A controlled trial of light therapy for the treatment of pediatric seasonal affective disorder.
To evaluate the efficacy of light therapy for the treatment of pediatric seasonal affective disorder (SAD). 28 children (aged 7 to 17 years) at two geographically distinct sites were enrolled in a double-blind, placebo-controlled, crossover trial of bright-light treatment. Subjects initially entered a week-long baseline period during which they wore dark glasses for an hour a day. They were then randomly assigned to receive either active treatment (1 hour of bright-light therapy plus 2 hours of dawn simulation) or placebo (1 hour of clear goggles plus 5 minutes of low-intensity dawn simulation) for 1 week. The treatment phase was followed by a second dark-glasses phase lasting 1 to 2 weeks. After this phase, the children received the alternate treatment. Response was measured using the parent and child versions of the Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorders version (SIGH-SAD). Data were analyzed as change from baseline. SIGH-SAD-P total depression scores were significantly decreased from baseline during light therapy compared with placebo (one-way analysis of variance, rho = .009), and no differences were found between the placebo and control phases. Subscores of atypical and typical depression were also significantly decreased during the active treatment (rho = .004 and .028, respectively). A similar trend was noted with the SIGH-SAD-C, but this did not reach significance. At the end of the study, 78% of the parents questioned and 80% of the children questioned rated light therapy as the phase during which the child "felt best." Light therapy appears to be an effective treatment for pediatric SAD.


Physiological basis for the etiology, diagnosis, and treatment of adrenal disorders: Cushing's syndrome, adrenal insufficiency, and congenital adrenal hyperplasia.
The hypothalamic-pituitary-adrenal (HPA) axis is a classic neuroendocrine system. One of the best ways to understand the HPA axis is to appreciate its dynamics in the variety of diseases and syndromes that affect it. Excess glucocorticoid activity can be due to endogenous cortisol overproduction (spontaneous Cushing's syndrome) or exogenous glucocorticoid therapy (iatrogenic Cushing's syndrome). Endogenous Cushing's syndrome can be subdivided into ACTH-dependent and ACTH-independent, the latter of which is usually due to autonomous adrenal overproduction. The former can be due to a pituitary corticotroph tumor (usually benign) or ectopic ACTH production from tumors outside the pituitary; both of these tumor types overexpress the proopiomelanocortin gene. The converse of Cushing's syndrome is the lack of normal cortisol secretion and is usually due to adrenal destruction (primary adrenal insufficiency) or hypopituitarism (secondary adrenal insufficiency). Secondary adrenal insufficiency can also result from a rapid discontinuation of long-term, pharmacological glucocorticoid therapy because of HPA axis suppression and adrenal atrophy. Finally, mutations in the steroidogenic enzymes of the adrenal cortex can lead to congenital adrenal hyperplasia and an increase in precursor steroids, particularly androgens. When present in utero, this can lead to masculinization of a female fetus. An understanding of the dynamics of the HPA axis is necessary to master the diagnosis and differential diagnosis of pituitary-adrenal diseases. Furthermore, understanding the pathophysiology of the HPA axis gives great insight into its normal control.


Care of the Pregnant Patient With Inflammatory Bowel Disease.
Inflammatory bowel disease affects women in their peak reproductive years. Patients and physicians often have questions regarding the effect of inflammatory bowel disease on a woman's ability to conceive and to carry a pregnancy safely to term as well as the effect of inflammatory bowel disease and the medications used to treat it on pregnancy outcomes. Women with inflammatory bowel disease have the same rates of fertility as women without inflammatory bowel disease unless they have had prior surgery in the pelvis or active disease. However, women with inflammatory bowel disease do have higher rates of adverse pregnancy outcomes. A multidisciplinary approach involving gastroenterologists, obstetricians, and maternal-fetal medicine physicians should focus on preconception planning and disease optimization before pregnancy. Women with inflammatory bowel disease should be followed as high-risk obstetric patients. Most medications used to treat inflammatory bowel disease can be continued safely during pregnancy and lactation. The greatest risk to the pregnancy is active disease, which can be precipitated by discontinuation of effective maintenance medications. Preconception counseling should include education regarding the low risk of most inflammatory bowel disease medications during pregnancy and lactation and the high risk of a significant disease flare during pregnancy. This review outlines important considerations for obstetricians caring for women with inflammatory bowel disease before and during pregnancy and in the postpartum period.


Axicon lens for coherent matter waves.
We have realized a conical matter wave lens. The repulsive potential of a focused laser beam was used to launch a Bose-Einstein condensate into a radially expanding wavepacket whose perfect ring shape was ensured by energy conservation. In spite of significant interactions between atoms, the spatial and velocity widths of the ring along its radial dimension remained extremely narrow, as also confirmed by numerical simulations. Our results open the possibility for cylindrical atom optics without the perturbing effect of mean-field interactions.


Water Use Patterns of Sympatric Przewalski's Horse and Khulan: Interspecific Comparison Reveals Niche Differences.
Acquiring water is essential for all animals, but doing so is most challenging for desert-living animals. Recently Przewalski's horse has been reintroduced to the desert area in China where the last wild surviving member of the species was seen before it vanished from China in the 1960s. Its reintroduction placed it within the range of a close evolutionary relative, the con-generic Khulan. Determining whether or not these two species experience competition and whether or not such competition was responsible for the extinction of Przewalski's horses in the wild over 50 years ago, requires identifying the fundamental and realized niches of both species. We remotely monitored the presence of both species at a variety of water points during the dry season in Kalamaili Nature Reserve, Xinjiang, China. Przewalski's horses drank twice per day mostly during daylight hours at low salinity water sources while Khulans drank mostly at night usually at high salinity water points or those far from human residences. Spatial and temporal differences in water use enables coexistence, but suggest that Przewalski's horses also restrict the actions of Khulan. Such differences in both the fundamental and realized niches were associated with differences in physiological tolerances for saline water and human activity as well as differences in aggression and dominance.


Is Dry Needling Effective for the Management of Spasticity, Pain, and Motor Function in Post-Stroke Patients? A Systematic Review and Meta-Analysis.
To evaluate the effects of muscle dry needling alone or combined with other interventions on post-stroke spasticity (muscle tone), related pain, motor function, and pressure sensitivity. Electronic databases were searched for randomized controlled trials including post-stroke patients where at least one group received dry needling and outcomes were collected on spasticity and related pain. Secondary outcomes included motor function and pressure pain sensitivity. Data were extracted by two reviewers. The risk of bias was assessed with the Cochrane Risk of Bias tool, methodological quality was assessed with the Physiotherapy Evidence Database score, and the quality of evidence was assessed by the Grading of Recommendations Assessment, Development, and Evaluation approach. Between-groups mean differences (MDs) and standardized mean differences (SMDs) were calculated. Seven studies (three within the lower extremity, four in the upper extremity) were included. The meta-analysis found significantly large effect sizes of dry needling for reducing spasticity (SMD: -1.01, 95%confidence interval [CI] -1.68 to -0.34), post-stroke pain (SMD -1.01, 95%CI -1.73 to -0.30), and pressure pain sensitivity (SMD 1.21, 95% CI: 0.62 to 1.80) as compared with a comparative group at short-term follow-up. The effect on spasticity was found mainly in the lower extremity (MD -1.05, 95% CI: -1.32 to -0.78) at short-term follow-up. No effect on spasticity was seen at 4 weeks. No significant effect on motor function (SMD 0.16, 95% CI: -0.13 to 0.44) was observed. The risk of bias was generally low, but the imprecision of the results downgraded the level of evidence. Moderate evidence suggests a positive effect of dry needling on spasticity (muscle tone) in the lower extremity in post-stroke patients. The effects on related pain and motor function are inconclusive.


Characterizing the associative content of brain structures involved in habitual and goal-directed actions in humans: a multivariate FMRI study.
While there is accumulating evidence for the existence of distinct neural systems supporting goal-directed and habitual action selection in the mammalian brain, much less is known about the nature of the information being processed in these different brain regions. Associative learning theory predicts that brain systems involved in habitual control, such as the dorsolateral striatum, should contain stimulus and response information only, but not outcome information, while regions involved in goal-directed action, such as ventromedial and dorsolateral prefrontal cortex and dorsomedial striatum, should be involved in processing information about outcomes as well as stimuli and responses. To test this prediction, human participants underwent fMRI while engaging in a binary choice task designed to enable the separate identification of these different representations with a multivariate classification analysis approach. Consistent with our predictions, the dorsolateral striatum contained information about responses but not outcomes at the time of an initial stimulus, while the regions implicated in goal-directed action selection contained information about both responses and outcomes. These findings suggest that differential contributions of these regions to habitual and goal-directed behavioral control may depend in part on basic differences in the type of information that these regions have access to at the time of decision making.


A critique of western medical commentary on the People's Republic of China.
The American medical literature generally has given favorable reviews to the Chinese Communist experiment, which has often been credited with astonishing, unprecedented achievements in public health. Improvements are explicitly attributed to the Chinese political system, despite its acknowledged shortcomings from an American perspective. A survey of articles about Chinese medicine discloses numerous scientific flaws, eg, inadequate sampling, biased reporting, inappropriate attribution of causal relationships, lack of suitable controls, and ablation of conflicting data. The promulgation of such errors results in part from imprecise euphemistic language.


