All men with vasculogenic erectile dysfunction require a cardiovascular workup.
An association between erectile dysfunction and cardiovascular disease has long been recognized, and studies suggest that erectile dysfunction is an independent marker of cardiovascular disease risk. Therefore, assessment and management of erectile dysfunction may help identify and reduce the risk of future cardiovascular events, particularly in younger men. The initial erectile dysfunction evaluation should distinguish between predominantly vasculogenic erectile dysfunction and erectile dysfunction of other etiologies. For men believed to have predominantly vasculogenic erectile dysfunction, we recommend that initial cardiovascular risk stratification be based on the Framingham Risk Score. Management of men with erectile dysfunction who are at low risk for cardiovascular disease should focus on risk-factor control; men at high risk, including those with cardiovascular symptoms, should be referred to a cardiologist. Intermediate-risk men should undergo noninvasive evaluation for subclinical atherosclerosis. A growing body of evidence supports the use of emerging prognostic markers to further understand cardiovascular risk in men with erectile dysfunction, but few markers have been prospectively evaluated in this population. In conclusion, we support cardiovascular risk stratification and risk-factor management in all men with vasculogenic erectile dysfunction.


New regulators of biofilm development in Candida glabrata.
Biofilm formation plays an important role in fungal pathogenesis. In this work, we used a genetic screen in order to identify and characterize genes involved in the formation of biofilms by the opportunistic fungal pathogen Candida glabrata. We identified the Cst6p transcription factor as a negative regulator of the EPA6 gene that encodes an adhesin central to C. glabrata biofilm formation. Analysis of single and double mutant strains showed that Cst6p acts in a pathway independent of the Yak1/Sir4 pathway also known to regulate expression of EPA6 and consequently biofilm formation. In contrast, we showed that the chromatin remodelling Swi/Snf complex positively regulates biofilm formation in C. glabrata. RT-qPCR experiments demonstrated that EPA6 expression, and thus biofilm formation, depends on the integrity of the Sir complex. Finally, we showed that Swi/Snf-dependent regulation of biofilm formation is adhesin-specific.


Extracranial stereotactic radioablation: results of a phase I study in medically inoperable stage I non-small cell lung cancer.
Surgical resection is standard therapy for patients with stage I non-small cell lung cancer (NSCLC), however, many patients are medically inoperable. We set out to investigate a new therapy akin to brain radiosurgery called extracranial stereotactic radioablation (ESR) in a phase I trial. Eligible patients included those with clinically staged T1 or T2 (tumor size, < or = 7 cm) N0M0 biopsy confirmed NSCLC. All patients had comorbid medical problems that precluded thoracotomy. The median age was 75 years, and the median Karnofsky performance status was 80. ESR was administered in three separate fractions over 2 weeks. Three to five patients were treated within each dose cohort starting at 800 cGy per fraction (total, 2,400 cGy) followed by successive dose escalations of 200 cGy per fraction (total increase per cohort, 600 cGy). Waiting periods occurred between dose cohorts to observe toxicity. Patients with T1 vs T2 tumors underwent separate independent dose escalations. A total of 37 patients were enrolled since February 2000. One patient experienced grade 3 pneumonitis, and another patient had grade 3 hypoxia. For the entire population, there was no appreciable decline in cardiopulmonary function as measured by symptoms, physical examination, need for oxygen supplementation, pulmonary function testing, arterial blood gas determinations, or regular chest imaging. Both T-stage groups ultimately reached and tolerated 2,000 cGy per fraction for three fractions (total, 6,000 cGy). The maximum tolerated dose for this therapy in either T-stage group has yet to be reached. Tumors responded to treatment in 87% of patients (complete response, 27%). After a median follow-up period of 15.2 months, six patients experienced local failure, all of whom had received doses of < 1,800 cGy per fraction. Very high radiation dose treatments were tolerated in this population of medically inoperable patients with stage I NSCLC using ESR techniques.


Kaposi sarcoma is a therapeutic target for vitamin D(3) receptor agonist.
Kaposi sarcoma (KS) is responsive to a number of different steroid hormones, such as glucocorticoids and retinoids. An active metabolite of vitamin D, 1alpha,25 dihydroxyvitamin D(3), was used to study the effect of this steroid hormone in KS. Steroid hormones exert their effect through their cognate nuclear receptors, which for vitamin D metabolites is the vitamin D receptor (VDR). It was first shown that KS cell lines and primary tumor tissue express high levels of VDR, whereas endothelial cells had minimal expression and fibroblasts had no expression. Second, KS cell growth was inhibited by VDR agonist 1alpha,25 dihydroxyvitamin D(3) with a 50% inhibitory concentration of 5 x 10 -8 mol/L, whereas endothelial cells and fibroblast cells showed no response. Studies on the mechanism of KS tumor growth inhibition by 1alpha,25 dihydroxyvitamin D(3) showed that production of autocrine growth factors interleukin (IL)-6 and IL-8 was reduced in a dose-dependent manner, whereas no effect was observed on vascular endothelial growth factor and basic fibroblast growth factor. Transcription initiated at the IL-6 promoter was repressed by VDR agonist. The DNA sequences required to mediate this repression were localized to nucleotides -225/-110 in the 5'-flanking region. The antitumor activity of VDR agonists was also confirmed in KS tumor xenograft and after topical application in patients with KS. 1alpha,25 Dihydroxyvitamin D(3) and its analogs may thus be candidates for clinical development in KS.


Priming for self-esteem influences the monitoring of one's own performance.
Social cues have subtle effects on a person, often without them being aware. One explanation for this influence involves implicit priming of trait associations. To study this effect, we activated implicit associations in participants of 'being Clever' or 'being Stupid' that were task relevant, and studied its behavioural impact on an independent cognitive task (the n-back task). Activating a representation of 'Clever' caused participants to slow their reaction times after errors on the working memory task, while the reverse pattern was seen for associations to 'Stupid'. Critically, these behavioural effects were absent in control conditions. Using functional magnetic resonance imaging, we show that the neural basis of this effect involves the anterior paracingulate cortex (area 32) where activity tracked the observed behavioural pattern, increasing its activity during error monitoring in the 'Clever' condition and decreasing in the 'Stupid' condition. The data provide a quantitative demonstration of how implicit cues, which specifically target a person's self-concept, influences the way we react to our own behaviour and point to the anterior paracingulate cortex as a critical cortical locus for mediating these self-concept related behavioural regulations.


Effect of Diazoxide Preconditioning on Cultured Rat Myocardium Microvascular Endothelial Cells against Apoptosis and Relation of PI3K/Akt Pathway.
Anti-apoptotic mechanism for cell protection on reperfusion may provide a new method to reduce reperfusion injury. The aim of the present study is to explore the effect of mitochondrial ATP sensitive potassium channel (Mito-KATP) opener diazoxide (DZ) preconditioning on hypoxia/reoxygen (H/R) injury of rat myocardium microvascular endothelial cells (MMECs) against apoptosis and relation of PI3K/Akt pathway. Animal experimentation. The rat MMECs were cultivated, and H/R model was made to imitate ischemia-reperfusion injury. The cells were seeds in 96-wellplates (100μL/hole) or in 6cm diameter dishes (2 mL/dish) with the density of 1×106/mL and randomly divided into 4 groups (n=6 each): control group (Group N), hypoxia-regoxygen group (Group H/R), Diazoxide preconditioning+H/R group (Group DZ) and Diazoxide preconditioning +mitochondrial KATP blocker 5-hydroxydecanoate (5-HD) + H/R group (Group DZ+5-HD). The cells were exposed to 2h hypoxia followed by 2h reoxygenation. Diazoxide 100μmol/L and diazoxide 100μmol/L+ 5-HD100μmol/L were added to the culture medium 2h before hypoxia in DZ and DZ+5-HD groups respectively. Each group was observed the proliferation in MTT, apoptotic rate in Annexin V-FITC/PI double standard, cell structure of Hoechst staining, and the levels of PI3K, Akt and p53 mRNA by RT-qPCR. Compared with Group N, apoptotic rate of Group H/R increased (p<0.01) and the vitality decreased significantly (p<0.05), and the expression of PI3K, Akt and p53 mRNA elevated in Group H/R (p<0.05). Compared with Group H/R, apoptotic rate and p53 mRNA level of Group DZ depressed significantly (p<0.01, p<0.05), while the vitality, PI3K and Akt mRNA levels increased (p<0.05). Compared with Group DZ, apoptotic rate and p53 mRNA level of Group DZ+5-HD increased significantly (p<0.01, p<0.05), but the vitality, PI3K and Akt mRNA levels decreased (p<0.05). Under the condition of H/R, mito-KATP opened by DZ may depend on PI3K/Akt pathway to regulate expression level of the downstream p53 mRNA to inhibit apoptosis and improve viability of MMECs at the same time.


Epilepsy risk among survivors of intensive care unit hospitalization for sepsis.
To determine whether survivors of intensive care unit (ICU) hospitalizations with sepsis experience higher epilepsy risk than survivors of ICU hospitalizations without sepsis, and to identify sepsis survivors at highest risk. We used linked, administrative health care databases to conduct a population-based, retrospective matched cohort study of adult Ontario residents discharged from an ICU between January 1, 2010, and December 31, 2015, identified using the Discharge Abstract Database. We used propensity scores to match patients who experienced sepsis during their index ICU hospitalization with up to 4 patients who did not experience sepsis. We applied marginal Cox proportional hazards regression to estimate the risk of epilepsy within 2 years following the index ICU hospitalization. Among sepsis survivors, Cox proportional hazards regression was used to identify factors associated with epilepsy. A total of 143,892 patients were included, 32,252 (22.4%) of whom were exposed. Sepsis survivors were at significantly higher epilepsy risk (hazard ratio [HR] 1.44, 95% confidence interval [CI] 1.15-1.80). The risk of epilepsy marginally decreased with increasing age (HR 0.97, 95% CI 0.96-0.99); patients with chronic kidney disease (HR 2.25, 95% CI 1.48-3.43) were at highest risk. In this real-world analysis, sepsis survivors, particularly those who are younger and have chronic kidney disease, are at significantly higher epilepsy risk. These findings indicate that sepsis may be an unrecognized epilepsy risk factor.


