Investigation of Early Syphilis Trends Among Men Who Have Sex With Men to Identify Gaps in Screening and Case-Finding in Baltimore City, Maryland.
Syphilis incidence is increasing across the United States among men who have sex with men (MSM). Early latent (EL) versus primary and secondary (P&S) syphilis may be an indicator of delayed diagnosis and increased opportunity for transmission. To inform syphilis control strategies and identify potential gaps in case finding, we described recent syphilis trends among MSM and compared characteristics of syphilis cases by diagnosis stage. We used public health surveillance data on P&S and EL syphilis diagnoses reported to the Baltimore City Health Department between 2009 and 2015. Differences across diagnosis stage were assessed using Cochran-Armitage and χ tests. Between 2009 and 2015, Baltimore City Health Department received 2436 reports of P&S and EL diagnoses. The majority (61%) of reports were among MSM, among whom 86% were black and 67% were human immunodeficiency virus (HIV)-infected. During this period, P&S and EL syphilis increased by 85% and 245%, respectively (P < 0.0001). MSM with EL versus P&S syphilis were similarly likely to be Black, more likely to be older (P < 0.05), HIV coinfected (P < 0.001), and diagnosed in private health care settings (P < 0.0001), but less likely to report multiple (P < 0.001) and anonymous sex partners (P < 0.001). In Baltimore City, syphilis diagnoses, particularly EL diagnoses, are increasing rapidly and are concentrated among Black HIV-infected MSM. Significant gaps in identifying MSM with P&S syphilis may exist, specifically among HIV-infected MSM, and those diagnosed in private health care settings. Strategies to address these gaps may include local guidelines and provider education to screen MSM more frequently than CDC currently recommends and regardless of HIV status or risk.


Signal transmission through the CXC chemokine receptor 4 (CXCR4) transmembrane helices.
The atomic-level mechanisms by which G protein-coupled receptors (GPCRs) transmit extracellular ligand binding events through their transmembrane helices to activate intracellular G proteins remain unclear. Using a comprehensive library of mutations covering all 352 residues of the GPCR CXC chemokine receptor 4 (CXCR4), we identified 41 amino acids that are required for signaling induced by the chemokine ligand CXCL12 (stromal cell-derived factor 1). CXCR4 variants with each of these mutations do not signal properly but remain folded, based on receptor surface trafficking, reactivity to conformationally sensitive monoclonal antibodies, and ligand binding. When visualized on the structure of CXCR4, the majority of these residues form a continuous intramolecular signaling chain through the transmembrane helices; this chain connects chemokine binding residues on the extracellular side of CXCR4 to G protein-coupling residues on its intracellular side. Integrated into a cohesive model of signal transmission, these CXCR4 residues cluster into five functional groups that mediate (i) chemokine engagement, (ii) signal initiation, (iii) signal propagation, (iv) microswitch activation, and (v) G protein coupling. Propagation of the signal passes through a "hydrophobic bridge" on helix VI that coordinates with nearly every known GPCR signaling motif. Our results agree with known conserved mechanisms of GPCR activation and significantly expand on understanding the structural principles of CXCR4 signaling.


Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women.
To investigate the prospective association of low-density lipoprotein (LDL) particle diameter with the incidence of fatal and nonfatal coronary artery disease (CAD). A nested case-control study. Cases and controls were identified from a population-based sample of men and women combining all of the 5 cross-sectional surveys conducted from 1979 to 1990 of the Stanford Five-City Project (FCP). Incident CAD cases were identified through FCP surveillance between 1979 and 1992. Controls were matched by sex, 5-year age groups, survey time point, ethnicity, and FCP treatment condition. The sample included 124 matched pairs: 90 pairs of men and 34 pairs of women. LDL peak particle diameter (LDL size) was determined by gradient gel electrophoresis on plasma samples collected during the cross-sectional surveys (stored at 70 degrees C for 5-15 years). Established CAD risk-factor data were available from FCP baseline measurements. LDL size was smaller among CAD cases than controls (mean +/- SD) (26.17 +/- 1.00 nm vs 26.68 +/- 0.90 nm; P<.001). The association was graded across control quintiles of LDL size. The significant case-control difference in LDL size was independent of levels of high-density lipoprotein cholesterol (HDL-C), non-HDL cholesterol (non-HDL-C), triglyceride, smoking, systolic blood pressure, and body mass index, but was not significant after adjusting for the ratio of total cholesterol (TC) to HDL-C (TC:HDL-C). Among all the physiological risk factors, LDL size was the best differentiator of CAD status in conditional logistic regression. However, when added to the physiological parameters above, the TC:HDL-C ratio was found to be a stronger independent predictor of CAD status. LDL size was significantly smaller in CAD cases than in controls in a prospective, population-based study. These findings support other evidence of a role for small, dense LDL particles in the etiology of atherosclerosis.


Effects of soy or rye supplementation of high-fat diets on colon tumour development in azoxymethane-treated rats.
Evidence is accumulating that a diet high in plant-derived foods may be protective against cancer. One class of plant component under increasing investigation is the phytoestrogens of which there are two main groups: the isoflavones, found mainly in soy products, and the lignans, which are more ubiquitous and are found in fruit, vegetables and cereals with high levels being found in flaxseed. In this study, we have used carefully balanced high-fat (40% energy) diets: a control diet (containing low isoflavone soy protein as the sole protein source), a rye diet (the control diet supplemented with rye bran) and a soy diet (containing as protein source a high isoflavone soy protein). The effect of these diets on the development of colonic cancer was studied in F-344 rats treated with the carcinogen, azoxymethane (two doses of 15 mg/kg given 1 week apart). Colons from treated animals were examined for aberrant crypt foci (ACF) and tumours after 12 and 31 weeks. Results after 12 weeks showed no differences in the total number of ACF in the control, soy or rye bran groups. However, the soy group had increased numbers of small ACF (less than four crypts/focus) while the rye group had decreased numbers of large ACF (greater than six crypts/focus). Examination of colons after 31 weeks gave similar low numbers of ACF in each group with no differences in multiplicity. There were no differences in the number of tumours between the control (1.36 tumours/rat) and soy (1.38 tumours/rat) groups. However, there was a significant decrease in the number of tumours in the rye group (0.17 tumours/rat). These results suggest that soy isoflavones have no effect on the frequency of colonic tumours in this model while rye bran supplementation decreases the frequency of colon cancer. This effect is due not to a decrease in early lesions but in their progression to larger multi-crypt ACF. The study also supports the hypothesis that larger ACF are more predictive of subsequent tumorigenicity.


The duration of pubertal growth peak among three skeletal classes.
Pubertal growth peak is closely associated with a rapid increase in mandibular length and offers a wide range of therapeutic modifiability. The aim of the present study was to determine and compare the mean ages of onset and duration of pubertal growth peak among three skeletal classes. A retrospective cross-sectional study was conducted using lateral cephalograms of 230 subjects with growth potential (110 males, 120 females). Subjects were categorized into three classes (Class I = 81, Class II = 82, Class III = 67), according to the sagittal relationship established between the maxilla and the mandible. The cervical vertebral maturation stage was recorded by means of Baccetti's method. The mean ages at CS3 and CS4 and the CS3-CS4 age interval were compared between boys and girls and among three skeletal classes. Pubertal growth peak occurred on average four months earlier in girls than boys (p = 0.050). The average duration of pubertal growth peak was 11 months in Class I, seven months in Class II and 17 months in Class III subjects. Interclass differences were highly significant (Cohen's d > 0.08). However, no significant difference was found in the timing of pubertal growth peak onset among three skeletal classes (p = 0.126 in boys, p = 0.262 in girls). Girls enter pubertal growth peak on average four months earlier than boys. Moreover, the duration of pubertal growth peak is on average four months shorter in Class II and six months longer in Class III subjects as compared to Class I subjects.


The Geneva Emotional Competence Test (GECo): An ability measure of workplace emotional intelligence.
Emotional intelligence (EI) has been frequently studied as a predictor of work criteria, but disparate approaches to defining and measuring EI have produced rather inconsistent findings. The conceptualization of EI as an ability to be measured with performance-based tests is by many considered the most appropriate approach, but only few tests developed in this tradition exist, and none of them is designed to specifically assess EI in the workplace. The present research introduces the Geneva Emotional Competence test (GECo)-a new ability EI test measuring emotion recognition (assessed using video clips of actors), emotion understanding, emotion regulation in oneself, and emotion management in others (all assessed with situational judgment items of work-related scenarios). For the situational judgment items, correct and incorrect response options were developed using established theories from the emotion and organizational field. Five studies (total N = 888) showed that all subtests had high measurement precision (as assessed with Item Response Theory), and correlated in expected ways with other EI tests, cognitive intelligence, personality, and demographic variables. Further, the GECo predicted performance in computerized assessment center tasks in a sample of professionals, and explained academic performance in students incrementally above another ability EI test. Because of its theory-based scoring, good psychometric properties, and focus on the workplace, the GECo represents a promising tool for studying the role of four major EI components in organizational outcomes. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


[Genetic diseases of the mitochondrial DNA in humans].
Mitochondrial diseases are a group of disorders produced by defects in the oxidative phosphorylation system (Oxphos system), the final pathway of the mitochondrial energetic metabolism, resulting in a deficiency of the biosynthesis of ATP. Part of the polypeptide subunits involved in the Oxphos system are codified by the mitochondrial DNA. In the last years, mutations in this genetic system have been described and associated to well defined clinical syndromes. The clinical features of these disorders are very heterogeneous affecting, in most cases, to different organs and tissues and their correct diagnosis require precise clinical, morphological, biochemical and genetic data. The peculiar genetic characteristics of the mitochondrial DNA (maternal inheritance, polyplasmia and mitotic segregation) give to these disorders very distinctive properties. The English version of this paper is available at: http://www.insp.mx/salud/index.html.


