Burden, Determinants, and Pharmacological Management of Hypertension in HIV-Positive Patients and Populations: A Systematic Narrative Review.
Hypertension among HIV-positive populations has emerged as a new threat to the health and well being of people living with HIV, particularly among those receiving antiretroviral therapy. We reviewed the global evidence on the burden of disease (including prevalence and incidence), determinants of hypertension among HIV-positive populations, and the pharmacological management of hypertension in HIV-positive patients. We systematically searched PubMed-MEDLINE and EMBASE from January 2000 through February 2015 for relevant studies and traced their citations through the ISI Web of Science. We also searched the websites of the World Health Organisation, the International Society of Hypertension, and the International AIDS Society and constructed a narrative data synthesis. Hypertension is common in HIV-positive populations, with prevalence estimates ranging from 4.7 to 54.4% in high-income countries, and from 8.7 to 45.9% in low- and middle-income countries. The role of HIV-specific factors including disease severity, duration of disease, and treatments on the presence of hypertension in HIV-positive patients is reported, but patterns remain unclear. The clinical management of hypertension in HIV-positive patients is similar to those with hypertension in the general population; however, additional considerations should be given to potential drug interactions between antihypertensive agents and antiretroviral drugs to inform the clinician's selection of these therapies. Hypertension is common in HIV-positive populations and remains an important comorbidity affecting mortality outcomes. Further research examining the development of hypertension and its associated care in HIV-positive patients is required to optimize management of the dual conditions.


Pulmonary hypertension in wild type mice and animals with genetic deficit in KCa2.3 and KCa3.1 channels.
In vascular biology, endothelial KCa2.3 and KCa3.1 channels contribute to arterial blood pressure regulation by producing membrane hyperpolarization and smooth muscle relaxation. The role of KCa2.3 and KCa3.1 channels in the pulmonary circulation is not fully established. Using mice with genetically encoded deficit of KCa2.3 and KCa3.1 channels, this study investigated the effect of loss of the channels in hypoxia-induced pulmonary hypertension. Male wild type and KCa3.1-/-/KCa2.3T/T(+DOX) mice were exposed to chronic hypoxia for four weeks to induce pulmonary hypertension. The degree of pulmonary hypertension was evaluated by right ventricular pressure and assessment of right ventricular hypertrophy. Segments of pulmonary arteries were mounted in a wire myograph for functional studies and morphometric studies were performed on lung sections. Chronic hypoxia induced pulmonary hypertension, right ventricular hypertrophy, increased lung weight, and increased hematocrit levels in either genotype. The KCa3.1-/-/KCa2.3T/T(+DOX) mice developed structural alterations in the heart with increased right ventricular wall thickness as well as in pulmonary vessels with increased lumen size in partially- and fully-muscularized vessels and decreased wall area, not seen in wild type mice. Exposure to chronic hypoxia up-regulated the gene expression of the KCa2.3 channel by twofold in wild type mice and increased by 2.5-fold the relaxation evoked by the KCa2.3 and KCa3.1 channel activator NS309, whereas the acetylcholine-induced relaxation - sensitive to the combination of KCa2.3 and KCa3.1 channel blockers, apamin and charybdotoxin - was reduced by 2.5-fold in chronic hypoxic mice of either genotype. Despite the deficits of the KCa2.3 and KCa3.1 channels failed to change hypoxia-induced pulmonary hypertension, the up-regulation of KCa2.3-gene expression and increased NS309-induced relaxation in wild-type mice point to a novel mechanism to counteract pulmonary hypertension and to a potential therapeutic utility of KCa2.3/KCa3.1 activators for the treatment of pulmonary hypertension.


Hearing the Voices of Australian Thyroid Cancer Survivors: Qualitative Thematic Analysis of Semistructured Interviews Identifies Unmet Support Needs.
Background: Most thyroid cancer survivors regain their physical health-related quality of life, but psychological and social deficits persist. The nature of these detriments remains poorly understood and they are insufficiently captured by survey data alone. To address this, qualitative data exploring the breadth and depth of thyroid cancer survivors' experiences and priorities for supportive care are required. Methods: Twenty semistructured interviews were undertaken with a purposive, maximum variation sample of thyroid cancer survivors. Interviews were transcribed verbatim and coded independently by two researchers. A hybrid model of inductive and realistic codebook analysis was undertaken with themes developed. Results: Patient experiences centered around three themes: (1) impact of diagnosis and treatment, (2) thyroid cancer does not happen in isolation, and (3) role of clinicians and formalized support structures. The word "cancer" had negative connotations, but for many, the reality of their experience was more positive. Despite feeling "lucky" at the relative low-risk nature of thyroid cancer, many patients reported fatigue, weight gain, and difficulty returning to usual activities; concerns that were largely dismissed or minimized by clinicians. Few were offered any support beyond their treating doctors; where patients attempted to access formalized supportive care, little was available or appropriate. Life stage and concurrent family and social stressors greatly impacted patients' ability to cope with diagnosis and treatment. Addressing thyroid cancer in isolation felt inappropriate without appreciating the broader context of their lives. Interactions with clinicians were largely positive, particularly where information was communicated as a means of empowering patients to participate in shared decision-making and where clinicians "checked in" emotionally with patients. Information about initial treatments was largely adequate but information on longer term effects and follow-up was lacking. Many patients felt that clinicians focused on physical well-being and scan results, missing opportunities to provide psychological support. Conclusions: Thyroid cancer survivors can struggle to navigate their cancer journey, particularly with regard to psychological and social functioning. There is a need to acknowledge these impacts at the time of clinical encounters, as well as develop information resources and support structures that can be individualized to optimize holistic well-being for those in need.


Mutation in pore domain uncovers cation- and voltage-sensitive recovery from inactivation in KAT1 channel.
Effects of threonine substitution by glutamine at position 256 in the pore of the KAT1 channel have been investigated by voltage-clamp, using heterologous gene expression in Xenopus oocytes. The major discrepancy in T256Q from the wild-type channel (wt) was cation specific. While K(+) currents were reduced in a largely scalar fashion, the NH(4)(+) current exhibited slow, voltage-dependent inhibition during hyperpolarization. The same effects could be induced in wt, or intensified in T256Q, by addition of the impermeant cation methylammonium (MA(+)) to the bath. This stresses that both the mutation and MA(+) affect a mechanism already present in the wt. Assuming that current inhibition could be described as entry of the channel into an inactive state, we modeled in both wt and in T256Q the relaxation kinetics of the clamp currents by a C-O-I gating scheme, where C (closed) and I (inactivated) are nonconductive states, and O is an open state allowing K(+) and NH(4)(+) passage. The key reaction is the transition I-O. This cation-sensitive transition step ensures release of the channel from the inactive state and is approximately 30 times smaller in T256Q compared to wt. It can be inhibited by external MA(+) and is stimulated strongly by K(+) and weakly by NH(4)(+). This sensitivity of gating to external cations may prevent K(+) leakage from cation-starved cells.


Visual and circadian responses to light in aged retinally degenerate mice.
The progression of photoreceptor degeneration in retinally degenerate (rd) mice commences early in postnatal development resulting in the complete loss of rods by 60-70 days of age followed by the more protracted loss of cones. We have previously shown that rd mice 80 days of age are capable of phase shifting their circadian locomotor rhythms in response to brief pulses of light and these animals show the same sensitivity as wild-type (+/+) controls. If surviving cones mediate these circadian responses, then one would expect the sensitivity of the circadian system in rd mice to decline with age and parallel the loss of cones. We demonstrate that aging rd mice (80-767 days of age) remain capable of photically regulating circadian locomotor rhythms in a manner indistinguishable from +/+ mice. Circadian responses to light do not parallel cone cell degeneration in rd mice. In contrast to the circadian responses to light, old (> 210 days of age) rd mice show no visually-evoked behavioral or electroretinogram (ERG) responses.


Wheat leaf rust severity as affected by plant density and species proportion in simple communities of wheat and wild oats.
ABSTRACT While it is generally accepted that dense stands of plants exacerbate epidemics caused by foliar pathogens, there is little experimental evidence to support this view. We grew model plant communities consisting of wheat and wild oats at different densities and proportions and exposed these communities to Puccinia recondita to induce wheat leaf rust. Wild oats was included because it is a common competitor of wheat and may act as a barrier to the dispersal of P. recondita spores among wheat plants. Disease severity was estimated as percentage of wheat flag leaves covered by rust lesions. Seeding density rarely had a significant influence on rust severity, probably because of compensation due to increased tillering at low seeding densities. In contrast, increasing the proportion of wheat in mixtures with wild oats consistently increased wheat leaf rust severity. Regression parameters describing wheat leaf rust severity as a function of wheat seeding density did not differ significantly between pure wheat stands and wheat-wild oat mixtures and, thus, failed to support an effect of wild oats on wheat leaf rust other than through its competitive impact on wheat tiller density.


Rapid shallow breathing index and its predictive accuracy measured under five different ventilatory strategies in the same patient group.
The rapid shallow breathing index (RSBI) is commonly used clinically for predicting the outcome of weaning from mechanical ventilation. We compared the RSBI and its predictive accuracies measured under 5 ventilatory strategies before weaning trials. Ninety-eight patients were included and divided into successful (n=71) and failed (n=27) groups based on their weaning outcomes. The RSBI was randomly measured when patients spontaneously breathed 21% O2 with no ventilator support (the control strategy) or were connected to ventilator breathing with 21% or 40% O2 and 0 or 5 cm H2O of continuous positive airway pressure (CPAP). We found that the RSBI values did not exhibit significant differences among the 4 ventilator strategies, but all were higher than that of the control; this remained valid in the non-chronic obstructive pulmonary disease (COPD) subgroup, but not in the COPD subgroup. Values of the area under the receiver operating characteristic curve of the RSBI for the 5 strategies were 0.51-0.62 with no significant difference between any 2 strategies. The incidences of adverse reactions (respiratory rate > or =35 breaths/min or oxygen saturation < or =89% for > or =1 min) were relatively high for the 21% O2-0 and 5 cm H2O CPAP groups (20 patients each) and low for the 40% O(2)-5 cmH2O CPAP group (2 patients). We concluded that RSBI values increased with the use of a ventilator, but not with additional applications of 40% 02 and/or 5 cm H2O CPAP. Their accuracies for predicting weaning outcome were unaltered by any of these interventions, but the incidence of adverse reactions increased with the use of the ventilator and decreased with additional 40% O2 supplementation.