Sex- and age-specific effects of nutrition in early gestation and early postnatal life on hypothalamo-pituitary-adrenal axis and sympathoadrenal function in adult sheep.
The early-life environment affects risk of later metabolic disease, including glucose intolerance, insulin resistance and obesity. Changes in hypothalamo-pituitary-adrenal (HPA) axis and sympathoadrenal function may underlie these disorders. To determine consequences of undernutrition in early gestation and/or immediately following weaning on HPA axis and sympathoadrenal function, 2- to 3-year-old Welsh Mountain ewes received 100% (C, n = 39) or 50% nutritional requirements (U, n = 41) from 1-31 days gestation, and 100% thereafter. From weaning (12 weeks) to 25 weeks of age, male and female offspring were then either fed ad libitum (CC, n = 22; UC, n = 19) or were undernourished (CU, n = 17; UU, n = 22) such that body weight was reduced to 85% of their individual target, based on a growth trajectory calculated from weights taken between birth and 12 weeks. From 25 weeks, ad libitum feeding was restored for all offspring. At 1.5 and 2.5 years, adrenocorticotropic hormone (ACTH) and cortisol concentrations were measured at baseline and in response to corticotropin-releasing factor (CRF) (0.5 microg kg(1)) plus arginine vasopressin (AVP) (0.1 microg kg(1)). At 2.5 years, HPA axis and sympathoadrenal (catecholamine) responses to a transport and isolation stress test were also measured. In females, post-weaning undernutrition reduced pituitary output (ACTH) but increased adrenocortical responsiveness (cortisol:ACTH area under curve) during CRF/AVP challenge at 1.5 years and increased adrenomedullary output (adrenaline) to stress at 2.5 years. In males, cortisol responses to stress at 2.5 years were reduced in those with slower growth rates from 12 to 25 weeks. Early gestation undernutrition was associated with increased adrenocortical output in 2.5-year-old females only. Pituitary and adrenal responses were also related to adult body composition. Thus, poor growth in the post-weaning period induced by nutrient restriction has sex- and age-specific effects on HPA and sympathoadrenal function. With altered glucose tolerance previously reported in this model, this may have long-term detrimental effects on metabolic homeostasis and cardiovascular function.


Hydrogeologic controls on the transport and fate of nitrate in ground water beneath riparian buffer zones: results from thirteen studies across the United States.
During the last two decades there has been growing interest in the capacity of riparian buffer zones to remove nitrate from ground waters moving through them. Riparian zone sediments often contain organic carbon, which favors formation of reducing conditions that can lead to removal of nitrate through denitrification. Over the past decade the National Water Quality Assessment (NAWQA) Program has investigated the transport and fate of nitrate in ground and surface waters in study areas across the United States. In these studies riparian zone efficiency in removing nitrate varied widely as a result of variations in hydrogeologic factors. These factors include (1) denitrification in the up-gradient aquifer due to the presence of organic carbon or other electron donors, (2) long residence times (>50 years) along ground-water flow paths allowing even slow reactions to completely remove nitrate, (3) dilution of nitrate enriched waters with older water having little nitrate, (4) bypassing of riparian zones due to extensive use of drains and ditches, and (5) movement of ground water along deep flow paths below reducing zones. By developing a better understanding of the hydrogeologic settings in which riparian buffer zones are likely to be inefficient we can develop improved nutrient management plans.


Establishment of an in-use testing method for evaluating disinfection of surgical instruments using the duck hepatitis B model.
Nosocomial transmission of hepatitis B virus (HBV), associated with interventional procedures, has been attributed to its survival on improperly decontaminated instruments. To date, guidelines for chemical disinfection of potentially contaminated heat-sensitive instruments have been based largely on extrapolation of data from in-vitro disinfectant testing. Direct infectivity testing has not been possible for HBV because of the lack of a practical culture assay or susceptible experimental animal model. In this study the related duck hepadnavirus was used to simulate in-vivo transmission of a HBV during surgery, and to evaluate the effectiveness of 2% glutaraldehyde disinfection of surgical laparoscopes. Multiple laparoscopic liver biopsies were performed on 'biohazardous' duck hepatitis B (DHBV) positive ducks. Laparoscopes were then subjected to different disinfection regimes using 2% glutaraldehyde, and residual infectivity tested by placing their tips into the peritoneal cavities of uninfected four-day-old ducklings. Direct transmission of DHBV occurred in all ducks when laparoscopes were not washed. Rinsing with water lowered the transmission rate to 64% and no infection transmission occurred after 5 min of contact time with the disinfectant. In contrast, previous in-vitro studies had shown complete viral inactivation after a shorter period of disinfection. It is postulated that the longer inactivation time observed in our study may be a result of surface interactions of virus and instrument, interfering with disinfectant access or activity. Tests of instrument surface samples for viral DNA by the polymerase chain reaction (PCR) did not correlate with transmission of virus infection in vivo. PCR is an inappropriate test for evaluating the efficacy of disinfectant action despite its sensitivity. This in use method will allow testing of other decontamination procedures and their effectiveness on more complex surgical instruments.


Traditional Japanese Kampo Medicine: Clinical Research between Modernity and Traditional Medicine-The State of Research and Methodological Suggestions for the Future.
The Japanese traditional herbal medicine, Kampo, has gradually reemerged and 148 different formulations (mainly herbal extracts) can be prescribed within the national health insurance system. The objective of this article is to introduce Kampo and to present information from previous clinical studies that tested Kampo formulae. In addition, suggestions on the design of future research will be stated. The literature search was based on a summary, up until January 2009, by the Japanese Society of Oriental Medicine and included only those trials which were also available in either Pubmed or ICHUSHI (Japan Medical Abstracts Society). We included 135 studies, half of these studies (n = 68) used a standard control and 28 a placebo control. Thirty-seven trials were published in English [all randomized controlled trials (RCTs)] and the remaining articles were in Japanese only. The sample size for most studies was small (two-third of the studies included less than 100 patients) and the overall methodological quality appeared to be low. None of the studies used Kampo diagnosis as the basis for the treatment. In order to evaluate Kampo as a whole treatment system, certain aspects should be taken into account while designing studies. RCTs are the appropriate study design to test efficacy or effectiveness; however, within the trial the treatment could be individualized according to the Kampo diagnosis. Kampo is a complex and individualized treatment with a long tradition, and it would be appropriate for further research on Kampo medicine to take this into account.


Systematic review of the incidence and prevalence of genital warts.
Anogenital warts (AGWs) are a common, highly infectious disease caused by the human papillomavirus (HPV), whose high recurrence rates contribute to direct medical costs, productivity loss and increased psychosocial impact. Because of the lack of a systematic review of the epidemiology of AGWs in the literature, this study reviewed the published medical literature on the incidence and prevalence of AGWs. A comprehensive literature search was performed on the worldwide incidence and prevalence of AGWs between 2001 and 2012 using the PubMed and EMBASE databases. An additional screening of abstracts from relevant sexual health and infectious disease conferences from 2009 to 2011 was also conducted. Only original studies with general adult populations (i.e., at least including ages 20 through 40 years) were included. The overall (females and males combined) reported annual incidence of any AGWs (including new and recurrent) ranged from 160 to 289 per 100,000, with a median of 194.5 per 100,000. New AGW incidence rates among males ranged from 103 to 168 per 100,000, with a median of 137 per 100,000 and among females from 76 to 191 per 100,000, with a median of 120.5 per 100,000 per annum. The reported incidence of recurrent AGWs was as high as 110 per 100,000 among females and 163 per 100,000 among males. Incidence peaked before 24 years of age in females and between 25 and 29 years of age among males. The overall prevalence of AGWs based on retrospective administrative databases or medical chart reviews or prospectively collected physician reports ranged from 0.13% to 0.56%, whereas it ranged from 0.2% to 5.1% based on genital examinations. The literature suggests that AGWs are widespread and the prevalence depends on study methodology as suggested by higher rates reported from routine genital examinations versus those from treatment records. However, there remains a need for more population-based studies from certain regions including Africa, Latin America and Southern Asia to further elucidate the global epidemiology of this disease.


Change Appeals: How Referencing Change Boosts Curiosity and Promotes Persuasion.
Does merely referencing that an object or entity has changed affect people's attitudes and intentions toward it? This research investigates the possibility that change references spark curiosity and information seeking, which can have a positive or negative effect on people's evaluations of a target stimulus, depending on the information environment. Seven experiments reveal that referencing that an object or entity has changed decreases perceptions of its longevity, but also sparks curiosity about it-a desire to learn more. This curiosity motivates people to seek information about the object or entity, which can enhance or depress their evaluations depending on whether that information search leads to favorable or unfavorable information. When further information is unavailable, change references appear to have a negative impact on people's evaluations, consistent with well-established longevity biases. This research suggests that change references have an important and generalizable impact on persuasive outcomes and pinpoints the conditions surrounding and processes driving this effect.


Design, Synthesis, Biological Evaluation and Molecular Docking Studies of Some New Sulfonamides Possessing 1,4-Benzodioxane Nucleus.
In the current research work we have reported a series of N-aryl-2,3-dihydrobenzo[1,4]dioxine-6-sulfonamides 3 and their N-substituted derivatives 6 and 7, obtained from 3 with benzyl chloride and ethyl iodide, respectively. The synthesis was accomplished as a multistep sequence. The structural confirmations were established by 1H NMR, IR and EIMS spectral techniques. Butyrylcholinesterase (BChE), acetylcholinesterase (AChE) and lipoxygenase (LOX) enzymes were used in this study. It was observed that most of the compounds prepared exhibit a moderate activity against BChE and AChE but promisingly good activity against lipoxygenase. Among the parent sulfonamides 3a, 3b, 3c and 3e showed the proficient antimicrobial activities, while from the derivatives 6a, 6c, 7a, 7b and 7c were found active against the selected panel of bacterial and fungal species. Hemolytic activity was also conducted to check their therapeutic utility. All the compounds were computationally docked against LOX, BChE and AChE enzymes.


Virtual Sensing and Virtual Reality: How New Technologies Can Boost Research on Crowd Dynamics.
The collective behavior of human crowds often exhibits surprisingly regular patterns of movement. These patterns stem from social interactions between pedestrians such as when individuals imitate others, follow their neighbors, avoid collisions with other pedestrians, or push each other. While some of these patterns are beneficial and promote efficient collective motion, others can seriously disrupt the flow, ultimately leading to deadly crowd disasters. Understanding the dynamics of crowd movements can help urban planners manage crowd safety in dense urban areas and develop an understanding of dynamic social systems. However, the study of crowd behavior has been hindered by technical and methodological challenges. Laboratory experiments involving large crowds can be difficult to organize, and quantitative field data collected from surveillance cameras are difficult to evaluate. Nevertheless, crowd research has undergone important developments in the past few years that have led to numerous research opportunities. For example, the development of crowd monitoring based on the virtual signals emitted by pedestrians' smartphones has changed the way researchers collect and analyze live field data. In addition, the use of virtual reality, and multi-user platforms in particular, have paved the way for new types of experiments. In this review, we describe these methodological developments in detail and discuss how these novel technologies can be used to deepen our understanding of crowd behavior.