Comparison of the therapeutic efficacy of phonophoresis and iontophoresis using dexamethasone sodium phosphate in the management of patients with knee osteoarthritis.
Many treatment options, including non-pharmacological and pharmacological measures, have been recommended in the management of osteoarthritis (OA). Among the non-pharmacological approach is physiotherapy, which involves the use of physical modalities like, heat therapy, exercise therapy, electrical stimulation, therapeutic ultrasound, iontophoresis, and phonophoresis. This study was therefore designed to compare the effectiveness of 0.4% Dexamethasone sodium phosphate (DEX-P) phonophoresis (PH) with 0.4% DEX-P iontophoresis (ION) therapy in the management of patients with knee joint OA. Fifty patients (19 males and 31 females) with a mean age of 53.6 +/- 8.9 years were randomly assigned to PH or ION groups with 25 patients in each group. Ultrasound waves of 1 MHz frequency was applied for 5 minutes to the target knee, so also was the direct current for 10 minutes for 10 sessions treatment period. Western Ontario and McMaster University Osteoarthritis Index (WOMAC) scores, 20 meters ambulatory time, and knee range of motion (ROM) were evaluated before and after therapy as the outcome measures. At the end of two weeks, significant improvement in total WOMAC scores was observed in 15 (60%) and 16 (64%) patients in the PH and ION groups respectively, indicating no significant difference in the improvement rate. Twenty (20) metres ambulatory time and knee range of motion also improved significantly in both groups, yet these variables showed no significant difference between the two groups. Both therapeutic modalities were found to be effective and generally well tolerated after 10 treatment sessions. DEX-P phonophoresis was not superior to DEX-P iontophoresis in the treatment of patients with OA of the knee.


Insulin and glucose responses during bed rest with isotonic and isometric exercise.
The effects of daily intensive isotonic (68% maximum oxygen uptake (VO2 max)) and isometric (21% maximum extension force) leg exercise on plasma insulin and glucose responses to an oral glucose tolerance test (OGTT) during 14-day bed-rest (BR) periods were investigated in seven young healthy men. The OGTT was given during ambulatory control and on day 10 of the no-exercise, isotonic, and isometric exercise BR periods during the 15-wk study. The subjects were placed on a controlled diet (mean +/- SD = 344 +/- 34 g CHO/day and 3,073 +/- 155 (SD) kcal/day) starting 10 days before each BR period. During BR, basal plasma glucose concentration remained unchanged with no exercise, but increased (P less than 0.05) to 87-89 mg/100 ml with both exercise regimens on day 2, and then fell slightly below control levels on day 13. The fall of glucose content (-11 to -15%) during BR was independent of the exercise regimen and was an adjustment for the loss of plasma vol. The intensity of the response of insulin and glucose to the OGTT (integrated area under the curves) was inversely proportional to the total daily energy expenditure during BR; i.e., the largest response with no exercise, then isometric, isotonic, and ambulatory exercise. It was estimated that at least 1,020 kcal/day must be provided by supplemental exercise to restore the hyperinsulinemia to control levels.


A subset of metastatic pancreatic ductal adenocarcinomas depends quantitatively on oncogenic Kras/Mek/Erk-induced hyperactive mTOR signalling.
Oncogenic Kras-activated robust Mek/Erk signals phosphorylate to the tuberous sclerosis complex (Tsc) and deactivates mammalian target of rapamycin (mTOR) suppression in pancreatic ductal adenocarcinoma (PDAC); however, Mek and mTOR inhibitors alone have demonstrated minimal clinical antitumor activity. We generated transgenic mouse models in which mTOR was hyperactivated either through the Kras/Mek/Erk cascade, by loss of Pten or through Tsc1 haploinsufficiency. Primary cancer cells were isolated from mouse tumours. Oncogenic signalling was assessed in vitro and in vivo, with and without single or multiple targeted molecule inhibition. Transcriptional profiling was used to identify biomarkers predictive of the underlying pathway alterations and of therapeutic response. Results from the preclinical models were confirmed on human material. Reduction of Tsc1 function facilitated activation of Kras/Mek/Erk-mediated mTOR signalling, which promoted the development of metastatic PDACs. Single inhibition of mTOR or Mek elicited strong feedback activation of Erk or Akt, respectively. Only dual inhibition of Mek and PI3K reduced mTOR activity and effectively induced cancer cell apoptosis. Analysis of downstream targets demonstrated that oncogenic activity of the Mek/Erk/Tsc/mTOR axis relied on Aldh1a3 function. Moreover, in clinical PDAC samples, ALDH1A3 specifically labelled an aggressive subtype. These results advance our understanding of Mek/Erk-driven mTOR activation and its downstream targets in PDAC, and provide a mechanistic rationale for effective therapeutic matching for Aldh1a3-positive PDACs.


Neurosurgery and shaving: what's the evidence?
Many neurosurgeons remove their patients' hair before surgery. They claim that this practice reduces the chance of postoperative surgical site infections, and facilitates planning, attachment of the drapes, and closure. However, most patients dread this procedure. The authors performed the first systematic review on shaving before neurosurgical procedures to investigate whether this commonly performed procedure is based on evidence. They systematically reviewed the literature on wound infections following different shaving strategies. Data on the type of surgery, surgeryrelated infections, preoperative shaving policy, decontamination protocols, and perioperative antibiotics protocols were collected. The search detected 165 articles, of which 21 studies-involving 11,071 patients-were suitable for inclusion. Two of these studies were randomized controlled trials. The authors reviewed 13 studies that reported on the role of preoperative hair removal in craniotomies, 14 on implantation surgery, 5 on bur hole procedures, and 3 on spine surgery. Nine studies described shaving policies in pediatric patients. None of these papers provided evidence that preoperative shaving decreases the occurrence of postoperative wound infections. The authors conclude that there is no evidence to support the routine performance of preoperative hair removal in neurosurgery. Therefore, properly designed studies are needed to provide evidence for preoperative shaving recommendations.


Perspectives of an international education initiative in children's palliative care.
Education is viewed as central to improving future palliative care for children and families across all countries. International education initiatives will ensure practitioners are aware of global health issues and can provide culturally sensitive care. Creative and innovative means of meeting such directives are required to achieve meaningful student learning. This paper focuses on one innovation, a children's palliative care workshop using case studies as a teaching method, with nursing students from the USA and nursing and midwifery students from the UK. Key learning points arising from student evaluation were recorded under three main themes, these were: differences across countries, similarities across countries, and making learning fun and memorable. Findings indicated that this joint learning activity was viewed positively by all students and has enabled them to learn with and from each other, potentially impacting on their future practice.


BMPs and FGFs target Notch signalling via jagged 2 to regulate tooth morphogenesis and cytodifferentiation.
The Notch signalling pathway is an evolutionarily conserved intercellular signalling mechanism that is essential for cell fate specification and proper embryonic development. We have analysed the expression, regulation and function of the jagged 2 (Jag2) gene, which encodes a ligand for the Notch family of receptors, in developing mouse teeth. Jag2 is expressed in epithelial cells that give rise to the enamel-producing ameloblasts from the earliest stages of tooth development. Tissue recombination experiments showed that its expression in epithelium is regulated by mesenchyme-derived signals. In dental explants cultured in vitro, the local application of fibroblast growth factors upregulated Jag2 expression, whereas bone morphogenetic proteins provoked the opposite effect. Mice homozygous for a deletion in the Notch-interaction domain of Jag2 presented a variety of severe dental abnormalities. In molars, the crown morphology was misshapen, with additional cusps being formed. This was due to alterations in the enamel knot, an epithelial signalling structure involved in molar crown morphogenesis, in which Bmp4 expression and apoptosis were altered. In incisors, cytodifferentiation and enamel matrix deposition were inhibited. The expression of Tbx1 in ameloblast progenitors, which is a hallmark for ameloblast differentiation and enamel formation, was dramatically reduced in Jag2(-/-) teeth. Together, these results demonstrate that Notch signalling mediated by Jag2 is indispensable for normal tooth development.


Detailing radio frequency heating induced by coronary stents: a 7.0 Tesla magnetic resonance study.
The sensitivity gain of ultrahigh field Magnetic Resonance (UHF-MR) holds the promise to enhance spatial and temporal resolution. Such improvements could be beneficial for cardiovascular MR. However, intracoronary stents used for treatment of coronary artery disease are currently considered to be contra-indications for UHF-MR. The antenna effect induced by a stent together with RF wavelength shortening could increase local radiofrequency (RF) power deposition at 7.0 T and bears the potential to induce local heating, which might cause tissue damage. Realizing these constraints, this work examines RF heating effects of stents using electro-magnetic field (EMF) simulations and phantoms with properties that mimic myocardium. For this purpose, RF power deposition that exceeds the clinical limits was induced by a dedicated birdcage coil. Fiber optic probes and MR thermometry were applied for temperature monitoring using agarose phantoms containing copper tubes or coronary stents. The results demonstrate an agreement between RF heating induced temperature changes derived from EMF simulations versus MR thermometry. The birdcage coil tailored for RF heating was capable of irradiating power exceeding the specific-absorption rate (SAR) limits defined by the IEC guidelines by a factor of three. This setup afforded RF induced temperature changes up to +27 K in a reference phantom. The maximum extra temperature increase, induced by a copper tube or a coronary stent was less than 3 K. The coronary stents examined showed an RF heating behavior similar to a copper tube. Our results suggest that, if IEC guidelines for local/global SAR are followed, the extra RF heating induced in myocardial tissue by stents may not be significant versus the baseline heating induced by the energy deposited by a tailored cardiac transmit RF coil at 7.0 T, and may be smaller if not insignificant than the extra RF heating observed under the circumstances used in this study.


Impact of Taiwanese culture on beliefs about expressing anxiety and engaging in physical activity: a discursive analysis of the literature.
This paper analysed the scholarly discourse about the influence of Taiwanese culture on beliefs about expressing anxiety and engaging in physical activity from literature review. The well-being of individuals with mental illness is promoted by the World Health Organization. Reducing barriers to treatment and care in community health-service systems requires cultural understanding. However, little is known about the influence of Taiwanese culture on physical activity programmes for people with anxiety disorders in Taiwan. A discursive analysis of the literature. Literature was used to examine the impact of Taiwanese culture on beliefs about anxiety and physical activity from historical, economic, social, political and geographical perspectives. Taiwanese cultural beliefs about anxiety and physical activity can be summarised into six themes. Beliefs about anxiety are reflected in three themes: anxiety and shame, beliefs against direct communication and beliefs about anxiety and external forces. Beliefs about engaging in physical activity are reflected in three themes: beliefs about human action, the relationship between health and physical activity and priority of academic achievement. This paper exposes the hidden power of culture to influence Taiwanese beliefs about anxiety and physical activity. Three negative beliefs about anxiety influence the expression of anxiety symptoms and help-seeking behaviours. Two positive and one negative belief about physical activity significantly affect choice of activity type and level of participation in physical activity. Anxiety and physical activity have a dynamic relationship and both are deeply influenced by Taiwanese culture. An awareness of cultural influences on beliefs about anxiety and physical activity is important when encouraging Taiwanese people with anxiety disorders to engage in physical activity. This awareness may help nurses understand better how their patients perceive anxiety and physical activity, leading to more appropriate physical activity programmes to improve both physical and psychological well-being.