Identification and site of action of the remaining four putative pseudouridine synthases in Escherichia coli.
There are 10 known putative pseudouridine synthase genes in Escherichia coli. The products of six have been previously assigned, one to formation of the single pseudouridine in 16S RNA, three to the formation of seven pseudouridines in 23S RNA, and three to the formation of three pseudouridines in tRNA (one synthase makes pseudouridine in 23S RNA and tRNA). Here we show that the remaining four putative synthase genes make bona fide pseudouridine synthases and identify which pseudouridines they make. RluB (formerly YciL) and RluE (formerly YmfC) make pseudouridine2605 and pseudouridine2457, respectively, in 23S RNA. RluF (formerly YjbC) makes the newly discovered pseudouridine2604 in 23S RNA, and TruC (formerly YqcB) makes pseudouridine65 in tRNA(Ile1) and tRNA(Asp). Deletion of each of these synthase genes individually had no effect on exponential growth in rich media at 25 degrees C, 37 degrees C, or 42 degrees C. A strain lacking RluB and RluF also showed no growth defect under these conditions. Mutation of a conserved aspartate in a common sequence motif, previously shown to be essential for the other six E. coli pseudouridine synthases and several yeast pseudouridine synthases, also caused a loss of in vivo activity in all four of the synthases studied in this work.


Classifying and Measuring Human Resources for Health and Rehabilitation: Concept Design of a Practices- and Competency-Based International Classification.
The burden of physical impairments and disabilities is growing across high-, middle-, and low-income countries, but populations across the globe continue to lack access to basic physical rehabilitation. Global shortages, uneven distributions, and insufficient skill mix of human resources for health and rehabilitation (HRH&R) contribute to such inequitable access. However, there are no international standards to classify HRH&R and to promote their global monitoring and development. In this article, we conceptually develop an international classification of HRH&R based on the concept of monitoring HRH&R through their stock of practices and competencies, and not simply counting rehabilitation professionals such as physical or occupational therapists. This concept accounts for the varying HRH&R configurations as well as the different training, competencies, or practice regulations across locations, even within the same profession. Our perspective specifically develops the concept of a proposed classification, its structure, and possible applications. Among the benefits, stakeholders using the classification would be able to: (1) collect locally valid and internationally comparable data on HRH&R; (2) account for the rehabilitation practices and competencies among nonspecialized rehabilitation workers (eg, in less resourced/specialized contexts); (3) track competency upgrades or practice extensions over time; (4) implement competency-based human resources management practices, such as linking remuneration to competency levels rather than to professional categories; and (5) inform the development of (inter-)professional education, practice regulation, or even task-shifting processes for the whole of HRH&R. The proposed classification standard, still in a concept-development stage, could help drive policies to achieve the "right" stock of HRH&R, in terms of practices and competencies.


Gallium arsenide-induced increase in serum corticosterone is not responsible for suppression of the IgM antibody response.
Previous investigations demonstrated gallium arsenide (GaAs) to be an immunosuppressive agent that alters the function of all cell types involved in the generation of a primary antibody response. In those studies, GaAs was administered as a particulate compound that remained in the lung at least 14 days after exposure. The extended presence of the particulate in the lung may induce a stress response that leads to the release of endogenous corticosteroids. In addition, some of the observed immunomodulatory effects of GaAs were similar to immunological alterations reported to be induced by corticosteroids. The present studies were designed to determine whether suppression of the immunoglobulin (Ig) M antibody-forming calls (AFC) response by GaAs was a result of a GaAs-induced increase in serum corticosterone. GaAs (50-200 mg/kg) significantly decreased the weights of both the thymus and spleen and the cellularity of the spleen. In addition, there was a GaAs-induced decrease in the CD4+/CD8+ thymocyte subpopulations and a concomitant increase in CD4+ and CD8+ cells. Within the spleen, there were no alterations in the percentages of CD4, CD8 or Ig-positive cells. However, when expressed as an absolute cell number, there was a 50% decrease in the numbers of CD4+ and CD8+ cells in the spleen. GaAs also dose-dependently suppressed (50-75%) the IgM AFC response. The GaAs-induced changes in cell populations and immune organ weights were correlated with an increase (6- to 10-fold) in serum corticosterone levels. The treatment of mice with the glucocorticoid antagonist mifepristone (also called RU 486) blocked the observed alterations in splenic and thymic cell populations induced by GaAs.(ABSTRACT TRUNCATED AT 250 WORDS)


Interferon-alpha-associated monoarthritis.
The therapeutic indications for interferons (IFNs) have increased in recent years to include many different diseases of viral and malignant origin. Autoimmune phenomena may occur with IFN therapy, but arthritis is uncommon. In this case report, we describe a patient who developed monoarthritis in the knee after IFN-alpha therapy for chronic hepatitis B infection. A synovial fluid assay by polymerase chain reaction was negative for hepatitis B virus DNA and serum transaminase levels were normal as the arthritis developed. The patient was thought to have arthritis due to IFN-alpha treatment. A connection between IFN-alpha therapy and an induced autoimmune disorder is discussed.


Demonstration of low density lipoprotein receptors in mouse teratocarcinoma stem cells and description of a method for producing receptor-deficient mutant mice.
Familial hypercholesterolemia, a widespread human genetic disorder implicated in vascular and coronary disease, has had no laboratory animal counterpart that would enable the pathogenesis to be analyzed and drugs to be tested in vivo. The primary lesion in some patients is known to occur in the cells' initial handling of the major cholesterol-carrying lipoprotein of plasma. It entails a deficiency in the specific cell surface receptor that binds low density lipoprotein (LDL), with a consequent alteration in the control of cholesterol metabolism. The present study was undertaken to devise a practical scheme for producing, from developmentally versatile mouse teratocarcinoma stem cells, whole-animal models with a comparable genetic lesion. This requires first learning whether the tumor stem cells in culture express LDL receptors, and next establishing a selection or screening procedure to identify receptor-deficient mutants in mutagenized cell cultures. The results show that the teratocarcinoma cells do in fact have specific high-affinity LDL receptors which are similar to those reported for fibroblasts and the parenchymal cells of specialized tissues and different from those of phagocytic cells. Sterols suppressed the otherwise efficient binding, internalization, and degradation of LDL ((125)I-labeled) by the cells. Acetylation of LDL blocked the binding. Only LDL and not high density lipoprotein (HDL) was bound. After LDL uptake and degradation, the liberated cholesterol led, as expected, to increased cholesteryl ester formation; it also suppressed activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase [HMG CoA reductase; mevalonate: NADP(+) oxidoreductase (CoA-acylating), EC 220.127.116.11], the rate-limiting step in cholesterol biosynthesis. Cells with LDL receptors were readily visualized by administering a fluorescent derivative of LDL; in the fluorescence microscope, labeling was seen in all cells. Cells with experimentally depressed receptors, yielding little fluorescence, were separable from those with normal fluorescence in the fluorescence-activated cell sorter. Thus, two methods for isolating receptor-deficient cells from mutagenized cultures are now available, either by visual recognition of low-fluorescing or nonfluorescing colonies in culture plates or by electronic cell sorting. Such mutants in an appropriate line of teratocarcinoma cells can then be passaged into blastocysts for full somatic tissue differentiation and germ-line development into mice.


How dieting makes some fatter: from a perspective of human body composition autoregulation.
Dieting makes you fat - the title of a book published in 1983 - embodies the notion that dieting to control body weight predisposes the individual to acquire even more body fat. While this notion is controversial, its debate underscores the large gap that exists in our understanding of basic physiological laws that govern the regulation of human body composition. A striking example is the key role attributed to adipokines as feedback signals between adipose tissue depletion and compensatory increases in food intake. Yet, the relative importance of fat depletion per se as a determinant of post-dieting hyperphagia is unknown. On the other hand, the question of whether the depletion of lean tissues can provide feedback signals on the hunger-appetite drive is rarely invoked, despite evidence that food intake during growth is dominated by the impetus for lean tissue deposition, amidst proposals for the existence of protein-static mechanisms for the regulation of growth and maintenance of lean body mass. In fact, a feedback loop between fat depletion and food intake cannot explain why human subjects recovering from starvation continue to overeat well after body fat has been restored to pre-starvation values, thereby contributing to 'fat overshooting'. In addressing the plausibility and mechanistic basis by which dieting may predispose to increased fatness, this paper integrates the results derived from re-analysis of classic longitudinal studies of human starvation and refeeding. These suggest that feedback signals from both fat and lean tissues contribute to recovering body weight through effects on energy intake and thermogenesis, and that a faster rate of fat recovery relative to lean tissue recovery is a central outcome of body composition autoregulation that drives fat overshooting. A main implication of these findings is that the risk of becoming fatter in response to dieting is greater in lean than in obese individuals.


Astrocyte elevated gene-1 is a novel modulator of HIV-1-associated neuroinflammation via regulation of nuclear factor-κB signaling and excitatory amino acid transporter-2 repression.
Astrocyte elevated gene-1 (AEG-1), a novel human immunodeficiency virus (HIV)-1 and tumor necrosis factor (TNF)-α-inducible oncogene, has generated significant interest in the field of cancer research as a therapeutic target for many metastatic aggressive tumors. However, little is known about its role in astrocyte responses during HIV-1 central nervous system (CNS) infection and whether it contributes toward the development of HIV-associated neurocognitive disorders (HAND). Therefore, in this study, we investigated changes in AEG-1 CNS expression in HIV-1-infected brain tissues and elucidated a potential mechanism of AEG-1-mediated regulation of HAND. Immunoblotting and immunohistochemical analyses of HIV-1 seropositive and HIV-1 encephalitic human brain tissues revealed significantly elevated levels of AEG-1 protein. Immunohistochemical analyses of HIV-1 Tat transgenic mouse brain tissues also showed a marked increase in AEG-1 staining. Similar to in vivo observations, cultured astrocytes expressing HIV-1 Tat also revealed AEG-1 and cytokine up-regulation. Astrocytes treated with HAND-relevant stimuli, TNF-α, interleukin (IL)-1β, and HIV-1, also significantly induced AEG-1 expression and nuclear translocation via activation of the nuclear factor (NF)-κB pathway. Co-immunoprecipitation studies demonstrated IL-1β- or TNF-α-induced AEG-1 interaction with NF-κB p65 subunit. AEG-1 knockdown decreased NF-κB activation, nuclear translocation, and transcriptional output in TNF-α-treated astrocytes. Moreover, IL-1β treatment of AEG-1-overexpressing astrocytes significantly lowered expression of excitatory amino acid transporter 2, increased expression of excitatory amino acid transporter 2 repressor ying yang 1, and reduced glutamate clearance, a major transducer of excitotoxic neuronal damage. Findings from this study identify a novel transcriptional co-factor function of AEG-1 and further implicate AEG-1 in HAND-associated neuroinflammation.


