P38 Signal Transduction Pathway Has More Cofactors on Apoptosis of SGC-7901 Gastric Cancer Cells Induced by Combination of Rutin and Oxaliplatin.
Currently, gastric cancer treatment is mainly based on first-line intervention with oxaliplatin (OXA) after surgical resection, but the application of OXA has been limited due to the toxic side effects caused by the cumulative dose. The toxicity of OXA mainly includes hepatotoxicity, nephrotoxicity, and ototoxicity, and there is an urgent clinical need to find alternatives that are less toxic and more effective. Rutin (RT) is a natural flavonoid with many biological activities. Studies have found that RT inhibits tumor cell growth and enhances their sensitivity toward certain drugs. As the underlying impact of RT on gastric cancer and its molecular mechanism remain poorly understood, we performed a series of experiments to determine whether RT has the effect of treating gastric cancer, and whether it can cooperate with OXA to treat gastric cancer and its related mechanisms. In the present study, we founded that RT suppressed cell viability, inhibited cell proliferation by causing G0/G1 arrest, and induced apoptosis in SGC 7901 cells. And RT can play as an antitumor agent together with OXA. The mechanism of RT-induced apoptosis may be associated with the activation of the p38/Caspase signal pathway. These results demonstrated the potential of RT as a promising therapeutic compound to treat gastric cancer. At the same time, RT can synergize with OXA to reduce the dose of OXA and reduce the toxicity.


Strategy diversity stabilizes mutualism through investment cycles, phase polymorphism, and spatial bubbles.
There is continuing interest in understanding factors that facilitate the evolution and stability of cooperation within and between species. Such interactions will often involve plasticity in investment behavior, in response to the interacting partner's investments. Our aim here is to investigate the evolution and stability of reciprocal investment behavior in interspecific interactions, a key phenomenon strongly supported by experimental observations. In particular, we present a comprehensive analysis of a continuous reciprocal investment game between mutualists, both in well-mixed and spatially structured populations, and we demonstrate a series of novel mechanisms for maintaining interspecific mutualism. We demonstrate that mutualistic partners invariably follow investment cycles, during which mutualism first increases, before both partners eventually reduce their investments to zero, so that these cycles always conclude with full defection. We show that the key mechanism for stabilizing mutualism is phase polymorphism along the investment cycle. Although mutualistic partners perpetually change their strategies, the community-level distribution of investment levels becomes stationary. In spatially structured populations, the maintenance of polymorphism is further facilitated by dynamic mosaic structures, in which mutualistic partners form expanding and collapsing spatial bubbles or clusters. Additionally, we reveal strategy-diversity thresholds, both for well-mixed and spatially structured mutualistic communities, and discuss factors for meeting these thresholds, and thus maintaining mutualism. Our results demonstrate that interspecific mutualism, when considered as plastic investment behavior, can be unstable, and, in agreement with empirical observations, may involve a polymorphism of investment levels, varying both in space and in time. Identifying the mechanisms maintaining such polymorphism, and hence mutualism in natural communities, provides a significant step towards understanding the coevolution and population dynamics of mutualistic interactions.


Endoreduplicative standards for calibration of flow cytometric C-Value measurements.
It has been estimated that there are, globally, as many as 400,000 species of the angiosperms (the flowering plants). Of these, a minimal proportion has been characterized at the cytological level. Urgency is required in initiating a systematic and comprehensive census, due to species extinction as a consequence of anthropogenic activities. Fundamental to eukaryotes is the 2C-value, the amount of DNA contained within the nucleus of the unreduced gametes. Flow cytometry provides an ideal method for determining C-values, but the values archived in the Kew Plant C-value Database represent <2% of these species. Complicating the issue is a proliferation of different, and inconsistent standards for C-value measurements utilizing flow cytometry, and variability associated with different instrument platforms and using different staining procedures. In previous work, the use of flow cytometry for analysis of plant nuclear DNA contents for species spanning much of the range of genome sizes found in the angiosperms was described. For this work, an endoreduplicative species (Arabidopsis thaliana L.) was particularly helpful as an internal standard for genome size calibration. Such a standard is compromised if it overlaps in DNA content than that of the species whose genome size is sought. This report describes the use of a second species displaying endoreduplication, Capsicum annuum L., for similar standardization. The results (a) indicate accurate reporting of nuclear DNA contents across a range 0.32-423.68 pg, (b) confirm that endoreduplication increases nuclear DNA contents by complete replication of the genome, and (c) provide a means for quality control of linearity in instrumentation over defined dynamic ranges.


Species Introduction in a Tropical Lake: A newly introduced piscivore can produce population changes in a wide range of trophic levels.
Probably in early 1967, a piscivore from South America, Cichla ocellaris, was introduced to Gatun Lake in the Panama Canal Zone. As this predator population spread through the lake, the initial effect was dramatic reductions in almost all secondary consumers. These species reductions produced, in turn, second- and third-order changes at other trophic levels of the ecosystem. The resulting changes in the lake community can be seen best by examining the general Gatun Lake food web. The decrease in numbers of the important planktivore Melaniris has resulted in changes within the zooplankton community, as illustrated by the cladoceran Ceriodaphnia. The tertiary-consumer populations, such as tarpon, black terns, kingfishers, and herons, formerly dependent on small fishes for food, appear less frequently in the Cichla areas of the lake. There has also been, possibly, a resurgence of the local mosquito populations (which are malaria vectors), caused by the reduction in the populations of insect-eating fishes. Even the primary producers may be affected by this introduction. Although at present the Gatun Lake ecosystem is undergoing rapid changes, we anticipate an eventual return to some form of equilibrium. However, it will be some time before we can evaluate the permanence or transience of the many changes produced in the trophic levels by the introduction of a single, top-level predator to this lake system.


PPAR-γ Mediates Ta-VNS-Induced Angiogenesis and Subsequent Functional Recovery after Experimental Stroke in Rats.
Neoangiogenesis after cerebral ischemia in mammals is insufficient to restore neurological function, illustrating the need to design better strategies for improving outcomes. Our previous study has suggested that transcutaneous auricular vagus nerve stimulation (ta-VNS) induced angiogenesis and improved neurological functions in a rat model of cerebral ischemia/reperfusion (I/R) injury. However, the mechanisms involved need further exploration. Peroxisome proliferator-activated receptor-γ (PPAR-γ), well known as a ligand-modulated nuclear transcription factor, plays a crucial role in the regulation of cerebrovascular structure and function. Hence, the present study was designed to explore the role of PPAR-γ in ta-VNS-mediated angiogenesis and uncover the possible molecular mechanisms against ischemic stroke. Adult male Sprague-Dawley rats were transfected with either PPAR-γ small interfering RNA (siRNA) or lentiviral vector without siRNA prior to surgery and subsequently received ta-VNS treatment. The expression and localization of PPAR-γ in the ischemic boundary after ta-VNS treatment were examined. Subsequently, neurological deficit scores, neuronal damage, and infarct volume were all evaluated. Additionally, microvessel density, endothelial cell proliferation condition, and the expression of angiogenesis-related molecules in the peri-infarct cortex were measured. We found that the expression of PPAR-γ in the peri-infarct cortex increased at 14 d and reached normal levels at 28 d after reperfusion. Ta-VNS treatment further upregulated PPAR-γ expression in the ischemic cortex. PPAR-γ was mainly expressed in neurons and astrocytes. Furthermore, ta-VNS-treated I/R rats showed better neurobehavioral recovery, alleviated neuronal injury, reduced infarct volume, and increased angiogenesis, as indicated by the elevated levels of brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and phosphorylated endothelial nitric oxide synthase (P-eNOS). Surprisingly, the beneficial effects of ta-VNS were weakened after PPAR-γ silencing. Our results suggest that PPAR-γ is a potential mediator of ta-VNS-induced angiogenesis and neuroprotection against cerebral I/R injury.


Increased expression of miR142 and miR155 in glial and immune cells after traumatic brain injury may contribute to neuroinflammation via astrocyte activation.
Traumatic brain injury (TBI) is associated with the pathological activation of immune-competent cells in the brain, such as astrocytes, microglia and infiltrating immune blood cells, resulting in chronic inflammation and gliosis. This may contribute to the secondary injury after TBI, thus understanding of these processes is crucial for the development of effective treatments of post-traumatic pathologies. MicroRNAs (miRNAs, miRs) are small noncoding RNAs, functioning as posttranscriptional regulators of gene expression. The increased expression of inflammation-associated microRNAs miR155 and miR142 has been reported after TBI in rats. However, expression of these miRNAs in the human brain post-TBI is not studied and their functions are not well understood. Moreover, circulating miR155 and miR142 are candidate biomarkers. Therefore, we characterized miR142 and miR155 expression in the perilesional cortex and plasma of rats that underwent lateral fluid-percussion injury, a model for TBI and in the human perilesional cortex post-TBI. We demonstrated higher miR155 and miR142 expression in the perilesional cortex of rats 2 weeks post-TBI. In plasma, miR155 was associated with proteins and miR142 with extracellular vesicles, however their expression did not change. In the human perilesional cortex miR155 was most prominently expressed by activated astrocytes, whereas miR142 was expressed predominantly by microglia, macrophages and lymphocytes. Pro-inflammatory medium from macrophage-like cells stimulated miR155 expression in astrocytes and overexpression of miR142 in these cells further potentiated a pro-inflammatory state of activated astrocytes. We conclude that miR155 and miR142 promote brain inflammation via astrocyte activation and may be involved in the secondary brain injury after TBI.


