R2R3-NaMYB8 regulates the accumulation of phenylpropanoid-polyamine conjugates, which are essential for local and systemic defense against insect herbivores in Nicotiana attenuata.
Although phenylpropanoid-polyamine conjugates (PPCs) occur ubiquitously in plants, their biological roles remain largely unexplored. The two major PPCs of Nicotiana attenuata plants, caffeoylputrescine (CP) and dicaffeoylspermidine, increase dramatically in local and systemic tissues after herbivore attack and simulations thereof. We identified NaMYB8, a homolog of NtMYBJS1, which in BY-2 cells regulates PPC biosynthesis, and silenced its expression by RNA interference in N. attenuata (ir-MYB8), to understand the ecological role(s) of PPCs. The regulatory role of NaMYB8 in PPC biosynthesis was validated by a microarray analysis, which revealed that transcripts of several key biosynthetic genes in shikimate and polyamine metabolism accumulated in a NaMYB8-dependent manner. Wild-type N. attenuata plants typically contain high levels of PPCs in their reproductive tissues; however, NaMYB8-silenced plants that completely lacked CP and dicaffeoylspermidine showed no changes in reproductive parameters of the plants. In contrast, a defensive role for PPCs was clear; both specialist (Manduca sexta) and generalist (Spodoptera littoralis) caterpillars feeding on systemically preinduced young stem leaves performed significantly better on ir-MYB8 plants lacking PPCs compared with wild-type plants expressing high levels of PPCs. Moreover, the growth of M. sexta caterpillars was significantly reduced when neonates were fed ir-MYB8 leaves sprayed with synthetic CP, corroborating the role of PPCs as direct plant defense. The spatiotemporal accumulation and function of PPCs in N. attenuata are consistent with the predictions of the optimal defense theory: plants preferentially protect their most fitness-enhancing and vulnerable parts, young tissues and reproductive organs, to maximize their fitness.


Diet Soda and Sugar-Sweetened Soda Consumption in Relation to Incident Diabetes in the Northern Manhattan Study.
Artificially (diet) and sugar-sweetened (regular) soda consumption have been associated with an increased risk of diabetes, but the literature on diet soda is inconsistent and the mechanisms unclear. We examined the relation between diet soda and regular soda consumption with the risk of incident diabetes in a longitudinal multiethnic population-based cohort. The study population included 2019 participants (mean ± SD age: 69 ± 10 y; 64% women; 23% white, 22% black, 53% Hispanic) in the Northern Manhattan Study who were free of diabetes and stroke at baseline. Soda consumption was assessed by a food-frequency questionnaire at baseline and examined continuously and categorically (<1/mo: sugar-sweetened = 908, diet = 1615; 1/mo-6/wk: sugar-sweetened = 830, diet = 298; daily: sugar-sweetened = 281, diet = 106). Weibull regression models were used to estimate the associations between soda consumption and incident diabetes, adjusting for demographics and vascular risk factors including body mass index (BMI) and calorie consumption. During a mean ± SD follow-up of 11 ± 5 y, 368 participants developed diabetes. Sugar-sweetened soda was positively associated with incident diabetes (per soda per day HR = 1.15, 95% CI: 1.02, 1.31). The observed association between diet soda and elevated risk of diabetes was largely explained by BMI at the time of diet assessment, though the association remained strong and independent of BMI among those who were overweight or obese (daily compared to <1/mo: HR = 1.63, 95% CI: 1.04, 2.55). This study supports the importance of sugar-sweetened beverage consumption in the diabetes epidemic. However, the results support previous studies suggesting that switching to artificially sweetened diet beverages may not lower the risk of diabetes, as diet soda consumption cannot be ruled out as an independent diabetes risk factor.


Constraints to species' elevational range shifts as climate changes.
Predicting whether the ranges of tropical species will shift to higher elevations in response to climate change requires models that incorporate data on topography and land use. We incorporated temperature gradients and land-cover data from the current ranges of species in a model of range shifts in response to climate change. We tested four possible scenarios of amphibian movement on a tropical mountain: movement upslope through and to land cover suitable for the species; movement upslope to land-cover types that will not sustain survival and reproduction; movement upslope to areas that previously were outside the species' range; and movement upslope to cooler areas within the current range. Areas in the final scenario will become isolated as climate continues to change. In our scenarios more than 30% of the range of 21 of 46 amphibian species in the tropical Sierra Nevada de Santa Marta is likely to become isolated as climate changes. More than 30% of the range of 13 amphibian species would shift to areas that currently are unlikely to sustain survival and reproduction. Combined, over 70% of the current range of seven species would become thermally isolated or shift to areas that currently are unlikely to support survival and reproduction. The constraints on species' movements to higher elevations in response to climate change can increase considerably the number of species threatened by climate change in tropical mountains.


Natural products in modern life science.
With a realistic threat against biodiversity in rain forests and in the sea, a sustainable use of natural products is becoming more and more important. Basic research directed against different organisms in Nature could reveal unexpected insights into fundamental biological mechanisms but also new pharmaceutical or biotechnological possibilities of more immediate use. Many different strategies have been used prospecting the biodiversity of Earth in the search for novel structure-activity relationships, which has resulted in important discoveries in drug development. However, we believe that the development of multidisciplinary incentives will be necessary for a future successful exploration of Nature. With this aim, one way would be a modernization and renewal of a venerable proven interdisciplinary science, Pharmacognosy, which represents an integrated way of studying biological systems. This has been demonstrated based on an explanatory model where the different parts of the model are explained by our ongoing research. Anti-inflammatory natural products have been discovered based on ethnopharmacological observations, marine sponges in cold water have resulted in substances with ecological impact, combinatory strategy of ecology and chemistry has revealed new insights into the biodiversity of fungi, in depth studies of cyclic peptides (cyclotides) has created new possibilities for engineering of bioactive peptides, development of new strategies using phylogeny and chemography has resulted in new possibilities for navigating chemical and biological space, and using bioinformatic tools for understanding of lateral gene transfer could provide potential drug targets. A multidisciplinary subject like Pharmacognosy, one of several scientific disciplines bridging biology and chemistry with medicine, has a strategic position for studies of complex scientific questions based on observations in Nature. Furthermore, natural product research based on intriguing scientific questions in Nature can be of value to increase the attraction for young students in modern life science.


