Mortality in Multicenter Critical Care Trials: An Analysis of Interventions With a Significant Effect.
We aimed to identify all treatments that affect mortality in adult critically ill patients in multicenter randomized controlled trials. We also evaluated the methodological aspects of these studies, and we surveyed clinicians' opinion and usual practice for the selected interventions. MEDLINE/PubMed, Scopus, and Embase were searched. Further articles were suggested for inclusion from experts and cross-check of references. We selected the articles that fulfilled the following criteria: publication in a peer-reviewed journal; multicenter randomized controlled trial design; dealing with nonsurgical interventions in adult critically ill patients; and statistically significant effect in unadjusted landmark mortality. A consensus conference assessed all interventions and excluded those with lack of reproducibility, lack of generalizability, high probability of type I error, major baseline imbalances between intervention and control groups, major design flaws, contradiction by subsequent larger higher quality trials, modified intention to treat analysis, effect found only after adjustments, and lack of biological plausibility. For all selected studies, we recorded the intervention and its comparator, the setting, the sample size, whether enrollment was completed or interrupted, the presence of blinding, the effect size, and the duration of follow-up. We found 15 interventions that affected mortality in 24 multicenter randomized controlled trials. Median sample size was small (199 patients) as was median centers number (10). Blinded trials enrolled significantly more patients and involved more centers. Multicenter randomized controlled trials showing harm also involved significantly more centers and more patients (p = 0.016 and p = 0.04, respectively). Five hundred fifty-five clinicians from 61 countries showed variable agreement on perceived validity of such interventions. We identified 15 treatments that decreased/increased mortality in critically ill patients in 24 multicenter randomized controlled trials. However, design affected trial size and larger trials were more likely to show harm. Finally, clinicians view of such trials and their translation into practice varied.


The Impact of Lifetime Victimization and Polyvictimization on Adolescents in Québec: Mental Health Symptoms and Gender Differences.
This study documents lifetime experiences of victimizations, polyvictimization, and trauma symptoms among 1,400 adolescents from the province of Québec. The vast majority (81%) of adolescents were victimized during their lifetime, with most victims (82%) being the target of more than one form of victimization. Polyvictimization accounted for most variability in scores of depression, posttraumatic stress disorder (PTSD), and anger/ aggression compared to individual victimization categories. Sexual victimization and maltreatment still made an independent contribution in predicting all trauma scores once polyvictimization was considered. Gender differences were found in the victimization experiences contributing to the prediction of mental health symptoms. Sexual victimization was a significant predictor of PTSD and anger/aggression symptoms for girls, whereas witnessing violence predicted anger and PTSD symptoms for boys, and assault predicted their anger. This study outlines the importance of assessing various types of victimization among adolescents. Systematic data and observation of trends on child victimization are needed in Canada and elsewhere.


Regeneration, repair and remembering identity: the three Rs of Hox gene expression.
Hox genes encode transcription factors that specify embryonic positional identity in cells and guide tissue differentiation. Recent advances have greatly increased our understanding of the epigenetic mechanisms that ensure the faithful expression of Hox genes in adult cells and which involve the interplay of histone methylation, demethylation and intergenic transcription of long non-coding RNAs. The transcriptional memory of Hox genes poses both an opportunity and a challenge for regenerative medicine. Matching the positional identity of transplanted stem cells with that of the host environment, as reflected by their respective Hox profiles, is likely to be required to achieve regenerative healing. Strategies to manipulate the plasticity of Hox gene expression will probably become a major focus in regenerative medicine.


Crystallization and preliminary X-ray diffraction studies of the quorum-sensing regulator TraM from Agrobacterium tumefaciens.
TraM is a 11.4 kDa protein involved in the control of the conjugal transfer of Agrobacterium tumefaciens Ti plasmids by quorum-sensing. TraM was overexpressed and purified from Escherichia coli. This protein binds to the transcriptional regulator TraR, abolishing its function. Size-exclusion chromatography and dynamic light scattering show that the recombinant protein has an apparent molecular weight of 30 kDa in solution. Crystals have been obtained of both native and selenomethionine-substituted TraM by the vapour-diffusion method. Crystals diffract to 1.67 A and belong to the space group P2(1)2(1)2, with unit-cell parameters a = 76.43, b = 47.09, c = 47.46 A and two molecules in the asymmetric unit. A two-wavelength MAD data set for the selenomethionine-substituted form has been collected to a resolution of 2.0 A. The selenium substructure (five out of six possible sites) has been solved using direct methods.


Genetics and pharmacogenetics in heart failure.
Heart failure is a heterogeneous disease, the development and pathophysiology of which involves complex interactions between genetic and environmental factors. It is well known that there are several heritable forms of heart failure in which genetic variation makes an individual more likely to develop the disease; however, less is clear about the degree to which genetics plays a role in the pathogenesis of more classic forms of heart failure. Several studies have been performed in patients with heart failure to determine the influence of modifier genes on exercise capacity, cardiovascular and pulmonary function, and outcomes, including survival. Given the variability in the response to pharmacologic treatment in patients with heart failure, there is an emerging interest in the optimal pharmacologic intervention for a given genotype in patients with heart failure. This review focuses primarily on several modifier genes, principally those associated with regulation of the adrenergic and rennin-angiotensin-aldosterone systems and those important to vascular control in heart failure, as well as the impact of these genes in the response to treatment.


Glutamate biosensors based on diamond and graphene platforms.
l-Glutamate is one of the most important neurotransmitters in the mammalian central nervous system, playing a vital role in many physiological processes and implicated in several neurological disorders, for which monitoring of dynamic levels of extracellular glutamate in the living brain tissues may contribute to medical understanding and treatments. Electrochemical sensing of glutamate has been developed recently mainly using platinum, carbon fibre and carbon nanotube electrodes. In the present work, we explore the fabrication and properties of electrochemical glutamate sensors fabricated on doped chemical vapour deposition diamond electrodes and graphene nanoplatelet structures. The sensors incorporate platinum nanoparticles to catalyse the electrooxidation of hydrogen peroxide, glutamate oxidase to oxidise glutamate, and a layer of poly-phenylenediamine to impart selectivity. The performance of the devices was compared to a similar sensor fabricated on glassy carbon. Both the diamond and the graphene sensor showed very competitive performance compared to the majority of existing electrochemical sensors. The graphene based sensor showed the best performance of the three investigated in terms of sensitivity, linear dynamic range and long term stability, whereas it was found that the diamond device showed the best limit of detection.


Bisphosphonates and other bone agents for breast cancer.
Bone is the most common site of metastatic disease associated with breast cancer (BC). Bisphosphonates inhibit osteoclast-mediated bone resorption, and novel targeted therapies such as denosumab inhibit other key bone metabolism pathways. We have studied these agents in both early breast cancer and advanced breast cancer settings. This is an update of the review originally published in 2002 and subsequently updated in 2005 and 2012. To assess the effects of bisphosphonates and other bone agents in addition to anti-cancer treatment: (i) in women with early breast cancer (EBC); (ii) in women with advanced breast cancer without bone metastases (ABC); and (iii) in women with metastatic breast cancer and bone metastases (BCBM). In this review update, we searched Cochrane Breast Cancer's Specialised Register, CENTRAL, MEDLINE, Embase, the World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov on 19 September 2016. We included randomised controlled trials (RCTs) comparing: (a) one treatment with a bisphosphonate/bone-acting agent with the same treatment without a bisphosphonate/bone-acting agent; (b) treatment with one bisphosphonate versus treatment with a different bisphosphonate; (c) treatment with a bisphosphonate versus another bone-acting agent of a different mechanism of action (e.g. denosumab); and (d) immediate treatment with a bisphosphonate/bone-acting agent versus delayed treatment of the same bisphosphonate/bone-acting agent. Two review authors independently extracted data, and assessed risk of bias and quality of the evidence. The primary outcome measure was bone metastases for EBC and ABC, and a skeletal-related event (SRE) for BCBM. We derived risk ratios (RRs) for dichotomous outcomes and the meta-analyses used random-effects models. Secondary outcomes included overall survival and disease-free survival for EBC; we derived hazard ratios (HRs) for these time-to-event outcomes where possible. We collected toxicity and quality-of-life information. GRADE was used to assess the quality of evidence for the most important outcomes in each treatment setting. We included 44 RCTs involving 37,302 women.In women with EBC, bisphosphonates were associated with a reduced risk of bone metastases compared to placebo/no bisphosphonate (RR 0.86, 95% confidence interval (CI) 0.75 to 0.99; P = 0.03, 11 studies; 15,005 women; moderate-quality evidence with no significant heterogeneity). Bisphosphonates provided an overall survival benefit with time-to-event data (HR 0.91, 95% CI 0.83 to 0.99; P = 0.04; 9 studies; 13,949 women; high-quality evidence with evidence of heterogeneity). Subgroup analysis by menopausal status showed a survival benefit from bisphosphonates in postmenopausal women (HR 0.77, 95% CI 0.66 to 0.90; P = 0.001; 4 studies; 6048 women; high-quality evidence with no evidence of heterogeneity) but no survival benefit for premenopausal women (HR 1.03, 95% CI 0.86 to 1.22; P = 0.78; 2 studies; 3501 women; high-quality evidence with no heterogeneity). There was evidence of no effect of bisphosphonates on disease-free survival (HR 0.94, 95% 0.87 to 1.02; P = 0.13; 7 studies; 12,578 women; high-quality evidence with significant heterogeneity present) however subgroup analyses showed a disease-free survival benefit from bisphosphonates in postmenopausal women only (HR 0.82, 95% CI 0.74 to 0.91; P < 0.001; 7 studies; 8314 women; high-quality evidence with no heterogeneity). Bisphosphonates did not significantly reduce the incidence of fractures when compared to placebo/no bisphosphonates (RR 0.77, 95% CI 0.54 to 1.08, P = 0.13, 6 studies, 7602 women; moderate-quality evidence due to wide confidence intervals). We await mature overall survival and disease-free survival results for denosumab trials.In women with ABC without clinically evident bone metastases, there was no evidence of an effect of bisphosphonates on bone metastases (RR 0.96, 95% CI 0.65 to 1.43; P = 0.86; 3 studies; 330 women; moderate-quality evidence with no heterogeneity) or overall survival (RR 0.89, 95% CI 0.73 to 1.09; P = 0.28; 3 studies; 330 women; high-quality evidence with no heterogeneity) compared to placebo/no bisphosphonates however the confidence intervals were wide. One study reported a trend towards an extended period of time without a SRE with bisphosphonate compared to placebo (low-quality evidence). One study reported quality of life and there was no apparent difference in scores between bisphosphonate and placebo (moderate-quality evidence).In women with BCBM, bisphosphonates reduced the SRE risk by 14% (RR 0.86, 95% CI 0.78 to 0.95; P = 0.003; 9 studies; 2810 women; high-quality evidence with evidence of heterogeneity) compared with placebo/no bisphosphonates. This benefit persisted when administering either intravenous or oral bisphosphonates versus placebo. Bisphosphonates delayed the median time to a SRE with a median ratio of 1.43 (95% CI 1.29 to 1.58; P < 0.00001; 9 studies; 2891 women; high-quality evidence with no heterogeneity) and reduced bone pain (in 6 out of 11 studies; moderate-quality evidence) compared to placebo/no bisphosphonate. Treatment with bisphosphonates did not appear to affect overall survival (RR 1.01, 95% CI 0.91 to 1.11; P = 0.85; 7 studies; 1935 women; moderate-quality evidence with significant heterogeneity). Quality-of-life scores were slightly better with bisphosphonates than placebo at comparable time points (in three out of five studies; moderate-quality evidence) however scores decreased during the course of the studies. Denosumab reduced the risk of developing a SRE compared with bisphosphonates by 22% (RR 0.78, 0.72 to 0.85; P < 0.001; 3 studies, 2345 women). One study reported data on overall survival and observed no difference in survival between denosumab and bisphosphonate.Reported toxicities across all settings were generally mild. Osteonecrosis of the jaw was rare, occurring less than 0.5% in the adjuvant setting (high-quality evidence). For women with EBC, bisphosphonates reduce the risk of bone metastases and provide an overall survival benefit compared to placebo or no bisphosphonates. There is preliminary evidence suggestive that bisphosphonates provide an overall survival and disease-free survival benefit in postmenopausal women only when compared to placebo or no bisphosphonate. This was not a planned subgroup for these early trials, and we await the completion of new large clinical trials assessing benefit for postmenopausal women. For women with BCBM, bisphosphonates reduce the risk of developing SREs, delay the median time to an SRE, and appear to reduce bone pain compared to placebo or no bisphosphonate.