Postoperative observation of children after endoscopic type 1 posterior laryngeal cleft repair.
To report the perioperative management and surgical outcomes in a large series of pediatric patients with endoscopically repaired type 1 posterior laryngeal cleft (PLC). Case series with chart review. Urban, tertiary care, free-standing pediatric hospital. Patients who underwent endoscopic carbon dioxide laser-assisted repair of type 1 posterior laryngeal clefts between January 2006 and December 2012. Medical records were reviewed. Fifty-four patients (34 male) underwent repair of type 1 PLC. Median age was 25.5 months (range, 2-120 months). Indications for repair included aspiration (n = 39; 72%), chronic bronchitis (n = 13; 24%), and stridor with feeds (n = 2; 4%). No children remained intubated postoperatively. Thirty-three patients (61%) stayed in overnight observation ("Obs PLC") and 21 patients (39%) stayed in the pediatric intensive care unit ("PICU PLC") postoperatively. Between Obs PLC and PICU PLC groups, there was no significant difference in age (mean 22 vs 30 months, respectively; P = .28). Comorbidities were similar between the groups. Symptoms improved in 41 of the 54 patients (76%). No postoperative complications were noted. Two patients required revision PLC repair. The cost of admitting a patient to a lower acuity location was estimated to be 60% less per day than cost of a PICU admission. The endoscopic surgical repair of a type 1 PLC is successful and has a low morbidity and complication rate. Patients may be safely managed in an observation unit and without postoperative intubation. This approach achieved a marked cost reduction in postoperative care.


Scan-stratified case-control sampling for modeling blood-brain barrier integrity in multiple sclerosis.
Multiple sclerosis (MS) is an immune-mediated neurological disease that causes morbidity and disability. In patients with MS, the accumulation of lesions in the white matter of the brain is associated with disease progression and worse clinical outcomes. Breakdown of the blood-brain barrier in newer lesions is indicative of more active disease-related processes and is a primary outcome considered in clinical trials of treatments for MS. Such abnormalities in active MS lesions are evaluated in vivo using contrast-enhanced structural MRI, during which patients receive an intravenous infusion of a costly magnetic contrast agent. In some instances, the contrast agents can have toxic effects. Recently, local image regression techniques have been shown to have modest performance for assessing the integrity of the blood-brain barrier based on imaging without contrast agents. These models have centered on the problem of cross-sectional classification in which patients are imaged at a single study visit and pre-contrast images are used to predict post-contrast imaging. In this paper, we extend these methods to incorporate historical imaging information, and we find the proposed model to exhibit improved performance. We further develop scan-stratified case-control sampling techniques that reduce the computational burden of local image regression models, while respecting the low proportion of the brain that exhibits abnormal vascular permeability.


Interventions for providers to promote a patient-centred approach in clinical consultations.
Communication problems in health care may arise as a result of healthcare providers focusing on diseases and their management, rather than people, their lives and their health problems. Patient-centred approaches to care delivery in the patient encounter are increasingly advocated by consumers and clinicians and incorporated into training for healthcare providers. However, the impact of these interventions directly on clinical encounters and indirectly on patient satisfaction, healthcare behaviour and health status has not been adequately evaluated. To assess the effects of interventions for healthcare providers that aim to promote patient-centred care (PCC) approaches in clinical consultations. For this update, we searched: MEDLINE (OvidSP), EMBASE (OvidSP), PsycINFO (OvidSP), and CINAHL (EbscoHOST) from January 2000 to June 2010. The earlier version of this review searched MEDLINE (1966 to December 1999), EMBASE (1985 to December 1999), PsycLIT (1987 to December 1999), CINAHL (1982 to December 1999) and HEALTH STAR (1975 to December 1999). We searched the bibliographies of studies assessed for inclusion and contacted study authors to identify other relevant studies. Any study authors who were contacted for further information on their studies were also asked if they were aware of any other published or ongoing studies that would meet our inclusion criteria. In the original review, study designs included randomized controlled trials, controlled clinical trials, controlled before and after studies, and interrupted time series studies of interventions for healthcare providers that promote patient-centred care in clinical consultations. In the present update, we were able to limit the studies to randomized controlled trials, thus limiting the likelihood of sampling error. This is especially important because the providers who volunteer for studies of PCC methods are likely to be different from the general population of providers. Patient-centred care was defined as a philosophy of care that encourages: (a) shared control of the consultation, decisions about interventions or management of the health problems with the patient, and/or (b) a focus in the consultation on the patient as a whole person who has individual preferences situated within social contexts (in contrast to a focus in the consultation on a body part or disease). Within our definition, shared treatment decision-making was a sufficient indicator of PCC. The participants were healthcare providers, including those in training. We classified interventions by whether they focused only on training providers or on training providers and patients, with and without condition-specific educational materials. We grouped outcome data from the studies to evaluate both direct effects on patient encounters (consultation process variables) and effects on patient outcomes (satisfaction, healthcare behaviour change, health status). We pooled results of RCTs using standardized mean difference (SMD) and relative risks (RR) applying a fixed-effect model. Forty-three randomized trials met the inclusion criteria, of which 29 are new in this update. In most of the studies, training interventions were directed at primary care physicians (general practitioners, internists, paediatricians or family doctors) or nurses practising in community or hospital outpatient settings. Some studies trained specialists. Patients were predominantly adults with general medical problems, though two studies included children with asthma. Descriptive and pooled analyses showed generally positive effects on consultation processes on a range of measures relating to clarifying patients' concerns and beliefs; communicating about treatment options; levels of empathy; and patients' perception of providers' attentiveness to them and their concerns as well as their diseases. A new finding for this update is that short-term training (less than 10 hours) is as successful as longer training.The analyses showed mixed results on satisfaction, behaviour and health status. Studies using complex interventions that focused on providers and patients with condition-specific materials generally showed benefit in health behaviour and satisfaction, as well as consultation processes, with mixed effects on health status. Pooled analysis of the fewer than half of included studies with adequate data suggests moderate beneficial effects from interventions on the consultation process; and mixed effects on behaviour and patient satisfaction, with small positive effects on health status. Risk of bias varied across studies. Studies that focused only on provider behaviour frequently did not collect data on patient outcomes, limiting the conclusions that can be drawn about the relative effect of intervention focus on providers compared with providers and patients. Interventions to promote patient-centred care within clinical consultations are effective across studies in transferring patient-centred skills to providers. However the effects on patient satisfaction, health behaviour and health status are mixed. There is some indication that complex interventions directed at providers and patients that include condition-specific educational materials have beneficial effects on health behaviour and health status, outcomes not assessed in studies reviewed previously. The latter conclusion is tentative at this time and requires more data. The heterogeneity of outcomes, and the use of single item consultation and health behaviour measures limit the strength of the conclusions.


Focal ischemia in the cerebral cortex has an effect on the neurohypophysis. I. Ultrastructural changes in capillary vessels of the neurohypophysis after focal ischemia of the cerebral cortex.
In our investigations we have reported that photochemical reaction leading to brain ischemia can also be precipitated with visible light from a non-coherent light source. It was revealed that focal cerebral ischemia after photochemical reaction cause the alterations in the capillaries ultrastructure and perivascular spaces of the barrier-competent regions of the brain. The purpose of this study is to first characterize the ultrastructural morphological consequences of photochemically induced ischemia in the cerebral cortex on the capillaries of neurohypophysis as the barrier-free region of the brain. We used a model of ischemic brain damage due to obliteration of microvessels following the photochemical reaction. Rats were treated with an intravenous injection of rose bengal and irradiated from a halogen lamp source through an intact cranium to precipitate microvascular damage. Material for electron microscopic studies were sampled from the neurohypophysis 1 and 4 days after irradiation (4 animals in each group) in experimental group and 1 and 4 days after a rose bengal injection in control group. Investigations in transmission electron microscopy revealed platelet aggregation on the endothelium preceded by its early ultrastructural damage. In the capillaries of the neurohypophysis, one and four days after irradiation, numerous microthrombi adhering to the damaged endothelium were present. The capillary vessels contained a continuous, rather than a fenestrated endothelium. The basement membrane was thickened, blurred and locally multiplicated. Our results show that experimentally-induced thrombosis of cortical microvessels leads to alterations in the capillaries of neurohypophysis.


Abnormal mammary gland development in MMTV-CBLC transgenic mouse.
The CBL family of E3 ubiquitin ligases regulates cell signaling in a number of tissues by promoting degradation of tyrosine kinase receptors such as epidermal growth factor receptor. CBLC, the third member of the CBL family, is expressed in epithelial tissues, including the mammary gland. A transgenic mouse strain expressing a tetracyclin-inducible CBLC in the mammary gland was derived. It was found that CBLC transgene expression reduces the number and length of ducts during the development of the gland. In vivo results support the concept of CBLs as negative regulators of cell proliferation. Alternatively, the phenotype may be due to increased apoptosis. This mouse model may be used to further study regulatory components of the CBL pathway and may be crossed with mice susceptible to develop mammary tumors.


Melatonin Induces Cell Apoptosis in AGS Cells Through the Activation of JNK and P38 MAPK and the Suppression of Nuclear Factor-Kappa B: a Novel Therapeutic Implication for Gastric Cancer.
Melatonin, synthesized by the pineal gland and released into the blood, appears to have antitumour properties; however, the mechanisms of its anti-cancer effects are largely unknown, especially in stomach cancer. Here, we explore the antitumour activity of melatonin in a gastric cancer cell line (AGS) and analyse its molecular mechanisms. AGS cells were treated with melatonin, and cell viability was assessed using a CCK-8 assay. Flow cytometry was performed to evaluate apoptosis, and protein expression was examined by Western blotting. Melatonin significantly inhibited cell viability, clone formation, and cell migration and invasion and induced apoptosis in AGS cells. Moreover, MAPK pathways (p38, JNK and ERK) were activated by melatonin treatment, which also significantly increased caspase-3 cleavage and Bax protein expression and decreased Bcl-2 protein expression in a time-dependent manner. Our results demonstrate that p38 and JNK inhibitors (SB203580 and SP600125, respectively) prevented melatonin-induced apoptosis; thus, the propensity of p38 MAPK and JNK to promote apoptosis could be at least partly due to the inhibition of NF-x03BA;B p65 activation by p38 and JNK. Finally, melatonin was able to strengthen cisplatin-mediated antitumour effects in human gastric carcinoma cells by up-regulating the expression of Bax, down-regulating the expression of Bcl-2 and activating the caspase-dependent apoptotic pathway. Melatonin induced apoptosis in AGS cells by activating the caspase-dependent apoptotic pathway and by inhibiting the nuclear translocation of NF-x03BA;B p65, two processes that are regulated by p38 and JNK. Furthermore, melatonin significantly enhanced the anti-tumour effects of cisplatin, with low systemic toxicity. These new findings suggest that melatonin may act as a potent anti-tumour agent and may have great potential as an adjuvant therapy in the future.


