[The pediatrician and sports].
In contrast to recreative sports, competition should not be allowed in children without regulations and supervision. Physical handicaps should be carefully looked for through a thorough pre-participation examination and appropriate physical activities should be defined for handicapped children. Hypoactivity, fear of accident and functional deterioration cause more damage to these children than physical training which may include competition provided the underlying disease is adequately treated. Regular physical exercise appears to provide significant physical and psychological benefits which are effective beyond the period of physical activity. Stress and aggressivity linked to competition do not seem to have harmful effects on child mental health, with an exception for elite adolescent athletes for whom more information is needed. These athletes are at risk for orthopaedic lesions by overuse as well as disturbances of cardiac and endocrine functions which may disqualify them temporarily for sport events. Treatments designed to boost performance such as anabolic steroids, amphetamines or blood transfusions should be strictly forbidden.


Extra-intestinal localization of Goussia sp. (Apicomplexa) oocysts in Rana dalmatina (Anura: Ranidae), and the fate of infection after metamorphosis.
Although coccidia of the genus Goussia are common parasites of fish, only 2 species have been described in amphibians: G. hyperolisi from common reed frogs Hyperolius viridiflavus from Kenya and G. neglecta from unspecified European water frogs of the genus Rana from Germany. The genus Goussia is characterized by an oocyst, with a fine oocyst wall, containing 4 dizoic sporocysts that are composed of 2 valves joined by a longitudinal suture and lacking a Stieda body (typical for the genus Eimeria). To date, infections in amphibians were generally considered to be specific to the intestine of aquatic larval stages (tadpoles) of anurans. Herein, we report on: (1) the presence of oocysts of Goussia sp. in an extra-intestinal location (liver) of tadpoles of the agile frog R. dalmatina and (2) the presence of oocysts in the liver of both juvenile and subadult R. dalmatina. These observations represent novel traits for Goussia infections in amphibians; they may explain the vertical transmission of Goussia in tadpoles.


Single-Cell Transcriptomics of Regulatory T Cells Reveals Trajectories of Tissue Adaptation.
Non-lymphoid tissues (NLTs) harbor a pool of adaptive immune cells with largely unexplored phenotype and development. We used single-cell RNA-seq to characterize 35,000 CD4+ regulatory (Treg) and memory (Tmem) T cells in mouse skin and colon, their respective draining lymph nodes (LNs) and spleen. In these tissues, we identified Treg cell subpopulations with distinct degrees of NLT phenotype. Subpopulation pseudotime ordering and gene kinetics were consistent in recruitment to skin and colon, yet the initial NLT-priming in LNs and the final stages of NLT functional adaptation reflected tissue-specific differences. Predicted kinetics were recapitulated using an in vivo melanoma-induction model, validating key regulators and receptors. Finally, we profiled human blood and NLT Treg and Tmem cells, and identified cross-mammalian conserved tissue signatures. In summary, we describe the relationship between Treg cell heterogeneity and recruitment to NLTs through the combined use of computational prediction and in vivo validation.


Meat, beyond the plate. Data-driven hypotheses for understanding consumer willingness to adopt a more plant-based diet.
A shift towards reduced meat consumption and a more plant-based diet is endorsed to promote sustainability, improve public health, and minimize animal suffering. However, large segments of consumers do not seem willing to make such transition. While it may take a profound societal change to achieve significant progresses on this regard, there have been limited attempts to understand the psychosocial processes that may hinder or facilitate this shift. This study provides an in-depth exploration of how consumer representations of meat, the impact of meat, and rationales for changing or not habits relate with willingness to adopt a more plant-based diet. Multiple Correspondence Analysis was employed to examine participant responses (N = 410) to a set of open-ended questions, free word association tasks and closed questions. Three clusters with two hallmarks each were identified: (1) a pattern of disgust towards meat coupled with moral internalization; (2) a pattern of low affective connection towards meat and willingness to change habits; and (3) a pattern of attachment to meat and unwillingness to change habits. The findings raise two main propositions. The first is that an affective connection towards meat relates to the perception of the impacts of meat and to willingness to change consumption habits. The second proposition is that a set of rationales resembling moral disengagement mechanisms (e.g., pro-meat justifications; self-exonerations) arise when some consumers contemplate the consequences of meat production and consumption, and the possibility of changing habits.


Malaria Intermittent Preventive Treatment (IPTi) pharmacovigilance in Malawi: A case of Lilongwe district.
Intermittent Preventive Treatment with Sulfadoxine-Pyrimethamine in infants (SP-IPTi) is a malaria control strategy which, together with the delivery of routine childhood immunizations, as recommended by the World Health Organization (WHO) was implemented in Lilongwe district of Malawi from September 2008 to November in 2009. A study was performed by Lilongwe District Health Office (DHO) in collaboration with funding from UNICEF to evaluate the safety of SP-IPTi and identify potential new Adverse Events (AEs) spontaneously identified, reported, monitored and evaluated. A cohort event monitoring study was conducted on 15, 000 infants in 4 Health Facilities (HFs) after administration of SP-IPTi to infants during routine immunizations. A total of about 50 Community Health Workers (CHWs) and volunteers were trained in pharmacovigilance and were supervised by senior personnel in all the five HFs.Infants received half tablets of SP immediately after receiving DPT-HepB+Hib (Pentavalent) 2 vaccine / (IPTi 1), Pentavalent 3 / (IPTi 2) at 10 and 14 weeks respectively and Measles vaccines/(IPTi 3) at 9 months. These children were recorded and their mothers were given diary cards with pictures of possible AEs. Community Health Workers (CHWs) and volunteers followed up every child after 10 days of administration/registration to collect the diary cards where parents indicated types of AEs observed on their children as well as starting and end dates of such possible AEs.The indicated AEs were entered into a computer database from all the collected diary cards according to HFs. Possible side effects/AEs that were looked for were; persistent crying, fever, vomiting, diarrhoea, skin rashes, abdominal pains, insomnia, nausea, mouth sores, and itching among other related possible side effects. A total of 15,105 children received the IPTi and were followed in all four health facilities. Out of this, 50.3% (7,594) were male while 49.7% (7, 511) were females. Of these, 19.2% [1247], 95% CI (276-304) developed AEs as follows; 42% persistent crying, 28% fever, 18% vomiting, 5.2% skin rashes and 6.8% presented with other minor symptoms while 80.8% (13,858) did not develop any side effect. 43.2% (1254) of those who showed symptoms were IPTi1 recipients, 35.3% (1022) received IPTi2 while 21.5% (624) were from those who received IPTi3. This study showed that simultaneous administration of SP-IPTi together with immunizations was a safe strategy for implementation with very minimal serious AEs to infants. In this case therefore, strategies towards strengthening such spontaneous reporting in Malawi should not only be left to service providers but also to beneficiaries or their caregivers.


Active aortitis in relapsing polychondritis.
Relapsing polychondritis (RP) is a rare inflammatory multiorgan disorder affecting cartilaginous structures and other connective tissues. Serious cardiovascular complications have been reported in patients with RP, the most frequent being aortic or mitral regurgitation and aortic aneurysms. Aortitis is a very rare complication. An unusual case of active aortitis in a patient with RP, despite intensive immunosuppressive treatment, is described with a special emphasis on the pathological findings.


Factors associated with the development of motor fluctuations and dyskinesias in Parkinson disease.
Motor fluctuations and dyskinesias can cause disability and reduce quality of life for patients with Parkinson disease (PD). To evaluate factors associated with the development of motor fluctuations and dyskinesias and to assess the sequence in which they occur in individual patients. We performed a retrospective analysis of data from a randomized clinical trial comparing pramipexole dihydrochloride and levodopa as initial treatment for PD. Subjects were followed up for 48 to 58 months and evaluated at 3-month intervals for the presence of motor fluctuations and dyskinesias. Academic and private practices. Patients Three hundred one patients with early Parkinson disease were enrolled in this study between October 2, 1996, and August 21, 1997, and were observed through August 24, 2001, when the last patient enrolled completed 4 years of follow-up. Order of appearance of motor fluctuations and dyskinesias, time to the first occurrence of motor fluctuations, and time to the first occurrence of dyskinesias. One hundred eighty-nine subjects (62.8%) developed motor complications. Of these, 71 (37.6%) developed fluctuations but not dyskinesias, 23 (12.2%) developed dyskinesias but not fluctuations, 48 (25.4%) developed fluctuations before dyskinesias, 33 (17.5%) developed dyskinesias before fluctuations, and 14 (7.4%) developed both at the same time. Factors significantly associated with earlier occurrence of dyskinesia were Hoehn and Yahr stage of 2 or higher, cumulative levodopa dose, cumulative levodopa equivalent dose (levodopa plus pramipexole), and occurrence of motor fluctuations. Pramipexole treatment was associated with later occurrence of dyskinesias. Factors associated with earlier occurrence of motor fluctuations were cumulative levodopa dose, cumulative levodopa equivalent dose, and occurrence of dyskinesias. Factors associated with later occurrence of motor fluctuations were age at onset of 65 years or older and pramipexole treatment. Higher cumulative levodopa doses and higher cumulative levodopa equivalent doses (levodopa plus pramipexole) were associated with the earlier occurrence of motor complications. Motor fluctuations and dyskinesias appear to be interrelated because the presence of one is associated with the earlier development of the other.


Impact of Resection Technique on Perioperative Outcomes and Surgical Margins after Partial Nephrectomy for Localized Renal Masses: A Prospective Multicenter Study.
The impact of resection technique on partial nephrectomy outcomes is controversial. The aim of this study was to evaluate the pattern of resection techniques during partial nephrectomy and the impact on perioperative outcomes, acute kidney injury, positive surgical margins and the achievement of the Trifecta (negative surgical margins, no perioperative Clavien-Dindo grade 2 or greater surgical complications and no postoperative acute kidney injury). We prospectively collected data on consecutive patients with cT1-2N0M0 renal masses treated with partial nephrectomy at a total of 16 referral centers from September 2014 to March 2015. After partial nephrectomy the resection technique was classified by the surgeon as enucleation, enucleoresection or resection according to the SIB (Surface-Intermediate-Base) margin scores 0 to 2, 3 or 4 and 5, respectively. Multivariable logistic regression analysis was done to evaluate the potential impact of the resection technique on postoperative surgical complications, positive surgical margins, acute kidney injury and Trifecta achievement. Overall 507 patients were included in analysis. The resection technique was classified as enucleation in 266 patients (52%), enucleoresection in 150 (30%) and resection in 91 (18%). The resection technique (enucleoresection vs enucleation and resection) was the only significant predictor of positive surgical margins. Tumor complexity, surgical approach (open and laparoscopic vs robotic) and resection technique (enucleoresection vs enucleation) were significant predictors of Clavien-Dindo grade 2 or greater surgical complications. The surgical approach (open and laparoscopic vs robotic), the resection technique (enucleoresection vs enucleation) and warm ischemia time were significantly associated with postoperative acute kidney injury and Trifecta achievement. Resection techniques significantly impact surgical complications, early functional outcomes and positive surgical margins after partial nephrectomy of localized renal masses.