For Motion Assistance Humans Prefer to Rely on a Robot Rather Than on an Unpredictable Human.
Objective: The last decades have seen a surge of robots for physical training and work assistance. How to best control these interfaces is unknown, although arguably the interaction should be similar to human movement assistance. Methods: We compare the behaviour and assessment of subjects tracking a moving target with assistance from (i) trajectory guidance (as typically used in robots for physical training), (ii) a human partner, and (iii) the reactive robot partner of Takagi et al. Results: Trajectory guidance was recognised as robotic, while the robot partner was felt as human-like. However, trajectory guidance was preferred to assistance from a human partner, which was recognised as less predictable. The robot partner also was felt to be more predictable and helpful than a human partner, and was preferred. Conclusions: While subjects like to rely on predictable interaction, such as in trajectory guidance, the control reactivity of the robot partner is essential for perceiving an interaction as human-like.


The interaction between a non-pathogenic and a pathogenic strain synergistically enhances extra-intestinal virulence in Escherichia coli.
Finding two or more genotypes of a single species within an infected sample is a not infrequent event. In this work, three Escherichia coli strains of decreasing extra-intestinal virulence (pathogenic B2S and B1S strains, and the avirulent K-12 MG1655 strain) were tested in septicaemia and urinary tract infection (UTI) mouse models, either separately or in pairs. Survival was monitored and bacteria were counted in various organs. Serum interleukin (IL)-6, tumour necrosis factor alpha (TNFα) and IL-10 were measured. We show that a mix of high amounts of B1S or of MG1655 with low amounts of B2S killed more rapidly (B1S), or killed more mice (MG1655), than either high amounts of B1S, high amounts of MG1655 or low amounts of B2S separately in the mouse septicaemia model. This bacterial synergy persisted when high amounts of dead or abnormal-LPS K-12 cells were injected together with a low amount of B2S. In both septicaemia and UTI models, significantly more bacteria were recovered from the organs of mice injected with the MG1655/B2S mix than from those of mice injected with the inocula separately. Consistently, in the septicaemia model, more IL-6 was secreted before death by the mice that were injected with the mix of bacteria than by the mice that were injected with the inocula separately. The synergistically enhanced mortality in the case of co-infection in the septicaemia model persisted in RFcγ(-/-), Myd88(-/-) and IL-6(-/-) knockout mice. This synergistically increased virulence resulting from the interaction between an avirulent and a pathogenic strain of the same bacterial species raises questions about the role of avirulent bacteria in the development of some extra-intestinal infections.


Pharmaceutical Characterization of Tropomyosin Receptor Kinase B-Agonistic Antibodies on Human Induced Pluripotent Stem (hiPS) Cell-Derived Neurons.
Brain-derived neurotrophic factor (BDNF) is a central modulator of neuronal development and synaptic plasticity in the central nervous system. This renders the BDNF-modulated tropomyosin receptor kinase B (TrkB) a promising drug target to treat synaptic dysfunctions. Using GRowth factor-driven expansion and INhibition of NotCH (GRINCH) during maturation, the so-called GRINCH neurons were derived from human-induced pluripotent stem cells. These GRINCH neurons were used as model cells for pharmacologic profiling of two TrkB-agonistic antibodies, hereafter referred to as AB2 and AB20 In next-generation sequencing studies, AB2 and AB20 stimulated transcriptional changes, which extensively overlapped with BDNF-driven transcriptional modulation. In regard to TrkB phosphorylation, both AB2 and AB20 were only about half as efficacious as BDNF; however, with respect to the TrkB downstream signaling, AB2 and AB20 displayed increased efficacy values, providing a stimulation at least comparable to BDNF in respect to VGF transcription, as well as of AKT and cAMP response element-binding protein phosphorylation. In a complex structure of the TrkB-d5 domain with AB20, determined by X-ray crystallography, the AB20 binding site was found to be allosteric in regard to the BDNF binding site, whereas AB2 was known to act orthosterically with BDNF. In agreement with this finding, AB2 and AB20 acted synergistically at greater concentrations to drive TrkB phosphorylation. Although TrkB downstream signaling declined faster after pulse stimulation with AB20 than with AB2, AB20 restimulated TrkB phosphorylation more efficiently than AB2. In conclusion, both antibodies displayed some limitations and some benefits in regard to future applications as therapeutic agents.


Pharmacophoric modifications lead to superpotent αvβ3 integrin ligands with suppressed α5β1 activity.
The selective targeting of the αvβ3 integrin subtype without affecting the structurally closely related receptor α5β1 is crucial for understanding the details of their biological and pathological functions and thus of great relevance for diagnostic and therapeutic approaches in cancer treatment. Here, we present the synthesis of highly active RGD peptidomimetics for the αvβ3 integrin with remarkable selectivity against α5β1. Incorporation of a methoxypyridine building block into a ligand scaffold and variation of different functional moieties led to αvβ3-antagonistic activities in the low nanomolar or even subnanomolar range. Furthermore, docking studies were performed to give insights into the binding modes of the novel compounds. The presented library comprises powerful ligands for specific addressing and blocking of the αvβ3 integrin subtype, thereby representing privileged tools for integrin-based personalized medicine.


Crossing the transition chasm: experiences and recommendations for improving transitional care of young adults, parents and providers.
Transition from paediatric to adult healthcare has received little attention in the Netherlands. This study aimed to: (i) map experiences with the transfer to adult care of young adults with chronic conditions; and (ii) identify recommendations for transitional care of young adults, their parents and healthcare providers. Semi-structured interviews with 24 young adults after transfer (aged 15-22 years; diagnosed with haemophilia, diabetes mellitus, spina bifida, congenital heart disorders, cystic fibrosis, juvenile rheumatoid arthritis or sickle cell disease), 24 parents and 17 healthcare providers. Thematic analysis was performed. Only the haemophilia department offered a structured transition programme, most patients had not been prepared for transition. Experiences and views of patients, parents and professionals mainly overlapped and were condensed into four core themes. Two are related to moving to adult care: (1) 'leaving paediatric care is a logical step'. Leaving familiar surroundings was harder for parents than for young adults who displayed a positive 'wait-and-see' attitude; and (2) 'transition is complicated by cultural gaps between paediatric and adult services'. Young adults and parents felt lost after transfer and recommended their peers 'to be alert and involved'. Providers also recognized the cultural chasm between both services and worried about non-compliance, lost to follow-up and lack of independence. Two other themes indicated priorities for improvement: (3) 'better patient and parent preparation' for differences between healthcare settings and for new roles and responsibilities with respect to self-management; and (4) 'more collaboration and personal links' between paediatric and adult care providers. Action is required to cross the chasm between paediatric and adult-oriented care. Preparation for transition should start early and focus on strengthening adolescents' independency without undermining parental involvement. Building bridges between services, gaining trust and investing in new personal relations is a challenge for all parties involved: transition is about responding and bonding.


Phloem turgor and the regulation of sucrose loading in Ricinus communis L.
The influence of plant water relations on phloem loading was studied in Ricinus communis L. Phloem transport was maintained in response to bark incisions even at severe water deficits. Water stress was associated with a net increase in the solute content of the sieve tubes, which resulted in maintenance of a positive phloem turgor pressure Ψp. There was a significant increase in solute flux through the phloem with decreasing xylem water potential (Ψ). In addition, sugar uptake by leaf discs was examined in media adjusted to different water potentials with either sorbitol (a relatively impermeant solute) or ethylene glycol (a relatively permeant solute). The limitations in this experimental system are discussed. The results nevertheless indicated that sucrose uptake can be stimulated by a reduction in cell Ψp, but that it is little affected by cell Ψ or solute potential Ψs. On the basis of these data we suggest that sucrose loading is turgor-pressure dependent. This may provide the mechanism by which transport responds to changes in sink demand in the whole plant.