Noninvasive Prenatal Detection of Trisomy 21 by Targeted Semiconductor Sequencing: A Technical Feasibility Study.
To develop an alternate noninvasive prenatal testing method for the assessment of trisomy 21 (T21) using a targeted semiconductor sequencing approach. A customized AmpliSeq panel was designed with 1,067 primer pairs targeting specific regions on chromosomes 21, 18, 13, and others. A total of 235 samples, including 30 affected with T21, were sequenced with an Ion Torrent Proton sequencer, and a method was developed for assessing the probability of fetal aneuploidy via derivation of a risk score. Application of the derived risk score yields a bimodal distribution, with the affected samples clustering near 1.0 and the unaffected near 0. For a risk score cutoff of 0.345, above which all would be considered at "high risk," all 30 T21-positive pregnancies were correctly predicted to be affected, and 199 of the 205 non-T21 samples were correctly predicted. The average hands-on time spent on library preparation and sequencing was 19 h in total, and the average number of reads of sequence obtained was 3.75 million per sample. With the described targeted sequencing approach on the semiconductor platform using a custom-designed library and a probabilistic statistical approach, we have demonstrated the feasibility of an alternate method of assessment for fetal T21.


Activation of AMPK/TSC2/PLD by alcohol regulates mTORC1 and mTORC2 assembly in C2C12 myocytes.
Ethanol (EtOH) decreases muscle protein synthesis, and this is associated with reduced mammalian target of rapamycin complex (mTORC)1 and increased mTORC2 activities. In contrast, phospholipase D (PLD) and its metabolite phosphatidic acid (PA) positively regulate mTORC1 signaling, whereas their role in mTORC2 function is less well defined. Herein, we examine the role that PLD and PA play in EtOH-mediated mTOR signaling. C2C12 myoblasts were incubated with EtOH for 18 to 24 hours. For PA experiments, cells were pretreated with the drug for 25 minutes followed by 50-minute incubation with PA in the presence or absence of EtOH. The phosphorylation state of various proteins was assessed by immunoblotting. Protein-protein interactions were determined by immunoprecipitation and immunoblotting. PLD activity was measured using the Amplex Red PLD assay kit. PA concentrations were determined with a total PA assay kit. PA levels and PLD activity increased in C2C12 myocytes exposed to EtOH (100 mM). Increased PLD activity was blocked by inhibitors of AMP-activated protein kinase (AMPK) (compound C) and phosphoinositide 3-kinase (PI3K) (wortmannin). Likewise, suppression of PLD activity with CAY10594 prevented EtOH-induced Akt (S473) phosphorylation. PLD inhibition also enhanced the binding of Rictor to mSin1 and the negative regulatory proteins Deptor and 14-3-3. Addition of PA to myocytes decreased Akt phosphorylation, but changes in mTORC2 activity were not associated with altered binding of complex members and 14-3-3. PA increased S6K1 phosphorylation, with the associated increase in mTORC1 activity being regulated by reduced phosphorylation of AMPKα (T172) and its target tuberous sclerosis protein complex (TSC)2 (S1387). This resulted in increased Rheb and RagA/RagC GTPase interactions with mTOR, as well as suppression of mTORC2. EtOH-induced increases in PLD activity and PA may partially counterbalance the adverse effects of this agent. EtOH and PA regulate mTORC1 via a PI3K/AMPK/TSC2/PLD signaling cascade. PA stimulates mTORC1 function and suppresses activation of mTORC2 as part of an mTORC1/2 feedback loop.


Multiple viral infection in Penaeus monodon shrimp postlarvae in an Indian hatchery.
Moribund Penaeus monodon postlarvae (PL8-PL10) in a hatchery in India were found to be simultaneously infected by 3 different viruses. They were highly infected with monodon baculovirus (MBV) and hepatopancreatic parvovirus (HPV) by histology and with white spot syndrome virus (WSSV) by non-nested polymerase chain reaction (PCR). Apparently healthy postlarvae tested from the same hatchery were positive for MBV and WSSV by nested PCR only. Tissue sections of such postlarvae did not show any histopathological changes. The simultaneous occurrence of these 3 viruses in hatchery-reared postlarval P. monodon is being reported for the first time.


Video gait analysis for ambulatory children with cerebral palsy: Why, when, where and how!
This paper outlines the application of video gait analysis (VGA) for children with cerebral palsy (CP) when full instrumented three dimensional gait analysis (3DGA) is either not indicated or not available. Gait analysis is an important part of the assessment of ambulant children with CP for diagnosing gait deviations and for evaluating change. Many regard 3DGA as the most informative method of assessing gait, however, it is not always accessible, practical, or feasible and the detail obtained is not always indicated. VGA in conjunction with other carefully selected outcome measures can provide a comprehensive gait assessment in situations where 3DGA is not available or not indicated. Indications for VGA use include: documenting change in gait pattern over time, frequent monitoring in the rehabilitation phase following treatments and interventions (including surgery, spasticity management, serial casting and intensive therapy), monitoring orthotic changes, and for very young children and those with behavioural/cognitive issues that preclude them from cooperating with a 3DGA. Simple and inexpensive VGA systems can be set up in most settings. In an effort to make the process more objective and reliable a number of observational gait scales have been developed. Of these the Edinburgh Gait Score (EGS) has the strongest psychometric properties and is the most comprehensive by including both the coronal and the sagittal planes. While 3DGA remains an important part of complex clinical decision-making, there is also an increasingly important role for VGA. Guidelines need to be developed for its use within the field of gait analysis.


Failure of standard antimicrobial therapy in children aged 3-59 months with mild or asymptomatic HIV infection and severe pneumonia.
To determine whether children aged 3-59 months with mild or non-symptomatic human immunodeficiency virus (HIV) infection and WHO-defined severe pneumonia have a higher failure rate than do HIV-uninfected children when treated with the standard WHO treatment of parenteral penicillin or oral amoxicillin. This study was a planned sub-analysis of a randomized trial of 3-59-month-old children presenting with WHO-defined severe pneumonia (the APPIS study). We included two sites with high HIV prevalence in Durban, South Africa and Ndola, Zambia. Primary outcome measures were clinical treatment failure at day 2 and day 14. CLINICALTRIALS.GOV IDENTIFIER: CT00227331http://www.clinicaltrialsgov/show/NCT00227331). Of the 523 children enrolled, HIV status was known for 464 participants; 106 (23%) of these were infected with HIV. By day 2, 57 (12.3%) children had failed treatment and 110 (23.7%) failed by day 14. Twenty (18.9%) HIV-infected children failed by day 2 compared with 37 (10.3%) uninfected children (adjusted odds ratio (OR) 2.07; 95% confidence interval (CI): 1.07-4.00). Thirty-four (32.1%) HIV-infected children failed treatment by day 14 compared with 76 (21.2%) uninfected children (adjusted OR 1.88; 95% CI: 1.11-3.17). Analysis stratified by age showed that the greatest differential in treatment failure at day 2 and day 14 occurred in the children aged 3-5 months. HIV-infected children with severe pneumonia fail WHO-standard treatment with parenteral penicillin or amoxicillin at day 2 and day 14 more often than do HIV-uninfected children, especially young infants. Standard case management of acute respiratory infection (ARI) using WHO treatment guidelines is inadequate in areas of high HIV prevalence and reappraisal of empiric antimicrobial therapy is urgently needed for severe pneumonia associated with HIV-1.


MGEScan-non-LTR: computational identification and classification of autonomous non-LTR retrotransposons in eukaryotic genomes.
Computational methods for genome-wide identification of mobile genetic elements (MGEs) have become increasingly necessary for both genome annotation and evolutionary studies. Non-long terminal repeat (non-LTR) retrotransposons are a class of MGEs that have been found in most eukaryotic genomes, sometimes in extremely high numbers. In this article, we present a computational tool, MGEScan-non-LTR, for the identification of non-LTR retrotransposons in genomic sequences, following a computational approach inspired by a generalized hidden Markov model (GHMM). Three different states represent two different protein domains and inter-domain linker regions encoded in the non-LTR retrotransposons, and their scores are evaluated by using profile hidden Markov models (for protein domains) and Gaussian Bayes classifiers (for linker regions), respectively. In order to classify the non-LTR retrotransposons into one of the 12 previously characterized clades using the same model, we defined separate states for different clades. MGEScan-non-LTR was tested on the genome sequences of four eukaryotic organisms, Drosophila melanogaster, Daphnia pulex, Ciona intestinalis and Strongylocentrotus purpuratus. For the D. melanogaster genome, MGEScan-non-LTR found all known 'full-length' elements and simultaneously classified them into the clades CR1, I, Jockey, LOA and R1. Notably, for the D. pulex genome, in which no non-LTR retrotransposon has been annotated, MGEScan-non-LTR found a significantly larger number of elements than did RepeatMasker, using the current version of the RepBase Update library. We also identified novel elements in the other two genomes, which have only been partially studied for non-LTR retrotransposons.


The locus coeruleus is directly implicated in L-DOPA-induced dyskinesia in parkinsonian rats: an electrophysiological and behavioural study.
Despite being the most effective treatment for Parkinson's disease, L-DOPA causes a development of dyskinetic movements in the majority of treated patients. L-DOPA-induced dyskinesia is attributed to a dysregulated dopamine transmission within the basal ganglia, but serotonergic and noradrenergic systems are believed to play an important modulatory role. In this study, we have addressed the role of the locus coeruleus nucleus (LC) in a rat model of L-DOPA-induced dyskinesia. Single-unit extracellular recordings in vivo and behavioural and immunohistochemical approaches were applied in rats rendered dyskinetic by the destruction of the nigrostriatal dopamine neurons followed by chronic treatment with L-DOPA. The results showed that L-DOPA treatment reversed the change induced by 6-hydroxydopamine lesions on LC neuronal activity. The severity of the abnormal involuntary movements induced by L-DOPA correlated with the basal firing parameters of LC neuronal activity. Systemic administration of the LC-selective noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine did not modify axial, limb, and orolingual dyskinesia, whereas chemical destruction of the LC with ibotenic acid significantly increased the abnormal involuntary movement scores. These results are the first to demonstrate altered LC neuronal activity in 6-OHDA lesioned rats treated with L-DOPA, and indicate that an intact noradrenergic system may limit the severity of this movement disorder.


