Reactive and proactive aggression: Differential links with emotion regulation difficulties, maternal criticism in adolescence.
Proactive and reactive functions of aggression are thought to manifest through different familial and emotional processes, even though they often co-occur. We investigated direct and indirect pathways through which maternal criticism and emotion regulation (ER) difficulties relate to reactive and proactive aggression in adolescence. Further, we examined how maternal criticism and emotion dysregulation interrelate, both concurrently and over time. Participants were 482 Dutch adolescents (M = 15.03, SD = 0.45, 57% boys) who self-reported on their ER difficulties, perceived maternal criticism, and reactive/proactive aggression. Cross-lagged panel modeling across four annual measurements revealed direct bidirectional links over time between maternal criticism and emotion dysregulation. Positive links over time from maternal criticism to proactive (but not reactive) aggression were also present. Emotion dysregulation and proactive aggression were linked only indirectly via maternal criticism. Gender did not significantly moderate these links. By revealing differential developmental pathways involving adolescents' ER and maternal criticism, the present study offers support for the dual function model of aggression. Aggr. Behav. 41:214-226, 2015. © 2015 Wiley Periodicals, Inc.


High-density lipoprotein: a novel target for antirestenosis therapy.
Restenosis is an integral pathological process central to the recurrent vessel narrowing after interventional procedures. Although the mechanisms for restenosis are diverse in different pathological conditions, endothelial dysfunction, inflammation, vascular smooth muscle cell (SMC) proliferation, and myofibroblasts transition have been thought to play crucial role in the development of restenosis. Indeed, there is an inverse relationship between high-density lipoprotein (HDL) levels and risk for coronary heart disease (CHD). However, relatively studies on the direct assessment of HDL effect on restenosis are limited. In addition to involvement in the cholesterol reverse transport, many vascular protective effects of HDL, including protection of endothelium, antiinflammation, antithrombus actions, inhibition of SMC proliferation, and regulation by adventitial effects may contribute to the inhibition of restenosis, though the exact relationships between HDL and restenosis remain to be elucidated. This review summarizes the vascular protective effects of HDL, emphasizing the potential role of HDL in intimal hyperplasia and vascular remodeling, which may provide novel prophylactic and therapeutic strategies for antirestenosis.


Efficacy of Alveolar Vertical Distraction Osteogenesis and Autogenous Bone Grafting for Dental Implants: Systematic Review and Meta-Analysis.
The aim of this study was to assess the efficacy of alveolar vertical distraction osteogenesis and autogenous bone grafting in terms of bone gain, bone resorption, and implant survival and success rates and investigate the relationship between bone gain and resorption after alveolar vertical distraction osteogenesis. A systematic search was done using MEDLINE, EMBASE, the Cochrane Library, and KoreaMed from inception to April 30, 2014. Supplementary manual searches of published full-text articles were also performed. Searches of four electronic databases and manual searches resulted in 1,538 articles. After selection, four studies were included in the systematic review and meta-analysis. The difference in bone gain at the end of distraction or bone grafting was statistically significant (weighted mean difference [WMD] 1.86, 95% CI 0.03 to 3.69, P = .05; heterogeneity: I(2) = 78%, P = .01). However, there was not a statistically significant difference between alveolar distraction osteogenesis and onlay bone grafting (WMD 0.30, 95% CI -0.99 to 1.59, P = .065). Bone resorption between the end of treatment and the time of implant placement was not statistically significant (WMD -0.12, 95% CI -1.10 to 0.85, P = .80; heterogeneity: I(2) = 78%, P = .01). A simple equation related to bone gain and resorption after alveolar vertical distraction was induced from these results. There was not a statistically significant difference between alveolar distraction osteogenesis and onlay bone grafting in terms of bone gain and bone resorption.


Mechanism of rate-dependent pH changes in the sheep cardiac Purkinje fibre.
1. The mechanism of the rate-dependent decrease in intracellular pH (pHi) and its recovery were studied in isolated sheep cardiac Purkinje fibres. Intracellular Na+ activity (aiNa) and pHi were measured using ion-selective microelectrodes. Twitches were elicited by field stimulation or by depolarizing pulses applied using a two-microelectrode voltage clamp. 2. A 3 Hz train of short (50 ms) depolarizing voltage-clamp pulses induced a reversible fall in pHi which was accompanied by a reversible increase in aiNa. A train of longer (200 ms) pulses also produced a fall in pHi which was now paralleled by a decrease in aiNa. These observations indicate that the rate-dependent acidosis is not dependent upon a rise in aiNa. 3. Neither the fall in pHi nor the increase in aiNa seen upon an increase in action potential frequency was inhibited by amiloride (1 mmol l-1) which indicates that Na+-H+ exchange is not involved in the generation of the acidosis. Furthermore, the rate-dependent acidosis was not abolished in Na+-free solution (Li+ or N-methyl glucamine substituted) indicating that other Na+-requiring processes (such as Na+-Ca2+ exchange) are not a necessary requirement. Rate-dependent pHi changes were also unaffected by the stilbene compound DIDS indicating no participation by Cl--HCO-3 exchange. 4. The rate-dependent acidosis was inhibited by the organic calcium antagonist D600 (20 mumol l-1) which also inhibited twitch tension. This suggests that the acidosis is related to the activation by Ca2+ of developed tension. D600 also inhibited the rate-dependent rise in aiNa (field stimulation). 5. The rate-dependent acidosis was not inhibited by cyanide (2 mmol l-1) but it was blocked by iodoacetate (0.5 mmol l-1) and by 2-deoxyglucose (DOG) (10 mmol l-1, applied in glucose-free solution). These results suggest that the acidosis is generated metabolically via stimulation of glycolysis, following an increase in contraction. Contributions from aerobic metabolism are likely to be small. 6. Twitch tension was inhibited by ryanodine (10 mumol l-1) but the drug had little inhibitory effect on the rate-dependent acidosis. A tonic component of tension was observed, however, in the presence of ryanodine. The lack of effect of ryanodine upon the rate-induced acidosis is discussed. 7. The half-time of pHi recovery from the frequency-dependent acidosis was consistently shorter than that from an intracellular acid load induced by adding and then removing external NH4Cl (10 mmol l-1).(ABSTRACT TRUNCATED AT 400 WORDS)


DengueTools: innovative tools and strategies for the surveillance and control of dengue.
Dengue fever is a mosquito-borne viral disease estimated to cause about 230 million infections worldwide every year, of which 25,000 are fatal. Global incidence has risen rapidly in recent decades with some 3.6 billion people, over half of the world's population, now at risk, mainly in urban centres of the tropics and subtropics. Demographic and societal changes, in particular urbanization, globalization, and increased international travel, are major contributors to the rise in incidence and geographic expansion of dengue infections. Major research gaps continue to hamper the control of dengue. The European Commission launched a call under the 7th Framework Programme with the title of 'Comprehensive control of Dengue fever under changing climatic conditions'. Fourteen partners from several countries in Europe, Asia, and South America formed a consortium named 'DengueTools' to respond to the call to achieve better diagnosis, surveillance, prevention, and predictive models and improve our understanding of the spread of dengue to previously uninfected regions (including Europe) in the context of globalization and climate change.The consortium comprises 12 work packages to address a set of research questions in three areas:Research area 1: Develop a comprehensive early warning and surveillance system that has predictive capability for epidemic dengue and benefits from novel tools for laboratory diagnosis and vector monitoring.Research area 2: Develop novel strategies to prevent dengue in children.Research area 3: Understand and predict the risk of global spread of dengue, in particular the risk of introduction and establishment in Europe, within the context of parameters of vectorial capacity, global mobility, and climate change.In this paper, we report on the rationale and specific study objectives of 'DengueTools'. DengueTools is funded under the Health theme of the Seventh Framework Programme of the European Community, Grant Agreement Number: 282589 Dengue Tools.


The Gene Expression Barcode 3.0: improved data processing and mining tools.
The Gene Expression Barcode project, http://barcode.luhs.org, seeks to determine the genes expressed for every tissue and cell type in humans and mice. Understanding the absolute expression of genes across tissues and cell types has applications in basic cell biology, hypothesis generation for gene function and clinical predictions using gene expression signatures. In its current version, this project uses the abundant publicly available microarray data sets combined with a suite of single-array preprocessing, quality control and analysis methods. In this article, we present the improvements that have been made since the previous version of the Gene Expression Barcode in 2011. These include a variety of new data mining tools and summaries, estimated transcriptomes and curated annotations.


Correcting for the effects of natural abundance in stable isotope resolved metabolomics experiments involving ultra-high resolution mass spectrometry.
Stable isotope tracing with ultra-high resolution Fourier transform-ion cyclotron resonance-mass spectrometry (FT-ICR-MS) can provide simultaneous determination of hundreds to thousands of metabolite isotopologue species without the need for chromatographic separation. Therefore, this experimental metabolomics methodology may allow the tracing of metabolic pathways starting from stable-isotope-enriched precursors, which can improve our mechanistic understanding of cellular metabolism. However, contributions to the observed intensities arising from the stable isotope's natural abundance must be subtracted (deisotoped) from the raw isotopologue peaks before interpretation. Previously posed deisotoping problems are sidestepped due to the isotopic resolution and identification of individual isotopologue peaks. This peak resolution and identification come from the very high mass resolution and accuracy of FT-ICR-MS and present an analytically solvable deisotoping problem, even in the context of stable-isotope enrichment. We present both a computationally feasible analytical solution and an algorithm to this newly posed deisotoping problem, which both work with any amount of 13C or 15N stable-isotope enrichment. We demonstrate this algorithm and correct for the effects of 13C natural abundance on a set of raw isotopologue intensities for a specific phosphatidylcholine lipid metabolite derived from a 13C-tracing experiment. Correction for the effects of 13C natural abundance on a set of raw isotopologue intensities is computationally feasible when the raw isotopologues are isotopically resolved and identified. Such correction makes qualitative interpretation of stable isotope tracing easier and is required before attempting a more rigorous quantitative interpretation of the isotopologue data. The presented implementation is very robust with increasing metabolite size. Error analysis of the algorithm will be straightforward due to low relative error from the implementation itself. Furthermore, the algorithm may serve as an independent quality control measure for a set of observed isotopologue intensities.