An Immune Atlas of T Cells in Transplant Rejection: Pathways and Therapeutic Opportunities.
Short-term outcomes in allotransplantation are excellent due to technical and pharmacological advances; however, improvement in long-term outcomes has been limited. Recurrent episodes of acute cellular rejection, a primarily T cell-mediated response to transplanted tissue, have been implicated in the development of chronic allograft dysfunction and loss. Although it is well established that acute cellular rejection is primarily a CD4 + and CD8 + T cell mediated response, significant heterogeneity exists within these cell compartments. During immune responses, naïve CD4 + T cells are activated and subsequently differentiate into specific T helper subsets under the influence of the local cytokine milieu. These subsets have distinct phenotypic and functional characteristics, with reported differences in their contribution to rejection responses specifically. Of particular relevance are the regulatory subsets and their potential to promote tolerance of allografts. Unraveling the specific contributions of these cell subsets in the context of transplantation is complex, but may reveal new avenues of therapeutic intervention for the prevention of rejection.


Implications of amino acid sensing and dietary protein to the aging process.
Every organism must adapt and respond appropriately to the source of nutrients available in its environment. Different mechanisms and pathways are involved in detecting the intracellular and extracellular levels of macronutrients including amino acids. Detection of amino acids in food sources is provided by taste cells expressing T1R1 and T1R3 type receptors. Additionally, cells of the intestine, pancreas or heart sense amino acids extracellularly. Neuronal and hormonal regulation integrates and coordinates the signals at the organismal level. Amino acid-sensitive mechanisms including GCN2 protein, mTOR and LYNUS machinery adjust cellular process according to the availability of specific amino acids. Triggering these mechanisms by genetic manipulations or by external manipulations with diets has a significant impact on lifespan. In model organisms, the restriction of protein or specific amino acids within the diet leads to lifespan-extending effects. However, the translation of results from model organisms to application in humans has to take into account lifestyle, psychology, social aspects and the possibility to choose what to eat and how it is cooked.


Phonological changes after the application of therapy approach based on distinctive features in the treatment of phonological disorder.
This study aimed to compare the phonological changes due to the application of a speech therapy approach based on distinctive features, using two types of target sounds (the ones which emphasize the contrast, and others which reinforce the distinctive features) in the treatment of phonological disorder. The sample was constituted by seven children with phonological disorder (four boys and three girls), with ages between 3 years and 10 months and 6 years and 9 months. The children were classified according to the severity of the phonological disorder and then underwent treatment based on the Modified Maximal Oppositions Model. Two subjects were grouped for each degree; one subject was treated by "contrast" and the other one by "reinforcement" of the distinctive features in which they showed difficulties. The moderate-severe degree was the only one to include only one subject. After 20 therapy sessions, the phonological changes before and after the treatment were analyzed, considering the type of stimulus presented ("contrast" or "reinforcement"). All subjects, either treated by "contrast" or "reinforcement", showed an increase in their Percentage of Consonants Correct (PCC), in the number of acquired sounds and of generalizations in their phonological inventories. It was verified that both groups presented changes in their phonological inventories. On the comparative analysis between the groups, it was observed that both groups, treated by "contrast" and by "reinforcement", demonstrated differences regarding the types of generalizations studied.


Postural instability in patients with diabetic sensory neuropathy.
Recent survey evidence suggests that sensory ataxia due to diabetic neuropathy may be a more frequent and serious problem than is commonly recognized. This view is further supported by research that confirms the major contribution of the somatosensory system to the control of posture. We therefore sought to determine the effects of significant diabetic distal symmetrical polyneuropathy on the control of posture. Fifty-one subjects, divided into three groups, participated in this study. Seventeen had diabetes and significant sensory neuropathy, 17 had diabetes and no neuropathy, and 17 had neither diabetes nor neuropathy. The subjects were matched across groups, and stringent exclusion criteria were applied. Postural stability during quiet standing was measured using a force platform. In addition to electrophysiological and quantitative sensory tests of neuropathy, a number of physical and functional characteristics were measured for all subjects. Postural instability was found to be significantly associated with sensory neuropathy, but not with diabetes per se. Patients with sensory neuropathy demonstrated between 66 and 117% more instability than did control subjects (depending on the testing condition). Based on multiple linear regression analyses, the most significant correlates of instability were the quantitative sensory measures of neuropathy and age. The loss of sensory perception secondary to diabetic distal symmetrical sensory neuropathy has a markedly detrimental effect on postural stability. The deficit is greatest when visual or vestibular cues are absent or degraded. Patients with neuropathy need to be informed of the postural consequences of this condition to limit the potential morbidity caused by falls.


Effects of Cd, Cu, Ni, and Zn on brown tide alga Aureococcus anophagefferens growth and metal accumulation.
Trace metals play important roles in regulating phytoplankton growth and could influence algal bloom development. Laboratory studies were conducted to evaluate the influence of environmentally relevant concentrations of Cd, Cu, Ni, and Zn on Aureococcus anophagefferens bloom (brown tide) development. Results show that the elevated Ni(2+) concentrations, e.g. those of brown tide waters in the northeastern US, greatly stimulated A. anophagefferens growth (as compared to the control without Ni addition), yet, only low amounts of dissolved Ni were sequestered, thus leaving excessive Ni directly promoting A. anophagefferens blooms. The medium effective concentration EC(50) (Me(2+)) suggests A. anophagefferens has similar Cd sensitivity but much greater Cu tolerance as compared to cyanobacteria, as such, excessive Cu could indirectly promote A. anophagefferens blooms by inhibiting competitors such as Synechococcus sp. The effects of Ni and Cu promoting growth are consistent with the recent genomic study of this alga. In addition, Zn(2+) concentrations lower than those in brown tide waters enhance A. anophagefferens growth, but Zn sequestration in A. anophagefferens would not substantially reduce total dissolved Zn in these waters. Overall, this study, showing that excessive Cu and Ni likely promote brown tides, provides evidence for trace metal linkages in algal bloom development.


An epizootic of eastern equine encephalitis virus, Maine, USA in 2009: outbreak description and entomological studies.
From July to September, 2009, an outbreak of eastern equine encephalitis virus (EEEv) occurred in five counties in Maine. The virus was isolated from 15 horses, 1 llama, and pheasants in three separate captive flocks. One wild turkey, screened before translocation, also showed exposure to the virus in January 2010. Two pools of Culiseta melanura (Coquillett) tested positive for EEEv during routine seasonal surveillance in York County in September, but none of the mosquitoes collected during rapid response surveys tested positive. There were more Cs. melanura in July, August, and September 2009 than in preceding (2006-08) and subsequent (2010-11) years. August and September Cs. melanura abundances were correlated with July rainfall, and abundance of all species combined was correlated with total rainfall for the meteorological summer. This outbreak represents a substantial expansion of the range of EEEv activity in northern New England.


Evaluation of pain incidence and pain management in a South African paediatric trauma unit.
OBJECTIVES. To evaluate pain incidence and pain management in a South African paediatric trauma unit, and to compare the usefulness of 5 different assessment tools. DESIGN. A prospective observational study, using the Numerical Rating Scale for pain (NRS pain), Numerical Rating Scale for anxiety (NRS anxiety), the Alder Hey Triage Pain Score (AHTPS), the COMFORT behaviour scale and the Touch Visual Pain Scale (TVPS). All patients were assessed at admission; those who were hospitalised were again assessed every 3 hours until discharge. RESULTS. A total of 165 patients, with a mean age of 5.3 years (range 0 - 13), were included. NRS scores were indicative of moderate to severe pain in 13.3% of the patients, and no pain in 24% at admission. Two-thirds of the patients received no analgesics; for them, NRS pain, AHTPS and TVP scores were lower than the scores for the other children. CONCLUSION. Pain and anxiety incidences in this paediatric trauma unit are relatively low. Implementation of a standard pain assessment tool in the emergency department triage system can improve pain management. The AHTPS is the most promising for use in non-Western settings.


Congestive heart failure secondary to gemcitabine nab-paclitaxel in patients with pancreatic cancer.
Gemcitabine plus nab-paclitaxel is a novel combination chemotherapy that is currently being used in patients with metastatic pancreatic cancer. Phase III trials have shown improved survival, response rates, and disease-free progression. The most significant side-effects include peripheral neuropathy and myelotoxicity. Review of literature has shown rare cases of congestive heart failure associated with gemcitabine plus nab-paclitaxel. We describe two cases of women who were treated with gemcitabine plus nab-paclitaxel for pancreatic adenocarcinoma who developed acute exacerbation of congestive heart failure. Two women with pancreatic adenocarcinoma were both treated with gemcitabine plus nab-paclitaxel and developed acute decompensated heart failure requiring hospitalization and standard treatment for heart failure including i.v. diuretics. Once chemotherapy was discontinued, symptoms resolved. Based on review of literature, as far as we are aware of, this is the first report of congestive heart failure as an adverse effect of combination therapy. Both patients had evidence of diastolic dysfunction which may have predisposed them to cardiac toxicity secondary to gemcitabine plus nab-paclitaxel. The exact mechanism of action is currently unknown and requires further studies. However, it is imperative for physicians to be aware of this adverse effect and closely monitor patients with underlying heart disease who are undergoing treatment with gemcitabine plus nab-paclitaxel.


Using Participatory Action Research to Develop a Working Model That Enhances Psychiatric Nurses' Professionalism: The Architecture of Stability.
Ward rules in psychiatric care aim to promote safety for both patients and staff. Simultaneously, ward rules are associated with increased patient violence, leading to neither a safe work environment nor a safe caring environment. Although ward rules are routinely used, few studies have explicitly accounted for their impact. To describe the process of a team development project considering ward rule issues, and to develop a working model to empower staff in their daily in-patient psychiatric nursing practices. The design of this study is explorative and descriptive. Participatory action research methodology was applied to understand ward rules. Data consists of audio-recorded group discussions, observations and field notes, together creating a data set of 556 text pages. More than 100 specific ward rules were identified. In this process, the word rules was relinquished in favor of adopting the term principles, since rules are inconsistent with a caring ideology. A linguistic transition led to the development of a framework embracing the (1) Principle of Safety, (2) Principle of Structure and (3) Principle of Interplay. The principles were linked to normative guidelines and applied ethical theories: deontology, consequentialism and ethics of care. The work model reminded staff about the principles, empowered their professional decision-making, decreased collegial conflicts because of increased acceptance for individual decisions, and, in general, improved well-being at work. Furthermore, the work model also empowered staff to find support for their decisions based on principles that are grounded in the ethics of totality.