Spatial predictions of Rhodesian Human African Trypanosomiasis (sleeping sickness) prevalence in Kaberamaido and Dokolo, two newly affected districts of Uganda.
The continued northwards spread of Rhodesian sleeping sickness or Human African Trypanosomiasis (HAT) within Uganda is raising concerns of overlap with the Gambian form of the disease. Disease convergence would result in compromised diagnosis and treatment for HAT. Spatial determinants for HAT are poorly understood across small areas. This study examines the relationships between Rhodesian HAT and several environmental, climatic and social factors in two newly affected districts, Kaberamaido and Dokolo. A one-step logistic regression analysis of HAT prevalence and a two-step logistic regression method permitted separate analysis of both HAT occurrence and HAT prevalence. Both the occurrence and prevalence of HAT were negatively correlated with distance to the closest livestock market in all models. The significance of distance to the closest livestock market strongly indicates that HAT may have been introduced to this previously unaffected area via the movement of infected, untreated livestock from endemic areas. This illustrates the importance of the animal reservoir in disease transmission, and highlights the need for trypanosomiasis control in livestock and the stringent implementation of regulations requiring the treatment of cattle prior to sale at livestock markets to prevent any further spread of Rhodesian HAT within Uganda.


The role of an interface in stabilizing reaction intermediates for hydrogen evolution in aprotic electrolytes.
By combining idealized experiments with realistic quantum mechanical simulations of an interface, we investigate electro-reduction reactions of HF, water and methanesulfonic acid (MSA) on the single crystal (111) facets of Au, Pt, Ir and Cu in organic aprotic electrolytes, 1 M LiPF6 in EC/EMC 3:7W (LP57), the aprotic electrolyte commonly used in Li-ion batteries, 1 M LiClO4 in EC/EMC 3:7W and 0.2 M TBAPF6 in 3 : 7 EC/EMC. In our previous work, we have established that LiF formation, accompanied by H2 evolution, is caused by a reduction of HF impurities and requires the presence of Li at the interface, which catalyzes the HF dissociation. In the present paper, we find that the measured potential of the electrochemical response for these reduction reactions correlates with the work function of the electrode surfaces and that the work function determines the potential for Li+ adsorption. The reaction path is investigated further by electrochemical simulations suggesting that the overpotential of the reaction is related to stabilizing the active structure of the interface having adsorbed Li+. Li+ is needed to facilitate the dissociation of HF which is the source of protons. Further experiments on other proton sources, water and methanesulfonic acid, show that if the hydrogen evolution involves negatively charged intermediates, F- or HO-, a cation at the interface can stabilize them and facilitate the reaction kinetics. When the proton source is already significantly dissociated (in the case of a strong acid), there is no negatively charged intermediate and thus the hydrogen evolution can proceed at much lower overpotentials. This reveals a situation where the overpotential for electrocatalysis is related to stabilizing the active structure of the interface, facilitating the reaction rather than providing the reaction energy.


GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables.
This article is the first of a series providing guidance for use of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system of rating quality of evidence and grading strength of recommendations in systematic reviews, health technology assessments (HTAs), and clinical practice guidelines addressing alternative management options. The GRADE process begins with asking an explicit question, including specification of all important outcomes. After the evidence is collected and summarized, GRADE provides explicit criteria for rating the quality of evidence that include study design, risk of bias, imprecision, inconsistency, indirectness, and magnitude of effect. Recommendations are characterized as strong or weak (alternative terms conditional or discretionary) according to the quality of the supporting evidence and the balance between desirable and undesirable consequences of the alternative management options. GRADE suggests summarizing evidence in succinct, transparent, and informative summary of findings tables that show the quality of evidence and the magnitude of relative and absolute effects for each important outcome and/or as evidence profiles that provide, in addition, detailed information about the reason for the quality of evidence rating. Subsequent articles in this series will address GRADE's approach to formulating questions, assessing quality of evidence, and developing recommendations.


Transjugular intrahepatic portosystemic shunts for patients with active variceal hemorrhage unresponsive to sclerotherapy.
Despite urgent sclerotherapy, active variceal hemorrhage has a 70%-90% mortality rate in patients with advanced age, sepsis, renal or pulmonary compromise, tense ascites, or deep coma. The aim of this study was to test the safety and efficacy of transjugular intrahepatic portosystemic shunt (TIPS) performed semiemergently and preceded by stabilization by balloon tamponade in such patients. Patients with actively bleeding esophageal or contiguous gastric varices despite sclerotherapy were assessed for risk of dying after emergent portacaval shunt. Those considered to be at high risk were stabilized by balloon tamponade and vasopressin/nitroglycerin and TIPS placed semiurgently within 12 hours. Balloon tamponade and pharmacological therapy were discontinued within 24 hours after TIPS in all cases. Thirty-two patients met entry criteria, and 2 were excluded due to portal vein thrombosis. TIPS was successfully placed in 29 of 30 patients and achieved hemostasis in all. Thirty-day and 6-week survival rates were 63% and 60%, respectively; in those without aspiration, the 6-week survival rate was 90%. After a median follow-up period of 920 days, 46% of the original cohort was alive. Only 2 episodes of early rebleeding and 4 late rebleeds occurred. Eight patients developed encephalopathy. Stent stenosis requiring dilation occurred in 6 of 11 patients within 6 months. TIPS is highly effective as salvage therapy in high-risk patients with active variceal hemorrhage despite endoscopic sclerotherapy.


Mortality in Severe Human Immunodeficiency Virus-Tuberculosis Associates With Innate Immune Activation and Dysfunction of Monocytes.
Case fatality rates among hospitalized patients diagnosed with human immunodeficiency virus (HIV)-associated tuberculosis remain high, and tuberculosis mycobacteremia is common. Our aim was to define the nature of innate immune responses associated with 12-week mortality in this population. This prospective cohort study was conducted at Khayelitsha Hospital, Cape Town, South Africa. Hospitalized HIV-infected tuberculosis patients with CD4 counts <350 cells/µL were included; tuberculosis blood cultures were performed in all. Ambulatory HIV-infected patients without active tuberculosis were recruited as controls. Whole blood was stimulated with Escherichia coli derived lipopolysaccharide, heat-killed Streptococcus pneumoniae, and Mycobacterium tuberculosis. Biomarkers of inflammation and sepsis, intracellular (flow cytometry) and secreted cytokines (Luminex), were assessed for associations with 12-week mortality using Cox proportional hazard models. Second, we investigated associations of these immune markers with tuberculosis mycobacteremia. Sixty patients were included (median CD4 count 53 cells/µL (interquartile range [IQR], 22-132); 16 (27%) died after a median of 12 (IQR, 0-24) days. Thirty-one (52%) grew M. tuberculosis on blood culture. Mortality was associated with higher concentrations of procalcitonin, activation of the innate immune system (% CD16+CD14+ monocytes, interleukin-6, tumour necrosis factor-ɑ and colony-stimulating factor 3), and antiinflammatory markers (increased interleukin-1 receptor antagonist and lower monocyte and neutrophil responses to bacterial stimuli). Tuberculosis mycobacteremia was not associated with mortality, nor with biomarkers of sepsis. Twelve-week mortality was associated with greater pro- and antiinflammatory alterations of the innate immune system, similar to those reported in severe bacterial sepsis.


Sleep-disordered breathing in children.
The first series of children with obstructive sleep apnoea syndrome was reported in 1976. Later it became apparent that children may have breathing disorders during sleep without frank apnoea or 'hypopnoeas'. This pattern could be detected by measuring the oesophageal pressure. This led to the concept of sleep-disordered breathing as a spectrum that combines obstructive sleep apnoea syndrome and the upper airway resistance syndrome. Studies that do not take into account this spectrum may misclassify symptomatic patients as 'primary snorers'. The exact prevalence of sleep-disordered breathing in children is unknown but may be as high as 11%. There is a familial predisposition to sleep-disordered breathing. Nasal obstruction and mouth breathing influence facial growth, which may further lead to difficulty in breathing while asleep. Symptoms include an increase in total sleep time, nonspecific behavioural difficulties, hyperactivity, irritability, bed-wetting and morning headaches. Clinical signs include failure to thrive, increased respiratory effort with nasal flaring and suprasternal or intercostal retractions. Also, abnormal paradoxical inward motion of the chest may occur during sleep. Excessive daytime sleepiness and obesity are not always present. Untreated children may develop cardiovascular complications. The condition is treatable with continuous or bilevel positive airway pressure, and may be cured with surgery.


Association study of a brain-derived neurotrophic-factor genetic polymorphism and mood disorders, age of onset and suicidal behavior.
Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin growth factor family, has been implicated in both mood disorders and suicidal behavior. This study has examined the association between the BDNF gene Val66Met polymorphism and mood disorders, age of onset and suicidal behavior in a Chinese sample population. The genotype and allele frequencies for the BDNF gene Val66Met polymorphism did not differ comparing depression groups (total, bipolar disorder or major depression) and control subjects. Furthermore, it was not demonstrated that this BDNF polymorphism was associated with age of onset or suicidal history in our mood disorder patients. Based on these results, it seems reasonable to suggest that this polymorphism is unlikely to play a major role in the genetic susceptibility to mood disorders. Given the fact that the positive association between BDNF gene Val66Met polymorphism and bipolar disorder has only been demonstrated for a Caucasian population but not for a Japanese analog or our Chinese sample, it appears likely that this association is ethnicity dependent.