Effects of Tai Chi exercise on physical and psychological health of older people.
Tai Chi is a traditional Chinese form of conditioning exercise derived from martial arts and rooted in eastern philosophy and Chinese Medicine. Based on the inter-relatedness of mind, body and spirit this form of exercise focuses on producing an inner calmness which is thought to have both physical and psychological therapeutic value. This article provides a brief overview of selected current evidence examining the relationship between Tai Chi and physical, neurocognitive and psychosocial outcomes in older people. This is an emerging and growing area of research and improvements have often been reported in health functioning, physical and emotional health, reducing falls, fear of falling and risk of falls, and possibly enhancing cardiovascular functioning in older adults although the effects on bone density, cognitive and immunological functioning are less clear. Results overall are inconsistent and health improvements have not been evident in all studies. Tai Chi is becoming increasingly popular in practice, and more recent evidence is emerging which is based on experimental and longitudinal designs, although many of the proposed benefits of Tai Chi are yet to be validated in large, randomised controlled trials.


Bariatric Surgery Modulates Urinary Levels of MicroRNAs Involved in the Regulation of Renal Function.
Background: Obesity and diabetes cause chronic kidney disease with a common pathophysiology that is characterized by the accumulation of collagen in the extracellular matrix. Recent evidence has implicated the epithelial-to-mesenchymal transition (EMT) as a key step in this pathology with regulation by microRNAs. Weight loss leads to improvements in renal function; therefore, this study hypothesized that bariatric-surgery aided weight loss would lead to changes in urinary microRNAs involved in the regulation of renal function. Materials and methods: Twenty-four bariatric patients undergoing Roux-en-Y gastric bypass and sleeve gastrectomy donated urine pre-operatively and at 2-6 months and 1-2 years post-operatively. Urine samples were also obtained from 10 healthy weight and 7 morbidly obese non-surgical controls. Expression levels of kidney microRNAs were assessed in urine and the function of microRNAs was assessed through the in vitro transfection of HK-2 cells, a kidney proximal tubule cell line. Results: Levels of miR 192, miR 200a, and miR 200b were upregulated in urine following bariatric surgery. This increase was consistent across surgical type and diabetes status and was maintained and enhanced with time. Bariatric surgery alters urinary miR 192 expression from levels seen in morbidly obese patients to levels seen in healthy weight control patients. In mechanistic studies, the transfection of miR 192 in HK-2 cells increased miR 200a expression and decreased ZEB2, a key transcriptional promoter of kidney fibrosis. Conclusions: Bariatric surgery increased miR 192 and miR 200 urinary levels, key anti-fibrotic microRNAs that could contribute to a renal-protective mechanism and may be of value as urinary biomarkers following surgery. These findings suggest that urinary microRNAs may represent potential novel biomarkers for obesity-associated renal function.


The IASLC Lung Cancer Staging Project: Proposals for Coding T Categories for Subsolid Nodules and Assessment of Tumor Size in Part-Solid Tumors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer.
This article proposes codes for the primary tumor categories of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) and a uniform way to measure tumor size in part-solid tumors for the eighth edition of the tumor, node, and metastasis classification of lung cancer. In 2011, new entities of AIS, MIA, and lepidic predominant adenocarcinoma were defined, and they were later incorporated into the 2015 World Health Organization classification of lung cancer. To fit these entities into the T component of the staging system, the Tis category is proposed for AIS, with Tis (AIS) specified if it is to be distinguished from squamous cell carcinoma in situ (SCIS), which is to be designated Tis (SCIS). We also propose that MIA be classified as T1mi. Furthermore, the use of the invasive size for T descriptor size follows a recommendation made in three editions of the Union for International Cancer Control tumor, node, and metastasis supplement since 2003. For tumor size, the greatest dimension should be reported both clinically and pathologically. In nonmucinous lung adenocarcinomas, the computed tomography (CT) findings of ground glass versus solid opacities tend to correspond respectively to lepidic versus invasive patterns seen pathologically. However, this correlation is not absolute; so when CT features suggest nonmucinous AIS, MIA, and lepidic predominant adenocarcinoma, the suspected diagnosis and clinical staging should be regarded as a preliminary assessment that is subject to revision after pathologic evaluation of resected specimens. The ability to predict invasive versus noninvasive size on the basis of solid versus ground glass components is not applicable to mucinous AIS, MIA, or invasive mucinous adenocarcinomas because they generally show solid nodules or consolidation on CT.


Randomized Trial of a Supportive Psychotherapy for Parents of Adolescents and Young Adults With Hematologic Malignancies.
Cancer regularly disrupts health and developmental trajectories in adolescents and young adults (AYAs). Parents have been shown to have a substantial impact on the health and cancer survivorship activities of AYA patients in the form of symptom management. However, no randomized controlled trial has evaluated a coping support intervention (CSI) program for parents of AYAs with cancer aged 18 to 40 years. From November 30, 2012, to August 29, 2016, parents of AYAs with hematologic malignancies were randomized in a phase III controlled trial (1:1 ratio, stratified sampling) to either the research-based CSI AYA-Parents group (CSI group; n=82) or the standard care (SC) group (n=70). CSI consisted of 5 sessions to achieve the enhancement of parental adaptive coping as the primary outcome (per the adaptive coping scale of the 28-item Brief COPE, a validated multidimensional self-assessment-questionnaire recommended for clinical cancer research). Measures of adaptive coping, depression, and mental health were collected at pre-CSI (measurement date T1), at the end of the intervention sessions (measurement date T2), and at follow-up (3 months). We calculated mean change scores in outcomes and estimated intervention effect sizes (Cohen's d) for changes from T1 to T2/T3, with 0.2 indicating a small effect, 0.5 a medium effect, and 0.8 a large effect. All statistical tests were 2-sided. In the intention-to-treat analysis, the CSI group significantly improved their adaptive coping compared with the SC group (95% CI, 0.30-2.54; P=.013; d=0.405), whereas adaptive coping in the SC group deteriorated. The CSI group also experienced a significant decrease in depressive symptoms and improved mental health with clinical significance (95% CI, -1.98 to -0.30; P=.008; d=0.433, and 95% CI, -0.19 to 3.97; P=.074; d=0.292, respectively). Sensitivity analyses confirmed the robustness of the main intention-to-treat analysis. CSI improved effectively adaptive coping and depression in parents of AYAs with hematologic malignancies. It may represent a novel family-based approach in AYA oncology care.


Interrelation of energy intake, body size, and physical activity with prostate cancer in a large prospective cohort study.
Energy restriction reduces prostate tumor growth in transplantable tumor models in rodents, which suggests that excessive energy intake may contribute to the risk of prostate cancer. The association of total energy intake across the normal range with prostate cancer has not been consistent in epidemiological studies. We prospectively evaluated the joint associations of energy intake and body size or physical activity with prostate cancer. Participants were 46786 male health professionals ages 40-75 years at baseline in 1986 who were free of cancer diagnosis. Between 1986 and 2000, we documented 2896 incident prostate cancer cases (excluding stage T1a) by review of medical records and histopathology reports. Of these, 339 were metastatic or fatal cases. We used Cox proportional hazards regression to estimate the multivariate relative risk (RR) of prostate cancer associated with energy intake measured using a food frequency questionnaire, overall and stratified by body mass index, waist size, physical activity, as well as by age and family history of prostate cancer. There was no association between energy intake and total prostate cancer incidence. However, a modest increased risk of metastatic or fatal disease with energy intake was suggested [RR comparing extreme quintiles: 1.38, 95% confidence interval (CI) 0.96-1.98, P(trend) = 0.06]. This association was most pronounced in men with a lower body mass index (in stratum < 24 kg/m(2): RR = 1.76, 95% CI 0.92-3.39; P(interaction) = 0.04), smaller waist size [in stratum <or= 37 inches: RR = 1.91, 95% CI 0.83-4.36; P(interaction) = 0.03], and who were more physically active [in stratum >or= median: RR = 1.74, 95% CI 0.93-3.26; P(interaction) = 0.09]. Also, the association of energy intake with metastatic and fatal prostate cancer was restricted to men who were younger [in stratum <or= 65 years old: RR = 2.60, 95% CI 1.26-5.39; P(interaction) = 0.04] or who had a positive family history [RR = 3.33, 95% CI 1.26-8.76; P(interaction) = 0.04]. Although energy intake is known to be imperfectly measured by questionnaire, we observed a positive association between energy intake and metastatic or fatal prostate cancer among men who were leaner, more physically active, younger, and who had a family history of prostate cancer. Our observations suggest the testable hypothesis that the elevated risk of clinically important prostate cancer in men with a high energy intake may be attributable to certain metabolic profiles that favor enhanced growth factor production over an increase in adiposity.


Laboratory-Based Physical and Physiological Test Results That Serve as Predictors of Male, Amateur Road Cyclists' Performance Levels.
Coetzee, B, and Malan, D. Laboratory-based physical and physiological test results that serve as predictors of male, amateur road cyclists' performance levels. J Strength Cond Res 32(10): 2897-2906, 2018-The purposes of this study were first, to determine the practical significant differences of laboratory-based physical and physiological test results between a selected group of successful and less successful amateur, male road cyclists from Africa; and second, to determine the significance, adequacy, accurateness, and usefulness of laboratory-based physical and physiological test results to serve as predictors of these amateur, male road cyclists' performance levels. Male road cyclists, identified as the top amateur road cyclists of the cycling federations of 13 African countries, were subjected to a test battery for the measurement of lower-body flexibility, abdominal strength, peak and average anaerobic power output as well as maximum aerobic power. Practical significant differences between the successful and less successful road cyclists were found for almost all the Wingate related variables, some of the sub-maximum parameters, and most of the maximum physiological variables. Finally, the abdominal muscle strength test value, vertical jump distance, Wingate relative peak power, and respiratory compensation point expressed as percentage of V[Combining Dot Above]O2max and as relative power output were the physiological components that acted as adequate, accurate, and useful predictors of performance levels. Coaches and sport scientists should therefore include these components in testing protocols that are aimed at evaluating and improving cyclists' physical conditioning programs.