The role of cannabinoids in modulating emotional and non-emotional memory processes in the hippocampus.
Cannabinoid agonists generally have a disruptive effect on memory, learning, and operant behavior that is considered to be hippocampus-dependent. Nevertheless, under certain conditions, cannabinoid receptor activation may facilitate neuronal learning processes. For example, CB(1) receptors are essential for the extinction of conditioned fear associations, indicating an important role for this receptor in neuronal emotional learning and memory. This review examines the diverse effects of cannabinoids on hippocampal memory and plasticity. It shows how the effects of cannabinoid receptor activation may vary depending on the route of administration, the nature of the task (aversive or not), and whether it involves emotional memory formation (e.g., conditioned fear and extinction learning) or non-emotional memory formation (e.g., spatial learning). It also examines the memory stage under investigation (acquisition, consolidation, retrieval, extinction), and the brain areas involved. Differences between the effects of exogenous and endogenous agonists are also discussed. The apparently biphasic effects of cannabinoids on anxiety is noted as this implies that the effects of cannabinoid receptor agonists on hippocampal learning and memory may be attributable to a general modulation of anxiety or stress levels and not to memory per se. The review concludes that cannabinoids have diverse effects on hippocampal memory and plasticity that cannot be categorized simply into an impairing or an enhancing effect. A better understanding of the involvement of cannabinoids in memory processes will help determine whether the benefits of the clinical use of cannabinoids outweigh the risks of possible memory impairments.


Understanding Town Centre Performance in Wales: Using GIS to Develop a Tool for Benchmarking.
Welsh Government policy establishes town centres as central places of community activity and local prosperity, recognising the positive impact towns have on the local economy and the well-being and cohesion felt amongst local communities. In light of this, recent declines in the usage of town centres are a major cause for concern. These have not been experienced uniformly across all towns, with some towns out-performing others. This paper applies principles outlined in Welsh Government's Planning Policy Wales to develop a tool which classifies a sample of 71 towns and cities in Wales based on their centre and catchment characteristics. Catchment areas have been delineated using a Spatial Interaction Model to account for complex consumer behaviours and competition between centres. The tool identifies six distinct types of towns alongside key socio-economic catchment area characteristics. Once developed, we demonstrate our tool's application by exploring variations in town centre performance between and within each town type. Case study examples exemplify how policymakers may use this tool to benchmark between towns, evaluating the suitability of a town's retail offering based on its performance relative to the benchmark, guiding decisions relating to the types of businesses and uses a town should pursue to improve its appeal to its catchment community. In conclusion, several recommendations to policymakers are suggested.


Relations between ameboid movement and membrane-controlled electrical currents.
We have studied the pattern of electrical currents through amebas (mainly Chaos chaos) with an ultrasensitive extracellular vibrating probe. Amebas drive both steady currents and current pulses through themselves. Relatively steady current with an average surface density of 0.1-0.2 muA/cm2 enters the rear quarter of an ameba and leaves its pseudopods. Streaming reversals are preceded by changes in this current pattern and the region with the largest new inward current becomes the new tail. Ion substitution studies suggest that some of the steady inward current is carried by calcium ions. Characteristic stimulated pulses of current sometimes follow the close approach of the vibrating probe to the side of an advancing pseudopod. Such a pulse enters the cytoplasm through a small patch of membrane near the probe (and seems to leave through the adjacent membrane), is usually followed by hyaline cap and then by pseudopod initiation, is calcium dependent, lasts about 5-10 s, and has a peak density of about 0.4 muA/cm2. Spontaneous pulses of similar shape and duration may enter or leave any part of an animal. They are much less localized, tend to have higher peak densities, and occur in physiological salt solutions at about 0.2-4 times per minute. Retraction of a pseudopod is always accompanied or preceded by a spontaneous pulse which leaves its sides.


Carbon nanotube crossed junction by two step dielectrophoresis.
The crossed junction formed between a multi walled carbon nanotube (MWCNT) and a bundle of single walled carbon nanotube (SWCNT) is investigated. The junction is fabricated by orthogonally assembling the MWCNT and SWCNT by a two-step dielectrophoresis process. The conventional dielectrophoresis method to self-assemble carbon nanotubes has been modified to be able to align single MWCNT and SWCNT at predefined location on a substrate. At room temperature, the junction has an ohmic behavior with junction resistance of about 500 KOmega or a conductance of 0.05 (e2/h). At 77 K, the onset of a Schottky-like behavior was observed. The resulting junction has an extremely tiny area of less than 20 nm2 and yet supports a current density of 10(7) A/cm2 at 1 V. The proposed fabrication technique is a convenient way to fabricate novel prototype devices to investigate material properties and new device architecture. Following further optimization, this cross-junction can be an interesting candidate for cross-bar like interconnects, with potential applications in dense logic and memory circuits.


Morphological and molecular characterization of an African freshwater fish trypanosome, including its development in a leech vector.
Trypanosomes are ubiquitous blood parasites of fishes and at least 16 species were originally described infecting African freshwater fishes. This number was later reduced to six and in the late 1990s it was proposed that most records of freshwater fish trypanosomes across Africa are Trypanosoma mukasai Hoare, 1932. Recently, results from a molecular analysis of fish trypanosomes from the Okavango Delta, Botswana, reported the presence of at least two genotypic groups and concluded that the identification of T. mukasai remains problematic. The aims of the present study were thus to elucidate the life cycle of a freshwater fish trypanosome from southern Africa and to do a morphological and molecular characterization of this parasite from both the fish host and leech vector. To locate trypanosome stages, leeches were removed from fishes captured in the Phongolo River, South Africa, and fish blood films and leech squashes were Giemsa-stained and screened. To determine whether trypanosome stages in fishes and leeches were of the same genotype, DNA was extracted and fragments of the 18S rDNA gene were amplified and sequenced. Trypanosomes were detected in the fish families Cichlidae, Clariidae, Mochokidae and Schilbeidae. Sequence data showed that the trypanosome from one of the leeches, identified as Batracobdelloides tricarinata (Blanchard, 1897), was highly similar to those obtained from the plain squeaker, Synodontis zambezensis, with 0.7% difference recorded between them. From morphological and molecular data presented here, it is clear that the trypanosomes from Phongolo are closely related to those of the Okavango and should be considered as a single diverse species with genetic differentiation between 0.4-2.9%, under the 3-5% differences expected to be seen between true distinct species within the rRNA. Developmental stages of the trypanosome found in the leech B. tricarinata supports its status as the vector and the molecular evidence shows the relationship between the trypanosome in the fish and leech, but also illustrates the exceptional genetic and morphological diversity of a single species of trypanosome between host species. The work presented here provides us with clear information to take further steps in resolving the taxonomy and systematics of African freshwater fish trypanosomes.


An essay about health professionals' attitudes to lesbian, gay, bisexual and transgender parents seeking healthcare for their children.
This paper is a polemic essay about an important but sometimes controversial subject. Lesbian, gay, bisexual and transgender (LGBT) clients can be reluctant to reveal their sexual orientation to health professionals from whom they may be seeking health care for their children. Family-centred care (FCC), where care is planned around the whole family not just the individual child, is widely used across the world, but unless all aspects of the families who present for care are respected, care delivery is compromised. This is particularly important for minority groups and potentially vulnerable families such as LGBT. This descriptive essay discusses the use of health services by LGBT parents, how seeking health care is influenced by perceived perceptions of LGBT people held by health professionals, and examines factors affecting such seeking of health care. We show that LGBT people may be unwilling to disclose sexual identity to health professionals when seeking health care for their children. Health professional's attitudes can be affected by factors such as gender, age, religious and political affiliations, education level and previous interactions with LGBT people. We conclude our argument with the assertion that all parents, including those from minority groups such as LGBT, who bring their children for health care need supportive family-centred care, and only by ensuring that the health professionals delivering care are well educated about all aspects of sexuality will care be family-centred.


