16% vs 23%+/-15% P<0.01). UC or CD serum caused a significant increase in iNOS compared to control (UC: 300%+/-21%; CD: 275%+/-27% vs 108%+/-14%, P<0.01). Apoptosis/necrosis characteristics did not differ significantly in either experiment. Increased proliferation activity was detected in the presence of CD serum or after treatment with L-NAME. Cultures showed tube-like formations after 24 h treatment with CD serum. IBD sera evoked changes in the ratio of eNOS/iNOS, whereas did not influence the viability of HUVEC. These involved down-regulation of eNOS and up-regulation of iNOS simultaneously, leading to increased proliferation activity and possibly a reduced anti-inflammatory protection of endothelial cells.


Human Mesenchymal Stromal Cells Improve Cardiac Perfusion in an Ovine Immunocompetent Animal Model.
Mesenchymal stromal cells (MSCs) hold considerable promise in the treatment of ischemic heart disease. Most preclinical studies of MSCs for acute myocardial infarction (AMI) have been performed either in syngeneic animal models or with human cells in xenogeneic immunodeficient animals. A preferable pre-clinical model, however, would involve human MSCs in an immunocompetent animal. AMI was generated in adult sheep by inducing ischemia reperfusion of the second diagonal branch. Sheep (n = 10) were randomized to receive an intravenous injection of human MSCs (1 × 10(6) cells/kg) or phosphate buffered saline. Cardiac function and remodeling were evaluated with echocardiography. Perfusion scintigraphy was used to identify sustained myocardial ischemia. Interaction between human MSCs and ovine lymphocytes was assessed by a mixed lymphocyte response (MLR). Sheep receiving human MSCs showed significant improvement in myocardial perfusion at 1 month compared with baseline measurements. There was no change in ventricular dimensions in either group after 1 month of AMI. No adverse events or symptoms were observed in the sheep receiving human MSCs. The MLR was negative. The immunocompetent ovine AMI model demonstrates the clinical safety and efficacy of human MSCs. The human cells do not appear to be immunogenic, further suggesting that immunocompetent sheep may serve as a suitable pre-clinical large animal model for testing human MSCs.