Disorder-enhanced transport in photonic quasicrystals.
Quasicrystals are aperiodic structures with rotational symmetries forbidden to conventional periodic crystals; examples of quasicrystals can be found in aluminum alloys, polymers, and even ancient Islamic art. Here, we present direct experimental observation of disorder-enhanced wave transport in quasicrystals, which contrasts directly with the characteristic suppression of transport by disorder. Our experiments are carried out in photonic quasicrystals, where we find that increasing disorder leads to enhanced expansion of the beam propagating through the medium. By further increasing the disorder, we observe that the beam progresses through a regime of diffusive-like transport until it finally transitions to Anderson localization and the suppression of transport. We study this fundamental phenomenon and elucidate its origins by relating it to the basic properties of quasicrystalline media in the presence of disorder.


Catatonia after benzodiazepine withdrawal.
The use of benzodiazepine medication is associated with a variety of acute and well-recognized withdrawal syndromes including anxiety, agitation, insomnia, and confusion. Catatonia has not previously been described. We report five patients who became catatonic after withdrawal of benzodiazepines. All five were older individuals (53-88 years) who had acutely become immobile, mute, and rigid with refusal or inability to eat or drink. Each of the five showed pronounced and rapid improvement after administration of low-dose lorazepam, which has previously been reported to be effective in the treatment of catatonia. Careful review of the records showed that each of the patients had been taking benzodiazepine medication for anywhere from 6 months to 15 years and that it had been rapidly tapered or abruptly discontinued 2 to 7 days before the onset of catatonia. These cases illustrate that severe and potentially life-threatening catatonia can develop in the wake of benzodiazepine withdrawal. Older individuals may be particularly vulnerable to this side effect.


Preliminary lessons from COVID-19 disruptions of small-scale fishery supply chains.
The ongoing COVID-19 pandemic and associated mitigation measures have disrupted global systems that support the health, food and nutrition security, and livelihoods of billions of people. These disruptions have likewise affected the small-scale fishery (SSF) sector, disrupting SSF supply chains and exposing weaknesses in the global seafood distribution system. To inform future development of adaptive capacity and resilience in the sector, it is important to understand how supply chain actors are responding in the face of a macroeconomic shock. Comparing across seven SSF case studies in four countries, we explore how actors are responding to COVID-19 disruptions, identify constraints to adaptive responses, and describe patterns of disruption and response across cases. In all cases examined, actors shifted focus to local and regional distribution channels and particularly drew on flexibility, organization, and learning to re-purpose pre-existing networks and use technology to their advantage. Key constraints to reaching domestic consumers included domestic restrictions on movement and labor, reduced spending power amongst domestic consumers, and lack of existing distribution channels. In addition, the lack of recognition of SSFs as essential food-producers and inequities in access to technology hampered efforts to continue local seafood supply. We suggest that the initial impacts from COVID-19 highlight the risks in of over-reliance on global trade networks. The SSFs that were able to change strategies most successfully had local organizations and connections in place that they leveraged in innovative ways. As such, supporting local and domestic networks and flexible organizations within the supply chain may help build resilience in the face of future macroeconomic shocks. Importantly, bolstering financial wellbeing and security within the domestic market both before and during such large-scale disruptions is crucial for supporting ongoing supply chain operations and continued food provision during macroeconomic crises.


Neuronal generation from somatic stem cells: current knowledge and perspectives on the treatment of acquired and degenerative central nervous system disorders.
Stem cell transplantation through cell replacement or as vector for gene delivery is a potential strategy for the treatment of neurodegenerative diseases. Several studies have reported the transdifferentiation of different somatic stem cells into neurons in vitro or after transplantation into animal models. This observation has pointed out the perspective of using an ethical and accessible cell source to "replace" damaged neurons or provide support to brain tissue. However, recent findings such as the cell fusion phenomenon have raised some doubts about the real existence of somatic stem cell plasticity. In this review, we will discuss current evidence and controversial issues about the neuroneogenesis from various sources of somatic cells focusing on the techniques of isolation, expansion in vitro as well as the inductive factors that lead to transdifferentiation in order to identify the factors peculiar to this process. The morphological, immunochemical, and physiological criteria to correctly judge whether the neuronal transdifferentation occurred are critically presented. We will also discuss the transplantation experiments that were done in view of a possible clinical therapeutic application. Animal models of stroke, spinal cord and brain trauma have improved with Mesenchymal Stem Cells or Bone Marrow transplantation. This improvement does not seem to depend on the replacement of the lost neurons but may be due to increased expression levels of neurotrophic factors, thus suggesting a beneficial effect of somatic cells regardless of transdifferentiation. Critical understanding of available data on the mechanisms governing the cell fate reprogramming is a necessary achievement toward an effective cell therapy.


No evidence of JC virus reactivation in natalizumab treated multiple sclerosis patients: an 18 month follow-up study.
Natalizumab, used as therapy for multiple sclerosis (MS), has been associated with progressive multifocal leucoencephalopathy (PML), a potentially fatal disease caused by JC virus (JCV), which is not predictable by specific markers. This study evaluated whether JCV reactivation occurred in the urine and/or plasma in 42 MS patients treated with natalizumab over 18 months, and followed by a thorough monitoring programme. 42 patients (F/M: 24/18, mean age 34.4±8.9 years) were followed-up by: urine and plasma JCV-DNA PCR assay, immune cell subsets analysis, clinical and MRI evaluation, quality of life, fatigue and mood assessment. JCV data. At baseline, 11/42 (26%) patients had JCV viruria, persistent at serial controls. One patient acquired viruria at month 1 and one patient at month 12. No patient had JCV viraemia at baseline; three patients acquired viraemic (one at month 6, one at month 13 (both transiently) and one at month 12 (persistently viraemic)). The prevalence of JCV in both urine and plasma did not change significantly from baseline to months 12 and 18. No patient had clinical or MRI evidence of PML. Immunological data. Circulating B cells showed greater expansion (300% increase in absolute number) since the first infusion. NK cell count doubled with no change in percentage while T cell count increased with a reduced percentage, reflecting a clear redistribution in the lymphocyte compartment. CD4+ and CD8+ T cells increased proportionally, with no change in their percentage. Clinical data. 27 patients (64%) were disease free after 1 year. A marked improvement in quality of life was reported by 72% of patients. No evidence of subclinical JCV reactivation was found in our natalizumab treated MS patients up to 18 months of therapy, notwithstanding the marked increase in circulating B cells observed. Moreover, the efficacy of natalizumab, its tolerability and the positive impact on quality of life were confirmed in this study.


Staged unilateral lung volume reduction surgery: from mini-invasive to minimalist treatment strategies.
Lung volume reduction surgery (LVRS) entailing unilateral or bilateral non-anatomical resection of severely damaged emphysematous tissue carried out by thoracoscopic or open surgical approaches, under general anesthesia with single-lung ventilation, has resulted in significant and long-lasting clinical and functional benefit. Unfortunately, the morbidity rates reported by simultaneous bilateral resectional LVRS has led to raise criticism regarding its cost-effectiveness and has stimulated in recent years the development of less invasive bronchoscopic and surgical non-resectional methods of treatment that are preferentially performed in a staged unilateral fashion. We had previously proposed an innovative LVRS modality, which did not entail any resection of lung tissue and was electively carried out according to a staged unilateral strategy by a multiport thoracoscopic access, through thoracic epidural anesthesia in conscious, spontaneously ventilating patients (awake LVRS). The awake LVRS resulted in significant clinical benefit paralleling that achieved by the resectional method with lower morbidity rates and shorter hospital stay. Moreover, the awake LVRS proved also suitable to be employed in stringently selected patients to perform redo procedures following previous successful bilateral LVRS. More recently, in order to minimize the global surgery- and anesthesia-related traumas, we have modified our original non-resectional method by adopting a single thoracoscopic access as well as an anesthesia protocol entailing use of a simple intercostal block with target control sedation, to realize an ultra-minimally invasive or minimalist LVRS. Hence, a deeper investigation of the pros and cons of staged unilateral LVRS strategies as well as of the novel surgical non-resectional and redo LVRS is warranted in order to verify, the optimal strategies of treatment, which will prove to reduce the typical LVRS-related morbidity while assuring the most durable benefit in patients with advanced emphysema.


Trends in fruit and vegetable consumption among U.S. men and women, 1994-2005.
Eating a diet high in fruits and vegetables as part of an overall healthful diet can help lower chronic disease risk and aid in weight management. Increasing the percentage of Americans who consume enough fruits and vegetables every day is part of the Healthy People 2010 objectives for the nation. Assessing trends in consumption of these foods is important for tracking public health initiatives to meet this goal and for planning future objectives. We assessed total and sex-specific changes in daily consumption of fruits and vegetables among 1,227,969 adults in the 50 U.S. states and the District of Columbia who participated in the Behavioral Risk Factor Surveillance System from 1994 through 2005. To estimate changes in consumption according to dietary recommendations that were in place during the years examined, we used geometric mean and the percentage of people eating fruits or vegetables or both five or more times per day. Estimates were standardized for sex, age, and race/ethnicity and analyzed by multivariate regression. From 1994 through 2005, the geometric mean frequency of consumption of fruits and vegetables declined slightly (standardized change: men and women, -0.22 times/day; men, -0.26 times/day; women, -0.17 times/day). The proportion of men and women eating fruits or vegetables or both five or more times per day was virtually unchanged (men, 20.6% vs 20.3%; women, 28.4% vs 29.6%); however, we found small increases for men aged 18 to 24 years and for women who were aged 25 to 34 years, non-Hispanic black, or nonsmokers. Consumption of fruit juice and non-fried potatoes declined for both sexes. The frequency of fruit and vegetable consumption changed little from 1994 through 2005. If consumption is to be increased, we must identify and disseminate promising individual and environmental strategies, including policy change.


Aspalathin, a C-glucosyl dihydrochalcone from rooibos improves the hypoglycemic potential of metformin in type 2 diabetic (db/db) mice.
Metformin is the first line therapy of type 2 diabetics, but continued reduction of their life expectancy warrants further investigation into alternative treatment strategies. This study reports on the combinational use of metformin with aspalathin, a C-glucosyl dihydrochalcone with known glucose lowering and antioxidant properties, as an effective hypoglycemic therapy in a type 2 diabetic (db/db) mouse model. When tested as a monotherapy, a low dose of aspalathin (13 mg/kg) showed no effect, while a high dose (130 mg/kg) has already displayed a better potential than metformin in protecting against diabetes associated symptoms in db/db mice. Thus, it remains of interest to determine whether this dihydrochalcone can improve the efficacy of metformin. The results showed that this combination therapy was more effective than the use of metformin as a monotherapy in ameliorating diabetes associated symptoms, including abnormal raised fasting plasma glucose levels, impaired glucose tolerance, as well as excessively increased body weights and fat content. The treated mice also had reduced food and water consumption when compared to untreated controls, with a pronounced effect evident in the last week of treatment. Therefore, this study supports further investigations into the ameliorative effect of combination therapy of metformin and aspalathin against diabetes associated symptoms.