Improved identification of patients with coronary artery disease by the use of new lipid and lipoprotein biomarkers.
Increasing attention is being directed toward new lipid and lipoprotein biomarkers as risk factors for coronary artery disease, although limited information is available on the diagnostic accuracy of these new biomarkers for the identification of patients with coronary artery disease. In the present study, levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, lipoprotein-associated phospholipase A2 (Lp-PLA2), and oxidized LDL/HDL cholesterol were determined in 431 apparently healthy men and women without clinical evidence of coronary artery disease who were matched for age and gender with 490 men and women with coronary artery disease who participated in the Second Fragmin and Fast Revascularization During Instability in Coronary Artery Disease (FRISC-II) trial. Diagnostic accuracy was determined by receiver-operating characteristic curve analysis by measuring the area under the curve. The diagnostic accuracies of each lipid or lipoprotein biomarker (in descending order of area under the curve) were 0.867 for oxidized LDL/HDL cholesterol (95% confidence interval [CI] 0.844 to 0.890), 0.826 for oxidized LDL (95% CI 0.800 to 0.852), 0.775 for 1/HDL cholesterol (95% CI 0.745 to 0.805), 0.764 for total/HDL cholesterol (95% CI 0.733 to 0.795), 0.631 for triglycerides (95% CI 0.594 to 0.667), 0.597 for Lp-PLA2 (95% CI 0.558 to 0.615), 0.577 for LDL cholesterol (95% CI 0.539 to 0.615), and 0.520 for total cholesterol (95% CI 0.482 to 0.537). In conclusion, these findings indicate that the ratio of oxidized LDL to HDL cholesterol was a more potent biomarker for discriminating between subjects with and without coronary artery disease than traditionally measured lipids and lipoproteins and Lp-PLA2.


Perceived discrimination, socioeconomic disadvantage and refraining from seeking medical treatment in Sweden.
To analyse the association between perceived discrimination and refraining from seeking required medical treatment and the contribution of socioeconomic disadvantage. Data from the Swedish National Survey of Public Health 2004 were used for analysis. Respondents were asked whether they had refrained from seeking required medical treatment during the past 3 months. Perceived discrimination was based on whether respondents reported that they had been treated in a way that made them feel humiliated (due to ethnicity/race, religion, gender, sexual orientation, age or disability). The Socioeconomic Disadvantage Index (SDI) was developed to measure economic deprivation (social welfare beneficiary, being unemployed, financial crisis and lack of cash reserves). Swedish population-based survey of 14,736 men and 17,115 women. Both perceived discrimination and socioeconomic disadvantage were independently associated with refraining from seeking medical treatment. Experiences of frequent discrimination even without any socioeconomic disadvantage were associated with three to nine-fold increased odds for refraining from seeking medical treatment. A combination of both frequent discrimination and severe SDI was associated with a multiplicative effect on refraining from seeking medical treatment, but this effect was statistically more conclusive among women (OR = 11.6, 95% CI 8.1 to 16.6; Synergy Index (SI) = 2.0 (95% CI 1.2 to 3.2)) than among men (OR = 12, 95% CI 7.7 to 18.7; SI = 1.6 (95% CI 1.3 to 2.1)). The goal of equitable access to healthcare services cannot be achieved without public health strategies that confront and tackle discrimination in society and specifically in the healthcare setting.


Practical lessons for bringing policy-makers on board in sexual and reproductive health research.
The need to translate research into policy, i.e. making research findings a driving force in agenda-setting and policy change, is increasingly acknowledged. However, little is known about translation mechanisms in the field of sexual and reproductive health (SRH) outside North American or European contexts. This paper seeks to give an overview of the existing knowledge on this topic as well as to document practical challenges and remedies from the perspectives of researchers involved in four SRH research consortium projects in Latin America, sub-Saharan Africa, China and India. A literature review and relevant project documents were used to develop an interview guide through which researchers could reflect on their experiences in engaging with policy-makers, and particularly on the obstacles met and the strategies deployed by the four project consortia to circumvent them. Our findings confirm current recommendations on an early and steady involvement of policy-makers, however they also suggest that local barriers between researchers and policy-making spheres and individuals can represent major hindrances to the realization of translation objectives. Although many of the challenges might be common to different contexts, creating locally-adapted responses is deemed key to overcome them. Researchers' experiences also indicate that - although inevitable - recognizing and addressing these challenges is a difficult, time- and energy-consuming process for all partners involved. Despite a lack of existing knowledge on translation efforts in SRH research outside North American or European contexts, and more particularly in low and middle-income countries, it is clear that existing pressure on health and policy systems in these settings further complicates them. This article brings together literature findings and researchers' own experiences in translating research results into policy and highlights the major challenges research conducted on sexual and reproductive health outside North American or European contexts can meet. Future SRH projects should be particularly attentive to these potential obstacles in order to tailor appropriate and consistent strategies within their existing resources.


A National Study of Live Hospice Discharges between 2000 and 2012.
Live hospice discharges represent a potential vulnerability in the Medicare hospice benefit. Little is known about how live discharges have varied over time. To identify trends in live hospice discharges between 2000 and 2012. Retrospective cohort study of Medicare hospice discharges. In this study, we examined live discharges in the first six months of 2000, 2006, 2008, 2010, and 2012. A live discharge was classified as a burdensome transition if hospice discharge was followed by hospital admission, and then there was a hospice readmission within 2 days of hospital discharge. The adjusted rate of overall live discharges and burdensome transitions was examined with a multivariate mixed-effects logistic model that adjusted for age, gender, race, and hospice primary diagnosis. The model contained an interaction term for year and hospice tax status. The unadjusted overall rate of live discharges increased from 13.7% in 2000 to 18.1% in 2012. For-profit hospice programs had an adjusted live discharge rate of 17.7% in 2000 and 22.7% in 2012. During the same period, the adjusted live discharge rate for nonprofit hospice programs increased from 15.2% to 16.3%. The overall rate of burdensome transitions increased from 2.9% in 2000 to 5.3% in 2012. Similar to the overall rate of live discharge, for-profit hospices had a higher rate of burdensome transitions (6.4%) than nonprofit hospices (4.0%) in 2012. Live hospice discharges and burdensome transitions increased between 2000 and 2012. For-profit hospice programs demonstrated larger increases than nonprofit hospice programs.


Current-induced hydrogen tautomerization and conductance switching of naphthalocyanine molecules.
The bistability in the position of the two hydrogen atoms in the inner cavity of single free-base naphthalocyanine molecules constitutes a two-level system that was manipulated and probed by low-temperature scanning tunneling microscopy. When adsorbed on an ultrathin insulating film, the molecules can be switched in a controlled fashion between the two states by excitation induced by the inelastic tunneling current. The tautomerization reaction can be probed by resonant tunneling through the molecule and is expressed as considerable changes in the conductivity of the molecule. We also demonstrated a coupling of the switching process so that the charge injection in one molecule induced tautomerization in an adjacent molecule.


