Mosquito repellents for malaria prevention.
Malaria is an important cause of illness and death across endemic regions. Considerable success against malaria has been achieved within the past decade mainly through long-lasting insecticide-treated nets (LLINs). However, elimination of the disease is proving difficult as current control methods do not protect against mosquitoes biting outdoors and when people are active. Repellents may provide a personal protection solution during these times. To assess the impact of topical repellents, insecticide-treated clothing, and spatial repellents on malaria transmission. We searched the following databases up to 26 June 2017: the Cochrane Infectious Diseases Group Specialized Register; the Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE; Embase; US AFPMB; CAB Abstracts; and LILACS. We also searched trial registration platforms and conference proceedings; and contacted organizations and companies for ongoing and unpublished trials. We included randomized controlled trials (RCTs) and cluster-randomized controlled trials of topical repellents proven to repel mosquitoes; permethrin-treated clothing; and spatial repellents such as mosquito coils. We included trials that investigated the use of repellents with or without LLINs, referred to as insecticide-treated nets. Two review authors independently reviewed trials for inclusion, extracted the data, and assessed the risk of bias. A third review author resolved any discrepancies. We analysed data by conducting meta-analysis and stratified by whether the trials had included LLINs. We combined results from cRCTs with individually RCTs by adjusting for clustering and presented results using forest plots. We used GRADE to assess the certainty of the evidence. Eight cRCTs and two RCTs met the inclusion criteria. Six trials investigated topical repellents, two trials investigated insecticide-treated clothing, and two trials investigated spatial repellents.Topical repellentsSix RCTS, five of them cluster-randomized, investigated topical repellents involving residents of malaria-endemic regions. Four trials used topical repellents in combination with nets, but two trials undertaken in displaced populations used topical repellents alone. It is unclear if topical repellents can prevent clinical malaria (RR 0.65, 95% CI 0.4 to 1.07, very low certainty evidence) or malaria infection (RR 0.84, 95% CI 0.64 to 1.12, low-certainty evidence) caused by P. falciparum. It is also unclear if there is any protection against clinical cases of P. vivax (RR 1.32, 95% CI 0.99 to 1.76, low-certainty evidence) or incidence of infections (RR 1.07, 95% CI 0.80 to 1.41, low-certainty evidence). Subgroup analysis of trials including insecticide-treated nets did not show a protective effect of topical repellents against malaria. Only two studies did not include insecticide-treated nets, and they measured different outcomes; one reported a protective effect against clinical cases of P. falciparum (RR 0.40, 95% CI 0.23 to 0.71); but the other study measured no protective effect against malaria infection incidence caused by either P. falciparum or P. vivax.Insecticide-treated clothingInsecticide-treated clothing were investigated in trials conducted in refugee camps in Pakistan and amongst military based in the Colombian Amazon. Neither study provided participants with insecticide-treated nets. In the absence of nets, treated clothing may reduce the incidence of clinical malaria caused by P. falciparum by approximately 50% (RR 0.49, 95% CI 0.29 to 0.83, low-certainty evidence) and P. vivax (RR 0.64, 95% CI 0.40 to 1.01, low-certainty evidence).Spatial repellentsTwo cluster-randomized RCTs investigated mosquito coils for malaria prevention. We do not know the effect of spatial repellents on malaria prevention (RR 0.24, 95% CI 0.03 to 1.72, very low certainty evidence). There was large heterogeneity between studies and one study had high risk of bias. There is insufficient evidence to conclude topical or spatial repellents can prevent malaria. There is a need for better designed trials to generate higher certainty of evidence before well-informed recommendations can be made. Adherence to daily compliance remains a major limitation. Insecticide-treated clothing may reduce risk of malaria infection in the absence of insecticide-treated nets; further studies on insecticide-treated clothing in the general population should be done to broaden the applicability of the results.


Attenuation of ephrinB2 reverse signaling decreases vascularized area and preretinal vascular tuft formation in the murine model of oxygen-induced retinopathy.
EphB4 and ephrinB2 are known key regulators of retinal vascular development, but due to their capacity for bidirectional signaling, delineation of their individual roles in this process remains unclear. To better dissect out individual contributions, a model of proliferative retinopathy in mice with attenuated ephrinB2 reverse signaling was studied. It was hypothesized that endothelial ephrinB2 reverse signaling regulates hypoxia-induced capillary sprouting, as well as the pathologic formation of neovascular tufts in postnatal retinal microvascular networks. Genetically manipulated mice with attenuated ephrinB2 reverse signaling (ephrinB2(lacZ/+)), along with wild-type (WT) controls, were exposed to oxygen-induced retinopathy (OIR), a postnatal model of proliferative retinopathy. At peak disease (postnatal day 18), microvascular networks were analyzed to examine intraretinal revascularization, capillary sprouting, and pathologic neovascularization responses. EphB4 and phosphorylated ephrinB protein expression patterns along retinal microvessels were also assessed. EphrinB2(lacZ/+) mice exhibited reduced hypoxia-induced revascularization (P ≤ 0.04) and reduced formation of neovascular tufts (P < 0.001), as compared with WT controls. Corresponding to the observed inhibition of retinal angiogenesis, ephrinB2(lacZ/+) retinas displayed an increased number of blind-ended capillary sprout tips (P < 0.02) and endothelial filopodial processes (P = 0.001). In WT and ephrinB2(lacZ/+) OIR-exposed retinas, ephrinB was confined to endothelial cells, with expression detected along angiogenic vascular processes including neovascular tufts and blind-ended capillary sprouts. EphrinB2 reverse signaling is a regulator of key processes during retinal vascularization and controls pathologic retinal angiogenesis through direct effects on capillary sprouting and endothelial filopodia formation.


D-cycloserine as adjunct to brief computerised CBT for spider fear: Effects on fear, behaviour, and cognitive biases.
In anxiety disorders, cognitive behavioural therapy (CBT) improves information-processing biases such as implicit fear evaluations and avoidance tendencies, which predicts treatment response. Thus, these cognitive biases might constitute important treatment targets. This study investigated (i) whether information-processing biases could be changed following single-session computerised CBT for spider fear, and (ii) whether this effect could be augmented by administration of D-cycloserine (DCS). Spider-fearful individuals were randomized to receiving either 250 mg of DCS (n = 21) or placebo (n = 17). Three hours after drug administration, they received single-session computerized CBT, characterized by psychoeducation and exposure elements. Spider fear was assessed using self-report, behavioural, and information processing (Extrinsic Affective Simon Task & Approach Avoidance Task) measures at baseline (before drug administration), post-treatment, 1-day, and 1-month follow-up. Linear mixed-effects analyses indicated significant improvements on self-report and behavioural spider fear indices following CBT, but not on cognitive bias measures. There was no evidence of an augmentation effect of DCS on any outcome. Cognitive bias measures at 1-day were not predictive of 1-month follow-up spider fear in adjusted linear regression analyses. Results might be biased by limited representativeness of the sample (high education and intelligence, largely Caucasian ethnicity, young age). The study was also only powered for detection of medium-sized DCS effects. These findings do not provide evidence for information-processing biases relating to treatment outcome following computerised CBT for spider fear or augmentation with DCS.


Cryotherapy after total knee replacement: a survey of current practice.
Cryotherapy is commonly used during physiotherapeutic rehabilitation after total knee replacement (TKR). Evidence for treatment effectiveness is contradictory and there are no clinical guidelines to inform treatment protocols within this patient group. The present survey investigated current cryotherapy practice after TKR throughout the United Kingdom (UK). A postal survey, containing open and closed questions, was distributed to senior inpatient orthopaedic physiotherapists (n = 453). The response rate was 67% (304/453) and 58% (263/453) of the responses were completed by physiotherapists who treated TKR patients in the acute phase. Of these, 33% (85/263) routinely applied some form of cryotherapy after TKR. Physiotherapists working in the private sector were more likely to use cryotherapy and had greater access to Cryocuff equipment. The two main methods of cryotherapy application were the Cryocuff device, 59% (155/263) and crushed ice, 30% (79/263). Treatments were applied most frequently between 24 and 48 hours post-surgery, for 20 minutes, twice a day. Lack of proven efficacy was the most frequently stated reason for not applying cryotherapy treatment, and swelling was the most common indicator for treatment. There was particular uncertainty about the physical management of the Cryocuff device. There was little consensus with regard to treatment indicators, method of application and the management of cryotherapy after TKR. The results highlight a lack of consistency in the application of cryotherapy after TKR, indicating a need for further research.


Stability of the human Hsp90-p50Cdc37 chaperone complex against nucleotides and Hsp90 inhibitors, and the influence of phosphorylation by casein kinase 2.
The molecular chaperone Hsp90 is regulated by co-chaperones such as p50Cdc37, which recruits a wide selection of client protein kinases. Targeted disruption of the Hsp90-p50Cdc37 complex by protein-protein interaction (PPI) inhibitors has emerged as an alternative strategy to treat diseases characterized by aberrant Hsp90 activity. Using isothermal microcalorimetry, ELISA and GST-pull down assays we evaluated reported Hsp90 inhibitors and nucleotides for their ability to inhibit formation of the human Hsp90β-p50Cdc37 complex, reconstituted in vitro from full-length proteins. Hsp90 inhibitors, including the proposed PPI inhibitors gedunin and H2-gamendazole, did not affect the interaction of Hsp90 with p50Cdc37 in vitro. Phosphorylation of Hsp90 and p50Cdc37 by casein kinase 2 (CK2) did not alter the thermodynamic signature of complex formation. However, the phosphorylated complex was vulnerable to disruption by ADP (IC50 = 32 µM), while ATP, AMPPNP and Hsp90 inhibitors remained largely ineffective. The differential inhibitory activity of ADP suggests that phosphorylation by CK2 primes the complex for dissociation in response to a drop in ATP/ADP levels. The approach applied herein provides robust assays for a comprehensive biochemical evaluation of potential effectors of the Hsp90-p50Cdc37 complex, such as phosphorylation by a kinase or the interaction with small molecule ligands.