Removal of the cyanotoxin anatoxin-a by drinking water treatment processes: a review.
Anatoxin-a (ANTX-a) is a potent alkaloid neurotoxin, produced by several species of cyanobacteria and detected throughout the world. The presence of cyanotoxins, including ANTX-a, in drinking water sources is a potential risk to public health. This article presents a thorough examination of the cumulative body of research on the use of drinking water treatment technologies for extracellular ANTX-a removal, focusing on providing an analysis of the specific operating parameters required for effective treatment and on compiling a series of best-practice recommendations for owners and operators of systems impacted by this cyanotoxin. Of the oxidants used in drinking water treatment, chlorine-based processes (chlorine, chloramines and chlorine dioxide) have been shown to be ineffective for ANTX-a treatment, while ozone, advanced oxidation processes and permanganate can be successful. High-pressure membrane filtration (nanofiltration and reverse osmosis) is likely effective, while adsorption and biofiltration may be effective but further investigation into the implementation of these processes is necessary. Given the lack of full-scale verification, a multiple-barrier approach is recommended, employing a combination of chemical and non-chemical processes.


Taking personal responsibility: Nurses' and assistant nurses' experiences of good nursing practice in psychiatric inpatient care.
Therapeutic nurse-patient relationships are considered essential for good nursing practice in psychiatric inpatient care. Previous research suggests that inpatient care fails to fulfil patients' expectations in this regard, and that nurses might experience the reality of inpatient care as an obstruction. The aim of the present study was to explore nurses' and assistant nurses' experiences of good nursing practice in the specific context of psychiatric inpatient care. Qualitative interviews were conducted with 12 skilled, relationship-oriented nurses and assistant nurses in order to explore their experiences with nursing practice related to psychiatric inpatient care. Interviews were transcribed and analysed using an interpretive descriptive approach. Findings describe good nursing practice as a matter of nurses and assistant nurses taking personal responsibility for their actions and for the individual patient as a person. Difficulties in providing dignified nursing care and taking personal responsibility cause them to experience feelings of distress and frustration. Shared values and nursing leadership supports being moral and treating patients with respect, having enough time supports being present and connecting with patients, and working as a part of a competent team with critical daily discussions and diversity supports being confident and building trust. The findings suggest that taking personal responsibility is integral to good nursing practice. If unable to improve poor circumstances, nurses might be forced to promote their own survival by refuting or redefining their responsibility. Nurses need to prioritize being with patients and gain support in shaping their own nursing practice. Nursing leadership should provide moral direction and defend humanistic values.


Refining the Genomic Region Containing a Major Locus Controlling Fruit Maturity in Peach.
Maturity date (MD), defined as the duration between the first calendar day of the year and maturity, and fruit development period (FDP), defined as the duration between full bloom and maturity, are highly variable in peach [Prunus persica (L.) Batsch]. There is a need to discover molecular markers associated with these traits in order to enhance the efficiency and reliability of breeding for extending the harvest season in peach. An association mapping population consisting of 132 peach accessions was phenotypically evaluated for MD and FDP, and genotypically characterized using the genotyping-by-sequencing (GBS) approach. The phenotypic and genotypic data collected were used to conduct a genome-wide association study (GWAS). The GWAS identified three SNPs on chromosome 4 that are significantly associated with both FDP and MD. These three SNPs covered a region of 43,067 bp; we referred to this region as the MD/FDP locus. Seven genes were identified in the MD/FDP locus. One or more of these genes is believed to regulate some aspect of maturity in peach. The data reported here is expected to aid in marker-assisted seedling selection (MASS) targeted towards widening peach germplasm for maturity, particularly early maturity.


Spontaneous regression of malignant melanoma - is it based on the interplay between host immune system and melanoma antigens?
Malignant melanoma (MM) is the most aggressive and uneasily treatable form of skin cancer. Up to 90% of deaths because of skin tumours are estimated to be caused by this malignancy. Spontaneous regression is described as a partial or complete disappearance of cancer. It can be defined if the clinical and histological diagnosis of malignancy is verified and any therapeutic intervention potentially inducing mechanisms leading to regression has not been applied. Regression occurs more frequently in melanoma than in other types of tumours; it is reported to be six times higher than in other malignancies. Up to 50% of primary MM is reported to undergo spontaneous regression. However, spontaneous regression of the metastatic form of tumour is a rare phenomenon observed in only 0.23% of cases. The most frequently mentioned factors leading to spontaneous regression of MM are operative trauma, infection, vaccination (BCG and rabies vaccines) and immunological factors. Other well-documented circumstances associated with regression of metastatic MM include blood transfusion and various endocrine factors.


Elevated aspartate aminotransferase and monocyte counts predict unfavorable prognosis in patients with malignant pleural mesothelioma.
Limited biomarkers predicting prognosis of malignant pleural mesothelioma (MPM) have been identified. The present study aims to assess potential laboratory prognostic factors of MPM. We retrospectively reviewed the clinical data of 105 patients with MPM. The overall survival and prognostic factors were assessed by Kaplan-Meier curves and Cox regression analysis. A receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cut-off values. The mean age of the 105 patients (62 men, 43 women) was 56.0 years. The major clinical presentations were dyspnea, cough and chest pain. The most common laboratory abnormalities were thrombocytosis and elevated monocyte count. Significant prognostic factors on univariate analysis were performance status (PS), serum albumin, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), monocyte, platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR) and treatment strategy. Multivariate analysis showed PS, AST, monocyte, and treatment strategy were statistically significant (p<0.05). Higher AST level and monocyte count were both related to the presence of anemia (p=0.001 and 0.010, respectively) and higher ALP level (p=0.049 and 0.001, respectively). A higher AST level was also associated with higher alanine aminotransferase (ALT) and LDH level (p<0.05). A higher monocyte count was also correlated with male patients, higher white blood cell (WBC), platelet, neutrophil counts, lower red blood cell (RBC) and LMR counts (p<0.05). In conclusion, our data show that PS<2, normal AST level, lower monocyte count, and multimodality treatment are independent positive prognostic factors of MPM. The elevated AST and monocyte levels represent unfavorable prognostic biomarkers of MPM.


Optimization of a polydopamine (PD)-based coating method and polydimethylsiloxane (PDMS) substrates for improved mouse embryonic stem cell (ESC) pluripotency maintenance and cardiac differentiation.
Myocardiocyte derived from pluripotent stem cells, such as induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs), is a promising cell source for cardiac tissue engineering. Combined with microfluidic technologies, a heart-on-a-chip is very likely to be developed and function as a platform for high throughput drug screening. Polydimethylsiloxane (PDMS) silicone elastomer is a widely-used biomaterial for the investigation of cell-substrate interactions and biochip fabrication. However, the intrinsic PDMS surface hydrophobicity inhibits cell adhesion on the PDMS surface, and PDMS surface modification is required for effective cell adhesion. Meanwhile, the formulation of PDMS also affects the behaviors of the cells. To fabricate PDMS-based biochips for ESC pluripotency maintenance and cardiac differentiation, PDMS surface modification and formulation were optimized in this study. We found that a polydopamine (PD) with gelatin coating greatly improved the ESC adhesion, proliferation and cardiac differentiation on its surface. In addition, different PDMS substrates varied in their surface properties, which had different impacts on ESCs, with the 40 : 1 PDMS substrate being more favorable for ESC adhesion and proliferation as well as embryoid body (EB) attachment than the other PDMS substrates. Moreover, the ESC pluripotency was best maintained on the 5 : 1 PDMS substrate, while the cardiac differentiation of the ESCs was optimal on the 40 : 1 PDMS substrate. Based on the optimized coating method and PDMS formulation, biochips with two different designs were fabricated and evaluated. Compared to the single channels, the multiple channels on the biochips could provide larger areas and accommodate more nutrients to support improved ESC pluripotency maintenance and cardiac differentiation. These results may contribute to the development of a real heart-on-a-chip for high-throughput drug screening in the future.


Unravelling the role of leadership in motivation of health workers in a Moroccan public hospital: a realist evaluation.
This study aimed at opening the black box of the relationship between leadership and motivation of health workers by focusing on a high-performance hospital in Morocco. We adopted the realist evaluation approach and used the case study design to test the initial programme theory we formulated on the basis of a scoping review on complex leadership. We used the Intervention-Context-Actors-Mechanism-Outcome Configuration as a heuristic tool to identify plausible causal configurations. Since 2000, the Ministry of Health in Morocco initiated many reforms in the frame of the governmental deconcentration process called 'advanced regionalisation'. The implementation of these reforms is hampered by inadequate human resource management capacities of local health system managers. Yet, the National 'Concours Qualité', a national quality assurance programme implemented since 2007, demonstrated that there are many islands of excellence. We explore how leadership may play a role in explaining these islands of excellence. We carried out a document review, 18 individual interviews and 3 group discussions (with doctors, administrators and nurses), and non-participant observations during a 2-week field visit in January-February 2018. We confirmed that effective leaders adopt an appropriate mix of transactional, transformational and distributed leadership styles that fits the mission, goals, organisational culture and nature of tasks of the organisation and the individual characteristics of the personnel when organisational culture is conducive. Leadership effectiveness is conditioned by the degree of responsiveness to the basic psychological needs of autonomy, competence and relatedness, perceived organisational support and perceived supervisor support. Transactional and overcontrolling leadership behaviour decreased the satisfaction of the need for autonomy and mutual respect. By distributing leadership responsibilities, complex leaders create an enabling environment for collective efficacy and creative problem solving. We found indications that in the Moroccan context, well-performing hospitals could be characterised by a good fit between leadership styles, organisational characteristics and individual staff attributes.