Delivery of tumor-homing TRAIL sensitizer with long-acting TRAIL as a therapy for TRAIL-resistant tumors.
Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) has attracted great interest as a cancer therapy because it selectively induces death receptor (DR)-mediated apoptosis in cancer cells while sparing normal tissue. However, recombinant human TRAIL demonstrates limited therapeutic efficacy in clinical trials, possibly due to TRAIL-resistance of primary cancers and its inherent short half-life. Here we introduce drug delivery approaches to maximize in vivo potency of TRAIL in TRAIL-resistant tumor xenografts by (1) extending the half-life of the ligand with PEGylated TRAIL (TRAILPEG) and (2) concentrating a TRAIL sensitizer, selected from in vitro screening, in tumors via tumor-homing nanoparticles. Antitumor efficacy of TRAILPEG with tumor-homing sensitizer was evaluated in HCT116 and HT-29 colon xenografts. Western blot, real-time PCR, immunohistochemistry and cell viability assays were employed to investigate mechanisms of action and antitumor efficacy of the combination. We discovered that doxorubicin (DOX) sensitizes TRAIL-resistant HT-29 colon cancer cells to TRAIL by upregulating mRNA expression of DR5 by 60% in vitro. Intravenously administered free DOX does not effectively upregulate DR5 in tumor tissues nor demonstrate synergy with TRAILPEG in HT-29 xenografts, but rather introduces significant systemic toxicity. Alternatively, when DOX was encapsulated in hyaluronic acid-based nanoparticles (HAC/DOX) and intravenously administered with TRAILPEG, DR-mediated apoptosis was potentiated in HT-29 tumors by upregulating DR5 protein expression by 70% and initiating both extrinsic and intrinsic apoptotic pathways with reduced systemic toxicity compared to HAC/DOX or free DOX combined with TRAILPEG (80% vs. 40% survival rate; 75% vs. 34% tumor growth inhibition). This study demonstrates a unique approach to overcome TRAIL-based therapy drawbacks using sequential administration of a tumor-homing TRAIL sensitizer and long-acting TRAILPEG.


HIV-related outcome disparities between transgender women living with HIV and cisgender people living with HIV served by the Health Resources and Services Administration's Ryan White HIV/AIDS Program: A retrospective study.
In the United States, approximately one-fifth of transgender women are living with HIV-nearly one-half of Black/African American (Black) transgender women are living with HIV. Limited data are available on HIV-related clinical indicators among transgender women. This is because of a lack of robust transgender data collection and research, especially within demographic subgroups. The objective of this study was to examine retention in care and viral suppression among transgender women accessing the Health Resources and Services Administration's (HRSA) Ryan White HIV/AIDS Program (RWHAP)-supported HIV care, compared with cisgender women and cisgender men. We assessed the association between gender (cisgender or transgender) and (1) retention in care and (2) viral suppression using 2016 client-level RWHAP Services Report data. Multivariable modified Poisson regression models adjusting for confounding by age, race, health care coverage, housing, and poverty level, overall and stratified by race/ethnicity, were used to calculate adjusted prevalence ratios (aPRs) and 95% confidence intervals (CIs). In 2016, the RWHAP served 6,534 transgender women (79.8% retained in care, 79.0% virally suppressed), 143,173 cisgender women (83.7% retained in care, 84.0% virally suppressed), and 382,591 cisgender men (81.0% retained in care, 85.9% virally suppressed). Black transgender women were less likely to be retained in care than Black cisgender women (aPR: 0.95, 95% CI: 0.92-0.97, p < 0.001). Black transgender women were also less likely to reach viral suppression than Black cisgender women (aPR: 0.55, 95%I CI: 0.41-0.73, p < 0.001) and Black cisgender men (aPR: 0.55, 95% CI: 0.42-0.73, p < 0.001). A limitation of the study is that RWHAP data are collected for administrative, not research, purposes, and clinical outcome measures, including retention and viral suppression, are only reported to the RWHAP for the approximately 60% of RWHAP clients engaged in RWHAP-supported outpatient medical care. In this study, we observed disparities in HIV clinical outcomes among Black transgender women. These results fill an important gap in national HIV data about transgender people with HIV. Reducing barriers to HIV medical care for transgender women is critical to decrease disparities among this population.


NMR studies of active-site properties of human carbonic anhydrase II by using (15) N-labeled 4-methylimidazole as a local probe and histidine hydrogen-bond correlations.
By using a combination of liquid and solid-state NMR spectroscopy, (15) N-labeled 4-methylimidazole (4-MI) as a local probe of the environment has been studied: 1) in the polar, wet Freon CDF3 /CDF2 Cl down to 130 K, 2) in water at pH 12, and 3) in solid samples of the mutant H64A of human carbonic anhydrase II (HCA II). In the latter, the active-site His64 residue is replaced by alanine; the catalytic activity is, however, rescued by the presence of 4-MI. For the Freon solution, it is demonstrated that addition of water molecules not only catalyzes proton tautomerism but also lifts its quasidegeneracy. The possible hydrogen-bond clusters formed and the mechanism of the tautomerism are discussed. Information about the imidazole hydrogen-bond geometries is obtained by establishing a correlation between published (1) H and (15) N chemical shifts of the imidazole rings of histidines in proteins. This correlation is useful to distinguish histidines embedded in the interior of proteins and those at the surface, embedded in water. Moreover, evidence is obtained that the hydrogen-bond geometries of His64 in the active site of HCA II and of 4-MI in H64A HCA II are similar. Finally, the degeneracy of the rapid tautomerism of the neutral imidazole ring His64 reported by Shimahara et al. (J. Biol. Chem.- 2007, 282, 9646) can be explained with a wet, polar, nonaqueous active-site conformation in the inward conformation, similar to the properties of 4-MI in the Freon solution. The biological implications for the enzyme mechanism are discussed.


Lung mucociliary transport during high-frequency ventilation.
The effects of high-frequency, low-tidal-volume ventilation (HFV) and conventional intermittent positive-pressure ventilation (IPPV) on lung mucociliary transport were compared in 5 anesthetized, intubated mongrel dogs using a radioactive label. An aerosol of [99mTc]sulfur colloid was delivered to the dogs' airways and the subsequent clearance of isotope was followed over 4 h of either HFV or IPPV. After 4 h of IPPV, approximately 8 to 10% of the initial activity had cleared from the lung. By contrast, practically all the isotope remained in the lung after 4 h of HFV. Although the reasons for this were not definitely established in this study, several other observations were made that relate to this question. First, large amounts of mucus were visible in the trachea immediately after each of the 4-h HFV studies, whereas this was so in only one of the IPPV studies. Second, in 5 of 6 studies, a bolus of radioactive label placed on the posterior trachea after 4 h of HFV was noticed to disperse and move rapidly toward distal airways under the influence of HFV. Third, despite these findings of disturbed mucociliary transport during HFV, measurements of tracheal velocity, using a radioactive bolus technique during conventional ventilation, were the same after 4 h of HFV as after 4 h of IPPV (18.4 +/- 2.6 and 15.0 +/- 1.6 mm/min, respectively). We conclude that in the anesthetized dog HFV may alter mucociliary transport. This is unlikely to be the result of major structural damage to the mucosal surface, because tracheal mucous velocity measured after 4 h of HFV was not different from that after IPPV. It may be partly explained, however, by the retrograde flow of mucus that was observed during HFV in 5 of 6 studies.


Transaortic transcatheter aortic valve replacement through a right minithoracotomy with the balloon-expandable Sapien 3 valve.
Transaortic transcatheter aortic valve replacement performed through a right anterolateral minithoracotomy at the second intercostal space is a safe and standardized minimally invasive procedure carrying important clinical advantages for the patient, in particular, no damage to the ventricular apex, preservation of the diseased peripheral arteries and no cross of the aortic arch with the delivery system, meaning a lower risk of calcium dislodgement and neurological complications. Using the third-generation, balloon-expandable Edwards Sapien™ 3 transcatheter heart valve and the Certitude™ delivery system, the transaortic procedure is easily performed under fluoroscopic and echocardiographic guidance. Compared with the transapical procedure, the transaortic technique requires an inversely mounted stent valve and follows the standard guidelines for valve positioning and deployment under rapid pacing. The transaortic approach through a right anterolateral minithoracotomy at the second intercostal space combines the positive aspects of both transfemoral and transapical valve replacements without the risks of either procedure (left ventricular, coronary and peripheral vascular injuries).


Profile of upregulated inflammatory proteins in sera of Myasthenia Gravis patients.
This study describes specific patterns of elevated inflammatory proteins in clinical subtypes of myasthenia gravis (MG) patients. MG is a chronic, autoimmune neuromuscular disease with antibodies most commonly targeting the acetylcholine receptors (AChRab), which causes fluctuating skeletal muscle fatigue. MG pathophysiology includes a strong component of inflammation, and a large proportion of patients with early onset MG additionally present thymus hyperplasia. Due to the fluctuating nature and heterogeneity of the disease, there is a great need for objective biomarkers as well as novel potential inflammatory targets. We examined the sera of 45 MG patients (40 AChRab seropositive and 5 AChRab seronegative), investigating 92 proteins associated with inflammation. Eleven of the analysed proteins were significantly elevated compared to healthy controls, out of which the three most significant were: matrix metalloproteinase 10 (MMP-10; p = 0.0004), transforming growth factor alpha (TGF-α; p = 0.0017) and extracellular newly identified receptor for advanced glycation end-products binding protein (EN-RAGE) (also known as protein S100-A12; p = 0.0054). Further, levels of MMP-10, C-X-C motif ligand 1 (CXCL1) and brain derived neurotrophic factor (BDNF) differed between early and late onset MG. These novel targets provide valuable additional insight into the systemic inflammatory response in MG.


Identification of a putative operon involved in fructooligosaccharide utilization by Lactobacillus paracasei.
The growth and activity of some Lactobacillus and Bifidobacterium strains are stimulated by the presence of nondigestible fructooligosaccharides (FOS), which are selectively fermented by specific intestinal bacteria. Consumption of FOS, therefore, enriches for those bacteria that possess metabolic pathways necessary for FOS metabolism. In this study, a DNA microarray consisting of 7,680 random genomic library fragments of Lactobacillus paracasei 1195 was used to examine genes involved in the utilization of FOS in this organism. Differential expression profiles between cells grown on FOS and those grown on glucose provided a basis for identifying genes specifically induced by FOS. Several of the FOS-induced genes shared sequence identity with genes encoding beta-fructosidases and components of phosphoenolpyruvate-dependent phosphotransferase systems (PTS). These genes were organized in a putative operon, designated the fos operon, that may play an essential role in FOS utilization. The complete 7,631-bp nucleotide sequence of the putative fos operon was determined and consists of fosABCDXE genes, which encode a putative fructose/mannose PTS (FosABCDX) and a beta-fructosidase precursor (FosE). The latter contains an N-terminal signal peptide sequence and cell wall sorting signals at the C-terminal region, suggesting its localization at the cell wall. Inactivation of the fosE gene led to impaired growth on FOS and other beta-fructose-linked carbohydrates. Transcriptional analysis by reverse transcriptase PCR suggested that fosABCDXE was cotranscribed as a single mRNA during growth on FOS. Expression array analysis revealed that when glucose was added to FOS-grown cells, transcription of the FOS-induced genes was repressed, indicating that FOS metabolism is subject to catabolite regulation.