Boswellia serrata: an overall assessment of in vitro, preclinical, pharmacokinetic and clinical data.
Non-steroidal anti-inflammatory drug (NSAID) intake is associated with high prevalence of gastrointestinal or cardiovascular adverse effects. All efforts to develop NSAIDs that spare the gastrointestinal tract and the cardiovasculature are still far from achieving a breakthrough. In the last two decades, preparations of the gum resin of Boswellia serrata (a traditional ayurvedic medicine) and of other Boswellia species have experienced increasing popularity in Western countries. Animal studies and pilot clinical trials support the potential of B. serrata gum resin extract (BSE) for the treatment of a variety of inflammatory diseases like inflammatory bowel disease, rheumatoid arthritis, osteoarthritis and asthma. Moreover, in 2002 the European Medicines Agency classified BSE as an 'orphan drug' for the treatment of peritumoral brain oedema. Compared to NSAIDs, it is expected that the administration of BSE is associated with better tolerability, which needs to be confirmed in further clinical trials. Until recently, the pharmacological effects of BSE were mainly attributed to suppression of leukotriene formation via inhibition of 5-lipoxygenase (5-LO) by two boswellic acids, 11-keto-β-boswellic acid (KBA) and acetyl-11-keto-β-boswellic acid (AKBA). These two boswellic acids have also been chosen in the monograph of Indian frankincense in European Pharmacopoiea 6.0 as markers to ensure the quality of the air-dried gum resin exudate of B. serrata. Furthermore, several dietary supplements advertise the enriched content of KBA and AKBA. However, boswellic acids failed to inhibit leukotriene formation in human whole blood, and pharmacokinetic data revealed very low concentrations of AKBA and KBA in plasma, being far below the effective concentrations for bioactivity in vitro. Moreover, permeability studies suggest poor absorption of AKBA following oral administration. In view of these results, the previously assumed mode of action - that is, 5-LO inhibition - is questionable. On the other hand, 100-fold higher plasma concentrations have been determined for β-boswellic acid, which inhibits microsomal prostaglandin E synthase-1 and the serine protease cathepsin G. Thus, these two enzymes might be reasonable molecular targets related to the anti-inflammatory properties of BSE. In view of the results of clinical trials and the experimental data from in vitro studies of BSE, and the available pharmacokinetic and metabolic data on boswellic acids, this review presents different perspectives and gives a differentiated insight into the possible mechanisms of action of BSE in humans. It underlines BSE as a promising alternative to NSAIDs, which warrants investigation in further pharmacological studies and clinical trials.


Schizophrenia spectrum and other psychotic disorders.
The DSM-5 list of diagnoses concerning schizophrenia spectrum and other psychotic disorders is expected to be revised and graduated from mild to severe. The proposed changes for the diagnosis of schizophrenia affect demands for characteristic symptoms, clarify relation to pervasive developmental disorders, and eliminate the classic subtypes of schizophrenia. A dimensional assessment will be measured on a 0-4 point scale. It is recommended that the concept of attenuated psychosis syndrome is further investigated. The propositions affecting characteristic symptoms of schizophrenia might increase diagnostic reliability and validity, but it is estimated to exclude about 2 % of patients currently diagnosed with DSM-IV schizophrenia from fulfilling criteria for DSM-5 schizophrenia. It might generate a problem for future young patients if the changes concerning demands on characteristic symptoms turn out to be more restrictive, leaving out a percentage of patients with psychotic symptoms from a diagnosis of schizophrenia; which in practice opens possibilities for intensive treatment options. On the other hand, not including attenuated psychosis syndrome at the present might protect patients from stigmatization and pharmacological treatment on poor indication. The introduction of dimensional assessments may make schizophrenia subtyping redundant and has the potential to enrich clinical practice and bridge communication between child and adolescent and adult psychiatry. The most recent guidelines for assessment and treatment of children and adolescents with schizophrenia are from 2001. They provide differentiated recommendations regarding diagnostics, assessment of symptoms and functioning and treatment strategies. There is an urgent need for updated guidelines in this field, especially concerning specific treatment guidelines.


Prevalence of mood and anxiety disorder in self reported irritable bowel syndrome (IBS). An epidemiological population based study of women.
Irritable bowel syndrome (IBS) is commonly regarded as a functional disorder, and is hypothesized to be associated with anxiety and depression. This evidence mainly rests on population-based studies utilising self-report screening instruments for psychopathology. Other studies applying structured clinical interviews are generally based on small clinical samples, which are vulnerable to biases. The extant evidence base for an association between IBS and psychopathology is hence not conclusive. The aim of this study was therefore to re-examine the hypothesis using population-based data and psychiatric morbidity established with a structured clinical interview. Data were derived from a population-based epidemiological study (n = 1077). Anxiety and mood disorders were established using the Structured Clinical Interview for DSM-IV-TR (SCID-I/NP) and the General Health Questionnaire (GHQ-12). Current and lifetime IBS was self-reported. Hypertension and diabetes were employed as comparison groups as they are expected to be unrelated to mental health. Current IBS (n = 69, 6.4%) was associated with an increased likelihood of current mood and/or anxiety disorders (OR = 2.62, 95%CI 1.49 - 4.60). Half the population reporting a lifetime IBS diagnosis also had a lifetime mood or anxiety disorder. Exploratory analyses demonstrated an increased prevalence of IBS across most common anxiety and mood disorders, the exception being bipolar disorder. The association with IBS and symptoms load (GHQ-12) followed a curved dose response pattern. In contrast, hypertension and diabetes were consistently unrelated to psychiatric morbidity. IBS is significantly associated with anxiety and mood disorders. This study provides indicative evidence for IBS as a disorder with a psychosomatic aspect.


Discordant changes in epicardial and microvascular coronary physiology after cardiac transplantation: Physiologic Investigation for Transplant Arteriopathy II (PITA II) study.
Investigating changes in coronary physiology that occur after cardiac transplantation has been challenging. Simultaneous and independent assessment of the epicardial artery by measuring fractional flow reserve (FFR) and of the microvasculature by calculating the index of microvascular resistance (IMR) with a single coronary pressure wire may be useful. Twenty-five asymptomatic patients with normal coronary angiograms underwent FFR, thermodilution-derived IMR and coronary flow reserve (CFR) and intravascular ultrasound (IVUS) evaluation soon after cardiac transplantation and 1 year later. FFR significantly worsened (0.90 +/- 0.05 at baseline to 0.85 +/- 0.06 at 1 year, p = 0.004). FFR correlated strongly with percent plaque volume as measured by IVUS (r = -0.58, p < 0.0001). IMR improved significantly (29.2 +/- 15.9 at baseline to 19.3 +/- 7.6 units at 1 year, p = 0.007). CFR increased, but not significantly (2.6 +/- 1.4 at baseline to 3.2 +/- 1.2 at 1 year, p = not significant). Diabetes and donor heart ischemic time independently predicted baseline IMR. Treatment with rapamycin independently predicted FFR at 1 year. New coronary physiologic measures, FFR and IMR, show that epicardial artery physiology worsens and correlates with anatomic changes, whereas microvascular physiology improves during the first year after cardiac transplantation. CFR, the traditional method for evaluating coronary circulatory physiology, did not identify these changes.