Long-chain fatty alcohols from evening primrose oil inhibit the inflammatory response in murine peritoneal macrophages.
Evening primrose (Oenothera biennis L., Onagraceae) is a wild medicinal plant of Central American origin that is now one of the most widely used herbal medicines in different parts of the world. Oil extracted from it seeds is traditionally used in the treatment of eczema, asthma, rheumatoid arthritis, breast problem, premenstrual and menopausal syndrome, all they have an inflammatory component. The present study demonstrates the in vitro anti-inflammatory effect of long-chain fatty alcohols, minor compounds isolated from Evening primrose oil (EPO). A mixture of long chain fatty alcohols (LCFAs) was isolated from the non-triacylglycerol fraction of the EPO. Hexacosanol (C26OH: 38.65%), tetracosanol (C24OH: 31.59%), docosanol (C22OH: 11.36%) and octocosanol (C28OH: 7.64%), were the major constituents, identified and quantified by GC and GC-MS. LCFA was tested with LPS stimulated murine peritoneal macrophage. This fraction, significantly and dose-dependently decreased nitric oxide production induced by LPS (P<0.001) and the inhibitory effect seems to be consequence of an action at the level of the inducible nitric-oxide synthethase (iNOS) gene enzyme expression rather than to a direct inhibitory action on enzyme activity. The release of PLA2 and TXB2 also was significantly inhibited by LCFAs (P<0.001) although LCFAs did not affect to PGE2 generation, however the western blot assay showed that LCFAs reduced cyclooxygenase-2 enzyme gene expression at all doses assayed. In the same way, the secretion of inflammatory cytokines interleukin 1β (IL-1β) and tumour necrosis factor α (TNF-α) from LPS-stimulated murine macrophage, were also significantly reduced (P<0.001). These results demonstrates the anti-inflammatory activity of LCFAs, providing an additional value about the role of bioactive minor compounds in the beneficial effect of EPO and supports its traditional uses in inflammatory processes management.


Intrathecal clonidine as an adjuvant to hyperbaric bupivacaine in patients undergoing inguinal herniorrhaphy: A randomized double-blinded study.
Clonidine is added to intrathecal local anesthetics to improve intraoperative analgesia and to increase the duration of sensory and motor block. Aim of this study was to evaluate and compare the effects of addition of two different doses of clonidine (15 and 30 mcg) to 11 mg hyperbaric bupivacaine in patients undergoing inguinal herniorrhaphy surgery under spinal anesthesia. Seventy-five patients enrolled in the study were randomly divided into three groups of 25 each. Group I patients received 11 mg hyperbaric bupivacaine, whereas groups II and III received 15 mcg and 30 mcg clonidine, respectively, as an adjuvant to 11 mg hyperbaric bupivacaine. The volume of solution was kept constant to 2.4 ml by adding saline wherever needed. Highest level of sensory block, time to achieve this level, and highest Bromage scale recorded were comparable among the groups. The mean time to two-segment regression, regression of sensory block to L3 dermatome, and mean duration of motor block were the greatest in group III followed by group II and group I. There was significant fall in mean arterial pressure (MAP) in groups II and III as compared to group I (P = 0.04). Episodes of hypotension were more in group III than in group II. 30 mcg clonidine was associated with more incidence and duration of hypotension than 15 μg of clonidine. 15 mcg clonidine added to 11 mg hyperbaric bupivacaine provides better sensory and motor blockade for inguinal herniorrhaphy.


Melatonin suppression of aerobic glycolysis (Warburg effect), survival signalling and metastasis in human leiomyosarcoma.
Leiomyosarcoma (LMS) represents a highly malignant, rare soft tissue sarcoma with high rates of morbidity and mortality. Previously, we demonstrated that tissue-isolated human LMS xenografts perfused in situ are highly sensitive to the direct anticancer effects of physiological nocturnal blood levels of melatonin which inhibited tumour cell proliferative activity, linoleic acid (LA) uptake and metabolism to 13-hydroxyoctadecadienoic acid (13-HODE). Here, we show the effects of low pharmacological blood concentrations of melatonin following oral ingestion of a melatonin supplement by healthy adult human female subjects on tumour proliferative activity, aerobic glycolysis (Warburg effect) and LA metabolic signalling in tissue-isolated LMS xenografts perfused in situ with this blood. Melatonin markedly suppressed aerobic glycolysis and induced a complete inhibition of tumour LA uptake, 13-HODE release, as well as significant reductions in tumour cAMP levels, DNA content and [(3) H]-thymidine incorporation into DNA. Furthermore, melatonin completely suppressed the phospho-activation of ERK 1/2, AKT, GSK3β and NF-kB (p65). The addition of S20928, a nonselective melatonin antagonist, reversed these melatonin inhibitory effects. Moreover, in in vitro cell culture studies, physiological concentrations of melatonin repressed cell proliferation and cell invasion. These results demonstrate that nocturnal melatonin directly inhibited tumour growth and invasion of human LMS via suppression of the Warburg effect, LA uptake and other related signalling mechanisms. An understanding of these novel signalling pathway(s) and their association with aerobic glycolysis and LA metabolism in human LMS may lead to new circadian-based therapies for the prevention and treatment of LMS and potentially other mesenchymally derived solid tumours.


Ce-Fe-modified zeolite-rich tuff to remove Ba(2+)-like (226)Ra(2+) in presence of As(V) and F(-) from aqueous media as pollutants of drinking water.
The sorption behavior of the Ba(2+)-like (226)Ra(2+) in the presence of H2AsO4(-)/HAsO4(2-) and F(-) from aqueous media using Ce-Fe-modified zeolite-rich tuff was investigated in this work. The Na-modified zeolite-rich tuff was also considered for comparison purposes. The zeolite-rich tuff collected from Wyoming (US) was in contact with NaCl and CeCl3-FeCl3 solutions to obtain the Na- and Ce-Fe-modified zeolite-rich tuffs (ZUSNa and ZUSCeFe). These zeolites were characterized by scanning electron microscopy and X-ray diffraction. The BET-specific surface and the points of zero charge were determined as well as the content of Na, Ce and Fe by neutron activation analysis. The textural characteristics and the point of zero charge were changed by the presence of Ce and Fe species in the zeolitic network. A linear model described the Ba(2+)-like (226)Ra(2+) sorption isotherms and the distribution coefficients (Kd) varied with respect to the metallic species present in the zeolitic material. The As(V) oxianionic chemical species and F(-) affected this parameter when the Ba(2+)-like (226)Ra(2+)-As(V)-F(-) solutions were in contact with ZUSCeFe. The H2AsO4(-)/HAsO4(2-) and F(-) were adsorbed by ZUSCeFe in the same amount, independent of the concentration of Ba(2+)-like (226)Ra(2+) in the initial solution.


Urodynamic and clinical effects of noninvasive and minimally invasive treatments in elderly men with lower urinary tract symptoms stratified according to the grade of obstruction.
We investigated the symptomatic and urodynamic effects of several noninvasive and minimally invasive treatment modalities to quantify these effects and to compare subjective and objective results within groups with various degrees of obstruction. In a prospective study at one center, 487 patients who completed a full screening program including urodynamic investigation started treatment with watchful waiting, terazosin, transurethral microwave thermotherapy, or laser treatment of the prostate; they were re-evaluated symptomatically and urodynamically after 6 months of therapy. The symptomatic and urodynamic results of 87 patients from another center who underwent transurethral resection of the prostate and who had their second urodynamic evaluation 6 months after surgery were also included. In patients without bladder outlet obstruction (BOO), improvement in maximum flow and symptom scores with little change in the degree of obstruction was most apparent, whereas a decrease of detrusor pressure at maximum flow was observed mainly in patients with BOO. The urodynamic effect but not the symptomatic effect of treatments depended on the initial grade of BOO. Urodynamic changes were more marked in the minimally invasive treatment groups compared with the noninvasive treatment groups. In symptomatic patients with benign prostatic hyperplasia, symptomatic improvement in the short term does not seem to depend on changes in urodynamic parameters. Future well-controlled studies focusing on the durability of symptomatic and urodynamic effects will be needed to illustrate the relative potential of urodynamic and other clinical parameters to predict a favorable response to current and innovative treatments.


Neurophysiological signatures of hand motor response to dual-transcranial direct current stimulation in subacute stroke: a TMS and MEG study.
Dual transcranial direct current stimulation (tDCS) to the bilateral primary motor cortices (M1s) has potential benefits in chronic stroke, but its effects in subacute stroke, when behavioural effects might be expected to be greater, have been relatively unexplored. Here, we examined the neurophysiological effects and the factors influencing responsiveness of dual-tDCS in subacute stroke survivors. We conducted a randomized sham-controlled crossover study in 18 survivors with first-ever, unilateral subcortical ischaemic stroke 2-4 weeks after stroke onset and 14 matched healthy controls. Participants had real dual-tDCS (with an ipsilesional [right for controls] M1 anode and a contralesional M1 [left for controls] cathode; 2 mA for 20mins) and sham dual-tDCS on separate days, with concurrent paretic [left for controls] hand exercise. Using transcranial magnetic stimulation (TMS) and magnetoencephalography (MEG), we recorded motor evoked potentials (MEPs), the ipsilateral silent period (iSP), short-interval intracortical inhibition, and finger movement-related cortical oscillations before and immediately after tDCS. Stroke survivors had decreased excitability in ipsilesional M1 with a relatively excessive transcallosal inhibition from the contralesional to ipsilesional hemisphere at baseline compared with controls, as quantified by decreased MEPs and increased iSP duration. Dual-tDCS led to increased MEPs and decreased iSP duration in ipsilesional M1. The magnitude of the tDCS-induced MEP increase in stroke survivors was predicted by baseline contralesional-to-ipsilesional transcallosal inhibition (iSP) ratio. Baseline post-movement synchronization in α-band activity in ipsilesional M1 was decreased after stroke compared with controls, and its tDCS-induced increase correlated with upper limb score in stroke survivors. No significant adverse effects were observed during or after dual-tDCS. Task-concurrent dual-tDCS in subacute stroke can safely and effectively modulate bilateral M1 excitability and inter-hemispheric imbalance and also movement-related α-activity.