Relative changes with contraction in the central excitability state of the tibialis anterior and calf muscles.
F responses were recorded from the surface of the tibialis muscle and medial aspect of the soleus muscle in 14 normal subjects. The persistence (that is the fraction of measurable F responses found with a series of supramaximal stimuli) and average F amplitudes (measured peak-to-peak and based on at least five F responses) were determined both at rest and with isometric contraction with the ankle maintained at 90 degrees. Although the persistence at rest was significantly less in the tibialis anterior soleus than the (p less than 0.001), no significant difference was found with the muscles contracted. This was associated with a significant increase in both average F amplitudes and average F amplitude/direct motor response ratios in the tibialis anterior in comparison to the soleus. In four of the subjects, studies were also performed when the H reflex in the soleus muscle was eliminated by thigh compression. Comparable changes in both F response persistence and average F amplitude were found with and without an H reflex. These data indicate that, in contrast to the situation at rest, with isometric contraction the "central excitatory state" of the tibialis anterior is at least as great as in its antagonist antigravity muscles and that this is not due simply to increased large fiber reflex input associated with agonist contraction.


Incidence and risk factors of silent brain infarcts in the population-based Rotterdam Scan Study.
The prevalence of silent brain infarcts in healthy elderly people is high, and these lesions are associated with an increased risk of stroke. The incidence of silent brain infarcts is unknown. We investigated the incidence and cardiovascular risk factors for silent brain infarcts. The Rotterdam Scan Study is a prospective, population-based cohort study of 1077 participants 60 to 90 years of age. All participants underwent cranial MRI in 1995 to 1996, and 668 participants had a second MRI in 1999 to 2000 (response rate, 70%) with a mean interval of 3.4 years. We assessed cardiovascular risk factors by interview and physical examination at baseline. Associations between risk factors and incident silent infarcts were analyzed by multiple logistic regression. Ninety-three participants (14%) had > or =1 new infarcts on the second MRI; of these, 81 had only silent and 12 had symptomatic infarcts. The incidence of silent brain infarcts strongly increased with age and was 5 times higher than that of symptomatic stroke. A prevalent silent brain infarct strongly predicted a new silent infarct on the second MRI (age- and sex-adjusted odds ratio, 2.9; 95% confidence interval, 1.7 to 5.0). Age, blood pressure, diabetes mellitus, cholesterol and homocysteine levels, intima-media thickness, carotid plaques, and smoking were associated with new silent brain infarcts in participants without prevalent infarcts. The incidence of silent brain infarcts on MRI in the general elderly population strongly increases with age. The cardiovascular risk factors for silent brain infarcts are similar to those for stroke.


Skeletal muscle susceptibility to clofibrate induction of lesions in rats.
Morphological changes induced by clofibrate in type-1 predominant soleus, type-2 predominant tensor fasciae latae, and type-1 and -2 mixed biceps femoris muscles and diaphragm in rats were investigated. Administration of the agent at 500 or 750 mg/kg/day by oral gavage for 14 or 28 days caused lesions in the soleus muscle and diaphragm, bur no changes in the tensor fasciae latae and biceps femoris muscles. In soleus muscle, vacuolation of muscle fibers was observed in all animals treated with clofibrate, and degeneration of muscle fibers and infiltration of leukocytes were noted at 750 mg/kg/day. In diaphragm, vacuolation of muscle fibers was also observed in all animals treated with clofibrate, and these lesions were located in type-1 skeletal muscles densely stained with NADH-TR. The vacuoles seen in soleus muscle and diaphragm were positive for oil red O staining. In addition, increase of lipid droplets and mitochondrial hypertrophy was seen in soleus muscle, ultrastructurally. These data suggest that sensitivity to clofibrate-induced muscle toxicity differs among muscles, with type-1 fibers being susceptible.


A bi-functional xyloglucan galactosyltransferase is an indispensable salt stress tolerance determinant in Arabidopsis.
Salinity is an abiotic stress that substantially limits crop production worldwide. To identify salt stress tolerance determinants, we screened for Arabidopsis mutants that are hypersensitive to salt stress and designated these mutants as short root in salt medium (rsa). One of these mutants, rsa3-1, is hypersensitive to NaCl and LiCl but not to CsCl or to general osmotic stress. Reactive oxygen species (ROS) over-accumulate in rsa3-1 plants under salt stress. Gene expression profiling with Affymetrix microarray analysis revealed that RSA3 controls expression of many genes including genes encoding proteins for ROS detoxification under salt stress. Map-based cloning showed that RSA3 encodes a xyloglucan galactosyltransferase, which is allelic to a gene previously named MUR3/KAM1. The RSA3/MUR3/KAM1-encoded xylogluscan galactosyltransferase regulates actin microfilament organization (and thereby contributes to endomembrane distribution) and is also involved in cell wall biosynthesis. In rsa3-1, actin cannot assemble and form bundles as it does in the wild-type but instead aggregates in the cytoplasm. Furthermore, addition of phalloidin, which prevents actin depolymerization, can rescue salt hypersensitivity of rsa3-1. Together, these results suggest that RSA3/MUR3/KAM1 along with other cell wall-associated proteins plays a critical role in salt stress tolerance by maintaining the proper organization of actin microfilaments in order to minimize damage caused by excessive ROS.


An insight into the photodynamic approach versus copper formulations in the control of Pseudomonas syringae pv. actinidiae in kiwi plants.
In the last decade, the worldwide production of kiwi fruit has been highly affected by Pseudomonas syringae pv. actinidiae (Psa), a phytopathogenic bacterium; this has led to severe economic losses that are seriously affecting the kiwi fruit trade. The available treatments for this disease are still scarce, with the most common involving frequently spraying the orchards with copper derivatives, in particular cuprous oxide (Cu2O). However, these copper formulations should be avoided due to their high toxicity; therefore, it is essential to search for new approaches for controlling Psa. Antimicrobial photodynamic therapy (aPDT) may be an alternative approach to inactivate Psa. aPDT consists in the use of a photosensitizer molecule (PS) that absorbs light and by transference of the excess of energy or electrons to molecular oxygen forms highly reactive oxygen species (ROS) that can affect different molecular targets, thus being very unlikely to lead to the development of microbe resistance. The aim of the present study was to evaluate the effectiveness of aPDT to photoinactivate Psa, using the porphyrin Tetra-Py+-Me and different light intensities. The degree of inactivation of Psa was assessed using the PS at 5.0 μM under low irradiance (4.0 mW cm-2). Afterward, ex vivo experiments, using artificially contaminated kiwi leaves, were conducted with a PS at 50 μM under 150 mW cm-2 and sunlight irradiation. A reduction of 6 log in the in vitro assays after 90 min of irradiation was observed. In the ex vivo tests, the decrease was lower, approximately 1.8 log reduction at an irradiance of 150 mW cm-2, 1.2 log at 4.0 mW cm-2, and 1.5 log under solar radiation. However, after three successive cycles of treatment under 150 mW cm-2, a 4 log inactivation was achieved. No negative effects were observed on leaves after treatment. Assays using Cu2O were also performed at the recommended concentration by law (50 g h L-1) and at concentrations 10 times lower, in which at both concentrations, Psa was efficiently inactivated (5 log inactivation) after a few minutes of treatment, but negative effects were observed on the leaves after treatment.


Gene expression profiling reveals reproducible human lung adenocarcinoma subtypes in multiple independent patient cohorts.
Published reports suggest that DNA microarrays identify clinically meaningful subtypes of lung adenocarcinomas not recognizable by other routine tests. This report is an investigation of the reproducibility of the reported tumor subtypes. Three independent cohorts of patients with lung cancer were evaluated using a variety of DNA microarray assays. Using the integrative correlations method, a subset of genes was selected, the reliability of which was acceptable across the different DNA microarray platforms. Tumor subtypes were selected using consensus clustering and genes distinguishing subtypes were identified using the weighted difference statistic. Gene lists were compared across cohorts using centroids and gene set enrichment analysis. Cohorts of 31, 72, and 128 adenocarcinomas were generated for a total of 231 microarrays, each with 2,553 reliable genes. Three adenocarcinoma subtypes were identified in each cohort. These were named bronchioid, squamoid, and magnoid according to their respective correlations with gene expression patterns from histologically defined bronchioalveolar carcinoma, squamous cell carcinoma, and large-cell carcinoma. Tumor subtypes were distinguishable by many hundreds of genes, and lists generated in one cohort were predictive of tumor subtypes in the two other cohorts. Tumor subtypes correlated with clinically relevant covariates, including stage-specific survival and metastatic pattern. Most notably, bronchioid tumors were correlated with improved survival in early-stage disease, whereas squamoid tumors were associated with better survival in advanced disease. DNA microarray analysis of lung adenocarcinomas identified reproducible tumor subtypes which differ significantly in clinically important behaviors such as stage-specific survival.


Rheumatoid constrictive pericarditis.
A 73-yr-old woman with a 4 yr history of rheumatoid arthritis presented with the clinical features of congestive cardiac failure. She had a good early response to standard therapy although she subsequently developed recurrent biventricular failure. The preservation of good ventricular function on echocardiography in the face of clinical evidence of myocardial insufficiency raised the possibility of constrictive pericarditis, which was confirmed on cardiac catheterization. Constrictive pericarditis should be considered in patients with rheumatoid arthritis who develop unexplained cardiac failure. Early diagnosis requires a high index of suspicion and cardiac catheterization may be necessary to confirm the diagnosis. Medical treatment is largely ineffective and pericardiectomy should be considered.