Controlling hypertension immediately post stroke: a cost utility analysis of a pilot randomised controlled trial.
Elevated blood pressure (BP) levels are common following acute stroke. However, there is considerable uncertainty if and when antihypertensive therapy should be initiated. Economic evaluation alongside a double-blind randomised placebo-controlled trial (National Research Register Trial Number N0484128008) of 112 hypertensive patients receiving an antihypertensive regimen (labetalol or lisinopril) within 36 hours post stroke versus 59 receiving placebo. Outcomes were incremental cost per incremental: QALY, survivor, and patient free from death or severe disability (modified Rankin scale score < 4) at three months and 14 days post stroke. Actively treated patients on average had superior outcomes and lower costs than controls at three months. From the perspective of the acute hospital setting, there was a 96.5% probability that the incremental cost per QALY gained at three months is below pound30,000, although the probability may be overstated due to data limitations. Antihypertensive therapy when indicated immediately post stroke may be cost-effective compared with placebo from the acute hospital perspective. Further research is required to confirm both efficacy and cost-effectiveness and establish whether benefits are maintained over a longer time horizon.


Baroreceptor reflexes in human hypertension.
We studied the control of arterial pressure by the carotid sinus baroreceptors in 35 hypertensive humans, using a variable pressure neck chamber to alter carotid sinus transmural pressure in a graded fashion. The results were compared with those obtained from 11 normotensives. As in normotensives, reduction in carotid transmural pressure caused a linearly related pressor response and vice versa. However, whereas in normotensives the pressure response was greater than the depressor, the reverse was the case in hypertensives. Furthermore, the pressor response decreased and the depressor response increased progressively with an increase in severity of the hypertension. Thus while in normotensives the carotid baroreflex is more effective in protecting against hypotension, in hypertensives the antihypertensive function of the reflex is favored. Similar differences between hypertensives and normotensives were found with respect to the carotid baroreceptor control of heart rate. In eight hypertensives, reflex changes in heart rate also were studied by injection of phenylephrine and trinitroglycerine to vary not only carotid baroreceptor activity, but also activity of extracarotid baroreceptors. The results were compared with results of similar studies on eight normotensives. These comparisons suggest that, whereas the carotid baroreceptor reflex remains active in hypertension, reflexes stemming from extracarotid baroreceptor areas are much diminished.


Quantum simulation of frustrated classical magnetism in triangular optical lattices.
Magnetism plays a key role in modern technology and stimulates research in several branches of condensed matter physics. Although the theory of classical magnetism is well developed, the demonstration of a widely tunable experimental system has remained an elusive goal. Here, we present the realization of a large-scale simulator for classical magnetism on a triangular lattice by exploiting the particular properties of a quantum system. We use the motional degrees of freedom of atoms trapped in an optical lattice to simulate a large variety of magnetic phases: ferromagnetic, antiferromagnetic, and even frustrated spin configurations. A rich phase diagram is revealed with different types of phase transitions. Our results provide a route to study highly debated phases like spin-liquids as well as the dynamics of quantum phase transitions.


A resting-state fMRI study of obese females between pre- and postprandial states before and after bariatric surgery.
Past studies utilizing resting-state functional MRI (rsfMRI), have shown that obese humans exhibit altered activity in brain areas related to reward compared to normal-weight controls. However, to what extent bariatric surgery-induced weight loss alters resting-state brain activity in obese humans is less well-studied. Thus, we measured the fractional amplitude of low-frequency fluctuations from eyes-closed, rsfMRI in obese females (n = 11, mean age = 42 years, mean BMI = 41 kg/m2 ) in both a pre- and postprandial state at two time points: four weeks before, and four weeks after bariatric surgery. Several brain areas showed altered resting-state activity following bariatric surgery, including the putamen, insula, cingulate, thalamus and frontal regions. Activity augmented by surgery was also dependent on prandial state. For example, in the fasted state, activity in the middle frontal and pre- and postcentral gyri was found to be decreased after surgery. In the sated state, activity within the insula was increased before, but not after surgery. Collectively, our results suggest that resting-state neural functions are rapidly affected following bariatric surgery and the associated weight loss and change in diet.


The use of embryonic stem cells for regulatory developmental toxicity testing in vitro--the current status of test development.
The future chemical policy of the European Union as well as the 7th amendment of the cosmetic directive is calling for the development of alternative tests to animal experimentation for toxicological safety testing. In the field of embryotoxicity one of the most promising in vitro models are based on embryonic stem cells. The embryonic stem cell test has already been validated in comparison to in vivo results in an international blind collaboration study. The presented review is discussing the use, limitations and further needs for the test in order to be fully suitable for regulatory acceptance. In this context, it is summarized which requirements for an in vitro embryotoxicity test have to be fulfilled for regulatory toxicity testing. In addition, an overview about the current status of test development of other embryonic stem cell tests is presented. Several workshops have reviewed the progress of in vitro tests for developmental toxicity testing. A general consensus of these workshops has been that one single test will not be sufficient to cover all manifestations of developmental toxicity. The establishment of a test battery for developmental toxicity is required. This will be even more challenging since the principles of a composing test strategy and its validation have not been defined yet. Finally, the unique possibility of combining the human embryonic stem cell technology and the microarray techniques might lead to a deeper understanding of the toxicological mechanisms of human developmental toxicants.


miRNA studies in in vitro and in vivo activated hepatic stellate cells.
To understand which and how different miRNAs are implicated in the process of hepatic stellate cell (HSC) activation. We used microarrays to examine the differential expression of miRNAs during in vitro activation of primary HSCs (pHSCs). The transcriptome changes upon stable transfection of rno-miR-146a into an HSC cell line were studied using cDNA microarrays. Selected differentially regulated miRNAs were investigated by quantitative real-time polymerase chain reaction during in vivo HSC activation. The effect of miRNA mimics and inhibitor on the in vitro activation of pHSCs was also evaluated. We found that 16 miRNAs were upregulated and 26 were downregulated significantly in 10-d in vitro activated pHSCs in comparison to quiescent pHSCs. Overexpression of rno-miR-146a was characterized by marked upregulation of tissue inhibitor of metalloproteinase-3, which is implicated in the regulation of tumor necrosis factor-α activity. Differences in the regulation of selected miRNAs were observed comparing in vitro and in vivo HSC activation. Treatment with miR-26a and 29a mimics, and miR-214 inhibitor during in vitro activation of pHSCs induced significant downregulation of collagen type I transcription. Our results emphasize the different regulation of miRNAs in in vitro and in vivo activated pHSCs. We also showed that miR-26a, 29a and 214 are involved in the regulation of collagen type I mRNA.