Searches for electroweak production of charginos, neutralinos, and sleptons decaying to leptons and W, Z, and Higgs bosons in pp collisions at 8 TeV.
Searches for the direct electroweak production of supersymmetric charginos, neutralinos, and sleptons in a variety of signatures with leptons and [Formula: see text], [Formula: see text], and Higgs bosons are presented. Results are based on a sample of proton-proton collision data collected at center-of-mass energy [Formula: see text] with the CMS detector in 2012, corresponding to an integrated luminosity of 19.5 [Formula: see text]. The observed event rates are in agreement with expectations from the standard model. These results probe charginos and neutralinos with masses up to 720 [Formula: see text], and sleptons up to 260 [Formula: see text], depending on the model details.


Decreased progression to rheumatoid arthritis or other connective tissue diseases in patients with palindromic rheumatism treated with antimalarials.
To determine whether the use of antimalarials is associated with a reduction in the risk of developing rheumatoid arthritis (RA) or other connective tissue diseases in patients with palindromic rheumatism. We conducted a retrospective cohort study based on a review of medical records to evaluate the outcome of patients with palindromic rheumatism referred to an academic center from 1986 to 1996: 113 patients complied with the selection criteria, including diagnostic criteria for palindromic rheumatism and onset of disease since 1980. After adjusting for potential confounders, Kaplan-Meier methods and Cox regression models were used to estimate the risk of developing RA or other connective tissue disease in patients who had received antimalarials compared to those who had not. Age of disease onset was 40+/-12 yrs, and mean disease duration 4.8+/-4 yrs; two-thirds of the patients were female. Sixty-two (55%) patients received antimalarials, for a mean duration of therapy of 28 mo. Thirty-three (29%) patients developed RA, 3 developed systemic lupus, and 4 developed other connective tissue diseases. Twenty (32%) patients in the antimalarial group developed a secondary disease, compared to 20 (39%) who did not receive therapy. Statistically significant differences were observed comparing time to event in both groups. The estimated median time to development of a chronic disease was 162 months in treated and 56 months in untreated patients. After adjusting for other variables in the Cox regression models, significant risk reduction in the development of a secondary disease was observed for antimalarial use (hazard ratio = 0.24; 95% CI 0.09-0.61). For RA, the risk reduction was 0.19 (95% CI 0.07-0.57). We conducted a sensitivity analysis around our censoring estimates. The risk reduction remained statistically significant, with 0.36 for RA and 0.41 for RA or other connective tissue disease. Use of antimalarials in patients with palindromic rheumatism is associated with a reduction in the risk of developing subsequent RA or other connective tissue disease.


Characterization of the genomically encoded fosfomycin resistance enzyme from Mycobacterium abscessus.
Mycobacterium abscessus belongs to a group of rapidly growing mycobacteria (RGM) and accounts for approximately 65-80% of lung disease caused by RGM. It is highly pathogenic and is considered the prominent Mycobacterium involved in pulmonary infection in patients with cystic fibrosis and chronic pulmonary disease (CPD). FosM is a putative 134 amino acid fosfomycin resistance enzyme from M. abscessus subsp. bolletii that shares approximately 30-55% sequence identity with other vicinal oxygen chelate (VOC) fosfomycin resistance enzymes and represents the first of its type found in any Mycobacterium species. Genes encoding VOC fosfomycin resistance enzymes have been found in both Gram-positive and Gram-negative pathogens. Given that FosA enzymes from Gram-negative bacteria have evolved optimum activity towards glutathione (GSH) and FosB enzymes from Gram-positive bacteria have evolved optimum activity towards bacillithiol (BSH), it was originally suggested that FosM might represent a fourth class of enzyme that has evolved to utilize mycothiol (MSH). However, a sequence similarity network (SSN) analysis identifies FosM as a member of the FosX subfamily, indicating that it may utilize water as a substrate. Here we have synthesized MSH and characterized FosM with respect to divalent metal ion activation and nucleophile selectivity. Our results indicate that FosM is a Mn2+-dependent FosX-type hydrase with no selectivity toward MSH or other thiols as analyzed by NMR and mass spectroscopy.


Trimethoprim-associated hyponatremia.
Hyponatremia associated with diuretic use can be clinically difficult to differentiate from the syndrome of inappropriate antidiuretic hormone secretion (SIADH). We report a case of a 28-year-old man with HIV (human immunodeficiency virus) and Pneumocystis pneumonia who developed hyponatremia while receiving trimethoprim-sulfamethoxazole (TMP/SMX). Serum sodium level on admission was 135 mEq/L (with a history of hyponatremia) and decreased to 117 mEq/L by day 7 of TMP/SMX treatment. In the setting of suspected euvolemia and Pneumocystis pneumonia, he was treated initially for SIADH with fluid restriction and tolvaptan without improvement in serum sodium level. A diagnosis of hyponatremia secondary to the diuretic effect of TMP subsequently was confirmed, with clinical hypovolemia and high renin, aldosterone, and urinary sodium levels. Subsequent therapy with sodium chloride stabilized serum sodium levels in the 126- to 129-mEq/L range. After discontinuation of TMP/SMX treatment, serum sodium, renin, and aldosterone levels normalized. TMP/SMX-related hyponatremia likely is underdiagnosed and often mistaken for SIADH. It should be considered for patients on high-dose TMP/SMX treatment and can be differentiated from SIADH by clinical hypovolemia (confirmed by high renin and aldosterone levels). TMP-associated hyponatremia can be treated with sodium supplementation to offset ongoing urinary losses if the TMP/SMX therapy cannot be discontinued. In this Acid-Base and Electrolyte Teaching Case, a less common cause of hyponatremia is presented, and a stepwise approach to the diagnosis is illustrated.


Plasma observations near neptune: initial results from voyager 2.
The plasma science experiment on Voyager 2 made observations of the plasma environment in Neptune's magnetosphere and in the surrounding solar wind. Because of the large tilt of the magnetic dipole and fortuitous timing, Voyager entered Neptune's magnetosphere through the cusp region, the first cusp observations at an outer planet. Thus the transition from the magnetosheath to the magnetosphere observed by Voyager 2 was not sharp but rather appeared as a gradual decrease in plasma density and temperature. The maximum plasma density observed in the magnetosphere is inferred to be 1.4 per cubic centimeter (the exact value depends on the composition), the smallest observed by Voyager in any magnetosphere. The plasma has at least two components; light ions (mass, 1 to 5) and heavy ions (mass, 10 to 40), but more precise species identification is not yet available. Most of the plasma is concentrated in a plasma sheet or plasma torus and near closest approach to the planet. A likely source of the heavy ions is Triton's atmosphere or ionosphere, whereas the light ions probably escape from Neptune. The large tilt of Neptune's magnetic dipole produces a dynamic magnetosphere that changes configuration every 16 hours as the planet rotates.


HIV treatment as prevention: principles of good HIV epidemiology modelling for public health decision-making in all modes of prevention and evaluation.
Public health responses to HIV epidemics have long relied on epidemiological modelling analyses to help prospectively project and retrospectively estimate the impact, cost-effectiveness, affordability, and investment returns of interventions, and to help plan the design of evaluations. But translating model output into policy decisions and implementation on the ground is challenged by the differences in background and expectations of modellers and decision-makers. As part of the PLoS Medicine Collection "Investigating the Impact of Treatment on New HIV Infections"--which focuses on the contribution of modelling to current issues in HIV prevention--we present here principles of "best practice" for the construction, reporting, and interpretation of HIV epidemiological models for public health decision-making on all aspects of HIV. Aimed at both those who conduct modelling research and those who use modelling results, we hope that the principles described here will become a shared resource that facilitates constructive discussions about the policy implications that emerge from HIV epidemiology modelling results, and that promotes joint understanding between modellers and decision-makers about when modelling is useful as a tool in quantifying HIV epidemiological outcomes and improving prevention programming.


Comparison of Rearranged During Transfection (RET) Gene Rearrangements in Primary Versus Metastatic Non-Small Cell Lung Cancer (NSCLC).
BACKGROUND RET rearrangements have been reported in 30% of papillary thyroid carcinomas and 1-2% of non-small cell lung cancer (NSCLC). In these tumors, RET gene fusion product provides a constitutively active tyrosine kinase (TKR), leading to uncontrolled cellular proliferation, differentiation, and migration. In this investigation we assessed the positivity rate of RET gene rearrangement in primary and metastatic non-small cell lung cancer and explored their relationships. MATERIAL AND METHODS Between January 2013 and May 2015, we collected 384 cases of primary metastatic non-small cell lung cancer, which included 246 matched metastatic tumors cases from multiple centers. The RET rearrangement uniformity in metastatic lymph nodes and tumor specimens were contrasted and the relationships between RET rearrangement and patients' clinical features were investigated. RESULTS For those 384 cases, 7 (1.82%) cases had tumors with identified RET rearrangement. Among the 246 paired cases, 3 (1.22%) cases of primary tumor had identified RET rearrangement and 2 (0.81%) cases of metastases had identified RET rearrangement. The sensitivity was 66.67% (2/3) and the specificity was 100% (243/243). CONCLUSIONS The results of this research indicate that the metastases of non-small cell lung cancer can predict RET rearrangement of the primary tumor tissue in the majority of cases. Testing for RET rearrangement in metastases can be used as an alternative to testing of primary tumor tissue if it is inaccessible.


Confirmation of the pleiotropic control of leaflet shape and number of seeds per pod by the Ln gene in induced soybean mutants.
Most soybean cultivars possess broad leaflets; however, a recessive allele on the Ln locus is known to cause the alteration of broad to narrow leaflets. The recessive allele ln has also been considered to increase the number of seeds per pod (NSP) and has the potential to improve yield. Recently, Gm-JAG1 (Glyma20g25000), a gene controlling Ln, has been shown to complement leaf shape and silique length in Arabidopsis mutants. However, whether Gm-JAG1 is responsible for those traits in soybean is not yet known. In this study, we investigated the pleiotropic effect of soybean Ln gene on leaflet shape and NSP by using two independent soybean Gm-jag1 mutants and four ln near isogenic lines (NILs). The leaflet shape was evaluated using a leaf image analysis software, SmartLeaf, which was customized from SmartGrain. The leaflets of both the Gm-jag1 mutants were longer and narrower than those of the wild-type plants. Interestingly, the image analysis results clarified that the perimeter of the mutant leaflets did not change, although their leaflet area decreased. Furthermore, one mutant line with narrow leaflets showed significantly higher NSP than that in the wild (or Ln) genotype, indicating that soybean Ln gene pleiotropically controls leaflet shape and NSP.