Zwitterionic chitosan derivative, a new biocompatible pharmaceutical excipient, prevents endotoxin-mediated cytokine release.
Chitosan is a cationic polymer of natural origin and has been widely explored as a pharmaceutical excipient for a broad range of biomedical applications. While generally considered safe and biocompatible, chitosan has the ability to induce inflammatory reactions, which varies with the physical and chemical properties. We hypothesized that the previously reported zwitterionic chitosan (ZWC) derivative had relatively low pro-inflammatory potential because of the aqueous solubility and reduced amine content. To test this, we compared various chitosans with different aqueous solubilities or primary amine contents with respect to the intraperitoneal (i.p.) biocompatibility and the propensity to induce pro-inflammatory cytokine production from macrophages. ZWC was relatively well tolerated in ICR mice after i.p. administration and had no pro-inflammatory effect on naïve macrophages. Comparison with other chitosans indicates that these properties are mainly due to the aqueous solubility at neutral pH and relatively low molecular weight of ZWC. Interestingly, ZWC had a unique ability to suppress cytokine/chemokine production in macrophages challenged with lipopolysaccharide (LPS). This effect is likely due to the strong affinity of ZWC to LPS, which inactivates the pro-inflammatory function of LPS, and appears to be related to the reduced amine content. Our finding warrants further investigation of ZWC as a functional biomaterial.


Azelaic acid 15% gel once daily versus twice daily in papulopustular rosacea.
Twice-daily azelaic acid (AzA) is the conventional regimen for papulopustular rosacea, but once-daily AzA may be equally effective, with greater convenience and dosing flexibility. In order to test this hypothesis, an exploratory study was conducted. The evaluable efficacy population of this 12-week double-blind, parallel-group study included 72 patients and the population that was used to report safety results included 92 patients. Baseline characteristics were comparable between the once-daily and twice-daily study groups. Evaluations were performed at baseline and at weeks 4, 8, and 12. No significant difference was found between the once-daily and twice-daily groups at the end of study therapy in mean investigator global assessment (IGA) scores, treatment success, or treatment response. The mean number of inflammatory lesions, the intensity of erythema intensity, and the intensity of telangiectasia at treatment end were likewise not significantly different (P>.205 for all). More than 90% of subjects in each group rated cosmetic acceptability of this AzA gel as satisfactory or better. Based on these findings and those of prior studies, once-daily AzA 15% gel can therefore be utilized as a safe, effective, and economical dosing option for the treatment of mild-to-moderate papulopustular rosacea. Once-daily dosing of AzA 15% gel was well accepted by patients and can offer considerable dosing flexibility and convenience for the patient as well as for the dermatologist.


[Predictors of compliance with highly active antiretroviral therapy in Brasília, Distrito Federal, Brazil, 1999-2000].
Non-compliance with highly active antiretroviral therapy can reduce treatment efficacy and lead to viral resistance. Side effects can interfere with patients' quality of life. Our objectives were to estimate levels of treatment compliance and investigate the main predictors of non-compliance. The study design was cross-sectional. For purposes of comparison, two different percentage cut-offs for compliance were defined for "proper compliance", namely the adequate ingestion of at least 80% or 95% of the prescribed medicines, respectively. Semi-structured interviews were performed in a sequential sample of 150 patients during out-patient visits to the Day Hospital in Central Brasilia. Mean compliance was 85.8%. Variables associated with non-compliance were age, schooling, employment status, monthly personal and family income, illegal substance use, family and community structure, presence of opportunistic infections when HIV was diagnosed, and treatment side effects. Prevalence ratios varied from 1.6 to 4.5. We conclude that social and economic variables, as well as those related to individual habits, were the main predictors of compliance. Few variables related to clinical status or treatment were associated with compliance.


Electronic and school-based victimization: unique contexts for adjustment difficulties during adolescence.
Previous research suggests that school-based and electronic victimization have similar negative consequences, yet it is unclear whether these two contexts offer overlapping or unique associations with adolescents' adjustment. 802 ninth-graders (43% male, mean age = 15.84 years), majority being Caucasian (82%), completed measures assessing the prevalence of school and electronic victimization, as well as self-reports on self-esteem, self-efficacy, anxiety, depressive symptoms, and locus of control. Results revealed that the majority of adolescents did not report being victimized in either the electronic (75.3%) or the school (72.9%) context. Victimization in both contexts was associated with lower self-esteem and self-efficacy as well as higher stress, anxiety, depressive symptoms, and locus of control. Importantly, even after controlling for school-based victimization, electronic victimization remained as a significant predictor for all outcome measures. Different types of electronic victimization were also associated with different psychological outcomes. The findings suggest that it is important to distinguish between victimization contexts and specific adjustment outcomes as school and health officials continue to battle the effects of peer victimization.


Randomised Controlled Trial Evaluating Active versus Passive Waiting for Speech-Language Pathology.
High demand for speech-language pathology means children sometimes wait over 12 months for services, missing out on timely support. Waiting can be a time of stress, concern, and powerlessness for caregivers. Provision of information via a website may support families and encourage active waiting. The aim of this study was to compare children's speech, intelligibility, language, and literacy outcomes, and caregivers' satisfaction and empowerment in active versus passive waiting conditions. Ninety-seven preschool-aged children referred to a community health speech-language pathology service in Australia were screened for eligibility. Eligible children (n =42) with speech/language difficulties were randomly allocated to: (a) active waiting (provision of a purpose-built website; n = 20), or (b) passive waiting (control group; n = 22). Pre- and post-assessments (after 6 months on a waiting list) were completed with children and caregivers by a speech-language pathologist blinded to group allocations. Intention to treat (n =36) and per-protocol analyses (n =30) were conducted to measure group differences in child and caregiver outcomes at post-assessment using one-way ANCOVA, controlling for baseline scores. There were no statistically significant differences between groups for children's speech, intelligibility, language, and literacy, or caregivers' empowerment and satisfaction. Children in both groups made minimal gains over 6 months. Provision of an active waiting website did not lead to statistically significant change in child or caregiver outcomes, and children in both groups made little progress over a 6-month period. Early speech-language pathology intervention delivered with appropriate dosage is needed to optimise children's outcomes. Until timely and effective speech-language pathology intervention can be provided for all who need it, provision of early assessments may be beneficial. There remains a need for effective ways to support children and families on waiting lists.


Histone deacetylase inhibitors augment antitumor efficacy of herpes-based oncolytic viruses.
Replication-conditional (oncolytic) mutants of herpes simplex virus (HSV), are considered promising therapeutic alternatives for human malignancies, and chemotherapeutic adjuvants are increasingly sought to augment their efficacy. Histone deacetylase (HDAC) inhibitors are a new class of antineoplastic agents because of their potent activity in growth arrest, differentiation, and apoptotic death of cancer cells. The ability of the HDAC inhibitors to upregulate exogenous transgene expression and inhibit interferon (IFN) responses prompted our exploration of their use in improving the antitumor efficacy of oncolytic HSV. We discovered that the yield of viral progeny increased significantly when cultured glioma cells were treated with HDAC inhibitors before viral infection. Valproic acid (VPA), a commonly used antiepileptic agent with HDAC inhibitory activity, proved most effective when used to treat glioma cells before viral infection, but not concomitantly with viral infection. Pretreatment with VPA inhibited the induction of several IFN-responsive antiviral genes, augmented the transcriptional level of viral genes, and improved viral propagation, even in the presence of type I IFNs. Moreover, VPA pretreatment improved the propagation and therapeutic efficacy of oncolytic HSV in a human glioma xenograft model in vivo. These findings indicate that HDAC inhibitors can improve the efficacy of tumor virotherapies.


School performance, psychiatric comorbidity, and healthcare utilization in pediatric multiple sclerosis: A nationwide population-based observational study.
Pediatric multiple sclerosis (MS) may hamper educational achievements due to psychiatric comorbidity and cognitive impairment. Our aims were to investigate school performance, psychiatric comorbidity, and healthcare utilization following pediatric MS and to differentiate between disability in MS and that arising from a non-brain-related chronic disease. We included all children (<18 years) with MS onset during 2008-2015 in Denmark with a medical record-validated MS diagnosis. The control groups were children from the general population or children with non-brain-related chronic diseases. Outcomes were register-based on 9-12 grade point average, psychiatric comorbidity, and healthcare visits. Cohorts were children with MS (n = 92), control children matched to children with MS (n = 920), children with non-brain-related chronic diseases (n = 9108), and "healthy" children with neither MS nor brain-related chronic disease (n = 811,464). School performance in grades 9-12 was similar, but children with MS compared to those with non-brain-related chronic disease had an almost doubled hazard for psychiatric comorbidity (hazard ratio = 1.87; 95% confidence interval = 1.38-2.53; p < 0.0001) and a higher rate of all hospital visits (p < 0.0001) but a lower rate of hospital admissions (p = 0.001). Children with MS have a seemingly standard school performance but increased psychiatric comorbidity and a high rate of healthcare utilization.


Pan-cancer analysis of the extent and consequences of intratumor heterogeneity.
Intratumor heterogeneity (ITH) drives neoplastic progression and therapeutic resistance. We used the bioinformatics tools 'expanding ploidy and allele frequency on nested subpopulations' (EXPANDS) and PyClone to detect clones that are present at a ≥10% frequency in 1,165 exome sequences from tumors in The Cancer Genome Atlas. 86% of tumors across 12 cancer types had at least two clones. ITH in the morphology of nuclei was associated with genetic ITH (Spearman's correlation coefficient, ρ = 0.24-0.41; P < 0.001). Mutation of a driver gene that typically appears in smaller clones was a survival risk factor (hazard ratio (HR) = 2.15, 95% confidence interval (CI): 1.71-2.69). The risk of mortality also increased when >2 clones coexisted in the same tumor sample (HR = 1.49, 95% CI: 1.20-1.87). In two independent data sets, copy-number alterations affecting either <25% or >75% of a tumor's genome predicted reduced risk (HR = 0.15, 95% CI: 0.08-0.29). Mortality risk also declined when >4 clones coexisted in the sample, suggesting a trade-off between the costs and benefits of genomic instability. ITH and genomic instability thus have the potential to be useful measures that can universally be applied to all cancers.