A decomposition of trends in poverty among children of immigrants.
Poverty levels among all children in the United States have tended to fluctuate in the past 30 years. However, among the children of immigrants, child poverty increased steadily and rapidly from about 12% in 1970 to 33% in the late 1990s before declining to about 21% in 2000. Using 1970, 1980, 1990, and 2000 Public Use Microdata Samples data, we identified key factors that underlie the fluctuations in immigrant child poverty from 1969 to 1999 and the divergence from children of natives. We found that roughly half the absolute increase in immigrant child poverty can be linked to changing conditions in the U.S. economy that make it more difficult to lift a family out of poverty than 30 years ago. These changes occurred disproportionately among children of parents with lower levels of education, employment, and U.S. experience but not among racial/ethnic minorities. Poverty risks among various racial and ethnic groups converged over time. The relative increase in poverty for immigrant versus native children owes largely to the divergence between immigrant and native families in racial/ethnic composition, parental education, and employment.


The transcription factor Zic4 promotes tentacle formation and prevents epithelial transdifferentiation in Hydra.
The molecular mechanisms that maintain cellular identities and prevent dedifferentiation or transdifferentiation remain mysterious. However, both processes are transiently used during animal regeneration. Therefore, organisms that regenerate their organs, appendages, or even their whole body offer a fruitful paradigm to investigate the regulation of cell fate stability. Here, we used Hydra as a model system and show that Zic4, whose expression is controlled by Wnt3/β-catenin signaling and the Sp5 transcription factor, plays a key role in tentacle formation and tentacle maintenance. Reducing Zic4 expression suffices to induce transdifferentiation of tentacle epithelial cells into foot epithelial cells. This switch requires the reentry of tentacle battery cells into the cell cycle without cell division and is accompanied by degeneration of nematocytes embedded in these cells. These results indicate that maintenance of cell fate by a Wnt-controlled mechanism is a key process both during homeostasis and during regeneration.


Sensitivity of spore germination and germ tube elongation of Saccharina japonica to metal exposure.
The sensitivity of early life stages of the brown seaweed Saccharina japonica to six metals (Cd, Cu, Hg, Ni, Pb, Zn) and two waste-water samples were investigated and a new toxicity bioassay developed. The two endpoints used were spore germination and germ tube elongation with an exposure time of 24 h. Optimal test conditions determined for photon irradiance, pH, salinity and temperature were darkness, pH 8, 35‰ and 15°C, respectively. The toxicity ranking of five metals was: Hg (EC(50) of 41 and 42 μg l(-1)) > Cu (120 and 81 μg l(-1)) > Ni (2,009 and 1,360 μg l(-1)) > Zn (3,024 and 3,897 μg l(-1)) > Pb (4,760 and 4,429 μg l(-1)) > Cd (15,052 and 7,541 μg l(-1)) for germination and germ tube elongation, respectively. The sensitivities to Cd, Cu and Ni were greater in germ tube elongation than in germination process. When tested against two different waste-water samples (processed animal and printed circuit board waste-water) values of EC(50) were between 21.29 and 32.02% for germination and between 5.33 and 8.98% for germ tube elongation. Despite differences in their chemical composition, the toxic effects of waste-water samples, as indicated by EC(50) values, did not differ significantly for the same endpoints. The CV range for both germination and germ tube elongation was between 4.61 and 37.69%, indicating high levels of precision of the tests. The results compare favourably with those from more established test procedures employing micro- and macroalgae. The advantages and potential limitations of the bioassay for the assessment of anthropogenic impacts on coastal ecosystems and commercial cultivation areas in near-shore environments are discussed.


Heritability of venous biomechanics.
Altered venous biomechanics may contribute to the pathogenesis of venous diseases, and their heritability is less known. Seventy-eight monozygotic twin pairs (aged 42.4 ± 16.8 years) and 24 same-sex dizygotic twin pairs (aged 50.5 ± 16.1 years) were examined. Anteroposterior and mediolateral diameters of the common femoral vein were measured by ultrasonography. Measurements were made both in supine and in standing body positions, with or without controlled forced expiration (Valsalva test). High correlation of diameter, capacity, and distensibility values was found between twin pairs. The univariate heritability (A), shared (C), and unshared (E) environmental effects model has shown 39.3% genetic component of the variance of low pressure, 37.9% of high-pressure venous capacity, and 36.4% of maximal capacity changes, even after elimination of sex, age, and body weight effects. Bivariate Cholesky analysis revealed substantial covariance of inherited body weight and venous capacity components (57.0%-81.4%). Femoral vein capacity and elasticity depend ≈30% to 40% on genetic factors, and this value in the standing body position can reach 50%. A relatively high genetic covariance was found between weight and femoral vein capacity and elasticity. Our work might yield some new insights into the inheritance of venous diseases that are associated with altered venous biomechanics and help elucidate the involved genes.


Silver nanoparticles: a mechanism of action on moulds.
Silver nanoparticles (AgNPs) are widely used in all branches of industry. However, their mechanisms of action towards moulds have not been studied yet. Thus we conducted this study in which we have used laser desorption/ionization time-of-flight mass spectrometry (LDI-ToF-MS) analysis to determine metabolomic changes, and microscopic analysis (transmission electron microscopy, fluorescent microscopy) to observe changes in mould cells. The AgNP treatment caused the downregulation of 162 (15 ppm) and 284 (62 ppm), and 19 (15 ppm) and 29 (62 ppm) metabolites of Aspergillus niger and Penicillium chrysogenum, respectively. All influenced features were below m/z 600 (mass-to-charge ratio). We have observed silver ions and their clusters (Ag, Ag2, and Ag3) accumulated in the mould mycelium. As well as, mono-silver ion adducts with nucleotide derivatives (Coenzyme A), amino acids (phenylglycine), peptides (LeuSerAlaLeuGlu) and lipids (fatty acids, diacylglycerophosphoglycerols, monoglicerides and glycerophospholipids). The ultrastructure analysis revealed many sever alterations due to the action of AgNPs, such us shortening and condensation of hyphae, ultrastructural reorganisation, cell plasmolysis, increased vacuolisation, numerous membranous structures, collapsed cytoplasm, accumulation of lipid material, condensed mitochondria, disintegration of organelles, nuclear deformation, condensation and fragmentation of chromatin, creation of apoptotic bodies, as well as a new inside cell wall in P. chrysogenum.


[Vitamin K antagonists : Is their prescription really "medical malpractice" today?]
Atrial fibrillation and venous thromboembolisms are frequent cardiovascular diseases. Until a few years ago only vitamin K antagonists (VKA) were available for oral anticoagulation as primary and secondary prevention of thrombembolic events. Currently, the non-vitamin K dependent new oral anticoagulants (NOAC) dabigatran, rivaroxaban, apixaban and edoxaban are approved for use. The approval studies, meta-analyses and data from registries provide evidence for the superiority of NOAC vs. VKA with respect to reduction of thrombembolisms and reduced bleeding complications; therefore, in the 2016 European Society of Cardiology (ESC) guidelines the use of NOAC is recommended as first line therapy for anticoagulation in atrial fibrillation (recommendation grade I/evidence level A). In patients with mechanical heart valve replacement and severe renal dysfunction VKA are still clearly indicated. This also holds true for prophylaxis of secondary thromboembolic events in tumor patients. Thus, even today therapy with VKA must not be regarded as medical malpractice, especially when a good adjustment of the international normalized ratio can be achieved; however, for many patients NOAC represent a very good alternative and lead to at least equal results with less effort for the prescribing physician and the patient.


SU-E-T-644: Incorporating High Dose Inhomogeneity into SBRT Treatment Planning.
By encouraging greater dose inhomogeneity in the PTV, SBRT allows higher doses to be delivered to the target, and thus improves local control and treatment outcome. This work aims to incorporate the high dose inhomogeneity constraint into SBRT treatment planning in safer manner. Two approaches are proposed to achieve high dose inhomogeneity: (1) implicitly reduce dose uniformity by increasing the error tolerance for the PTV; (2) explicitly add specific localized information by introducing the structure, located at 5 mm to 1 cm inside the PTV, and prescribe a higher dose. We formulate the inverse planning problem in a total-variation minimization framework to reduce the complexity of the fluence maps. The optimization problem was solved with a fast and efficient first-order method called TFOCS. For validation, 15-beam IMRT plans were generated for a lung SBRT case, where normal tissue constrains are directly taken from the RTOG lung SBRT protocol 0915. The inhomogeneous plans generated from the two approaches were compared with a homogeneous plan in terms of dose distributions. Both inhomogenous plans delivered higher doses to the target compared with the homogenous plan, with a ∼10% increase in max dose. The implicit approach increased the high dose spillage (outside PTV) to 0.52%, leading to more tissue damage. On the other hand, the explicit approach maintained the high dose spillage at a lower level of 0.18%, similar to that of the homogenous plan. Moreover, with local information of the PTV, the explicit approach allocated the hot spots around the center of the PTV, ensuring the safety and effectiveness of SBRT. The proposed method using specific localized information inside the PTV can safely and effectively deliver high doses to the target and lead to improved local control.