Nitrite complexes of the rare earth elements.
The coordination chemistry of the nitrite anion has been investigated with rare earth elements, and the resulting complexes were structurally characterized. Among them, the first homoleptic examples of nitrite complexes of samarium, ytterbium and yttrium are described. The coordination behavior of the nitrite ion is directly controlled by the ionic radius of the metal cation. While the nitrito ligand is stable in the coordination sphere of cerium(iii), it is readily reduced by SmI2.


A manganese superoxide dismutase (MnSOD) from red lip mullet, Liza haematocheila: Evaluation of molecular structure, immune response, and antioxidant function.
Manganese superoxide dismutase (MnSOD) is a nuclear-encoded antioxidant metalloenzyme. The main function of this enzyme is to dismutase the toxic superoxide anion (O2-) into less toxic hydrogen peroxide (H2O2) and oxygen (O2). Structural analysis of mullet MnSOD (MuMnSOD) was performed using different bioinformatics tools. Pairwise alignment revealed that the protein sequence matched to that derived from Larimichthys crocea with a 95.2% sequence identity. Phylogenetic tree analysis showed that the MuMnSOD was included in the category of teleosts. Multiple sequence alignment showed that a SOD Fe-N domain, SOD Fe-C domain, and Mn/Fe SOD signature were highly conserved among the other examined MnSOD orthologs. Quantitative real-time PCR showed that the highest MuMnSOD mRNA expression level was in blood cells. The highest expression level of MuMnSOD was observed in response to treatment with both Lactococcus garvieae and lipopolysaccharide (LPS) at 6 h post treatment in the head kidney and blood. Potential ROS-scavenging ability of the purified recombinant protein (rMuMnSOD) was examined by the xanthine oxidase assay (XOD assay). The optimum temperature and pH for XOD activity were found to be 25 °C and pH 7, respectively. Relative XOD activity was significantly increased with the dose of rMuMnSOD, revealing its dose dependency. Activity of rMuMnSOD was inhibited by potassium cyanide (KCN) and N-N'-diethyl-dithiocarbamate (DDC). Moreover, expression of MuMnSOD resulted in considerable growth retardation of both gram-positive and gram-negative bacteria. Results of the current study suggest that MuMnSOD acts as an antioxidant enzyme and participates in the immune response in mullet.


Growth response of acute myeloblastic leukemia cells to recombinant human thrombopoietin.
Thrombopoietin (TPO) is a newly identified hematopoietic growth factor that stimulates both megakaryopoiesis and thrombopoiesis through its interaction with a specific cell surface receptor encoded by the c-mpl proto-oncogene. In an effort to investigate the effect of TPO on human myeloid leukemia cells, the expression of c-mpl and the proliferative response to recombinant human (rh) TPO were investigated in a series of patients with acute myeloblastic leukemia (AML). Of 50 cases of AML, the c-mpl mRNA was detectable by means of Northern blot analysis in 26 cases, and the in vitro treatment with rhTPO led to proliferation of AML cells in 22 cases. The c-mpl expression and proliferative response to rhTPO was observed in all subtypes of AML and did not correlate with French-American-British classification, whereas all cases of M7-type AML cells expressed c-mpl and proliferated in response to rhTPO. Furthermore, rhTPO-induced proliferation of AML cells was augmented with the addition of interleukin-3 (IL-3), IL-6, stem cell factor, or granulocyte-macrophage colony-stimulating factor. These results suggested that c-mpl may be functional in terms of supporting proliferation of various types of AML cells and that TPO may contribute, at least in part, to abnormal growth of the cells, especially in combination with other hematopoietic growth factors.


Gamma interferon is the lymphokine and beta interferon the monokine responsible for inhibition of fibroblast collagen production and late but not early fibroblast proliferation.
Human peripheral blood mononuclear cells activated with concanavalin A (Con A) or lipopolysaccharide (LPS) produce, respectively, lymphokines (LK) of 50,000 Mr or monokines (MK) of 20,000 Mr that inhibit the growth and collagen production of cultured human dermal fibroblasts. Because antigenic typing of the antiviral activity of these LK and MK preparations revealed that LK contained mainly gamma interferon (IFN-gamma), and MK, primarily IFN-beta, we investigated if any of the fibroblast-inhibiting activities could be attributed to human IFN. Unlike LK and MK, which act within 24 h to inhibit the growth of subconfluent foreskin and adult dermal fibroblasts, samples of purified, natural derived IFN-alpha, -beta, and -gamma and recombinant DNA-derived IFN-alpha 2 and -gamma were ineffective inhibitors at 24 h and required 48-72 h to significantly inhibit growth. However, all IFN did mimic LK/MK action in causing concentration-dependent inhibition of collagen production by confluent fibroblast microcultures. Furthermore, the collagen production-inhibiting activity of Con A-induced LK supernatant and its 50,000 Mr fraction was completely suppressed by 10(3) neutralizing U/ml of either polyclonal or monoclonal antibody to IFN-gamma, while polyclonal antibodies to IFN-alpha and -beta had no effect. Similarly, the collagen production-inhibiting activity of LPS-induced MK supernatant and its 20,000 Mr fraction was suppressed by polyclonal anti-IFN-beta but not by anti-IFN-alpha or -gamma. Anti-IFN failed to reverse early-acting LK or MK growth-inhibiting activities. These data suggest collagen production-inhibiting LK and MK are IFN-gamma and IFN-beta, respectively, and that early acting, growth-inhibiting LK and MK are not IFN.


Oral tolerance and pyruvate dehydrogenase in patients with primary biliary cirrhosis.
Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized by the immunological destruction of intralobular bile ducts and serum anti-mitochondrial antibodies (AMA). Based upon previous work of oral tolerance and autoimmunity, we hypothesized that feeding the mitochondrial autoantigens of PBC would alter the clinical course and the level of antimitochondrial antibodies. The bovine pyruvate dehydrogenase complex (PDC) was purified and 5 mg fed in gelatin capsules to 6 patients with early stage PBC for 6 months. Antimitochondrial antibodies and liver biochemistries were measured at every 3 months for 12 months. The clinical trial was completed for all patients except for 1 who showed deterioration of pre-existing skin rash during treatment, which disappeared within 2 weeks after treatment was discontinued. However, after 1 year, neither the titers of AMAs nor liver biochemistries were significantly changed by this treatment. This is the first trial to test the efficacy of oral tolerance induction in PBC. However, the data, which limited in scope, did not demonstrate efficacy and further highlights the difficulties in showing continuing evidence of tolerance induction in autoimmunity.