Spontaneous in vitro immortalization of breast epithelial cells from a patient with Li-Fraumeni syndrome.
Individuals with germ line mutations in the p53 gene, such as Li-Fraumeni syndrome (LFS), have an increased occurrence of many types of cancer, including an unusually high incidence of breast cancer. This report documents that normal breast epithelial cells obtained from a patient with LFS (with a mutation at codon 133 of the p53 gene) spontaneously immortalized in cell culture while the breast stromal fibroblasts from this same patient did not. Spontaneous immortalization of human cells in vitro is an extremely rare event. This is the first documented case of the spontaneous immortalization of breast epithelial cells from a patient with LFS in culture. LFS patient breast stromal fibroblasts infected with a retroviral vector containing human papillomavirus type 16 E7 alone were able to immortalize, whereas stromal cells obtained from patients with wild-type p53, similarly infected with human papillomavirus type 16 E7, did not. The present results indicate a protective role of normal pRb-like functions in breast stromal fibroblasts but not in breast epithelial cells and reinforces an important role of wild-type p53 in the regulation of the normal growth and development of breast epithelial tissue.


Alternative splicing of intrinsically disordered regions and rewiring of protein interactions.
Alternatively spliced protein segments tend to be intrinsically disordered and contain linear interaction motifs and/or post-translational modification sites. An emerging concept is that differential inclusion of such disordered segments can mediate new protein interactions, and hence change the context in which the biochemical or molecular functions are carried out by the protein. Since genes with disordered regions are enriched in regulatory and signaling functions, the resulting protein isoforms could alter their function in different tissues and organisms by rewiring interaction networks through the recruitment of distinct interaction partners via the alternatively spliced disordered segments. In this manner, the alternative splicing of mRNA coding for disordered segments may contribute to the emergence of new traits during evolution, development and disease.


Can economic indicators predict infectious disease spread? A cross-country panel analysis of 13 European countries.
Aims: It is unclear how economic factors impact on the epidemiology of infectious disease. We evaluated the relationship between incidence of selected infectious diseases and economic factors, including economic downturn, in 13 European countries between 1970 and 2010. Methods: Data were obtained from national communicable disease surveillance centres. Negative binomial forms of the generalised additive model (GAM) and the generalised linear model were tested to see which best reflected transmission dynamics of: diphtheria, pertussis, measles, meningococcal disease, hepatitis B, gonorrhoea, syphilis, hepatitis A and salmonella. Economic indicators were gross domestic product per capita (GDPpc), unemployment rates and (economic) downturn. Results: GAM models produced the best goodness-of-fit results. The relationship between GDPpc and disease incidence was often non-linear. Strength and directions of association between population age, tertiary education levels, GDPpc and unemployment were disease dependent. Overdispersion for almost all diseases validated the assumption of a negative binomial relationship. Downturns were not independently linked to disease incidence. Conclusions: Social and economic factors can be correlated with many infections. However, the trend is not always in the same direction, and these associations are often non-linear. Economic downturn or recessions as indicators of increased disease risk may be better replaced by GDPpc or unemployment measures.


Is paromomycin an effective and safe treatment against cutaneous leishmaniasis? A meta-analysis of 14 randomized controlled trials.
High cost, poor compliance, and systemic toxicity have limited the use of pentavalent antimony compounds (SbV), the treatment of choice for cutaneous leishmaniasis (CL). Paromomycin (PR) has been developed as an alternative to SbV, but existing data are conflicting. We searched PubMed, Scopus, and Cochrane Central Register of Controlled Trials, without language restriction, through August 2007, to identify randomized controlled trials that compared the efficacy or safety between PR and placebo or SbV. Primary outcome was clinical cure, defined as complete healing, disappearance, or reepithelialization of all lesions. Data were extracted independently by two investigators, and pooled using a random-effects model. Fourteen trials including 1,221 patients were included. In placebo-controlled trials, topical PR appeared to have therapeutic activity against the old world and new world CL, with increased local reactions, when used with methylbenzethonium chloride (MBCL) compared to when used alone (risk ratio [RR] for clinical cure, 2.58 versus 1.01: RR for local reactions, 1.60 versus 1.07). In SbV-controlled trials, the efficacy of topical PR was not significantly different from that of intralesional SbV in the old world CL (RR, 0.70; 95% confidence interval, 0.26-1.89), whereas topical PR was inferior to parenteral SbV in treating the new world CL (0.67; 0.54-0.82). No significant difference in efficacy was found between parenteral PR and parenteral SbV in the new world CL (0.88; 0.56-1.38). Systemic side effects were fewer with topical or parenteral PR than parenteral SbV. Topical PR with MBCL could be a therapeutic alternative to SbV in selected cases of the old world CL. Development of new formulations with better efficacy and tolerability remains to be an area of future research.


Monte Carlo and Lambertian light guide models of the light output from scintillation crystals at megavoltage energies.
A new model of the light output from single-crystal scintillators in megavoltage energy x-ray beams has been developed, based on the concept of a Lambertian light guide model (LLG). This was evaluated in comparison with a Monte Carlo (MC) model of optical photon transport, previously developed and reported in the literature, which was used as a gold standard. The LLG model was developed to enable optimization of scintillator detector design. In both models the dose deposition and light propagation were decoupled, the scintillators were cuboids, split into a series of cells as a function of depth, with Lambertian side and entrance faces, and a specular exit face. The signal in a sensor placed 1 and 1000 mm beyond the exit face was calculated. Cesium iodide (CSI) crystals of 1.5 and 3 mm square cross section and 1, 5, and 10 mm depth were modeled. Both models were also used to determine detector signal and optical gain factor as a function of CsI scintillator thickness, from 2 to 10 mm. Results showed a variation in light output with position of dose deposition of a factor of up to approximately 5, for long, thin scintillators (such as 10 X 1.5 x 1.5 mm3). For short, fat scintillators (such as 1 X 3 X 3 mm3) the light output was more uniform with depth. MC and LLG generally agreed to within 5%. Results for a sensor distance of 1 mm showed an increase in light output the closer the light originates to the exit face, while a distance of 1000 mm showed a decrease in light output the closer the light originates to the exit face. For a sensor distance of 1 mm, the ratio of signal for a 10 mm scintillator to that for a 2 mm scintillator was 1.98, whereas for the 1000 mm distance the ratio was 3.00. The ratio of quantum efficiency (QE) between 10 and 2 mm thicknesses was 4.62. We conclude that these models may be used for detector optimization, with the light guide model suitable for parametric study.


Ptgr1 expression is regulated by NRF2 in rat hepatocarcinogenesis and promotes cell proliferation and resistance to oxidative stress.
Prostaglandin reductase-1 (Ptgr1) is an alkenal/one oxidoreductase that is involved in the catabolism of eicosanoids and lipid peroxidation such as 4-hydroxynonenal (4-HNE). Recently, we reported that Ptgr1 is overexpressed in human clinical and experimentally induced samples of hepatocellular carcinoma (HCC). However, how the expression of this gene is regulated and its role in carcinogenesis are not yet known. Here, we studied parameters associated with antioxidant responses and the mechanisms underlying the induction of Ptgr1 expression by the activation of Nuclear Factor (erythroid-derived-2)-like-2 (NRF2). For these experiments, we used two protocols of induced hepatocarcinogenesis in rats. Furthermore, we determined the effect of PTGR1 on cell proliferation and resistance to oxidative stress in cell cultures of the epithelial liver cell line, C9. Ptgr1 was overexpressed during the early phase in altered hepatocyte foci, and this high level of expression was maintained in persistent nodules until tumors developed. Ptgr1 expression was regulated by NRF2, which bound to an antioxidant response element at -653bp in the rat Ptgr1 gene. The activation of NRF2 induced the activation of an antioxidant response that included effects on proteins such as glutamate-cysteine ligase, catalytic subunit, NAD(P)H dehydrogenase quinone-1 (NQO1) and glutathione-S-transferase-P (GSTP1). These effects may have produced a reduced status that was associated with a high proliferation rate in experimental tumors. Indeed, when Ptgr1 was stably expressed, we observed a reduction in the time required for proliferation and a protective effect against hydrogen peroxide- and 4-HNE-induced cell death. These data were consistent with data showing colocalization between PTGR1 and 4-HNE protein adducts in liver nodules. These findings suggest that Ptgr1 and antioxidant responses act as a metabolic adaptation and could contribute to proliferation and cell-death evasion in liver tumor cells. Furthermore, these data indicate that Ptgr1 could be used to design early diagnostic tools or targeted therapies for HCC.


Functional treatment versus plaster for simple elbow dislocations (FuncSiE): a randomized trial.
Elbow dislocations can be classified as simple or complex. Simple dislocations are characterized by the absence of fractures, while complex dislocations are associated with fractures. After reduction of a simple dislocation, treatment options include immobilization in a static plaster for different periods of time or so-called functional treatment. Functional treatment is characterized by early active motion within the limits of pain with or without the use of a sling or hinged brace. Theoretically, functional treatment should prevent stiffness without introducing increased joint instability. The primary aim of this randomized controlled trial is to compare early functional treatment versus plaster immobilization following simple dislocations of the elbow. The design of the study will be a multicenter randomized controlled trial of 100 patients who have sustained a simple elbow dislocation. After reduction of the dislocation, patients are randomized between a pressure bandage for 5-7 days and early functional treatment or a plaster in 90 degrees flexion, neutral position for pro-supination for a period of three weeks. In the functional group, treatment is started with early active motion within the limits of pain. Function, pain, and radiographic recovery will be evaluated at regular intervals over the subsequent 12 months. The primary outcome measure is the Quick Disabilities of the Arm, Shoulder, and Hand score. The secondary outcome measures are the Mayo Elbow Performance Index, Oxford elbow score, pain level at both sides, range of motion of the elbow joint at both sides, rate of secondary interventions and complication rates in both groups (secondary dislocation, instability, relaxation), health-related quality of life (Short-Form 36 and EuroQol-5D), radiographic appearance of the elbow joint (degenerative changes and heterotopic ossifications), costs, and cost-effectiveness. The successful completion of this trial will provide evidence on the effectiveness of a functional treatment for the management of simple elbow dislocations. The trial is registered at the Netherlands Trial Register (NTR2025).