Maximal dose-response of vitamin-K2 (menaquinone-4) on undercarboxylated osteocalcin in women with osteoporosis.
Low concentrations of serum vitamin K accompany high concentrations of undercarboxylated osteocalcin (ucOC) and osteoporotic fractures. Although vitamin K2 (MK-4) is approved as a therapeutic agent for the treatment of osteoporosis in some countries, the dose-response is unknown. The objective of this study was to assess the improvement in carboxylation of osteocalcin (OC) in response to escalating doses of MK-4 supplementation. A nine-week, open-labeled, prospective cohort study was conducted in 29 postmenopausal women who suffered hip or vertebral compression fractures. Participants took low-dose MK-4 (0.5 mg) for 3 weeks (until the second visit), then medium-dose MK-4 (5 mg) for 3 weeks (until the third visit), then high-dose MK-4 (45 mg) for 3 weeks. The mean ± SD age of the participants was 69 ± 9 years. MK-4 dose (p < 0.0001), but neither age nor other relevant medications (e.g. bisphosphonates) correlated with improvement in %ucOC. As compared to baseline concentrations (geometric mean ± SD) of 16.8 ± 2.4, 0.5 mg supplementation halved %ucOC to 8.7 ± 2.2 (p < 0.0001) and the 5-mg dose halved %ucOC again (to 3.9 ± 2.2; p = 0.0002 compared to 0.5-mg dose). However, compared to 5 mg/day, there was no additional benefit of 45 mg/day (%ucOC 4.6; p = NS vs. 5-mg dose). MK-4 supplementation resulted in borderline increases in γ-carboxylated osteocalcin (glaOC; p = 0.07). There were no major side effects of MK-4 supplementation. In postmenopausal women with osteoporotic fractures, supplementation with either 5 or 45 mg/day of MK-4 reduces ucOC to concentrations typical of healthy, pre-menopausal women.


A surface-hopping method for semiclassical calculations of cross sections for radiative association with electronic transitions.
A semiclassical method based on surface-hopping techniques is developed to model the dynamics of radiative association with electronic transitions. It can be proven that this method is an extension of the established semiclassical formula used in the characterization of diatomic molecule-formation. Our method is tested for diatomic molecules. It gives the same cross sections as the former semiclassical formula but, contrary to the former method, it allows us to follow the fate of the trajectories after the emission of a photon. This means that we can characterize the rovibrational states of the stabilized molecules. Using semiclassical quantization, we can obtain quantum state-resolved cross sections or emission spectra for the radiative association process. The calculated semiclassical state-resolved spectra show general agreement with the result of quantum mechanical perturbation theory. Furthermore, our surface-hopping model is not only applicable for the description of radiative association but it can be used for semiclassical characterization of any molecular process where spontaneous emission occurs.


Correction of steal syndrome secondary to hemodialysis access fistulas: a simplified quantitative technique.
Correction of symptomatic vascular steal distal to an arteriovenous fistula requires either fistula ligation or banding. Ligation carries the obvious disadvantage of destruction of a functioning angioaccess, whereas banding procedures have been plagued by the complexity of many of the reported techniques and by the difficulty of balancing fistula flow with distal perfusion. In this study a simple plication technique is described that avoids the introduction of any additional foreign material and that quantifies distal perfusion by means of intraoperative pulse volume recordings. Five patients have been treated by this method, two with autologous vein fistulas and three with bridge fistulas using polytetrafluorethylene. All five have had resolution of their ischemic symptoms with an increase in intraoperative pulse volume recordings of 5 mm or more. Only three of the patients had restoration of the radial pulse, which was not a specific end point of the banding procedure. Furthermore, all fistulas remained patent for at least 6 months and continued to provide adequate flows for hemodialysis. Banding/plication is clearly preferable to fistula closure for the management of steal syndrome. The method described herein is simple and hemodynamically identifies the minimal constriction that will resolve symptoms and preserve fistula flow.


Grasping uncertainty: effects of sensorimotor memories on high-level planning of dexterous manipulation.
For successful object manipulation, the central nervous system must appropriately coordinate digit placement and force distribution. It is known that digit force planning is significantly influenced by previous manipulations even when object properties cannot be predicted on a trial-to-trial basis. We sought to determine whether this effect extends beyond force control to the coordination of digit placement and force. Subjects grasped and lifted an object whose center of mass (CM) was changed unpredictably across trials. Grasp planning was quantified by measuring the torque generated on the object at lift onset. We found that both digit placement and force were systematically affected by the CM experienced on the previous trial. Additionally, the negative covariation between digit forces and positions typically found for predictable CM presentations was also found for unpredictable CM trials. A follow-up experiment revealed that these effects were not dependent on visual feedback of object roll during object lift on the previous trial. We conclude that somatosensory feedback from previous grasp experience alone can affect high-level grasp planning by constraining the relation between digit force and position even when the task behavioral consequences cannot be reliably predicted. As learning of manipulations often involves interactions with objects in novel environments, the present findings are an important step to understanding the control strategies associated with the integration of sensorimotor memories and motor planning.


The effects of different forms of daily exercise on metabolic function following short-term overfeeding and reduced physical activity in healthy young men: study protocol for a randomised controlled trial.
Short-term overfeeding combined with reduced physical activity impairs metabolic function and alters the expression of key genes within adipose tissue. We have shown that daily vigorous-intensity running can prevent these changes independent of any net effect on energy imbalance. However, which type, intensity and/or duration of exercise best achieves these benefits remains to be ascertained. Forty-eight healthy young men will be recruited and randomly allocated to one of four experimental conditions for 1 week: (1) to ingest 50% more energy than normal by over-consuming their habitual diet whilst simultaneously restricting their physical activity below 4000 steps day-1 (i.e. energy surplus; SUR group); (2) the same regimen but with a daily 45-min bout of vigorous-intensity arm crank ergometry at 70% of maximum oxygen uptake (SUR + ARM group); (3) the same regimen but with a daily 45-min bout of moderate-intensity treadmill walking at 50% of maximum oxygen uptake (SUR + MOD group); (4) the same regimen but with the addition of intermittent short bouts of walking during waking hours (SUR + BREAKS group). Critically, all exercise groups will receive additional dietary energy intake to account for the energy expended by exercise, thus maintaining a matched energy surplus. At baseline and follow-up, fasted blood samples, abdominal subcutaneous adipose tissue and skeletal muscle biopsies will be obtained and oral glucose tolerance tests conducted. This study will establish the impact of different forms of daily exercise on metabolic function at the whole-body level as well as within adipose tissue and skeletal muscle in the context of a standardised energy surplus. ISRCTN, ISRCTN18311163 . Registered on 24 June 2015.


A study to determine the efficacy of combination LED light therapy (633 nm and 830 nm) in facial skin rejuvenation.
The use of visible or near infrared spectral light alone for the purpose of skin rejuvenation has been previously reported. A method of light emitting diode (LED) photo rejuvenation incorporating a combination of these wavelengths and thus compounding their distinct stimulation of cellular components is proposed.Objective. To assess the efficacy and local tolerability of combination light therapy in photo rejuvenation of facial skin. Thirty-one subjects with facial rhytids received nine light therapy treatments using the Omnilux LED system. The treatments combined wavelengths of 633 nm and 830 nm with fluences of 126 J/cm(2) and 66 J/cm(2) respectively. Improvements to the skin surface were evaluated at weeks 9 and 12 by profilometry performed on periorbital casts. Additional outcome measures included assessments of clinical photography and patient satisfaction scores. Key profilometry results Sq, Sa, Sp and St showed significant differences at week 12 follow-up; 52% of subjects showed a 25%-50% improvement in photoaging scores by week 12; 81% of subjects reported a significant improvement in periorbital wrinkles on completion of follow-up. Omnilux combination red and near infrared LED therapy represents an effective and acceptable method of photo rejuvenation. Further study to optimize the parameters of treatment is required.


Polyphenols: Extraction Methods, Antioxidative Action, Bioavailability and Anticarcinogenic Effects.
Being secondary plant metabolites, polyphenols represent a large and diverse group of substances abundantly present in a majority of fruits, herbs and vegetables. The current contribution is focused on their bioavailability, antioxidative and anticarcinogenic properties. An overview of extraction methods is also given, with supercritical fluid extraction highlighted as a promising eco-friendly alternative providing exceptional separation and protection from degradation of unstable polyphenols. The protective role of polyphenols against reactive oxygen and nitrogen species, UV light, plant pathogens, parasites and predators results in several beneficial biological activities giving rise to prophylaxis or possibly even to a cure for several prevailing human diseases, especially various cancer types. Omnipresence, specificity of the response and the absence of or low toxicity are crucial advantages of polyphenols as anticancer agents. The main problem represents their low bioavailability and rapid metabolism. One of the promising solutions lies in nanoformulation of polyphenols that prevents their degradation and thus enables significantly higher concentrations to reach the target cells. Another, more practiced, solution is the use of mixtures of various polyphenols that bring synergistic effects, resulting in lowering of the required therapeutic dose and in multitargeted action. The combination of polyphenols with existing drugs and therapies also shows promising results and significantly reduces their toxicity.


Formation of Renal Cysts and Tumors in Vhl/Trp53-Deficient Mice Requires HIF1α and HIF2α.
The von Hippel-Lindau (VHL) tumor suppressor gene is inactivated in the majority of clear cell renal cell carcinomas (ccRCC), but genetic ablation of Vhl alone in mouse models is insufficient to recapitulate human tumorigenesis. One function of pVHL is to regulate the stability of the hypoxia-inducible factors (HIF), which become constitutively activated in the absence of pVHL. In established ccRCC, HIF1α has been implicated as a renal tumor suppressor, whereas HIF2α is considered an oncoprotein. In this study, we investigated the contributions of HIF1α and HIF2α to ccRCC initiation in the context of Vhl deficiency. We found that deleting Vhl plus Hif1a or Hif2a specifically in the renal epithelium did not induce tumor formation. However, HIF1α and HIF2α differentially regulated cell proliferation, mitochondrial abundance and oxidative capacity, glycogen accumulation, and acquisition of a clear cell phenotype in Vhl-deficient renal epithelial cells. HIF1α, but not HIF2α, induced Warburg-like metabolism characterized by increased glycolysis, decreased oxygen consumption, and decreased ATP production in mouse embryonic fibroblasts, providing insights into the cellular changes potentially occurring in Vhl mutant renal cells before ccRCC formation. Importantly, deletion of either Hif1a or Hif2a completely prevented the formation of renal cysts and tumors in Vhl/Trp53 mutant mice. These findings argue that both HIF1α and HIF2α exert protumorigenic functions during the earliest stages of cyst and tumor formation in the kidney. Cancer Res; 76(7); 2025-36. ©2016 AACR.