Evolution of gene order conservation in prokaryotes.
As more complete genomes are sequenced, conservation of gene order between different organisms is emerging as an informative property of the genomes. Conservation of gene order has been used for predicting function and functional interactions of proteins, as well as for studying the evolutionary relationships between genomes. The reasons for the maintenance of gene order are still not well understood, as the organization of the prokaryote genome into operons and lateral gene transfer cannot possibly account for all the instances of conservation found. Comprehensive studies of gene order are one way of elucidating the nature of these maintaining forces. Gene order is extensively conserved between closely related species, but rapidly becomes less conserved among more distantly related organisms, probably in a cooperative fashion. This trend could be universal in prokaryotic genomes, as archaeal genomes are likely to behave similarly to bacterial genomes. Gene order conservation could therefore be used as a valid phylogenetic measure to study relationships between species. Even between very distant species, remnants of gene order conservation exist in the form of highly conserved clusters of genes. This suggests the existence of selective processes that maintain the organization of these regions. Because the clusters often span more than one operon, common regulation probably cannot be invoked as the cause of the maintenance of gene order. Gene order conservation is a genomic measure that can be useful for studying relationships between prokaryotes and the evolutionary forces shaping their genomes. Gene organization is extensively conserved in some genomic regions, and further studies are needed to elucidate the reason for this conservation.


Knee Fix or Replace Trial (KFORT): a randomized controlled feasibility study.
The aim of this study was to assess the feasibility of conducting a full-scale, appropriately powered, randomized controlled trial (RCT) comparing internal fracture fixation and distal femoral replacement (DFR) for distal femoral fractures in older patients. Seven centres recruited patients into the study. Patients were eligible if they were greater than 65 years of age with a distal femoral fracture, and if the surgeon felt that they were suitable for either form of treatment. Outcome measures included the patients' willingness to participate, clinicians' willingness to recruit, rates of loss to follow-up, the ability to capture data, estimates of standard deviation to inform the sample size calculation, and the main determinants of cost. The primary clinical outcome measure was the EuroQol five-dimensional index (EQ-5D) at six months following injury. Of 36 patients who met the inclusion criteria, five declined to participate and eight were not recruited, leaving 23 patients to be randomized. One patient withdrew before surgery. Of the remaining patients, five (23%) withdrew during the follow-up period and six (26%) died. A 100% response rate was achieved for the EQ-5D at each follow-up point, excluding one missing datapoint at baseline. In the DFR group, the mean cost of the implant outweighed the mean cost of many other items, including theatre time, length of stay, and readmissions. For a powered RCT, a total sample size of 1400 would be required with 234 centres recruiting over three years. At six months, the EQ-5D utility index was lower in the DFR group. This study found that running a full-scale trial in this country would not be feasible. However, it may be feasible to undertake an international multicentre trial, and our findings provide some guidance about the power of such a study, the numbers required, and some challenges that should be anticipated and addressed. Cite this article: Bone Joint J 2019;101-B:1408-1415.


Deep brain stimulation of the posteromedial hypothalamus: indications, long-term results, and neurophysiological considerations.
The aim of this study was to review the indications for and results of deep brain stimulation (DBS) of the posterior hypothalamus (pHyp) in the treatment of drug-refractory and severe painful syndromes of the face, disruptive and aggressive behavior associated with epilepsy, and below-average intelligence. The preoperative clinical picture, functional imaging studies, and overall clinical results in the literature are discussed. All patients underwent stereotactic implantation of deep-brain electrodes within the pHyp. Data from several authors have been collected and reported for each clinical entity, as have clinical results, adverse events, and neurophysiological characteristics of the pHyp. The percentage of patients with chronic cluster headache who responded to DBS was 50% in the overall reported series. The response rate was 100% for short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing and for chronic paroxysmal hemicrania, although only 2 patients and 1 patient, respectively, have been described as having these conditions. None of the 4 patients suffering from refractory neuropathic trigeminal pain benefited from the procedure (0% response rate), whereas all 5 patients (100%) affected with refractory trigeminal neuralgia (TN) due to multiple sclerosis (MS) and undergoing pHyp DBS experienced a significant decrease in pain attacks within the first branch of cranial nerve V. Six (75%) of 8 patients presenting with aggressive behavior and mental retardation benefited from pHyp stimulation; 6 patients were part of the authors' series and 2 were reported in the literature. In carefully selected patients, DBS of the pHyp can be considered an effective procedure for the treatment of refractory trigeminal autonomic cephalalgias, aggressive behavior, and MS-related TN in the first trigeminal branch. Only larger and prospective studies along with multidisciplinary approaches (including, by necessity, neuroimaging studies) can lead us to better patient selection that would reduce the rate of nonresponders.


Modulation of appetitive motivation by prefrontal cortical mu-opioid receptors is dependent upon local dopamine D1 receptor signaling.
Opioid neurotransmission has been implicated in psychiatric disorders featuring impaired control over appetitive motivation, such as addiction and binge-eating disorder. We have previously shown that infusions of the μ-opioid receptor (μOR) agonist DAMGO into the ventromedial prefrontal cortex (vmPFC) induced hyperphagia, increased motor activity, and augmented sucrose-reinforced responding in the task progressive ratio (PR) task, which assesses the motivational value of an incentive. These effects were not reproduced by intra-PFC infusion of a variety of dopamine (DA) agonists and antagonists, suggesting that manipulation of intra-PFC DA systems alone is not sufficient to reproduce μOR-like effects. Nevertheless, this does not rule out interactions between PFC DA and μ-opioid systems. Here we used intra-vmPFC drug cocktails containing DAMGO and SCH 23390 (a DA D1 receptor antagonist) to determine whether increases in appetitive motivation and motor activity elicited by intra-vmPFC μOR stimulation require intact signaling through vmPFC D1 receptors. Blockade of D1 receptors with SCH 23390 attenuated the enhancement of PR breakpoint, and increases in exploratory-like behavior and feeding initiation elicited by intra-vmPFC μOR stimulation. These results establish that intra-vmPFC D1 signaling is required for the expression of behavioral effects evoked by μOR stimulation within the PFC, and further suggest that D1 tone plays an enabling or permissive role in the expression of μOR -elicited effects. Simultaneous targeting of both μ-opioid and D1 systems may represent a more efficacious treatment strategy (compared to μOR blockade alone) for psychiatric disorders characterized by dysregulated appetitive motivation.


Ped_Outlier software for automatic identification of within-family outliers.
A high-throughput resequencing technology has brought family based studies back into genetic research focus. Within-family outliers (the individuals whose phenotype is very much unlike the phenotype of relatives) may carry rare variants of large effects and thus resequencing of these provides a highly powered strategy for rare variants detection. On the other hand, such outliers may complicate search for common variants of smaller effects, because they may obscure a real linkage signal. We have developed a program Ped_Outlier allowing automatic detection of within-family outliers in a sample of pedigrees of arbitrary structure and size. We tested our program by identification of within-family outliers for adult height and intracranial volume in large pedigree. Results of linkage analysis of these traits demonstrated that identification of within-family outliers is one of the important steps of pedigree analysis. The program Ped_outlier is freely available at http://mga.bionet.nsc.ru/soft/index.html.


Predictors of family caregiver ratings of patient quality of life in Alzheimer disease: cross-sectional results from the Canadian Alzheimer's Disease Quality of Life Study.
To assess whether the core symptoms of Alzheimer disease (AD) and caregiver factors consistently predict family caregiver ratings of patient quality of life (QOL) as assessed by a variety of QOL measures in a large national sample. : Cross-sectional. Fifteen dementia and geriatric clinics across Canada. : Family caregivers (n = 412) of community-living patients with AD of all severities. Caregiver ratings of patient QOL using three utility indexes, the European Quality of Life-5 Dimensions, Quality of Well-Being Scale and Health Utilities Index; a global QOL visual analogue scale; a disease-specific measure, the Quality of Life-Alzheimer's Disease; and a generic health status measure, the Short Form-36. Patient cognition was assessed with the cognitive subscale of the Alzheimer's Disease Assessment Scale and Mini-Mental State Examination, function with the Disability Assessment for Dementia, and behavioral and psychological symptoms with the Neuropsychiatric Inventory and the Geriatric Depression Scale. Caregiver burden was assessed with the Zarit Burden Interview and caregiver depression with the Center for Epidemiologic Studies Depression scale. One-way analysis of variance and fully adjusted multiple linear regression were used to assess the relationship between patient dementia symptom and caregiver variables with QOL ratings. In multivariable analyses, caregiver ratings of patient function and depressive symptoms were the only consistent independent predictors of caregiver-rated QOL across the QOL measures. Caregiver ratings of patient function and depression were consistent independent predictors of caregiver-rated QOL, using a spectrum of QOL measures, while measures of patient cognition and caregiver burden and depression were not. These findings support the continued use of caregiver ratings as an important source of information about patient QOL and endorse the inclusion in AD clinical trials of caregiver-rated measures of patient function, depression, and QOL.


Prevention of Progression in Myopia: A Systematic Review.
The prevalence of myopia has increased worldwide in recent decades and now is endemic over the entire industrial world. This increase is mainly caused by changes in lifestyle and behavior. In particular, the amount of outdoor activities and near work would display an important role in the pathogenesis of the disease. Several strategies have been reported as effective. Spectacles and contact lenses have shown only slight results in the prevention of myopia and similarly ortokerathology should not be considered as a first-line strategy, given the high risk of infectious keratitis and the relatively low compliance for the patients. Thus, to date, atropine ophthalmic drops seem to be the most effective treatment for slowing the progression of myopia, although the exact mechanism of the effect of treatment is still uncertain. In particular, low-dose atropine (0.01%) was proven to be an effective and safe treatment in the long term due to the lowest rebound effect with negligible side effects.


Overexpression of A3 adenosine receptor in peripheral blood mononuclear cells in rheumatoid arthritis: involvement of nuclear factor-kappaB in mediating receptor level.
A3 adenosine receptor (A3AR) upregulation has been found in cells of synovial tissue and in peripheral blood mononuclear cells (PBMC) of rats with adjuvant-induced arthritis. We investigated A3AR levels in PBMC of patients with rheumatoid arthritis (RA) and in mitogen-activated PBMC from healthy subjects. We examined the role of nuclear factor-kappaB (NF-kappaB), a transcription factor present in the A3AR promoter, in mediating receptor upregulation. A3AR and NF-kappaB protein levels were evaluated in PBMC of RA patients (n = 23) and healthy subjects by Western blot. A3AR and NF-kappaB levels were also analyzed in phytohemagglutinin (PHA) and lipopolysaccharide (LPS)-stimulated PBMC in the presence and absence of antibodies against interleukin 2 (IL-2) and tumor necrosis factor-alpha (TNF-alpha). Reverse transcription-polymerase chain reaction was performed in PHA-stimulated PBMC of healthy subjects to determine A3AR expression. A3AR was overexpressed in PBMC of RA patients compared to healthy subjects and was directly correlated to an increase in NF-kappaB. Similar findings were observed in PHA and LPS-stimulated PBMC from healthy subjects. Antibodies against IL-2 or TNF-alpha prevented the increase in A3AR and NF-kappaB expression. Overexpression of A3AR was found in PBMC of RA patients. Receptor upregulation was induced by inflammatory cytokines controlling the expression of the A3AR transcription factor NF-kappaB.