Long-term use of HU210 adversely affects spermatogenesis in rats by modulating the endocannabinoid system.
Recent societal acceptance of cannabinoids as recreational and therapeutic drugs has posed a potential hazard to male reproductive health. Mammals have a highly sophisticated endogenous cannabinoid (ECS) system that regulates male (and female) reproduction and exo-cannabinoids may influence it adversely. Therefore it is imperative to determine their effects on male reproduction so that men can make informed choices as to their use. Here, an animal model was used to administer HU210, a synthetic analogue of Δ9-tetrahydrocannabinol (THC) and potent cannabinoid receptor (CB) agonist to determine its effects on reproductive organ weights, spermatogenesis, testicular histology and sperm motility. Its effects on the physiological endocannabinoid system were also investigated. Spermatogenesis was markedly impaired with reductions in total sperm count after 2 weeks of exposure. Spermatogenic efficiency was depleted, and Sertoli cell number decreased as exposure time increased with seminiferous tubules showing germ cell depletion developing into atrophy in some cases. Sperm motility was also adversely affected with marked reductions from 2 weeks on. HU210 also acted on the sperm's endocannabinoid system. Long-term use of exo-cannabinoids has adverse effects on both spermatogenesis and sperm function. These findings highlight the urgent need for studies evaluating the fertility potential of male recreational drug users. HU210, a selective agonist for CB1 and CB2 cannabinoid receptors impairs spermatogenesis and sperm motility and deregulates the endocannabinoid system.


LDL cholesterol still a problem in old age? A Mendelian randomization study.
Observational studies in older subjects have shown no or inverse associations between cholesterol levels and mortality. However, in old age plasma low-density lipoprotein cholesterol (LDL-C) may not reflect the lifetime level due to reverse causality, and hence the risk may be underestimated. In the current study, we used an LDL genetic risk score (GRS) to overcome this problem. A weighted GRS was created using 51 single nucleotide polymorphisms associated with LDL-C levels. The LDL GRS was calculated in three Dutch cohorts: the Leiden Longevity Study (LLS) (n = 3270), the Leiden 85-plus study (n = 316) and the Rotterdam Study (n = 4035). We assessed the association between the LDL GRS and LDL-C levels, chronological age, familial longevity and mortality. Up to 90 years of age, in each age stratum individuals with high LDL GRS had higher LDL-C levels (P = 0.010 to P = 1.1 x 10(-16)). The frequency of LDL-increasing alleles decreased with increasing age [β = -0.021 (SE = 0.01) per year, P = 0.018]. Moreover, individuals with a genetic predisposition for longevity had significantly lower LDL GRS compared with age-matched individuals of the general population [LLS nonagenarians vs > 90 years: β = 0.73 (SE = 0.33), P = 0.029, LLS offspring vs partners: β = 0.66 (SE = 0.23), P = 0.005]. In longitudinal analysis, high GRS was associated with increased all-cause mortality in individuals > 90 years, with a 13% increased risk in individuals with the highest LDL GRS (P-trend = 0.043). Results of the current study indicate that a genetic predisposition to high LDL-C levels contributes to mortality throughout life, including in the oldest old, and a beneficial LDL genetic risk profile is associated with familial longevity.


[Nutrition aspects in obese before and after bariatric surgery].
To determine the physical-nutritional profile of obese patients submitted to bariatric surgery at the HC/UFPE. Two-hundred-and-five patients were evaluated retrospectively during the period of 2002 through 2006. Analysis considered clinical history for diabetes type 2 (DM 2), high blood pressure (HBP) and metabolic syndrome (MS). The preoperative nutritional status was evaluated by MBI and the biochemistry (hemoglobin, hematocrit, albumin, total proteins, triglycerides (TG), cholesterol associated with the lipoprotein of high (HDLc) and low (LDLc) density and fasting glycemia (FG). During the postoperative periods (6, 12, 18, 24 months), we evaluated the nutritional status through measures of weight, weight loss, weight loss percentage (%WL), MBI and biochemistry including iron, ferritin, transferrin. Seventy-one and two-tenth percent were female, age was 38.4 + or - 9.96 years, and MBI preoperative was 48.6 + or - 8.9 Kg /m2. MS diagnosis was present in 26.8%, HBP was present in 52.7% and DM 2 was detected in 11.7%. The biochemistry disclosed TG, it raised LDLc, and FG, and all other parameters were normal. The anthropometrical evolution demonstrated gradual loss, reaching at the 24 months, MBI 31.7 + or - 5.82 Kg/m2 (p< 0.001) and greater %WL, 36%. Values of TG, LDLc and FG reached normality at the 6th postoperative month: 104.4mg/dL(p=0.018), 95.5mg/dL(p=0.263) and 84.8g/dL(p=0.004) respectively; the transferrin showed reduced values at the 6th month. A larger prevalence of the symptoms occurred in 6th month: hair loss (19%), vomiting (18%), and food intolerances (12.2%). The bariatric surgery was an efficient procedure to promote weight loss and its maintenance in two years, as well as improvement of biochemical parameters and comorbidities, with reduced clinical-nutritional symptoms and/or prevented by nutritional monitoring.


Virtual touch tissue quantification of acoustic radiation force impulse: a new ultrasound elastic imaging in the diagnosis of thyroid nodules.
Virtual touch tissue quantification (VTQ) of acoustic radiation force impulse (ARFI) is a new quantitative technique to measure tissue stiffness. The study was aimed to assess the usefulness of VTQ in the diagnosis of thyroid nodules. 173 pathologically proven thyroid nodules in 142 patients were included and all were examined by conventional ultrasound (US), conventional elasticity imaging (EI) and VTQ of ARFI. The tissue stiffness for VTQ was expressed as shear wave velocity (SWV) (m/s). Receiver-operating characteristic curve (ROC) analyses were performed to assess the diagnostic performance. Intra- and inter-observer reproducibility of VTQ measurement was assessed. The SWVs of benign and malignant thyroid nodules were 2.34±1.17 m/s (range: 0.61-9.00 m/s) and 4.82±2.53 m/s (range: 2.32-9.00 m/s) respectively (P<0.001). The mean SWV ratios between each nodule and the adjacent thyroid tissue were 1.19±0.67 (range: 0.31-6.87) for benign and 2.50±1.54 (range: 0.85-6.69) for malignant nodules (P<0.001). ROC analyses indicated that the area under the curve was 0.861 (95% CI : 0.804, 0.918) (P<0.001) for SWV and 0.831(95% CI : 0.761, 0.900)(P<0.001) for the SWV ratio. The cutoff points for the differential diagnosis were 2.87 m/s for SWV and 1.59 for SWV ratio. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value for EI were 65.9%, 66.7%, 66.5%, 40.3%, and 85.1%, respectively, and were 63.6%-75%, 82.2%-88.4%, 80.3%-82.1%, 58.9%-65.1%, and 87.7%-90.5%, respectively, for VTQ. The diagnostic value of VTQ is the highest for nodules >20 mm and lowest for those ≤10 mm. The correlation coefficients were 0.904 for intraobserver measurement and 0.864 for interobserver measurement. VTQ of ARFI provides quantitative and reproducible information about the tissue stiffness, which is useful for the differentiation between benign and malignant thyroid nodules. The diagnostic performance of VTQ is higher than that of conventional EI.


GWAS identifies 14 loci for device-measured physical activity and sleep duration.
Physical activity and sleep duration are established risk factors for many diseases, but their aetiology is poorly understood, partly due to relying on self-reported evidence. Here we report a genome-wide association study (GWAS) of device-measured physical activity and sleep duration in 91,105 UK Biobank participants, finding 14 significant loci (7 novel). These loci account for 0.06% of activity and 0.39% of sleep duration variation. Genome-wide estimates of ~ 15% phenotypic variation indicate high polygenicity. Heritability is higher in women than men for overall activity (23 vs. 20%, p = 1.5 × 10-4) and sedentary behaviours (18 vs. 15%, p = 9.7 × 10-4). Heritability partitioning, enrichment and pathway analyses indicate the central nervous system plays a role in activity behaviours. Two-sample Mendelian randomisation suggests that increased activity might causally lower diastolic blood pressure (beta mmHg/SD: -0.91, SE = 0.18, p = 8.2 × 10-7), and odds of hypertension (Odds ratio/SD: 0.84, SE = 0.03, p = 4.9 × 10-8). Our results advocate the value of physical activity for reducing blood pressure.


VSV-G pseudotyped, MuLV-based, semi-replication-competent retrovirus for cancer treatment.
Low levels of gene delivery in vivo using replication-defective retroviral vectors have severely limited their application for clinical protocols. To overcome this problem, we describe here a semi-replication-competent retrovirus (s-RCR) in which the gag-pol and envelope (VSV-G, vesicular stomatitis virus G protein) genes were split into two vectors. This system offers potential advantages over both replication-defective vectors, in terms of efficiency of in vivo spread through a tumor, and all-in-one replication-competent vectors in terms of the payload of therapeutic genes that can be carried. We achieved a viral titer of s-RCR viruses approximately 70-fold higher than VSV-G pseudotyped, replication-defective vectors. In addition, s-RCR vectors induced tumor killing by the cytotoxicity of VSV-G during viral spread. Inclusion of the herpes simplex virus thymidine kinase (HSVtk30) gene into vectors significantly improved tumor killing activity followed by ganciclovir (GCV) treatment in vitro under conditions of low-level viral replication. However, at high levels of viral spread, VSV-G-mediated cytotoxicity predominated. Xenografts of human fibrosarcoma HT1080 cells, preinfected by semi-replicative green fluorescent protein vectors (semi-GFP), were completely non-tumorigenic in nude mice. Implantation of cells preinfected by semi-replicative TK30 vectors (semi-TK30) mixed with parental HT1080 cells at a ratio of 1:1 efficiently prevented tumor growth in mice treated by GCV. Direct intratumoral injection of HT1080 tumors growing in nude mice, or B16 murine melanoma in immunocompetent mice, with semi-TK30 viruses significantly prolonged survival. Injection of autologous cells (B16) producing semi-TK30 vector into B16 tumors prolonged survival only in mice treated with GCV but not with phosphate-buffered saline (PBS). In contrast, when xenogeneic cells (293T) producing semi-TK30 vectors were injected into B16 tumors, an optimal survival advantage was obtained in mice treated with PBS rather than GCV. These data indicate that complex interactions exist between direct cytotoxicity of VSV-G and HSVtk expression when placed in the context of additional immune parameters, which combine to determine the efficacy of the therapy. Taken together, our data suggest that s-RCR vectors have some potential advantages for development to deliver genes into tumors for cancer treatment but that a combination of factors will impact on the decision as to whether the s-RCR strategy is worth developing to full clinical trials.