Effects of Ions and Small Compounds on the Structure of Aβ42 Monomers.
Aggregation of amyloid-β (Aβ) proteins in the brain is a hallmark of Alzheimer's disease. This phenomenon can be promoted or inhibited by adding small molecules to the solution where Aβ is embedded. These molecules affect the ensemble of conformations sampled by Aβ monomers even before aggregation starts. Here, we perform extensive all-atom replica exchange molecular dynamics (REMD) simulations to provide a comparative study of the ensemble of conformations sampled by Aβ42 monomers in solutions that promote (i.e., aqueous solution containing NaCl) and inhibit (i.e., aqueous solutions containing scyllo-inositol or 4-aminophenol) aggregation. Simulations performed in pure water are used as our reference. We find that secondary-structure content is only affected in an antagonistic manner by promoters and inhibitors at the C-terminus and the central hydrophilic core. Moreover, the end of the C-terminus binds more favorably to the central hydrophobic core region of Aβ42 in NaCl adopting a type of strand-loop-strand structure that is disfavored by inhibitors. Nonpolar residues that form the dry core of larger aggregates of Aβ42 (e.g., PDB ID 2BEG) are found at close proximity in these strand-loop-strand structures, suggesting that their formation could play an important role in initiating nucleation. In the presence of inhibitors, the C-terminus binds the central hydrophilic core with a higher probability than in our reference simulation. This sensitivity of the C-terminus, which is affected in an antagonistic manner by inhibitors and promoters, provides evidence for its critical role in accounting for aggregation.


The Pattern of Non-AIDS-defining Cancers in the HIV Population: Epidemiology, Risk Factors and Prognosis. A Review.
The advent of highly active antiretroviral therapy (HAART) has significantly reduced the incidence of AIDS events, including AIDS-defining malignancies. Nevertheless, several cohort studies conducted in the post-HAART period have reported an increasing risk of non-AIDS-defining cancers (NADC). Overall, the potential mechanisms leading to an increased risk of developing NADCs probably involve multiple known and unknown factors. In addition to ageing, chronic inflammation and ongoing immune system dysregulation, other contributing factors are co-infection with potentially oncogenic viruses (HBV, HCV, HPV, EBV) and high-risk behaviours such as tobacco smoking. As a consequence of these risk factors, high standardized incidence ratios have been consistently reported, mainly in cohort studies regarding smoking-related cancers (lung cancer, but also pharyngeal and kidney cancer), due to the far more common cigarette smoking habit in the HIV-population. Also in the setting of infection-related malignancies, the high frequency of liver cancer, as a consequence of HBV and HCV co-infection is well known. Similarly, HPV infection accounts for the higher risk of anal cancer. On the same line, Hodgkin lymphoma is more frequent in the HIV population, due to the dysregulation and proliferation of EBV-infected lymphocytes. Several studies addressed the direct relationship between immunosuppression and cancer progression, showing that subjects with HIV infection experience higher cancer-specific mortality, as compared to the general population, independently of cancer stage or cancer treatment. In the HIV population, for many NADCs, the prognosis is still worse as compared to the general population. However, an improvement has been reported over the last decades, mainly thanks to more available and adequate treatment chances.


Effects of testosterone on skeletal growth in lambs as assessed by labeling index of chondrocytes in the metacarpal bone growth plate.
The effects of testosterone on the epiphyseal growth plate of metacarpal bones of growing sheep were evaluated in 20 rams, 20 wethers, and 20 wethers receiving subcutaneous testosterone replacement therapy. Two animals from each testosterone treatment group were slaughtered at 14-d intervals from 49 to 133 d, and then at 28-d intervals until 217 d, for a total of 10 slaughter ages. Immediately after slaughter, the cannon bones were dissected of extraneous tissue, weighed, and their lengths measured. Growth plates from the metacarpal bones were isolated and explants were cultured for 24 h in medium containing [3H]thymidine. After autoradiography, labeling index was calculated as the ratio of labeled to total nuclei in the resting and proliferative zones of the growth plate. Testosterone increased (P < .03) weight and length of the metacarpal bone. Increased bone length due to testosterone was associated, in part, with a higher (P < .05) labeling index in chondrocytes of the proliferative zone of the growth plate. Labeling indices in the resting zone chondrocytes of rams were higher near the time of puberty. Accelerated growth followed by cessation of growth occurs concurrently with puberty in males of several species and is accompanied by an increase in the blood concentration of testosterone. Testosterone may mediate this accelerated growth by first increasing bone growth and then depleting the source of stem cells in the cartilage growth plate, the site where growth in length of long bones occurs.


Challenges in patient safety improvement research in the era of electronic health records.
Electronic health record (EHR) data repositories contain large volumes of aggregated, longitudinal clinical data that could allow patient safety researchers to identify important safety issues and conduct comprehensive evaluations of health care delivery outcomes. However, few health systems have successfully converted this abundance of data into useful information or knowledge for safety improvement. In this paper, we use a case study involving a project on missed/delayed follow-up of test results to discuss real-world challenges in using EHR data for patient safety research. We identify three types of challenges that pose as barriers to advance patient safety improvement research: 1) gaining approval to access/review EHR data; 2) interpreting EHR data; 3) working with local IT/EHR personnel. We discuss the complexity of these challenges, all of which are unlikely to be unique to this project, and outline some key next steps that must be taken to support research that uses EHR data to improve safety. We recognize that all organizations face competing priorities between clinical operations and research. However, to leverage EHRs and their abundant data for patient safety improvement research, many current data access and security policies and procedures must be rewritten and standardized across health care organizations. These efforts are essential to help make EHRs and EHR data useful for progress in our journey to safer health care.


Elevated expression of tyrosine kinase DDR2 in primary biliary cirrhosis.
Primary biliary cirrhosis (PBC) is characterized by chronic progressive destruction of small intrahepatic bile ducts with portal inflammation and cholestasis, leading to fibrosis. We utilized a novel restriction analysis system to profile the expression of tyrosine kinases (TKs). This methodology targets a conserved sequence present in the majority of human TKs, and exploits the known restriction map of the TK cDNA sequences. We isolated mRNA from biliary epithelial cell (BEC)-enriched cell fractions, amplified the TK transcripts using degenerative primers, and identified specific TKs by restriction enzyme digest analysis and then performed in situ hybridization. BEC-enriched samples from PBC livers displayed marked expression of discoidin domain receptor-2 (DDR2), whereas, non-diseased livers showed no detectable DDR2. Furthermore, in situ hybridization of PBC livers revealed that DDR2 is expressed in the small bile duct epithelial regions as well as in fibroblasts/stromal cells of fibrotic regions. A similar pattern was observed in livers of primary sclerosing cholangitis (PSC), although the amount of small ducts that were positively stained was lower than in PBC. Furthermore, cirrhotic livers of patients with other diseases, including alcoholic liver disease and chronic hepatitis C, DDR2 transcripts were noted only within fibrotic lesions and the degree of intensity was much lower than in PBC and PSC. DDR2, a TK that is stimulated by fibrillar collagens that accumulate in cirrhotic livers, is present at elevated levels in the small bile ducts of PBC patients. DDR2 is part of a positive feedback loop in which its enhanced expression leads to enhanced deposition of fibrillar collagens (types I andIII). These fibrillar collagens can also provide binding sites for immune mediators, such as cytokines and chemokines. Therefore, unusually high DDR2 expression in the bile ducts of PBC patients could contribute to duct injury by altering local cytokine levels and thereby increasing immune-mediated damage.


Undergraduate nursing students' experiences when examining nursing skills in clinical simulation laboratories with high-fidelity patient simulators: A phenomenological research study.
Simulation has become a widely used and established pedagogy for teaching clinical nursing skills. Nevertheless, the evidence in favour of this pedagogical approach is weak, and more knowledge is needed in support of its use. The aim of this study was (a) to explore the experiences of undergraduate nursing students when examining knowledge, skills and competences in clinical simulation laboratories with high-fidelity patient simulators and (b) to analyse these students' learning experiences during the examination. A phenomenological approach was used, and qualitative interviews were conducted among 23 second-year undergraduate nursing students-17 women and 6 men. The findings revealed that, irrespective of whether they passed or failed the examination, it was experienced as a valuable assessment of the students' knowledge and skills. Even if the students felt that the examination was challenging, they described it as a learning opportunity. In the examination, the students were able to integrate theory with practice, and earlier established knowledge was scrutinised when reflecting on the scenarios. The examination added aspects to the students' learning that prepared them for the real world of nursing in a safe environment without risking patient safety. The study findings suggest that examinations in clinical simulation laboratories can be a useful teaching strategy in nursing education. The use of high-fidelity patient simulators made the examination authentic. The reflections and feedback on the scenario were described as significant for the students' learning. Undergraduate nursing students can improve their knowledge, understanding, competence and skills when such examinations are performed in the manner used in this study.


The social role of touch in humans and primates: behavioural function and neurobiological mechanisms.
Grooming is a widespread activity throughout the animal kingdom, but in primates (including humans) social grooming, or allo-grooming (the grooming of others), plays a particularly important role in social bonding which, in turn, has a major impact on an individual's lifetime reproductive fitness. New evidence from comparative brain analyses suggests that primates have social relationships of a qualitatively different kind to those found in other animal species, and I suggest that, in primates, social grooming has acquired a new function of supporting these. I review the evidence for a neuropeptide basis for social bonding, and draw attention to the fact that the neuroendrocrine pathways involved are quite unresolved. Despite recent claims for the central importance of oxytocin, there is equally good, but invariably ignored, evidence for a role for endorphins. I suggest that these two neuropeptide families may play different roles in the processes of social bonding in primates and non-primates, and that more experimental work will be needed to tease them apart.