Obesity and psychological traits associated with eating disorders among Cypriot adolescents: comparison of 2003 and 2010 cohorts.
Increasing rates of overweight and eating disorders among young people are a concern. The aim of this study was to compare the prevalence of overweight/obesity among Cypriot adolescents between cohorts from 2003 and 2010 and to determine whether body mass index (BMI) was associated with psychological traits linked to eating disorders. Anthropometric measures were done on a representative sample of students aged 10-18 years and the Eating Disorder Inventory-3rd version (EDI-3) and 26-item Eating Attitudes Test (EAT-26) scales were completed by 13-18-year-olds. Mean waist circumference of the 2010 cohort of 10-18-year-olds was 3.6 cm higher in boys and 5.5 cm higher in girls than the 2003 cohort. Mean BMI was higher in 2010 only in the 16-18-year-old age group. More adolescents on the higher end of the weight spectrum had pathological scores n the eating disorder scales. Obesity and maladaptive eating attitudes are common in Cypriot adolescents.


Genome-wide association analysis of anti-TNF drug response in patients with rheumatoid arthritis.
Treatment strategies blocking tumour necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA). However, a significant subset of patients does not respond for unknown reasons. Currently, there are no means of identifying these patients before treatment. This study was aimed at identifying genetic factors predicting anti-TNF treatment outcome in patients with RA using a genome-wide association approach. We conducted a multistage, genome-wide association study with a primary analysis of 2 557 253 single-nucleotide polymorphisms (SNPs) in 882 patients with RA receiving anti-TNF therapy included through the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry and the database of Apotheekzorg. Linear regression analysis of changes in the Disease Activity Score in 28 joints after 14 weeks of treatment was performed using an additive model. Markers with p<10(-3) were selected for replication in 1821 patients from three independent cohorts. Pathway analysis including all SNPs with p<10(-3) was performed using Ingenuity. 772 markers showed evidence of association with treatment outcome in the initial stage. Eight genetic loci showed improved p value in the overall meta-analysis compared with the first stage, three of which (rs1568885, rs1813443 and rs4411591) showed directional consistency over all four cohorts studied. We were unable to replicate markers previously reported to be associated with anti-TNF outcome. Network analysis indicated strong involvement of biological processes underlying inflammatory response and cell morphology. Using a multistage strategy, we have identified eight genetic loci associated with response to anti-TNF treatment. Further studies are required to validate these findings in additional patient collections.


Pure single photon generation by type-I PDC with backward-wave amplification.
We explore a promising method of generating pure heralded single photons. Our approach is based on parametric down-conversion in a periodically-poled waveguide. However, unlike conventional downconversion sources, the photon pairs are counter-propagating: one travels with the pump beam in the forward direction while the other is backpropagating towards the laser source. Our calculations reveal that these downconverted two-photon states carry minimal spectral correlations within each photon-pair. This approach offers the possibility to employ a new range of downconversion processes and materials like PPLN (previously considered unsuitable due to its unfavorable phasematching properties) to produce heralded pure single photons over a broad frequency range.


Teratogenic evaluation of 2,4,5-T.
The herbicide 2,4,5-trichlorophenoxyacetic acid is teratogenic and fetocidal in two strains of mice when administered either subcutaneously or orally and in one strain of rats when administered orally. The incidences of both cystic kidney and cleft palate were increased in the C57BL/6 mice as well as the incidence of cleft palate in the AKR mice. The incidence of cystic kidney was also increased in the rats. In addition, an increase in the ratio of liver weight to body weight in the mouse fetus and the occurrence of hemorrhagic gastrointestinal tract in the rat fetus suggest that this compound also has fetotoxic properties.


Effects of prolonged administration of lovastatin, an inhibitor of cholesterol synthesis, on the morphology and function of rat Leydig cells.
We examined the effects of a prolonged treatment with lovastatin, a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, on the morphology and function of rat Leydig cells. Twenty-four h after the first lovastatin injection, no conspicuous ultrastructural changes were found, but isolated Leydig cells showed a notable reduction in their basal and HCG-stimulated testosterone production. By prolonging lovastatin administration (daily injections for 3 and 5 days), Leydig cells progressively recovered their secretory activity, and this was associated with a striking proliferation of smooth endoplasmic reticulum and peroxisomes. The hypothesis is discussed that these morphologic changes are the counterpart of an enhanced newly synthesis of HMG-CoA reductase, that is the expression of a compensatory response of Leydig cells aimed at maintaining an adequate production of cholesterol (i.e. testosterone precursors) in spite of the chronic competitive inhibition of HMG-CoA reductase by lovastatin.


The Affordable Care Act: overview and implications for county and city behavioral health and intellectual/developmental disability programs.
The author begins by reviewing the 5 key intended actions of the Affordable Care Act (ACA)-insurance reform, coverage reform, quality reform, performance reform, and information technology reform. This framework provides a basis for examining how populations served and service programs will change at the county and city levels as a result of the ACA, and how provider staff also will change over time as a result of these developments. The author concludes by outlining immediate next steps for county and city programs.


Advances in carnitine in chronic uremia.
Carnitine is a conditionally essential metabolite that plays a critical role in cell physiology. Carnitine is necessary for fatty acid transport to sites of beta-oxidation in the mitochondria, where it helps to prevent organic acid accumulation. Because of these key regulatory functions, carnitine represents a crucial determinant of mitochondrial energy metabolism, whose deficiency may lead to metabolic and clinical disturbances. Loss of carnitine through dialytic membranes occurs in maintenance hemodialysis, resulting in potential carnitine depletion and relative increments of esterified carnitine forms. Carnitine supplementation has been shown to counteract such alterations and may be associated with clinical benefit. In particular, carnitine supplementation in patients on hemodialysis may enhance response to erythropoietin, resulting in improved hematologic status. Carnitine was also reported to improve exercise tolerance and intradialytic symptoms. Carnitine supplementation may enhance insulin resistance, inflammatory and antioxidant status, protein balance, lipid profile, and cardiac function. Carnitine administration can be useful for selected patients on dialysis who do not adequately respond to standard therapy.


Identification of Multiple QTLs Linked to Neuropathology in the Engrailed-1 Heterozygous Mouse Model of Parkinson's Disease.
Motor symptoms in Parkinson's disease are attributed to degeneration of midbrain dopaminergic neurons (DNs). Heterozygosity for Engrailed-1 (En1), one of the key factors for programming and maintenance of DNs, results in a parkinsonian phenotype featuring progressive degeneration of DNs in substantia nigra pars compacta (SNpc), decreased striatal dopamine levels and swellings of nigro-striatal axons in the SwissOF1-En1+/- mouse strain. In contrast, C57Bl/6-En1+/- mice do not display this neurodegenerative phenotype, suggesting that susceptibility to En1 heterozygosity is genetically regulated. Our goal was to identify quantitative trait loci (QTLs) that regulate the susceptibility to PD-like neurodegenerative changes in response to loss of one En1 allele. We intercrossed SwissOF1-En1+/- and C57Bl/6 mice to obtain F2 mice with mixed genomes and analyzed number of DNs in SNpc and striatal axonal swellings in 120 F2-En1+/- 17 week-old male mice. Linkage analyses revealed 8 QTLs linked to number of DNs (p = 2.4e-09, variance explained = 74%), 7 QTLs linked to load of axonal swellings (p = 1.7e-12, variance explained = 80%) and 8 QTLs linked to size of axonal swellings (p = 7.0e-11, variance explained = 74%). These loci should be of prime interest for studies of susceptibility to Parkinson's disease-like damage in rodent disease models and considered in clinical association studies in PD.


[Accidents in delta sailing].
We interviewed a group of 259 deltasailors about their injuries which befell them in Switzerland during their sports activity. They reported on 257 incidents, 8% of which were contusions and 24% resulted in fractures. 70% of all injuries affected the arms or legs, whereas 30% were located on the head or trunk. An accident occurred far more often during the landing phase (72%) than at take-off (28%). The mean hospital stay was noticeably longer for injured women (15 days) than for men (8 days).


The efficacy of imiquimod 5% cream (Aldara® in the treatment of aural plaque in horses: a pilot open-label clinical trial.
Aural plaques affect at least 22% of horses and can be asymptomatic or cause ear sensitivity. Immunohistochemical and electron microscopy studies have shown a strong association between aural plaques and papilloma virus. The purpose of this study was to investigate the efficacy of imiquimod 5% cream, an immune response modifier with potent antiviral activity, in the treatment of equine aural plaques. Twenty-one horses were enrolled and 16 completed the study. Imiquimod 5% cream was applied three times a week, every other week. When both ears were affected only the worst affected ear was treated. Adverse effects in all horses included marked local inflammation, exudation and thick crust formation at the site of treatment and the adjacent skin. Removal of the crust before treatment was painful and required sedation in most horses. Complete resolution of lesions was noted in all horses immediately post-treatment and the long-term resolution rate was 87.5%. Duration of therapy ranged from 1.5 to 8 months (median: 2.9 mean: 3.5). All horses were followed-up for 12-22 months after treatment was discontinued and only two horses had a recurrence of lesions. Clinical signs related to the aural plaques prior to treatment were reported in 11 of 16 (68.8%) horses and included resistance to touching the ears and bridling. Complete resolution of these signs was reported by the owners in all of the horses followed-up for at least 12 months. In conclusion, the topical application of imiquimod 5% cream is an efficacious treatment for aural plaques in horses.