Prevention and management of postprostatectomy sexual dysfunctions. Part 1: choosing the right patient at the right time for the right surgery.
Sexual dysfunction is common in patients following radical prostatectomy (RP) for prostate cancer (PCa). To review the available literature concerning prevention and management strategies for post-RP erectile function (EF) impairment in terms of preoperative patient characteristics and intra- and postoperative factors that may influence EF recovery. A literature search was performed using Google and PubMed database for English-language original and review articles either published or e-published up to November 2011. The literature demonstrates great inconsistency in what constitutes normal EF before surgery and what a man may consider a normal erection after RP. The use of validated psychometric instruments with recognised cut-offs for normalcy and severity during the pre- and postoperative evaluation should be routinely considered. Therefore, a comprehensive discussion with the patient about the true prevalence of postoperative erectile dysfunction (ED), the concept of spontaneous or pharmacologically assisted erections, and the difference between "back to baseline" EF and "erections adequate enough to have successful intercourse" clearly emerge as key issues in the eventual understanding of the prevention of ED and promotion of satisfactory EF recovery post-RP. Patient factors (including age, baseline EF, and status of comorbid conditions), cancer selection (unilateral vs bilateral nerve sparing), type of surgery (ie, intra- vs inter- vs extrafascial surgeries), surgical techniques (ie, open, laparoscopic, and robot-assisted RP), and surgeon factors (ie, surgical volume and surgical skill) represent the key significant contributors to EF recovery. The complexity of the issues discussed throughout this review culminates in the simple concept that optimal outcomes are achieved by the careful choice of the correct patient for the correct type of surgery.


Prolonged hypoxia augments L-citrulline transport by system A in the newborn piglet pulmonary circulation.
Pulmonary arterial endothelial cells (PAECs) express the enzymes needed for generation of l-arginine from intracellular l-citrulline but do not express the enzymes needed for de novo l-citrulline synthesis. Hence, l-citrulline levels in PAECs are dependent on l-citrulline transport. Once generated, l-arginine can be converted to l-citrulline and nitric oxide (NO) by the enzyme NO synthase. We sought to determine whether hypoxia, a condition aetiologically linked to pulmonary hypertension, alters the transport of l-citrulline and the expression of the sodium-coupled neutral amino acid transporters (SNATs) in PAECs from newborn piglets. PAECs isolated from newborn piglets were cultured under normoxic and hypoxic conditions and used to measure SNAT1, 2, 3, and 5 protein expression and (14)C-l-citrulline uptake. SNAT1 protein expression was increased, while SNAT2, SNAT3, and SNAT5 expression was unaltered in hypoxic PAECs. (14)C-l-citrulline uptake was increased in hypoxic PAECs. Studies with inhibitors of System A (SNAT1/2) and System N (SNAT3/5) revealed that the increased (14)C-l-citrulline uptake was largely due to System A-mediated transport. Additional studies were performed to evaluate SNAT protein expression and l-citrulline levels in lungs of piglets with chronic hypoxia-induced pulmonary hypertension and comparable age controls. Lungs from piglets raised in chronic hypoxia exhibited greater SNAT1 expression and higher l-citrulline levels than lungs from controls. Increased SNAT1 expression and the concomitant enhanced ability to transport l-citrulline in PAECs could represent an important regulatory mechanism to counteract NO signalling impairments known to occur during the development of chronic hypoxia-induced pulmonary hypertension in newborns.


FBXW7 mutations typically found in human cancers are distinct from null alleles and disrupt lung development.
FBXW7 is the substrate recognition component of a SCF-type E3 ubiquitin ligase. It has multiple targets such as Notch1, c-Jun, and cyclin E that function in critical developmental and signalling pathways. Mutations in FBXW7 are often found in many types of cancer. In most cases, these mutations do not inactivate the protein, but are mono-allelic missense changes at specific arginine resides involved in substrate binding. We have hypothesized that FBXW7 mutations are selected in cancers for reasons other than haploinsufficiency or full loss-of-function. Given that the existing mutant Fbxw7 mice carry null alleles, we created a mouse model carrying one of the commonly occurring point mutations (Fbxw7(R482Q)) in the WD40 substrate recognition domain of Fbxw7. Mice heterozygous for this mutation apparently developed normally in utero, died perinatally due to a defect in lung development, and in some cases showed cleft palate and eyelid fusion defects. By comparison, Fbxw7(+/-) mice were viable and developed normally. Fbxw7(-/-) animals died of vascular abnormalities at E10.5. We screened known FBXW7 targets for changes in the lungs of the Fbxw7(R482Q/+) mice and found Tgif1 and Klf5 to be up-regulated. Fbxw7(R482Q) alleles are not functionally equivalent to heterozygous or homozygous null alleles, and we propose that they are selected in tumourigenesis because they cause a selective or partial loss of FBXW7 function.


Undifferentiated pleomorphic sarcoma of the liver presenting as a unilocular cyst.
A malignant fibrous histiocytoma, recently referred to as an undifferentiated pleomorphic sarcoma (UPS), is very rare in the liver, and only 34 cases of primary hepatic malignant fibrous histiocytoma have been reported in the English literature. We report a rare case of a hepatic UPS presenting as a unilocular cystic lesion with respect to histopathologic features, the newly revised diagnostic criteria, and the differential diagnosis. A 60-year-old man presented for evaluation of epigastric pain of 7 months duration. Abdominal computed tomography revealed a hypodense, unilocular cystic mass in the right lobe of the liver, measuring 14.0X11.1 cm. A right lobectomy was performed. Grossly, the cut surface showed a single, well-circumscribed unilocular cystic tumor mass containing dark red-brown necrotic debris and blood clots, which occupied most of the mass. Microscopically, the tumor consisted of haphazardly arranged mononuclear pleomorphic tumor cells, admixed with abundant osteoclast-like multinucleated giant cells. Immunohistochemically, the tumor cells expressed vimentin only. The histopathologic and immunohistochemical findings were compatible with a UPS. The patient is alive and well 41 months after surgery without recurrence. Clinically, most of the hepatic UPSs are solid masses. Only two cases have presented as multilocular cystic masses. A primary hepatic UPS presenting as a unilocular cyst has never been reported. A UPS should be included in the differential diagnosis of unilocular cystic lesions in the liver.


Effectiveness of the head CT choice decision aid in parents of children with minor head trauma: study protocol for a multicenter randomized trial.
Blunt head trauma is a common cause of death and disability in children worldwide. Cranial computed tomography (CT), the reference standard for the diagnosis of traumatic brain injury (TBI), exposes children to ionizing radiation which has been linked to the development of brain tumors, leukemia, and other cancers. We describe the methods used to develop and test the effectiveness of a decision aid to facilitate shared decision-making with parents regarding whether to obtain a head CT scan or to further observe their child at home. This is a protocol for a multicenter clinician-level parallel randomized trial to compare an intervention group receiving a decision aid, 'Head CT Choice', to a control group receiving usual care. The trial will be conducted at five diverse emergency departments (EDs) in Minnesota and California. Clinicians will be randomized to decision aid or usual care. Parents visiting the ED with children who are less than 18-years-old, have experienced blunt head trauma within 24 hours, and have one or two risk factors for clinically-important TBI (ciTBI) from the Pediatric Emergency Care Applied Research Network head injury clinical prediction rules will be eligible for enrollment. We will measure the effect of Head CT Choice on: (1) parent knowledge regarding their child's risk of ciTBI, the available diagnostic options, and the risks of radiation exposure associated with a cranial CT scan (primary outcome); (2) parent engagement in the decision-making process; (3) the degree of conflict parents experience related to feeling uninformed; (4) patient and clinician satisfaction with the decision made; (5) the rate of ciTBI at seven days; (6) the proportion of patients in whom a cranial CT scan is obtained; and (7) seven-day healthcare utilization. To capture these outcomes, we will administer parent and clinician surveys immediately after each clinical encounter, obtain video recordings of parent-clinician discussions, administer parent healthcare utilization diaries, analyze hospital billing records, review the electronic medical record, and conduct telephone follow-up. This multicenter trial will robustly assess the effectiveness of a decision aid on patient-centered outcomes, safety, and healthcare utilization in parents of children with minor head trauma in five diverse EDs. ClinicalTrials.gov registration number: NCT02063087. Registration date February 13, 2014.


[Emergency psychiatry in Belgium; a challenge for the mental health services].
In Belgium emergency psychiatry is a discipline that has developed only recently, following two federal pilot projects, one in 1993 and one in 2002. At present there are 10 subsidised psychiatric emergency rooms (pers) in Belgium, serving about 13,000 patients annually. Many of those seeking help are 'revolving-door' patients, but the pers also serve patients who have had no prior contact with the mental health care service. The disorders that are encountered most often have to do with substance abuse (about 30%) and mood disorders (17%). More than 4 in 10 patients were admitted to a psychiatric clinic after being referred to a per. Research suggests that the link to continuous care may reduce the 'revolving-door' phenomenon.


Significant Association Between Polymorphisms of Wnt Antagonist Genes and Lung Cancer.
Further elucidation of the molecular mechanisms underlying lung cancer (LC) is essential for the development of new effective therapeutic agents. Recently, involvement of Wnt antagonists in oncogenesis has been demonstrated in several cancers. The investigation of their contribution to lung carcinogenesis is still under investigation. We aimed to investigate whether there is a susceptibility or preventive effect of Wnt antagonist gene polymorphisms on the development and/or prognosis of LC. We investigated 110 LC patients and 160 controls. Single-nucleotide polymorphisms of Wnt antagonist genes including DKK2 (rs17037102), DKK3 (rs3206824), DKK3 intron4 G/C (rs7396187), DKK4 (rs2073664), and sFRP4 (rs1802074) were analyzed using nested polymerase chain reaction and restriction fragment length polymorphism. Results showed that patients with DKK3 AA compared with controls have a decreased risk of LC (adjusted for smoking habit, body mass index, and familial history) (P = 0.02; odds ratio [OR],0.08; 95% confidence interval [95% CI], 0.01-0.7). It was found that, for sFRP4 polymorphism, patients with GG and GA genotypes versus AA genotype controls showed a decreased risk for LC (P = 0.01; [OR, 0.19; 95% CI, 0.05-0.73 for GG genotype]; [OR = 0.18, 95% CI, 0.04-0.72 for GA genotype]). In addition, a decreased risk of LC was also found for the genotype combination of DKK3 (rs3206824) GG and sFRP4 AG + GG (P = 0.004; OR, 0.12; 95% CI, 0.02-0.58). We suggest that these 2 polymorphisms have a protective effect on LC in this study.


Reducing the Meta-Emotional Problem Decreases Physiological Fear Response during Exposure in Phobics.
Anxiety disorders may not only be characterized by specific symptomatology (e.g., tachycardia) in response to the fearful stimulus (primary problem or first-level emotion) but also by the tendency to negatively evaluate oneself for having those symptoms (secondary problem or negative meta-emotion). An exploratory study was conducted driven by the hypothesis that reducing the secondary or meta-emotional problem would also diminish the fear response to the phobic stimulus. Thirty-three phobic participants were exposed to the phobic target before and after undergoing a psychotherapeutic intervention addressed to reduce the meta-emotional problem or a control condition. The electrocardiogram was continuously recorded to derive heart rate (HR) and heart rate variability (HRV) and affect ratings were obtained. Addressing the meta-emotional problem had the effect of reducing the physiological but not the subjective symptoms of anxiety after phobic exposure. Preliminary findings support the role of the meta-emotional problem in the maintenance of response to the fearful stimulus (primary problem).