Periodicity in the autocorrelation function as a mechanism for regularly occurring zero crossings or extreme values of a Gaussian process.
The problem of zero crossings is of great historical prevalence and promises extensive application. The challenge is to establish precisely how the autocorrelation function or power spectrum of a one-dimensional continuous random process determines the density function of the intervals between the zero crossings of that process. This paper investigates the case where periodicities are incorporated into the autocorrelation function of a smooth process. Numerical simulations, and statistics about the number of crossings in a fixed interval, reveal that in this case the zero crossings segue between a random and deterministic point process depending on the relative time scales of the periodic and nonperiodic components of the autocorrelation function. By considering the Laplace transform of the density function, we show that incorporating correlation between successive intervals is essential to obtaining accurate results for the interval variance. The same method enables prediction of the density function tail in some regions, and we suggest approaches for extending this to cover all regions. In an ever-more complex world, the potential applications for this scale of regularity in a random process are far reaching and powerful.


Molecular mechanisms associated with 46,XX disorders of sex development.
In the female gonad, distinct signalling pathways activate ovarian differentiation while repressing the formation of testes. Human disorders of sex development (DSDs), such as 46,XX DSDs, can arise when this signalling is aberrant. Here we review the current understanding of the genetic mechanisms that control gonadal development, with particular emphasis on those that drive or inhibit ovarian differentiation. We discuss how disruption to these molecular pathways can lead to 46,XX disorders of ovarian development. Finally, we look at recently characterized novel genes and pathways that contribute and speculate how advances in technology will aid in further characterization of normal and disrupted human ovarian development.


Protein delivery into cells using inorganic nanoparticle-protein supramolecular assemblies.
The delivery of proteins into cells is a potential game changer for a wide array of therapeutic purposes, including cancer therapy, immunomodulation and treatment of inherited diseases. In this review, we present recently developed nanoassemblies for protein delivery that utilize strategies that range from direct assembly, encapsulation and composite formation. We will discuss factors that affect the efficacy of nanoassemblies for delivery from the perspective of both nanoparticles and proteins. Challenges in the field, particularly achieving effective cytosolar protein delivery through endosomal escape or evasion are discussed.


Comparison of certolizumab pegol with other anticytokine agents for treatment of rheumatoid arthritis: a multiple-treatment Bayesian metaanalysis.
To compare the clinical efficacy of certolizumab pegol (CZP) with that of other anticytokine agents indicated for the treatment of rheumatoid arthritis (RA) with identical therapeutic indication (anti-tumor necrosis factor-α, anti-interleukin 1 or 6), with the objective of determining the noninferiority of CZP. A systematic review was performed to identify randomized controlled trials that assessed the efficacy of anticytokine agents in combination with conventional disease-modifying antirheumatic drugs (DMARD) after 6 months of treatment, using the American College of Rheumatology (ACR) response criteria, in patients with RA who have shown inadequate response to DMARD including methotrexate. Indirect treatment comparisons were carried out by a multiple-treatment Bayesian random-effects metaanalysis. Data were analyzed using the Markov chain Monte Carlo simulation. Noninferiority of CZP was assessed in comparison with a predefined equivalence margin of 5%. Nineteen placebo-controlled studies were identified: 14 evaluated the efficacy of 5 anti-TNF-α agents (infliximab, etanercept, adalimumab, golimumab, CZP) and 5 evaluated efficacy of 2 anti-interleukin agents (anakinra, tocilizumab). Every treatment showed significant efficacy versus placebo in individual studies. The multiple-treatment metaanalysis showed a highest OR for CZP on ACR20 response. Metaanalysis indicates that the efficacy of CZP according to ACR20 response is superior to that of infliximab, adalimumab, and anakinra, and equivalent or superior to that of etanercept, golimumab, and tocilizumab. According to ACR50 response, the efficacy of CZP is equivalent or superior to that of all other anticytokines. Results of this original multiple-treatment Bayesian metaanalysis indicate that certolizumab pegol is at least as efficacious as the preexisting antirheumatic anticytokine biotherapies.


Effectiveness of laxatives in elderly--a cross sectional study in nursing homes.
Laxatives are efficient drugs, but the effectiveness has been questioned. In nursing homes, the prevalence of constipation is high and laxatives are commonly used drugs. The aims of the study were to assess the effectiveness of laxative therapy in an everyday setting in Norwegian nursing homes, study differences between treatment regimens and factors associated with normal bowel function. A cross-sectional study. After giving informed consent, residents above 60 years of age using laxatives for functional constipation were included, and their characteristics, medical history, use of drugs and bowel functions were recorded. Normal bowel function was defined as bowel movements from 3 times/week to 3 times/day and stool consistency 3-5 on Bristol Stool Form Scale. Out of 647 residents in the nursing homes, 197 were included and 116 (59%) had normal bowel function. The treatment effect did not differ significantly between the laxatives, treatment regimens or expected efficacy of the regimens. The treatment was unsatisfactorily adapted to individual needs. In subjects with normal bowel function, 113 (97%) had persistent complaints; 68 (59.5%), 10 (8.0%), 34 (28.6%) and 26 (22.5%) reported straining, manual manoeuvre to facilitate bowel movements, feeling of incomplete bowel movements, and feeling of anorectal obstruction respectively. Good nutritional status, previous or present cancer disease and anxiety/depression were predictors of normal bowel function. Treatment of constipation in nursing homes was unsatisfactory. Nearly all patients with normal stool frequency and consistence had some persistent complaints. Improved nutrition and individualization of the treatment could improve the outcome.


Factors shaping initial decision-making to self-test amongst cohabiting couples in urban Blantyre, Malawi.
In sub-Saharan Africa, most new HIV infections occur in stable relationships, making couples testing an important intervention for HIV prevention. We explored factors shaping the decision-making of cohabiting couples who opted to self-test in Blantyre, Malawi. Thirty-four self-tested participants (17 couples) were interviewed. Motivators for HIV self-testing (HIVST) emerged at three main levels. Individual motivations included perceived benefits of access to treatment, and self-checking of serostatus in the hope of having been cured by prolonged treatment or faith-healing. HIVST was considered convenient, confidential, reassuring and an enabling new way to test with one's partner. Partnership motivations included both positive (mutual encouragement) and negative (suspected infidelity) aspects. For women, long-term health and togetherness were important goals that reinforced motivations for couples testing, whereas men often needed persuasion despite finding HIVST more flexible and less onerous than facility-based testing. Internal conflict prompted some partners to use HIVST as a way of disclosing their previously concealed HIV positive serostatus. Thus, the implementation of community-based HIVST should acknowledge and appropriately respond to decision-making processes within couples, which are shaped by gender roles and relationship dynamics.


Assessment of efficacy and safety of the herbal medicinal product BNO 1016 in chronic rhinosinusitis.
The objective of this clinical trial (CRS-02) was to assess the efficacy, safety and tolerability of two dosages of the herbal medicinal product BNO 1016 (Sinupret extract) in patients with chronic rhinosinusitis (CRS). 929 patients suffering from CRS were enrolled in this randomised placebo-controlled trial with a treatment period of 12 weeks. The primary endpoint was the mean Major Symptom Score (MSS) in week 8 and week 12 compared to placebo. Secondary endpoints included further MSS related parameters and responder rates over time. Pharmacoeconomic endpoints were also analysed. Finally, safety and tolerability were evaluated. Sinupret extract was not superior over placebo regarding the primary endpoint. However, the results of the secondary endpoints showed a clear trend towards superior efficacy. Therefore, additional post-hoc sensitivity analyses were performed in patients with a baseline MSS over 9 and persistence of disease more than 1 year diagnosed by specialists in otorhinolaryngology. Those patients significantly benefited from Sinupret extract. Therapy was superior for the primary endpoint analysis. Patients were less impaired with respect to work and daily activities. A good safety and tolerability of Sinupret extract was assured in all patients. Sinupret extract can safely be administered in patients with CRS. Although the primary endpoint of the study was not significant, a post-hoc subgroup analysis in patients whose disease was diagnosed by a specialist revealed a pronounced treatment effect. Effects in that subgroup were even stronger with longer disease persistence and stronger severity.


Maintaining binding in working memory: comparing the effects of intentional goals and incidental affordances.
Much research on memory for binding depends on incidental measures. However, if encoding associations benefits from conscious attention, then incidental measures of binding memory might not yield a sufficient understanding of how binding is accomplished. Memory for letters and spatial locations was compared in three within-participants tasks, one in which binding was not afforded by stimulus presentation, one in which incidental binding was possible, and one in which binding was explicitly to be remembered. Some evidence for incidental binding was observed, but unique benefits of explicit binding instructions included preserved discrimination as set size increased and drastic reduction in false alarms to lures that included a new spatial location and an old letter. This suggests that substantial cognitive benefits, including enhanced memory for features themselves, might occur through intentional binding, and that incidental measures of binding might not reflect these advantages.


Modeling Interactions between Speech Production and Perception: Speech Error Detection at Semantic and Phonological Levels and the Inner Speech Loop.
Production and comprehension of speech are closely interwoven. For example, the ability to detect an error in one's own speech, halt speech production, and finally correct the error can be explained by assuming an inner speech loop which continuously compares the word representations induced by production to those induced by perception at various cognitive levels (e.g., conceptual, word, or phonological levels). Because spontaneous speech errors are relatively rare, a picture naming and halt paradigm can be used to evoke them. In this paradigm, picture presentation (target word initiation) is followed by an auditory stop signal (distractor word) for halting speech production. The current study seeks to understand the neural mechanisms governing self-detection of speech errors by developing a biologically inspired neural model of the inner speech loop. The neural model is based on the Neural Engineering Framework (NEF) and consists of a network of about 500,000 spiking neurons. In the first experiment we induce simulated speech errors semantically and phonologically. In the second experiment, we simulate a picture naming and halt task. Target-distractor word pairs were balanced with respect to variation of phonological and semantic similarity. The results of the first experiment show that speech errors are successfully detected by a monitoring component in the inner speech loop. The results of the second experiment show that the model correctly reproduces human behavioral data on the picture naming and halt task. In particular, the halting rate in the production of target words was lower for phonologically similar words than for semantically similar or fully dissimilar distractor words. We thus conclude that the neural architecture proposed here to model the inner speech loop reflects important interactions in production and perception at phonological and semantic levels.