Conceptualization, Development and Psychometric Evaluations of a New Medication-Related Health Literacy Instrument: The Chinese Medication Literacy Measurement.
There is a need for valid and reliable instruments to focus on medication aspects of health literacy and help healthcare professionals address patients' barriers to medication use. This cross-sectional study describes the conceptualization, development, and psychometric properties of the first Chinese Medication Literacy Measurement (ChMLM) to assess the level of health literacy on medication use. The 17-item ChMLM (ChMLM-17) and its short form, 13-item ChMLM (ChMLM-13), consist of four sections (vocabulary, over-the-counter labels, prescription labels, and advertisements) to cover six domains of medication-related health literacy. Multistage stratified quota sampling was attempted to recruit a representative sample in Taiwan. Receiver operating characteristic curves were used to identify the cut-off point for differentiating high and low medication literacy. Psychometric analyses were performed (n = 1410) to assess the reliability and validity separately on all samples and sociodemographic subgroups. The 17- and 13-item versions both had high construct validity among all patients and patients with low medication literacy. The developed ChMLM-17 and ChMLM-13 is expected to help healthcare providers and researchers to accurately measure medication-related health literacy and improve medication use in the real-world practice.


Chinese Herbal Medicine Treatment Improves the Overall Survival Rate of Individuals with Hypertension among Type 2 Diabetes Patients and Modulates In Vitro Smooth Muscle Cell Contractility.
Type 2 diabetes (T2D) is a chronic, multifactorial, and metabolic disorder accounting for 90% diabetes cases worldwide. Among them, almost half of T2D have hypertension, which is responsible for cardiovascular disease, morbidity, and mortality in these patients. The Chinese herbal medicine (CHM) prescription patterns of hypertension individuals among T2D patients have yet to be characterized. This study, therefore, aimed to determine their prescription patterns and evaluate the CHM effect. A cohort of one million randomly sampled cases from the National Health Insurance Research Database (NHIRD) was used to investigate the overall survival rate of CHM users, and prescription patterns. After matching CHM and non-CHM users for age, gender and date of diagnosis of hypertension, 980 subjects for each group were selected. The CHM users were characterized with slightly longer duration time from diabetes to hypertension, and more cases for hyperlipidaemia. The cumulative survival probabilities were higher in CHM users than in non-CHM users. Among these top 12 herbs, Liu-Wei-Di-Huang-Wan, Jia-Wei-Xiao-Yao-San, Dan-Shen, and Ge-Gen were the most common herbs and inhibited in vitro smooth muscle cell contractility. Our study also provides a CHM comprehensive list that may be useful in future investigation of the safety and efficacy for individuals with hypertension among type 2 diabetes patients.


Strongly bound noncovalent (SO3)n:H2CO complexes (n = 1, 2).
The potential energy surfaces (PES) for the SO3:H2CO and (SO3)2:H2CO complexes were thoroughly examined at the MP2/aug-cc-pVDZ computational level. Heterodimers and trimers are held together primarily by SO chalcogen bonds, supplemented by weaker CHO and/or OC bonds. The nature of the interactions is probed by a variety of means, including electrostatic potentials, AIM, NBO, energy decomposition, and electron density redistribution maps. The most stable dimer is strongly bound, with an interaction energy exceeding 10 kcal mol(-1). Trimers adopt the geometry of the most stable dimer, with an added SO3 molecule situated so as to interact with both of the original molecules. The trimers are strongly bound, with total interaction energies of more than 20 kcal mol(-1). Most such trimers show positive cooperativity, with shorter SO distances, and three-body interaction energies of nearly 3 kcal mol(-1).


The molecular genetic basis of herbivory between butterflies and their host plants.
Interactions between herbivorous insects and their host plants are a central component of terrestrial food webs and a critical topic in agriculture, where a substantial fraction of potential crop yield is lost annually to pests. Important insights into plant-insect interactions have come from research on specific plant defences and insect detoxification mechanisms. Yet, much remains unknown about the molecular mechanisms that mediate plant-insect interactions. Here we use multiple genome-wide approaches to map the molecular basis of herbivory from both plant and insect perspectives, focusing on butterflies and their larval host plants. Parallel genome-wide association studies in the cabbage white butterfly, Pieris rapae, and its host plant, Arabidopsis thaliana, pinpointed a small number of butterfly and plant genes that influenced herbivory. These genes, along with much of the genome, were regulated in a dynamic way over the time course of the feeding interaction. Comparative analyses, including diverse butterfly/plant systems, showed a variety of genome-wide responses to herbivory, as well as a core set of highly conserved genes in butterflies as well as their host plants. These results greatly expand our understanding of the genomic causes and evolutionary consequences of ecological interactions across two of nature's most diverse taxa, butterflies and flowering plants.


Diffusive and quantum effects of water properties in different states of matter.
The enthalpy, entropy, and free energy of water are important physical quantities for understanding many interesting phenomena in biological systems. However, conventional approaches require different treatments to incorporate quantum and diffusive effects of water in different states of matter. In this work, we demonstrate the use of the two-phase thermodynamic (2PT) model as a unified approach to obtain the properties of water over the whole phase region of water from short (∼20 ps) classical molecular dynamics trajectories. The 2PT model provides an effective way to separate the diffusive modes (gas-like component) from the harmonic vibrational modes (solid-like component) in the vibrational density of states (DoS). Therefore, both diffusive and quantum effect can be properly accounted for water by applying suitable statistical mechanical weighting functions to the DoS components. We applied the 2PT model to systematically examine the enthalpy, entropy, and their temperature dependence of five commonly used rigid water models. The 2PT results are found to be consistent with those obtained from more sophisticated calculations. While the thermodynamic properties determined from different water models are largely similar, the phase boundary determined from the equality of free energy is very sensitive to the small inaccuracy in the values of enthalpy and absolute entropy. The enthalpy, entropy, and diffusivity of water are strongly interrelated, which challenge further improvement of rigid water model via parameter fitting. Our results show that the 2PT is an efficient method for studying the properties of water under various chemical and biological environments.


[Metformin and kidney].
Metformin is the first choice among drugs used for the treatment of type II diabetes mellitus mainly because of several advantages: proven hypoglycemic effect, good safety profile, virtually no risk of hypoglycemia, body weight reduction, lipid-lowering effect, efficacy in preventing micro- and macrovascular complications as well as adverse cardiac and cerebrovascular events and reduced cost. Previous reports had shown an increased risk of lactic acidosis in patients receiving metformin. However, the current Guidelines have greatly limited this risk to certain categories of patients, such as those with severe chronic renal failure, particularly when predisposing risk factors such as administration of iodinated contrast are present. In this review, we reported the main data of the literature on the use of metformin in patients with chronic renal failure and both highly expected benefits and high potential risks.


Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.
Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.


Thought Leader Perspectives on Participant Protections in Precision Medicine Research.
Precision medicine research is rapidly taking a lead role in the pursuit of new ways to improve health and prevent disease, but also presents new challenges for protecting human subjects. The extent to which the current "web" of legal protections, including technical data security measures, as well as measures to restrict access or prevent misuse of research data, will protect participants in this context remains largely unknown. Understanding the strength, usefulness, and limitations of this constellation of laws, regulations, and procedures is critical to ensuring not only that participants are protected, but also that their participation decisions are accurately informed. To address these gaps, we conducted in-depth interviews with a diverse group of 60 thought-leaders to explore their perspectives on the protections associated with precision medicine research.


Immunological memory transferred with CD4 T cells specific for tuberculosis antigens Ag85B-TB10.4: persisting antigen enhances protection.
High levels of death and morbidity worldwide caused by tuberculosis has stimulated efforts to develop a new vaccine to replace BCG. A number of Mycobacterium tuberculosis (Mtb)-specific antigens have been synthesised as recombinant subunit vaccines for clinical evaluation. Recently a fusion protein of TB antigen Ag85B combined with a second immunodominant TB antigen TB10.4 was emulsified with a novel non-phospholipid-based liposomal adjuvant to produce a new subunit vaccine, investigated here. Currently, there is no consensus as to whether or not long-term T cell memory depends on a source of persisting antigen. To explore this and questions regarding lifespan, phenotype and cytokine patterns of CD4 memory T cells, we developed an animal model in which vaccine-induced CD4 memory T cells could transfer immunity to irradiated recipients. The transfer of protective immunity using Ag85B-TB10.4-specific, CD45RB(low) CD62L(low) CD4 T cells was assessed in sub-lethally irradiated recipients following challenge with live BCG, used here as a surrogate for virulent Mtb. Donor T cells also carried an allotype marker allowing us to monitor numbers of antigen-specific, cytokine-producing CD4 T cells in recipients. The results showed that both Ag85B-TB10.4 and BCG vaccination induced immunity that could be transferred with a single injection of 3x10(6) CD4 T cells. Ten times fewer numbers of CD4 T cells (0.3x10(6)) from donors immunised with Ag85B-TB10.4 vaccine alone, transferred equivalent protection. CD4 T cells from donors primed by BCG and boosted with the vaccine similarly transferred protective immunity. When BCG challenge was delayed for 1 or 2 months after transfer (a test of memory T cell survival) recipients remained protected. Importantly, recipients that contained persisting antigen, either live BCG or inert vaccine, showed significantly higher levels of protection (p<0.01). Overall the numbers of IFN-gamma-producing CD4 T cells were poorly correlated with levels of protection. The Ag85B-TB10.4 vaccine, with or without BCG-priming, generated TB-specific CD4 T cells that transferred protective immunity in mice challenged with BCG. The level of protection was enhanced in recipients containing a residual source of specific antigen that could be either viable or inert.


Water, sanitation and hygiene for the prevention of diarrhoea.
Ever since John Snow's intervention on the Broad St pump, the effect of water quality, hygiene and sanitation in preventing diarrhoea deaths has always been debated. The evidence identified in previous reviews is of variable quality, and mostly relates to morbidity rather than mortality. We drew on three systematic reviews, two of them for the Cochrane Collaboration, focussed on the effect of handwashing with soap on diarrhoea, of water quality improvement and of excreta disposal, respectively. The estimated effect on diarrhoea mortality was determined by applying the rules adopted for this supplement, where appropriate. The striking effect of handwashing with soap is consistent across various study designs and pathogens, though it depends on access to water. The effect of water treatment appears similarly large, but is not found in few blinded studies, suggesting that it may be partly due to the placebo effect. There is very little rigorous evidence for the health benefit of sanitation; four intervention studies were eventually identified, though they were all quasi-randomized, had morbidity as the outcome, and were in Chinese. We propose diarrhoea risk reductions of 48, 17 and 36%, associated respectively, with handwashing with soap, improved water quality and excreta disposal as the estimates of effect for the LiST model. Most of the evidence is of poor quality. More trials are needed, but the evidence is nonetheless strong enough to support the provision of water supply, sanitation and hygiene for all.