[Anxiety, depression and sleep disorders in Parkinson's disease: a complex interaction between body and mind].
Anxiety and depression in Parkinson's disease (PD) are often unrecognized, partially due to a complex relationship with sleep disorders and other PD-related symptoms.
 AIM: To gain more insight in anxiety, depression and sleep disorders in PD, their reciprocal interaction and relationship with other (non)motor symptoms.
 METHOD: With three epidemiological studies in this thesis article we describe: the symptom dimensions of anxiety, motor symptoms and autonomic failure; predictors of the course of anxiety; and the temporal relationship between anxiety, depression and insomnia in PD.
 RESULTS: Anxiety in PD has one affective and various somatic symptom dimensions. There is a symptomatic overlap between anxiety and symptoms of motor and autonomic dysfunctions. Anxiety, depression and impulsive-compulsive behaviors in de novo PD show a parallel course. Cognitive dysfunctions and REM-sleep behaviour disorder are risk factors for anxiety in PD patients. The relationship between insomnia and anxiety and depression is bi-directional.
 CONCLUSION: There is an overlap, co-morbidity and interaction between anxiety, depression, sleep disorders and (non)motor symptoms, which warrants a multi-disciplinary approach to PD. Sleep disorders and cognitive dysfunctions may provide starting points for treatment and preventions of anxiety in PD.


Summit: Scaling Deep Learning Interpretability by Visualizing Activation and Attribution Summarizations.
Deep learning is increasingly used in decision-making tasks. However, understanding how neural networks produce final predictions remains a fundamental challenge. Existing work on interpreting neural network predictions for images often focuses on explaining predictions for single images or neurons. As predictions are often computed from millions of weights that are optimized over millions of images, such explanations can easily miss a bigger picture. We present Summit, an interactive system that scalably and systematically summarizes and visualizes what features a deep learning model has learned and how those features interact to make predictions. Summit introduces two new scalable summarization techniques: (1) activation aggregation discovers important neurons, and (2) neuron-influence aggregation identifies relationships among such neurons. Summit combines these techniques to create the novel attribution graph that reveals and summarizes crucial neuron associations and substructures that contribute to a model's outcomes. Summit scales to large data, such as the ImageNet dataset with 1.2M images, and leverages neural network feature visualization and dataset examples to help users distill large, complex neural network models into compact, interactive visualizations. We present neural network exploration scenarios where Summit helps us discover multiple surprising insights into a prevalent, large-scale image classifier's learned representations and informs future neural network architecture design. The Summit visualization runs in modern web browsers and is open-sourced.


Evaluating SKI as a candidate gene for non-syndromic cleft lip with or without cleft palate.
Non-syndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common of all congenital malformations and has a multifactorial etiology. Findings in mice suggest that the v-ski sarcoma viral oncogene homolog (SKI) gene is a candidate gene for orofacial clefting. In humans, a significant association between rs2843159 within SKI and NSCL/P has been reported in patients from the Philippines and South America. In the South American patients, the association was driven by the subgroup of patients with non-syndromic cleft lip only (NSCLO). Here we investigated the association with rs2843159 in a Mayan Mesoamerican population (172 NSCL/P patients and 366 controls). In addition, we analyzed the phenotypic subgroups NSCLO and non-syndromic cleft of lip and palate (NSCLP). A trend towards association between rs2843159 and NSCL/P was observed in the Mayan cohort (P = 0.097), and we found a stronger association in the NSCLP subgroup (P = 0.072) despite a limited sample size. To investigate whether other common variants within the SKI gene contribute to NSCL/P susceptibility in European and Asian populations, we also analyzed genotypic data from two recent genome-wide association studies using set-based statistical approaches. These analyses detected a trend toward association in the European population. Our data provide limited support for the hypothesis that common SKI variants are susceptibility factors for NSCL/P.


Resolution of acute gastroenteritis symptoms in children and adults treated with a novel polyphenol-based prebiotic.
To test efficacy and durability of a polyphenol-based prebiotic treatment for acute gastroenteritis in a 300 patient double-blinded clinical study. A two-arm randomized, double-blinded, placebo-controlled clinical study was conducted at two public health centers in Managua, Nicaragua. Potential subjects who qualified based on inclusion and exclusion criteria were randomly assigned to one of two treatment arms. Two thirds of the subjects (n = 200) received a single titrated 0.5-2 ounce liquid dose of a novel polyphenol-based prebiotic (Aliva(TM)) diluted with 2 to eight ounces of oral rehydration solution (ORS). One third of the subjects (n = 100) were randomized to receive two liquid ounces of a taste and color-matched placebo diluted in eight ounces of ORS. The outcome variables measured included stool consistency, stomach discomfort, gas and bloating, and heartburn/indigestion. The study subjects ranked their stool consistency and the severity of their subjective symptoms at specified intervals from immediately prior to treatment, to five days post treatment. All subjects recorded their symptoms in a study diary. The study subjects also recorded the time and consistencies of all stools in their study diary. Stool consistency was compared to the picture and descriptions on the Bristol Stool Chart, and any stool rated greater than Type 4 was considered unformed. The clinical study team reviewed the study diaries with subjects during daily follow-up calls and close-out visits, and recorded the data in case report forms. After receiving a single dose, Aliva treated subjects reported shorter median time to their last unformed stool (1 h 50 min) than placebo treated subjects (67 h 50 min.), a statistically significant difference [95%CI: -3178-(-2018), P = 0.000]. Aliva treated subjects also reported shorter median their time to last unformed stool (TTLUS) (1 hrs 50 min) than placebo treated subjects (67 h 50 min), which was also a statistically significant difference (P = 0.000).The percentage of subjects recording TTLUS was greater for those who received Aliva vs placebo at 30 min (P = 0.027), 2 h (P = 0.000), 24 h (P = 0.000), 48 h (P = 0.000), 72 h (P = 0.000), and 5 d (P = 0.000) post dose. There were 146 study subjects 14 years old or older, which was the criteria set for reliable self-reporting of subjective symptoms. Of those 146 subjects, 142 reported stomach pain and discomfort during screening. From 90 minutes [95%CI: -1.8-(-0.01), P = 0.048] through 5 d [95%CI: -3.4-(-1.9), P = 0.000), the subjects treated with Aliva experienced significantly less stomach pain and discomfort than those who received placebo. Of those same 146 participants, 114 subjects reported gas and bloating during screening. Similarly, subjects who received Aliva experienced significantly less gas and bloating from 2 h [95%CI: -1.7-(-0.39), P = 0.030] through 5 d (95%CI: -2.0-0.42, P = 0.005) compared with the placebo arm. In this double-blind, randomized clinical study, subjects with acute gastroenteritis receiving Aliva prebiotic showed significant and sustained improvement of multiple symptoms vs those receiving placebo.


Ground-based airglow imaging interferometer. Part 1: instrument and observation.
A ground-based airglow imaging interferometer (GBAII) is proposed to measure simultaneously the temperature and wind in the mesopause region by using airglow emissions of the O2(0-1) band. Since it employs a wide angle Michelson interferometer with a large air gap, combined with the rotational temperature measurement, both the phase and spectral information can be obtained from the imaging results. Based on the optimization and calibrations for the optical system in the laboratory, we developed and assembled a prototype of a GBAII, and carried out one observation at the observatory of Xi'an University of Technology on 12 June 2012. The observed temperatures fall mainly on the range of 167-196 K, while both the zonal and meridional winds faintly show the feature of half-day oscillation. The consistent trends between the observation results and the standard atmospheric models suggest that the GBAII has achieved our basic design goals.


Reducible, dibromomaleimide-linked polymers for gene delivery.
Polycations have been successfully used as gene transfer vehicles both in vitro and in vivo; however, their cytotoxicity has been associated with increasing molecular weight. Polymers that can be rapidly degraded after internalization are typically better tolerated by mammalian cells compared to their non-degradable counterparts. Here, we report the use of a dibromomaleimide-alkyne (DBM-alkyne) linking agent to reversibly bridge cationic polymer segments for gene delivery and to provide site-specific functionalization by azide-alkyne cycloaddition chemistry. A panel of reducible and non-reducible, statistical copolymers of (2-dimethylamino)ethyl methacrylate (DMAEMA) and oligo(ethylene glycol)methyl ether methacrylate (OEGMA) were synthesized and evaluated. When complexed with plasmid DNA, the reducible and non-reducible polymers had comparable DNA condensation properties, sizes, and transfection efficiencies. When comparing cytotoxicity, the DBM-linked, reducible polymers were significantly less toxic than the non-reducible polymers. To demonstrate polymer functionalization by click chemistry, the DBM-linked polymers were tagged with an azide-fluorophore and were used to monitor cellular uptake. Overall, this polymer system introduces the use of a reversible linker, DBM-alkyne, to the area of gene delivery and allows for facile, orthogonal, and site-specific functionalization of gene delivery vehicles.


Temperature-Sensitive Resistance to Wheat streak mosaic virus in CO960333 and KS06HW79 Wheat.
Temperature-sensitive resistance (TSR) that can protect against losses to Wheat streak mosaic virus (WSMV) has been described in elite wheat germplasm. A TSR identified in the advanced breeding line CO960333 and its derivative KS06HW79 was examined in growth-chamber tests conducted under constant temperature regimes of 18, 21, and 24°C against an array of WSMV isolates. At 18°C, all tested isolates systemically infected the pedigree parents, while the progeny line CO960333 remained free of symptoms; at 24°C, all lines were susceptible. At the intermediate temperature of 21°C, the TSR of KS06HW79 was effective in contrast to the TSRs of KS03HW12 and 'RonL'. In field trials conducted in 2011 and 2012, the TSR expressed in KS06HW79 conferred complete protection against yield losses from inoculation with the Sidney 81 isolate of WSMV, while the TSR of RonL conferred similar protection in 2012 but allowed small losses in 2011. The resistance expressed by KS06HW79 is likely not due to the Wsm1 gene because it did not contain the tightly linked J15 sequence-characterized amplified region (SCAR) DNA marker. These findings suggest that KS06HW79 could be an additional TSR source of value to wheat-breeding programs seeking to control losses from WSMV.