Multiple neutralizing B-cell epitopes of human T-cell leukemia virus type 1 (HTLV-1) identified by human monoclonal antibodies. A basis for the design of an HTLV-1 peptide vaccine.
We have generated 153 human mAb reacting with natural envelope glycoprotein-gp46 of human T-cell leukemia virus type-1 (HTLV-1) by the EBV-transformation of B lymphocytes obtained from patients with HTLV-1-associated myelopathy (HAM)/Tropical spastic paraparesis (TSP). Twenty-four of these mAb had neutralizing activity of HTLV-1 as determined by an HTLV-1-induced syncytium formation inhibition assay in vitro. The reactivity of these neutralizing mAb was studied by using 9 different synthetic peptides covering immunodominant regions of the gp46. Thirteen out of these 24 neutralizing mAb reacted with gp46 peptide 175-199, whereas one mAb reacted with gp46 213-236 and another one with gp46 288-317. The other 9 neutralizing mAb did not react with any of these peptides. Fine epitope mapping of the mAb reacting with gp46 peptide 175-199 revealed the presence of 4 distinct neutralizing B-cell epitopes on this region; (1)187-193, (2)191-196, (3)193-199, and (4) continuous conformational B-cell epitope. The competitive antibody-binding inhibition experiments by soluble phase synthetic peptides showed that the binding activity of these neutralizing mAb to the corresponding synthetic peptides is equal to or a little lower than that to native gp46 protein, suggesting that synthetic peptides can form structure very similar to the neutralizing epitopes on native gp46 protein. The present study is the first systematic demonstration of multiple neutralizing B-cell epitopes of HTLV-1 in human HTLV-1 infection. It would be possible to prepare a synthetic peptide vaccine against HTLV-1 based on these newly identified multiple linear neutralizing B-cell epitopes of HTLV-1.


Ethnic-specific differences in vitamin D status is associated with adiposity.
Low circulating 25 hydroxyvitamin D [25(OH)D] concentrations are common in obesity (BMI ≥30 kg/m(2)) and a negative relationship with body fat distribution has recently been reported. Ethnic-specific differences in body fat distribution have been described with South Asians are reported to have greater visceral adipose tissue (VAT), which could influence circulating 25(OH)D concentrations. The objective of this study is to investigate the relationship between plasma 25(OH)D, adiposity, and body fat distribution in Europeans and South Asians. 187 Europeans and 192 South Asians were assessed for demographics, anthropometrics, and plasma 25(OH)D concentrations. Subcutaneous adipose tissue (SAT) and VAT were quantified by CT scan, and percent body fat by DEXA. Data were assessed by general linear models. South Asians had lower (P<0.001) plasma 25(OH)D concentrations and higher VAT (P = 0.04) than Europeans. Plasma 25(OH)D concentrations were negatively (P<0.05) associated with BMI, waist circumference, percent body fat, total adipose tissue, VAT, and SAT in unadjusted models and negatively (P<0.05) associated with VAT, SAT, and percent body fat after adjusting for BMI, ethnicity, age, and season of blood collection in males and females. When percent body fat, VAT, and SAT were included in the same model, only VAT remained negatively (P<0.05) associated with plasma 25(OH)D concentrations. Ethnicity remained significant in all models (P<0.001). Compared to other adipose tissue compartments, VAT may have a distinct role in determining plasma 25(OH)D concentrations, which may account for the lower levels in South Asians.


Implications of environmental and pathogen-specific determinants on clinical presentations and disease outcome in melioidosis patients.
Melioidosis is gaining recognition as an emerging infectious disease with diverse clinical manifestations and high-case fatality rates worldwide. However, the molecular epidemiology of the disease outside the endemic regions such as northeast part of Thailand and northern Australia remains unclear. Clinical data and B. pseudomallei isolates obtained from 199 culture-confirmed cases of melioidosis diagnosed during 2006-2016 in South India were used to elucidate the host and pathogen specific variable virulence determinants associated with clinical presentations and disease outcome. Further, we determined the temporal variations and the influence of ecological factors on B.pseudomallei Lipopolysaccharide (LPS) genotypes causing infections. Severe forms of the disease were observed amongst 169 (85%) patients. Renal dysfunction and infection due to B.pseudomallei harboring BimABm variant had significant associations with severe forms of the disease. Diabetes mellitus, septicemic melioidosis and infection due to LPSB genotype were independent risk factors for mortality. LPSB (74%) and LPSA (20.6%) were the prevalent genotypes causing infections. Both genotypes demonstrated temporal variations and had significant correlations with rainfall and humidity. Our study findings suggest that the pathogen specific virulence traits under the influence of ecological factors are the key drivers for geographical variations in the molecular epidemiology of melioidosis.


Use of interactive teaching techniques to introduce mental health training to medical schools in a resource poor setting.
There are currently no practising psychiatrists in Somaliland. In 2007 the first medical students graduated from universities in Somaliland without mental health training. We aimed to pilot an intensive but flexible package of mental health training to all senior medical students and interns using interactive training techniques and to evaluate its effectiveness by assessing knowledge, skills and attitudes. Teaching techniques included didactic lectures, case based discussion groups and role playing. Informal feedback informed a flexible teaching package. Assessment tools designed specifically for this course included a pre and post course MCQ exam and an OSCE. Changes in students' attitudes were evaluated using a questionnaire administered before and after the course. In addition, a questionnaire administered following the course evaluated the changes students perceived in their knowledge and attitudes to mental health. The MCQ improved from 50.7% pre course to 64.4% post course (p = 9.73 E-08). Students achieved an average overall OSCE mark of 71%. The pre and post attitudes questionnaire was most significantly different for statements relevant to aetiology, stigma and the overlap between mental and physical health. The statement most strongly agreed with after the course was 'I now understand more about the overlap between mental and physical health'. Interactive teaching provided a learning experience for both students and trainers. On site and distance learning based on the teaching described here has widened the scope of the training possible in psychiatry and allowed the provision of regular teaching, supervision and peer support in Somaliland. However, the current lack of local expertise means that important issues of sustainability need to be considered in future work.


Galectin-7 Regulates Keratinocyte Proliferation and Differentiation through JNK-miR-203-p63 Signaling.
Galectin-7, a member of the β-galactoside-binding protein family, is primarily expressed in stratified epithelial cells, including keratinocytes. There is information in the literature suggesting a role for this protein in regulation of keratinocyte survival and growth, but the underlying mechanism remains relatively unknown. Moreover, its expression pattern in the epidermis suggests that it is also involved in the regulation of keratinocyte differentiation. Here, we demonstrate that galectin-7 knockdown results in reduced differentiation and increased proliferation of keratinocytes. Using microarray and deep-sequencing analyses, we found that galectin-7 positively and negatively regulates microRNA (miR)-203 and miR-146a expression, respectively. We show that galectin-7 regulates keratinocyte differentiation and proliferation through miR-203 but not miR-146a. A knockdown of either galectin-7 or miR-203 in keratinocytes increases expression of p63, an essential transcription factor involved in skin development. Rescue of miR-203 expression in a galectin-7 knockdown model reduces p63 expression to baseline. Increased galectin-7 expression upregulates c-Jun N-terminal kinase (JNK) protein levels, which is required for miR-203 expression. Finally, we establish that galectin-7 can be associated with JNK1 and protect it from ubiquitination and degradation. Thus, our data suggest an intracellular function of galectin-7: regulation of keratinocyte proliferation and differentiation through the JNK1-miR-203-p63 pathway.


Conversion of neutral to alkaline liver fructose 1,6-bisphosphatase: changes in molecular properties of the enzyme.
Removal of the NH(2)-terminal region of fructose 1,6-bisphosphatase from rabbit liver by digestion with subtillisin, or changes in conformation in this region of the protein produced by exposure to low concentrations of urea, result in similar changes in catalytic and allosteric properties of the enzyme. These changes include shift of the pH optimum to more alkaline pH, and loss of sensitivity to inhibition by AMP. The conformation changes are monitored by changes in the fluorescence of the single tryptophan residue, which is located near the NH(2)-terminus. Thus, the tryptophan-containing peptide appears to determine the functional properties of the native enzyme.


Academic Cross-Pollination: The Role of Disciplinary Affiliation in Research Collaboration.
Academic collaboration is critical to knowledge production, especially as teams dominate scientific endeavors. Typical predictors of collaboration include individual characteristics such as academic rank or institution, and network characteristics such as a central position in a publication network. The role of disciplinary affiliation in the initiation of an academic collaboration between two investigators deserves more attention. Here, we examine the influence of disciplinary patterns on collaboration formation with control of known predictors using an inferential network model. The study group included all researchers in the Institute of Clinical and Translational Sciences (ICTS) at Washington University in St. Louis. Longitudinal data were collected on co-authorships in grants and publications before and after ICTS establishment. Exponential-family random graph models were used to build the network models. The results show that disciplinary affiliation independently predicted collaboration in grant and publication networks, particularly in the later years. Overall collaboration increased in the post-ICTS networks, with cross-discipline ties occurring more often than within-discipline ties in grants, but not publications. This research may inform better evaluation models of university-based collaboration, and offer a roadmap to improve cross-disciplinary collaboration with discipline-informed network interventions.


Prognostic value of reduced left ventricular ejection fraction at start of hemodialysis therapy on cardiovascular and all-cause mortality in end-stage renal disease patients.
Cardiac failure is directly affected by left ventricular (LV) dysfunction, and particularly LV systolic dysfunction is strongly associated with survival in ESRD patients. The aim of this study was to determine the prognostic value of reduced LV ejection fraction (LVEF) measured at the time of initiation of hemodialysis (HD) in incident HD patients. 1254 consecutive ESRD patients who electively started HD therapy were screened by echocardiography within 1 month after its inception. They were divided into five groups according to LVEF levels with a decrease of 0.1 each and were followed up for up to 7 years. Survival was examined with the Kaplan-Meier method and compared using the log-rank test. Among the 1254 patients, LVEF levels ≥0.6, 0.5 to 0.6, 0.4 to 0.5, 0.3 to 0.4, and <0.3 were seen in 842 (67.1%), 247 (19.7%), 107 (8.5%), 41 (3.3%), and 17 (1.4%) patients, respectively. On Kaplan-Meier analysis, 7-year event-free rates from cardiovascular death were 84.2, 83.7, 73.6, 59.4, and 30.9% in order of groups with decreasing LVEF of 0.1 each, respectively. Seven-year event-free rates from all-cause death were 69.2, 61.7, 57.1, 45.9, and 23.1% in the respective groups. Even after adjustment for other risk factors, decreasing LVEF was a strong independent predictor for cardiovascular death. Reduced LVEF on starting HD therapy could stratify risk of cardiovascular and all-cause mortality in ESRD patients. Screening by echocardiography at start of HD therapy might be recommended to predict prognosis in patients with ESRD.