Opportunistic salpingectomy at benign gynecological surgery for reducing ovarian cancer risk: a 10-year single centre experience from China and a literature review.
Current evidences indicate that the fallopian tube plays a major role in the pathogenesis of epithelial ovarian cancer (EOC). Salpingectomy represents a novel and potentially effective risk-reducing option. In this study, there were 1822 patients diagnosed and treated for EOC or primary peritoneal cancer (PPC) at Department of Gynecologic Oncology, Tianjin Medical University Cancer Institute and Hospital from January 1, 2007 to April 30, 2017. Among them, 198 patients with a history of gynecological surgery because of benign diseases were enrolled to analyze further. Using 1:2 case-control study, we found that the incidence of EOC was significantly decreased in the population with salpingectomy, compared to women with fallopian tube reserved (P<0.05). At the same period, there were 4339 patients receiving opportunistic salpingectomy in our centre because of benign gynecological diseases. The results showed the rate of bilateral salpingectomy was annually increased from 2007 to 2017 (22.02% to 60.22%), which showed approximately threefold increase in a decade. In general, factors affecting the rate of salpingectomy included age, child number, menopause or not, marital status, educational status, income status, and with or without family history of tumor. Therefore, based on ten years experiences from our centre, it is recommended that physician should discuss with appropriate patients to perform opportunistic bilateral salpingectomy at the time of receiving benign gynecological surgery for preventing ovarian cancer. Moreover, the prospective, large scale and multi-centre studies to evaluate the safety and efficacy of salpingectomy as a preventive strategy for ovarian cancer warrant to conduct in the future.


Do standing, lifting, climbing, or long hours of work during pregnancy have an effect on fetal growth?
We assessed prospectively the impact of length of the work week and job activity on fetal growth. Among 575 women who worked during pregnancy, neither prolonged standing, frequent lifting, or climbing at work, nor a high composite activity score showed an association with fetal growth, as measured by birthweight for gestational age. Long hours of work, however, did reduce fetal growth. Infants of women working long hours late in pregnancy showed decreases in gestation-adjusted birthweight of about 80 gm (95% confidence limits = -238, +74 gm), compared with women working 20 hours or less. When long hours (> 40 hours per week) were combined with job activity, the estimated reductions ranged up to 350 gm. At lower weights (< or = 3,000 gm), categorical analyses showed elevated odds ratios (1.1-1.8) for climbing, lifting, and long hours and for the combination of prolonged standing with a lengthy work week. These results indicate that long weeks of physically demanding work could lead to fetal growth reductions that may be clinically significant. Consistent with this suggestion, infants of women who worked part-time had the highest mean birthweights. Hours of work, not only job tasks, may be important for pregnant workers.


Gamma knife radiosurgery of brain metastasis from malignant pleural mesothelioma--report of three cases with autopsy study in a case.
The median survival time of malignant pleural mesothelioma (MPM) has been 9 months. Given the short survival, there have been only few cases in which brain metastases have been diagnosed and treated before death. Three cases of brain metastases treated by gamma knife radiosurgery (GKR) are reported. Case I showed a metastatic lesion in the right frontal lobe which was treated by GKR two years after diagnosis of MPM. The lesion markedly reduced and the symptoms were improved, But the patient died of progression of pleural tumor four months after GKR. A year and three months after the diagnosis, asymptomatic bifrontal lesions were treated with GKR. However, Case 2 died of abdominal mass a month after. Case 3 showed headache one and half year after the diagnosis. Three brain lesions were treated by GKR, which disappeared in 4 months. The patient died of new multiple brain metastases and periventricular dissemination seven months after. The autopsy revealed a MPM occupying the left pleural cavity. No neoplastic lesion was found in gamma knife-treated sites. The cause of death was the mass effect by new metastatic lesions. GKR was found effective also for the treatment of brain metastasis of MPM.


Comparison of two methods of presenting risk information to patients about the side effects of medicines.
To determine whether the use of verbal descriptors suggested by the European Union (EU) such as "common" (1-10% frequency) and "rare" (0.01-0.1%) effectively conveys the level of risk of side effects to people taking a medicine. Randomised controlled study with unconcealed allocation. 120 adults taking simvastatin or atorvastatin after cardiac surgery or myocardial infarction. Cardiac rehabilitation clinics at two hospitals in Leeds, UK. A written statement about one of the side effects of the medicine (either constipation or pancreatitis). Within each side effect condition half the patients were given the information in verbal form and half in numerical form (for constipation, "common" or 2.5%; for pancreatitis, "rare" or 0.04%). The estimated likelihood of the side effect occurring. Other outcome measures related to the perceived severity of the side effect, its risk to health, and its effect on decisions about whether to take the medicine. The mean likelihood estimate given for the constipation side effect was 34.2% in the verbal group and 8.1% in the numerical group; for pancreatitis it was 18% in the verbal group and 2.1% in the numerical group. The verbal descriptors were associated with more negative perceptions of the medicine than their equivalent numerical descriptors. Patients want and need understandable information about medicines and their risks and benefits. This is essential if they are to become partners in medicine taking. The use of verbal descriptors to improve the level of information about side effect risk leads to overestimation of the level of harm and may lead patients to make inappropriate decisions about whether or not they take the medicine.


Inherent optical properties of the coccolithophore: Emiliania huxleyi.
A realistic nonspherical model for Emiliania huxleyi (EHUX) is built, based on electron micrographs of coccolithophore cells. The Inherent Optical Properties (IOP) of the EHUX are then calculated numerically by using the discrete dipole approximation. The coccolithophore model includes a near-spherical core with the refractive index of 1.04 + m(i)j, and a carbonate shell formed by smaller coccoliths with refractive index of 1.2 + m(i)j, where m(i) = 0 or 0.01 and j(2) = -1. The reported IOP are the Mueller scattering matrix, backscattering probability, and depolarization ratio. Our calculation shows that the Mueller matrices of coccolithophores show different angular dependence from those of coccoliths.


Development and preliminary testing of PROGRESS: a Web-based education program for prostate cancer survivors transitioning from active treatment.
This formative research study describes the development and preliminary evaluation of a theory-guided, online multimedia psycho-educational program (PROGRESS) designed to facilitate adaptive coping among prostate cancer patients transitioning from treatment into long-term survivorship. Guided by the Cognitive-Social Health Information Processing Model (C-SHIP) and using health communications best practices, we conducted a two-phase, qualitative formative research study with early stage prostate cancer patients (n = 29) to inform the Web program development. Phase 1 included individual (n = 5) and group (n = 12) interviews to help determine intervention content and interface. Phase 2 employed iterative user/usability testing (n = 12) to finalize the intervention. Interview data were independently coded and collectively analyzed to achieve consensus. Survivors expressed interest in action-oriented content on (1) managing treatment side effects, (2) handling body image and comorbidities related to overweight/obesity, (3) coping with emotional and communication issues, (4) tips to reduce disruptions of daily living activities, and (5) health skills training tools. Patients also desired the use of realistic and diverse survivor images. Incorporation of an established theoretical framework, application of multimedia intervention development best practices, and an evidence-based approach to content and format resulted in a psycho-educational tool that comprehensively addresses survivors' needs in a tailored fashion. The results suggest that an interactive Web-based multimedia program is useful for survivors if it covers the key topics of symptom control, emotional well-being, and coping skills training; this tool has the potential to be disseminated and implemented as an adjunct to routine clinical care.


Smoke exposure is associated with a lower prevalence of serum thyroid autoantibodies and thyrotropin concentration elevation and a higher prevalence of mild thyrotropin concentration suppression in the third National Health and Nutrition Examination Survey (NHANES III).
Few modifiable exposures influencing autoimmune thyroid disease have been identified. Studies evaluating cigarette smoke and thyroid disorders have yielded conflicting results. The relationship between smoking and thyroid abnormalities was evaluated in the 1988-1994 Third National Health and Nutrition Examination Survey (NHANES III), a cross-sectional study that used a complex, multistage, stratified, clustered sampling approach to reflect the entire noninstitutionalized United States population. Among 18,148 persons who underwent thyroid testing, data regarding age, gender, iodine status, smoke exposure, and thyroid tests were complete for 16,046 persons. After excluding those taking thyroid-altering medications, 15,592 remaining subjects were analyzed. Subjects with serum cotinine levels greater than 15 ng/ml were classified as smokers. Outcome measures included the presence of 1) antithyroperoxidase antibody levels of 0.5 IU/ml or more or antithyroglobulin antibody levels of 1.0 IU/ml or more, 2) TSH concentration greater than 4.5 mU/liter, 3) TSH concentration less than 0.1 mU/liter, and 4) TSH concentration of 0.1-0.4 mU/liter. Fewer smokers (11%, 95% confidence interval (CI) = [10-13%]) had thyroid autoantibodies compared with nonsmokers (18%, 95% CI = [17-19%]). Prevalence in smokers after adjustment for age, gender, race-ethnicity, and iodine status was 13%, 95% CI = [12-15%]. Fewer smokers (2.6%, 95% CI = [2.0-3.2%]) had elevated TSH compared with nonsmokers (5.5%, 95% CI = [4.7-6.3%]). The adjusted rate in smokers was 3.4%, 95% CI = [2.6-4.3%]). Among persons with thyroid autoantibodies, smokers had 40% lower odds of TSH elevation compared with nonsmokers (adjusted odds ratio [95% CI] = 0.6 [0.4-0.97]). Among persons without TSH elevation, smoke exposure was associated with 200% greater odds of low normal TSH 0.1-0.4 mU/liter (adjusted odds ratio [95% CI] = 2.0 [1.3-2.9]). Smoking appears to be negatively associated with serological evidence of thyroid autoimmunity and hypothyroidism and positively associated with mild TSH decreases. Eliminating smoke exposure may help prevent the low normal TSH measurements that are characteristic of mild hyperthyroidism. Understanding the underlying mechanism could help identify potential pathways for the prevention of autoimmune thyroid disease.