Altered development of dopaminergic neurons differentiated from stem cells from human exfoliated deciduous teeth of a patient with Down syndrome.
Down syndrome (DS) is a common developmental disorder resulting from the presence of an additional copy of chromosome 21. Abnormalities in dopamine signaling are suggested to be involved in cognitive dysfunction, one of the symptoms of DS, but the pathophysiological mechanism has not been fully elucidated at the cellular level. Stem cells from human exfoliated deciduous teeth (SHED) can be prepared from the dental pulp of primary teeth. Importantly, SHED can be collected noninvasively, have multipotency, and differentiate into dopaminergic neurons (DN). Therefore, we examined dopamine signaling in DS at the cellular level by isolating SHED from a patient with DS, differentiating the cells into DN, and examining development and function of DN. Here, SHED were prepared from a normal participant (Ctrl-SHED) and a patient with DS (DS-SHED). Initial experiments were performed to confirm the morphological, chromosomal, and stem cell characteristics of both SHED populations. Next, Ctrl-SHED and DS-SHED were differentiated into DN and morphological analysis of DN was examined by immunostaining. Functional analysis of DN was performed by measuring extracellular dopamine levels under basal and glutamate-stimulated conditions. In addition, expression of molecules involved in dopamine homeostasis was examined by quantitative real-time polymerase chain reaction and immunostaining. Statistical analysis was performed using two-tailed Student's t-tests. Compared with Ctrl-SHED, DS-SHED showed decreased expression of nestin, a neural stem-cell marker. Further, DS-SHED differentiated into DN (DS-DN) exhibiting decreased neurite outgrowth and branching compared with Ctrl-DN. In addition, DS-DN dopamine secretion was lower than Ctrl-DN dopamine secretion. Moreover, aberrant expression of molecules involved in dopaminergic homeostasis was observed in DS-DN. Our results suggest that there was developmental abnormality and DN malfunction in the DS-SHED donor in this study. In the future, to clarify the detailed mechanism of dopamine-signal abnormality due to DN developmental and functional abnormalities in DS, it is necessary to increase the number of patients for analysis. Non-invasively harvested SHED may be very useful in the analysis of DS pathology.


Approaching biomarkers of membranous nephropathy from a murine model to human disease.
Membranous glomerulonephropathy (MN) is the most prevalent cause of nephrotic syndrome in adult humans. However, the specific biomarkers of MN have not been fully elucidated. We examined the alterations in gene expression associated with the development of MN. Murine MN was induced by cationic bovine serum albumin (cBSA). After full-blown MN, cDNA microarray analysis was performed to identify gene expression changes, and highly expressed genes were evaluated as markers both in mice and human kidney samples. MN mice revealed clinical proteinuria and the characteristic diffuse thickening of the glomerular basement membrane. There were 175 genes with significantly different expressions in the MN kidneys compared with the normal kidneys. Four genes, metallothionein-1 (Mt1), cathepsin D (CtsD), lymphocyte 6 antigen complex (Ly6), and laminin receptor-1 (Lamr1), were chosen and quantified. Mt1 was detected mainly in tubules, Lamr1 was highly expressed in glomeruli, and CtsD was detected both in tubules and glomeruli. The high expressions of Lamr1 and CtsD were also confirmed in human kidney biopsies. The murine MN model resembled the clinical and pathological features of human MN and may provide a tool for investigating MN. Applying cDNA microarray analysis may help to identify biomarkers for human MN.


Comparison of techniques for determination of chondrocyte viability after thermal injury.
To compare 2 methods of quantitating chondrocyte viability and to determine chondrocyte response to thermal injury over time. 108 stifle joints from 54 adult rats. Cartilage from the distal aspect of the femur was treated ex vivo with radiofrequency energy at a probe setting that would result in immediate partial-thickness chondrocyte death; untreated sections served as controls. Explants were cultured, and cell viability was compared by use of lactate dehydrogenase (LDH) histochemical staining and calcein AM and ethidium homodimer-1 confocal laser microscopy (CLM) cell viability staining. Terminal deoxynucleotidyl transferase-mediated X-dUTP nick end labeling (TUNEL) was used to detect apoptosis. All labeling studies were performed 0, 1, 3, 7, 14, and 21 days after treatment. In the treated tissues, a greater percentage of viable cells were found with CLM, compared with LDH staining. This result contrasted that of control tissues in which LDH staining indicated a greater percentage of live cells than CLM. The greatest number of TUNEL-positive chondrocytes was present at day 3, declining at later time intervals. CLM and LDH histochemistry techniques yield different absolute numbers of live and dead cells, resulting in differing percentages of live or dead cells with each technique. These differences may be related to the enzymes responsible for activation in each technique and the susceptibility of these enzymes to thermal injury. Results of TUNEL indicate that apoptosis contributes to chondrocyte death after thermal injury, with a peak signal identified 3 days after insult.


Mitochondrial respiratory chain-dependent generation of superoxide anion and its release into the intermembrane space.
It has been generally accepted that superoxide anion generated by the mitochondrial respiratory transport chain are vectorially released into the mitochondrial matrix, where they are converted to hydrogen peroxide through the catalytic action of Mn-superoxide dismutase. Release of superoxide anion into the intermembrane space is a controversial topic, partly unresolved by the reaction of superoxide anion with cytochrome c, which faces the intermembrane space and is present in this compartment at a high concentration. This study was aimed at assessing the topological site(s) of release of superoxide anion during respiratory chain activity. To address this issue, mitoplasts were prepared from isolated mitochondria by digitonin treatment to remove portions of the outer membrane along with portions of cytochrome c. EPR analysis in conjunction with spin traps of antimycin-supplemented mitoplasts revealed the formation of a spin adduct of superoxide anion. The EPR signal was (i) abrogated by superoxide dismutase, (ii) decreased competitively by exogenous ferricytochrome c and (iii) broadened by the membrane-impermeable spin-broadening agent chromium trioxalate. These results confirm the production and release of superoxide anion towards the cytosolic side of the inner mitochondrial membrane. In addition, co-treatment of mitoplasts with myxothiazol and antimycin A, resulting in an inhibition of the oxidation of ubiquinol to ubisemiquinone, abolished the EPR signal, thus suggesting that ubisemiquinone autoxidation at the outer site of the complex-III ubiquinone pool is a pathway for superoxide anion formation and subsequent release into the intermembrane space. The generation of superoxide anion towards the intermembrane space requires consideration of the mitochondrial steady-state values for superoxide anion and hydrogen peroxide, the decay pathways of these oxidants in this compartment and the implications of these processes for cytosolic events.


Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders.
Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatment regimen and the course of the epilepsy in 66 patients for which well-documented medical information was available. We find that the use of sodium channel blockers was often associated with clinically relevant seizure reduction or seizure freedom in children with early infantile epilepsies (<3 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (≥3 months) and sometimes induced seizure worsening. Regarding the genetic findings, truncating mutations were exclusively seen in patients with late onset epilepsies and lack of response to sodium channel blockers. Functional characterization of four selected missense mutations using whole cell patch-clamping in tsA201 cells-together with data from the literature-suggest that mutations associated with early infantile epilepsy result in increased sodium channel activity with gain-of-function, characterized by slowing of fast inactivation, acceleration of its recovery or increased persistent sodium current. Further, a good response to sodium channel blockers clinically was found to be associated with a relatively small gain-of-function. In contrast, mutations in patients with late-onset forms and an insufficient response to sodium channel blockers were associated with loss-of-function effects, including a depolarizing shift of voltage-dependent activation or a hyperpolarizing shift of channel availability (steady-state inactivation). Our clinical and experimental data suggest a correlation between age at disease onset, response to sodium channel blockers and the functional properties of mutations in children with SCN2A-related epilepsy.


The enforcement of cooperation by policing.
Policing is regarded as an important mechanism for maintaining cooperation in human and animal social groups. A simple model providing a theoretical overview of the coevolution of policing and cooperation has been analyzed by Frank (1995, 1996b, 2003, 2009), and this suggests that policing will evolve to fully suppress cheating within social groups when relatedness is low. Here, we relax some of the assumptions made by Frank, and investigate the consequences for policing and cooperation. First, we address the implicit assumption that the individual cost of investment into policing is reduced when selfishness dominates. We find that relaxing this assumption leads to policing being favored only at intermediate relatedness. Second, we address the assumption that policing fully recovers the loss of fitness incurred by the group owing to selfishness. We find that relaxing this assumption prohibits the evolution of full policing. Finally, we consider the impact of demography on the coevolution of policing and cooperation, in particular the role for kin competition to disfavor the evolution of policing, using both a heuristic "open" model and a "closed" island model. We find that large groups and increased kin competition disfavor policing, and that policing is maintained more readily than it invades. Policing may be harder to evolve than previously thought.


IMP3 signatures of fallopian tube: a risk for pelvic serous cancers.
Recent advances suggest fallopian tube as the main cellular source for women's pelvic serous carcinoma (PSC). In addition to TP53 mutations, many other genetic changes are involved in pelvic serous carcinogenesis. IMP3 is an oncofetal protein which has recently been observed to be overexpressed in benign-looking tubal epithelia. Such findings prompted us to examine the relationship between IMP3 over-expression, patient age and the likelihood of development of PSC. Fallopian tubes from three groups (low-risk, high-risk, and PSC) of patients with matched ages were studied. Age was recorded in 10 years intervals ranging from age 20 to older than 80. The number of IMP3 signatures (defined by 10 or more tubal secretory cells stained positively and continuously in benign appearing tubal mucosa) from both tubal fimbria and ampulla segments was measured. The data was analyzed by standard contingency table and Poisson distribution methods after age adjustment. IMP3 overexpression was also examined in serous tubal intraepithelial carcinoma and PSC. The positive IMP3-stained cells are mainly tubal secretory cells. The absolute number of tubal IMP3 signatures increased significantly within each age group. Age remained a significant risk factor for serous neoplasia after age adjustment. IMP3 signatures were more frequent in the patients of both high-risk and PSC groups. The presence of IMP3 signatures in tubal mucosa was significantly associated with tubal or pelvic serous carcinogenesis (p < 0.001). The findings suggest that tubal secretory cells with IMP3 signatures showing growth advantage could potentially serve as a latent precancer biomarker for tubal or pelvic serous carcinomas in women.