Patients' ratings of genetic conditions validate a taxonomy to simplify decisions about preconception carrier screening via genome sequencing.
Advances in genome sequencing and gene discovery have created opportunities to efficiently assess more genetic conditions than ever before. Given the large number of conditions that can be screened, the implementation of expanded carrier screening using genome sequencing will require practical methods of simplifying decisions about the conditions for which patients want to be screened. One method to simplify decision making is to generate a taxonomy based on expert judgment. However, expert perceptions of condition attributes used to classify these conditions may differ from those used by patients. To understand whether expert and patient perceptions differ, we asked women who had received preconception genetic carrier screening in the last 3 years to fill out a survey to rate the attributes (predictability, controllability, visibility, and severity) of several autosomal recessive or X-linked genetic conditions. These conditions were classified into one of five taxonomy categories developed by subject experts (significantly shortened lifespan, serious medical problems, mild medical problems, unpredictable medical outcomes, and adult-onset conditions). A total of 193 women provided 739 usable ratings across 20 conditions. The mean ratings and correlations demonstrated that participants made distinctions across both attributes and categories. Aggregated mean attribute ratings across categories demonstrated logical consistency between the key features of each attribute and category, although participants perceived little difference between the mild and serious categories. This study provides empirical evidence for the validity of our proposed taxonomy, which will simplify patient decisions for results they would like to receive from preconception carrier screening via genome sequencing.


MUTYH prevents OGG1 or APEX1 from inappropriately processing its substrate or reaction product with its C-terminal domain.
MutY homolog (MUTYH) excises adenine opposite 8-oxoguanine (8-oxoG) in DNA, thus preventing occurrence of G:C to T:A transversion. In cell-free extract prepared from the thymocytes of wild type but not MUTYH-null mice, adenine opposite 8-oxoG in DNA was excised by MUTYH, however, the generated apurinic (AP) site opposite 8-oxoG mostly remained unincised. Recombinant mouse MUTYH (mMUTYH) efficiently excised adenine opposite 8-oxoG and prevented mouse AP endonuclease (mAPEX1) from incising the generated AP site. In contrast, an AP site opposite 8-oxoG created by uracil DNA glycosylase or tetrahydrofuran opposite 8-oxoG was efficiently incised by mAPEX1 in the presence of an excess amount of mMUTYH. Mutant mMUTYH with R361A or G365D substitution, excised adenine opposite 8-oxoG as efficiently as did wild-type mMUTYH, but failed to prevent mAPEX1 from incising the generated AP site. Wild-type mMUTYH bound duplex oligonucleotides containing A:8-oxoG pair with a lower apparent K(d) than that of the mutants, and prevented OGG1 from excising 8-oxoG opposite adenine or the generated AP site. The G365D mutant failed to prevent OGG1 from excising 8-oxoG opposite the generated AP site, thus indicating that the protection of its own product by mMUTYH is an intrinsic function which depends on the C-terminal domain of mMUTYH.


Primary baerveldt versus trabeculectomy study after 5 years of follow-up.
Although the Baerveldt glaucoma implant (BGI) initially was reserved for refractory glaucoma, its role in the surgical management of glaucoma has shifted towards a primary treatment choice. We performed a randomized prospective study to compare BGI surgery and trabeculectomy (TE) in patients without previous ocular surgery. We included 119 glaucoma patients without previous ocular surgery. One eye of each subject was randomized to either a BGI or TE. Follow-up visits were at 1 day, 2 weeks, 6 weeks, 3 months, 6 months and 1, 2, 3, 4 and 5 years postoperatively. Primary outcomes were intraocular pressure (IOP) and failure rate. Secondary outcomes were medication, anterior chamber laser flare value and complications. After 5 years, an IOP of 12.7 ± 3.9 mmHg (mean ± SD) was achieved in the TE group and 12.9 ± 3.9 mmHg in the BGI group. We found no statistically significant difference in failure rate between the groups (p = 0.72). More BGI patients needed additional medication to control their IOP (85%; 1.9 ± 1.2 types of glaucoma medication) compared to the TE patients (57%; 0.5 ± 0.9 types of glaucoma medication). Diplopia was significantly more present in the BGI group than in the TE group (27% versus 4%; p < 0.001). The self-limiting complication rate was similar in both groups. Our study demonstrates that, in the long term, the final IOP and failure rate are similar after TE and BGI surgery. However, the need for additional medication after BGI surgery is higher than after TE. Also, the increased risk of developing diplopia after BGI surgery must be taken into consideration.


Measuring molecular interactions in solution using multi-wavelength analytical ultracentrifugation: combining spectral analysis with hydrodynamics.
In 1926, the Swedish scientist Theodor Svedberg was awarded the Nobel Prize in Chemistry for his work on a disperse system, and for studying the colloidal properties of proteins. This work was, to a large extent, made possible by his invention of a revolutionary tool, the analytical ultracentrifuge. These days, technological advances in hardware and computing have transformed the field of analytical ultracentrifugation (AUC) by enabling entirely new classes of experiments and modes of measurement unimaginable by Svedberg, making AUC once again an indispensable tool for modern biomedical research. In this article these advances and their impact on studies of interacting molecules will be discussed, with particular emphasis on a new method termed multi-wavelength analytical ultracentrifugation (MWL-AUC). Novel detectors allow us to add a second dimension to the separation of disperse and heterogeneous systems: in addition to the traditional hydrodynamic separation of colloidal mixtures, it is now possible to identify the sedimenting molecules by their spectral absorbance properties. The potential for this advance is significant for the study of a large range of systems. A further advance has occurred in data management and computational capabilities, opening doors to improved analysis methods, as well as direct networking with the instrument, facilitating data acquisition and data handling, and significant increases in data density from faster detectors with higher resolution capability.


Resistance arm training in patients with COPD: A Randomized Controlled Trial.
The study aimed to evaluate the effect of upper extremity resistance training for patients with COPD on dyspnea during activity of daily living (ADL), arm function, arm exercise capacity, muscle strength, and health-related quality of life (HRQL). Patients were randomly assigned to an intervention or control group. The intervention group underwent arm resistance training. The control group performed a sham. Both groups exercised three times a week for 6 weeks. Dyspnea during ADL and HRQL were measured using the Chronic Respiratory Disease Questionnaire (CRDQ). Arm function and exercise capacity were measured using the 6-min pegboard and ring test (6PBRT) and the unsupported upper limb exercise test (UULEX), respectively. Muscle strength for the biceps, triceps, and anterior and middle deltoids was obtained using an isometric dynamometer. Thirty-six patients with COPD (66 ± 9 years) participated in the study. Compared with the control group, the magnitude of change in the intervention group was greater for the 6PBRT (P = .03), UULEX (P = .01), elbow flexion force (P = .01), elbow extension force (P = .02), shoulder flexion force (P = .029), and shoulder abduction force (P = .01). There was no between-group difference in dyspnea during ADL, HRQL, or symptoms during the 6PBRT or UULEX (all P values > .08). Resistance-based arm training improved arm function, arm exercise capacity, and muscle strength in patients with COPD. No improvement in dyspnea during ADL, HRQL, or symptoms was demonstrated.


Condom failure and pre-exposure prophylaxis use experience among female sex workers in Ethiopia: a qualitative study.
Female sex workers (FSW) remain a highly exposed group for HIV/STIs due to different factors including condom failure. In Ethiopia, pre-exposure prophylaxis (PrEP) has recently been introduced as an intervention strategy to prevent new HIV infections, but knowledge about FSWs' experiences of condom failure and PrEP use remains scarce. Therefore, this study explores FSWs' experiences concerning condom failure and their attitudes towards, and experiences of, PrEP uptake. A qualitative study using in-depth interviews was conducted among FSWs in Addis Ababa. A manifest and latent content analysis method was applied to identify categories and emerging themes. Seventeen FSWs (10 who started on PrEP, 1 who discontinued, and 6 who didn't start) were interviewed. FSWs described the reasons behind condom failure, the mechanisms they used to minimize the harm, and their attitudes towards PrEP use. FSWs struggled with the continuous risk of condom failure due to factors related to clients' and their own behavior. PrEP was mentioned as one the strategies FSWs used to minimize the harm resulting from condom failure, but PrEP use was compounded with doubts that deterred FSWs from uptake. FSWs' misconceptions, their lack of confidence, and PrEP side effects were also mentioned as the main challenges to start taking PrEP and/or to maintain good adherence. The demands and behavior of the clients and FSWs' own actions and poor awareness were factors that increased the exposure of FSWs to condom failure. In addition, the challenges associated with PrEP uptake suggest the need for user-friendly strategies to counteract these barriers and facilitate PrEP uptake.


Research resource: the dynamic transcriptional profile of sertoli cells during the progression of spermatogenesis.
Sertoli cells (SCs), the only somatic cells within seminiferous tubules, associate intimately with developing germ cells. They not only provide physical and nutritional support but also secrete factors essential to the complex developmental processes of germ cell proliferation and differentiation. The SC transcriptome must therefore adapt rapidly during the different stages of spermatogenesis. We report comprehensive genome-wide expression profiles of pure populations of SCs isolated at 5 distinct stages of the first wave of mouse spermatogenesis, using RNA sequencing technology. We were able to reconstruct about 13 901 high-confidence, nonredundant coding and noncoding transcripts, characterized by complex alternative splicing patterns with more than 45% comprising novel isoforms of known genes. Interestingly, roughly one-fifth (2939) of these genes exhibited a dynamic expression profile reflecting the evolving role of SCs during the progression of spermatogenesis, with stage-specific expression of genes involved in biological processes such as cell cycle regulation, metabolism and energy production, retinoic acid synthesis, and blood-testis barrier biogenesis. Finally, regulatory network analysis identified the transcription factors endothelial PAS domain-containing protein 1 (EPAS1/Hif2α), aryl hydrocarbon receptor nuclear translocator (ARNT/Hif1β), and signal transducer and activator of transcription 1 (STAT1) as potential master regulators driving the SC transcriptional program. Our results highlight the plastic transcriptional landscape of SCs during the progression of spermatogenesis and provide valuable resources to better understand SC function and spermatogenesis and its related disorders, such as male infertility.