When phonology fails: orthographic neighbourhood effects in dyslexia.
Both cerebral hemispheres contain phonological, orthographic and semantic representations of words, however there are between-hemisphere differences in the relative engagement and specialization of the different representations. Taking orthographic processing for example, previous studies suggest that orthographic neighbourhood size (N) has facilitatory effects in the right but not the left hemispheres. To pursue the nature of this asymmetric N effect, in particular whether there are individual differences in such specialisation, we examined N in a case of developmental dyslexia, FM. We first describe the nature of his difficulties, which are mainly severe phonological deficits. Employing the divided visual field paradigm with FM revealed a greater sensitivity in the right than in the left hemisphere to orthographic variables, with a significant inhibitory N effect in the left, but not right hemisphere. Such inhibition, to a lesser degree, was found among a group of adults with dyslexia but not among age-matched normal readers. We argue that enhanced sensitivity to orthographic cues is developed in some cases of dyslexia when a normal, phonology-based left hemisphere word recognition processing is not achieved. The interpretation presented here is cast in terms of differences between people with dyslexia and typical readers that originate in the atypical way in which orthographic representations are initially set up.


Pharmacy Services beyond the Basics: A Qualitative Study to Explore Perspectives of Pharmacists towards Basic and Enhanced Pharmacy Services in Pakistan.
Enhanced pharmacy services have been identified as a mechanism to address medicines and drug-related problems. The aim of the study was to explore the perspectives of practicing pharmacists on the scope of pharmacy service provision in Pakistan. This qualitative study was conducted at the Department of Pharmacy, the Islamia University of Bahawalpur (IUB). Face-to-face, in-depth interviews were conducted with practicing pharmacists at the university who were undertaking postgraduate studies. All interviews were audio-recorded, transcribed verbatim, and analyzed using thematic analysis. A total of 13 pharmacists were interviewed. The analysis of data yielded four themes and 12 subthemes. The themes included the current scenario of pharmacy services, the benefits of pharmacy services, barriers to implementation of pharmacy services, and strategies to improve their delivery. Pharmacist participants reported that patient-oriented pharmacy services have not been properly implemented in Pakistan. Pharmacists appear to be undertaking only conventional roles at various levels within the healthcare system. The participants indicated multiple benefits of patient-oriented pharmacy services, including safe and effective use of medicines, minimization of drug-related problems, and financial benefits to the healthcare system. Based on the findings, policy-makers are required to take the necessary steps to overcome pharmacist-related and policy-related barriers associated with the implementation of patient-oriented pharmacy services in Pakistan.


Cereus sinensis Polysaccharide and Its Immunomodulatory Properties in Human Monocytic Cells.
In this study, the extraction conditions of the crude polysaccharide from Cereus sinensis were optimized by response surface methodology. The optimum extraction conditions were: a ratio of raw material to water volume of 1:80 (g/mL); an extraction temperature of 72 °C; and an extraction time of 3 h. Then, a purified polysaccharide named Cereus sinensis polysaccharide-1 (CSP-1) was obtained from the crude polysaccharide by the Diethylaminoethyl cellulose-52 (DEAE-52) cellulose chromatography column and Sephadex G-100 column. The molecular weight and monosaccharide composition of CSP-1 was determined through Gel Permeation Chromatography (GPC) and Gas Chromatography-Mass Spectrometer (GS-MS), respectively. The results showed that CSP-1 with an average molecular weight of 56,335 Da was composed of l-(-)-Fucose, d-(+)-Mannose, d-Glucose and mainly possessed 1→2, 1→2, 6, 1→4, and 1→4, 6 of glycosyl linkages. The immunomodulatory activities of CSP-1 were also evaluated using lipopolysaccharide (LPS)-induced human monocytic (THP-1) cells. The results demonstrated that CSP-1 dose-dependently protected against LPS-induced toxicity, and CSP-1 significantly inhibited the Toll-like receptor 4 (TLR-4) mRNA, myeloid differentiation factor 88 (MyD88) mRNA and tumour necrosis factor receptor-associated factor-6 (TRAF-6) mRNA expression of the LPS-induced THP-1 cells, as well as suppressing reactive oxygen species (ROS) generation.


Phosphoregulation of the autophagy machinery by kinases and phosphatases.
Eukaryotic cells use post-translational modifications to diversify and dynamically coordinate the function and properties of protein networks within various cellular processes. For example, the process of autophagy strongly depends on the balanced action of kinases and phosphatases. Highly conserved from the budding yeast Saccharomyces cerevisiae to humans, autophagy is a tightly regulated self-degradation process that is crucial for survival, stress adaptation, maintenance of cellular and organismal homeostasis, and cell differentiation and development. Many studies have emphasized the importance of kinases and phosphatases in the regulation of autophagy and identified many of the core autophagy proteins as their direct targets. In this review, we summarize the current knowledge on kinases and phosphatases acting on the core autophagy machinery and discuss the relevance of phosphoregulation for the overall process of autophagy.


Craniofacial changes and symptoms of sleep-disordered breathing in healthy children.
The main cause of mouth breathing and sleep-disordered breathing (SDB) in childhood is associated with upper airway narrowing to varying degrees. The aim of this study was to assess the prevalence of morphological and functional craniofacial changes and the main clinical symptoms of SDB in healthy children. A cross-sectional observational study was conducted. A sample comprising 687 healthy schoolchildren, aged 7-12 years old and attending public schools, was assessed by medical history, clinical medical and dental examination, and respiratory tests. The self-perceived quality of life of mouth breathing children was obtained by a validated questionnaire. Out of the total sample, 520 children were nose breathers (NB) while 167 (24.3%) were mouth breathers (MB); 32.5% had severe hypertrophy of the palatine tonsils, 18% had a Mallampati score of III or IV, 26.1% had excessive overjet and 17.7% had anterior open bite malocclusion. Among the MB, 53.9% had atresic palate, 35.9% had lip incompetence, 33.5% reported sleepiness during the day, 32.2% often sneezed, 32.2% had a stuffy nose, 19.6% snored, and 9.4% reported having the feeling to stop breathing while asleep. However, the self-perception of their quality of life was considered good. High prevalence of facial changes as well as signs and symptoms of mouth breathing were found among health children, requiring early diagnosis and treatment to reduce the risk of SDB.


Characterization of the auxin-inducible SAUR-AC1 gene for use as a molecular genetic tool in Arabidopsis.
The small auxin up RNA (SAUR) genes were originally characterized in soybean, where they encode a set of unstable transcripts that are rapidly induced by auxin. In this report, the isolation of a SAUR gene, designated SAUR-AC1, from Arabidopsis thaliana (L.) Heynh. ecotype Columbia is described. The promoter of the SAUR-AC1 gene contains putative regulatory motifs conserved among soybean SAUR promoters, as well as sequences implicated in the regulation of other genes in response to auxin. The transcribed region is approximately 500 bp in length and contains no introns. Highly conserved sequences located within the SAUR-AC1 transcript include the central portion of the coding region and a putative mRNA instability sequence (DST) located in the 3' untranslated region. Accumulation of SAUR-AC1 mRNA is readily induced by natural and synthetic auxins and by the translational inhibitor cycloheximide. Moreover, several auxin- and gravity-response mutants of Arabidopsis exhibit decreased accumulation of the SAUR-AC1 mRNA in elongating etiolated seedlings. In particular, in the axr2-1 mutant the SAUR-AC1 transcript accumulates to less than 5% of wild-type levels. These studies indicate that SAUR-AC1 will be a useful probe of auxin-induced gene expression in Arabidopsis and will facilitate the functional analysis of both transcriptional and posttranscriptional regulatory elements.


Evaluation and definitive management of medically inoperable early stage non-small-cell lung cancer. Part 2: newer treatment modalities.
Lung cancer is estimated to be the second most commonly diagnosed cancer in both men and women in 2006, and the leading causes of cancer mortality. Non-small-cell lung cancer represents the majority of such cases. Most of these patients have locally advanced disease at presentation and are not eligible for curative resection. For the minority of patients who are technically resectable at presentation, lobectomy or pneumonectomy and pathologic mediastinal nodal staging offer the best overall survival. The high rate of comorbid medical illness and poor baseline pulmonary function in this population, however, make many such early-stage patients medically inoperable. For these patients, conventional single-modality radiotherapy has been the primary definitive treatment option, as discussed in part 1 of this article, which appeared in last month's issue. Numerous retrospective reports demonstrate long-term disease-free and overall survival data that are modestly superior to that expected after observation, but both local and distant failure continue to be significant risks. Investigation of radiotherapy dose escalation is ongoing, in an effort to improve local control while maintaining minimal toxicity. Additionally, emerging evidence suggests that new modalities, such as stereotactic radiosurgery and radiofrequency ablation, may also be potentially curative treatment alternatives. These modalities are addressed in part 2.