[Evaluation of the protein quality of silaged corn ear products with different crude fiber contents].
The assessment of the protein quality of silaged maize ear products was carried out on the basis of crude protein and amino acid analyses and of N balance measurings with growing pigs including comparative studies with maize corns and cereals. The differences found in the amino acid concentrations between the individual maize ear products could be verified on the basis of the analysed values of husks, cobs and corns. There were no significant differences in the parameters of total protein utilization (PNu, b-value) between the studied silages. The differing crude fibre content resulted, however, in reverse shifts in N excretion in faeces and urine, i.e. diminished protein digestibility was compensated by improved intermediary utilization.


Boosting syntax training with temporally regular musical primes in children with cochlear implants.
Previous research has suggested the use of rhythmic structures (implemented in musical material) to improve linguistic structure processing (i.e., syntax processing), in particular for populations showing deficits in syntax and temporal processing (e.g., children with developmental language disorders). The present study proposes a long-term training program to improve syntax processing in children with cochlear implants, a population showing syntax processing deficits in perception and production. The training program consisted of morphosyntactic training exercises (based on speech processing) that were primed by musical regular primes (8 sessions) or neutral baseline primes (environmental sounds) (8 sessions). A crossover design was used to train 10 deaf children with cochlear implants. Performance in grammatical processing, non-word repetition, attention and memory was assessed before and after training. Training increased performance for syntax comprehension after both prime types but for grammaticality judgements and non-word repetition only when musical primes were used during training. For the far-transfer tests, some effects were also observed for attention tasks, especially if fast and precise sequential analysis (sequencing) was required, but not for memory tasks. The findings extend the previously observed beneficial short-term effects of regular musical primes in the laboratory to long-term training effects. Results suggest that the musical primes improved the processing of the syntactic training material, thus enhancing the training effects on grammatical processing as well as phonological processing and sequencing of speech signals. The findings can be interpreted within the dynamic attending theory (postulating the modulation of attention over time) and associated oscillatory brain activity. Furthermore, the findings encourage the use of rhythmic structures (even in non-verbal materials) in language training programs and outline perspectives for rehabilitation.


Hospital factors and racial disparities in mortality after surgery for breast and colon cancer.
Black patients have worse prognoses than whites with breast or colorectal cancer. Mechanisms underlying such disparities have not been fully explored. We examined the role of hospital factors in racial differences in late mortality after surgery for breast or colon cancer. Patients undergoing surgery after new diagnosis of breast or colon cancer were identified using the Surveillance Epidemiology and End Results-Medicare linked database (1995 to 2005). The main outcome measure was mortality at 5 years. Proportional hazards models were used to assess relationships between race and late mortality, accounting for patient factors, socioeconomic measures, and hospital factors. Fixed and random effects models were used to account for quality differences across hospitals. Black patients, compared with white patients, had lower 5-year overall survival rates after surgery for breast (62.1% v 70.4%, respectively; P < .001) and colon cancer (41.3% v 45.4%, respectively; P < .001). After controlling for age, comorbidity, and stage, black race remained an independent predictor of mortality for breast (adjusted hazard ratio [HR] = 1.25; 95% CI, 1.16 to 1.34) and colon cancer (adjusted HR = 1.13; 95% CI, 1.07 to 1.19). After risk adjustment, hospital factors explained 36% and 54% of the excess mortality for black patients with breast cancer and colon cancer, respectively. Hospitals with large minority populations had higher late mortality rates independent of race. Hospital factors, including quality, are important mediators of the association between race and mortality for breast and colon cancer. Hospital-level quality improvement should be a major component of efforts to reduce disparities in cancer outcomes.


CDK promotes interactions of Sld3 and Drc1 with Cut5 for initiation of DNA replication in fission yeast.
Cyclin-dependent kinase (CDK) plays essential roles in the initiation of DNA replication in eukaryotes. Although interactions of CDK-phosphorylated Sld2/Drc1 and Sld3 with Dpb11 have been shown to be essential in budding yeast, it is not known whether the mechanism is conserved. In this study, we investigated how CDK promotes the assembly of replication proteins onto replication origins in fission yeast. Phosphorylation of Sld3 was found to be dependent on CDK in S phase. Alanine substitutions at CDK sites decreased the interaction with Cut5/Dpb11 at the N-terminal BRCT motifs and decreased the loading of Cut5 onto replication origins. This defect was suppressed by overexpression of drc1(+). Phosphorylation of a conserved CDK site, Thr-111, in Drc1 was critical for interaction with Cut5 at the C-terminal BRCT motifs and was required for loading of Cut5. In a yeast three-hybrid assay, Sld3, Cut5, and Drc1 were found to form a ternary complex dependent on the CDK sites of Sld3 and Drc1, and Drc1-Cut5 binding enhanced the Sld3-Cut5 interaction. These results show that the mechanism of CDK-dependent loading of Cut5 is conserved in fission yeast in a manner similar to that elucidated in budding yeast.


Reduced virulence caused by meiotic instability of the TOX2 chromosome of the maize pathogen Cochliobolus carbonum.
The mechanisms by which pathogenic fungi evolve are poorly understood. Production of the host-selective cyclic peptide HC-toxin is controlled by a complex locus, TOX2, in the plant pathogen Cochliobolus carbonum. Crosses between toxin-producing (Tox2+) and toxin-nonproducing (Tox2-) isolates, as well as crosses between isolates in which the TOX2 genes were on chromosomes of different size, yielded progeny that had lost one or more copies of one or more of the TOX2 genes. Of approximately 200 progeny analyzed, eight (4%) had lost at least one TOX2 gene. All of them still had at least one functional copy of all of the known genes required for HC-toxin production (HTS1, TOXA, TOXC, and TOXE). Most deletion strains could be explained by simple chromosome breaks resulting in the loss of major contiguous portions (0.8 to 1.4 Mb) of the 3.5-Mb TOX2 chromosome, whereas others had more complicated patterns. All deletion strains had normal growth and were fertile, indicating that the 1.4 Mb of DNA contained no essential housekeeping genes. Most strains were also still virulent (Tox2+), but two had a novel phenotype of reduced virulence (RV), characterized by smaller lesions that expanded at a reduced rate and an inability to colonize plants systemically. Although the RV strains made no detectable HC-toxin in culture, the RV phenotype was dependent on the presence of a functional copy of HTS1, which encodes the central enzyme in HC-toxin biosynthesis. We propose that the RV strains still make a low level of HC-toxin, at least in planta, and that this is due to the loss of one or more genes that contribute to, but are not absolutely required for, HC-toxin synthesis.


Policy-Oriented Research on Improved Physician Incentives for Higher Value Health Care.
Policy makers (both public and private) are seeking ways to improve the value delivered within our health care system, that is, using fewer resources to provide the same benefit to patients, or using equivalent resources to provide more benefit. One strategy is to alter the predominant fee-for-service (FFS) economic incentives in the current system. To inform such policy changes, this paper identifies areas in which little is known about the effects of specific incentives (FFS, salary, etc.) on the two components of value: resource use and quality. Specific suggestions are offered regarding research that would be informative for policy makers, focusing on fundamental "building block" studies rather than overall evaluations of complex interventions, such as accountable care organizations. This research would better identify critical aspects of the FFS model and salary-based payments that are particularly problematic, as well as situations in which FFS or salary may be less problematic. The research would also explore when alternatives, such as episode-based payment might be feasible, or simply be hypothetical solutions. The availability of electronic health record-based data in various delivery systems would allow many of these studies to be accomplished in 3-5 years with budgets manageable by public and private funding sources.


Silver nanoparticles induced reactive oxygen species via photosynthetic energy transport imbalance in an aquatic plant.
The rapid growth in silver nanoparticles (AgNPs) commercialization has increased environmental exposure, including aquatic ecosystem. It has been reported that the AgNPs have damaging effects on photosynthesis and induce oxidative stress, but the toxic mechanism of AgNPs is still a matter of debate. In the present study, on the model aquatic higher plant Spirodela polyrhiza, we found that AgNPs affect photosynthesis and significantly inhibit Photosystem II (PSII) maximum quantum yield (Fv/Fm) and effective quantum yield (ΦPSII). The changes of non-photochemical fluorescence quenching (NPQ), light-induced non-photochemical fluorescence quenching [Y(NPQ)] and non-light-induced non-photochemical fluorescence quenching [Y(NO)] showed that AgNPs inhibit the photo-protective capacity of PSII. AgNPs induce reactive oxygen species (ROS) that are mainly produced in the chloroplast. The activity of ribulose-1, 5-bisphosphate carboxylase-oxygenase (Rubisco) was also very sensitive to AgNPs. The internalized Ag, regardless of whether the exposure was Ag+ or AgNPs had the same capacity to generate ROS. Our results support the hypothesis that intra-cellular AgNP dissociate into high toxic Ag+. Rubisco inhibition leads to slowing down of CO2 assimilation. Consequently, the solar energy consumption decreases and then the excess excitation energy promotes ROS generation in chloroplast.


SNPlice: variants that modulate Intron retention from RNA-sequencing data.
The growing recognition of the importance of splicing, together with rapidly accumulating RNA-sequencing data, demand robust high-throughput approaches, which efficiently analyze experimentally derived whole-transcriptome splice profiles. We have developed a computational approach, called SNPlice, for identifying cis-acting, splice-modulating variants from RNA-seq datasets. SNPlice mines RNA-seq datasets to find reads that span single-nucleotide variant (SNV) loci and nearby splice junctions, assessing the co-occurrence of variants and molecules that remain unspliced at nearby exon-intron boundaries. Hence, SNPlice highlights variants preferentially occurring on intron-containing molecules, possibly resulting from altered splicing. To illustrate co-occurrence of variant nucleotide and exon-intron boundary, allele-specific sequencing was used. SNPlice results are generally consistent with splice-prediction tools, but also indicate splice-modulating elements missed by other algorithms. SNPlice can be applied to identify variants that correlate with unexpected splicing events, and to measure the splice-modulating potential of canonical splice-site SNVs. SNPlice is freely available for download from https://code.google.com/p/snplice/ as a self-contained binary package for 64-bit Linux computers and as python source-code. firstname.lastname@example.com or firstname.lastname@example.com Supplementary data are available at Bioinformatics online.