Implementation of a digital cognitive behavioral therapy for insomnia pathway in primary care.
Background Insomnia is a prevalent and debilitating disorder commonly managed by family physicians. Insomnia guidelines recommend cognitive behavioral therapy for insomnia (CBTi) as the 'first-line' treatment. However, family physicians report limited time, knowledge, access, support, and referral options to manage patients with CBTi. Consequently, many patients with insomnia are prescribed potentially harmful and addictive sedative-hypnotic medicines (e.g. benzodiazepines). Family physicians require an insomnia management pathway that is specifically tailored to the guideline-recommendations, time demands, and capacity of family practice. Methods This mixed-methods implementation trial will test the feasibility, acceptability and effectiveness of a comprehensive digital insomnia management pathway in family practice. This novel pathway includes digital recruitment of family physicians, automatic identification of patients whose electronic medical records contain recent sedative-hypnotic prescriptions using a software management pathway and real-time notifications prompting physicians to refer patients to a well-established digital CBTi program. At least 10 family physicians and 375 patients with insomnia will be recruited. Physicians will be provided with an eBook to guide gradual sedative-hypnotic withdrawal. Feasibility and acceptability will be assessed from the perspective of patients and physicians. Effectiveness will be determined by co-primary outcomes: cessation of sedative-hypnotic use, and improvement in self-reported insomnia symptoms from baseline to 12-month follow-up. Analysis of trends in costs, cost-effectiveness and cost-utility analyses will be conducted from a societal perspective. Results and discussion This implementation trial will pave the way for future scaling-up of this insomnia management pathway to improve access to CBTi and reduce reliance on sedative-hypnotic medicines in family practice. Trial Registration: This trial was prospectively registered on the Australian and New Zealand Clinical Trials Registry (ANZCTR) (ACTRN12619001539123).


Infections after Transplantation of Bone Marrow or Peripheral Blood Stem Cells from Unrelated Donors.
Infection is a major complication of hematopoietic cell transplantation. Prolonged neutropenia and graft-versus-host disease are the 2 major complications with an associated risk for infection, and these complications differ according to the graft source. A phase 3, multicenter, randomized trial (Blood and Marrow Transplant Clinical Trials Network [BMT CTN] 0201) of transplantation of bone marrow (BM) versus peripheral blood stem cells (PBSC) from unrelated donors showed no significant differences in 2-year survival between these graft sources. In an effort to provide data regarding whether BM or PBSC could be used as a preferential graft source for transplantation, we report a detailed analysis of the infectious complications for 2 years after transplantation from the BMT CTN 0201 trial. A total of 499 patients in this study had full audits of infection data. A total of 1347 infection episodes of moderate or greater severity were documented in 384 (77%) patients; 201 of 249 (81%) of the evaluable patients had received a BM graft and 183 of 250 (73%) had received a PBSC graft. Of 1347 infection episodes, 373 were severe and 123 were life-threatening and/or fatal; 710 (53%) of these episodes occurred on the BM arm and 637 (47%) on the PBSC arm, resulting in a 2-year cumulative incidence 84.7% (95% confidence interval [CI], 79.6 to 89.8) for BM versus 79.7% (95% CI, 73.9 to 85.5) for PBSC, P = .013. The majority of these episodes, 810 (60%), were due to bacteria, with a 2-year cumulative incidence of 72.1% and 62.9% in BM versus PBSC recipients, respectively (P = .003). The cumulative incidence of bloodstream bacterial infections during the first 100 days was 44.8% (95% CI, 38.5 to 51.1) for BM versus 35.0% (95% CI, 28.9 to 41.1) for PBSC (P = .027). The total infection density (number of infection events/100 patient days at risk) was .67 for BM and .60 for PBSC. The overall infection density for bacterial infections was .4 in both arms; for viral infections, it was .2 in both arms; and for fungal/parasitic infections, it was .04 and .05 for BM and PBSC, respectively. The cumulative incidence of infection before engraftment was 47.9% (95% CI, 41.5 to 53.9) for BM versus 32.8% (95% CI, 27.1 to 38.7) for PBSC (P = .002), possibly related to quicker neutrophil engraftment using PBSC. Infections remain frequent after unrelated donor hematopoietic cell transplantation, particularly after BM grafts.


Interferons in relapsing remitting multiple sclerosis: a systematic review.
Recombinant interferons have been approved by many national regulatory agencies for treatment of relapsing remitting multiple sclerosis, but widespread discussion continues about their true effectiveness, benefits, side-effects, and costs. With the Cochrane Collaboration methodology, we reviewed all published, randomised, placebo-controlled trials of recombinant interferons undertaken in patients with relapsing remitting multiple sclerosis between 1993 and 2002. Our primary aim was to find out whether recombinant interferons reduced the number of patients who had clinical exacerbations and disease progression, compared with placebo. The seven trials that met our criteria included 1215 randomised patients: data from 667 (55%) were available for analysis at 1 year's and from 919 (76%) at 2 years' follow-up. Interferon seemed to reduce the number of patients who had exacerbations during the first year of treatment (relative risk 0.73, 95% CI 0.54-0.99), but results at 2 years' follow-up were not robust and were difficult to interpret because of the many dropouts. Although the number of patients who had exacerbations (0.81, 0.74-0.89) or progressed (0.70, 0.55-0.88) during the first 2 years fell significantly in the protocol analysis, results were inconclusive after sensitivity analyses for exacerbations (1.11, 0.73-1.68) and disease progression (1.31, 0.60-2.89). Data were insufficient to establish whether steroid use and admissions to hospital were reduced in the interferon group. Similarly, MRI outcome data could not be analysed quantitatively. Side-effects were common, and acute toxic effects adversely affected quality of life. Recombinant interferons slightly reduce the number of patients who have exacerbations during first year of treatment. Their clinical effect beyond 1 year is uncertain and new trials are needed to assess their long-term effectiveness and side-effects.


Enhancing primary care for complex patients. Demonstration project using multidisciplinary teams.
Communication between community-based providers is often sporadic and problem-focused. To implement collaborative community-based care among providers distant from one another and to improve or maintain the health of high-risk community-dwelling patients, with a focus on medication use. Six primary health care teams were formed of a family physician, a pharmacist, and a home care case manager (nurse). Three of these teams also had a family physician's office nurse. Teams received training and decided on processes of care that included a home visit, medication history, and weekly 1.5-hour face-to-face team meetings. In 151 team conferences, 705 medication or health issues were identified for 182 patients over 6 months. Medication adherence was improved at 3 and 6 months. After 6 months, all providers had a greater understanding of the roles of the other providers. Primary health care teams developed in this study require few structural changes to existing health care systems, but will require more reimbursement options.


VDAC3 as a sensor of oxidative state of the intermembrane space of mitochondria: the putative role of cysteine residue modifications.
Voltage-Dependent Anion selective Channels (VDAC) are pore-forming mitochondrial outer membrane proteins. In mammals VDAC3, the least characterized isoform, presents a set of cysteines predicted to be exposed toward the intermembrane space. We find that cysteines in VDAC3 can stay in different oxidation states. This was preliminary observed when, in our experimental conditions, completely lacking any reducing agent, VDAC3 presented a pattern of slightly different electrophoretic mobilities. This observation holds true both for rat liver mitochondrial VDAC3 and for recombinant and refolded human VDAC3. Mass spectroscopy revealed that cysteines 2 and 8 can form a disulfide bridge in native VDAC3. Single or combined site-directed mutagenesis of cysteines 2, 8 and 122 showed that the protein mobility in SDS-PAGE is influenced by the presence of cysteine and by the redox status. In addition, cysteines 2, 8 and 122 are involved in the stability control of the pore as shown by electrophysiology, complementation assays and chemico-physical characterization. Furthermore, a positive correlation between the pore conductance of the mutants and their ability to complement the growth of porin-less yeast mutant cells was found. Our work provides evidence for a complex oxidation pattern of a mitochondrial protein not directly involved in electron transport. The most likely biological meaning of this behavior is to buffer the ROS load and keep track of the redox level in the inter-membrane space, eventually signaling it through conformational changes.


Fabrication and magnetic properties of Ni nanospheres encapsulated in a fullerene-like carbon.
A very simple, efficient, and economical synthetic technique, which produces fascinating fullerene-like Ni-C (graphitic) core-shell nanostructures at a relatively low temperature, is reported. The thermal dissociation of Ni acetylacetonate is carried out in a closed vessel cell (Swagelok) that was heated at 700 degrees C for 3 h. The encapsulation of ferromagnetic Ni nanospheres into the onion structured graphitic layers is obtained in a one-stage, single precursor reaction, without a catalyst, that possesses interesting magnetic properties. The magnetoresistance (MR) property of Ni nanospheres encapsulated in a fullerene-like carbon was measured, which shows large negative MR, of the order of 10%. The proposed mechanism for the formation of the Ni-C core-shell system is based on the segregation and the surface flux formed in the Ni and carbon particles during the reaction under autogenic pressure at elevated temperature.


Effectiveness of a cervical pessary for women who did not deliver 48 h after threatened preterm labor (Assessment of perinatal outcome after specific treatment in early labor: Apostel VI trial).
Preterm birth is a major cause of neonatal mortality and morbidity. As preventive strategies are largely ineffective, threatened preterm labor is a frequent problem that affects approximately 10 % of pregnancies. In recent years, risk assessment in these women has incorporated cervical length measurement and fetal fibronectin testing, and this has improved the capacity to identify women at increased risk for delivery within 14 days. Despite these improvements, risk for preterm birth continues to be increased in women who did not deliver after an episode of threatened preterm labor, as indicated by a preterm birth rate between 30 to 60 % in this group of women. Currently no effective treatment is available. Studies on maintenance tocolysis and progesterone have shown ambiguous results. The pessary has not been evaluated in women with threatened preterm labor, however studies in asymptomatic women with a short cervix show reduced rates of preterm birth rates as well as perinatal complications. The APOSTEL VI trial aims to assess the effectiveness of a cervical pessary in women who did not deliver within 48 h after an episode of threatened preterm labor. This is a nationwide multicenter open-label randomized clinical trial. Women with a singleton or twin gestation with intact membranes, who were admitted for threatened preterm labor, at a gestational age between 24 and 34 weeks, a cervical length between 15 and 30 mm and a positive fibronectin test or a cervical length below 15 mm, who did not deliver after 48 h will be eligible for inclusion. Women will be allocated to a pessary or no intervention (usual care). Primary outcome is preterm delivery < 37 weeks. Secondary outcomes are amongst others a composite of perinatal morbidity and mortality. Sample size is based on an expected 50 % reduction of preterm birth before 37 weeks (two-sided test, α 0.05 and β 0.2). Two hundred women with a singleton pregnancy need to be randomized. Analysis will be done by intention to treat. The APOSTEL VI trial will provide evidence whether a pessary is effective in preventing preterm birth in women who did not deliver 48 h after admission for threatened preterm labor and who remain at high risk for preterm birth. Trial is registered at the Dutch Trial Register: http://www.trialregister.nl , NTR4210, date of registration: October 16th 2013.