Pharmacological evidence for a key role of voltage-gated K+ channels in the function of rat aortic smooth muscle cells.
The role of voltage-dependent (I(K(v))) and large conductance Ca(2+)-activated (BK(Ca)) K(+) currents in the function of the rat aorta was investigated using specific BK(Ca) and K(V) channel inhibitors in single rat aortic myocytes (RAMs) with patch-clamp technique and in endothelium-denuded aortic rings with isometric tension measurements. The whole-cell K(+) currents were recorded in RAMs dialysed with 200 and 444 nm Ca(2+) and in perforated-patch configuration. Electrophysiological analysis demonstrated that I(K(v)) appeared at >/=-40 mV, while BK(Ca) (isolated using 1 microm paxilline) were seen positive to -20 mV in all conditions. Voltage-dependent characteristics, but not maximal conductance, of I(K(v)) was significantly altered in increased [Ca(2+)](i). Correolide (1 microm) (a K(V)1 channel blocker) did not inhibit the I(K(v)), whereas millimolar concentration of TEA (IC(50)=3.1+/-0.6 mm, n=5) and 4-aminopyridine (4-AP, IC(50)=5.9+/-1.9 mm, n=7) suppressed I(K(v)). These results and immunocytochemical analysis suggest the K(V)2.1 channel to be a molecular correlate for I(K(v)). In nonstimulated aortic rings 1-5 mm TEA and 4-AP (inhibitors of I(K(v))), but not paxilline (1 microm), caused contraction. The frequency of contractile responses to TEA and 4-AP was increased in the presence of 10 mm KCl, which itself did not significantly affect the aortic basal tone. Phenylephrine (15-40 nm) induced sustained tension with superimposed slow oscillatory contractions (termed OWs). OWs were blocked by diltiazem, ryanodine and cyclopiazonic acid, suggesting the involvement of L-type Ca(2+) channels and ryanodine-sensitive Ca(2+) stores in this process. TEA and 4-AP, but not IbTX, paxilline or correolide, increased the duration and amplitude of OWs, indicating that I(K(v)) is involved in the control of oscillatory activity. In conclusion, our findings suggest that the K(V)2.1-mediated I(K(v)), and not BK(Ca), plays an important role in the regulation of the excitability and contractility of rat aorta.


Venous malformations: clinical diagnosis and treatment.
Venous malformation (VM) is the most common type of congenital vascular malformation (CVM). They are present at birth and are often symptomatic, causing morbidity and pain. VMs can be challenging to diagnose and are often confused with hemangioma in terminology as well as with imaging. An accurate clinical history and cross-sectional imaging are critical for diagnosis and for devising management. This manuscript will review imaging approaches to diagnosing VMs and current treatment strategies.


Electromagnetic energy as a bridge between atomic and cellular levels in the genetics approach to cancer treatment.
Literature on magnetic fields (MF) and gene expression, as well as on DNA damage, supports the hypothesis that electromagnetic energy may act at atomic level influencing genetic stability. According to quantum physics, MF act on the interconversion of singlet and triplet spin states, and therefore on genetic instability, activating oxidative processes connected to biological free radicals formation, particularly ROS. In the above frame, the results of in vitro and in vivo laboratory trials have been analyzed. The use of a static MF amplitude modulated by 50 Hz MF, with a time average total intensity of 5.5 mT, has been shown to influence tumor cell functions such as cell proliferation, apoptosis, p53 expression, inhibition of tumor growth and prolongation of survival in animals, evidence that MF can be more effective than chemotherapy (cyclophosphamide) in inhibiting metastatic spread and growth, having synergistic activity with chemotherapy (Cis-platin), and no observable side effects or toxicity in animals or in humans. The beneficial biological/clinical effects observed, without any adverse effects, have been confirmed by various authors and augur well for the potentiality of this new approach to treat genetically based diseases like cancer. Further studies are needed to develop a quantum physics approach to biology, allowing a stable bridge to be built between atomic and cellular levels, therefore developing quantum biology.


Descriptive epidemiology of physical activity in African-American women.
We assessed walking for exercise and moderate and strenuous physical activity in relation to both demographic and health-related characteristics among African-American women from various parts of the United States who participate in the Black Women's Health Study. The data were collected in 1995 by mail questionnaire from 64,524 U.S. black women aged 21 to 69 years. The 64,101 women who provided data on physical activity are the subjects of the present report. The present study revealed low levels of physical activity among the African-American women: 57% reported an hour or less per week walking for exercise, 18% reported moderate activity, and 61% reported strenuous physical activity. Strenuous physical activity increased with education. Higher levels of walking for exercise and moderate and strenuous activity were associated with higher levels of participation in strenuous exercise in high school. Physical activity levels are low in African-American women. Based on the findings of the present study it may be suggested that educational efforts to increase levels of physical activity should start at an early age.


Decreased approach behavior and nucleus accumbens immediate early gene expression in response to Parkinsonian ultrasonic vocalizations in rats.
Many individuals with Parkinson disease (PD) have difficulty producing normal speech and voice, resulting in problems with interpersonal communication and reduced quality of life. Translational animal models of communicative dysfunction have been developed to assess disease pathology. However, it is unknown whether acoustic feature changes associated with vocal production deficits in these animal models lead to compromised communication. In rodents, male ultrasonic vocalizations (USVs) have a well-established role in functional inter-sexual communication. To test whether acoustic deficits in USVs observed in a PTEN-induced putative kinase 1 (PINK1) knockout (KO) PD rat model compromise communication, we presented recordings of male PINK1 KO USVs and normal wild-type (WT) USVs to female rat listeners. We measured approached behavior and immediate early gene expression (c-Fos) in brain regions implicated in auditory processing and sexual motivation. Our results suggest that females show reduced approach in response to PINK1 KO USVs compared with WT. Moreover, females exposed to PINK1 KO USVs had lower c-Fos immunolabeling in the nucleus accumbens, a region implicated in sexual motivation. These results are the first to demonstrate that vocalization deficits in a rat PD model result in compromised communication. Thus, the PINK1 KO PD model may be valuable for assessing treatments aimed at restoring vocal communicative function.


Plasmodium vivax Merozoite Surface Protein 1 Paralog as a Mediator of Parasite Adherence to Reticulocytes.
Plasmodium vivax parasites preferentially invade reticulocytes in human beings. P. vivax merozoite surface protein 1 (PvMSP1) and PvMSP1 paralog (PvMSP1P) may have important functions in reticulocyte adherence during invasion. These proteins share similar structures, including the presence of two epidermal growth factor (EGF)-like and glycosylphosphatidylinositol (GPI)-anchored domains at the C terminus. However, there have been no reports concerning the functional activity of PvMSP1P in reticulocyte adherence during P. vivax invasion. In this study, the ability of PvMSP1P-19 to bind to reticulocytes and normocytes was analyzed. The reticulocyte binding activity of PvMSP1P-19 was 4.0-fold higher than its normocyte binding activity. The binding of PvMSP1P-19 to reticulocytes and normocytes was inhibited in a dose-dependent manner by antibodies from immunized rabbits and by antibodies from vivax parasite-infected patients. Consistently, antibodies against PvMSP1P inhibited parasite invasion during short-term in vitro cultivation. Similar to the case for PvDBPII binding activity, PvMSP1P-19 binding activity was reduced in chymotrypsin-treated reticulocytes. However, no significant difference between the binding of PvMSP1P-19 to Duffy-positive and Duffy-negative erythrocytes was found. The minimal binding motif of PvMSP1P-19 was characterized using synthetic peptides. The results showed that the residues at amino acid positions 1791 to 1808 may have an important function in mediating merozoite adherence to reticulocytes. The positively charged residues within the EGF-like domain were shown to constitute a key binding motif. This work presents strong evidence supporting the role of PvMSP1P in host target cell selection and invasion of Duffy-independent pathway in P. vivax Moreover, PvMSP1P-19-specific antibodies may confer protection against P. vivax reinvasion.


Influence of the Electrochemical Properties of the Bacteriochlorophyll Dimer on Triplet Energy-Transfer Dynamics in Bacterial Reaction Centers.
Energetics, protein dynamics, and electronic coupling are the key factors in controlling both electron and energy transfer in photosynthetic bacterial reaction centers (RCs). Here, we examine the rates and mechanistic pathways of the P+HA- radical-pair charge recombination, triplet state formation, and subsequent triplet energy transfer from the triplet state of the bacteriochlorophyll dimer (P) to the carotenoid in a series of mutant RCs (L131LH + M160LH (D1), L131LH + M197FH (D2), and L131LH + M160LH + M197FH (T1)) of Rhodobacter sphaeroides. In these mutants, the electronic structure of P is perturbed and the P/P+ midpoint potential is systematically increased due to addition of hydrogen bonds between P and the introduced residues. High-resolution, broad-band, transient absorption spectroscopy on the femtosecond to microsecond timescale shows that the charge recombination rate increases and the triplet energy transfer rate decreases in these mutants relative to the wild type (WT). The increase of the charge recombination rate is correlated to the increase in the energy level of P+HA- and the increase in the P/P+ midpoint potential. On the other hand, the decrease in rate of triplet energy transfer in the mutants can be explained in terms of a lower energy of 3P and a shift in the electron spin density distribution in the bacteriochlorophylls of P. The triplet energy-transfer rate follows the order of WT > L131LH + M197FH > L131LH + M160LH > L131LH + M160LH + M197FH, both at room temperature and at 77 K. A pronounced temperature dependence of the rate is observed for all of the RC samples. The activation energy associated to this process is increased in the mutants relative to WT, consistent with a lower 3P energy due to the addition of hydrogen bonds between P and the introduced residues.