Trends in the prevalence of overweight and obesity among young Australians, 1985, 1997, and 2004.
To determine secular trends in overweight/obesity among 7- to 15-year-olds for the periods 1985, 1997, and 2004. Data from representative surveys conducted in New South Wales, Australia, in 1985, 1997, and 2004 were analyzed. Height and weight were measured, and BMI categories were created using International Obesity Task Force definitions. Students were grouped as Grades 2 + 4 + 6 and 8 + 10. The prevalences of overweight/obesity for 1985, 1997, and 2004 were 10.9%, 20.6%, and 25.7% among the younger boys and 10.6%, 19.5%, and 26.1% among the older boys. The average annual rate of increase for 1985 to 1997 was 0.81% and for 1997 to 2004 was 0.73% among the younger boys and was 0.74% and 0.94% for the two periods among the older boys. The prevalences of overweight/obesity in 1985, 1997, and 2004 were 14.0%, 22.0%, and 24.8% among the younger girls and 8.3%, 17.9%, and 19.8% among the older girls, respectively. The average annual rates of increase for the two periods were 0.8% and 0.4% among the younger girls and 0.80% and 0.27% among the older girls. Change in the prevalence of overweight/obesity and socioeconomic status were not associated. Over the period 1985 to 1997, the prevalence of overweight and obesity increased significantly among the younger and older boys and the younger girls. The prevalence of overweight, but not obesity, increased among the older girls over this period. Over the period 1997 to 2004, the prevalence of overweight/obesity combined increased significantly among boys of both age groups but not among girls.


C-peptide activates AMPKα and prevents ROS-mediated mitochondrial fission and endothelial apoptosis in diabetes.
Vasculopathy is a major complication of diabetes; however, molecular mechanisms mediating the development of vasculopathy and potential strategies for prevention have not been identified. We have previously reported that C-peptide prevents diabetic vasculopathy by inhibiting reactive oxygen species (ROS)-mediated endothelial apoptosis. To gain further insight into ROS-dependent mechanism of diabetic vasculopathy and its prevention, we studied high glucose-induced cytosolic and mitochondrial ROS production and its effect on altered mitochondrial dynamics and apoptosis. For the therapeutic strategy, we investigated the vasoprotective mechanism of C-peptide against hyperglycemia-induced endothelial damage through the AMP-activated protein kinase α (AMPKα) pathway using human umbilical vein endothelial cells and aorta of diabetic mice. High glucose (33 mmol/L) increased intracellular ROS through a mechanism involving interregulation between cytosolic and mitochondrial ROS generation. C-peptide (1 nmol/L) activation of AMPKα inhibited high glucose-induced ROS generation, mitochondrial fission, mitochondrial membrane potential collapse, and endothelial cell apoptosis. Additionally, the AMPK activator 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside and the antihyperglycemic drug metformin mimicked protective effects of C-peptide. C-peptide replacement therapy normalized hyperglycemia-induced AMPKα dephosphorylation, ROS generation, and mitochondrial disorganization in aorta of diabetic mice. These findings highlight a novel mechanism by which C-peptide activates AMPKα and protects against hyperglycemia-induced vasculopathy.


Evaluation of a modified double-disc synergy test for detection of extended spectrum beta-lactamases in AMPC beta-lactamase-producing proteus mirabilis.
The detection of extended-spectrum beta-lactamases (ESBLs) in gram-negative bacteria that produce AmpC beta-lactamases is problematic. In the present study, the performance of modified double-disc synergy test (MDDST) that employs a combination of cefepime and piperacillin-tazobactam for the detection of Proteus mirabilis producing extended spectrum and AmpC beta-lactamases was evaluated and compared with double-disc synergy test (DDST) and NCCLS phenotypic disc confirmatory test (NCCLS-PDCT). A total of 90 clinical isolates of P. mirabilis , which met the CLSI (Clinical and Laboratory Standards Institute) screening criteria that these had broth microdilution (BMD) MIC of > or =2 mg/mL for at least one extended spectrum cephalosporin [ceftazidime (CAZ), cefotaxime (CTX) and cefpodoxime], were selected for the study. MDDST detected ESBLs in 40/90 of the isolates, whereas DDST detected ESBLs in only 25 isolates. NCCLS-PDCT could detect ESBLs in 39 isolates using CAZ and CAZ + clavulanic acid (CLA) combination, whereas CTX and CTX + CLA combination could detect only 37 isolates as ESBL positive. As many as 34/40 ESBL positive isolates were confirmed to be AmpC beta-lactamase positive by the modified three-dimensional test (MTDT). MDDST and NCCLS-PDCT could detect ESBLs in all the 34 AmpC positive isolates, whereas DDST could detect ESBLs in only 19 isolates. The study demonstrated that MDDST is superior to DDST and as sensitive as NCCLS-PDCT. However, MDDST seems to have enhanced potential for the detection of ESBLs in AmpC beta-lactamase-producing P. mirabilis .


Robustness against extinction by stochastic sex determination in small populations.
Sexually reproducing populations with a small number of individuals may go extinct by stochastic fluctuations in sex determination, causing all their members to become male or female in a generation. In this work we calculate the time to extinction of isolated populations with fixed number N of individuals that are updated according to the Moran birth and death process. At each time step, one individual is randomly selected and replaced by its offspring resulting from mating with another individual of the opposite sex; the offspring can be male or female with equal probability. A set of N time steps is called a generation, the average time it takes for the entire population to be replaced. The number k of females fluctuates in time, similarly to a random walk, and extinction, which is the only asymptotic possibility, occurs when k=0 or k=N. We show that it takes only one generation for an arbitrary initial distribution of males and females to approach the binomial distribution. This distribution, however, is unstable and the population eventually goes extinct in 2(N)/N generations. We also discuss the robustness of these results against bias in the determination of the sex of the offspring, a characteristic promoted by infection by the bacteria Wolbachia in some arthropod species or by temperature in reptiles.


[MÉDERI MODEL NUTRITIONAL CARE HOSPITAL].
the need for nutritional care models, to address the problem of malnutrition in hospitals, involves developing mederi Nutrition Care Model in order to raise the quality of health care, and promote good practices of Clinical Nutrition. To describe the process of nutrition and metabolic support, aimed at measuring the effectiveness of the model, which is currently a center of national and international reference. descriptive, evaluative, transversal and observational. Includes analysis of consolidated since the implementation of the model in 2008 through 2014. Information The number of study subjects was 163 575, variables to test the efficacy measures were: productivity and perceived quality of nutritional care. made analysis of the key processes in which the model is based, nutritional adult and neonatal hospital care, nutritional support, supervision of food services, and teaching and research, is an increase in productivity of the service 591% , increasing the percentage of patient satisfaction from 50% to 95.8%. the success of a model of nutritional care lies in the consolidation of administrative, healthcare facilities, which in turn promotes the development of human talent, teaching and research in nutrition.


Quantitative characterization of nanoparticles in blood by transmission electron microscopy with a window-type microchip nanopipet.
Transmission electron microscopy (TEM) is a unique and powerful tool for observation of nanoparticles. However, due to the uneven spatial distribution of particles conventionally dried on copper grids, TEM is rarely employed to evaluate the spatial distribution of nanoparticles in aqueous solutions. Here, we present a microchip nanopipet with a narrow chamber width for sorting nanoparticles from blood and preventing the aggregation of the particles during the drying process, enabling quantitative analysis of their aggregation/agglomeration states and the particle concentration in aqueous solutions. This microchip is adaptable to all commercial TEM holders. Such a nanopipet proves to be a simple and convenient sampling device for TEM image-based quantitative characterization.


GTP hydrolysis of TC10 promotes neurite outgrowth through exocytic fusion of Rab11- and L1-containing vesicles by releasing exocyst component Exo70.
The use of exocytosis for membrane expansion at nerve growth cones is critical for neurite outgrowth. TC10 is a Rho family GTPase that is essential for specific types of vesicular trafficking to the plasma membrane. Recent studies have shown that TC10 and its effector Exo70, a component of the exocyst tethering complex, contribute to neurite outgrowth. However, the molecular mechanisms of the neuritogenesis-promoting functions of TC10 remain to be established. Here, we propose that GTP hydrolysis of vesicular TC10 near the plasma membrane promotes neurite outgrowth by accelerating vesicle fusion by releasing Exo70. Using Förster resonance energy transfer (FRET)-based biosensors, we show that TC10 activity at the plasma membrane decreased at extending growth cones in hippocampal neurons and nerve growth factor (NGF)-treated PC12 cells. In neuronal cells, TC10 activity at vesicles was higher than its activity at the plasma membrane, and TC10-positive vesicles were found to fuse to the plasma membrane in NGF-treated PC12 cells. Therefore, activity of TC10 at vesicles is presumed to be inactivated near the plasma membrane during neuronal exocytosis. Our model is supported by functional evidence that constitutively active TC10 could not rescue decrease in NGF-induced neurite outgrowth induced by TC10 depletion. Furthermore, TC10 knockdown experiments and colocalization analyses confirmed the involvement of Exo70 in TC10-mediated trafficking in neuronal cells. TC10 frequently resided on vesicles containing Rab11, which is a key regulator of recycling pathways and implicated in neurite outgrowth. In growth cones, most of the vesicles containing the cell adhesion molecule L1 had TC10. Exocytosis of Rab11- and L1-positive vesicles may play a central role in TC10-mediated neurite outgrowth. The combination of this study and our previous work on the role of TC10 in EGF-induced exocytosis in HeLa cells suggests that the signaling machinery containing TC10 proposed here may be broadly used for exocytosis.


SGS1, the Saccharomyces cerevisiae homologue of BLM and WRN, suppresses genome instability and homeologous recombination.
The Escherichia coli gene recQ was identified as a RecF recombination pathway gene. The gene SGS1, encoding the only RecQ-like DNA helicase in Saccharomyces cerevisiae, was identified by mutations that suppress the top3 slow-growth phenotype. Relatively little is known about the function of Sgs1p because single mutations in SGS1 do not generally cause strong phenotypes. Mutations in genes encoding RecQ-like DNA helicases such as the Bloom and Werner syndrome genes, BLM and WRN, have been suggested to cause increased genome instability. But the exact DNA metabolic defect that might underlie such genome instability has remained unclear. To better understand the cellular role of the RecQ-like DNA helicases, sgs1 mutations were analyzed for their effect on genome rearrangements. Mutations in SGS1 increased the rate of accumulating gross chromosomal rearrangements (GCRs), including translocations and deletions containing extended regions of imperfect homology at their breakpoints. sgs1 mutations also increased the rate of recombination between DNA sequences that had 91% sequence homology. Epistasis analysis showed that Sgs1p is redundant with DNA mismatch repair (MMR) for suppressing GCRs and for suppressing recombination between divergent DNA sequences. This suggests that defects in the suppression of rearrangements involving divergent, repeated sequences may underlie the genome instability seen in BLM and WRN patients and in cancer cases associated with defects in these genes.