NVC-422 inactivates Staphylococcus aureus toxins.
Bacterial pathogens have specific virulence factors (e.g., toxins) that contribute significantly to the virulence and infectivity of microorganisms within the human hosts. Virulence factors are molecules expressed by pathogens that enable colonization, immunoevasion, and immunosuppression, obtaining nutrients from the host or gaining entry into host cells. They can cause pathogenesis by inhibiting or stimulating certain host functions. For example, in systemic Staphylococcus aureus infections, virulence factors such as toxic shock syndrome toxin 1 (TSST-1), staphylococcal enterotoxin A (SEA), and staphylococcal enterotoxin B (SEB) cause sepsis or toxic shock by uncontrolled stimulation of T lymphocytes and by triggering a cytokine storm. In vitro, these superantigens stimulate the proliferation of human peripheral blood mononuclear cells (PBMC) and the release of many cytokines. NVC-422 (N,N-dichloro-2,2-dimethyltaurine) is a broad-spectrum, fast-acting topical anti-infective agent against microbial pathogens, including antibiotic-resistant microbes. Using mass spectrometry, we demonstrate here that NVC-422 oxidizes methionine residues of TSST-1, SEA, SEB, and exfoliative toxin A (ETA). Exposure of virulence factors to 0.1% NVC-422 for 1 h prevented TSST-1-, SEA-, SEB-, and ETA-induced cell proliferation and cytokine release. Moreover, NVC-422 also delayed and reduced the protein A- and clumping factor-associated agglutination of S. aureus cultures. These results show that, in addition to its well-described direct microbicidal activity, NVC-422 can inactivate S. aureus virulence factors through rapid oxidation of methionines.


Equivalence of mother and father ratings of ADHD in children.
Obtaining data from multiple informants provides a more comprehensive diagnostic picture in the assessment of attention deficit hyperactivity disorder (ADHD). Differences in symptom ratings have been observed between parent- and teacher-report scales, though less information is available regarding differences between mothers and fathers. To address this gap, this study examines the rater agreement between mothers and fathers on the Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV) ADHD Symptom Rating Scale (DSM-ADHD-SRS). The participants consisted of 337 children diagnosed with ADHD who underwent comprehensive neuropsychological assessment. Confirmatory factor analysis indicates that a three-factor model comprising inattention, hyperactivity, and impulsivity symptoms provides the best fit for both mothers' and fathers' ratings. Mothers provided higher mean ratings for the inattention scale. These results suggest that the factor structure for the DSM-ADHD-SRS is the same, regardless of parent gender. However, symptoms of inattention may vary depending upon which parent completes the ratings. This discrepancy could lead to differences in diagnostic impressions in clinical evaluations.


Parent-Mediated Interventions for Children With Autism Spectrum Disorder: A Systematic Review.
The purpose of this systematic review was to evaluate the evidence for the effectiveness of parent-mediated interventions on occupational performance of children with autism spectrum disorder (ASD). We conducted a search of academic databases using terms such as autism spectrum disorder, parent, caregiver, and intervention. Five hundred eighty-two articles were reviewed, and 109 were selected for full-text review. The final analysis included 13 articles. Strong evidence was found for the efficacy of parent-mediated intervention for increasing child joint attention. Moderate evidence was found for the improvement of language scores, expressive language, nonverbal communication, initiation and response to interaction, behavior, play, adaptive functioning, ASD symptoms, and social communication. This systematic review suggests that parent-mediated interventions for children with ASD can improve various aspects of communication and ASD symptoms, with emerging support for occupational performance. Occupational therapy practitioners are well suited to facilitate these interventions to support families with children with autism.


Aerodynamic and acoustic features of vocal effort.
The purpose of this study was to determine the aerodynamic and acoustic features of speech produced at comfortable, maximal and minimal levels of vocal effort. Prospective, quasi-experimental research design. Eighteen healthy participants with normal voice were included in this study. After task training, participants produced repeated syllable combinations at comfortable, maximal and minimal levels of vocal effort. A pneumotachometer and vented (Rothenberg) mask were used to record aerodynamic data, with simultaneous recording of the acoustic signal for subsequent analysis. Aerodynamic measures of subglottal pressure, translaryngeal airflow, maximum flow declination rate (MFDR), and laryngeal resistance were analyzed, along with acoustic measures of cepstral peak prominence (CPP) and its standard deviation (SD). Participants produced significantly greater subglottal pressure, translaryngeal airflow, and MFDR during maximal effort speech as compared with comfortable vocal effort. When producing speech at minimal vocal effort, participants lowered subglottal pressure, MFDR, and laryngeal resistance. Acoustic changes associated with changes in vocal effort included significantly higher CPP during maximal effort speech and significantly lower CPP SD during minimal effort speech, when each was compared with comfortable effort. For healthy speakers without voice disorders, subglottal pressure, translaryngeal airflow, and MFDR may be important factors that contribute to an increased sense of vocal effort. Changes in the cepstral signal also occur under conditions of increased or decreased vocal effort relative to comfortable effort.


A 35-Year Perspective (1975 to 2009) into the Long-Term Prognosis and Hospital Management of Patients Discharged from the Hospital After a First Acute Myocardial Infarction.
There are limited population-based data available describing trends in the long-term prognosis of patients discharged from the hospital after an initial acute myocardial infarction (AMI). Our objectives were to describe multidecade trends in post-discharge mortality and their association with hospital management practices in patients discharged from all medical centers in Central Massachusetts after a first AMI. Residents of the Worcester, Massachusetts, metropolitan area discharged from all hospitals in Central Massachusetts after a first AMI from 1975 to 2009 comprised the study population (n = 8,728). Multivariable-adjusted logistic regression analyses were used to examine the association between year of hospitalization and 1-year post-discharge mortality. The average age of this population was 66 years, and 40% were women. Patients hospitalized in 1999 to 2009, compared with those discharged in 1975 to 1984, were older, more likely to be women, and have multiple previously diagnosed co-morbidities. Hospital use of invasive cardiac interventions and medications increased markedly over time. Unadjusted 1-year mortality rates were 12.9%, 12.5%, and 15.8% for patients discharged during 1975 to 1984, 1986 to 1997, and 1999 to 2009, respectively. After adjusting for several demographic characteristics, clinical factors, and inhospital complications, there were no significant differences in the odds of dying at 1-year post-discharge during the years under study. After further adjustment for hospital treatment practices, the odds of dying at 1 year post-discharge was 2.43 (95% confidence interval = 1.83 to 3.23) times higher in patients hospitalized in 1999 to 2009 than in 1975 to 1984. In conclusion, the increased use of invasive cardiac interventions and pharmacotherapies was associated with enhanced long-term survival in patients hospitalized for a first AMI.


Finnish Diabetes Risk Score to predict type 2 diabetes in the Isfahan diabetes prevention study.
The strong association between the Finnish Diabetes Risk Score (FINDRISC) and risk of diabetes reported in European populations cannot necessarily be generalized to other populations. The aim of this study was to evaluate the ability of FINDRISC to predict progression to diabetes in an Iranian population without diabetes. A total of 1537 first-degree relatives (FDR) without diabetes of consecutive people with type 2 diabetes 30-70 years old (376 men and 1161 women) were examined and followed for a mean (SD) of 7.8 (1.7) years for diabetes incidence. We examined the incidence of diabetes across quartiles of FINDRISC and plotted a receiver operating characteristic (ROC) curve to assess discrimination. At baseline and through follow-up, participants underwent a standard 75-g 2-h oral glucose tolerance test. Data for the FINDRISC were available from each participant. During 12,046 person-years of follow-up, 41 men and 154 women developed diabetes. The incidence of type 2 diabetes was 14.0 per 1000 person-years in men and 16.9 in women. Those in the top quartile of FINDRISC were 21.7 times more likely to develop diabetes than those in the bottom quartile (relative risk 21.7; 95% CI 9.90, 47.39). The area under the ROC was 75.1% (95% CI 71.3, 78.8). The results of this study show that FINDRISC is a robust predictor of type 2 diabetes in high-risk individuals in Iran.


Buprenorphine suppresses cocaine self-administration by rhesus monkeys.
Cocaine abuse has reached epidemic proportions in the United States, and the search for an effective pharmacotherapy continues. Because primates self-administer most of the drugs abused by humans, they can be used to predict the abuse liability of new drugs and for preclinical evaluation of new pharmacotherapies for drug abuse treatment. Daily administration of buprenorphine (an opioid mixed agonist-antagonist) significantly suppressed cocaine self-administration by rhesus monkeys for 30 consecutive days. The effects of buprenorphine were dose-dependent. The suppression of cocaine self-administration by buprenorphine did not reflect a generalized suppression of behavior. These data suggest that buprenorphine would be a useful pharmacotherapy for treatment of cocaine abuse. Because buprenorphine is a safe and effective pharmacotherapy for heroin dependence, buprenorphine treatment may also attenuate dual abuse of cocaine and heroin.


Comparative evaluation of sea-urchin larval stage sensitivity to ocean acidification.
Changes in the marine carbonate system may affect various calcifying organisms. This study is aimed to compare the sensitivity of embryo-larval development of two species of sea urchins (Paracentrutos lividus and Lytechinus variegatus) collected and exposed to samples from different coastal zone (Spain and Brazil) to ocean acidification. The results showed that the larval stages are very sensitive to small changes in the seawater's pH. The larvae from P. lividus species showed to be more sensitive to acidified elutriate sediments than larvae from L. variegatus sea urchin. Furthermore, this study has demonstrated that the CO2 enrichment in aquatic ecosystems cause changes on the mobility of the metals: Zn, Cu, Fe, Al and As, which was presented different behavior among them. Although an increase on the mobility of metals was found, the results using the principal component analysis showed that the pH reduction show the highest correlations with the toxicity and is the main cause of embryo-larval development inhibition. In this comparative study it is demonstrated that both species are able to assess potential effects of the ocean acidification related to CO2 enrichment by both near future scenarios and the risk associated with CO2 leakages in the Carbon Capture and Storage (CCS) process, and the importance of comparative studies in different zones to improve the understanding of the impacts caused by ocean acidification.