Occupational hand dermatoses of hairdressers in Tainan City.
To determine the prevalence, clinical features, and patterns of hand dermatosis in hairdressers in Tainan, Taiwan, and to examine the associations between patterns of dermatosis and risk factors such as job description, work exposure, and sensitisation to common allergens. Interviews, examinations, and patch tests of the hairdressers from nine hairdressing stores randomly selected from Tainan City. Patch test agents included 41 substances with common allergens, shampoo preservatives, hair dyes, permanent waving and bleaching agents. 98 hairdressers finished the examination, 83% of them had occupational dermatosis and 32% had scissor induced scars or wounds. Most of the dermatoses belonged to either dry metacarpophalangeal dermatitis or eczema of the fingers. 44% of the hairdressers showed positive skin reaction to one or more patch test agents. The patch test results were different from previous reports in that the most common allergens were nickel, thimerosal, Captan, Kathon CG, and fragrance mix, and that the sensitivity to hair dye and permanent wave ingredients were low. The dry metacarpophalangeal dermatitis was associated with exposure to shampoo, and the eczema of the fingers with skin sensitivity to patch test agents. Hairdressers in Tainan City had a high prevalence of dermatoses including traumatic wounds, and allergic and irritant contact dermatitis. The rates of sensitivity to some of the common sensitising agents were different from previous reports.


Society for Cardiovascular Magnetic Resonance (SCMR) expert consensus for CMR imaging endpoints in clinical research: part I - analytical validation and clinical qualification.
Cardiovascular disease remains a leading cause of morbidity and mortality globally. Changing natural history of the disease due to improved care of acute conditions and ageing population necessitates new strategies to tackle conditions which have more chronic and indolent course. These include an increased deployment of safe screening methods, life-long surveillance, and monitoring of both disease activity and tailored-treatment, by way of increasingly personalized medical care. Cardiovascular magnetic resonance (CMR) is a non-invasive, ionising radiation-free method, which can support a significant number of clinically relevant measurements and offers new opportunities to advance the state of art of diagnosis, prognosis and treatment. The objective of the SCMR Clinical Trial Taskforce was to summarizes the evidence to emphasize where currently CMR-guided clinical care can indeed translate into meaningful use and efficient deployment of resources results in meaningful and efficient use. The objective of the present initiative was to provide an appraisal of evidence on analytical validation, including the accuracy and precision, and clinical qualification of parameters in disease context, clarifying the strengths and weaknesses of the state of art, as well as the gaps in the current evidence This paper is complementary to the existing position papers on standardized acquisition and post-processing ensuring robustness and transferability for widespread use. Themed imaging-endpoint guidance on trial design to support drug-discovery or change in clinical practice (part II), will be presented in a follow-up paper in due course. As CMR continues to undergo rapid development, regular updates of the present recommendations are foreseen.


A pilot study evaluating the effectiveness of individual inpatient cognitive-behavioural therapy in early psychosis.
Recent research indicates that cognitive-behaviour therapy (CBT) can be effective in ameliorating persistent positive symptoms in chronic psychotic patients. The effectiveness of CBT in acute and recent-onset psychosis has been little explored, although a recent pilot study indicated that CBT could significantly improve recovery in acutely psychotic inpatients. Short-term individual CBT was compared to supportive counselling/psychoeducation (SC) as an adjunct to standard inpatient hospital care and medication in 21 inpatients experiencing a recent-onset acute schizophrenic episode. Both groups showed significant reductions in Brief Psychiatric Rating Scale (BPRS) scores following treatment, although there were no group differences. Time to discharge did not differ significantly between the groups, although there was a greater variance for the SC patients. Two-year follow-up showed no significant differences between the groups, although the number of patients who relapsed, the number of relapses and the time to recurrence of psychotic symptoms was lower in the CBT group than the SC group. Interestingly, the time to readmission was shorter in the CBT group. CBT and SC are acceptable treatments for recent-onset acutely psychotic inpatients. A larger randomised controlled trial over multiple hospital sites is warranted.


The APC/C subunit Mnd2/Apc15 promotes Cdc20 autoubiquitination and spindle assembly checkpoint inactivation.
The fidelity of chromosome segregation depends on the spindle assembly checkpoint (SAC). In the presence of unattached kinetochores, anaphase is delayed when three SAC components (Mad2, Mad3/BubR1, and Bub3) inhibit Cdc20, the activating subunit of the anaphase-promoting complex (APC/C). We analyzed the role of Cdc20 autoubiquitination in the SAC of budding yeast. Reconstitution with purified components revealed that a Mad3-Bub3 complex synergizes with Mad2 to lock Cdc20 on the APC/C and stimulate Cdc20 autoubiquitination, while inhibiting ubiquitination of substrates. SAC-dependent Cdc20 autoubiquitination required the Mnd2/Apc15 subunit of the APC/C. General inhibition of Cdc20 ubiquitination in vivo resulted in high Cdc20 levels and a failure to establish a SAC arrest, suggesting that SAC establishment depends on low Cdc20 levels. Specific inhibition of SAC-dependent ubiquitination, by deletion of Mnd2, allowed establishment of a SAC arrest but delayed release from the arrest, suggesting that Cdc20 ubiquitination is also required for SAC inactivation.


Amygdalar function reflects common individual differences in emotion and pain regulation success.
Although the co-occurrence of negative affect and pain is well recognized, the mechanism underlying their association is unclear. To examine whether a common self-regulatory ability impacts the experience of both emotion and pain, we integrated neuroimaging, behavioral, and physiological measures obtained from three assessments separated by substantial temporal intervals. Our results demonstrated that individual differences in emotion regulation ability, as indexed by an objective measure of emotional state, corrugator electromyography, predicted self-reported success while regulating pain. In both emotion and pain paradigms, the amygdala reflected regulatory success. Notably, we found that greater emotion regulation success was associated with greater change of amygdalar activity following pain regulation. Furthermore, individual differences in degree of amygdalar change following emotion regulation were a strong predictor of pain regulation success, as well as of the degree of amygdalar engagement following pain regulation. These findings suggest that common individual differences in emotion and pain regulatory success are reflected in a neural structure known to contribute to appraisal processes.


Analysis of gene-gene interactions using gene-trait similarity regression.
Gene-gene interactions (G×G) are important to study because of their extensiveness in biological systems and their potential in explaining missing heritability of complex traits. In this work, we propose a new similarity-based test to assess G×G at the gene level, which permits the study of epistasis at biologically functional units with amplified interaction signals. Under the framework of gene-trait similarity regression (SimReg), we propose a gene-based test for detecting G×G. SimReg uses a regression model to correlate trait similarity with genotypic similarity across a gene. Unlike existing gene-level methods based on leading principal components (PCs), SimReg summarizes all information on genotypic variation within a gene and can be used to assess the joint/interactive effects of two genes as well as the effect of one gene conditional on another. Using simulations and a real data application to the Warfarin study, we show that the SimReg G×G tests have satisfactory power and robustness under different genetic architecture when compared to existing gene-based interaction tests such as PC analysis or partial least squares. A genome-wide association study with approx. 20,000 genes may be completed on a parallel computing system in 2 weeks.


Sustained wakefulness and visual attention: moderation by chronotype.
Attentional networks are sensitive to sleep deprivation and increased time awake. However, existing evidence is inconsistent and may be accounted for by differences in chronotype or time-of-day. We examined the effects of sustained wakefulness over a normal "socially constrained" day (following 18 h of sustained wakefulness), following a night of normal sleep, on visual attention as a function of chronotype. Twenty-six good sleepers (mean age 25.58; SD 4.26; 54 % male) completed the Attention Network Test (ANT) at two time points (baseline at 8 am; following 18-h sustained wakefulness at 2 am). The ANT provided mean reaction times (RTs), error rates, and the efficiency of three attentional networks-alerting, orienting, and executive control/conflict. The Morningness-Eveningness Questionnaire measured chronotype. Mean RTs were longer at time 2 compared to time 1 for those with increasing eveningness; the opposite was true for morningness. However, those with increasing morningness exhibited longer RT and made more errors, on incongruent trials at time 2 relative to those with increasing eveningness. There were no significant main effects of time or chronotype (or interactions) on attentional network scores. Sustained wakefulness produced differential effects on visual attention as a function of chronotype. Whilst overall our results point to an asynchrony effect, this effect was moderated by flanker type. Participants with increasing eveningness outperformed those with increasing morningness on incongruent trials at time 2. The preservation of executive control in evening-types following sustained wakefulness is likely driven by differences in circadian phase between chronotypes across the day.


[Malaria prophylaxis of West German travelers to Africa].
From May 1985 to July 1988, 11,445 German residents who had travelled to Africa filled in a questionnaire during the return flight and a second questionnaire sent to them 3 months later. 92.6% of the travellers had been on holiday and 99.3% of these holiday-makers were aware of the risk of malaria. Before and during their stay in the tropics 10,955 travellers (95.7%) had taken the chemoprophylaxis correctly, though in some instances the drugs prescribed were not in accordance with the guidelines existing at the time. However, 3227 of them (35.5%) discontinued the drugs too early, i.e. less than four weeks after their return. Only 4.3% of the travellers had taken proper precautions against mosquito bites. In view of the ever increasing numbers of people travelling to countries where malaria is endemic, doctors and travelers should be provided with more information and should be given more consistent advice on malaria prophylaxis.