Mechanism of nuclear factor of activated T-cells mediated FasL expression in corticosterone -treated mouse Leydig tumor cells.
Fas and FasL is important mediators of apoptosis. We have previously reported that the stress levels of corticosterone (CORT, glucocorticoid in rat) increase expression of Fas/FasL and activate Fas/FasL signal pathway in rat Leydig cells, which consequently leads to apoptosis. Moreover, our another study showed that nuclear factor of activated T-cells (NFAT) may play a potential role in up-regulation of FasL during CORT-treated rat Leydig cell. It is not clear yet how NFAT is involved in CORT-induced up-regulation of FasL. The aim of the present study is to investigate the molecular mechanisms of NFAT-mediated FasL expression in CORT-treated Leydig cells. Western blot analysis showed that NFAT2 expression is present in mouse Leydig tumor cell (mLTC-1). CORT-induced increase in FasL expression in mLTC-1 was ascertained by Western Blot analysis and CORT-induced increase in apoptotic frequency of mLTC-1 cells was detected by FACS with annexin-V labeling. Confocal imaging of NFAT2-GFP in mLTC-1 showed that high level of CORT stimulated NFAT translocation from the cytoplasm to the nucleus. RNA interference-mediated knockdown of NFAT2 significantly attenuated CORT-induced up-regulation of FasL expression in mLTC. These results corroborated our previous finding that NFAT2 is involved in CORT-induced FasL expression in rat Leydig cells and showed that mLTC-1 is a suitable model for investigating the mechanism of CORT-induced FasL expression. The analysis of reporter constructs revealed that the sequence between -201 and +71 of mouse FasL gene is essential for CORT-induced FasL expression. The mutation analysis demonstrated that CORT-induced FasL expression is mediated via an NFAT binding element located in the -201 to +71 region. Co-transfection studies with an NFAT2 expression vector and reporter construct containing -201 to +71 region of FasL gene showed that NFAT2 confer a strong inducible activity to the FasL promoter at its regulatory region. In addition, chromatin immunoprecipitation assay further confirmed the results of reporter gene studies by showing the specific binding of NFAT2 to the -201 to +71 region. In the present study, we demonstrated that NFAT2 directly stimulates transcription of FasL in high level CORT-treated mLTC-1. In conclusion, the present study provides further evidence for our finding that CORT-induced FasL expression in Leydig cells is mediated by NFAT.


Pharmacokinetic Properties of Orally Administered 4'-Cyano-2'-deoxyguanosine, a Novel Nucleoside Analog Inhibitor of the Hepatitis B Virus, in Viral Liver Injury Model Rats.
A nucleoside analog, 4'-cyano-2'-deoxyguanosine (CdG), which was developed as an inhibitor of the chronic hepatitis B virus (HBV), exhibited a superior antiviral activity against both wild-type and drugs-resistant HBV to marketed nucleoside analogs. In addition to previous pharmacokinetic studies of CdG in healthy rats, this study reports on an evaluation of the pharmacokinetic characteristics of CdG in a rat model of viral liver injury (VLI) induced by treatment with concanavalin A. Following an intravenous administration of CdG at a dose of 1 mg/kg, the plasma concentration profile of CdG in VLI model rats was found to be similar to that of healthy rats with no significant difference in kinetic parameters. However, when CdG was orally administered at a dose of 1 mg/kg, the maximum blood concentration was much lower in VLI model rats than in healthy rats. Interestingly, the amount of residual food in the stomachs in VLI model rats was significantly larger than that in healthy rats, indicating that the adsorption of CdG in the gastrointestinal tract was inhibited in the presence of food as well as other marketed nucleoside analogs. As observed in healthy rats, CdG was largely distributed to the liver compared to the kidney in the VLI model. These results suggest that liver pathology has only a minor effect on the pharmacokinetic properties of CdG, but the influence of food on CdG absorption needs to be considered.


Body mass index, waist circumference and waist to hip ratio and change in sex steroid hormones: the Massachusetts Male Ageing Study.
Cross-sectional data suggest that obesity, particularly central obesity, may be associated with decreased production of sex steroid hormones in men. However, longitudinal hormone data on men in relation to obesity status are limited. Previous studies have not consistently demonstrated whether sex steroids are associated specifically to body mass index or to measures of central obesity. Our objective was to examine the relation of obesity (body mass index > 30 kg/m2), and of central obesity (waist circumference > 100 cm or waist to hip ratio > 0.95) to longitudinal change in sex steroid hormones in men. Prospective follow-up of a population-based sample of men in Boston. Nine hundred forty-two (942) men in the Massachusetts Male Ageing Study with complete anthropometry and hormone data at baseline (1987-1989, ages 40-70) and follow-up (1995-1997). Free and total testosterone (FT and TT), dehydroepiandrosterone sulphate (DHEAS), and sex hormone-binding globulin (SHBG) were assessed using standardized methods. Health behaviours and medical history were obtained by structured interview. Repeated measures regression was used to describe trends in steroid hormones and SHBG in relation to obesity status, adjusting for age, smoking, alcohol, comorbidities, and physical activity. Obesity was associated with decreased levels of total and free testosterone, and of SHBG at follow-up relative to baseline. For any given baseline concentration of TT, FT or SHBG, follow-up levels were lowest among men who remained obese or who became obese during follow-up. This was true for all three indices of obesity. Central adiposity was associated with lower DHEAS levels at follow-up, while elevated body mass index was not. Obesity may predict greater decline in testosterone and SHBG levels with age. Central adiposity may be a more important predictor of decline in DHEAS than is body mass index.


RNF12 activates Xist and is essential for X chromosome inactivation.
In somatic cells of female placental mammals, one of the two X chromosomes is transcriptionally silenced to accomplish an equal dose of X-encoded gene products in males and females. Initiation of random X chromosome inactivation (XCI) is thought to be regulated by X-encoded activators and autosomally encoded suppressors controlling Xist. Spreading of Xist RNA leads to silencing of the X chromosome in cis. Here, we demonstrate that the dose dependent X-encoded XCI activator RNF12/RLIM acts in trans and activates Xist. We did not find evidence for RNF12-mediated regulation of XCI through Tsix or the Xist intron 1 region, which are both known to be involved in inhibition of Xist. In addition, we found that Xist intron 1, which contains a pluripotency factor binding site, is not required for suppression of Xist in undifferentiated ES cells. Analysis of female Rnf12⁻/⁻ knockout ES cells showed that RNF12 is essential for initiation of XCI and is mainly involved in the regulation of Xist. We conclude that RNF12 is an indispensable factor in up-regulation of Xist transcription, thereby leading to initiation of random XCI.


Biomimetic Thermal-sensitive Multi-transform Actuator.
Controllable and miniaturised mechanical actuation is one of the main challenges facing various emerging technologies, such as soft robotics, drug delivery systems, and microfluidics. Here we introduce a simple method for constructing actuating devices with programmable complex motions. Thermally responsive hydrogels based on poly(N-isopropylacrylamide) (PNIPAM) and its functionalized derivatives (f-PNIPAM) were used to control the lower critical solution temperature (LCST) or the temperature at which the gel volume changes. Techniques for ultra-violet crosslinking the monomer solutions were developed to generate gel sheets with controllable crosslink density gradients that allowed bending actuation to specified curvatures by heating through the LCST. Simple molding processes were then used to construct multi-transform devices with complex shape changes, including a bioinspired artificial flower that shows blossoming and reverse blossoming with a change in temperature.


Establishment of a cancer surveillance programme: the South African experience.
Cancer is projected to become a leading cause of morbidity and mortality in low-income and middle-income countries in the future. However, cancer incidence in South Africa is largely under-reported because of a lack of nationwide cancer surveillance networks. We describe present cancer surveillance activities in South Africa, and use the International Agency for Research on Cancer framework to propose the development of four population-based cancer registries in South Africa. These registries will represent the ethnic and geographical diversity of the country. We also provide an update on a cancer surveillance pilot programme in the Ekurhuleni Metropolitan District, and the successes and challenges in the implementation of the IARC framework in a local context. We examine the development of a comprehensive cancer surveillance system in a middle-income country, which might serve to assist other countries in establishing population-based cancer registries in a resource-constrained environment.


Magnetic resonance imaging apparent diffusion coefficients for histologically confirmed intracranial lesions in dogs.
Diffusion-weighted imaging is an advanced magnetic resonance imaging technique that is well established in the diagnosis of nonhemorrhagic infarction in people. However, recent investigations into intracranial neoplastic and inflammatory disease in people have identified variable and overlapping results. In this retrospective study of 37 dogs with histologically confirmed intracranial disease, we investigated whether histogram analysis of quantitative apparent diffusion coefficients (ADC) can differentiate specific disease processes. Disease categories included: meningiomas, glial cell tumors, choroid plexus tumors, pituitary tumors, inflammatory brain diseases, acute nonhemorrhagic infarcts, chronic nonhemorrhagic infarcts, and hemorrhagic infarcts. A wide range of ADC value distributions were identified within the disease groups, and there were overlapping ADC values between most groups. Low ADC values indicating restricted diffusion of water were identified in acute nonhemorrhagic infarcts as expected, but were also seen in meningiomas, glial cell tumors, and granulomatous meningoencephalitis. Based on this preliminary data it is unlikely that singular quantitative ADC values can be used to determine the histological type of canine intracranial disease.


Energy barriers to rotation in axially chiral analogues of 4-(dimethylamino)pyridine.
The barriers to enantiomerization of a series of axially chiral biaryl analogues of 4-(dimethylamino)pyridine (DMAP) 1-10 were determined experimentally by means of dynamic HPLC measurements and racemization studies. The barriers to rotation in derivatives 1-6 (based on the bicyclic 5-azaindoline core) were lower than those in the corresponding derivatives 7-10 (based on the monocyclic DMAP core). Semiempirical (PM3), ab initio Hartree-Fock (HF/STO-3G), and density functional theory (DFT/B3LYP/6-31G*) calculations reveal that these differences in barriers to rotation are the result of differing degrees of hybridization of the non-pyridyl nitrogen in the enantiomerization transition states (TSs). The importance of heteroatom hybridization as a factor in determining nonsteric contributions to barriers to rotation in azabiaryls of this type is discussed.