Serum estrogenicity and biological responses in African catfish raised in wastewater ponds in Ghana.
Reuse of wastewater for aquaculture improves the efficient use of water and promotes sustainability but the potential effects of endocrine disrupting compounds including estrogens in wastewater are an emerging challenge that needs to be addressed. We examined the biological effects of wastewater-borne estrogens on African catfish (Clarias gariepinus) raised in a wastewater stabilization pond (WSP) of a functioning municipal wastewater treatment plant, a wastewater polishing pond (WWP) of a dysfunctional treatment plant, and a reference pond (RP) unimpacted by wastewater, located in Ghana. Measurements of estrogen concentrations in pond water by liquid chromatography/tandem mass spectrometry showed that mean 17 β-estradiol concentrations were higher in the wastewater ponds (WWP, 6.6 ng/L±2.7 ng/L; WSP, 4.9 ng/L±1.0) than the reference (RP, 3.4±1.1 ng/L). Estrone concentrations were found to be highest in the WSP (7.8 ng/L±1.7) and lowest in the WWP (2.2 ng/L±2.4) with the RP intermediate (4.7±5.0). Fish serum estrogenicity assayed by E-SCREEN was significantly higher in female vs. male catfish in the RP and WSP but not in the WWP (p≤0.05). Histological examination of liver and gonad tissue showed no apparent signs of intersex or pathology in any ponds. The similarities in various measures of body indices between fish of this study and African catfish from freshwater systems suggest that aquaculture may be a suitable reuse option for treated municipal wastewater.


Attempted suicide in Oxford University students, 1976-1990.
During the 14 years between the beginning of academic year 1976-7 and the end of academic year 1989-90, 216 Oxford University students (119 females and 97 males) were referred to the general hospital in Oxford because of suicide attempts (254 in all). The rate of attempted suicide during university term-time (106/100,000) was lower than in other young people of similar age in Oxford City (164/100,000). The difference was particularly marked in females (178/100,000 v. 269/100,000). The lower rate in the students may in part reflect their generally higher socio-economic status. Very few of the attempts by the students appeared to be failed suicides. The most frequent problems faced by the students at the time of their attempts were interpersonal, especially difficulties regarding partners, followed by academic problems. The latter were usually problems with ongoing course work rather than with the Finals examinations. Approximately a quarter of the students had psychiatric problems, with personality disorders and depression being most common. At least 30% had a history of previous attempts. Suggestions are made concerning measures for improving the management and prevention of attempted suicide by students.


Bioplastique injection laryngoplasty: voice performance outcome.
To compare voice performance following Bioplastique injection with that following Isshiki thyroplasty. A 12 item, self-reported voice performance questionnaire was completed and observer-rated perceptual voice analysis scores were also measured, before and after Bioplastique injection, for 14 patients. Results were compared with our previously reported outcomes for 28 thyroplasty patients. Only 14 of 30 patients had complete datasets. For these patients, the mean pre-operative voice performance questionnaire score improved significantly, from 40.3 to 18.9 (p=0.002, Wilcoxon test). All perceptual analysis parameters showed significant improvement. These results compare favourably with the thyroplasty cohort (mean voice performance questionnaire score: pre-operative 35; post-operative 18; p<0.001). One Bioplastique patient developed contralateral paresis, requiring partial removal of the material 18 months later. Two thyroplasty patients experienced complications and three required revision. Both Bioplastique injection and Isshiki thyroplasty resulted in a significant improvement in both subjective and perceptual voice performance. Our data suggest that the effect size of the two interventions is approximately similar (in nonrandomised cohorts of surviving patients). As in many similar studies, the incomplete follow-up data reflect severe comorbidity. Bioplastique injection is a quicker procedure associated with fewer complications, and thus appears superior to framework surgery in patients with limited life expectancy.


The stochastic demography of two coexisting male morphs.
Abstract. If genetically distinct morphs coexist under a range of natural conditions, they should have equal long-run fitnesses across a wide range of different stochastic environments. In other words, the sequence and frequency of good and bad environments should not substantially impact long-run growth rates. When different morphs have contrasting life histories that vary with environmental conditions, however, it seems improbable that growth rates can be equivalent across a range of stochastic environments without invoking a strong stabilizing mechanism to explain their persistence. As yet, there has been no research characterizing the long-run stochastic growth rate (lambdaS) of different morphs across a wide range of stochastic environments. Assuming density independence, we show that the two genetic male morphs in the bulb mite (Rhizoglyphus robini-fighters, which are able to kill other mites, and benign scramblers-have similar lambdas in different Markovian environments (different simulated random sequences of good and bad habitats). Elasticity analyses revealed that Xs was most sensitive to perturbation of adult survival rate. A slight (biologically and statistically realistic) increase in scrambler adult survival equalized scrambler and fighter X,. The fitness equivalence of the two morphs suggests that stabilizing mechanisms, such as density or frequency dependence, required to maintain their coexistence, are weak. We advocate that stochastic demography can offer a powerful approach to identify and understand the circumstances under which genetic polymorphisms can be maintained in stochastic environments.


The active site of O-GlcNAc transferase imposes constraints on substrate sequence.
O-GlcNAc transferase (OGT) glycosylates a diverse range of intracellular proteins with O-linked N-acetylglucosamine (O-GlcNAc), an essential and dynamic post-translational modification in metazoans. Although this enzyme modifies hundreds of proteins with O-GlcNAc, it is not understood how OGT achieves substrate specificity. In this study, we describe the application of a high-throughput OGT assay to a library of peptides. We mapped sites of O-GlcNAc modification by electron transfer dissociation MS and found that they correlate with previously detected O-GlcNAc sites. Crystal structures of four acceptor peptides in complex with Homo sapiens OGT suggest that a combination of size and conformational restriction defines sequence specificity in the -3 to +2 subsites. This work reveals that although the N-terminal TPR repeats of OGT may have roles in substrate recognition, the sequence restriction imposed by the peptide-binding site makes a substantial contribution to O-GlcNAc site specificity.


Sperm deliver a new second messenger: NAADP.
NAADP is a highly potent mobilizer of Ca(2+), which in turn triggers Ca(2+)-induced Ca(2+) release pathways in a wide range of species. Nevertheless, NAADP is not presently classified as a second messenger because it has not been shown to increase in response to a physiological stimulus. We now report a dramatic increase in NAADP during sea urchin egg fertilization that was largely due to production in sperm upon contacting egg jelly. The NAADP bolus plays a physiological role upon delivery to the egg based on its ability to induce a cortical flash, a depolarization-induced activation of L-type Ca(2+) channels. Moreover, the sperm-induced cortical flash was eliminated in eggs desensitized to NAADP. We conclude that an NAADP increase plays a physiologically relevant role during fertilization and provides the first conclusive demonstration that NAADP is a genuine second messenger.