A simplified PBPK modeling approach for prediction of pharmacokinetics of four primarily renally excreted and CYP3A metabolized compounds during pregnancy.
During pregnancy, a drug's pharmacokinetics may be altered and hence anticipation of potential systemic exposure changes is highly desirable. Physiologically based pharmacokinetics (PBPK) models have recently been used to influence clinical trial design or to facilitate regulatory interactions. Ideally, whole-body PBPK models can be used to predict a drug's systemic exposure in pregnant women based on major physiological changes which can impact drug clearance (i.e., in the kidney and liver) and distribution (i.e., adipose and fetoplacental unit). We described a simple and readily implementable multitissue/organ whole-body PBPK model with key pregnancy-related physiological parameters to characterize the PK of reference drugs (metformin, digoxin, midazolam, and emtricitabine) in pregnant women compared with the PK in nonpregnant or postpartum (PP) women. Physiological data related to changes in maternal body weight, tissue volume, cardiac output, renal function, blood flows, and cytochrome P450 activity were collected from the literature and incorporated into the structural PBPK model that describes HV or PP women PK data. Subsequently, the changes in exposure (area under the curve (AUC) and maximum concentration (C max)) in pregnant women were simulated. Model-simulated PK profiles were overall in agreement with observed data. The prediction fold error for C max and AUC ratio (pregnant vs. nonpregnant) was less than 1.3-fold, indicating that the pregnant PBPK model is useful. The utilization of this simplified model in drug development may aid in designing clinical studies to identify potential exposure changes in pregnant women a priori for compounds which are mainly eliminated renally or metabolized by CYP3A4.


Assessment of single-dose benzodiazepines on insulin secretion, insulin sensitivity and glucose effectiveness in healthy volunteers: a double-blind, placebo-controlled, randomized cross-over trial [ISRCTN08745124].
The present study aimed at investigating in healthy volunteers the effects of diazepam and clonazepam on beta-cell function, insulin sensitivity and glucose effectiveness based on the frequently sampled intravenous (0.5 gkg-1) glucose tolerance test with minimal-model analysis. The study was designed as a double-blind, placebo-controlled, cross-over clinical trial. Diazepam (10 mg) and clonazepam (1 mg) were infused during 30 min to 15 male subjects with a mean age of 22 years (range: 20-29), after informed consent was given. Benzodiazepines were assayed by capillary gas chromatography with electron capture, insulin by radioimmunoassay and glucose by the enzymatic glucose oxidase method. Both benzodiazepines induced significant psychotropic effects. The acute insulin responses (AIR) were significantly and negatively correlated with the clonazepam plasma concentrations (r = -0.609, P < 0.05, n = 14). However, the mean AIR was not significantly different between the benzodiazepine-treated subjects and the controls. In addition, the parameters of glucose assimilation were significantly decreased as compared with placebo in the subgroup of 7 subjects with plasma clonazepam concentrations higher than 6.0 ng ml-1 (median and lower limit of effective therapeutic concentrations): 1.37 +/- 0.3 versus 2.84 +/- 0.60 x 10(-2)min-1 (P = 0.028) for the coefficient of glucose tolerance (Kg), 2.18 +/- 0.29 versus 3.71 +/- 0.89 x 10(-4)microUml-1min-1 (P = 0.018) for insulin sensitivity (Si) and 1.80 +/- 0.39 versus 3.59 +/- 0.71 x 10(-2)min-1 (P = 0.028) for glucose effectiveness at basal insulin (Sg). These parameters were not significantly modified when diazepam was administered; plasma levels of this drug however, were below the effective therapeutic concentrations (300 ng ml-1) from min 15 after the end of the perfusion. The present results suggest that a benzodiazepine, in particular clonazepam, may alter insulin secretion and insulin sensitivity after a single administration in healthy volunteers.


How important are rats as vectors of leptospirosis in the Mekong Delta of Vietnam?
Leptospirosis is a zoonosis known to be endemic in the Mekong Delta of Vietnam, even though clinical reports are uncommon. We investigated leptospira infection in rats purchased in food markets during the rainy season (October) (n=150), as well as those trapped during the dry season (February-March) (n=125) in the region using RT-PCR for the lipL32 gene, confirmed by 16S rRNA, as well as by the microscopic agglutination test (MAT). Results were compared with the serovar distribution of human cases referred from Ho Chi Minh City hospitals (2004-2012) confirmed by MAT (n=45). The MAT seroprevalence among rats was 18.3%. The highest MAT seroprevalence corresponded, in decreasing order, to: Rattus norvegicus (33.0%), Bandicota indica (26.5%), Rattus tanezumi (24.6%), Rattus exulans (14.3%), and Rattus argentiventer (7.1%). The most prevalent serovars were, in descending order: Javanica (4.6% rats), Lousiana (4.2%), Copenageni (4.2%), Cynopterie (3.7%), Pomona (2.9%), and Icterohaemorrhagiae (2.5%). A total of 16 rats (5.8%) tested positive by RT-PCR. Overall, larger rats tended to have a higher prevalence of detection. There was considerable agreement between MAT and PCR (kappa=0.28 [0.07-0.49]), although significantly more rats were positive by MAT (McNemar 29.9 (p<0.001). MAT prevalence was higher among rats during the rainy season compared with rats in the dry season. There are no current available data on leptospira serovars in humans in the Mekong Delta, although existing studies suggest limited overlapping between human and rat serovars. Further studies should take into account a wider range of potential reservoirs (i.e., dogs, pigs) as well as perform geographically linked co-sampling of humans and animals to establish the main sources of leptospirosis in the region.


Sigma 1 receptor: A novel therapeutic target in retinal disease.
Retinal degenerative diseases are major causes of untreatable blindness worldwide and efficacious treatments for these diseases are sorely needed. A novel target for treatment of retinal disease is the transmembrane protein Sigma 1 Receptor (Sig1R). This enigmatic protein is an evolutionary isolate with no known homology to any other protein. Sig1R was originally thought to be an opioid receptor. That notion has been dispelled and more recent pharmacological and molecular studies suggest that it is a pluripotent modulator with a number of biological functions, many of which are relevant to retinal disease. This review provides an overview of the discovery of Sig1R and early pharmacologic studies that led to the cloning of the Sig1R gene and eventual elucidation of its crystal structure. Studies of Sig1R in the eye were not reported until the late 1990s, but since that time there has been increasing interest in the potential role of Sig1R as a target for retinal disease. Studies have focused on elucidating the mechanism(s) of Sig1R function in retina including calcium regulation, modulation of oxidative stress, ion channel regulation and molecular chaperone activity. Mechanistic studies have been performed in isolated retinal cells, such as Müller glial cells, microglial cells, optic nerve head astrocytes and retinal ganglion cells as well as in the intact retina. Several compelling studies have provided evidence of powerful in vivo neuroprotective effects against ganglion cell loss as well as photoreceptor cell loss. Also described are studies that have examined retinal structure/function in various models of retinal disease in which Sig1R is absent and reveal that these phenotypes are accelerated compared to retinas of animals that express Sig1R. The collective evidence from analysis of studies over the past 20 years is that Sig1R plays a key role in modulating retinal cellular stress and that it holds great promise as a target in retinal neurodegenerative disease.


A regulatory SNP causes a human genetic disease by creating a new transcriptional promoter.
We describe a pathogenetic mechanism underlying a variant form of the inherited blood disorder alpha thalassemia. Association studies of affected individuals from Melanesia localized the disease trait to the telomeric region of human chromosome 16, which includes the alpha-globin gene cluster, but no molecular defects were detected by conventional approaches. After resequencing and using a combination of chromatin immunoprecipitation and expression analysis on a tiled oligonucleotide array, we identified a gain-of-function regulatory single-nucleotide polymorphism (rSNP) in a nongenic region between the alpha-globin genes and their upstream regulatory elements. The rSNP creates a new promoterlike element that interferes with normal activation of all downstream alpha-like globin genes. Thus, our work illustrates a strategy for distinguishing between neutral and functionally important rSNPs, and it also identifies a pathogenetic mechanism that could potentially underlie other genetic diseases.


Glycogen: the forgotten cerebral energy store.
The brain contains a significant amount of glycogen that is an order of magnitude smaller than that in muscle, but several-fold higher than the cerebral glucose content. Although the precise role of brain glycogen to date is unknown, it seems affected by focal activation, neurotransmitters, and overall electrical activity and hormones. Based on its relatively low concentration, the role of brain glycogen as a significant energy store has been discounted. This work reviews recent experimental evidence that brain glycogen is an important reserve of glucose equivalents: (1) glial glycogen can provide the majority of the glucose supply deficit during hypoglycemia for more than 100 min, consistent with the proposal that glial lactate is a fuel for neurons; (2) glycogen concentrations may be as high as 10 micromol/g, substantially higher than was thought previously; (3) glucose cycling in and out of glycogen amounts to approximately 1% of the cerebral metabolic rate of glucose (CMRglc) in human and rat brain, amounting to an effective stability of glycogen in the resting awake brain during euglycemia and hyperglycemia, (4) brain glycogen metabolism/concentrations are insulin/glucose sensitive; and (5) after a single episode of hypoglycemia, brain glycogen levels rebound to levels that exceed the pre-hypoglycemic concentrations (supercompensation). This experimental evidence supports the proposal that brain glycogen may be involved in the development of diabetes complications, specifically impaired glucose sensing (hypoglycemia unawareness) observed clinically in some diabetes patients under insulin treatment. It is proposed further that brain glycogen becomes important in any metabolic state where supply transiently cannot meet demand, such conditions that could occur during prolonged focal activation, sleep deprivation, seizures, and mild hypoxia.