Frontal cortex gray matter volume alterations in pathological gambling occur independently from substance use disorder.
Neuroimaging in pathological gambling (PG) allows studying brain structure independent of pharmacological/neurotoxic effects occurring in substance addiction. Because of high comorbidity of PG with substance use disorder (SUD), first results on structural deficits in PG are controversial. The current investigation is the first to examine gray matter (GM) volume alterations in PG controlling for the impact of SUD by comparing non-comorbid (PGPURE ) and two comorbid (PGALCOHOL and PGPOLY ) groups. Two hundred and five individuals were included in the analysis: 107 patients diagnosed with PG and 98 healthy controls (HCs). We employed voxel-based morphometry to look for GM volume differences between the groups controlling for age, smoking and depression. GM decreases in the superior medial and orbital frontal cortex occur independently of substance use in PGPURE compared with HCs. The frontal pattern of GM decrease was comparable with PGALCOHOL group where additionally GM volume was decreased in the anterior cingulate but increased in the amygdala. Moreover, regions in PGALCOHOL + POLY with reduced GM volume were the medial frontal, anterior cingulate and occipital lobe regions. PGALCOHOL + POLY not only exhibited structural deficits in comparison with HCs but also relative to PGPURE in the precuneus and post-central gyrus. We demonstrated specific frontal cortex GM deficits in PG without SUD comorbidities. Whereas some target regions reported in earlier studies might result from comorbid substance abuse, there seems to be a core set of frontal alterations associated with addicted gambling behaviour independent of toxic substance effects.


HPLC-based activity profiling: discovery of piperine as a positive GABA(A) receptor modulator targeting a benzodiazepine-independent binding site.
A plant extract library was screened for GABA(A) receptor activity making use of a two-microelectrode voltage clamp assay on Xenopus laevis oocytes. An ethyl acetate extract of black pepper fruits [Piper nigrum L. (Piperaceae) 100 microg/mL] potentiated GABA-induced chloride currents through GABA(A) receptors (composed of alpha(1), beta(2), and gamma(2S) subunits) by 169.1 +/- 2.4%. With the aid of an HPLC-based activity profiling approach, piperine (5) was identified as the main active compound, together with 12 structurally related less active or inactive piperamides (1-4, 6-13). Identification was achieved by on-line high-resolution mass spectrometry and off-line microprobe 1D and 2D NMR spectroscopy, using only milligram amounts of extract. Compound 5 induced a maximum potentiation of the chloride currents by 301.9 +/- 26.5% with an EC(50) of 52.4 +/- 9.4 microM. A comparison of the modulatory activity of 5 and other naturally occurring piperamides enabled insights into structural features critical for GABA(A) receptor modulation. The stimulation of chloride currents through GABA(A) receptors by compound 5 was not antagonized by flumazenil (10 microM). These data show that piperine (5) represents a new scaffold of positive allosteric GABA(A) receptor modulators targeting a benzodiazepine-independent binding site.


Haploinsufficiency of RPS14 in 5q- syndrome is associated with deregulation of ribosomal- and translation-related genes.
We have previously demonstrated haploinsufficiency of the ribosomal gene RPS14, which is required for the maturation of 40S ribosomal subunits and maps to the commonly deleted region, in the 5q- syndrome. Patients with Diamond-Blackfan anaemia (DBA) show haploinsufficiency of the closely related ribosomal protein RPS19, and show a consequent downregulation of multiple ribosomal- and translation-related genes. By analogy with DBA, we have investigated the expression profiles of a large group of ribosomal- and translation-related genes in the CD34(+) cells of 15 myelodysplastic syndrome (MDS) patients with 5q- syndrome, 18 MDS patients with refractory anaemia (RA) and a normal karyotype, and 17 healthy controls. In this three-way comparison, 55 of 579 ribosomal- and translation-related probe sets were found to be significantly differentially expressed, with approximately 90% of these showing lower expression levels in the 5q- syndrome patient group. Using hierarchical clustering, patients with the 5q- syndrome could be separated both from other patients with RA and healthy controls solely on the basis of the deregulated expression of ribosomal- and translation-related genes. Patients with the 5q- syndrome have a defect in the expression of genes involved in ribosome biogenesis and in the control of translation, suggesting that the 5q- syndrome represents a disorder of aberrant ribosome biogenesis.


The impact of paliperidone palmitate long-acting injection on hospital admissions in a mental health setting.
We screened 216 patients in a retrospective observational investigator-initiated study, of whom 45.37% patients (n=98) were retained after the inclusion criteria were applied. These patients had been prescribed paliperidone palmitate long-acting injection (PPLAI) with diagnoses of schizophrenia, schizoaffective disorder and bipolar affective disorder. We investigated whether PPLAI has an effect on the frequency and length of admissions to mental health inpatient units, the number of contacts with Crisis Resolution Home Treatment Teams (CRHTT) and frequency of home visits by the CRHTT per patient, over 6 years, split using a 'mirror image' method. In total, 85% of patients continued PPLAI for 1 year, 60% for 2 years and 47% for 3 years. In the sample of patients who continued with PPLAI for 3 years (n=48), the mean number of hospital admissions decreased from 1.03 to 0.35 per patient (P=0.001). The mean number of bed days decreased significantly from 53 to 24 bed days (P=0.0001). The median values showed similar significant differences. There were numerical differences but nonsignificant results between CRHTT's number of contacts and length of episodes across the study period. Our results indicate that PPLAI has been shown to be effective in the reduction of hospital admissions, relapse rates and length of inpatient stay.


Smoking-cessation prevalence among U.S. smokers of menthol versus non-menthol cigarettes.
The Food and Drug Administration currently is assessing the public health impact of menthol cigarettes. Whether menthol cigarettes pose increased barriers to quitting is a critical issue because previous declines in smoking prevalence have stalled. To explore whether menthol cigarette smokers are less likely to quit than non-menthol smokers at the population level and whether this relationship differs by race/ethnicity. Cross-sectional analyses of the 2003 and 2006/2007 Tobacco Use Supplement to the Current Population Survey were conducted in 2010. Multiple logistic regressions were used to calculate the adjusted odds of cessation for menthol smoking relative to non-menthol smoking. Five different sample restrictions were used to assess the robustness of the findings. In the broadest sample restriction, menthol smokers were less likely to have quit smoking (AOR=0.91, 95% CI=0.87, 0.96). This relationship holds among whites (AOR=0.93, 95% CI=0.88, 0.98) and blacks (AOR=0.81, 95% CI=0.67, 0.98). The magnitude of the relationship among Hispanics was similar to that among whites, but differed by Hispanic origin. Among those of Mexican origin, the AOR for menthol smokers was protective but not significant (AOR=1.29, 95% CI=0.99, 1.61), whereas among those of Puerto Rican origin, menthol smokers were less likely to have quit (AOR=0.57, 95% CI=0.37, 0.87). These findings were robust and significant in four of five sample restrictions. Smoking menthol cigarettes is associated with decreased cessation at the population level, and this association is more pronounced among black and Puerto Rican smokers. These findings support the recent calls to ban menthol flavoring in cigarettes.


Outcome of percutaneous nephrolithotomy in anomalous kidney: Is it different?
Various anomalous kidneys such as horseshoe kidney, crossed ectopic kidney, simple ectopic kidney, pelvic ectopic kidney, kidney with duplex system, and malrotated kidney are frequently associated with stone disease. Percutaneous nephrolithotomy (PCNL) is a challenging procedure in these patients because of abnormal orientation of kidney. Since 2005-2015, 86 patients underwent PCNL for stone removal in anomalous kidneys. Stone characteristics, type of calyceal puncture, number of punctures, need of relook procedures, mean hemoglobin drop, blood transfusion, mean operative time complications, mean hospital stay, stone free rate, and auxiliary procedure were analyzed. Totally 91 sessions of PCNL was done in 86 patients including five of horseshoe kidney who had bilateral stone disease. Mean age, duration of symptoms, stone size, and hospital stay was 29.6 ± 12.6 years, 2.18 ± 1.41 years, 4.40 ± 1.16, and 4.17 ± 2.11 days, respectively. Sixteen patients underwent relook procedure, out of which only 6 could have complete stone clearance. PCNL in anomalous kidney is a safe and feasible procedure similar to normally located kidney, but requires careful preoperative planning and intra- and post-operative vigilance.


Human Mind Control of Rat Cyborg's Continuous Locomotion with Wireless Brain-to-Brain Interface.
Brain-machine interfaces (BMIs) provide a promising information channel between the biological brain and external devices and are applied in building brain-to-device control. Prior studies have explored the feasibility of establishing a brain-brain interface (BBI) across various brains via the combination of BMIs. However, using BBI to realize the efficient multidegree control of a living creature, such as a rat, to complete a navigation task in a complex environment has yet to be shown. In this study, we developed a BBI from the human brain to a rat implanted with microelectrodes (i.e., rat cyborg), which integrated electroencephalogram-based motor imagery and brain stimulation to realize human mind control of the rat's continuous locomotion. Control instructions were transferred from continuous motor imagery decoding results with the proposed control models and were wirelessly sent to the rat cyborg through brain micro-electrical stimulation. The results showed that rat cyborgs could be smoothly and successfully navigated by the human mind to complete a navigation task in a complex maze. Our experiments indicated that the cooperation through transmitting multidimensional information between two brains by computer-assisted BBI is promising.


Targeting of liposomes via PSGL1 for enhanced tumor accumulation.
To improve the delivery of liposomes to tumors using P-selectin glycoprotein ligand 1 (PSGL1) mediated binding to selectin molecules, which are upregulated on tumorassociated endothelium. PSGL1 was orientated and presented on the surface of liposomes to achieve optimal selectin binding using a novel streptavidin-protein G linker molecule. Loading of PSGL1 liposomes with luciferin allowed their binding to e-selectin and activated HUVEC to be quantified in vitro and their stability, pharmacokinetics and tumor accumulation to be tested in vivo using murine models. PSGL1 liposomes showed 5-fold (p < 0.05) greater selectin binding than identically formulated control liposomes modified with ligand that did not contain the selectin binding domain. When added to HUVEC, PSGL1 liposomes showed >7-fold (p < 0.001) greater attachment than control liposomes. In in vivo studies PSGL1 liposomes showed similar stability and circulation to control liposomes but demonstrated a >3-fold enhancement in the level of delivery to tumors (p < 0.05). The technologies and strategies described here may contribute to clinical improvements in the selectivity and efficacy of liposomal drug delivery agents.


Preventing the introduction of meticillin-resistant Staphylococcus aureus into hospitals.
The objective of this review was to provide an up-to-date account of the interventions used to prevent the introduction of meticillin-resistant Staphylococcus aureus (MRSA) from the expanding community and livestock reservoirs into hospitals in the USA, Denmark, The Netherlands and Western Australia. A review of existing literature and local guidelines for the management of MRSA in hospitals was performed. In Denmark, The Netherlands and Western Australia, where the prevalence of MRSA is relatively low, targeted admission screening and isolation of predefined high-risk populations have been used for several decades to successfully control MRSA in the hospital. Furthermore, in Denmark and The Netherlands, all identified MRSA carriers undergo routine decolonisation, whereas only carriers of particularly transmissible or virulent MRSA clones are subjected to decolonisation in Western Australia. In the USA, which continues to be a high-prevalence MRSA country, policies vary by state and even by hospital, and whilst guidelines from professional organisations provide a framework for infection control practices, these guidelines lack the authority of a legislative mandate. In conclusion, the changing epidemiology of MRSA, exemplified by the recent emergence of MRSA in the community and in food animals, makes it increasingly difficult to accurately identify specific high-risk groups to screen for MRSA carriage. Understanding the changing epidemiology of MRSA in a local as well as global context is fundamental to prevent the introduction of MRSA into hospitals.