Public health management of antiviral drugs during the 2009 H1N1 influenza pandemic: a survey of local health departments in California.
The large-scale deployment of antiviral drugs from the Strategic National Stockpile during the 2009 H1N1 influenza response provides a unique opportunity to study local public health implementation of the medical countermeasure dispensing capability in a prolonged event of national significance. This study aims to describe the range of methods used by local health departments (LHDs) in California to manage antiviral activities and to gain a better understanding of the related challenges experienced by health departments and their community partners. This research employed a mixed-methods approach. First, a multi-disciplinary focus group of pandemic influenza planners from key stakeholder groups in California was convened in order to generate ideas and identify critical themes related to the local implementation of antiviral activities during the H1N1 influenza response. These qualitative data informed the development of a web-based survey, which was distributed to all 61 LHDs in California for the purpose of assessing the experiences of a representative sample of local health agencies in a large region. Forty-four LHDs participated in this study, representing 72% of the local public health agencies in California. While most communities dispensed a modest number of publicly purchased antivirals, LHDs nevertheless drew on their previous work and engaged in a number of antiviral activities, including: acquiring, allocating, distributing, dispensing, tracking, developing guidance, and communicating to the public and clinical community. LHDs also identified specific antiviral challenges presented by the H1N1 pandemic, including: reconciling multiple sources and versions of antiviral guidance, determining appropriate uses and recipients of publicly purchased antivirals, and staffing shortages. The 2009 H1N1 influenza pandemic presented an unusual opportunity to learn about the role of local public health in the management of antiviral response activities during a real public health emergency. Results of this study offer an important descriptive account of LHD management of publicly purchased antivirals, and provide practitioners, policy makers, and academics with a practice-based assessment of these events. The issues raised and the challenges faced by LHDs should be leveraged to inform public health planning for future pandemics and other emergency events that require medical countermeasure dispensing activities.


Gene-Metabolite Interaction in the One Carbon Metabolism Pathway: Predictors of Colorectal Cancer in Multi-Ethnic Families.
For personalized healthcare, the purpose of this study was to examine the key genes and metabolites in the one-carbon metabolism (OCM) pathway and their interactions as predictors of colorectal cancer (CRC) in multi-ethnic families. In this proof-of-concept study, we included a total of 30 participants, 15 CRC cases and 15 matched family/friends representing major ethnic groups in southern California. Analytics based on supervised machine learning were applied, with the target variable being specified as cancer, including the ensemble method and generalized regression (GR) prediction. Elastic Net with Akaike's Information Criterion with correction (AICc) and Leave-One-Out cross validation GR methods were used to validate the results for enhanced optimality, prediction, and reproducibility. The results revealed that despite some family members sharing genetic heritage, the CRC group had greater combined gene polymorphism-mutations than the family controls (p < 0.1) for five genes including MTHFR C677T, MTHFR A1298C, MTR A2756G, MTRR A66G, and DHFR 19bp. Blood metabolites including homocysteine (7 µmol/L), methyl-folate (40 nmol/L) with total gene mutations (≥4); age (51 years) and vegetable intake (2 cups), and interactions of gene mutations and methylmalonic acid (MMA) (400 nmol/L) were significant predictors (all p < 0.0001) using the AICc. The results were validated by a 3% misclassification rate, AICc of 26, and >99% area under the receiver operating characteristic curve. These results point to the important roles of blood metabolites as potential markers in the prevention of CRC. Future intervention studies can be designed to target the ways to mitigate the enzyme-metabolite deficiencies in the OCM pathway to prevent cancer.


Influence of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) common polymorphisms on outcome in treatment of melanoma patients with CTLA-4 blockade.
Blockade of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a down-regulator of T-cell activation, can cause cancer regression in patients with metastatic melanoma. However, not all patients respond well to the therapy and some develop severe autoimmune reactions. We hypothesized that common genetic variation in the CTLA4 gene could contribute to response to CTLA-4 blockade and the occurrence of autoimmune reactions. We investigated 7 common single nucleotide polymorphisms, SNPs, (rs733618, rs4553808, rs11571317, rs5742909, rs231775, rs3087243, and rs7565213) in 152 white melanoma patients who received CTLA-4 blockade. Three SNPs were associated with response to therapy: proximal promoter SNPs, rs4553808 [P=0.002; odds ratio (OR) 3.39; 95% confidence interval (CI), 1.62-7.10] and rs11571327 (P=0.02; OR 2.89; 95% CI, 1.23-6.83) and the nonsynonymous SNP rs231775 (Thr17Ala, P=0.009; OR 0.39; 95% CI, 0.18-0.82). A haplotype analysis including the 7 SNPs suggested that the common haplotype, TACCGGG could be associated with no response (P=0.02) whereas the haplotype TGCCAGG (P=0.06; OR 4.13; 95% CI, 1.17-14.5) could be associated with response to the treatment. No significant association was observed for occurrence of severe autoimmune reactions (grade III/IV) either by single SNP or haplotype analyses. Our results suggest that genetic variation in CTLA4 could influence response to CTLA-4 blockade therapy in metastatic melanoma patients, but further studies are necessary to confirm the observed associations.


Non-melanoma skin cancer may be a marker of poor prognosis in patients with non-Hodgkin's lymphoma.
According to recent results, patients with non-melanoma skin cancers are at increased risk of developing non-Hodgkin's lymphoma (NHL). The prognostic significance of this association is unknown. Two cohorts of patients with a first diagnosis of non-melanoma skin cancer and a subsequent diagnosis of either NHL (n = 170) or colon cancer (n = 435) were established using national cancer registry data in Denmark. Two other cohorts of patients in whom NHL (n = 600) or colon cancer (n = 1,541) was the patients' first known malignancy served as comparison groups. Mortality rates were compared using Cox's regression analysis. Among patients younger than 80 years at NHL diagnosis, a history of non-melanoma skin cancer was associated with significantly increased mortality [relative risk (RR) = 1.54; 95% confidence interval: 1.19-1.99]. This association was present in both men (RR = 1.38; 1.02-1.86) and women (RR = 2.15; 1.31-3.54) and was similar after both major subtypes of non-melanoma skin cancer. Overall, antedating non-melanoma skin cancer had no prognostic significance for colon cancer patients (RR = 1.00; 0.84-1.18). Whatever the underlying mechanism, our observation has potential clinical implications. If substantiated in other settings, NHL patients with prior non-melanoma skin cancer may constitute a subgroup of lymphoma patients in need of particular therapeutic attention.


Expressive Vocabulary in Language Learners From Two Ecological Settings in Three Language Communities.
This study compared multiple characteristics of girls' and boys' vocabulary in 6 different linguistic communities-1 urban and 1 rural setting in each of 3 countries. Two hundred fifty-two mothers in Argentina, Italy, and the United States completed vocabulary checklists for their 20-month-old children. Individual variability was substantial within each linguistic community. Minimal cross-linguistic differences were found in children's vocabulary size; however, differences among languages in the composition of children's vocabularies appeared possibly related to cultural valuing of different categories of words. Ecological setting differences within cultures appeared in children's vocabulary size, even when the composition of children's vocabularies was examined: Children living in urban areas were reported by their mothers to say significantly more words than children living in rural areas, particularly for Argentine and U.S. children. Girls had consistently larger vocabularies than boys. These findings are discussed in terms of contextual and child factors that together influence first language learning.


Leucine-rich repeat kinase 2 binds to neuronal vesicles through protein interactions mediated by its C-terminal WD40 domain.
Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial and sporadic Parkinson's disease (PD). LRRK2 is a complex protein that consists of multiple domains, including predicted C-terminal WD40 repeats. In this study, we analyzed functional and molecular features conferred by the WD40 domain. Electron microscopic analysis of the purified LRRK2 C-terminal domain revealed doughnut-shaped particles, providing experimental evidence for its WD40 fold. We demonstrate that LRRK2 WD40 binds and sequesters synaptic vesicles via interaction with vesicle-associated proteins. In fact, a domain-based pulldown approach combined with mass spectrometric analysis identified LRRK2 as being part of a highly specific protein network involved in synaptic vesicle trafficking. In addition, we found that a C-terminal sequence variant associated with an increased risk of developing PD, G2385R, correlates with a reduced binding affinity of LRRK2 WD40 to synaptic vesicles. Our data demonstrate a critical role of the WD40 domain within LRRK2 function.


Acupuncture for the treatment of obesity in adults: a systematic review and meta-analysis.
Meta-analysis was used to assess the clinical efficacy of acupuncture treatment for simple obesity and to provide evidence-based medical data for treating obesity with acupuncture. A comprehensive search of studies on MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and Chinese databases (Wan Fang,CNKI and VIP) from 1 January 1915 through 30 November 2015 (MEDLINE search updated through 31 December 2015) was performed. We included only randomised controlled trials (RCTs) that used acupuncture and sham acupuncture to treat simple obesity. The effect of acupuncture on simple obesity was measured using body mass index (BMI), body fat mass (BFM), waist circumference (WC), hip circumference (HC), and body weight (BW). The Jadad scale was used to assess methodological quality. The random effects model was used in the pooled analysis to adjust for the heterogeneity of the included studies, and funnel plots were used to examine publication bias. The differences between treatment groups were reported as mean differences (MD). Eleven RCTs were selected after all relevant literature from the electronic databases had been screened. There were 338 and 305 participants in the acupuncture and sham acupuncture groups, respectively. Auricular and electro acupuncture were both able to reduce BMI in obese patients (MD 0.47 kg/m2, 95% CI 0.35 to 0.58, p<0.001; MD 0.50 kg/m2, 95% CI 0.38 to 0.62, p<0.001). BFM change after acupuncture treatment compared with sham treatment was statistically significant (MD 0.66 kg, 95% CI 0.51 to 0.80, p<0.001). There were also significant differences in WC and HC between the acupuncture and sham acupuncture groups (MDwc2.02 cm, 95% CI 0.21 to 3.83, p=0.03; MDHC2.74 cm, 95% CI 1.21 to 4.27, p=0.0004). BW was not statistically significantly different between the acupuncture and sham acupuncture groups (MD 0.60 kg, 95% CI -0.20 to 1.39, p=0.14). Begg's test and funnel plots showed that the potential publication bias of the included studies was very slight (p>0.05). Acupuncture for simple obesity appeared to be an effective treatment, but more studies on the safety of acupuncture used to treat simple obesity are required.