Treatment of dural sinus thrombosis by urokinase infusion.
To gain a preliminary understanding of the role of thrombolytic therapy for the thrombosed dural sinus, we retrospectively reviewed our initial experience. Seven patients, ages 25 to 71, who presented with symptomatic dural sinus thrombosis and who failed a trial of medical therapy were treated with direct infusion of urokinase into the thrombosed sinus. Patients received urokinase doses ranging from 20,000 to 150,000 U/h with a mean infusion time of 163 hours (range 88 to 244 hours). Patency of the affected dural sinus was achieved with antegrade flow in all patients. Six patients either improved neurologically over their prethrombolysis state or were healthy after thrombolysis; one of them required angioplasty. The other patient improved after surgical repair of a residual dural arteriovenous fistula. The only complications were an infected femoral access site which resolved after treatment with antibiotics and hematuria which cleared after discontinuation of anticoagulation. Thrombolysis of the thrombosed dural sinus shows promise as a safe and efficacious treatment. The results of this study should provide the impetus for further research.


Melatonin reduces the need for sedation in ICU patients: a randomized controlled trial.
Critically ill patients suffer from physiological sleep deprivation and have reduced blood melatonin levels. This study was designed to determine whether nocturnal melatonin supplementation would reduce the need for sedation in patients with critical illness. A single-center, double-blind randomized placebo-controlled trial was carried out from July 2007 to December 2009, in a mixed medical-surgical Intensive Care Unit of a University hospital, without any form of external funding. Of 1158 patients admitted to ICU and treated with conscious enteral sedation, 82 critically-ill with mechanical ventilation >48 hours and Simplified Acute Physiology Score II>32 points were randomized 1:1 to receive, at eight p.m. and midnight, melatonin (3+3mg) or placebo, from the third ICU day until ICU discharge. Primary outcome was total amount of enteral hydroxyzine administered. Melatonin treated patients received lower amount of enteral hydroxyzine. Other neurological indicators (amount of some neuroactive drugs, pain, agitation, anxiety, sleep observed by nurses, need for restraints, need for extra sedation, nurse evaluation of sedation adequacy) seemed improved, with reduced cost for neuroactive drugs. Post-traumatic stress disorder prevalence did not differ between groups, nor did ICU or hospital mortality. Study limitations include the differences between groups before intervention, the small sample size, and the single-center observation. Long-term enteral melatonin supplementation may result in a decreased need for sedation, with improved neurological indicators and cost reduction. Further multicenter evaluations are required to confirm these results with different sedation protocols.


Adverse effects associated with herbal medicine.
Medical journals are now publishing case reports of adverse reactions to herbal therapy. With increasing use, and more importantly, increasing awareness of potential hazardous effects, these reports are liable to increase in frequency. It is also increasingly realised that herbs and drugs can interact in the same way that drug/drug interactions occur. This is particularly hazardous for the patient if the treating doctor is not aware of the herbal prescription. This article reviews the published material and highlights areas of major concern. Most of the serious adverse events reported relate to problems of product quality or adulteration.


A cautionary tale: the non-causal association between type 2 diabetes risk SNP, rs7756992, and levels of non-coding RNA, CDKAL1-v1.
Intronic single nucleotide polymorphisms (SNPs) in the CDKAL1 gene are associated with risk of developing type 2 diabetes. A strong correlation between risk alleles and lower levels of the non-coding RNA, CDKAL1-v1, has recently been reported in whole blood extracted from Japanese individuals. We sought to replicate this association in two independent cohorts: one using whole blood from white UK-resident individuals, and one using a collection of human pancreatic islets, a more relevant tissue type to study with respect to the aetiology of diabetes. Levels of CDKAL1-v1 were measured by real-time PCR using RNA extracted from human whole blood (n = 70) and human pancreatic islets (n = 48). Expression with respect to genotype was then determined. In a simple linear regression model, expression of CDKAL1-v1 was associated with the lead type 2 diabetes-associated SNP, rs7756992, in whole blood and islets. However, these associations were abolished or substantially reduced in multiple regression models taking into account rs9366357 genotype: a moderately linked SNP explaining a much larger amount of the variation in CDKAL1-v1 levels, but not strongly associated with risk of type 2 diabetes. Contrary to previous findings, we provide evidence against a role for dysregulated expression of CDKAL1-v1 in mediating the association between intronic SNPs in CDKAL1 and susceptibility to type 2 diabetes. The results of this study illustrate how caution should be exercised when inferring causality from an association between disease-risk genotype and non-coding RNA expression.


Formation of steady-state oxygen gradients in vitro: application to liver zonation.
We have developed a perfusion bioreactor system that allows the formation of steady state oxygen gradients in cell culture. In this study, gradients were formed in cultures of rat hepatocytes to study the role of oxygen in modulating cellular functions. A model of oxygen transport in our flat-plate reactor was developed to estimate oxygen distribution at the cell surface. Experimental measurements of outlet oxygen concentration from various flow conditions were used to validate model predictions. We showed that cell viability was maintained over a 24-h period when operating with a physiologic oxygen gradient at the cell surface from 76 to 5 mmHg O(2) at the outlet. Oxygen gradients have been implicated in the maintenance of regional compartmentalized metabolic and detoxification functions in the liver, termed zonation. In this system, physiologic oxygen gradients in reactor cultures contributed to a heterogeneous distribution of phosphoenolpyruvate carboxykinase (predominantly localized upstream) and cytochrome p450 2B (predominantly localized downstream) that correlates with the distribution of these enzymes in vivo. The oxygen gradient chamber provides a means of probing the oxygen effects in vitro over a continuous range of O(2) tensions. In addition, this system serves as an in vitro model of zonation that could be further extended to study the role of gradients in ischemia-reperfusion injury, toxicity, and bioartificial liver design.


A computational framework for modelling solid tumour growth.
The biology of cancer is a complex interplay of many underlying processes, taking place at different scales both in space and time. A variety of theoretical models have been developed, which enable one to study certain components of the cancerous growth process. However, most previous approaches only focus on specific aspects of tumour development, largely ignoring the influence of the evolving tumour environment. In this paper, we present an integrative framework to simulate tumour growth, including those model components that are considered to be of major importance. We start by addressing issues at the tissue level, where the phenomena are modelled as continuum partial differential equations. We extend this model with relevant components at the cellular or even sub-cellular level in a vertical fashion. We present an implementation of this framework, covering the major processes and treat the mechanical deformation due to growth, the biochemical response to hypoxia, blood flow, oxygenation and the explicit development of a vascular system in a coupled way. The results demonstrate the feasibility of the approach and its applicability to in silico studies of the influence of different treatment strategies (like the usage of novel anti-cancer drugs) for more effective therapy design.


Food Services Using Energy- and Protein-Fortified Meals to Assist Vulnerable Community-Residing Older Adults Meet Their Dietary Requirements and Maintain Good Health and Quality of Life: Findings from a Pilot Study.
The effects of "standard (STD)" vs. "protein- and energy-enriched (HEHP)" food-service meals on the nutrient intake, nutritional status, functional capacity, and wellbeing of older adults was investigated using a 12 week, double-blinded, parallel group design. All participants received dietetics counseling and either an STD (2.3 MJ and 30 g protein per meal) or a HEHP (4.6 MJ and 60 g protein) hot lunchtime meal for at least 3 days/week; those who did not want food-service meals were included in the control group (CON). Twenty-nine participants completed the study (STD = 7; HEHP = 12; CON = 10). From baseline to week 12, the HEHP subjects increased their mean daily energy intake from 6151 ± 376 kJ to 8228 ± 642 kJ (p = 0.002 for effect of time) and protein intake from 67 ± 4 g to 86 ± 8 g (p = 0.014 for effect of time). The MNA (Mini Nutritional Assessment) score was increased significantly in HEHP by 4.0 ± 1.1 points (p = 0.001), but not in the STD and CON groups (2.8 ± 2.1 points and 1.8 ± 1.1 points, p > 0.05). No difference was found for other clinical outcomes between the groups. The findings indicate that provision of HEHP-fortified food-service meals can increase energy and protein intake and improve the nutritional status of nutritionally at-risk older people.


The Role of Surface, Semantic and Grammatical Features on Simplification of Spanish Medical Texts: A User Study.
Simplifying medical texts facilitates readability and comprehension. While most simplification work focuses on English, we investigate whether features important for simplifying English text are similarly helpful for simplifying Spanish text. We conducted a user study on 15 Spanish medical texts using Amazon Mechanical Turk and measured perceived and actual difficulty. Using the median of the difficulty scores, we split the texts into easy and difficult groups and extracted 10 surface, 2 semantic and 4 grammatical features. Using t-tests, we identified those features that significantly distinguish easy text from difficult text in Spanish and compare with prior work in English. We found that easy Spanish texts use more repeated words and adverbs, less negations and more familiar words, similar to English. Also like English, difficult Spanish texts use more nouns and adjectives. However in contrast to English, easier Spanish texts contained longer sentences and used grammatical structures that were more varied.