Psychobiological Factors of Sexual Functioning in Aging Women - Findings From the Women 40+ Healthy Aging Study.
Background: A variety of biological and psychosocial factors are associated with women's sexual health in midlife and older age. Evidence suggests a decline in sexual functioning in the context of aging and the menopausal transition, including changes in sexual desire, arousal, lubrication, orgasm, pain, and/or contentment. However, not all women in midlife and older age experience such a decline, and it remains unclear how the endocrine environment and psychosocial aspects contribute to the maintenance of healthy sexual functioning. Therefore, the aim of this study was to examine psychobiological predictors of sexual functioning in healthy middle-aged and elderly females. Methods: A total of 93 healthy, sexually active women aged 40-73 years completed a battery of validated psychosocial questionnaires, including measures of sexual functioning (Female Sexual Function Index) and of protective psychological traits and interpersonal variables. The steroid hormones estrogen, testosterone, progesterone and dehydroepiandrosterone sulfate were determined in saliva samples, while follicle-stimulating hormone, luteinizing hormone and sex hormone-binding globulin were determined in dried blood spots. The findings were statistically adjusted for multiple testing. Results: Age and postmenopausal status were negatively associated with overall sexual functioning, arousal, and lubrication. Regression analyses revealed that relationship satisfaction, emotional support, self-esteem, optimism, and life satisfaction each significantly predicted overall sexual functioning or specific aspects of sexual functioning, including arousal, contentment, orgasm, and pain (all p < 0.029). For desire and lubrication, no associations were found with the tested psychosocial factors. In terms of steroid hormones, testosterone was positively linked to orgasm (p = 0.012). In this sample, 79.6% reported to have healthy sexual functioning according to the questionnaires' cutoff. Younger age (OR = 0.911, 95% CI 0.854-0.970, p = 0.004) and a higher level of emotional support (OR = 1.376, 95% CI 1.033-1.833, p = 0.029) were associated with the presence of healthy sexual functioning. Discussion: Although aging and menopause negatively affected aspects of sexual functioning, the accompanying endocrine correlates were not predictive for sexual functioning in this healthy sample of middle-aged and older females. Instead, our findings suggest that sexual functioning is highly dependent on psychosocial aspects related to well-being. Accordingly, personality traits such as optimism, and interpersonal aspects such as emotional support and relationship satisfaction were identified as important predictors of sexual functioning.


Laminar specific fMRI reveals directed interactions in distributed networks during language processing.
Interactions between top-down and bottom-up information streams are integral to brain function but challenging to measure noninvasively. Laminar resolution, functional MRI (lfMRI) is sensitive to depth-dependent properties of the blood oxygen level-dependent (BOLD) response, which can be potentially related to top-down and bottom-up signal contributions. In this work, we used lfMRI to dissociate the top-down and bottom-up signal contributions to the left occipitotemporal sulcus (LOTS) during word reading. We further demonstrate that laminar resolution measurements could be used to identify condition-specific distributed networks on the basis of whole-brain connectivity patterns specific to the depth-dependent BOLD signal. The networks corresponded to top-down and bottom-up signal pathways targeting the LOTS during word reading. We show that reading increased the top-down BOLD signal observed in the deep layers of the LOTS and that this signal uniquely related to the BOLD response in other language-critical regions. These results demonstrate that lfMRI can reveal important patterns of activation that are obscured at standard resolution. In addition to differences in activation strength as a function of depth, we also show meaningful differences in the interaction between signals originating from different depths both within a region and with the rest of the brain. We thus show that lfMRI allows the noninvasive measurement of directed interaction between brain regions and is capable of resolving different connectivity patterns at submillimeter resolution, something previously considered to be exclusively in the domain of invasive recordings.


Evaluation of adipocytokine levels and vascular functions in young aged to middle aged men with idiopathic hypogonadotrophic hypogonadism.
Hypogonadism has major effects on the urogenital system, in addition to other systems, the cardiovascular system in particular. There have been few studies conducted on markers of atherosclerosis, such as flow mediated dilatation (% FMD), carotid intima-media thickness (CIMT) and adipocytokine levels in idiopatic hypogonadotropic hypogonadal (IHH) males mostly in adult patients. The aim of this study was to evaluate the relationship between androgens and adipocytokines and parameters of vascular functions in hypogonadal men. The study population consisted of 11 treatment naive IHH patients (group 1) and 15 age-matched healthy control males (group 2). A fasting blood sample was obtained for leptin, adiponectin and resistin. The endothelial functions were evaluated by studying % FMD and CIMT by high resolution B-mode ultrasound. No significant differences in age, body mass index, systolic and diastolic blood pressure were recorded between the two groups. The leptin level was significantly higher in group 1, whereas adiponectin and resistin levels were same between two groups. There was a negative correlation between total testosterone and carotid intima-media thickness (r=-0.656, p=0.008), and a negative correlation between total testosterone and leptin level (r=-0.794, p<0.001). No correlation was found between leptin and CIMT (p=0.184). Testosterone deficiency in hypogonadal men is associated with vascular parameters of atherosclerosis. The findings may establish indications for testosterone replacement therapy in hypogonadal men.


Chemopreventive effects of Strobilanthes crispus leaf extract on azoxymethane-induced aberrant crypt foci in rat colon.
In this work, microscopic and histological studies suggest that Strobilanthes crispus ethanol extract reduce azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in rats. S. crispus is considered a traditional medicine and used as an antioxidant. Its leaf contains a large amount of phenolic compounds to which its radical scavenging role is attributed and enhance its ability to eradicate oxidative stress reactions. The study was designed to determine the chemopreventive effect of S. crispus ethanol extract in vivo and in vitro by elucidating the effect of the extract on intermediate biomarkers which can be used as effective predictors of colon cancer. S. crispus was analyzed for DPPH free radical scavenging, nitric oxide (NO) and ferric acid reduction. The results indicated that S. crispus oral administration significantly inhibited colorectal carcinogenesis induced by AOM as revealed by the reduction in the number of ACF. S. crispus down-regulated the expression of PCNA, Bcl2 and β-catenin. Additionally, it exerted a pronounced inhibitory effect on MDA and NO levels and stimulatory effect on CAT and GPx activities. These results demonstrate that S. crispus is a chemopreventive agent for colorectal cancer through the suppression of early and intermediate carcinogenic phases that may be related to its flavonoid content.


Quantitative measures of aggressive periodontitis show substantial heritability and consistency with traditional diagnoses.
Aggressive periodontitis (AgP) research nearly always classifies subjects into traditional discrete categories of localized or generalized, based upon degree of attachment loss (AL) and types of affected teeth. Since AL is continuous and quantitative, however, useful information is lost. We developed quantitative measures of AgP, compared these to traditional methods, and estimated heritabilities in families. We examined 237 healthy, 169 localized AgP, and 204 generalized AgP subjects. We used the site of maximum AL of each tooth to calculate means for each subject for different groups of teeth. We also applied principal components analysis (PCA) to condense variation among 28 teeth into three orthogonal (uncorrelated) variables. We used discriminant function analysis (DFA) to evaluate how well the quantitative measures match with traditional classifications. Quantitative trait heritabilities were estimated by variance components. PCA clustered first molars, incisors, and the other teeth into three groups. DFA showed that quantitative measures classified subjects consistent with traditional methods (87% to 94% agreement). Heritabilities ranged from 13.7% (P = 0.10) to 30.0% (P = 0.008) for quantitative measures, with highest values obtained for first molars. A combination of the principal component variables most heavily weighted on first molars and incisors gave the best model of disease susceptibility, with good separation of healthy versus diseased subjects, independent of disease extent or severity. Quantitative measures may provide improved precision and power for many kinds of periodontal research. Our finding of significant heritability supports their use in gene mapping studies of AgP susceptibility.


The aesthetic outcome of surgical correction for sagittal synostosis can be reliably scored by a novel method of preoperative and postoperative visual assessment.
Aims of surgical correction for isolated sagittal synostosis are functional and aesthetic. Multiple surgical techniques exist; however, reliable assessment of aesthetic outcome is poorly documented, limiting direct comparisons. The pinched appearance of the temporal regions is particularly challenging to correct. A visual analogue scale was designed to grade skull shape in patients who had total or subtotal calvarial remodeling for isolated sagittal synostosis. Twenty-two assessors graded preoperative and postoperative photographs from 42 consecutive cases of sagittal synostosis under a single surgeon. Five aspects were graded (i.e., narrow elongated skull, frontal bossing, temporal pinching, occipital bullet, and overall shape) from 0 (normal) to 100 (severe). Interobserver and intraobserver agreement were analyzed by calculating within-subject standard deviation, coefficient of variation, and intraclass correlation coefficient. Linear regression analysis determined predictors of outcome. Surgery improved outcome dramatically across all five aspects of skull shape, with a 72.6 to 76.4 percent decrease in severity score. Improvements in severity score were greater after total calvarial remodeling, and type of calvarial remodeling (total versus subtotal) was an independent predictor of outcome in all aspects of skull shape (p≤0.001). Temporal pinching was improved in a subset of patients who also had onlay bone grafts in this region. Calvarial remodeling is a powerful technique for improving skull shape. A panel can detect gross and subtle aesthetic changes after surgical correction of sagittal synostosis using a visual analogue scale, with moderate interobserver and intraobserver agreement. This provides a tool for future outcome assessment. Therapeutic, IV.