KnotPad: Visualizing and Exploring Knot Theory with Fluid Reidemeister Moves.
We present KnotPad, an interactive paper-like system for visualizing and exploring mathematical knots; we exploit topological drawing and math-aware deformation methods in particular to enable and enrich our interactions with knot diagrams. Whereas most previous efforts typically employ physically based modeling to simulate the 3D dynamics of knots and ropes, our tool offers a Reidemeister move based interactive environment that is much closer to the topological problems being solved in knot theory, yet without interfering with the traditional advantages of paper-based analysis and manipulation of knot diagrams. Drawing knot diagrams with many crossings and producing their equivalent is quite challenging and error-prone. KnotPad can restrict user manipulations to the three types of Reidemeister moves, resulting in a more fluid yet mathematically correct user experience with knots. For our principal test case of mathematical knots, KnotPad permits us to draw and edit their diagrams empowered by a family of interactive techniques. Furthermore, we exploit supplementary interface elements to enrich the user experiences. For example, KnotPad allows one to pull and drag on knot diagrams to produce mathematically valid moves. Navigation enhancements in KnotPad provide still further improvement: by remembering and displaying the sequence of valid moves applied during the entire interaction, KnotPad allows a much cleaner exploratory interface for the user to analyze and study knot equivalence. All these methods combine to reveal the complex spatial relationships of knot diagrams with a mathematically true and rich user experience.


The Protective Effect of an Eye Wash Solution on the Ocular Surface Damage Induced by Airborne Carbon Black Exposure.
To investigate the effects of an eye wash solution on the ocular surface damage induced by airborne carbon black (CB) exposure. Sprague-Dawley rats were exposed to ambient CB for 5 days. During the 5 days, a commercial eye wash solution (Eyebon-W) was used for irrigation twice daily on CB-exposed rat eyes; normal saline was used as the vehicle control. Lactic dehydrogenase (LDH) activity and matrix metallopeptidase (MMP)-9, histamine, and lactoferrin levels were measured in tears. The expression of inflammatory cytokines in the anterior segment of the eyeball was measured by Western blot analysis. The ocular surface staining scores, tear LDH activity, tear MMP-9, histamine, and lactoferrin concentrations, and the expression of interleukin-4 and interferon-γ in the eye were significantly increased in the CB group versus the normal control group. When compared with CB group, the Eyebon-W eye wash treatment significantly reversed these elevations induced by CB, including ocular staining scores, tear LDH activity, histamine and MMP-9 concentrations in the tear fluid, and the expression of interleukin-4 in the eye. On the other hand, saline irrigation only reduced the concentrations of histamine and MMP-9 in tear fluid and the expression of interferon-γ in the eye. Both Eyebon-W eye wash treatment and saline irrigation reversed CB-induced ocular surface injury, but the efficacy of Eyebon-W was more significant than that of the saline solution when compared with CB group. The use of an eye wash solution seems to play a protective role for the ocular surface when exposed to airborne particulate matter.


Ba-Wei-Di-Huang-Wan through its active ingredient loganin counteracts substance P-enhanced NF-κB/ICAM-1 signaling in rats with bladder hyperactivity.
Overt bladder afferent activation may exacerbate endogenous substance P (SP) release to induce intercellular adhesion molecule-1 (ICAM-1)-mediated inflammation and reactive oxygen species (ROS) production leading to hyperactive bladder. Ba-Wei-Die-Huang-Wan (BWDHW), a traditional Chinese medicine, has been used to treat lower urinary tract symptoms in patients by undefined mechanisms. We explored the possible mechanisms and the active components of BWDHW on exogenous SP-induced bladder hyperactivity. BWDHW contained six major components: loganin, paeoniflorin, 5-hydroxymethylfurfural, cinnamic acid, cinnamaldehyde, and paeonol by high-performance liquid chromatography. In urethane-anesthetized female Wistar rats, we evaluated transcystometrogram, pelvic afferent nerve activity by electrophysiologic recording techniques, ICAM-1 expression by Western blot and immunohistochemistry, ROS amount by an ultrasensitive chemiluminescence method and possible ROS sources from the different leukocytes by specific stains in SP-treated bladder. BWDHW and its major component loganin dose-dependently inhibited H2 O2 and HOCl activity in vitro. Intragastrical BWDHW (250 mg/kg) and loganin (5 mg/kg) twice daily for 2 weeks did not affect the baseline micturition parameters. Intra-arterial SP (20 µg/rat) through neurokinin-1 receptor activation increased voiding frequency (shortened intercontraction intervals), pelvic afferent nerve activity, bladder NF-κB/ICAM-1 expression, bladder ROS amount, neutrophils adhesion to venous endothelium, CD68 (monocyte/macrophage), and mast cell infiltration in the inflamed bladder. BWDHW and loganin pretreatment significantly depressed SP-enhanced pelvic afferent nerve activity, bladder NF-κB/ICAM-1 expression, leukocyte infiltration, and ROS amount, and subsequently improved bladder hyperactivity. In conclusion, our results suggest that BWDHW and its active component loganin improves bladder hyperactivity via inhibiting SP/neurokinin-1 receptor signaling and depressing NF-κB/ICAM-1 mediated oxidative injury and inflammation. Neurourol. Urodynam. 35:771-779, 2016. © 2015 Wiley Periodicals, Inc.


A Clinical Approach to the Diagnosis of Traumatic Encephalopathy Syndrome: A Review.
Chronic traumatic encephalopathy (CTE) refers to pathologic changes that have been found in some individuals with a history of repetitive traumatic impact to the head (hereinafter referred to as head trauma). These changes cannot be assessed during the clinical evaluation of a living patient. The neuropathologic features, taxonomy, history, role of biomarkers in diagnosis, and existing criteria of CTE are reviewed. Previous criteria have been proposed to approach the living patient; however, a unified, specific approach is needed for the practicing clinician. We propose a new diagnostic construct for the clinical syndrome associated with repetitive exposure to head trauma: traumatic encephalopathy syndrome. This clinical paradigm will provide the framework for a diagnosis of probable, possible, and unlikely traumatic encephalopathy syndrome, with included discussion regarding the minimum exposure, nature of the clinical course, and additional clinical features needed for diagnosis. While prospective longitudinal studies are ongoing to further elucidate the association of exposure to head trauma, clinical features, and the development of pathologic changes, a corresponding clinical construct for diagnosis is necessary.


Frequency and factors associated with recurrences of ocular toxoplasmosis in a referral centre in Colombia.
To determine the frequency and clinically related factors for recurrences in toxoplasmic retinochoroiditis in Colombian patients. Cross-sectional analysis based on clinical charts of patients examined during the period of September 2005 to July 2008 at the University medical centre in Quindio (Colombia). Patients with retinochoroidal lesions consistent with Toxoplasma infection were included. Comparisons were made with an index of recurrences adjusted for months of follow-up or of the available data of periods with and without recurrences The clinical charts of 56 patients were analysed. In total, 25 patients (44%) were seen during an active episode, and 31 patients during inactive periods. There were 25 patients (44%) without episodes of recurrence. The total number of recurrences was 80 episodes. The mean number of recurrences was of two recurrences each 11 years. Adjusted recurrences index indicated that the most important factors associated with recurrence were previous therapy with steroids without antibiotics and previous subconjunctival injection of steroids. The use of systemic steroids without antibiotics and subconjunctival injection of steroids were identified as the main factors related to recurrence in this group of patients.


Overview of virus and cancer relationships. Position paper.
The role of certain viruses in the etiology of some tumors is today indisputable, but there is a lack, however, of annoverview of the relationship between viruses and cancer with amultidisciplinary approach. For this reason, the Health Sciences Foundation has convened a group of professionals from different areas of knowledge to discuss the relationship between viruses and cancer, and the present document is the result of these deliberations. Although viruses cause only 10-15% of cancers, advances in oncology research are largely due to the work done during the last century on tumor viruses. The clearest cancer-inducing viruses are: HPV, HBV, HCV, EBV and, depending on the geographical area, HHV-8, HTLV-1 and HIV. HPVs, for example, are considered to be the causative agents of cervical carcinomas and, more recently, of a proportion of other cancers. Among the Herpes viruses, the association with the development of neoplasms is well established for EBV and HHV-8. Viruses can also be therapeutic agents in certain neoplasms and, thus, some oncolytic viruses with selective tropism for tumor cells have been approved for clinical use in humans. It is estimated that the prophylaxis or treatment of viral infections could prevent at least 1.5 million cancer deaths per year.


Chronic gentamicin nephrotoxicity. Continued tubular injury with preserved glomerular filtration function.
After an initial episode of acute tubular necrosis, apparent resistance to gentamicin nephrotoxicity develops in rats during prolonged drug administration. The authors studied this phenomenon by examining the autoradiographic distribution of 3H-gentamicin and 3H-thymidine during 5 weeks of gentamicin treatment and by analyzing renal structure and function after a 12-week course of treatment. These studies show that regenerating cells exclude gentamicin, but concentrate it again after maturation, and that the rate of thymidine incorporation is still high well after recovery from acute toxic injury. After 12 weeks of gentamicin, the glomerular filtration rate was only modestly diminished, whereas in vitro cortical organic ion transport was substantially impaired. Light and electron microscopy demonstrated all phases of injury and recovery among cells of most proximal tubules and evidence of chronic tubulointerstitial disease. It is concluded that "resistance" to gentamicin is a state of persistent tubular cell injury obscured functionally by preservation of the glomerular filtration rate and histologically by asynchrony of cell necrosis and regeneration.


The development of a liquid biopsy for head and neck cancers.
Developing non-invasive diagnostic tools in the field of head and neck oncology has been a challenge. Analysis of circulating tumour derivatives in a patient's blood has been explored in other solid cancers. This includes analysis of circulating tumour DNA, intact circulating tumour cells (CTCs) and exosomes. These circulating tumour derivatives provide avenues of investigation which can be representative of a patient's primary tumour signature and can be assessed from a patient's blood sample. In advanced stage cancer patients, these tumour derivatives are found in higher amounts, attributed to higher cellular turnover (apoptosis, autophagy), lysed CTCs and sloughing from necrotic tumours. Head and neck squamous cell carcinoma (HNSCC) patients often present with advanced disease associated with a poor 5-year survival of <50%. Outside of sophisticated imaging and clinical examination, there is a lack of available biomarkers to measure disease burden, and/or response to therapy. Implementation of a liquid biopsy in HNSCC through serial blood samples has the potential to detect metastatic events earlier, thereby allowing better selection of appropriate treatment choices, predict prognosis in patients with potentially curable disease, monitor systemic therapies and residual disease post-treatment.