Mitigation of impedance changes due to electroporation therapy using bursts of high-frequency bipolar pulses.
For electroporation-based therapies, accurate modeling of the electric field distribution within the target tissue is important for predicting the treatment volume. In response to conventional, unipolar pulses, the electrical impedance of a tissue varies as a function of the local electric field, leading to a redistribution of the field. These dynamic impedance changes, which depend on the tissue type and the applied electric field, need to be quantified a priori, making mathematical modeling complicated. Here, it is shown that the impedance changes during high-frequency, bipolar electroporation therapy are reduced, and the electric field distribution can be approximated using the analytical solution to Laplace's equation that is valid for a homogeneous medium of constant conductivity. Two methods were used to examine the agreement between the analytical solution to Laplace's equation and the electric fields generated by 100 µs unipolar pulses and bursts of 1 µs bipolar pulses. First, pulses were applied to potato tuber tissue while an infrared camera was used to monitor the temperature distribution in real-time as a corollary to the electric field distribution. The analytical solution was overlaid on the thermal images for a qualitative assessment of the electric fields. Second, potato ablations were performed and the lesion size was measured along the x- and y-axes. These values were compared to the analytical solution to quantify its ability to predict treatment outcomes. To analyze the dynamic impedance changes due to electroporation at different frequencies, electrical impedance measurements (1 Hz to 1 MHz) were made before and after the treatment of potato tissue. For high-frequency bipolar burst treatment, the thermal images closely mirrored the constant electric field contours. The potato tissue lesions differed from the analytical solution by 39.7 ± 1.3 % (x-axis) and 6.87 ± 6.26 % (y-axis) for conventional unipolar pulses, and 15.46 ± 1.37 % (x-axis) and 3.63 ± 5.9 % (y-axis) for high- frequency bipolar pulses. The electric field distributions due to high-frequency, bipolar electroporation pulses can be closely approximated with the homogeneous analytical solution. This paves way for modeling fields without prior characterization of non-linear tissue properties, and thereby simplifying electroporation procedures.


A Molecular Clock Infers Heterogeneous Tissue Age Among Patients with Barrett's Esophagus.
Biomarkers that drift differentially with age between normal and premalignant tissues, such as Barrett's esophagus (BE), have the potential to improve the assessment of a patient's cancer risk by providing quantitative information about how long a patient has lived with the precursor (i.e., dwell time). In the case of BE, which is a metaplastic precursor to esophageal adenocarcinoma (EAC), such biomarkers would be particularly useful because EAC risk may change with BE dwell time and it is generally not known how long a patient has lived with BE when a patient is first diagnosed with this condition. In this study we first describe a statistical analysis of DNA methylation data (both cross-sectional and longitudinal) derived from tissue samples from 50 BE patients to identify and validate a set of 67 CpG dinucleotides in 51 CpG islands that undergo age-related methylomic drift. Next, we describe how this information can be used to estimate a patient's BE dwell time. We introduce a Bayesian model that incorporates longitudinal methylomic drift rates, patient age, and methylation data from individually paired BE and normal squamous tissue samples to estimate patient-specific BE onset times. Our application of the model to 30 sporadic BE patients' methylomic profiles first exposes a wide heterogeneity in patient-specific BE onset times. Furthermore, independent application of this method to a cohort of 22 familial BE (FBE) patients reveals significantly earlier mean BE onset times. Our analysis supports the conjecture that differential methylomic drift occurs in BE (relative to normal squamous tissue) and hence allows quantitative estimation of the time that a BE patient has lived with BE.


The pharmacokinetics of milrinone in pediatric patients after cardiac surgery.
Milrinone has been shown to increase cardiac output in children after cardiac surgery, but pharmacokinetic analysis has not been used to identify effective dose regimens. The purpose of this study was to characterize the pharmacokinetics of milrinone in infants and children and to apply the results to the issue of dosing. Twenty children were studied after they underwent repair of congenital cardiac defects. Control hemodynamic measurement was made after the children were separated from cardiopulmonary bypass, and each patient was given a loading dose of 50 microg/kg progressively in 5 min. Hemodynamic measurements were recorded again at the end of the loading dose and when a blood sample was taken to determine milrinone plasma concentrations. Further blood samples were taken during the next 16 h for milrinone plasma concentration analysis. The pharmacokinetics of milrinone were analyzed using the population pharmacokinetic program NONMEM. The loading dose of milrinone resulted in a mean decrease in mean blood pressure of 12% and a mean increase in cardiac index of 18% at a mean peak plasma concentration of 235 ng/ml. The pharmacokinetics of milrinone were best described by a three-compartment model. In the optimal model, all volumes and distribution clearances were proportional to weight, and weight-normalized elimination clearance was proportional to age; ie., Cl1 = 2.5 x weight x (1 + 0.058 x age) where Cl1 is expressed as ml/min, and the units of weight and age are kg and months, respectively. A loading dose of 50 microg/kg effectively increases cardiac index in children after cardiac surgery. Simulations indicate that the peak plasma concentration can be maintained by following the loading dose of 50 microg/kg with an infusion of approximately 3 microg x kg(-1) x min(-1) for 30 min and then a maintenance infusion, which may require adjustment for age.


Growth Arrest Specific 1 (Gas1) Gene Overexpression in Liver Reduces the In Vivo Progression of Murine Hepatocellular Carcinoma and Partially Restores Gene Expression Levels.
The prognosis of hepatocellular carcinoma patients is usually poor, the size of tumors being a limiting factor for surgical treatments. Present results suggest that the overexpression of Gas1 (growth arrest specific 1) gene reduces the size, proliferating activity and malignancy of liver tumors. Mice developing diethylnitrosamine-induced hepatocellular carcinoma were subjected to hydrodynamic gene delivery to overexpress Gas1 in liver. This treatment significantly (p < 0.05) reduced the number of large tumors, while the difference in the total number of lesions was not significant. Moreover, the number of carcinoma foci in the liver and the number of lung metastases were reduced. These results are related with the finding that overexpression of Gas1 in Hepa 1-6 cells arrests cell cycle before S phase, with a significant (p < 0.01) and concomitant reduction in the expression of cyclin E2 gene. In addition, a triangular analysis of microarray data shows that Gas1 overexpression restores the transcription levels of 150 genes whose expression was affected in the diethylnitrosamine-induced tumors, thirteen of which are involved in the hedgehog signaling pathway. Since the in vivo Gas1 gene delivery to livers of mice carrying hepatocellular carcinoma reduces the size and proliferating activity of tumors, partially restoring the transcriptional profile of the liver, the present study opens promising insights towards a therapeutic approach for hepatocellular carcinoma.


Osteochondrosis, but not lameness, is more frequent among free-range pigs than confined herd-mates.
Organic pig production is expanding and amongst the objectives of organic farming are enhancing animal health and welfare. However, some studies have reported a higher prevalence of lameness and joint condemnation at slaughter in free-range/organic pigs than in conventionally raised pigs. Organic slaughter pigs have free-range housing in which indoor and outdoor access is compulsory, while in conventional farming the pigs are commonly confined to indoor pens. The present study evaluated the effects of free-range and confined housing on lameness prevalence in a herd of 106 finisher pigs, and whether osteochondrosis and Erysipelothrix rhusiopathiae associated arthritis influences these effects. We also evaluated the association between clinical lameness during the rearing period and joint condemnations at slaughter. Seventy free-range and 36 confined housed fattener pigs were scored for their gait twice during the rearing period and 848 joints were evaluated post mortem. Osteochondrosis was more frequent among free-range than confined pigs (P < 0.05), and when present it was also more severe (P < 0.001). Pigs with more numerous and more severe osteochondral lesions had their gait affected more than did pigs with fewer such lesions (P < 0.05). Hence it was a paradox that we did not detect more lameness among the free-range pigs than the confined pigs. E. rhusiopathiae associated arthritis was not diagnosed. The association between gait remarks/clinical lameness and joint condemnations at slaughter was not significant. The results indicate that free-range housing may have both positive and negative effects on locomotory traits. Free-range pigs may be less clinically affected by osteochondrosis than are confined pigs. One explanation for this effect may be strengthening of joint supportive tissue and pain relief promoted by exercise. Visual gait scoring missed serious joint lesions that probably were harmful to the pigs, and should therefore not be used as a sole indicator of joint/leg health in welfare inspection of pigs. The association between gait scores and joint condemnation appeared to be poor. This study was limited to one herd, and so more and larger studies on the effects of free-range housing on lameness severity and osteochondrosis development in pigs are recommended.


Use of crossed cylinder lens in photographic lens evaluation.
Two methods are described for testing cameras and camera lenses by utilizing the properties of the crossed cylinder lens, an ophthalmic test device. In the first, the cylinder lens is used in conjunction with a rectangular grid to defocus the star image formed by a collimator. This test permits quantitative determination of axial chromatic aberration, spherical aberration and its variations with wavelength, and coma of the lens. In the second, a segment of the cylinder lens is used as a supplementary lens attachment to the camera, which photographs a polar coordinate chart. Analysis of the photograph permits determination of the sagittal and tangential field curvatures, and also indicates errors in focal adjustment and misalignment of film plane with respect to the lens axis. Since these tests require cylinder lenses of smaller dioptric power and quality superior to that available from the ophthalmic lens industry, methods for the construction and synthesis of large-aperture, weak, cross cylinder lenses and segments thereof are given. Experimental details of the lens testing procedures, together with examples of photographic determination of the various camera and lens defects, are presented. A sensitive test for lateral chromatic aberration is included in an appendix.