Gene expression profiling during early acute febrile stage of dengue infection can predict the disease outcome.
We report the detailed development of biomarkers to predict the clinical outcome under dengue infection. Transcriptional signatures from purified peripheral blood mononuclear cells were derived from whole-genome gene-expression microarray data, validated by quantitative PCR and tested in independent samples. The study was performed on patients of a well-characterized dengue cohort from Recife, Brazil. The samples analyzed were collected prospectively from acute febrile dengue patients who evolved with different degrees of disease severity: classic dengue fever or dengue hemorrhagic fever (DHF) samples were compared with similar samples from other non-dengue febrile illnesses. The DHF samples were collected 2-3 days before the presentation of the plasma leakage symptoms. Differentially-expressed genes were selected by univariate statistical tests as well as multivariate classification techniques. The results showed that at early stages of dengue infection, the genes involved in effector mechanisms of innate immune response presented a weaker activation on patients who later developed hemorrhagic fever, whereas the genes involved in apoptosis were expressed in higher levels. Some of the gene expression signatures displayed estimated accuracy rates of more than 95%, indicating that expression profiling with these signatures may provide a useful means of DHF prognosis at early stages of infection.


Towards achieving Abuja targets: identifying and addressing barriers to access and use of insecticides treated nets among the poorest populations in Kenya.
Ensuring that the poor and vulnerable population benefit from malaria control interventions remains a challenge for malaria endemic countries. Until recently, ownership and use of insecticides treated nets (ITNs) in most countries was low and inequitable, although coverage has increased in countries where free ITN distribution is integrated into mass vaccination campaigns. In Kenya, free ITNs were distributed to children aged below five years in 2006 through two mass campaigns. High and equitable coverage were reported after the campaigns in some districts, although national level coverage remained low, suggesting that understanding barriers to access remains important. This study was conducted to explore barriers to ownership and use of ITNs among the poorest populations before and after the mass campaigns, to identify strategies for improving coverage, and to make recommendations on how increased coverage levels can be sustained. The study was conducted in the poorest areas of four malaria endemic districts in Kenya. Multiple data collection methods were applied including: cross-sectional surveys (n = 708 households), 24 focus group discussions and semi-structured interviews with 70 ITN suppliers. Affordability was reported as a major barrier to access but non-financial barriers were also shown to be important determinants. On the demand side key barriers to access included: mismatch between the types of ITNs supplied through interventions and community preferences; perceptions and beliefs on illness causes; physical location of suppliers and; distrust in free delivery and in the distribution agencies. Key barriers on the supply side included: distance from manufacturers; limited acceptability of ITNs provided through interventions; crowding out of the commercial sector and the price. Infrastructure, information and communication played a central role in promoting or hindering access. Significant resources have been directed towards addressing affordability barriers through providing free ITNs to vulnerable groups, but the success of these interventions depends largely on the degree to which other barriers to access are addressed. Only if additional efforts are directed towards addressing non-financial barriers to access, will high coverage levels be achieved and sustained.


The multifaceted interplay between attention and multisensory integration.
Multisensory integration has often been characterized as an automatic process. Recent findings indicate that multisensory integration can occur across various stages of stimulus processing that are linked to, and can be modulated by, attention. Stimulus-driven, bottom-up mechanisms induced by crossmodal interactions can automatically capture attention towards multisensory events, particularly when competition to focus elsewhere is relatively low. Conversely, top-down attention can facilitate the integration of multisensory inputs and lead to a spread of attention across sensory modalities. These findings point to a more intimate and multifaceted interplay between attention and multisensory integration than was previously thought. We review developments in the current understanding of the interactions between attention and multisensory processing, and propose a framework that unifies previous, apparently discordant, findings.


Liver toxicity associated with tuberculosis chemotherapy in the REMoxTB study.
Drug-induced liver injury (DILI) is a common complication of tuberculosis treatment. We utilised data from the REMoxTB clinical trial to describe the incidence of predisposing factors and the natural history in patients with liver enzyme levels elevated in response to tuberculosis treatment. Patients received either standard tuberculosis treatment (2EHRZ/4HR), or a 4-month regimen in which moxifloxacin replaced either ethambutol (isoniazid arm, 2MHRZ/2MHR) or isoniazid (ethambutol arm, 2EMRZ/2MR). Hepatic enzymes were measured at 0, 2, 4, 8, 12 and 17 weeks and as clinically indicated during reported adverse events. Patients included were those receiving at least one dose of drug and with two or more hepatic enzyme measurements. A total of 1928 patients were included (639 2EHRZ/4HR, 654 2MHRZ/2MHR and 635 2EMRZ/2MR). DILI was defined as peak alanine aminotransferase (ALT) ≥ 5 times the upper limit of normal (5 × ULN) or ALT ≥ 3 × ULN with total bilirubin > 2 × ULN. DILI was identified in 58 of the 1928 (3.0%) patients at a median time of 28 days (interquartile range IQR 14-56). Of 639 (6.4%) patients taking standard tuberculosis therapy, 41 experienced clinically significant enzyme elevations (peak ALT ≥ 3 × ULN). On standard therapy, 21.1% of patients aged >55 years developed a peak ALT/aspartate aminotransferase (AST) ≥ 3 × ULN (p = 0.01) and 15% of HIV-positive patients experienced a peak ALT/AST ≥ 3 × ULN compared to 9% of HIV-negative patients (p = 0.160). The median peak ALT/AST was higher in isoniazid-containing regimens vs no-isoniazid regimens (p < 0.05), and lower in moxifloxacin-containing arms vs no-moxifloxacin arms (p < 0.05). Patients receiving isoniazid reached a peak ALT ≥ 3 × ULN 9.5 days earlier than those on the ethambutol arm (median time of 28 days vs 18.5 days). Of the 67 Asian patients with a peak ALT/AST ≥ 3 × ULN, 57 (85.1%) were on an isoniazid-containing regimen (p = 0.008). Our results provide evidence of the risk of DILI in tuberculosis patients on standard treatment. Older patients on standard therapy, HIV-positive patients, Asian patients and those receiving isoniazid were at higher risk of elevated enzyme levels. Monitoring hepatic enzymes during the first 2 months of standard therapy detected approximately 75% of patients with a peak enzyme elevation ≥3 × ULN, suggesting this should be a standard of care. These results provide evidence for the potential of moxifloxacin in hepatic sparing.


Single-Molecule Sequencing Reveals Estrogen-Regulated Clinically Relevant lncRNAs in Breast Cancer.
Estrogen receptor (ER)α-positive tumors are commonly treated with ERα antagonists or inhibitors of estrogen synthesis, but most tumors develop resistance, and we need to better understand the pathways that underlie the proliferative and tumorigenic role of this estrogen-activated transcription factor. We here present the first single-molecule sequencing of the estradiol-induced ERα transcriptome in the luminal A-type human breast cancer cell lines MCF7 and T47D. Sequencing libraries were prepared from the polyadenylated RNA fraction after 8 hours of estrogen or vehicle treatment. Single-molecule sequencing was carried out in biological and technical replicates and differentially expressed genes were defined and analyzed for enriched processes. Correlation analysis with clinical expression and survival were performed, and follow-up experiments carried out using time series, chromatin immunoprecipitation and quantitative real-time PCR. We uncovered that ERα in addition to regulating approximately 2000 protein-coding genes, also regulated up to 1000 long noncoding RNAs (lncRNAs). Most of these were up-regulated, and 178 lncRNAs were regulated in both cell lines. We demonstrate that Long Intergenic Non-protein Coding RNA 1016 (LINC01016) and LINC00160 are direct transcriptional targets of ERα, correlate with ERα expression in clinical samples, and show prognostic significance in relation to breast cancer survival. We show that silencing of LINC00160 results in reduced proliferation, demonstrating that lncRNA expression have functional consequences. Our findings suggest that ERα regulation of lncRNAs is clinically relevant and that their functions and potential use as biomarkers for endocrine response are important to explore.


GABA(A) receptors, gephyrin and homeostatic synaptic plasticity.
Homeostatic synaptic plasticity describes the changes in synapse gain and function that occur in response to global changes in neuronal activity to maintain the stability of neuronal networks. In this review, we argue that a coordinated regulation of excitatory and inhibitory synaptic transmission is essential for maintaining CNS function while allowing both global and local changes in synaptic strength and connectivity. Therefore, we postulate that homeostatic synaptic plasticity depends on signalling cascades regulating in parallel the efficacy of glutamatergic and GABAergic transmission. Since neurotransmitter receptors interact closely with scaffolding proteins in the postsynaptic density, this coordinated regulation of excitatory and inhibitory synaptic transmission probably involves posttranslational modifications of scaffolding proteins, which in turn modulate local synaptic function. Here we review the current state of knowledge on the regulation of GABA(A) receptors and their main scaffolding protein gephyrin by posttranslational modifications; we outline future lines of research that might contribute to furthering our understanding of the molecular mechanisms regulating GABAergic synapse function and homeostatic plasticity.


GP recruitment and retention: a qualitative analysis of doctors' comments about training for and working in general practice.
General practice in the UK is experiencing difficulty with medical staff recruitment and retention, with reduced numbers choosing careers in general practice or entering principalships, and increases in less-than-full-time working, career breaks, early retirement and locum employment. Information is scarce about the reasons for these changes and factors that could increase recruitment and retention. The UK Medical Careers Research Group (UKMCRG) regularly surveys cohorts of UK medical graduates to determine their career choices and progression. We also invite written comments from respondents about their careers and the factors that influence them. Most respondents report high levels of job satisfaction. A noteworthy minority, however, make critical comments about general practice. Although their views may not represent those of all general practitioners (GPs), they nonetheless indicate a range of concerns that deserve to be understood. This paper reports on respondents' comments about general practice. ANALYSIS OF DOCTORS' COMMENTS: Training Greater exposure to general practice at undergraduate level could help to promote general practice careers and better inform career decisions. Postgraduate general practice training in hospital-based posts was seen as poor quality, irrelevant and run as if it were of secondary importance to service commitments. In contrast, general practice-based postgraduate training was widely praised for good formal teaching that met educational needs. The quality of vocational training was dependent upon the skills and enthusiasm of individual trainers. Recruitment problems Perceived deterrents to choosing general practice were its portrayal, by some hospital-based teachers, as a second class career compared to hospital medicine, and a perception of low morale amongst current GPs. The choice of a career in general practice was commonly made for lifestyle reasons rather than professional aspirations. Some GPs had encountered difficulties in obtaining posts in general practice suited to their needs, while others perceived discrimination. Newly qualified GPs often sought work as non-principals because they felt too inexperienced for partnership or because their domestic situation prevented them from settling in a particular area. Changes to general practice The 1990 National Health Service (NHS) reforms were largely viewed unfavourably, partly because they had led to a substantial increase in GPs' workloads that was compounded by growing public expectations, and partly because the two-tier system of fund-holding was considered unfair. Fund-holding and, more recently, GP commissioning threatened the GP's role as patient advocate by shifting the responsibility for rationing of health care from government to GPs. Some concerns were also expressed about the introduction of primary care groups (PCGs) and trusts (PCTs). Together, increased workload and the continual process of change had, for some, resulted in work-related stress, low morale, reduced job satisfaction and quality of life. These problems had been partially alleviated by the formation of GP co-operatives. Retention difficulties Loss of GPs' time from the NHS workforce occurs in four ways: reduced working hours, temporary career breaks, leaving the NHS to work elsewhere and early retirement. Child rearing and a desire to pursue interests outside medicine were cited as reasons for seeking shorter working hours or career breaks. A desire to reduce pressure of work was a common reason for seeking shorter working hours, taking career breaks, early retirement or leaving NHS general practice. Other reasons for leaving NHS general practice, temporarily or permanently, were difficulty in finding a GP post suited to individual needs and a desire to work abroad. A cultural change amongst medical educationalists is needed to promote general practice as a career choice that is equally attractive as hospital practice. The introduction of Pre-Registration House Officer (PRHO) placements in general practice and improved flexibility of GP vocational training schemes, together with plans to improve the quality of Senior House Officer (SHO) training in the future, are welcome developments and should address some of the concerns about poor quality GP training raised by our respondents. The reluctance of newly qualified GPs to enter principalships, and the increasing demand from experienced GPs for less-than-full-time work, indicates a need for a greater variety of contractual arrangements to reflect doctors' desires for more flexible patterns of working in general practice.


Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample.
Autism spectrum disorders are now recognized to occur in up to 1% of the population and to be a major public health concern because of their early onset, lifelong persistence, and high levels of associated impairment. Little is known about the associated psychiatric disorders that may contribute to impairment. We identify the rates and type of psychiatric comorbidity associated with ASDs and explore the associations with variables identified as risk factors for child psychiatric disorders. A subgroup of 112 ten- to 14-year old children from a population-derived cohort was assessed for other child psychiatric disorders (3 months' prevalence) through parent interview using the Child and Adolescent Psychiatric Assessment. DSM-IV diagnoses for childhood anxiety disorders, depressive disorders, oppositional defiant and conduct disorders, attention-deficit/hyperactivity disorder, tic disorders, trichotillomania, enuresis, and encopresis were identified. Seventy percent of participants had at least one comorbid disorder and 41% had two or more. The most common diagnoses were social anxiety disorder (29.2%, 95% confidence interval [CI)] 13.2-45.1), attention-deficit/hyperactivity disorder (28.2%, 95% CI 13.3-43.0), and oppositional defiant disorder (28.1%, 95% CI 13.9-42.2). Of those with attention-deficit/hyperactivity disorder, 84% received a second comorbid diagnosis. There were few associations between putative risk factors and psychiatric disorder. Psychiatric disorders are common and frequently multiple in children with autism spectrum disorders. They may provide targets for intervention and should be routinely evaluated in the clinical assessment of this group.


Intravenous ivabradine versus placebo in patients with low cardiac output syndrome treated by dobutamine after elective coronary artery bypass surgery: a phase 2 exploratory randomized controlled trial.
Low cardiac output syndrome (LCOS) is a severe condition which can occur after cardiac surgery, especially among patients with pre-existing left ventricular dysfunction. Dobutamine, its first-line treatment, is associated with sinus tachycardia. This study aims to assess the ability of intravenous ivabradine to decrease sinus tachycardia associated with dobutamine infused for LCOS after coronary artery bypass graft (CABG) surgery. In a phase 2, multi-center, single-blind, randomized controlled trial, patients with left ventricular ejection fraction below 40% presenting sinus tachycardia of at least 100 beats per minute (bpm) following dobutamine infusion for LCOS after CABG surgery received either intravenous ivabradine or placebo (three ivabradine for one placebo). Treatment lasted until dobutamine weaning or up to 48 h. The primary endpoint was the proportion of patients achieving a heart rate (HR) in the 80- to 90-bpm range. Secondary endpoints were invasive and non-invasive hemodynamic parameters and arrhythmia events. Nineteen patients were included. More patients reached the primary endpoint in the ivabradine than in the placebo group (13 (93%) versus 2 (40%); P = 0.04). Median times to reach target HR were 1.0 h in the ivabradine group and 5.7 h in the placebo group. Ivabradine decreased HR (112 to 86 bpm, P <0.001) while increasing cardiac index (P = 0.02), stroke volume (P <0.001), and systolic blood pressure (P = 0.03). In the placebo group, these parameters remained unchanged from baseline. In the ivabradine group, five patients (36%) developed atrial fibrillation (AF) and one (7%) was discontinued for sustained AF; two (14%) were discontinued for bradycardia. Intravenous ivabradine achieved effective and rapid correction of sinus tachycardia in patients who received dobutamine for LCOS after CABG surgery. Simultaneously, stroke volume and systolic blood pressure increased, suggesting a beneficial effect of this treatment on tissue perfusion. European Clinical Trials Database: EudraCT 2009-018175-14 . Registered February 2, 2010.


Identification of a signal-responsive nuclear export sequence in class II histone deacetylases.
Activation of muscle-specific genes by the MEF2 transcription factor is inhibited by class II histone deacetylases (HDACs) 4 and 5, which contain carboxy-terminal deacetylase domains and amino-terminal extensions required for association with MEF2. The inhibitory action of HDACs is overcome by myogenic signals which disrupt MEF2-HDAC interactions and stimulate nuclear export of these transcriptional repressors. Nucleocytoplasmic trafficking of HDAC5 is mediated by binding of the chaperone protein 14-3-3 to two phosphoserine residues (Ser-259 and Ser-498) in its amino-terminal extension. Here we show that HDAC4 and -5 each contain a signal-responsive nuclear export sequence (NES) at their extreme carboxy termini. The NES is conserved in another class II HDAC, HDAC7, but is absent in class I HDACs and the HDAC-related corepressor, MEF2-interacting transcription repressor. Our results suggest that this conserved NES is inactive in unphosphorylated HDAC5, which is localized to the nucleus, and that calcium-calmodulin-dependent protein kinase (CaMK)-dependent binding of 14-3-3 to phosphoserines 259 and 498 activates the NES, with consequent export of the transcriptional repressor to the cytoplasm. A single amino acid substitution in this NES is sufficient to retain HDAC5 in the nucleus in the face of CaMK signaling. These findings provide molecular insight into the mechanism by which extracellular cues alter chromatin structure to promote muscle differentiation and other MEF2-regulated processes.


Evidence of constitutional MLH1 epimutation associated to transgenerational inheritance of cancer susceptibility.
Constitutional epimutations of DNA mismatch repair (MMR) genes have been recently reported as a possible cause of Lynch syndrome. However, little is known about their prevalence, the risk of transmission through the germline and the risk for carriers to develop cancers. In this study, we evaluated the contribution of constitutional epimutations of MMR genes in Lynch syndrome. A cohort of 134 unrelated Lynch syndrome-suspected patients without MMR germline mutation was screened for constitutional epimutations of MLH1 and MSH2 by quantitative bisulfite pyrosequencing. Patients were also screened for the presence of EPCAM deletions, a possible cause of MSH2 methylation. Tumors from patients with constitutional epimutations were extensively analyzed. We identified a constitutional MLH1 epimutation in two proband patients. For one of them, we report for the first time evidence of transmission to two children who also developed early colonic tumors, indicating that constitutional MLH1 epimutations are associated to a real risk of transgenerational inheritance of cancer susceptibility. Moreover, a somatic BRAF mutation was detected in one affected child, indicating that tumors from patients carrying constitutional MLH1 epimutation can mimic MSI-high sporadic tumors. These findings may have important implications for future diagnostic strategies and genetic counseling.


Temperature dependence of the reduction of P(700)(+) by tightly bound plastocyanin in vivo.
The kinetics of reduction of P(700)(+), the stably oxidized electron donor of Photosystem I, by plastocyanin (PC) has been investigated by pump-probe optical spectroscopy in living cells of the green alga Chlamydomonas reinhardtii, between 277 and 318 K. The reduction of P(700)(+) in vivo is described by two kinetic components with lifetimes of 6 +/- 0.5 and 56 +/- 1 micros at room temperature. The rapid reduction phase, which is attributed to reduction of P(700)(+) by prebound PC, is thermally activated with an apparent activation barrier of 105-115 meV. The analysis of the in vivo reaction is consistent with (i) reduced PC and PS I forming a relatively tight binary complex that does not undergo kinetically limiting conformational reconfiguration and (ii) the activation barrier being determined principally by enthalpic contributions to the free energy change. Under the approximation that entropic contributions to the free energy change associated with this electron transfer reaction are negligible, a lower boundary value of the reorganization energy is estimated to be 0.54-0.63 eV, which is on the lower range of the distribution for intraprotein electron transfer reactions. This low activation barrier is discussed in terms of the optimization of primary donor reduction.


Clinical Presentation and Bacteriology of Eyebrow Infections: The Massachusetts Eye and Ear Infirmary Experience (2008-2015).
This study retrospectively reviews preseptal cellulitis and abscesses involving the eyebrow to elucidate the bacteriology and potential causative factors. A retrospective chart review was conducted to identify patients who had been diagnosed with preseptal cellulitis or abscess involving the eyebrow at the Massachusetts Eye and Ear Infirmary between 2008 and 2015. Demographic, clinical, and microbiological data were collected. Eighty patients with eyebrow infections were identified, of whom 49 (61.3%) were female and 31 (38.7%) were male. The median age was 37 years (range 14-67 years). Eyebrow abscess was present in 54 cases (67.5%), while 26 cases (32.5%) were limited to preseptal cellulitis without abscess formation. Methicillin-resistant Staphylococcus aureus was found in 20 abscesses (39.2% of culture results), and methicillin-sensitive S. aureus was found in 12 abscesses (23.5% of culture results). Coagulase-negative staphylococci were present in 7 eyebrow abscesses (13.7% of culture results). Clinical history was remarkable for eyebrow hair removal (tweezing, waxing, threading, or shaving) in 17 cases (21.3%), manipulation of acne lesions ("popping," "picking," or "squeezing") in 6 cases (7.5%), and both brow hair removal and acne manipulation in 1 case (1.3%). There is a high incidence of methicillin-resistant Staphylococcus aureus in the bacteriology of eyebrow infections. Empirical antibiotic coverage for methicillin-resistant Staphylococcus aureus should be strongly considered in any patient with an eyebrow area abscess or preseptal cellulitis. Individuals who practice cosmetic eyebrow grooming should be encouraged to consider hygiene practices, which could reduce the risk of infection.