Occupations, work characteristics and common mental disorder.
The present study aimed to assess the prevalence of common mental disorders (CMDs) by occupation in a representative sample of the English adult population. Another aim was to examine whether the increased risk of CMD in some occupations could be explained by adverse work characteristics. Method We derived a sample of 3425 working-age respondents from the Adult Psychiatric Morbidity Survey 2007. Occupations were classified by Standard Occupational Classification group, and CMD measured by the Revised Clinical Interview Schedule. Job characteristics were measured by questionnaire, and tested as explanatory factors in associations of occupation and CMD. After adjusting for age, gender, housing tenure and marital status, caring personal service occupations had the greatest risk of CMD compared with all occupations (odds ratio 1.73, 95% confidence interval 1.16-2.58). The prevalence of adverse psychosocial work characteristics did not follow the pattern of CMD by occupation. Work characteristics did not explain the increased risk of CMDs associated with working in personal service occupations. Contrary to our hypotheses, adding work characteristics individually to the association of occupation and CMD tended to increase rather than decrease the odds for CMD. As has been found by others, psychosocial work characteristics were associated with CMD. However, we found that in our English national dataset they could not explain the high rates of CMD in particular occupations. We suggest that selection into occupations may partly explain high CMD rates in certain occupations. Also, we did not measure emotional demands, and these may be important mediators of the relationship between occupation type and CMDs.


HbA1c overtesting and overtreatment among US adults with controlled type 2 diabetes, 2001-13: observational population based study.
What is the extent and effect of excessive testing for glycated hemoglobin (HbA1c) among adults with controlled type 2 diabetes? A retrospective analysis of data from a national administrative claims database included commercially insured individuals in the USA, 2001-13. Study patients were aged 18 years or older, had type 2 diabetes with stable glycemic control (two consecutive tests showing HbA1c<7.0% within 24 months), did not use insulin, had no history of severe hypoglycemia or hyperglycemia, and were not pregnant. HbA1c testing frequency was measured within 24 months after the second (index) HbA1c test, and classified as guideline recommended (≤ 2 times/year), frequent (3-4 times/year), and excessive (≥ 5 times/year). Changes in treatment regimen were ascertained within three months of the index test. Of 31,545 patients in the study cohort (mean age 58 years; mean index HbA1c 6.2%), HbA1c testing frequency was excessive in 6% and frequent in 55%. Despite good glycemic control at baseline, treatment was further intensified by addition of glucose lowering drugs or insulin in 8.4% of patients (comprising 13%, 9%, and 7% of those tested excessively, frequently, and per guidelines, respectively; P<0.001). Compared with guideline recommended testing, excessive testing was associated with treatment intensification (odds ratio 1.35 (95% confidence interval 1.22 to 1.50)). Excessive testing rates remained unchanged in 2001-08, but fell significantly after 2009. The odds of excessive testing was 46% lower in 2011 than in 2001-02. The study population is not representative of all US patients with type 2 diabetes because it was restricted to commercially insured adults with stable and controlled diabetes not receiving insulin treatment. The study design did not capture the underuse of HbA1c testing. In this US cohort of adults with stable and controlled type 2 diabetes, more than 60% received too many HbA1c tests, a practice associated with potential overtreatment with hypoglycemic drugs. Excessive testing contributes to the growing problem of waste in healthcare and increased patient burden in diabetes management. NDS and RGM are funded partly by the Agency for Healthcare Research and Quality (R18HS18339) and AcademyHealth Delivery System Science Fellowship (2013), respectively. No competing interests declared. Additional data are available from email@example.com.


Distinct sensitivities of the lateral prefrontal cortex and extrastriate body area to contingency between executed and observed actions.
Detecting relationships between our own actions and the subsequent actions of others is critical for our social behavior. Self-actions differ from those of others in terms of action kinematics, body identity, and feedback timing. Thus, the detection of social contingency between self-actions and those of others requires comparison and integration of these three dimensions. Neuroimaging studies have highlighted the role of the frontotemporal network in action representation, but the role of each node and their relationships are still controversial. Here, we conducted a functional MRI experiment to test the hypothesis that the lateral prefrontal cortex and lateral occipito-temporal cortex are critical for the integration processes for social contingency. Twenty-four adults performed right finger gestures and then observed them as feedback. We manipulated three parameters of visual feedback: action kinematics (same or different gestures), body identity (self or other), and feedback timing (simultaneous or delayed). Three-way interactions of these factors were observed in the left inferior and middle frontal gyrus (IFG/MFG). These areas were active when self-actions were directly fed back in real-time (i.e., the condition causing a sense of agency), and when participants observed gestures performed by others after a short delay (i.e., the condition causing social contingency). In contrast, the left extrastriate body area (EBA) was sensitive to the concordance of action kinematics regardless of body identity or feedback timing. Body identity × feedback timing interactions were observed in regions including the superior parietal lobule (SPL). An effective connectivity analysis supported the model wherein experimental parameters modulated connections from the occipital cortex to the IFG/MFG via the EBA and SPL. These results suggest that both social contingency and the sense of agency are achieved by hierarchical processing that begins with simple concordance coding in the left EBA, leading to the complex coding of social relevance in the left IFG/MFG.


Are patients being transferred to level-I trauma centers for reasons other than medical necessity?
In the United States, the Emergency Medical Treatment and Active Labor Act defines broad guidelines regarding interhospital transfer of patients who have sought care in the emergency department. However, patient transfers for nonmedical reasons are still considered a common practice. The purpose of this study was to evaluate the possible risk factors for hospital transfer in a population of patients unlikely to require transfer to a level-I center for medical reasons. A retrospective case-control national database study was performed with use of data from the National Trauma Data Bank (version 4.3). The study group consisted of patients with low Injury Severity Scores (< or =9) who were transferred to a level-I trauma center from another hospital. The controls were patients with low Injury Severity Scores who were treated at any hospital that was lower than a level-I trauma center and were not transferred. Hypothesized risk factors for hospital transfer were the age, gender, race, and insurance status of the patient; the time of day the transfer was received; and the number and type of comorbidities. The total sample included 97,393 patients, 21% of whom were transferred to a level-I trauma center. The odds ratios adjusted for all risk factors indicated that transfer rates were higher for male patients compared with female patients (adjusted odds ratio = 1.46), children compared with seniors (3.54), blacks compared with whites (1.28), evening or night transfers compared with morning or afternoon transfers (2.25), patients with Medicaid compared with those with other types of insurance (2.02), and for those with one or more comorbidities compared with those with no comorbidity (2.79). These results suggest the need for prospective studies to further investigate the relationships between hospital transfer and medical and nonmedical factors.


The safety and efficacy of endoscopic incision of orthotopic ureterocele in adult.
Endoscopic incision is a good management option for orthotopic ureterocele. But most of the literature has shown its efficacy only in children. We have done this retrospective study to evaluate the safety and efficacy of endoscopic incision of orthotopic ureterocele in adults. From March 2004 to January 2008, at our center, 26 adults underwent transurethral, transverse incision of an ureterocele. The perioperative data of these patients were retrospectively analyzed. The literature was reviewed to identify all the reported options for management of this relatively rare condition in adults. Unilateral ureterocele was present in 24 patients and two patients had bilateral ureterocele. One patient had associated upper tract stones. Three patients had associated stones in ureterocele. Transurethral, transverse incision of ureterocele was given in all patients. The mean postoperative hospital stay was 50.5 h. Twenty-three patients were available for follow-up at three, six and 12 months. All patients were symptom free. At three months ultrasound and intravenous urography revealed no residual ureterocele but four patients showed residual hydronephrosis, but with a decrease in the grade indicating decompression. Micturating cystourethrography revealed vesico-ureteral reflux (VUR) in two patients and the reflux persisted in one patient even at 6 months. We conclude that in adults, management with endoscopic incision of orthotopic ureterocele is safe and effective. VUR may occur in a few cases.


Clinical quantitative cardiac imaging for the assessment of myocardial ischaemia.
Cardiac imaging has a pivotal role in the prevention, diagnosis and treatment of ischaemic heart disease. SPECT is most commonly used for clinical myocardial perfusion imaging, whereas PET is the clinical reference standard for the quantification of myocardial perfusion. MRI does not involve exposure to ionizing radiation, similar to echocardiography, which can be performed at the bedside. CT perfusion imaging is not frequently used but CT offers coronary angiography data, and invasive catheter-based methods can measure coronary flow and pressure. Technical improvements to the quantification of pathophysiological parameters of myocardial ischaemia can be achieved. Clinical consensus recommendations on the appropriateness of each technique were derived following a European quantitative cardiac imaging meeting and using a real-time Delphi process. SPECT using new detectors allows the quantification of myocardial blood flow and is now also suited to patients with a high BMI. PET is well suited to patients with multivessel disease to confirm or exclude balanced ischaemia. MRI allows the evaluation of patients with complex disease who would benefit from imaging of function and fibrosis in addition to perfusion. Echocardiography remains the preferred technique for assessing ischaemia in bedside situations, whereas CT has the greatest value for combined quantification of stenosis and characterization of atherosclerosis in relation to myocardial ischaemia. In patients with a high probability of needing invasive treatment, invasive coronary flow and pressure measurement is well suited to guide treatment decisions. In this Consensus Statement, we summarize the strengths and weaknesses as well as the future technological potential of each imaging modality.