The Effect of Intravenous Immunoglobulin Combined with Corticosteroid on the Progression of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Meta-Analysis.
Intravenous immunoglobulin (IVIG) treatment is commonly used to treat Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) with controversial therapeutic effect. We conducted a comprehensive meta-analysis through combining the published eligible studies to evaluate the effectiveness of IVIG on SJS and TEN treatment. A total of 26 studies were selected from public available databases. The combination of IVIG and corticosteroid markedly reduced the recovery time (by 1.63 days, 95% CI: 0.83-2.43, P < 0.001), compared with solo corticosteroid group. The favorable effects were greater in Asian (2.19, 95% CI: 1.41-2.97, P < 0.001), TEN (2.56, 95% CI: 0.35-4.77, P = 0.023) and high-dose IVIG treated individuals (1.78, 95% CI: 0.42-3.14, P = 0.010). The hospitalization length reduced by 3.19 days (95% CI: 0.08-6.30, P = 0.045), though the outcome was proven to be unstable. We found heterogeneities, which sources were probably regional factors. Besides, IVIG was inclined to decrease SJS/TEN mortality (SMR: 0.84, 95% CI: 0.66-1.08, P = 0.178). This impact was possibly more profound when patients were treated with high dose IVIG (SMR: 0.74, 95% CI: 0.50-1.08, P = 0.116), or when patients were diagnosed as TEN (SMR: 0.68, 95% CI: 0.45-1.01, P = 0.058). Our current meta-analysis suggests that IVIG combined with corticosteroid could reduce recovery time for SJS and TEN. This effect is greater among Asian patients. Whereas, its impact on reducing mortality is not significant.


Ectopic expression of Arabidopsis ABC transporter MRP7 modifies cadmium root-to-shoot transport and accumulation.
Arabidopsis MRPs/ABCCs have been shown to remove various organic and inorganic substrates from the cytosol to other subcellular compartments. Here we first demonstrate that heterologous expression of AtMRP7 in tobacco (Nicotiana tabacum var. Xanthi) modifies cadmium accumulation, distribution and tolerance. Arabidopsis MRP7 was localized both in the tonoplast and in the plasma membrane when expressed in tobacco. Its overexpression increased tobacco Cd-tolerance and resulted in enhanced cadmium concentration in leaf vacuoles, indicating more efficient detoxification by means of vacuolar storage. Heterologous AtMRP7 expression also led to more efficient retention of Cd in roots, suggesting a contribution to the control of cadmium root-to-shoot translocation. The results underscore the use of AtMRP7 in plant genetic engineering to modify the heavy-metal accumulation pattern for a broad range of applications.


Prolonged suppressive antibiotic therapy for prosthetic joint infection in the elderly: a national multicentre cohort study.
During prosthetic joint infection (PJI), optimal surgical management with exchange of the device is sometimes impossible, especially in the elderly population. Thus, prolonged suppressive antibiotic therapy (PSAT) is the only option to prevent acute sepsis, but little is known about this strategy. We aimed to describe the characteristics, outcome and tolerance of PSAT in elderly patients with PJI. We performed a national cross-sectional cohort study of patients >75 years old and treated with PSAT for PJI. We evaluated the occurrence of events, which were defined as: (i) local or systemic progression of the infection (failure), (ii) death and (iii) discontinuation or switch of PSAT. A total of 136 patients were included, with a median age of 83 years [interquartile range (IQR) 81-88]. The predominant pathogen involved was Staphylococcus (62.1%) (Staphylococcus aureus in 41.7%). A single antimicrobial drug was prescribed in 96 cases (70.6%). There were 46 (33.8%) patients with an event: 25 (18%) with an adverse drug reaction leading to definitive discontinuation or switch of PSAT, 8 (5.9%) with progression of sepsis and 13 died (9.6%). Among patients under follow-up, the survival rate without an event at 2 years was 61% [95% confidence interval (CI): 51;74]. In the multivariate Cox analysis, patients with higher World Health Organization (WHO) score had an increased risk of an event [hazard ratio (HR) = 1.5, p = 0.014], whereas patients treated with beta-lactams are associated with less risk of events occurring (HR = 0.5, p = 0.048). In our cohort, PSAT could be an effective and safe option for PJI in the elderly.


The interplay of fibronectin functionalization and TGF-β1 presence on fibroblast proliferation, differentiation and migration in 3D matrices.
Defined biomimetic three-dimensional (3D) matrices are needed to decipher the complex cellular signalling during wound healing at high resolution in vitro. Soluble factors like TGF-β1 and adhesion promoting structural components of the extracellular matrix (ECM) are known to be key regulators of fibroblast behaviour. The ECM component fibronectin (FN) bears a complex function as adhesion promoter, fibrillar element and soluble factor binder. However, its implementation in biomimetic 3D matrices is frequently ill defined. To study the impact of FN on fibroblast cellular function under differentiating conditions (TGF-β1 stimulation), we functionalized 3D collagen I matrices with FN using two strategies: co-assembly and adsorptive immobilization. In comparison to co-assembly, adsorptive immobilization provided no alteration in collagen microstructure as well as mechanical properties. Moreover, this approach provided a controllable FN amount and a homogenous distribution of FN throughout collagen networks. A strong interplay of FN amount and TGF-β1 stimulation on fibroblast function was found in terms of proliferation, migration and myofibroblast differentiation. High levels of FN alone reduced proliferation and showed no effect on differentiation of fibroblasts, but increased migration. In contrast, fibroblast stimulation with high amounts of FN together with TGF-β1 increased proliferation. Independent of FN, the TGF-β1 stimulation enhanced mRNA expression of matrix components like collagen type I alpha 1 chain (Coll I(a1), FN with extra domain A (EDA-FN) and reduced cell migration. The latter cell behaviour indicated a FN independent differentiation into a myofibroblast phenotype. Overall, our 3D biomimetic matrices allow dissecting the overlapping action of the ECM protein FN and the soluble factor TGF-β1 on fibroblast proliferation, migration and differentiation in 3D microenvironments. Furthermore, this model enables the mimicking of important steps of the in vivo wound healing process in vitro.


Picuriste/injectionist use among Haitian immigrants in Miami-Dade County, Florida: implications for HIV-related theory.
We explore the risks reported to picuriste (injectionist) use in a non-probability sample of Haitian immigrant residents of Miami-Dade, Florida, using a mixed method approach. Picuristes typically have no formal medical training, and may use non-sterile needles. Face to face semi-structured interviews were conducted of picuristes (n = 10) and picuriste users (n = 25). We sought to corroborate the qualitative findings by fielding a survey based on the interviews in a community-based sample of 205 Haitian immigrants. The findings from the interviews indicate picuriste injections do not adhere 100% to established standards for safe injections, and may pose health risks that are similar to those that exist for injection drug users. Yet, of the survey respondents (n = 205), 17.6% reported obtaining picuriste injections. Our findings shed light on a normally hidden cultural health behavior, enhancing our understanding of picuriste practice and use among Haitian immigrant residents of Miami-Dade County, Florida. We suggest that medical care must be delivered in a culturally competent, culturally sensitive manner, with open dialogue between physician and patient regarding health beliefs and practices.


Pax9 is required for cardiovascular development and interacts with Tbx1 in the pharyngeal endoderm to control 4th pharyngeal arch artery morphogenesis.
Developmental defects affecting the heart and aortic arch arteries are a significant phenotype observed in individuals with 22q11 deletion syndrome and are caused by a microdeletion on chromosome 22q11. TBX1, one of the deleted genes, is expressed throughout the pharyngeal arches and is considered a key gene, when mutated, for the arch artery defects. Pax9 is expressed in the pharyngeal endoderm and is downregulated in Tbx1 mutant mice. We show here that Pax9-deficient mice are born with complex cardiovascular malformations that affect the outflow tract and aortic arch arteries with failure of the 3rd and 4th pharyngeal arch arteries to form correctly. Transcriptome analysis indicated that Pax9 and Tbx1 may function together, and mice double heterozygous for Tbx1/Pax9 presented with a significantly increased incidence of interrupted aortic arch when compared with Tbx1 heterozygous mice. Using a novel Pax9Cre allele, we demonstrated that the site of this Tbx1-Pax9 genetic interaction is the pharyngeal endoderm, therefore revealing that a Tbx1-Pax9-controlled signalling mechanism emanating from the pharyngeal endoderm is required for crucial tissue interactions during normal morphogenesis of the pharyngeal arch artery system.


Age influences the predictive value of Acute Physiology and Chronic Health Evaluation II and Intensive Care National Audit and Research Centre scoring models in patients admitted to Intensive Care Units after in-hospital cardiac arrest.
Outcomes following in-hospital cardiac arrest (IHCA) are generally poor though different patient populations may benefit to different degrees from admission to Intensive Care Units (ICUs). Risk stratification algorithms may be useful in identifying patients who are most likely to benefit from ICU admission and so may aid allocation of this scarce resource. We aimed to compare the performance of the Acute Physiology and Chronic Health Evaluation II (APACHE II) and Intensive Care National Audit and Research Centre (ICNARC) scoring systems in predicting outcome following ICU admission after IHCA in younger (≤69 years) and older (≥70 years) patients. We performed a retrospective observational study in two adult ICUs from January 2006 to February 2010 inclusive. Patients were divided into younger (≤69 years) and older (≥70 years) patients. The primary outcome measures were acute hospital mortality and area under the curve (AUC) calculation for receiver operating characteristic (ROC) analysis. Two hundred and sixty-one adult consecutive adult patients admitted following IHCA. Hospital mortality was 58.6%. ROC analysis demonstrated that ICNARC was more accurate than APACHE II in predicting acute hospital outcomes in the adult population (AUC 0.734 vs. 0.706). Both scoring systems performed weaker when predicting outcomes in younger patients compared to older patients (ICNARC AUC 0.655 vs. 0.810; APACHE II AUC 0.660 vs. 0.759). Both APACHE II and ICNARC predict outcome well in older patients. In younger patients, their value is less clear, and so they must be used with caution.


An in vitro cell irradiation protocol for testing photopharmaceuticals and the effect of blue, green, and red light on human cancer cell lines.
Traditionally, ultraviolet light (100-400 nm) is considered an exogenous carcinogen while visible light (400-780 nm) is deemed harmless. In this work, a LED irradiation system for in vitro photocytotoxicity testing is described. The LED irradiation system was developed for testing photopharmaceutical drugs, but was used here to determine the basal level response of human cancer cell lines to visible light of different wavelengths, without any photo(chemo)therapeutic. The effects of blue (455 nm, 10.5 mW cm(-2)), green (520 nm, 20.9 mW cm(-2)), and red light (630 nm, 34.4 mW cm(-2)) irradiation was measured for A375 (human malignant melanoma), A431 (human epidermoid carcinoma), A549 (human lung carcinoma), MCF7 (human mammary gland adenocarcinoma), MDA-MB-231 (human mammary gland adenocarcinoma), and U-87 MG (human glioblastoma-grade IV) cell lines. In response to a blue light dose of 19 J cm(-2), three cell lines exhibited a minimal (20%, MDA-MB-231) to moderate (30%, A549 and 60%, A375) reduction in cell viability, compared to dark controls. The other cell lines were not affected. Effective blue light doses that produce a therapeutic response in 50% of the cell population (ED50) compared to dark conditions were found to be 10.9 and 30.5 J cm(-2) for A375 and A549 cells, respectively. No adverse effects were observed in any of the six cell lines irradiated with a 19 J cm(-2) dose of 520 nm (green) or 630 nm (red) light. The results demonstrate that blue light irradiation can have an effect on the viability of certain human cancer cell types and controls should be used in photopharmaceutical testing, which uses high-energy (blue or violet) visible light activation.