Protein nitration impairs the myogenic tone of rat middle cerebral arteries in both ischemic and nonischemic hemispheres after ischemic stroke.
The myogenic response is crucial for maintaining vascular resistance to achieve constant perfusion during pressure fluctuations. Reduced cerebral blood flow has been reported in ischemic and nonischemic hemispheres after stroke. Ischemia-reperfusion injury and the resulting oxidative stress impair myogenic responses in the ischemic hemisphere. Yet, the mechanism by which ischemia-reperfusion affects the nonischemic side is still undetermined. The goal of the present study was to determine the effect of ischemia-reperfusion injury on the myogenic reactivity of cerebral vessels from both hemispheres and whether protein nitration due to excess peroxynitrite production is the underlying mechanism of loss of tone. Male Wistar rats were subjected to sham operation or 30-min middle cerebral artery occlusion/45-min reperfusion. Rats were administered saline, the peroxynitrite decomposition catalyst 5,10,15,20-tetrakis(4-sulfonatophenyl)prophyrinato iron (III), or the nitration inhibitor epicatechin at reperfusion. Middle cerebral arteries isolated from another set of control rats were exposed to ex vivo oxygen-glucose deprivation with and without glycoprotein 91 tat (NADPH oxidase inhibitor) or N(ω)-nitro-l-arginine methyl ester. Myogenic tone and nitrotyrosine levels were determined. Ischemia-reperfusion injury impaired the myogenic tone of vessels in both hemispheres compared with the sham group (P < 0.001). Vessels exposed to ex vivo oxygen-glucose deprivation experienced a similar loss of myogenic tone. Inhibition of peroxynitrite parent radicals significantly improved the myogenic tone. Peroxynitrite scavenging or inhibition of nitration improved the myogenic tone of vessels from ischemic (P < 0.001 and P < 0.05, respectively) and nonischemic (P < 0.01 and P < 0.05, respectively) hemispheres. Nitration was significantly increased in both hemispheres versus the sham group and was normalized with epicatechin treatment. In conclusion, ischemia-reperfusion injury impairs vessel reactivity in both hemispheres via nitration. We suggest that sham operation rather than the nonischemic side should be used as a control in preclinical stroke studies.


Lineage-specific imprinting and evolution of the zinc-finger gene ZIM2.
We have carried out an in-depth comparative analysis of a 100-kb genomic interval containing two imprinted genes, PEG3 and ZIM2, using sequences derived from human, mouse, and cow. In all three mammals, ZIM2 is located at a similar genomic distance and in the same orientation relative to PEG3, indicating the basic structural conservation of this imprinted locus. However, several lineage-specific changes have occurred that affect the exon structure and imprinting status of ZIM2. Human ZIM2 and PEG3 share a set of 5' exons and a common promoter, and both genes are paternally expressed. In contrast, mouse and cow Zim2 genes do not share 5' exons with Peg3, and Zim2 employs a separate downstream promoter in both species. The imprinting status of Zim2 is also not conserved among mammals; mouse Zim2 is expressed biallelically in testis but predominantly from the maternal allele in brain, while cow Zim2 is expressed biallelically in testis. The separate transcription of Zim2 and Peg3 and the change in promoter usage and imprinting status appear to have resulted from independent insertional events that have placed unrelated genes, Zim1 and Ast1, respectively, between Zim2 and Peg3 in mouse and cow. Our results suggest that PEG3 and ZIM2 represent the two original genes at this locus and that rearrangements have occurred independently in different mammalian lineages in recent evolutionary times. Our data also suggest that exon-sharing of human PEG3 and ZIM2 was not ancestral, but may represent a fusion event joining the two neighboring genes and bringing ZIM2 under paternal expression control. These observations are striking in light of the structural and functional conservation that typifies other imprinted domains and suggest that the PEG3/ZIM2 imprinted domain may have evolved in an unusual lineage-specific pattern.


Evaluation of the effectiveness of insecticide treated materials for household level dengue vector control.
To assess the operational effectiveness of long-lasting insecticide treated materials (ITMs), when used at household level, for the control of Aedes aegypti in moderately infested urban and suburban areas. In an intervention study, ITMs consisting of curtains and water jar-covers (made from PermaNet) were distributed under routine field conditions in 10 clusters (5 urban and 5 suburban), with over 4000 houses, in Trujillo, Venezuela. Impact of the interventions were determined by comparing pre-and post-intervention measures of the Breteau index (BI, number of positive containers/100 houses) and pupae per person index (PPI), and by comparison with indices from untreated areas of the same municipalities. The effect of ITM coverage was modeled. At distribution, the proportion of households with ≥1 ITM curtain was 79.7% in urban and 75.2% in suburban clusters, but decreased to 32.3% and 39.0%, respectively, after 18 months. The corresponding figures for the proportion of jars using ITM covers were 34.0% and 50.8% at distribution and 17.0% and 21.0% after 18 months, respectively. Prior to intervention, the BI was 8.5 in urban clusters and 42.4 in suburban clusters, and the PPI was 0.2 and 0.9, respectively. In both urban and suburban clusters, the BI showed a sustained 55% decrease, while no discernable pattern was observed at the municipal level. After controlling for confounding factors, the percentage ITM curtain coverage, but not ITM jar-cover coverage, was significantly associated with both entomological indices (Incidence Rate Ratio = 0.98; 95%CI 0.97-0.99). The IRR implied that ITM curtain coverage of at least 50% was necessary to reduce A. aegypti infestation levels by 50%. Deployment of insecticide treated window curtains in households can result in significant reductions in A. aegypti levels when dengue vector infestations are moderate, but the magnitude of the effect depends on the coverage attained, which itself can decline rapidly over time.


Upregulation of Parkin in endophilin mutant mice.
Several proteins encoded by PD genes are implicated in synaptic vesicle traffic. Endophilin, a key factor in the endocytosis of synaptic vesicles, was shown to bind to, and be ubiquitinated by, the PD-linked E3 ubiquitin ligase Parkin. Here we report that Parkin's level is specifically upregulated in brain and fibroblasts of endophilin mutant mice due to increased transcriptional regulation. Studies of transfected HEK293T cells show that Parkin ubiquitinates not only endophilin, but also its major binding partners, dynamin and synaptojanin 1. These results converge with the recently reported functional relationship of endophilin to the PD gene LRRK2 and with the identification of a PD-linked synaptojanin 1 mutation, in providing evidence for a link between PD and endocytosis genes.


Salvador-Warts-Hippo pathway regulates sensory organ development via caspase-dependent nonapoptotic signaling.
The fundamental roles for the Salvador-Warts-Hippo (SWH) pathway are widely characterized in growth regulation and organ size control. However, the function of SWH pathway is less known in cell fate determination. Here we uncover a novel role of the SWH signaling pathway in determination of cell fate during neural precursor (sensory organ precursor, SOP) development. Inactivation of the SWH pathway in SOP of the wing imaginal discs affects caspase-dependent bristle patterning in an apoptosis-independent process. Such nonapoptotic functions of caspases have been implicated in inflammation, proliferation, cellular remodeling, and cell fate determination. Our data indicate an effect on the Wingless (Wg)/Wnt pathway. Previously, caspases were proposed to cleave and activate a negative regulator of Wg/Wnt signaling, Shaggy (Sgg)/GSK3β. Surprisingly, we found that a noncleavable form of Sgg encoded from the endogenous locus after CRISPR-Cas9 modification supported almost normal bristle patterning, indicating that Sgg might not be the main target of the caspase-dependent nonapoptotic process. Collectively, our results outline a new function of SWH signaling that crosstalks to caspase-dependent nonapoptotic signaling and Wg/Wnt signaling in neural precursor development, which might be implicated in neuronal pathogenesis.


Advances in the REDCAT software package.
Residual Dipolar Couplings (RDCs) have emerged in the past two decades as an informative source of experimental restraints for the study of structure and dynamics of biological macromolecules and complexes. The REDCAT software package was previously introduced for the analysis of molecular structures using RDC data. Here we report additional features that have been included in this software package in order to expand the scope of its analyses. We first discuss the features that enhance REDCATs user-friendly nature, such as the integration of a number of analyses into one single operation and enabling convenient examination of a structural ensemble in order to identify the most suitable structure. We then describe the new features which expand the scope of RDC analyses, performing exercises that utilize both synthetic and experimental data to illustrate and evaluate different features with regard to structure refinement and structure validation. We establish the seamless interaction that takes place between REDCAT, VMD, and Xplor-NIH in demonstrations that utilize our newly developed REDCAT-VMD and XplorGUI interfaces. These modules enable visualization of RDC analysis results on the molecular structure displayed in VMD and refinement of structures with Xplor-NIH, respectively. We also highlight REDCAT's Error-Analysis feature in reporting the localized fitness of a structure to RDC data, which provides a more effective means of recognizing local structural anomalies. This allows for structurally sound regions of a molecule to be identified, and for any refinement efforts to be focused solely on locally distorted regions. The newly engineered REDCAT software package, which is available for download via the WWW from http://ifestos.cse.sc.edu, has been developed in the Object Oriented C++ environment. Our most recent enhancements to REDCAT serve to provide a more complete RDC analysis suite, while also accommodating a more user-friendly experience, and will be of great interest to the community of researchers and developers since it hides the complications of software development.


Regulation of IL-6 expression by oncostatin M.
Endothelial cells produce immunomodulatory cytokines in response to soluble mediators of inflammatory/immune reactions. We have previously demonstrated that the leukocyte-derived cytokine, oncostatin M (Onco M) can alter endothelial cell morphology, regeneration, and fibrinolytic activity in vitro. Here we demonstrate that Onco M stimulates the production of the pleiotropic cytokine, IL-6, in cultured human endothelial cells (HEC) in a time- and dose-dependent manner. Specific antibodies to IL-6 neutralize the growth-inhibitory activity for human breast carcinoma cells that is secreted by HEC in response to Onco M treatment. Specific immunoassays indicate greater than 10-fold increases in the IL-6 content of culture supernatants as early as 6 h post-treatment with Onco M (ED50 = 17 pM). This stimulation of IL-6 production by Onco M is associated with a sevenfold increase in intracellular levels of IL-6 mRNA. IL-1 alpha and TNF-alpha are also potent inducers of IL-6 production in these cells, the order of potency being IL-1 alpha greater than Onco M greater than TNF-alpha. TNF-alpha, but not IL-1 alpha, synergizes with Onco M to augment IL-6 production in HEC. HEC are 10 to 20 times more responsive to Onco M than are other nonendothelial cell types. In addition, HEC express 10 to 20 times greater numbers of high affinity cell-surface receptors for Onco M than do other nonendothelial cell types. Based on these findings, we propose that Onco M may represent a new immunomodulator regulating cytokine-induced gene products in endothelial cells.