Hepatitis B: review of development from the discovery of the "Australia Antigen" to end of the twentieth Century.
"Parenteral" or "serum" hepatitis is known to have afflicted man for centuries. However, it was not until the mid-1960s that the causative agent of this infection, the hepatitis B virus, was discovered. Since then, the biology and the replication strategy of the virus, and the clinical features and the epidemiology of the hepatitis B infection have been determined. Knowledge about the virus and the infection it causes led to the development of firstly, a plasma-derived vaccine and later a recombinant vaccine for the prevention of the infection. Integration of the hepatitis B vaccine into newborn vaccination programmes on a worldwide basis represents a major step in the effort to eliminate this infectious disease and its complications. Laboratory tests are available for the diagnosis and monitoring of the disease. Therapies have been developed to halt the progress of the chronic infection in affected individuals. While these developments have resulted in a decrease of the frequency of infection in many countries, particularly those that have implemented universal immunization of newborns, the chronic infection remains a significant global problem. Worldwide, over 300 million individuals are infected and each year, an estimated 1 million persons die from chronic complications of the disease including hepatocellular carcinoma and hepatic failure. The therapies currently available result in elimination of the virus in only a relatively small proportion of subjects and carry with it serious side effects. Geopolitical, economic and other factors hinder the vision of elimination of the infection through immunization programmes. Nevertheless, work continues to clarify further the underlying pathological mechanism of the infection, the host and viral factors that promote elimination or persistence of the virus in the human host. It is hoped that such investigations will reveal viral targets for the design of newer and potentially more effective drugs to treat the infection.


A Polarization Propagator for Nonlinear X-ray Spectroscopies.
A complex polarization propagator approach has been developed to third order and implemented in density functional theory (DFT), allowing for the direct calculation of nonlinear molecular properties in the X-ray wavelength regime without explicitly addressing the excited-state manifold. We demonstrate the utility of this propagator method for the modeling of coherent near-edge X-ray two-photon absorption using, as an example, DFT as the underlying electronic structure model. Results are compared with the corresponding near-edge X-ray absorption fine structure spectra, illuminating the differences in the role of symmetry, localization, and correlation between the two spectroscopies. The ramifications of this new technique for nonlinear X-ray research are briefly discussed.


Incidence Rates of Treated Mental Disorders in Childhood and Adolescence in a Complete Nationwide Birth Cohort.
To investigate incidences, cumulative incidence rates, and risk factors of diagnosed mental disorders in a complete nationwide birth cohort across the entire period of childhood and adolescence. Based on nationwide Danish registries, the entire cohort of all children born in 1995 was followed up to December 31, 2013. Data for children who migrated during the period were censored in the time analyses, and death before age 18 years was considered a competing risk. Incidence rates and cumulative incidence rates for any first-time-diagnosed mental disorder and 10 major categories of mental disorders according to ICD-10 criteria were calculated for 68,982 individuals. In addition, the effects of age, sex, and further child- and family-related risk factors on mental disorders were analyzed. The incidences of any mental disorder, substance use disorders, depression, and anxiety disorders showed an increase in adolescence, whereas those for autism spectrum disorders, attention-deficit/hyperactivity disorder, conduct disorder, and tic disorder increased during childhood and decreased thereafter. Males had higher incidence rates of any mental disorders, substance use disorders, autism spectrum disorders, ADHD, conduct disorder, and tic disorder. Females had higher risks for depressive, anxiety, obsessive-compulsive, and eating disorders. Several other risk and protective factors for any mental disorder were identified. The cumulative incidence rate at age 18 years amounted to 11.02% for any mental disorder. These findings provide the most comprehensive estimates of the development, incidence rates, and contributing risk factors of registered mental disorders for the entire period of childhood and adolescence that have been calculated so far.


Sequence Prediction With Sparse Distributed Hyperdimensional Coding Applied to the Analysis of Mobile Phone Use Patterns.
Modeling and prediction of temporal sequences is central to many signal processing and machine learning applications. Prediction based on sequence history is typically performed using parametric models, such as fixed-order Markov chains ( n -grams), approximations of high-order Markov processes, such as mixed-order Markov models or mixtures of lagged bigram models, or with other machine learning techniques. This paper presents a method for sequence prediction based on sparse hyperdimensional coding of the sequence structure and describes how higher order temporal structures can be utilized in sparse coding in a balanced manner. The method is purely incremental, allowing real-time online learning and prediction with limited computational resources. Experiments with prediction of mobile phone use patterns, including the prediction of the next launched application, the next GPS location of the user, and the next artist played with the phone media player, reveal that the proposed method is able to capture the relevant variable-order structure from the sequences. In comparison with the n -grams and the mixed-order Markov models, the sparse hyperdimensional predictor clearly outperforms its peers in terms of unweighted average recall and achieves an equal level of weighted average recall as the mixed-order Markov chain but without the batch training of the mixed-order model.


Insight into the cerebral hyperperfusion syndrome following carotid endarterectomy from the national Vascular Quality Initiative.
Cerebral hyperperfusion syndrome (CHS), characterized by severe ipsilateral headache, seizures, and intracranial hemorrhage, is a rare, poorly understood complication that can be fatal following carotid endarterectomy (CEA). The purpose of the study was to determine the factors associated with CHS as captured in the Vascular Quality Initiative. Analysis was conducted on 51,001 procedures captured from the CEA module of the Vascular Quality Initiative from 2003 to 2015. Preoperative, operative, and postoperative variables were considered for inclusion in logistic regression analyses to determine possible associations with CHS. The relative contribution of each variable to the overall model was determined using dominance analysis. The mean age was 70.2 ± 9.4 years; there were 39.6% female patients, 93.1% of white race, with 29.6% of CEAs being performed for symptomatic status. The overall rate of CHS was 0.18% (n = 94), with 55.1% occurring in asymptomatic and 44.9% occurring in symptomatic patients with an associated mortality rate of 38.2%. Multivariable analysis including preoperative variables showed that female gender (odds ratio [OR], 1.65; 95% confidence interval [CI], 1.09-2.51; P = .019), <1 month major ipsilateral stroke (OR, 5.36; 95% CI, 2.35-12.22; P < .001), coronary artery disease (OR, 1.77; 95% CI, 1.15-2.71; P = .009), and contralateral stenosis ≥70% (OR, 1.54; 95% CI, 1.00-2.36; P = .050) were independently associated with CHS and that <1 month major stroke was the most important contributor to the model. With the additional inclusion of operative and postoperative variables, female gender (OR, 1.75; 95% CI, 1.14-2.67; P = .010), <1 month ipsilateral major stroke (OR, 3.20; 95% CI, 1.32-7.74; P = .010), urgency (OR, 2.25; 95% CI, 1.38-3.67; P = .001), re-exploration (OR, 2.98; 95% CI, 1.27-6.97; P = .012), postoperative hypertension (OR, 4.09; 95% CI, 2.65-6.32; P < .001), postoperative hypotension (OR, 3.21; 95% CI, 1.97-5.24; P < .001), dysrhythmias (OR, 3.23; 95% CI, 1.64-6.38; P = .001), and postoperative myocardial infarction (OR, 2.84; 95% CI, 1.21-6.67; P = .017) were significantly associated with CHS, with postoperative blood pressure lability and cardiac complications having the strongest associations with CHS. The risk of CHS was highest in female patients and in those with a recent major stroke, coronary artery disease, and contralateral stenosis ≥70%. In addition, in adjusting for operative and postoperative variables, CHS was most significantly associated with postoperative blood pressure lability and cardiac complications. These data lend insight into a high-risk population for this devastating complication.


Stochastic models of dense or hollow nanoparticles and their scattering properties.
A family of stochastic models of disordered particles is proposed, obtained by clipping a Gaussian random field with a function that is space dependent. Depending on the shape of the clipping function, dense or hollow particles can be modelled. General expressions are derived for the form factor of the particles, for their average volume and surface area, and for their density and surface-area distributions against the distance to the particle centre. A general approximation for the form factor is also introduced, based on the density and surface-area distributions, which coincides with the Guinier and Porod expressions in the limits of low and high scattering vector magnitude q. The models are illustrated with the fitting of small-angle X-ray scattering (SAXS) data measured on Pt/Ni hollow nanoparticles. The SAXS analysis and modelling notably capture the collapse of the particles' porosity after being used as oxygen-reduction catalysts.


Detection of surface strain by three-dimensional digital holography.
Three-dimensional digital holography with three object-illuminating beams has been successfully used for the detection of surface strain in metallic objects. The optical setup that uses illuminating beams to irradiate the object from three directions means that all three object surface displacement components, x, y, and z, can be independently calculated and used to find the strain gradients on the surface. The results show the conversion of the complete surface displacement field into a surface strain field. The method is capable of measuring microstrains for out-of-plane surface displacements of less than 10 microm.


Effect of a simple two-step warfarin dosing algorithm on anticoagulant control as measured by time in therapeutic range: a pilot study.
The efficacy and safety of vitamin K antagonists for the prevention of thromboembolism are dependent on the time for which the International Normalized Ratio (INR) is in the therapeutic range. The objective of our study was to determine the effect of introducing a simple two-step dosing algorithm, as compared with dosing by anticoagulation clinic staffs on the basis of their experience, on time in therapeutic range (TTR) of warfarin therapy. We compared TTRs of all clinic patients before and after the introduction of a simple two-step dosing algorithm at a single anticoagulation clinic in Canada, between 1 August 2006 and 24 December 2008. TTR was calculated using the linear interpolation method of Rosendaal. We included 873 patients in the 'before' phase and 1088 patients in the 'after' phase. Introduction of the dosing algorithm significantly increased TTR of patients with a therapeutic INR range of 2-3 from 67.2% to 73.2% (P < 0.001), and that of patients with a therapeutic INR range of 2.5-3.5 from 49.8% to 63.8% (P < 0.001). The introduction of a simple two-step warfarin-dosing algorithm in place of dosing by experienced anticoagulation clinic staff significantly improved mean TTR for patients in a tertiary-care anticoagulation clinic. This inexpensive and widely applicable algorithm has the potential to improve warfarin control.