Vitamin C improves endothelial function of epicardial coronary arteries in patients with hypercholesterolaemia or essential hypertension--assessed by cold pressor testing.
There is evidence that formation of free radicals increases in patients with hypertension or hypercholesterolaemia, which may contribute to endothelial dysfunction of epicardial coronary arteries due to inactivation of the vasodilator NO. The present study was designed to test whether the abnormal constriction of epicardial coronary arteries due to sympathetic stimulation by the cold pressor test in patients with essential hypertension or hypercholesterolaemia could be reversed by administration of the antioxidant vitamin C. In 28 patients without relevant coronary artery stenosis the cold pressor test was performed before and after a 3 g infusion of vitamin C. In five normal controls the cold pressor test led to a similar increase in luminal area before and after vitamin C (3.7+/-1.3% and 1.9+/-0.8%, ns vs before vitamin C). In nine hypercholesterolaemic patients the cold pressor test led to a -14.1+/-2.8% reduction in cross-sectional area before vitamin C. This constriction was significantly improved after vitamin C to -7.6%+/-2.0, P=0.027 vs before vitamin C. In nine hypertensive patients, the cold pressor test led to a -17.1+/-3.2% decrease in cross-sectional area before vitamin C, which was improved to -7.1+/-3.1 after vitamin C, P=0.004 vs before vitamin C. This increase in luminal area was significant in each group in comparison with normal controls (each P<0.05). Administration of saline (placebo group, five patients) had no significant effect on cold pressor test-induced constriction (-6.9+/-3.9% before and -6. 8+/-3.7% after saline). The antioxidant vitamin C reverses cold pressor test-induced vasoconstriction of epicardial coronary arteries in patients with hypertension or hypercholesterolaemia. Our data suggest that enhanced oxidative stress contributes to impaired endothelial function in this patient population.


Severe, eosinophilic asthma in primary care in Canada: a longitudinal study of the clinical burden and economic impact based on linked electronic medical record data.
Stratification of patients with severe asthma by blood eosinophil counts predicts responders to anti-interleukin (IL)-5 (mepolizumab and reslizumab) and anti-IL-5 receptor α (benralizumab) therapies. This study characterized patients with severe asthma who could qualify for these biologics in a primary care setting. We retrospectively selected patients from July 1, 2010, to June 30, 2014, using a linked electronic medical records (EMR) database (IMS Evidence 360 EMR Canada) for > 950,000 patients in primary care in Ontario, Canada. Patients aged ≥ 12 years with ≥ 2 documented asthma diagnoses were identified as having severe asthma based on prescriptions for high-dosage inhaled corticosteroids (ICS) plus either a leukotriene receptor antagonist, long-acting β2-agonist (LABA), or theophylline filled on the same day. Patients' asthma was considered severe also if they received a prescription for ICS with oral corticosteroids (OCS) or an additional prescription for omalizumab. Patient characteristics, asthma-related medications, and blood eosinophil counts were captured using observed care patterns for the year prior to ICS/LABA and/or OCS prescription. Health care resource use (HCRU) and costs were captured throughout the 1-year follow-up period. We identified 212 patients who met the criteria for severe asthma. These patients required an average of 6.5 physician visits during the 1-year follow-up period (95% confidence interval 5.7-7.3), and 20 (9%) were referred to respiratory specialists. Overall, 56 patients (26%) with severe asthma had complete blood counts, of whom 23 (41%) had blood eosinophil counts ≥ 300 cells/μL and might be considered for anti-eosinophil therapies. Patients with severe asthma and blood eosinophil counts ≥ 300 cells/μL had more respiratory specialist referrals (17% vs. 12%) than patients with blood eosinophils < 300 cells/μL. Our data suggest that during 2010-2014, Ontario primary care patients with severe asthma and high blood eosinophil counts had greater HRCU than those with lower counts. Approximately 41% of patients with severe asthma could qualify for anti-eosinophil drugs based on blood eosinophil counts. However, the eosinophilic status of most patients was unknown. It is appropriate to increase awareness of the use of blood eosinophil counts to identify patients who could be considered for anti-eosinophil therapies.


A Tribute to the Mind, Methodology and Mentoring of Wayne Velicer.
Wayne Velicer is remembered for a mind where mathematical concepts and calculations intrigued him, behavioral science beckoned him, and people fascinated him. Born in Green Bay, Wisconsin on March 4, 1944, he was raised on a farm, although early influences extended far beyond that beginning. His Mathematics BS and Psychology minor at Wisconsin State University in Oshkosh, and his PhD in Quantitative Psychology from Purdue led him to a fruitful and far-reaching career. He was honored several times as a high-impact author, was a renowned scholar in quantitative and health psychology, and had more than 300 scholarly publications and 54,000+ citations of his work, advancing the arenas of quantitative methodology and behavioral health. In his methodological work, Velicer sought out ways to measure, synthesize, categorize, and assess people and constructs across behaviors and time, largely through principal components analysis, time series, and cluster analysis. Further, he and several colleagues developed a method called Testing Theory-based Quantitative Predictions, successfully applied to predicting outcomes and effect sizes in smoking cessation, diet behavior, and sun protection, with the potential for wider applications. With $60,000,000 in external funding, Velicer also helped engage a large cadre of students and other colleagues to study methodological models for a myriad of health behaviors in a widely applied Transtheoretical Model of Change. Unwittingly, he has engendered indelible memories and gratitude to all who crossed his path. Although Wayne Velicer left this world on October 15, 2017 after battling an aggressive cancer, he is still very present among us.


Mapping quantitative trait loci for open-field behavior in mice.
By performing a whole genome screen in an F2 intercross of two strains of mice (A/J and C57BL/6J), which differ markedly in their behavioral response to a brightly lit open field (O-F), we have mapped several quantitative trait loci (QTL) for this complex behavioral phenotype. QTL on chromosomes 1 and 10 were identified that affect both initial ambulation in the O-F (initial "response to novelty" ambulation) (lod of 7.1 and 8.8, respectively) and vertical rearings (lod of 4.5 and 8.5, respectively). For habituated O-F behavior, QTL were identified on chromosomes 3 and 10 for ambulation (lod of 4.1 and 14.7, respectively) and on chromosomes 1, 10, and 19 for vertical rearings (lod of 5.8, 6.0, and 4.7, respectively). The QTL on chromosome 1 (near D1Mit116; 101 cM) was specific for initial O-F ambulation behavior, whereas the QTL on chromosome 10 (near D10Mit237; 74 cM) affected both initial and habituated rearing behavior. Additional suggestive QTL (lod, > 2.8) were mapped to chromosomes 1, 8, 11, 15, and 19. The QTL on chromosomes 1, 10, and 19 individually explain from 3.2 to 12.7%. Collectively, the multiple independent QTL explain from 16.3 to 24.1% of the F2 population's phenotypic variance, depending on the trait. These identified QTL should prove useful for dissecting the genetic and behavioral dimensions of O-F behavior, fostering an understanding of individual differences.


Generation of a Metagenomics Proximity Ligation 3C Library of a Mammalian Gut Microbiota.
Microbial species thrive in very diverse environments and play fundamental roles in their equilibrium and dynamics. Metagenomics consists in extracting, sequencing, and studying the DNA present in ecosystems to better understand their regulation. Ideally, the maximal amount of information would be gathered from the full sequences of the genomes, episomes, and phages present in the microbial communities. Current high-throughput DNA sequencing produces reads ranging in size from a few dozen base pairs for the most commonly used technologies to several kb for emerging single-molecule real-time sequencing techniques. Although valuable information can be extracted from processing these DNA sequences into contigs, reconstructing full genomes remains a difficult task. Clustering contigs according to their similarities or read coverage covariations gives some insights on these genomes, but remains limited as viral sequences, or recent horizontal gene transfers, often differ from their host genomes. We recently developed meta3C, a proximity ligation approach that bins contigs in a sequence-independent way by quantifying and exploiting their tridimensional collisions frequencies in vivo. This technique has demonstrated a great potential to reconstruct genomes as well as to assign plasmids and phages to their hosts. It nevertheless requires a specific processing of the microbial samples before sequencing, which has to be carefully planned.


The color constancy of three-dimensional objects.
Human color constancy has been studied for over 100 years, and there is extensive experimental data for the case where a spatially diffuse light source illuminates a set of flat matte surfaces. In natural viewing, however, three-dimensional objects are viewed in three-dimensional scenes. Little is known about color constancy for three-dimensional objects. We used a forced-choice task to measure the achromatic chromaticity of matte disks, matte spheres, and glossy spheres. In all cases, the test stimuli were viewed in the context of stereoscopically viewed graphics simulations of three-dimensional scenes, and we varied the scene illuminant. We studied conditions both where all cues were consistent with the simulated illuminant change (consistent-cue conditions) and where local contrast was silenced as a cue (reduced-cue conditions). We computed constancy indices from the achromatic chromaticities. To first order, constancy was similar for the three test object types. There was, however, a reliable interaction between test object type and cue condition. In the consistent-cue conditions, constancy tended to be best for the matte disks, while in the reduced-cue conditions constancy was best for the spheres. The presence of this interaction presents an important challenge for theorists who seek to generalize models that account for constancy for flat tests to the more general case of three-dimensional objects.


Kinetic study of interaction between BRL 42715, beta-lactamases, and D-alanyl-D-alanine peptidases.
A detailed kinetic study of the interactions between BRL 42715, a beta-lactamase-inhibiting penem, and various beta-lactamases (EC 188.8.131.52) and D-alanyl-D-alanine peptidases (DD-peptidases, EC 22.214.171.124) is presented. The compound was a very efficient inactivator of all active-site serine beta-lactamases but was hydrolyzed by the class B, Zn(2+)-containing enzymes, with very different kcat values. Inactivation of the Streptomyces sp. strain R61 extracellular DD-peptidase was not observed, and the Actinomadura sp. strain R39 DD-peptidase exhibited a low level of sensitivity to the compound.