Proteolytic degradation of heat shock protein A2 occurs in response to oxidative stress in male germ cells of the mouse.
Does oxidative stress compromise the protein expression of heat shock protein A2 (HSPA2) in the developing germ cells of the mouse testis? Oxidative stress leads to the modification of HSPA2 by the lipid aldehyde 4-hydroxynonenal (4HNE) and initiates its degradation via the ubiquitin-proteasome system. Previous work has revealed a deficiency in HSPA2 protein expression within the spermatozoa of infertile men that have failed fertilization in a clinical setting. While the biological basis of this reduction in HSPA2 remains to be established, we have recently shown that the HSPA2 expressed in the spermatozoa of normozoospermic individuals is highly susceptible to adduction, a form of post-translational modification, by the lipid aldehyde 4HNE that has been causally linked to the degradation of its substrates. This modification of HSPA2 by 4HNE adduction dramatically reduced human sperm-egg interaction in vitro. Moreover, studies in a mouse model offer compelling evidence that the co-chaperone BCL2-associated athanogene 6 (BAG6) plays a key role in regulating the stability of HSPA2 in the testis, by preventing its ubiquitination and subsequent proteolytic degradation. Dose-dependent studies were used to establish a 4HNE-treatment regime for primary culture(s) of male mouse germ cells. The influence of 4HNE on HSPA2 protein stability was subsequently assessed in treated germ cells. Additionally, sperm lysates from infertile patients with established zona pellucida recognition defects were examined for the presence of 4HNE and ubiquitin adducts. A minimum of three biological replicates were performed to test statistical significance. Oxidative stress was induced in pachytene spermatocytes and round spermatids isolated from the mouse testis, as well as a GC-2 cell line, using 50-200 µM 4HNE or hydrogen peroxide (H2O2), and the expression of HSPA2 was monitored via immunocytochemistry and immunoblotting approaches. Using the GC-2 cell line as a model, the ubiquitination and degradation of HSPA2 was assessed using immunoprecipitation techniques and pharmacological inhibition of proteasomal and lysosomal degradation pathways. Finally, the interaction between BAG6 and HSPA2 was examined in response to 4HNE exposure via proximity ligation assays. HSPA2 protein levels were significantly reduced compared with controls after 4HNE treatment of round spermatids (P < 0.01) and GC-2 cells (P < 0.001) but not pachytene spermatocytes. Using GC-2 cells as a model, HSPA2 was shown to be both adducted by 4HNE and targeted for ubiquitination in response to cellular oxidative stress. Inhibition of the proteasome with MG132 prevented HSPA2 degradation after 4HNE treatment indicating that the degradation of HSPA2 is likely to occur via a proteasomal pathway. Moreover, our assessment of proteasome activity provided evidence that 4HNE treatment can significantly increase the proteasome activity of GC-2 cells (P < 0.05 versus control). Finally, 4HNE exposure to GC-2 cells resulted in the dissociation of HSPA2 from its regulatory co-chaperone BAG6, a key mediator of HSPA2 stability in male germ cells. While these experiments were performed using a mouse germ cell-model system, our analyses of patient sperm lysate imply that these mechanisms are conserved between mouse and human germ cells. This study suggests a causative link between non-enzymatic post-translational modifications and the relative levels of HSPA2 in the spermatozoa of a specific sub-class of infertile males. In doing so, this work enhances our understanding of failed sperm-egg recognition and may assist in the development of targeted antioxidant-based approaches for ameliorating the production of cytotoxic lipid aldehydes in the testis in an attempt to prevent this form of infertility. Not applicable. This work was supported by the National Health and Medical Research Council of Australia (APP1101953). The authors have no competing interests to declare.


Pediatric Septic Shock Collaborative Improves Emergency Department Sepsis Care in Children.
The pediatric emergency department (ED)-based Pediatric Septic Shock Collaborative (PSSC) aimed to improve mortality and key care processes among children with presumed septic shock. This was a multicenter learning and improvement collaborative of 19 pediatric EDs from November 2013 to May 2016 with shared screening and patient identification recommendations, bundles of care, and educational materials. Process metrics included minutes to initial vital sign assessment and to first and third fluid bolus and antibiotic administration. Outcomes included 3- and 30-day all-cause in-hospital mortality, hospital and ICU lengths of stay, hours on increased ventilation (including new and increases from chronic baseline in invasive and noninvasive ventilation), and hours on vasoactive agent support. Analysis used statistical process control charts and included both the overall sample and an ICU subgroup. Process improvements were noted in timely vital sign assessment and receipt of antibiotics in the overall group. Timely first bolus and antibiotics improved in the ICU subgroup. There was a decrease in 30-day all-cause in-hospital mortality in the overall sample. A multicenter pediatric ED improvement collaborative showed improvement in key processes for early sepsis management and demonstrated that a bundled quality improvement-focused approach to sepsis management can be effective in improving care.


Feasibility of ecological momentary assessment to study mood and risk behavior among young people who inject drugs.
To test the acceptability and feasibility of ecological momentary assessment (EMA) of mood and injection risk behavior among young people who inject drugs (PWID), using mobile phones. Participants were 185 PWID age 18-35 recruited from two sites of a large syringe service program in Chicago. After completing a baseline interview, participants used a mobile phone app to respond to momentary surveys on mood, substance use, and injection risk behavior for 15 days. Participants were assigned to receive surveys 4, 5, or 6 times per day. Participants were 68% male, 61% non-Hispanic white, 24% Hispanic, and 5% non-Hispanic Black. Out of 185 participants, 8% (n = 15) failed to complete any EMA assessments. Among 170 EMA responders, the mean number of days reporting was 10 (SD 4.7), the mean proportion of assessments completed was 0.43 (SD 0.27), and 76% (n = 130) completed the follow-up interview. In analyses adjusted for age and race/ethnicity, women were more responsive than men to the EMA surveys in days reporting (IRR = 1.33, 95% CI 1.13-1.56), and total number of surveys completed (IRR = 1.51, 95% CI 1.18-1.93). Homeless participants responded on fewer days (IRR = 0.76, 95% CI 0.64-0.90) and completed fewer surveys (IRR = 0.70, 95% CI 0.54-0.91), and were less likely to return for follow-up (p = 0.016). EMA responsiveness was not significantly affected by the number of assigned daily assessments. This study demonstrated high acceptability and feasibility of EMA among young PWID, with up to 6 survey prompts per day. However, homelessness significantly hampered successful participation.


Invasive Aspergillosis with Disseminated Skin Involvement in a Patient with Acute Myeloid Leukemia: A Rare Case.
Invasive pulmonary aspergillosis is most commonly seen in immunocompromised patients. Besides, skin lesions may also develop due to invasive aspergillosis in those patients. A 49-year-old male patient was diagnosed with acute myeloid leukemia. The patient developed bullous and zosteriform lesions on the skin after the 21st day of hospitalization. The skin biopsy showed hyphae. Disseminated skin aspergillosis was diagnosed to the patient. Voricanazole treatment was initiated. The patient was discharged once the lesions started to disappear.


Nut consumption and incidence of seven cardiovascular diseases.
Nut consumption has been found to be inversely associated with cardiovascular disease mortality, but the association between nut consumption and incidence of specific cardiovascular diseases is unclear. We examined the association between nut consumption and incidence of seven cardiovascular diseases. This prospective study included 61 364 Swedish adults who had completed a Food Frequency Questionnaire and were followed up for 17 years through linkage with the Swedish National Patient and Death Registers. Nut consumption was inversely associated with risk of myocardial infarction, heart failure, atrial fibrillation and abdominal aortic aneurysm in the age-adjusted and sex-adjusted analysis. However, adjustment for multiple risk factors attenuated these associations and only a linear, dose-response, association with atrial fibrillation (ptrend=0.004) and a non-linear association (pnon-linearity=0.003) with heart failure remained. Compared with no consumption of nuts, the multivariable HRs (95% CI) of atrial fibrillation across categories of nut consumption were 0.97 (0.93 to 1.02) for 1-3 times/month, 0.88 (0.79 to 0.99) for 1-2 times/week and 0.82 (0.68 to 0.99) for ≥3 times/week. For heart failure, the corresponding HRs (95% CI) were 0.87 (0.80 to 0.94), 0.80 (0.67 to 0.97) and 0.98 (0.76 to 1.27). Nut consumption was not associated with risk of aortic valve stenosis, ischaemic stroke or intracerebral haemorrhage. These findings suggest that nut consumption or factors associated with this nutritional behaviour may play a role in reducing the risk of atrial fibrillation and possibly heart failure. NCT01127711 and NCT01127698;Results.


Trained lay health workers reduce common mental disorder symptoms of adults with suicidal ideation in Zimbabwe: a cohort study.
Suicidal ideation may lead to deliberate self-harm which increases the risk of death by suicide. Globally, the main cause of deliberate self-harm is depression. The aim of this study was to explore prevalence of, and risk factors for, suicidal ideation among men and women with common mental disorder (CMD) symptoms attending public clinics in Zimbabwe, and to determine whether problem solving therapy delivered by lay health workers can reduce common mental disorder symptoms among people with suicidal ideation, using secondary analysis of a randomised controlled trial. At trial enrolment, the Shona Symptom Questionnaire (SSQ) was used to screen for CMD symptoms. In the intervention arm, participants received six problem-solving therapy sessions conducted by trained and supervised lay health workers, while those in the control arm received enhanced usual care. We used multivariate logistic regression to identify risk factors for suicidal ideation at enrolment, and cluster-level logistic regression to compare SSQ scores at endline (6 months follow-up) between trial arms, stratified by suicidal ideation at enrolment. There were 573 participants who screened positive for CMD symptoms and 75 (13.1%) reported suicidal ideation at baseline. At baseline, after adjusting for confounders, suicidal ideation was independently associated with being aged over 24, lack of household income (household income yes/no; adjusted odds ratio 0.52 (95% CI 0.29, 0.95); p = 0.03) and with having recently skipped a meal due to lack of food (adjusted odds ratio 3.06 (95% CI 1.81, 5.18); p < 0.001). Participants who reported suicidal ideation at enrolment experienced similar benefit to CMD symptoms from the Friendship Bench intervention (adjusted mean difference - 5.38, 95% CI -7.85, - 2.90; p < 0.001) compared to those who had common mental disorder symptoms but no suicidal ideation (adjusted mean difference - 4.86, 95% CI -5.68, - 4.04; p < 0.001). Problem-solving therapy delivered by trained and supervised lay health workers reduced common mental disorder symptoms among participants with suicidal thoughts who attended primary care facilities in Zimbabwe. pactr.org ldentifier: PACTR201410000876178.


Modification of ionic currents underlying action potentials in mouse nerve terminals by the thiol-oxidizing agent diamide.
The effect of diamide, a thiol-oxidizing agent, was tested using electrophysiological techniques to determine whether its ability to alter neuromuscular transmission in vitro could be attributed to alterations of ion channels controlling neuronal excitability and/or acetylcholine release. In mouse triangularis sterni preparations, diamide transiently increased the evoked release of acetylcholine and then blocked release. Extracellular recording of perineural waveforms associated with neuronal action potentials at motor nerve terminals showed that diamide reduced the waveforms associated with the delayed rectifier K+ current, a Ca2+ current and a Ca(2+)-activated K+ current (IK,Ca). Inhibition of quantal transmitter release was not associated with failure of action potentials to invade nerve terminals. Thus, diamide modifies the ionic currents underlying the nerve terminal action potential, some of these changes probably account for the complex effects of diamide on quantal transmission.