Prognostic nutritional index: a tool to predict the biological aggressiveness of gastric carcinoma.
The prognostic nutritional index (PNI), which is calculated based on the serum albumin concentration and the peripheral blood lymphocyte count, has been used to assess the immunological and nutritional condition of patients with digestive diseases. However, its value as an indicator of aggressiveness in gastric carcinoma has not been fully investigated. Two hundred and forty-eight cases of gastric carcinoma were studied with regard to the relationship between the preoperative PNI value and the clinicopathological characteristics of the patients. A lower preoperative PNI value significantly correlated with greater tumor depth, lymph node metastasis, lymphatic permeation, and venous invasion. Moreover, the PNI value proved to be an independent prognostic indicator in gastric carcinoma. The PNI value can be a useful tool to predict the prognosis of patients with gastric carcinoma.


A dynamic friction model for haptic simulation of needle insertion.
This paper describes a new friction model, termed the brush model, suitable for haptic simulations of needle insertion in virtual environments. A novel two-layer surface contact model is presented that provides real-time rendering of friction forces at haptic refresh rates. A significant modification to the brush model is also presented, leading to a new friction model, termed the fixed bristle brush model. Simulation results show that the two models can accurately reflect the experimentally observed friction characteristics. This paper presents a simulation of friction during needle insertion; results agree with the experimental observations.


The promise and pitfalls of sequence-based identification of plant-pathogenic fungi and oomycetes.
Sequences of selected marker loci have been widely used for the identification of specific pathogens and the development of sequence-based diagnostic methods. Although such approaches offer several advantages over traditional culture-based methods for pathogen diagnosis and identification, they have their own pitfalls. These include erroneous and incomplete data in reference databases, poor or oversimplified interpretation of search results, and problems associated with defining species boundaries. In this letter, we outline the potential benefits and drawbacks of using sequence data for identification and taxonomic deduction of plant-pathogenic fungi and oomycetes, using phytophthora as a primary example. We also discuss potential remedies for these pitfalls and address why coordinated community efforts are essential to make such remedies more efficient and robust.


A salmonid cell line (TO) for production of infectious salmon anaemia virus (ISAV).
A new cell line designated TO which provides a high yield of infectious salmon anaemia virus (ISAV) has been established. The cells originate from head kidney leukocytes isolated from Atlantic salmon and grow well at 20 degrees C in EMEM with 5% CO2 and without CO2 supplement in HMEM. The cells have at present been passed more than 150 times and no changes in morphology, growth or virus production have been observed. The virus infection results in cytopathic effects (CPE) within 9 d, and the virus titre obtained from centrifuged and filtrated cell lysates, measured as TCID50, was about 10(9.1) ml(-1). The virus isolated from lysates of infected cells by a sucrose gradient provided purified ISAV when examined by silver stained SDS-PAGE. Salmon injected with diluted virus supernatant showed mortalities, hematocrit values and clinical signs in accordance with infectious salmon anaemia.


Metabolic syndrome biomarkers predict lung function impairment: a nested case-control study.
Cross-sectional studies demonstrate an association between metabolic syndrome and impaired lung function. To define if metabolic syndrome biomarkers are risk factors for loss of lung function after irritant exposure. A nested case-control study of Fire Department of New York personnel with normal pre-September 11th FEV(1) and who presented for subspecialty pulmonary evaluation before March 10, 2008. We correlated metabolic syndrome biomarkers obtained within 6 months of World Trade Center dust exposure with subsequent FEV(1). FEV(1) at subspecialty pulmonary evaluation within 6.5 years defined disease status; cases had FEV(1) less than lower limit of normal, whereas control subjects had FEV(1) greater than or equal to lower limit of normal. Clinical data and serum sampled at the first monitoring examination within 6 months of September 11, 2001, assessed body mass index, heart rate, serum glucose, triglycerides and high-density lipoprotein (HDL), leptin, pancreatic polypeptide, and amylin. Cases and control subjects had significant differences in HDL less than 40 mg/dl with triglycerides greater than or equal to 150 mg/dl, heart rate greater than or equal to 66 bpm, and leptin greater than or equal to 10,300 pg/ml. Each increased the odds of abnormal FEV(1) at pulmonary evaluation by more than twofold, whereas amylin greater than or equal to 116 pg/ml decreased the odds by 84%, in a multibiomarker model adjusting for age, race, body mass index, and World Trade Center arrival time. This model had a sensitivity of 41%, a specificity of 86%, and a receiver operating characteristic area under the curve of 0.77. Abnormal triglycerides and HDL and elevated heart rate and leptin are independent risk factors of greater susceptibility to lung function impairment after September 11, 2001, whereas elevated amylin is protective. Metabolic biomarkers are predictors of lung disease, and may be useful for assessing risk of impaired lung function in response to particulate inhalation.


The effects of dietary taurine supplementation on bone mineral density in ovariectomized rats.
This study was performed to evaluate the effect of a diet rich in taurine (2.0 g/100 g) on bone metabolism in ovariectomized (OVX) rats. All rats were fed deionized water during the experimental period. Bone mineral density (BMD) and bone mineral content (BMC) of spine and femur were measured. Serum and urinary calcium and phosphorus content were determined. The levels serum osteocalcin and alkaline phosphatase (ALP) were used to assess bone formation. The rate of bone resorption was measured by the deoxypyridinoline (DPD) crosslink immunoassay and corrected for creatinine. Urinary Ca and P excretion, serum osteocalcin content, and the crosslink value were not significantly different between the Sham groups. The taurine supplemented, Sham group had higher spinal and femur BMC than those of the untreated control group, but the difference was not statistically significant. However, the taurine supplemented, Sham group had significantly higher spine and femur BMC per weight than those of the untreated control group. Within the OVX group, the taurine supplemented group had a lower crosslink value than the casein group. The taurine supplemented, OVX group had higher femur bone mineral content per weight than those of the control, OVX group, but the difference was not statistically significant. A study examining the long-term effect of taurine supplementation in humans is warranted.


The role of peer victimization, sexual identity, and gender on unhealthy weight control behaviors in a representative sample of Texas youth.
The aim of the study is to examine the association between victimization and unhealthy weight control behaviors (UWCB), accounting for other key correlates of UWCB while considering the moderating role of sexual identity and gender. This study used data from the 2017 Texas Youth Risk Behavior Survey (YRBS), a representative sample of students in grades 9-12 in the U.S. state of Texas, including 2,067 students (1,754 heterosexuals and 313 sexual minorities). We used survey-weighted logistic regression to examine the association of sexual identity, gender, and victimization (dating violence, cyberbullying, and school bullying) with UWCB, after adjusting for demographic information and indicators of weight, physical activity, and support from adults. Unhealthy weight control behaviors were associated with older age, being obese, lack of support from adults, low physical activity, and cyberbullying. A significant three-way interaction between gender, sexual identity and bullying showed that bullying was associated with high levels of UWCB among sexual minority males. Our study highlights the role of victimization in health behaviors for stigmatized groups, and the importance of school efforts to implement an equitable and safe learning environment for all students.


[Identification of mutation in the gene cystic fibrosis transmembrane regulator (CFTR) in Chilean patients with cystic fibrosis].
Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene, that codes for a chloride channel located in the apical surface of epithelial cells. The main role of this protein is the regulation of chloride transport, and secondarily, of sodium and water to the extracellular space. More than 900 gene mutations have been described, and their relative frequency in different populations depends on their ethnic origin. To report the findings of Chilean patients with cystic fibrosis, in whom the presence of 20 common mutations was analyzed. Fifty seven patients with established diagnosis or suspicion of CF were studied. The simultaneous identification of 20 mutations and the normal delta F508 allele was done using polymerase chain reactions with a commercial assay. Eight mutations were found. Fifty patients fulfilled diagnostic criteria proposed by the Consensus Panel of the CF Foundation and 66% of alleles were identified in this group. delta F508 mutation was found in 45%. We did not identify mutations in any of the remaining 7 patients. Our results suggest that the majority of undetected mutations are associated with atypical phenotypes or that some patients in this series could have other diseases. We recommend to include mutation analysis in the evaluation of Chilean patients with CF. It is useful to establish prognosis and genetic counselling.


Minimizing wildlife impacts for offshore wind energy development: Winning tradeoffs for seabirds in space and cetaceans in time.
Although offshore wind energy development (OWED) offers a much-needed renewable energy alternative to fossil fuels, holistic and effective methods for evaluating environmental impacts on wildlife in both space and time have been lacking. The lengthy environmental compliance process, estimated to incur a 7-10 year permitting timeline [1], has been identified as a significant impediment to offshore energy development in U.S. waters. During operation, seabirds can collide and be displaced by turbines. During episodic pre-operation phases, cetaceans are most heavily impacted acoustically by pile driving (and similarly seismic air gun surveys for oil and gas exploration). The varying nature of impacts in space and time leads us to conclude that sites should be selected in space to minimize long-term operational impacts on seabirds, and timing of surveying and construction activities to be conducted in times of the year when sensitive migratory marine mammals are least present. We developed a novel spatiotemporal decision support framework that interactively visualizes tradeoffs between OWED industry profits and wildlife sensitivities, in both space and time. The framework highlights sites on a map that are the most profitable and least sensitive to seabirds. Within the U.S. Mid-Atlantic study area, the New York Call Areas are particularly well optimized for minimal impact on seabirds with maximal profits to OWED. For a given site, pre-operational activities (e.g. pile driving and seismic air gun surveying) are advised by cetacean sensitivity across months of the year that minimize impacts on migratory cetaceans, particularly those of highest conservation concern such as the North Atlantic right whale (Eubalaena Glacialis). For instance, within optimal sites for the New York Call Area the least impacting months are May and June. Other taxa are certainly affected by OWED and should be incorporated into this framework, but data on their distributions and/or sensitivities is currently less well known. Built with open-source software made publicly available, the authors hope this framework will be extended even more comprehensively into the future as our knowledge on species distributions and OWED sensitivities expands for streamlining environmental compliance.