Effects of in-office bleaching agent combined with different desensitizing agents on enamel.
To analyze color change, microhardness and chemical composition of enamel bleached with in-office bleaching agent with different desensitizing application protocols. One hundred and seventeen polished anterior human enamel surfaces were obtained and randomly divided into nine groups (n = 13). After recording initial color, microhardness and chemical composition, the bleaching treatments were performed as G1: Signal Professional White Now POWDER&LIQUID FAST 38% Hydrogen peroxide(S); G2: S+Flor Opal/0.5% fluoride ion(F); G3: S+GC Tooth Mousse/Casein Phosphopeptide-Amorphous Calcium Phosphate (CPP-ACP) paste(TM); G4: S+UltraEZ/3% potassium nitrate&0.11% fluoride(U); G5: S+Signal Professional SENSITIVE PHASE 1/30% Nano-Hydroxyapatite (n-HAP) suspension(SP); G6: S-F mixture; G7: S-TM mixture; G8: S-U mixture; G9: S-SP mixture. Color, microhardness and chemical composition measurements were repeated after 1 and 14 days. The percentage of microhardness loss (PML) was calculated 1 and 14 days after bleaching. Data were analyzed with ANOVA, Welch ANOVA, Tukey and Dunnett T3 tests (p<0.05). Color change was observed in all groups. The highest ΔE was observed at G7 after 1 day, and ΔE at G8 was the highest after 14 days (p<0.05). A decrease in microhardness was observed in all groups except G6 and G7 after 1 day. The microhardness of all groups increased after 14 days in comparison with 1 day after bleaching (p>0.05). PML was observed in all groups except G6 and G7 after bleaching and none of the groups showed PML after 14 days. No significant changes were observed after bleaching at Ca and P levels and Ca/P ratios at 1 or 14 days after bleaching (p>0.05). F mass increased only in G2 and G6, 1 day after bleaching (p<0.05). The use of desensitizing agents containing fluoride, CPP-ACP, potassium nitrate or n-HAP after in-office bleaching or mixed in bleaching agent did not inhibit the bleaching effect. However, they all recovered microhardness of enamel 14 days after in-office bleaching.


Dyadic coping in Latino couples: validity of the Spanish version of the Dyadic Coping Inventory.
This study seeks to validate the Spanish version of the Dyadic Coping Inventory (DCI) in a Latino population with data from 113 heterosexual couples. Results for both partners confirm the factorial structure for the Spanish version (Subscales: Stress Communication, Emotion- and Problem-Focused Supportive, Delegated, and Negative Dyadic Coping, Emotion- and Problem-Focused Common Dyadic Coping, and Evaluation of Dyadic Coping; Aggregated Scales: Dyadic Coping by Oneself and by Partner) and support the discriminant validity of its subscales and the concurrent, and criterion validity of the subscales and aggregated scales. These results do not only indicate that the Spanish version of the DCI can be used reliably as a measure of coping in Spanish-speaking Latino couples, but they also suggest that this group relies on dyadic coping frequently and that this type of coping is associated with positive relationship functioning and individual coping. Limitations and implications are discussed.


A community-based cluster randomized survey of noncommunicable disease and risk factors in a peri-urban shantytown in Lima, Peru.
An estimated 863 million people-a third of the world's urban population-live in slums, yet there is little information on the disease burden in these settings, particularly regarding chronic preventable diseases. From March to May 2012, we conducted a cluster randomized survey to estimate the prevalence of noncommunicable diseases (NCDs) and associated risk factors in a peri-urban shantytown north of Lima, Peru. Field workers administered a questionnaire that included items from the WHO World Health Survey and the WHO STEPS survey of chronic disease risk factors. We used logistic regression to assess the associations of NCDs and related risk factors with age and gender. We accounted for sampling weights and the clustered sampling design using statistical survey methods. A total of 142 adults were surveyed and had a weighted mean age of 36 years (range 18-81). The most prevalent diseases were depression (12%) and chronic respiratory disease (8%), while lifetime prevalence of cancer, arthritis, myocardial infarction, and diabetes were all less than 5%. Fifteen percent of respondents were hypertensive and the majority (67%) was unaware of their condition. Being overweight or obese was common for both genders (53%), but abdominal obesity was more prevalent in women (54% vs. 10% in men, p < 0.001). Thirty-five percent of men binge drank and 34% reported current smoking; these behaviors were less common among women (4% binge drank, p < 0.001; 8% smoked, p = 0.002). Increasing age was associated with an increased risk of abdominal obesity (Odds Ratio (OR) = 1.04, 95% CI = 1.01, 1.07, p = 0.02), hypertension (OR = 1.06, 95% CI = 1.02, 1.10, p = 0.006), arthritis (OR = 1.07, 95% CI = 1.03, 1.11, p < 0.001) and cancer (OR = 1.13, 95% CI = 1.07, 1.20, p < 0.001) in adjusted models. The prevalences of other NCDs and related risk factors were similar when stratified by age or gender. This study underlines the important burden of noncommunicable disease in informal settlements in Peru and suggests that prevention and treatment interventions could be optimized according to age and gender.


Electrochemical detection of anti-breast-cancer agents in human serum by cytochrome P450-coated carbon nanotubes.
We report on the electrochemical detection of anti-cancer drugs in human serum with sensitivity values in the range of 8-925 nA/μM. Multi-walled carbon nanotubes were functionalized with three different cytochrome P450 isoforms (CYP1A2, CYP2B6, and CYP3A4). A model used to effectively describe the cytochrome P450 deposition onto carbon nanotubes was confirmed by Monte Carlo simulations. Voltammetric measurements were performed in phosphate buffer saline (PBS) as well as in human serum, giving well-defined current responses upon addition of increasing concentrations of anti-cancer drugs. The results assert the capability to measure concentration of drugs in the pharmacological ranges in human serum. Another important result is the possibility to detect pairs of drugs present in the same sample, which is highly required in case of therapies with high side-effects risk and in anti-cancer pharmacological treatments based on mixtures of different drugs. Our technology holds potentials for inexpensive multi-panel drug-monitoring in personalized therapy.


Metabolic regulation in mammalian hibernation: enzyme and protein adaptations.
Mammalian hibernation requires specific regulatory controls on metabolism to coordinate entry, maintenance, and arousal stages, as well as adjustments to many metabolic functions to support long-term dormancy. Several mechanisms of metabolic regulation are involved in potentiating survival. One of these is the reversible phosphorylation of regulatory enzymes, including glycogen phosphorylase, phosphofructokinase, pyruvate kinase, and pyruvate dehydrogenase. In particular, the sharp suppression of pyruvate dehydrogenase during hibernation shows the importance of control over mitochondrial oxidative metabolism for reducing metabolic rate. Fine control over specific enzymes also occurs via differential temperature effects on kinetic and allosteric properties. Analysis of temperature effects on the properties of pyruvate kinase, fructose-1,6-bisphosphatase, creatine kinase, and citrate synthase from ground squirrel or bat tissues shows a range of responses, some that would reduce enzyme activity in the hibernating state and some that would promote temperature-insensitive enzyme function. Reduced tissue phosphagen and adenylate levels, but not energy charge, may also contribute to overall metabolic suppression. New research is exploring the role of transcriptional and translational controls in hibernation via several approaches. For example, immunoblotting with antibodies to heat shock proteins (hsp 70 family) revealed the presence of constitutive hsc 70 in bat tissues but levels of the protein did not change between euthermic and hibernating states and neither the inducible hsp 70 nor the glucose-responsive protein grp 78 appeared during hibernation.


Effects of Bariatric Surgery on Renal Function in Obese Patients: A Systematic Review and Meta Analysis.
Obesity is an independent risk factor of development and progression of chronic kidney disease (CKD). Data on the benefits of bariatric surgery in obese patients with impaired kidney function have been conflicting. To explore whether there is improvement in glomerular filtration rate (GFR), proteinuria or albuminuria after bariatric surgery. We comprehensively searched the databases of MEDLINE, Embase, web of science and Cochrane for randomized, controlled trials and observational studies that examined bariatric surgery in obese subjects with impaired kidney function. Outcomes included the pre- and post-bariatric surgery GFR, proteinuria and albuminuria. In obese patients with hyperfiltration, we draw conclusions from studies using measured GFR (inulin or iothalamate clearance) unadjusted for BSA only. Study quality was evaluated using the Newcastle-Ottawa Scale. 32 observational studies met our inclusion criteria, and 30 studies were included in the meta-analysis. No matter in dichotomous data or in dichotomous data, there were statistically significant reduction in hyperfiltration, albuminuria and proteinuria after bariatric surgery. The main limitation of this meta-analysis is the lack of randomized controlled trials (RCTs). Another limitation is the lack of long-term follow-up. Bariatric surgery could prevent further decline in renal function by reducing proteinuria, albuminuria and improving glomerular hyperfiltration in obese patients with impaired renal function. However, whether bariatric surgery reverses CKD or delays ESRD progression is still in question, large, randomized prospective studies with a longer follow-up are needed.


Quantitation of mast cells and eosinophils in the bronchial mucosa of symptomatic atopic asthmatics and healthy control subjects using immunohistochemistry.
We have used fiberoptic bronchoscopy to obtain endobronchial biopsies in which mast cells and eosinophils were enumerated using monoclonal antibodies directed against mast cell tryptase (AA1) and the eosinophil cationic protein (EG2). Eleven symptomatic atopic asthmatics treated with beta 2-agonists alone and six normal subjects were studied. Over a period of 2 wk prior to bronchoscopy, patients recorded asthma symptom scores, bronchodilator usage, and twice-daily peak expiratory flow. Five days before bronchoscopy, methacholine responsiveness was assessed. Two biopsies were taken from the subcarinae, one of which was processed into araldite for immunostaining by the streptavidin biotin immunoperoxidase method and the other into Spurr resin for electron microscopy. The number of AA1 staining mast cells present in the bronchial mucosa was not significantly different in the epithelium or submucosa between the asthmatic and the normal subjects. However, in the biopsies from asthmatics, there were significantly greater numbers of EG2-staining eosinophils in the epithelium (median, 1.2/mm versus zero; p less than 0.005) and in the submucosa (median, 50/mm2 versus 1/mm2; p less than 0.001). Electron microscopy showed morphologic features of mast cell and eosinophil degranulation in the asthmatics. No correlation could be established between mast cell or eosinophil numbers and indices of disease activity of PC20 methacholine, which points to the complexity of mechanisms responsible for the symptoms and the airway hyperresponsiveness of asthma.