Temporal and seasonal variability of arsenic in drinking water wells in Matlab, southeastern Bangladesh: a preliminary evaluation on the basis of a 4 year study.
Temporal and seasonal variability of As concentrations in groundwater were evaluated in As-affected areas of Matlab, southeastern Bangladesh. Groundwater samples from 61 randomly selected tubewells were analyzed for As concentrations over a period of three years and four months (from July 2002 to November 2005) and monitored seasonally (three times a year). The mean As concentrations in the sampled tubewells decreased from 153 to 123 μg/L during July 2002 to November 2005. Such changes were pronounced in tubewells with As concentration >50 μg/L than those with As concentrations <50 μg/L. Similarly, individual wells revealed temporal variability, for example some wells indicated a decreasing trend, while some other wells indicated stable As concentration during the monitoring period. The mean As concentrations were significantly higher in Matlab North compared with Matlab South. The spatial variations in the mean As concentrations may be due to the differences in local geological conditions and groundwater flow patterns. The variations in mean As concentrations were also observed in shallow (<40 m) and deep (>40 m) wells. However, to adequately evaluate temporal and seasonal variability of As concentration, it is imperative to monitor As concentrations in tubewells over a longer period of time. Such long-term monitoring will provide important information for the assessment of human health risk and the sustainability of safe drinking water supplies.


BMI development of normal weight and overweight children in the PIAMA study.
There is evidence that rapid weight gain during the first year of life is associated with overweight later in life. However, results from studies exploring other critical periods for the development of overweight are inconsistent. The objective was to investigate BMI development to assess at what ages essential differences between normal weight and overweight children occur, and to assess which age intervals the most strongly influence the risk of overweight at 8 years of age. Longitudinal weight and height data were collected by annual questionnaires in a population of 3963 children participating in the PIAMA birth cohort study. BMI and BMI standard deviation scores (SDS) were calculated for every year from birth until 8 years of age. BMI, BMI SDS and BMI SDS change in each 1-year-age interval were compared between children with and without overweight at 8 years of age, using t-tests, logistic regression analysis and the analysis of response profiles method. At 8 years of age, 10.5% of the children were overweight. Already at the age of 1 year, these children had a significantly higher mean BMI SDS than normal weight 8-year-olds, (0.53 vs 0.04). In each 1-year-age interval the change in BMI SDS was significantly associated with overweight at 8 years with odds ratios increasing from 1.14 (95% CI 1.04-1.24) per 1 SDS increase at 0-1 year to 2.40 (95% CI 2.09-2.76) at 7-8 years. At every age, starting already in the first year of life, a rapid increase in BMI SDS was significantly associated with overweight risk at the age of 8 years. There was no evidence for a specific critical period for the development of overweight. Prevention of overweight should start early in life and be continued with age-specific interventions throughout childhood.


Chronic hepatitis B with advanced fibrosis or cirrhosis: impact of antiviral therapy.
Chronic hepatitis B virus (HBV) infection is a significant public health problem in the United States, with 1.25 million people infected with the virus. The long-term risks of chronic HBV infection include cirrhosis and hepatocellular carcinoma, which occur in 15% to 30% of those infected at birth or early in life and may lead to liver transplantation or death. During the past few years, the development and increased availability of oral antiviral agents have made treatment simpler, safer, and more tolerable for these patients. This article focuses on 3 of these drugs--lamivudine, adefovir, and entecavir--and their use in patients with chronic HBV infection and advanced hepatic fibrosis or cirrhosis.


Postnatal care for newborns in Bangladesh: The importance of health-related factors and location.
Bangladesh achieved Millennium Development Goal 4, a two thirds reduction in under-five mortality from 1990 to 2015. However neonatal mortality remains high, and neonatal deaths now account for 62% of under-five deaths in Bangladesh. The objective of this paper is to understand which newborns in Bangladesh are receiving postnatal care (PNC), a set of interventions with the potential to reduce neonatal mortality. Using data from the Bangladesh Maternal Mortality Survey (BMMS) 2010 we conducted logistic regression analysis to understand what socio-economic and health-related factors were associated with early postnatal care (PNC) by day 2 and PNC by day 7. Key variables studied were maternal complications (during pregnancy, delivery or after delivery) and contact with the health care system (receipt of any antenatal care, place of delivery and type of delivery attendant). Using data from the BMMS 2010 and an Emergency Obstetric and Neonatal Care (EmONC) 2012 needs assessment, we also presented descriptive maps of PNC coverage overlaid with neonatal mortality rates. There were several significant findings from the regression analysis. Newborns of mothers having a skilled delivery were significantly more likely to receive PNC (Day 7: OR = 2.16, 95% confidence interval (CI) 1.81, 2.58; Day 2: OR = 2.11, 95% 95% CI 1.76). Newborns of mothers who reported a complication were also significantly more likely to receive PNC with odds ratios varying between 1.3 and 1.6 for complications at the different points along the continuum of care. Urban residence and greater wealth were also significantly associated with PNC. The maps provided visual images of wide variation in PNC coverage and indicated that districts with the highest PNC coverage, did not necessarily have the lowest neonatal mortality rates. Newborns of mothers who had a skilled delivery or who experienced a complication were more likely to receive PNC than newborns of mothers with a home delivery or who did not report a complication. Given that the majority of women in Bangladesh have a home delivery, strategies are needed to reach their newborns with PNC. Greater focus is also needed to reach poor women in rural areas. Engaging community health workers to conduct home PNC visits may be an interim strategy as Bangladesh strives to increase skilled delivery coverage.


Diagnosis and management of acute diverticulitis.
Uncomplicated diverticulitis is localized diverticular inflammation, whereas complicated diverticulitis is diverticular inflammation associated with an abscess, phlegmon, fistula, obstruction, bleeding, or perforation. Patients with acute diverticulitis may present with left lower quadrant pain, tenderness, abdominal distention, and fever. Other symptoms may include anorexia, constipation, nausea, diarrhea, and dysuria. Initial laboratory studies include a complete blood count, basic metabolic panel, urinalysis, and measurement of C-reactive protein. Computed tomography, the most commonly performed imaging test, is useful to establish the diagnosis and the extent and severity of disease, and to exclude complications in selected patients. Colonoscopy is recommended four to six weeks after resolution of symptoms for patients with complicated disease or for another indication, such as age-appropriate screening. In mild, uncomplicated diverticulitis, antibiotics do not accelerate recovery, or prevent complications or recurrences. Hospitalization should be considered if patients have signs of peritonitis or there is suspicion of complicated diverticulitis. Inpatient management includes intravenous fluid resuscitation and intravenous antibiotics. Patients with a localized abscess may be candidates for computed tomography-guided percutaneous drainage. Fifteen to 30 percent of patients admitted with acute diverticulitis require surgical intervention during that admission. Laparoscopic surgery results in a shorter length of stay, fewer complications, and lower in-hospital mortality compared with open colectomy. The decision to proceed to surgery in patients with recurrent diverticulitis should be individualized and based on patient preference, comorbidities, and lifestyle. Interventions to prevent recurrences of diverticulitis include increased intake of dietary fiber, exercise, cessation of smoking, and, in persons with a body mass index of 30 kg per m(2) or higher, weight loss.


RNA interference against the putative insulin receptor substrate gene chico affects metamorphosis in Leptinotarsa decemlineata.
It is noted that insect insulin/insulin-like growth factor/target of rapamycin signaling is critical for the regulation of metamorphosis in holometabolous insects. However, the molecular mechanism remains undetermined. Our previous findings reveal that RNA interference (RNAi)-mediated knockdown of an insulin gene (LdILP2) in Leptinotarsa decemlineata disturbs both 20-hydroxyecdysone (20E) and juvenile hormone (JH) signaling, and impairs pupation. In the present paper, we further observed that the expression of the insulin receptor substrate gene chico (Ldchico) and the phosphoinositide-3-kinase gene pi3k (Ldpi3k92E) was repressed in LdILP2 depleted larvae. Moreover, RNAi of Ldchico or Ldpi3k92E decreased food consumption, affected absorption and metabolism of amino acids and sugars, and reduced expression of several 20E (LdEcR, LdHR3 and LdE75) and JH (LdJHAMT, LdKr-h1 and LdHairy) signaling genes. As a result, larval development was postponed and larval growth was inhibited. Intriguingly, knockdown of Ldchico, rather than Ldpi3k92E, impaired larval-pupal and pupal-adult ecdysis, and specifically repressed transcription of another 20E signaling gene LdUSP. Ingestion of 20E rescued the expression of LdEcR, LdHR3 and LdE75, whereas 20E feeding restored neither the decreased LdUSP mRNA level, nor the reduced pupation and adult emergence rates in Ldchico RNAi larvae. Therefore, Chico is critical for the regulation of larval-pupal-adult transition by a PI3K-independent pathway, perhaps through activation of USP in L. decemlineata.


The global regulator CodY regulates toxin gene expression in Bacillus anthracis and is required for full virulence.
In gram-positive bacteria, CodY is an important regulator of genes whose expression changes upon nutrient limitation and acts as a repressor of virulence gene expression in some pathogenic species. Here, we report the role of CodY in Bacillus anthracis, the etiologic agent of anthrax. Disruption of codY completely abolished virulence in a toxinogenic, noncapsulated strain, indicating that the activity of CodY is required for full virulence of B. anthracis. Global transcriptome analysis of a codY mutant and the parental strain revealed extensive differences. These differences could reflect direct control for some genes, as suggested by the presence of CodY binding sequences in their promoter regions, or indirect effects via the CodY-dependent control of other regulatory proteins or metabolic rearrangements in the codY mutant strain. The differences included reduced expression of the anthrax toxin genes in the mutant strain, which was confirmed by lacZ reporter fusions and immunoblotting. The accumulation of the global virulence regulator AtxA protein was strongly reduced in the mutant strain. However, in agreement with the microarray data, expression of atxA, as measured using an atxA-lacZ transcriptional fusion and by assaying atxA mRNA, was not significantly affected in the codY mutant. An atxA-lacZ translational fusion was also unaffected. Overexpression of atxA restored toxin component synthesis in the codY mutant strain. These results suggest that CodY controls toxin gene expression by regulating AtxA accumulation posttranslationally.