Adverse reactions to five new antidepressants.
Postmarketing adverse drug reaction reports for amoxapine, maprotiline hydrochloride, and trazodone hydrochloride and premarketing adverse drug reaction data for bupropion hydrochloride and nomifensine maleate are reviewed, and the role of the new agents in the management of depressive illness is discussed. Nomifensine was withdrawn from markets worldwide because of reports of serious hypersensitivity reactions, especially hemolytic anemia, and marketing of bupropion in the United States was delayed after seizures occurred in bulimic patients in clinical trials. Amoxapine and maprotiline, when taken in overdose attempts, are more toxic and cause more serious central nervous system reactions than the standard tricyclics. Acute renal failure and an increased mortality rate are associated with amoxapine overdose. Amoxapine causes several acute and chronic untoward neurologic and endocrine reactions not commonly associated with the standard tricyclics. For maprotiline and bupropion, maximum doses have been established because of dose-related seizures. Trazodone has minimal effect on cardiac conduction; its main cardiovascular effects are hypotension, orthostasis, and dizziness. The trazodone package insert has been revised to warn of priapism; patients with prolonged or inappropriate penile erections are instructed to discontinue the drug and notify the physician. Serious cardiovascular and neurologic toxicities are rare with trazodone overdose. Of the newly marketed antidepressants, only trazodone offers some advantages over the tricyclic and tetracyclic agents in the areas of side effects and toxicities. The number and type of patients exposed to a new drug during clinical trials is too small for detection of rare but potentially serious adverse effects.


Studying the neural bases of prism adaptation using fMRI: A technical and design challenge.
Prism adaptation induces rapid recalibration of visuomotor coordination. The neural mechanisms of prism adaptation have come under scrutiny since the observations that the technique can alleviate hemispatial neglect following stroke, and can alter spatial cognition in healthy controls. Relative to non-imaging behavioral studies, fMRI investigations of prism adaptation face several challenges arising from the confined physical environment of the scanner and the supine position of the participants. Any researcher who wishes to administer prism adaptation in an fMRI environment must adjust their procedures enough to enable the experiment to be performed, but not so much that the behavioral task departs too much from true prism adaptation. Furthermore, the specific temporal dynamics of behavioral components of prism adaptation present additional challenges for measuring their neural correlates. We developed a system for measuring the key features of prism adaptation behavior within an fMRI environment. To validate our configuration, we present behavioral (pointing) and head movement data from 11 right-hemisphere lesioned patients and 17 older controls who underwent sham and real prism adaptation in an MRI scanner. Most participants could adapt to prismatic displacement with minimal head movements, and the procedure was well tolerated. We propose recommendations for fMRI studies of prism adaptation based on the design-specific constraints and our results.


Adsorption mechanism of an antimicrobial peptide on carbonaceous surfaces: A molecular dynamics study.
Peptides are versatile molecules with applications spanning from biotechnology to nanomedicine. They exhibit a good capability to unbundle carbon nanotubes (CNT) by improving their solubility in water. Furthermore, they are a powerful drug delivery system since they can easily be uptaken by living cells, and their high surface-to-volume ratio facilitates the adsorption of molecules of different natures. Therefore, understanding the interaction mechanism between peptides and CNT is important for designing novel therapeutical agents. In this paper, the mechanisms of the adsorption of antimicrobial peptide Cecropin A-Magainin 2 (CA-MA) on a graphene nanosheet (GNS) and on an ultra-short single-walled CNT are characterized using molecular dynamics simulations. The results show that the peptide coats both GNS and CNT surfaces through preferential contacts with aromatic side chains. The peptide packs compactly on the carbon surfaces where the polar and functionalizable Lys side chains protrude into the bulk solvent. It is shown that the adsorption is strongly correlated to the loss of the peptide helical structure. In the case of the CNT, the outer surface is significantly more accessible for adsorption. Nevertheless when the outer surface is already covered by other peptides, a spontaneous diffusion, via the amidated C-terminus into the interior of the CNT, was observed within 150 ns of simulation time. We found that this spontaneous insertion into the CNT interior can be controlled by the polarity of the entrance rim. For the positively charged CA-MA peptide studied, hydrogenated and fluorinated rims, respectively, hinder and promote the insertion.


Using non-steroidal anti-inflammatory drugs in the treatment of depression.
clinicians have long noticed a correlation between physiological markers of inflammation and depression. The best-known example is the activation of the hypothalamus-pituitary-adrenal axis and cortisol secretion; however more recent studies have demonstrated increased salivary prostaglandins and plasma acute phase proteins in depressed patients. To date four randomised controlled trials have used celecoxib or rofecoxib as adjuncts to serotonin selective reuptake inhibitors in the treatment of depression. These suggested a statistically significant decrease in depressive symptoms in the patients taking NSAIDs and SSRIs, compared to patients taking SSRIs alone. Interpretation of these results is limited by the small sample size and short duration of these preliminary studies. The research only considers depressed patients receiving treatment in secondary care; no study has examined the effectiveness of NSAIDs as an adjunct in primary care, even though most cases of depression in the UK are managed in the community by general practitioners. we propose a multi-centre double-blinded randomised controlled trial with two objectives: to determine whether citalopram plus celecoxib dual therapy achieves a greater reduction in depressive symptoms (quantified using the Hamilton Depression Rating Scale (HDRS)) within four weeks, compared to citalopram monotherapy; and to determine whether citalopram plus celecoxib dual therapy is more likely to achieve remission (HDRS score ?7) of moderate to severe depression within six months, compared with citalopram monotherapy. The endpoints will be the reduction in HDRS score after 4 weeks of treatment, and the HDRS score after 26 weeks of treatment. The study will enrol 452 participants from general practices who have a moderate or severe, current or recurrent major depressive episode when medication with an SSRI is considered. The study population will be stratified according to age, sex, HDRS score, age of onset of first episode, number of previous depressive episodes and duration of current episode. The population will then be randomised into two groups. Subjects will be interviewed to determine HDRS score, measure blood pressure, count pills and discuss side-effects. This will occur weekly for the first four weeks, and every four weeks thereafter.


Magmatic vapor source for sulfur dioxide released during volcanic eruptions: evidence from mount pinatubo.
Sulfur dioxide (SO(2)) released by the explosive eruption of Mount Pinatubo on 15 June 1991 had an impact on climate and stratospheric ozone. The total mass of SO(2) released was much greater than the amount dissolved in the magma before the eruption, and thus an additional source for the excess SO(2) is required. Infrared spectroscopic analyses of dissolved water and carbon dioxide in glass inclusions from quartz phenocrysts demonstrate that before eruption the magma contained a separate, SO(2)-bearing vapor phase. Data for gas emissions from other volcanoes in subduction-related arcs suggest that preeruptive magmatic vapor is a major source of the SO(2) that is released during many volcanic eruptions.


The fourth law of thermodynamics: steepest entropy ascent.
When thermodynamics is understood as the science (or art) of constructing effective models of natural phenomena by choosing a minimal level of description capable of capturing the essential features of the physical reality of interest, the scientific community has identified a set of general rules that the model must incorporate if it aspires to be consistent with the body of known experimental evidence. Some of these rules are believed to be so general that we think of them as laws of Nature, such as the great conservation principles, whose 'greatness' derives from their generality, as masterfully explained by Feynman in one of his legendary lectures. The second law of thermodynamics is universally contemplated among the great laws of Nature. In this paper, we show that in the past four decades, an enormous body of scientific research devoted to modelling the essential features of non-equilibrium natural phenomena has converged from many different directions and frameworks towards the general recognition (albeit still expressed in different but equivalent forms and language) that another rule is also indispensable and reveals another great law of Nature that we propose to call the 'fourth law of thermodynamics'. We state it as follows: every non-equilibrium state of a system or local subsystem for which entropy is well defined must be equipped with a metric in state space with respect to which the irreversible component of its time evolution is in the direction of steepest entropy ascent compatible with the conservation constraints. To illustrate the power of the fourth law, we derive (nonlinear) extensions of Onsager reciprocity and fluctuation-dissipation relations to the far-non-equilibrium realm within the framework of the rate-controlled constrained-equilibrium approximation (also known as the quasi-equilibrium approximation). This article is part of the theme issue 'Fundamental aspects of nonequilibrium thermodynamics'.


Seroprotection at Different Levels of the Healthcare System After Routine Vaccination With Diphtheria-Tetanus-Pertussis whole cell-Hepatitis B-Haemophilus influenzae Type B in Lao People's Democratic Republic.
The Lao People's Democratic Republic continues to sustain a considerable burden of vaccine-preventable diseases because of incomplete vaccine coverage and weak vaccine responses. We have assessed seroconversion after routine vaccination with the pentavalent vaccine to capture weaknesses of vaccine management at the different levels of the healthcare system. A total of 1151 children (aged 8-28 months) with 3 documented doses of the pentavalent vaccine delivered at central hospitals in Vientiane and the provincial hospital, 3 district hospitals, and 10 health centers in Bolikhamxay province were enrolled. Sociodemographic information was collected with a standardized questionnaire. Serum samples were analyzed for antibodies against vaccine components, and bivariate and multivariable analyses were performed to identify risk factors for low vaccine responses. Seroprotection rates at the provincial, district, and health center level were as high as in central hospitals, but seroprotection rates in areas covered by remote health centers were significantly lower. Protective levels also rapidly decreased with age at sampling. Seroprotection rates in Bolikhamxay against the different components reached 70%-77% and were up to 20% higher than in previous studies in the same region; 18.8% more children received the hepatitis B vaccine birth dose and the hepatitis B virus infection rate was 4 times lower. Vaccine immunogenicity has dramatically improved in a central province, likely due to training and investment in the cold chain. Nevertheless, there remains a need to focus on the "last mile" in remote areas were most children are vaccinated through outreach activities.