Air temperature exposure and outdoor occupational injuries: a significant cold effect in Central Italy.
To investigate the short-term effect of air temperature on outdoor occupational injuries (out_OI) in Central Italy, also by taking different geographical factors and employment sectors of workers into account. Out_OI for all of Tuscany (Central Italy), from 2003 to 2010 (n=162,399), were provided by the National Institute of Insurance for Occupational Illness and Injury. Representative daily meteorological data of the geographical area under study were obtained from the European Reanalysis-interim climatological reanalysis archive. Relationships between short-term changes in air temperature and out_OI were studied through Generalised Additive Models. The exposure-response curves of out_OI and short-term changes in air temperature generally showed significant out_OI increases when cold conditions occurred. The air temperature breakpoint corresponded to the 10th centile (-0.8°C) of the air temperature time series used in this study: a 1°C decrease in temperature below the 10th centile corresponded to a 2.3% (CI 1.3% to 3.3%) increase of out_OI throughout all of Tuscany. The cold effect was strongest in plain areas, especially when out_OI occurred in vehicles other than cars. No relationships of injuries with temperature extremes were observed in workers who generally spend half or most of their time outdoors, such as construction, land and forestry workers. However, these latter outdoor workers showed significant linear associations of injuries with typical (far-from-extreme) temperatures. This large population-based study highlights the significant and independent effects of short-term air temperature changes (especially cold) in triggering out_OI. These findings represent the first step towards developing a geographically differentiated, operative outdoor-temperature-occupational-health warning system aimed at preventing outdoor work injuries.


Brief communication: foramen magnum-carotid foramina relationship: is it useful for species designation?
The anterior placement of the foramen magnum is often used to indicate bipedalism and therefore to distinguish hominid from nonhominid fossils. Often, only fragmentary cranial remains are found, and the placement of the foramen magnum must be determined by its relationship to another landmark. The purpose of this study was to test if hominid crania could be distinguished from nonhominid crania based on the relationship between the foramen magnum and the carotid foramina, and therefore to determine if the carotid foramina can be used to determine the anteriorness of the foramen magnum. The samples consisted of 16 modern human crania and 19 modern chimpanzee (Pan troglodytes) crania. Linear measurements were taken of (1) the distance from the anterior border of the foramen magnum to a chord connecting the carotid foramina and (2) total cranial length. An index of the distance of the foramen magnum from the bicarotid chord as a proportion of total cranial length was calculated to control for differences due to body size. Results indicate that on average, human crania can be distinguished from chimpanzee crania by using either (1) the distance of the foramen magnum from the bicarotid chord as a linear measurement or (2) this linear measurement as a proportion of total cranial length. Both measures are significantly smaller in the human sample; however, there was considerable overlap between species, indicating that the distance of the foramen magnum from the bicarotid chord is not a certain indicator for individual specimens.


Association between vitamin C intake and the risk of pancreatic cancer: a meta-analysis of observational studies.
Quantification of the association between the intake of vitamin C and risk of pancreatic cancer is still conflicting. We therefore conducted a meta-analysis to assess the association between them. Pertinent studies were identified by a search of PubMed and Web of Knowledge throughSeptember of 2014. A random effects model was used to combine the data for analysis. Sensitivity analysis and publication bias were conducted. Data from 17 studies including 4827 pancreatic cancer cases were used in this meta-analysis. Pooled results suggested that highest vitamin C intake amount versus lowest amount was significantlyassociated with reduced the risk of pancreatic cancer [summary relative risk (RR) = 0.705, 95% CI = 0.612-0.811, I(2) = 42.3%]. The associations were also significant both in Caucasian [summary RR = 0.741, 95% CI = 0.626-0.876], Asian [summary RR = 0.455, 95% CI = 0.275-0.754] and Mixed population [summary RR = 0.677, 95% CI = 0.508-0.901]. No publication bias was found. Our analysis suggested that the higher intake of vitamin C might reduce the risk of pancreatic cancer.


Public health and medical care for the world's factory: China's Pearl River Delta Region.
While the growth of urbanization, worldwide, has improved the lives of migrants from the hinterland, it also raises health risks related to population density, concentrated poverty and the transmission of infectious disease. Will megacity regions evolve into socially infected breeding grounds for the rapid transmission of disease, or can they become critical spatial entities for the protection and promotion of population health? We address this question for the Pearl River Delta Region (PRD) based on recent data from Chinese sources, and on the experience of how New York, Greater London, Tokyo and Paris have grappled with the challenges of protecting population health and providing their populations with access to health care services. In some respects, there are some important lessons from comparative experience for PRD, notably the importance of covering the entire population for health care services and targeting special programs for those at highest risk for disease. In other respects, PRD's growth rate and sheer scale make it a unique megacity region that already faces new challenges and will require new solutions.


Visual evoked potentials in multiple sclerosis before and after two years of interferon therapy.
Magnetic resonance imaging (MRI) is important in the diagnosis of and follow-up for the treatment of multiple sclerosis (MS); evoked potentials may be important if MRI is normal or cannot be performed. We assessed serial visual evoked potentials (VEPs) and cranial MRI in a group of clinically relapsing-remitting multiple sclerosis (N = 15) treated with interferon beta-lb (INFB-1b) and in normal subjects (N = 15). The investigations were done 1 week before INFB-lb therapy, 1 year later (N = 15), and 2 years later (N = 10). VEPs were abnormal in most of the patients; MRIs were abnormal in all patients. We used P100 latency as an electrophysiological index for the progress of illness. There were significant differences in VEPs between the beginning and ending of the interferon treatment. We concluded that VEPs would be a reliable index for following up the progress of MS under interferon therapy.


Lung cancer in smelter workers--interactions of metals as indicated by tissue levels.
The concentrations of the elements antimony, arsenic, cadmium, chromium, cobalt, lanthanum, lead, selenium, and zinc were determined in lung tissue of 85 decreased smelter workers by neutron activation analysis and atomic absorption spectrophotometry. The concentrations of all these elements, except zinc, were significantly higher among the workers as compared with rural referents. Workers who died from lung cancer (N = 7) had the lowest lung selenium content relative to other metals, both compared with workers with other diseases and with rural (N = 15) and urban (N = 10) referents. The low lung tissue levels may have influenced the development of lung cancer. The highest lung cadmium concentrations were observed in the lung cancer group, in which, however, smokers and ex-smokers were over-represented. The observations make it likely that the excess lung cancer risk in this smelter environment is multifactorial in character, involving interactions between both carcinogenic and anticarcinogenic factors.


The gender responsiveness of social marketing interventions focused on neglected tropical diseases.
Background: Gender is a determinant of health that intersects with other social stratifiers to shape the health and well-being of populations. Despite the recognition of gender in the global health agenda, limited evidence exists about the integration of gender considerations in interventions, including social marketing interventions, for the prevention and control of neglected tropical diseases. Social marketing is an ethical approach to behavior change aiming to benefit individuals, communities, and society. Since behaviors are gendered and affect disease transmission and healthcare patterns, one would expect social marketing interventions to be gender responsive.Objective: This study aims to understand the extent to which social marketing interventions focusing on neglected tropical diseases are gender responsive.Methods: This study uses data from social marketing interventions collected in a systematic review, this study examined 20 interventions addressing eight neglected tropical diseases in 13 countries. A modified version of the World Health Organization Gender Assessment Tool (GAT) was used to determine the gender responsiveness of the interventions, which was complemented by coding for intersectional sex and gender data. These results are presented in 12 themes.Results: One schistosomiasis intervention implemented in China was assessed as gender responsive. It was not possible to answer many questions from the GAT due to limited data reported in the publications describing the interventions. Despite this, strengths and limitations were found in all the interventions in relation to the use of sex and gender concepts, the disaggregation of data, the consideration of environmental factors, and the involvement of women or men in the different stages of the interventions.Conclusions: Many interventions showed positive actions towards gender responsiveness. However, only one was classified as gender responsive. Others failed to supply enough data for assessment. Recommendations about how sex and gender could be integrated into social marketing interventions are provided.


[Prognosis of chronic renal failure in patients with membranous nephropathy].
Two hundred eighty patients underwent renal biopsy during the period of 1995-1999 in five nephrological centers of Lithuania. All renal biopsies materials were examined in the State Center of Pathology. In 20 patients (7.1%) membranous nephropathy was found. The main clinical presentation at the moment of renal biopsy were nephrotic syndrome (55%) and arterial hypertension (55%). Glomerulosclerosis was found in 30% of patients, interstitial fibrosis--in 40% of patients. The results of analysis showed multiple risk factors for renal failure progression: initial renal failure (p=0.000), systolic and diastolic hypertension (p=0.009 and p=0.009), proteinuria (=1 g/l, =3 g/l) (p=0.026). Membranous nephropathy was found to have a relatively good long-term prognosis - the renal survival rate in 5 years was 84.2%. Kaplan-Meier survival analysis showed that initial renal failure was risk factor (logrank p=0.018, Breslov p=0.032) associated with development of end-stage renal disease in 5 years.


Effects of garage employment and tobacco smoking on breathing-zone concentrations of carbonyl compounds.
Exposure to carbonyl compounds may cause adverse health effects. The present study examined whether working in a garage and smoking can significantly affect personal "daily" exposure to a number of important carbonyl compounds. The study was carried out on 37 subjects including 22 garage workers (9 smokers and 13 nonsmokers) and 15 nongarage workers or so-called controls (4 smokers and 11 nonsmokers). Daily exposure was estimated using 48-hour integrated measurement of breathing-zone concentrations. The measurement involved the use of a passive carbonyl sampler and high performance liquid chromatography/fluorescence analysis technique. Each subject was measured for up to three measurement sessions. A wide range of breathing-zone concentrations (unit: microgram per cubic meter) was observed for each of the following carbonyls: formaldehyde (14.1-80.1); acetaldehyde (8.41-80.3); acetone (0.65-1096); acrolein (<0.14-3.71); propionaldehyde (1.08-14.6); crotonaldehyde (<0.13-2.80); benzaldehyde (1.79-9.91); and hexaldehyde (0.122-22.4). Statistical significance of smoking effects and working in a garage effects were assessed using SAS mixed models. The results show that the garage workers had significantly higher levels of formaldehyde and acetaldehyde than the controls, and that the smokers had significantly higher levels of acetaldehyde, propionaldehyde, and hexaldehyde, than the nonsmokers (P<.10). Garage employment and smoking appeared to increase breathing-zone concentrations of crotonaldehyde. In general, within-subject variations were smaller than between-subject variations on 48-hour averaged breathing-zone concentrations of carbonyl compounds.