Double-exposure phase calculation method in electronic speckle pattern interferometry based on holographic object illumination.
Multiple-exposure phase calculation procedures are widely used in electronic speckle pattern interferometry to calculate phase maps of displacements. We developed a double-exposure process based on holographic illumination of the object and the idea of the spatial carrier phase-shifting method to examine transient displacements. In our work, computer-generated holograms and a spatial light modulator were used to generate proper coherent illuminating masks. In this adjustment all phase-shifted states were at our disposal from one recorded speckle image for phase calculation. This technique can be used in the large scale of transient measurements. In this paper we illustrate the principle through several examples.


Microtubule cross-linking triggers the directional motility of kinesin-5.
Although assembly of the mitotic spindle is known to be a precisely controlled process, regulation of the key motor proteins involved remains poorly understood. In eukaryotes, homotetrameric kinesin-5 motors are required for bipolar spindle formation. Eg5, the vertebrate kinesin-5, has two modes of motion: an adenosine triphosphate (ATP)-dependent directional mode and a diffusive mode that does not require ATP hydrolysis. We use single-molecule experiments to examine how the switching between these modes is controlled. We find that Eg5 diffuses along individual microtubules without detectable directional bias at close to physiological ionic strength. Eg5's motility becomes directional when bound between two microtubules. Such activation through binding cargo, which, for Eg5, is a second microtubule, is analogous to known mechanisms for other kinesins. In the spindle, this might allow Eg5 to diffuse on single microtubules without hydrolyzing ATP until the motor is activated by binding to another microtubule. This mechanism would increase energy and filament cross-linking efficiency.


A case of bilateral uveitis and papillitis in a patient treated with pembrolizumab.
Drug-induced uveitis is a well-known effect of ocular inflammation that has been reported with many medications. Pembrolizumab is a newer generation of the anti-programmed cell death-1 monoclonal antibodies that was recently approved by the Food and Drug Administration for the treatment of advanced melanoma. Immune-mediated adverse events involving different organs have been reported in recent literature in association with this drug. We present the first reported case of uveitis in association with pembrolizumab therapy. An 82-year-old man with stage IV melanoma was started on pembrolizumab infusion treatment every 3 weeks. Two months after initiating therapy, he presented with bilateral severe anterior uveitis and papillitis with fast and complete recovery after withholding further pembrolizumab infusions and treatment with topical steroid. Uveitis recurred after restarting pembrolizumab therapy. In current clinical practice, many new drugs are being approved, requiring better characterization of the prevalence, onset, and nature of adverse events in order to aid development of effective management strategies. Ophthalmologists should keep in mind that drugs are always a possible cause of ocular inflammation in patients presenting with uveitis.


[Regulation of expression, function, and inflammatory responses of innate immune receptor Toll-like receptor-2 (TLR2) during inflammatory responses against infection].
Toll-like receptor-2 (TLR2) is one of the important innate immune receptors that play an important role in recognizing the pathogens and producing inflammatory cytokines. In this review, we focus on the regulatory mechanisms of expression, function and inflammatory responses of TLR2 during pathogenic infection in innate immune cells. We first showed that nontypeable Haemophilus influenzae (NTHi), an important human pathogen that exacerbates otitis media and chronic obstructive pulmonary diseases (COPD), induces inflammatory responses through activation of NF-κB via two distinct signals, NIK-IKKα/β-IκBα and MKK3/6-p38 pathways. Moreover, TLR2 was greatly up-regulated by NTHi through the positive IKK-IκBα-dependent NF-κB pathway and the negative MKK3/6-p38α/β pathway. Importantly, glucocorticoids synergistically enhance NTHi-induced TLR2 up-regulation likely via a negative cross-talk with the inhibitory p38 MAPK. The results provide novel insights into the role of glucocorticoids in regulating host defense and innate immune responses through TLR2 regulation. We next focused on the pathogenesis of cystic fibrosis (CF), a common lethal inherited disorder characterized by recurrent pulmonary infections and obstruction caused by chronic mucus hypersecretion and inflammation. We demonstrated an increased expression of TLR2, due to an enhanced DNA de-methylation and Sp1-dependent transcriptional activation in CF epithelial cells. Furthermore, a Th17 cytokine IL-17A synergistically increased TLR2 signal through an enhancement of p38 phosphorylation. These studies suggest the importance of TLR2 and IL-17 signals in the pathogenesis of CF. Finally, by focusing on neutrophils and CF airway epithelial cells, we identified curcumin as a potent inhibitor of TLR2-mediated inflammatory responses.


First Field Release of a Genetically Engineered, Self-Limiting Agricultural Pest Insect: Evaluating Its Potential for Future Crop Protection.
Alternative, biologically-based approaches for pest management are sorely needed and one approach is to use genetically engineered insects. Herein we describe a series of integrated field, laboratory and modeling studies with the diamondback moth, Plutella xylostella, a serious global pest of crucifers. A "self-limiting" strain of Plutella xylostella (OX4319L), genetically engineered to allow the production of male-only cohorts of moths for field releases, was developed as a novel approach to protect crucifer crops. Wild-type females that mate with these self-limiting males will not produce viable female progeny. Our previous greenhouse studies demonstrated that releases of OX4319L males lead to suppression of the target pest population and dilution of insecticide-resistance genes. We report results of the first open-field release of a non-irradiated, genetically engineered self-limiting strain of an agricultural pest insect. In a series of mark-release-recapture field studies with co-releases of adult OX4319L males and wild-type counterparts, the dispersal, persistence and field survival of each strain were measured in a 2.83 ha cabbage field. In most cases, no differences were detected in these parameters. Overall, 97.8% of the wild-type males and 95.4% of the OX4319L males recaptured dispersed <35 m from the release point. The predicted persistence did not differ between strains regardless of release rate. With 95% confidence, 75% of OX4319L males released at a rate of 1,500 could be expected to live between 3.5 and 5.4 days and 95% of these males could be expected to be detected within 25.8-34.9 m from the release point. Moth strain had no effect on field survival but release rate did. Collectively, these results suggest similar field behavior of OX4319L males compared to its wild-type counterpart. Laboratory studies revealed no differences in mating competitiveness or intrinsic growth rates between the strains and small differences in longevity. Using results from these studies, mathematical models were developed that indicate release of OX4319L males should offer efficacious pest management of P. xylostella. Further field studies are recommended to demonstrate the potential for this self-limiting P. xylostella to provide pest suppression and resistance management benefits, as was previously demonstrated in greenhouse studies.


Implications of crop model ensemble size and composition for estimates of adaptation effects and agreement of recommendations.
Climate change is expected to severely affect cropping systems and food production in many parts of the world unless local adaptation can ameliorate these impacts. Ensembles of crop simulation models can be useful tools for assessing if proposed adaptation options are capable of achieving target yields, whilst also quantifying the share of uncertainty in the simulated crop impact resulting from the crop models themselves. Although some studies have analysed the influence of ensemble size on model outcomes, the effect of ensemble composition has not yet been properly appraised. Moreover, results and derived recommendations typically rely on averaged ensemble simulation results without accounting sufficiently for the spread of model outcomes. Therefore, we developed an Ensemble Outcome Agreement (EOA) index, which analyses the effect of changes in composition and size of a multi-model ensemble (MME) to evaluate the level of agreement between MME outcomes with respect to a given hypothesis (e.g. that adaptation measures result in positive crop responses). We analysed the recommendations of a previous study performed with an ensemble of 17 crop models and testing 54 adaptation options for rainfed winter wheat (Triticum aestivum L.) at Lleida (NE Spain) under perturbed conditions of temperature, precipitation and atmospheric CO2 concentration. Our results confirmed that most adaptations recommended in the previous study have a positive effect. However, we also showed that some options did not remain recommendable in specific conditions if different ensembles were considered. Using EOA, we were able to identify the adaptation options for which there is high confidence in their effectiveness at enhancing yields, even under severe climate perturbations. These include substituting spring wheat for winter wheat combined with earlier sowing dates and standard or longer duration cultivars, or introducing supplementary irrigation, the latter increasing EOA values in all cases. There is low confidence in recovering yields to baseline levels, although this target could be attained for some adaptation options under moderate climate perturbations. Recommendations derived from such robust results may provide crucial information for stakeholders seeking to implement adaptation measures.


Pathways towards an effective immunotherapy for Parkinson's disease.
Immunizations that target specific types of immune responses are used commonly to prevent microbial infections. However, a range of immune responses may prove necessary to combat the ravages of neurodegenerative diseases. The goal is to eliminate the 'root' cause of neurodegenerative disorders, misfolded aggregated proteins, while harnessing adaptive immune responses to promote neural repair. However, immunization strategies used to elicit humoral immune responses against aberrant brain proteins have yielded mixed success. While specific proteins can be cleared, the failures in halting disease progression revolve, in measure, around adaptive immune responses that promote autoreactive T cells and, as such, induce a meningoencephalitis, accelerating neurodegeneration. Thus, alternative approaches for protein clearance and neural repair are desired. To this end, our laboratories have sought to transform autoreactive adaptive immune responses into regulatory neuroprotective cells in Parkinson's disease. In this context, induction of immune responses against modified brain proteins serves to break immunological tolerance, while eliciting adaptive immunity to facilitate neuronal repair. How to harness the immune response in the setting of Parkinson's disease requires a thorough understanding of the role of immunity in human disease and the ways to modify such immune responses to elicit therapeutic gain. These are discussed in this review.


Exfoliation of layered double hydroxides for enhanced oxygen evolution catalysis.
The oxygen evolution reaction is a key reaction in water splitting. The common approach in the development of oxygen evolution catalysts is to search for catalytic materials with new and optimized chemical compositions and structures. Here we report an orthogonal approach to improve the activity of catalysts without alternating their compositions or structures. Specifically, liquid phase exfoliation is applied to enhance the oxygen evolution activity of layered double hydroxides. The exfoliated single-layer nanosheets exhibit significantly higher oxygen evolution activity than the corresponding bulk layered double hydroxides in alkaline conditions. The nanosheets from nickel iron and nickel cobalt layered double hydroxides outperform a commercial iridium dioxide catalyst in both activity and stability. The exfoliation creates more active sites and improves the electronic conductivity. This work demonstrates the promising catalytic activity of single-layered double hydroxides for the oxygen evolution reaction.