Quantitative analysis of the probability of introducing equine encephalosis virus (EEV) into The Netherlands.
Equine encephalosis is a midge-borne viral disease of equines caused by equine encephalosis virus (EEV, Orbivirus, Reoviridae), and closely related to African horse sickness virus (AHSV). EEV and AHSV share common vectors and show similar transmission patterns. Until now EEV has caused outbreaks in Africa and Israel. This study aimed to provide insight in the probability of an EEV outbreak in The Netherlands caused by infected vectors or hosts, the contribution of potential source areas (risk regions) to this probability, and the effectiveness of preventive measures (sanitary regimes). A stochastic risk model constructed for risk assessment of AHSV introduction was adapted to EEV. Source areas were categorized in risk regions (high, low, and very low risk) based on EEV history and the presence of competent vectors. Two possible EEV introduction pathways were considered: importation of infected equines and importation of infected vectors along with their vertebrate hosts. The probability of EEV introduction (PEEV) was calculated by combining the probability of EEV release by either pathway and the probability of EEV establishment. The median current annual probability of EEV introduction by an infected equine was estimated at 0.012 (90% uncertainty interval 0.002-0.020), and by an infected vector at 4.0 10(-5) (90% uncertainty interval 5.3 10(-6)-2.0 10(-4)). Equines from high risk regions contributed most to the probability of EEV introduction with 74% on the EEV introduction by equines, whereas low and very low risk regions contributed 18% and 8%, respectively. International movements of horses participating in equestrian events contributed most to the probability of EEV introduction by equines from high risk regions (86%), but also contributed substantially for low and very low risk regions with 47% and 56%. The probability of introducing EEV into The Netherlands is much higher than the probability of introducing AHSV with equines from high risk countries contributing most. The introduction by an infected equine is the most likely pathway. Control measures before exportation of equines showed to have a strong mitigating effect on the probability of EEV introduction. The risk of EEV outbreaks should be taken into account when altering these import regulations.


[Pluripotent stem cells: maintenance of genetic and epigenetic stability and prospects of cell technologies].
Permanent lines of pluripotent stem cells can be obtained from humans and monkeys using different techniques and from different sources--inner cell mass of the blastocyst, primary germ cells, parthenogenetic oocytes, and mature spermatogonia--as well as by transgenic modification of various adult somatic cells. Despite different origin, all pluripotent lines demonstrate considerable similarity of the major biological properties: active self-renewal and differentiation into various somatic and germ cells in vitro and in vivo, similar gene expression profiles, and similar cell cycle structure. Ten years of intense studies on the stability of different human and monkey embryonic stem cells demonstrated that, irrespective of their origin, long-term in vitro cultures lead to the accumulation of chromosomal and gene mutations as well as epigenetic changes that can cause oncogenic transformation of cells. This review summarizes the research data on the genetic and epigenetic stability of different lines of pluripotent stem cells after long-term in vitro culture. These data were used to analyze possible factors of the genome and epigenome instability in pluripotent lines. The prospects of using pluripotent stem cells of different origin in cell therapy and pharmacological studies were considered.


Corporate power and the international trade regime preventing progressive policy action on non-communicable diseases: a realist review.
Transnational tobacco, alcohol and ultra-processed food corporations use the international trade regime to prevent policy action on non-communicable diseases (NCDs); i.e. to promote policy 'non-decisions'. Understanding policy non-decisions can be assisted by identifying power operating in relevant decision-making spaces, but trade and health research rarely explicitly engages with theories of power. This realist review aimed to synthesize evidence of different forms and mechanisms of power active in trade and health decision-making spaces to understand better why NCD policy non-decisions persist and the implications for future transformative action. We iteratively developed power-based theories explaining how transnational health-harmful commodity corporations (THCCs) utilize the international trade regime to encourage NCD policy non-decisions. To support theory development, we also developed a conceptual framework for analysing power in public health policymaking. We searched six databases and relevant grey literature and extracted, synthesized and mapped the evidence against the proposed theories. One hundred and four studies were included. Findings were presented for three key forms of power. Evidence indicates THCCs attempt to exercise instrumental power by extensive lobbying often via privileged access to trade and health decision-making spaces. When their legitimacy declines, THCCs have attempted to shift decision-making to more favourable international trade legal venues. THCCs benefit from structural power through the institutionalization of their involvement in health and trade agenda-setting processes. In terms of discursive power, THCCs effectively frame trade and health issues in ways that echo and amplify dominant neoliberal ideas. These processes may further entrench the individualization of NCDs, restrict conceivable policy solutions and perpetuate policymaking norms that privilege economic/trade interests over health. This review identifies different forms and mechanisms of power active in trade and health policy spaces that enable THCCs to prevent progressive action on NCDs. It also points to potential strategies for challenging these power dynamics and relations.


Aromatic Stabilization and Hybridization Trends in Photoelectron Imaging of Heterocyclic Radicals and Anions.
We examine the photoelectron spectra and laboratory-frame angular distributions in the photodetachment of furanide (C4H3O(-)), thiophenide (C4H3S(-)), and thiazolide (C3H2NS(-)) and compare the results to the previously reported studies of pyridinide (C5H4N(-)) and oxazolide (C3H2NO(-)). Using the mixed s-p model for the angular distributions, the results are interpreted in terms of the effective fractional p character of the highest-occupied molecular orbitals of these heterocyclic anions, revealing trends related to the aromaticity. We conclude that aromatic stabilization across a series of systems may be tracked using the photoelectron angular distributions. In addition, we report an improved (higher-precision) electron affinity (EA) for the thiophenyl radical, EA((•)C4H3S) = 2.089(8) eV. The EA of thiazolyl falls within the 2.5(1) eV range, but it is not clear if this determination corresponds to the 2- or 5-cyclic species or the 2-ring-open isomer. These results are analyzed in conjunction with the properties of other heterocyclic radicals (pyridinyl, furanyl, and oxazolyl) and interpreted in terms of the C-H bond dissociation energies (BDEs) of the corresponding closed-shell molecules. The BDEs of all five-membered-ring heterocyclics studied fall within the 116-120 kcal/mol range, contrasting the lower BDE = 110.4(2.0) kcal/mol of the more aromatic six-membered-ring pyridine. The observed aromaticity trends are consistent with the findings derived from the anion photoelectron angular distributions.


Preventing influenza: an overview of systematic reviews.
Many options are available for preventing people from getting infected by influenza virus, with vaccination being the most widely used. We assessed the evidence available in Cochrane systematic reviews. We found nine reviews, five of them addressing influenza vaccination, and four addressing medication. Vaccination is effective in healthy adults and children, but the effect is modest in adults, and for young children few data are available. In patients with asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis, more evidence is needed to determine effectiveness. Vaccination does not result in exacerbation of asthma. Neuraminidase inhibitors may also have a place in limiting the spread of infection, at least in adults. Amantadine and rimantadine seem effective but have unfavourable adverse-effect profiles. The popularity of homoeopathic Oscillococcinum, especially in France, is not supported by current evidence. In many areas, more clinical trials are needed, as the current evidence is inconclusive. Furthermore, several other measures that may be helpful in preventing influenza that have not been addressed in Cochrane reviews.


The Therapeutic Effects of Intracavernosal Plaque Excision in Peyronie's Disease: A None Grafting or Tunical Excising Procedure.
Current surgical treatments in Peyronie's disease are accompanied by complications such as penile shortening, loss of sensation, erectile dysfunction and recurrence of disease. The aim of this study was the evaluation of clinical results of intracavernosal plaque excision in Peyronie's disease. The operation was performed on 35 men. It was consisted of incising the tunica albuginea parallel to the plaque and through this incision, and the plaque was removed from the inside surface without excision or replacing the underlying tunica albuginea by grafts. All patients were evaluated before and periodically within 12 months after the surgery with measurement of penile length, curvature angle in the rigidity phase, and sexual satisfaction. The mean age of patients was 51.4±5.3 years (range 42-59 years). The angle of penile curvature was 25-45° (mean=35°). Thirty patients (86%) obtained a nearly complete straightening of penis. All patients restored their previous penile length without any disorder of sensation within the glans penis and expressed improvement of sexual activity. Intracavernosal plaque excision is a simple, easy and minimal invasive method that does not result in penile shortening, loss of sensation or erectile dysfunction. In properly selected patients, this technique can lead to acceptable elimination of penile curvature and sexual satisfaction.


Regulation of the PAI-1 promoter by circadian clock components: differential activation by BMAL1 and BMAL2.
Circadian variation in plasminogen activator inhibitor-1 (PAI-1) production likely contributes to increased risk of myocardial infarction and decreased efficacy of thrombolytic therapy during the morning. In this study, we characterize the abilities of fundamental molecular components of intrinsic circadian clocks to regulate the human PAI-1 promoter in transfected endothelial cells. Both CLOCK:BMAL1 and CLOCK:BMAL2 heterodimers activate the PAI-1 promoter through requisite proximal (-565 to -560 bp) and distal (-680 to -675 bp) E-box enhancers. Although the distal E-box overlaps the 4G/5G polymorphism of the PAI-1 promoter, allelic variation at this site does not influence CLOCK:BMAL1-and CLOCK:BMAL2-mediated transactivation. Together, CLOCK:BMAL1 and CLOCK:BMAL2 make additive contributions to PAI-1 gene transcription. While the abilities of these heterodimers to activate gene expression differ by twofold, the susceptibilities of these circadian activators to inhibition by period and cryptochrome proteins are equivalent and redox independent. Given that BMAL1 and BMAL2 differ in their spatiotemporal distributions, such distinctions may allow intrinsic circadian clocks to modulate the amplitudes of their oscillators, while maintaining circadian periodicity. In this way, fundamental circadian clock components may drive circadian variation in PAI-1, which in turn influences the pathogenesis, timing, and treatment of acute atherothrombotic events.


New antifouling silica hydrogel.
In this work, a new antifouling silica hydrogel was developed for potential biomedical applications. A zwitterionic polymer, poly(carboxybetaine methacrylate) (pCBMA), was produced via atom-transfer radical polymerization and was appended to the hydrogel network in a two-step acid-base-catalyzed sol-gel process. The pCBMA silica aerogels were obtained by drying the hydrogels under supercritical conditions using CO(2). To understand the effect of pCBMA on the gel structure, pCBMA silica aerogels with different pCBMA contents were characterized using scanning electron microscopy (SEM), nuclear magnetic resonance (NMR) spectroscopy, and the surface area from Brauner-Emmet-Teller (BET) measurements. The antifouling property of pCBMA silica hydrogel to resist protein (fibrinogen) adsorption was measured using enzyme-linked immunosorbent assay (ELISA). SEM images revealed that the particle size and porosity of the silica network decreased at low pCBMA content and increased at above 33 wt % of the polymer. The presence of pCBMA increased the surface area of the material by 91% at a polymer content of 25 wt %. NMR results confirmed that pCBMA was incorporated completely into the silica structure at a polymer content below 20 wt %. A protein adsorption test revealed a reduction in fibrinogen adsorption by 83% at 25 wt % pCBMA content in the hydrogel compared to the fibrinogen adsorption in the unmodified silica hydrogel.