Association between biologic therapies for chronic plaque psoriasis and cardiovascular events: a meta-analysis of randomized controlled trials.
Ustekinumab and briakinumab, monoclonal antibodies to the shared p40 subunit of interleukin (IL)-12 and IL-23, have shown efficacy in treating chronic plaque psoriasis (CPP). Preliminary reports of major adverse cardiovascular events (MACEs) in psoriasis patients receiving anti-IL-12/23 agents have prompted concern. To evaluate a possible association between biologic therapies for CPP and MACEs via meta-analysis. Randomized controlled trials (RCTs) of anti-IL-12/23 (ustekinumab and briakinumab) agents and anti-tumor necrosis factor α (TNF-α) agents (adalimumab, etanercept, and infliximab) used in treating CPP were reviewed using the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and Ovid MEDLINE from database inception to May 2011. The results of registered nonpublished completed studies were procured through abstract publications or poster presentations. Randomized, placebo-controlled, double-blind, monotherapy studies (with safety outcome data for MACE) of IL-12/23 antibodies and anti-TNF-α agents in adults. Studies of psoriatic arthritis were excluded. Two investigators independently searched data while 6 investigators reviewed the abstracted data. A total of 22 RCTs comprising 10 183 patients met the predefined inclusion criteria. The primary outcome measure was MACE, a composite end point of myocardial infarction, cerebrovascular accident, or cardiovascular death during the placebo-controlled phase of treatment in patients receiving at least 1 dose of study agent or placebo. Absolute risk differences were used as an effect measure. There was no evidence of statistical heterogeneity across the studies using the I(2) statistic (I(2) = 0), allowing for combination of trial results using the Mantel-Haenszel fixed-effects method. During the placebo-controlled phases of the anti-IL-12/23 studies, 10 of 3179 patients receiving anti-IL-12/23 therapies experienced MACEs compared with zero events in 1474 patients receiving placebo (Mantel-Haenszel risk difference, 0.012 events/person-year; 95% confidence interval [CI], -0.001 to 0.026; P =.12). In the anti-TNF-α trials, only 1 of 3858 patients receiving anti-TNF-α agents experienced a MACE compared with 1 of 1812 patients receiving placebo (Mantel-Haenszel risk difference, -0.0005 events/person-year; 95% CI, -0.010 to 0.009; P = .94). Compared with placebo, there was no significant difference in the rate of MACEs observed in patients receiving anti-IL-12/IL-23 antibodies or anti-TNF-α treatments. This study may have been underpowered to identify a significant difference.


Pulmonary abnormalities and carotid atherosclerosis in ex-smokers without airflow limitation.
It is well-established that COPD patients have a burden of vascular disease that cannot be fully-explained by smoking history but the mechanistic links between atherosclerosis and pulmonary disease in COPD patients are not well-understood. Moreover, in ex-smokers without symptoms or other evidence of COPD, subclinical pulmonary and vascular disease, although potentially present, has not been described or evaluated. Hence our aim was to use sensitive three-dimensional (3D) pulmonary and carotid imaging to quantify pulmonary airway/parenchyma abnormalities and atherosclerosis in ex-smokers without airflow limitation or symptoms consistent with COPD. We evaluated 61 subjects without airflow limitation including 34 never- (72 ± 6 years) and 27 ex-smokers (73 ± 9 years), who provided written informed consent to spirometry, plethysmography, (3)He magnetic resonance imaging (MRI) and carotid ultrasound (US) and, for ex-smokers alone, thoracic X-ray computed tomography (CT). Ex-smokers had significantly greater (3)He ventilation defect percent (VDP = 7%, p = 0.001) and carotid total plaque volume (TPV = 250 mm(3), p = 0.002) than never-smokers, although there were no significant differences for spirometry or plethysmography, and CT airway and emphysema measurements were normal. There were univariate relationships for (3)He VDP with carotid intima media thickness (IMT, r = 0.42, p = 0.004), TPV (r = 0.41, p = 0.006) and vessel wall volume (VWV, r = 0.40, p = 0.007). Multivariate models that included age, BMI, FEV1, DLCO and VDP showed that only VDP significantly predicted IMT (β = 0.41, p = 0.001), VWV (β = 0.45, p = 0.003) and TPV (β = 0.38, p = 0.005). In summary, there was imaging evidence of mild airways disease and carotid plaque burden that were related and significantly greater in ex-smokers without airflow limitation than in never-smokers.


Synthetic [NiFe] models with a fluxional CO ligand.
A [NiFe] complex [(dppe)Ni(pdt)FeCp*(CO)]+ was isolated and characterized as two isomers [1(CO)]+ and [1'(CO)]+. Heating the solution of [1(CO)]+ allowed it to convert into [1'(CO)]+. The one-electron oxidation of [1'(CO)]+ to [1'(CO)]2+ induced fluxional CO movement providing [1(CO)]2+. Recovery of [1(CO)]+ was realized by the one-electron reduction of [1(CO)]2+.


The relation of general socio-emotional processing to parenting specific behavior: a study of mothers with and without posttraumatic stress disorder.
Socio-emotional information processing during everyday human interactions has been assumed to translate to social-emotional information processing when parenting a child. Yet, few studies have examined whether this is indeed the case. This study aimed to improve on this by connecting the functional neuroimaging data when seeing socio-emotional interactions that are not parenting specific to observed maternal sensitivity. The current study considered 45 mothers of small children (12-42 months of age). It included healthy controls (HC) and mothers with interpersonal violence-related posttraumatic stress disorder (IPV-PTSD), as well as mothers without PTSD, both with and without IPV exposure. We found that anterior cingulate cortex (ACC) and ventromedial prefrontal cortex (vmPFC) activity correlated negatively with observed maternal sensitivity when mothers watched videos of menacing vs. prosocial adult male-female interactions. This relationship was independent of whether mothers were HC or had IPV-PTSD. We also found dorsolateral prefrontal cortex (dlPFC) activity to be correlated negatively with maternal sensitivity when mothers watched any kind of arousing adult interactions. With regards to ACC and vmPFC activity, we interpret our results to mean that the ease of general emotional information integration translates to parenting-specific behavior. Our dlPFC activity findings support the idea that the efficiency of top-down control of socio-emotional processing in non-parenting specific contexts may be predictive of parenting behavior.


An expert system for the quantification of fault rates in construction fall accidents.
Expert witness reports, prepared with the aim of quantifying fault rates among parties, play an important role in a court's final decision. However, conflicting fault rates assigned by different expert witness boards lead to iterative objections raised by the related parties. This unfavorable situation mainly originates due to the subjectivity of expert judgments and unavailability of objective information about the causes of accidents. As a solution to this shortcoming, an expert system based on a rule-based system was developed for the quantification of fault rates in construction fall accidents. The aim of developing DsSafe is decreasing the subjectivity inherent in expert witness reports. Eighty-four inspection reports prepared by the official and authorized inspectors were examined and root causes of construction fall accidents in Turkey were identified. Using this information, an evaluation form was designed and submitted to the experts. Experts were asked to evaluate the importance level of the factors that govern fall accidents and determine the fault rates under different scenarios. Based on expert judgments, a rule-based expert system was developed. The accuracy and reliability of DsSafe were tested with real data as obtained from finalized court cases. DsSafe gives satisfactory results.


Increase of the DNA strand assimilation activity of recA protein by removal of the C terminus and structure-function studies of the resulting protein fragment.
A proteolytic fragment of recA protein, missing about 15% of the protein at the C terminus, was found to promote assimilation of homologous single-stranded DNA into duplex DNA more efficiently than intact recA protein. This difference was not found if Escherichia coli single-stranded DNA binding protein was present. The ATPase activity of both intact recA protein and the fragment was identical. The difference in strand assimilation activity cannot be due to differences in single-stranded DNA affinity, since both the fragment and intact proteins bind to single-stranded DNA with nearly identical affinities. However, the fragment was found to bind double-stranded DNA more tightly and to aggregate more extensively than recA protein; both of these properties may be important in strand assimilation. Aggregation of the fragment was extensive in the presence of duplex DNA under the same condition where recA protein did not aggregate. The double-stranded DNA binding of both recA protein and the fragment responds to nucleotide cofactors in the same manner as single-stranded DNA binding, i.e. ADP weakens and ATP gamma S strengthens the association. The missing C-terminal region of recA protein includes a very acidic region that is homologous to other single-stranded DNA binding proteins and which has been implicated in DNA binding modulation. This C-terminal region may serve a similar function in recA protein, possibly inhibiting double-stranded DNA invasion. The possible role of the enhanced double-stranded DNA affinity of the fragment protein in the mechanism of strand assimilation is discussed.


Sodium channel current loss of function in induced pluripotent stem cell-derived cardiomyocytes from a Brugada syndrome patient.
Brugada syndrome predisposes to sudden death due to disruption of normal cardiac ion channel function, yet our understanding of the underlying cellular mechanisms is incomplete. Commonly used heterologous expression models lack many characteristics of native cardiomyocytes and, in particular, the individual genetic background of a patient. Patient-specific induced pluripotent stem (iPS) cell-derived cardiomyocytes (iPS-CM) may uncover cellular phenotypical characteristics not observed in heterologous models. Our objective was to determine the properties of the sodium current in iPS-CM with a mutation in SCN5A associated with Brugada syndrome. Dermal fibroblasts from a Brugada syndrome patient with a mutation in SCN5A (c.1100G>A, leading to Nav1.5_p.R367H) were reprogrammed to iPS cells. Clones were characterized and differentiated to form beating clusters and sheets. Patient and control iPS-CM were structurally indistinguishable. Sodium current properties of patient and control iPS-CM were compared. These results were contrasted with those obtained in tsA201 cells heterologously expressing sodium channels with the same mutation. Patient-derived iPS-CM showed a 33.1-45.5% reduction in INa density, a shift in both activation and inactivation voltage-dependence curves, and faster recovery from inactivation. Co-expression of wild-type and mutant channels in tsA201 cells did not compromise channel trafficking to the membrane, but resulted in a reduction of 49.8% in sodium current density without affecting any other parameters. Cardiomyocytes derived from iPS cells from a Brugada syndrome patient with a mutation in SCN5A recapitulate the loss of function of sodium channel current associated with this syndrome; including pro-arrhythmic changes in channel function not detected using conventional heterologous expression systems.