Tooth discoloration in patients with neonatal diabetes after transfer onto glibenclamide: a previously unreported side effect.
OBJECTIVE To assess if tooth discoloration is a novel side effect of sulfonylurea therapy in patients with permanent neonatal diabetes due to mutations in KCNJ11. RESEARCH DESIGN AND METHODS A total of 67 patients with a known KCNJ11 mutation who had been successfully transferred from insulin injections onto oral sulfonylureas were contacted and asked about the development of tooth discoloration after transfer. RESULTS Altered tooth appearance was identified in 5 of the 67 patients. This was variable in severity, ranging from mild discoloration/staining (n = 4) to loss of enamel (n = 1) and was only seen in patients taking glibenclamide (glyburide). CONCLUSIONS These previously unreported side effects may relate to the developing tooth and/or to the high local concentrations in the children who frequently chewed glibenclamide tablets or took it as a concentrated solution. Given the multiple benefits of sulfonylurea treatment for patients with activating KCNJ11 mutations, this association warrants further investigation but should not preclude such treatment.


ω-3 fatty acid treatment in multiple sclerosis (OFAMS Study): a randomized, double-blind, placebo-controlled trial.
To investigate whether ω-3 fatty acids reduce magnetic resonance imaging (MRI) and clinical disease activity in patients with multiple sclerosis, both as monotherapy and in combination with interferon beta-1a treatment. Multicenter, randomized, double-blind, placebo-controlled clinical trial conducted from 2004 to 2008. Thirteen public neurology departments in Norway. Patients aged 18 to 55 years with active relapsing-remitting multiple sclerosis, with a disability score equivalent to 5.0 or less on the Kurtzke Expanded Disability Status Scale. Ninety-two patients were randomized to ω-3 fatty acids (n = 46) or placebo capsules (n = 46). Administration of 1350 mg of eicosapentaenoic acid and 850 mg of docosahexaenoic acid daily or placebo. After 6 months, all patients in addition received subcutaneously 44 μg of interferon beta-1a 3 times per week for another 18 months. The primary outcome measure was MRI disease activity as measured by the number of new T1-weighted gadolinium-enhancing lesions during the first 6 months. Secondary outcome measures included MRI disease activity after 9 months and 24 months, relapse rate, disability progression, fatigue, quality of life, and safety. The cumulative number of gadolinium-enhancing MRI lesions during the first 6 months were similar in the ω-3 fatty acids and placebo groups (median difference, 1; 95% CI, 0 to 3; P = .09). No difference in relapse rate was detected after 6 (median difference, 0; 95% CI, 0 to 0; P = .54) or 24 (median difference, 0; 95% CI, 0 to 0; P = .72) months. The proportion of patients without disability progression was 70% in both groups (P > .99). No differences were detected in fatigue or quality-of-life scores, and no safety concerns appeared. Serum analyses of fatty acids showed an increase in ω-3 fatty acids (mean difference, 7.60; 95% CI, 5.57 to 7.91; P < .001) in the patients treated with ω-3 fatty acids compared with the placebo group. No beneficial effects on disease activity were detected from ω-3 fatty acids when compared with placebo as monotherapy or in combination with interferon beta-1a. Magnetic resonance imaging disease activity was reduced as expected by interferon beta-1a. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00360906.


Unexpected Molecular Sieving Properties of Zeolitic Imidazolate Framework-8.
We studied molecular sieving properties of zeolitic imidazolate framework-8 (ZIF-8) by estimating the thermodynamically corrected diffusivities of probe molecules at 35 °C. From helium (2.6 Å) to iso-C4H10 (5.0 Å), the corrected diffusivity drops 14 orders of magnitude. Our results further suggest that the effective aperture size of ZIF-8 for molecular sieving is in the range of 4.0 to 4.2 Å, which is significantly larger than the XRD-derived value (3.4 Å) and between the well-known aperture size of zeolite 4A (3.8 Å) and 5A (4.3 Å). Interestingly, because of aperture flexibility, the studied C4 hydrocarbon molecules that are larger than this effective aperture size still adsorb in the micropores of ZIF-8 with kinetic selectivities for iso-C4H8/iso-C4H10 of 180 and n-C4H10/iso-C4H10 of 2.5 × 10(6). These unexpected molecular sieving properties open up new opportunities for ZIF materials for separations that cannot be economically achieved by traditional microporous adsorbents such as synthetic zeolites.


Guidelines for Family-Centered Care in the Neonatal, Pediatric, and Adult ICU.
To provide clinicians with evidence-based strategies to optimize the support of the family of critically ill patients in the ICU. We used the Council of Medical Specialty Societies principles for the development of clinical guidelines as the framework for guideline development. We assembled an international multidisciplinary team of 29 members with expertise in guideline development, evidence analysis, and family-centered care to revise the 2007 Clinical Practice Guidelines for support of the family in the patient-centered ICU. We conducted a scoping review of qualitative research that explored family-centered care in the ICU. Thematic analyses were conducted to support Population, Intervention, Comparison, Outcome question development. Patients and families validated the importance of interventions and outcomes. We then conducted a systematic review using the Grading of Recommendations, Assessment, Development and Evaluations methodology to make recommendations for practice. Recommendations were subjected to electronic voting with pre-established voting thresholds. No industry funding was associated with the guideline development. The scoping review yielded 683 qualitative studies; 228 were used for thematic analysis and Population, Intervention, Comparison, Outcome question development. The systematic review search yielded 4,158 reports after deduplication and 76 additional studies were added from alerts and hand searches; 238 studies met inclusion criteria. We made 23 recommendations from moderate, low, and very low level of evidence on the topics of: communication with family members, family presence, family support, consultations and ICU team members, and operational and environmental issues. We provide recommendations for future research and work-tools to support translation of the recommendations into practice. These guidelines identify the evidence base for best practices for family-centered care in the ICU. All recommendations were weak, highlighting the relative nascency of this field of research and the importance of future research to identify the most effective interventions to improve this important aspect of ICU care.


Ethical considerations for modern molecular pathology.
Molecular pathology is becoming an increasingly important discipline in oncology as molecular tumor characteristics will increasingly determine targeted clinical cancer care. In recent years, many technological advances have taken place that contributed to the development of molecular pathology. However, attention to ethical aspects has been lagging behind as illustrated by the lack of publications or professional guidelines. Existing guidelines or publications on ethical aspects of DNA sequencing are mostly aimed at germline or tumor sequencing in clinical genetics or biomedical research settings. As a result, large differences have been demonstrated in the process of tumor sequencing analysis between laboratories. In this perspective we discuss the ethical issues to consider in molecular pathology by following the process of tumor DNA sequencing analysis from the preanalytical to postanalytical phase. For the successful and responsible use of DNA sequencing in clinical cancer care, several moral requirements must be met, for example, those related to the interpretation and returning of genetic results, informed consent, and the retrospective as well as future use of genetic data for biomedical research. Many ethical issues are new to pathology or more stringent than in current practice because DNA sequencing could yield sensitive and potentially relevant data, such as clinically significant unsolicited findings. The context of molecular pathology is unique and complex, but many issues are similar to those applicable to clinical genetics. As such, existing scholarship in this discipline may be translated to molecular pathology with some adaptations and could serve as a basis for guideline development. For responsible use and further development of clinical cancer care, we recommend that pathologists take responsibility for the adequate use of molecular analyses and be fully aware and capable of dealing with the diverse, complex, and challenging aspects of tumor DNA sequencing, including its ethical issues. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Using geographic information systems to evaluate cardiac arrest survival.
To evaluate cardiac arrest survival using geographical information systems (GIS) methodology. Patient data were obtained from a fire district Utstein-style adult cardiac arrest registry that also included address data. All incident locations were geocoded and fire station first-due areas were mapped by using the new computer-aided dispatch geographic data. Retrospective assignment of first-due versus second-due fire response unit was done by using a GIS "point-in-polygon" algorithm Survival to hospital admission was the primary outcome measure for incidents responded to by first-due versus second-due apparatus controlling for other potential predictors of survival using logistic regression. Cluster analysis was also performed to evaluate potential areas of high or low rates of survival. There were 461 eligible patients with an average age of 67+/-17 years, 63% were male, 53% had a witnessed arrest, bystander cardiopulmonary resuscitation was performed in 38%, bystander automatic external defibrillator (AED) Page: 1 was used in 0.01%, ventricular fibrillation or ventricular tachycardia were the presenting rhythms in 44%, the average response time was 5.5+/-2.1 minutes, and survival to hospital admission was 17%. There was no significant difference in response time between survivors (4.97 minutes) and non-survivors (5.52 minutes), (difference 0.55 minutes, 95%CI -0.08 to 1.18 min). The number of cardiac arrest calls varied from 1 to 49 for each station and the rate of second-due response varied from 0 to 19%. There was a nonsignificant association of survival to hospital admission for the first-due area cohort: odds ratio 0.70, 95% CI 0.38-1.29. GIS is a new methodology for analyzing EMS incident data. It adds a spatial component of analysis to traditional statistical techniques. No spatial difference was found on patient survival in this analysis.


Therapeutic strategies targeting endothelial function in humans: clinical implications.
Persistent oxidative stress in the vascular wall may lead to endothelial dysfunction, a pathological process widely implicated in the morbidities observed in a spectrum of cardiovascular disease. The production of reactive oxygen species (ROS) is regulated by various oxidase enzymes and mitochondrial electron transport mechanisms. Nitric oxide (NO) is a key mediator of endothelial function via its effect on endothelium dependent vascular relaxation. Therapeutic interventions aimed to increase NO bioavailability in the vasculature may improve the long term cardiovascular outcome for healthy individuals, high-risk subjects, and patients with advanced atherosclerosis. Current therapeutic strategies focus on enhancing synthesis or lowering oxidative inactivation of NO in human vasculature. Of the available therapeutic agents, angiotensin converting enzyme inhibitors and statins have shown most promise at improving endothelial function and cardiovascular outcome after long term administration. Other therapeutic approaches may also be useful towards improving endothelial dysfunction. These strategies include targeting NO synthesis by modulation of endothelial nitric oxide synthase (eNOS) coupling, such as folates and tetrahydrobiopterin. Evidence for the benefits of gene therapy to improve endothelial function is also emerging. However, the long term direct clinical benefit of these strategies aimed to improve endothelial function still remains unclear.