Association analysis of CFH, C2, BF, and HTRA1 gene polymorphisms in Chinese patients with polypoidal choroidal vasculopathy.
Polypoidal choroidal vasculopathy (PCV) is a major cause of serosanguinous maculopathy in Chinese patients with age-related macular degeneration (AMD). Variants in the CFH and HTRA1/LOC387715 genes are strongly associated with AMD in Caucasians and Chinese. Variants in the C2 and BF genes have been found to confer a significantly reduced risk of AMD. This study was undertaken to determine whether these associations occur in Chinese patients with PCV. Patients of Chinese ethnicity with clinically and angiographically diagnosed PCV and normal control subjects were recruited from the Singapore National Eye Centre. Five single-nucleotide polymorphisms (SNPs) in the CFH gene, two each within the C2 and BF genes and two variants located in the LOC387715 and HTRA1 genes, were screened in all patients and control subjects. Seventy-two patients with PCV and 93 normal control subjects were studied. A significant association was noted with CFH variants rs3753394 and rs800292 among the PCV cases (P = 0.0015 and P = 0.0045, respectively). Individuals homozygous for the TT genotype of rs3753394 had a significantly higher risk (P = 0.0076) of PCV (OR = 4.29; 95% CI: 1.47-12.50) than those carrying a single copy of the T allele (P = 0.3210; OR = 1.69; 95% CI: 0.60-4.78), after adjustment for such risk factors as age and sex. The genotype frequencies of rs11200638 and rs10490924 in HTRA1 and LOC387715, respectively, were also found to be significantly different between patients with PCV and normal control subjects (P = 0.00032 and P = 0.003, respectively). The AA genotype of rs11200638 and TT genotype of rs10490924 conferred a 4.9-fold (95% CI: 1.85-12.95) and 4.89-fold (95% CI: 1.85-12.90) increased risk of PCV, respectively, after adjustment for age and sex. The Y402H variant of CFH (rs1061170) and the BF and C2 variants were not significantly different in patients and normal control subjects. The SNPs rs3753394 and rs800292 of CFH and rs11200638 of HTRA1 are significantly associated with the risk of PCV in Chinese patients.


Is there any association between Toxoplasma gondii infection and depression? A systematic review and meta-analysis.
Toxoplasma gondii (T. gondii) is an obligate intracellular opportunistic parasite that is the causative agent of toxoplasmosis. This parasite accounts for mental disorders; however, the relationship between T. gondii infection and depressive disorder is unclear. Regarding this, the present systematic review and meta-analysis was conducted to investigate the scientific evidence regarding the potential association between major depression disorder (MDD) and Toxoplasma infection. For the purpose of the study, the articles related to the subject of interest were systematically searched in seven electronic databases. Special attention was given to the studies examining T. gondii seropositivity level in depressed patients and controls. The search process resulted in the identification of a total of 30 publications meeting the inclusion criteria and published up to April 2018 for the systematic review. Furthermore, 29 studies met the inclusion criteria to be entered into meta-analysis. Our meta-analysis involved the review of cross-sectional studies including 1657 depressed patients and 19565 individuals as controls and case-control studies entailing 1311 depressed cases and 6015 controls without depression. 1582 depressed people participated in cross-sectional studies whose results were reported as odds ratio (OR). In addition, the total number of participants was 15068 in this type of studies. Statistical analysis indicated that the pooled OR of the risk of anti-T. gondii IgG antibody in depressed individuals in case-control and cross-sectional studies was 1.15 (95% confidence interval (CI): 0.95-1.39). As the findings of the reviewed articles indicated, toxoplasmosis is not a risk factor for MDD. However, it is necessary to perform further research to clarify the detailed association between T. gondii and dysthymia or mild and moderate depression. Furthermore, it is recommended to better investigate the effect of antibody titers on the relationship between depression and T. gondii infection.


Mixed micelles of fluorocarbon and hydrocarbon surfactants. A small angle neutron scattering study.
Mixtures of the partly fluorinated cationic surfactant HFDePC (N-(1, 1,2,2-tetrahydroperfluorodecanyl)-pyridinium chloride and deuterated headgroup) with C16TAC, hexadecyl-trimethylammonium chloride, have been investigated using small angle neutron scattering with contrast matching. Earlier results from this system suggested that a demixing occurred, into two coexisting populations of micelles, hydrocarbon-rich and fluorocarbon-rich, respectively. The present results could be explained by one type of mixed micelles with an inhomogeneous distribution of fluorinated and hydrogenated surfactants within the micelles although a demixing cannot be definitely excluded.


Terminal solvent effects on the anisotropy barriers of Dy2 systems.
A family of three dinuclear dysprosium complexes have been successfully synthesized and studied in terms of their magnetic properties. Complexes 1 and 2 share the formula [Dy2(ovph)2Cl2(solvent)2], where H2ovph = pyridine-2-carboxylic acid [(2-hydroxy-3-methoxyphenyl)methylene] hydrazide, and solvent = DMF (1), i-PrOH (2), while complex 3, [Dy2(ovph)2Cl2(H2O)3(EtOH)], exhibits differences in terms of the identity and number of coordinated solvent molecules. Thus, we investigate the impact of terminally bonded solvent molecules on the slow relaxation dynamics of {Dy2} SMMs, a parameter which can sometimes be overlooked in the quest to attain higher energy barriers. Notably, the exchange of DMF for i-PrOH, both of which coordinate through a single oxygen atom, results in a near 2-fold increase in Ueff, from 58 to 98 K, for 1 and 2, respectively.


The topology of fullerenes.
Fullerenes are carbon molecules that form polyhedral cages. Their bond structures are exactly the planar cubic graphs that have only pentagon and hexagon faces. Strikingly, a number of chemical properties of a fullerene can be derived from its graph structure. A rich mathematics of cubic planar graphs and fullerene graphs has grown since they were studied by Goldberg, Coxeter, and others in the early 20th century, and many mathematical properties of fullerenes have found simple and beautiful solutions. Yet many interesting chemical and mathematical problems in the field remain open. In this paper, we present a general overview of recent topological and graph theoretical developments in fullerene research over the past two decades, describing both solved and open problems. WIREs Comput Mol Sci 2015, 5:96-145. doi: 10.1002/wcms.1207 Conflict of interest: The authors have declared no conflicts of interest for this article. For further resources related to this article, please visit the WIREs website.


The temporal patterns of disease severity and prevalence in schistosomiasis.
Schistosomiasis is one of the most widespread public health problems in the world. In this work, we introduce an eco-epidemiological model for its transmission and dynamics with the purpose of explaining both intra- and inter-annual fluctuations of disease severity and prevalence. The model takes the form of a system of nonlinear differential equations that incorporate biological complexity associated with schistosome's life cycle, including a prepatent period in snails (i.e., the time between initial infection and onset of infectiousness). Nonlinear analysis is used to explore the parametric conditions that produce different temporal patterns (stationary, endemic, periodic, and chaotic). For the time-invariant model, we identify a transcritical and a Hopf bifurcation in the space of the human and snail infection parameters. The first corresponds to the occurrence of an endemic equilibrium, while the latter marks the transition to interannual periodic oscillations. We then investigate a more realistic time-varying model in which fertility of the intermediate host population is assumed to seasonally vary. We show that seasonality can give rise to a cascade of period-doubling bifurcations leading to chaos for larger, though realistic, values of the amplitude of the seasonal variation of fertility.


In vitro antimicrobial susceptibility testing methods: agar dilution to 3D tissue-engineered models.
In the field of orthopaedic surgery, bacterial invasion of implants and the resulting periprosthetic infections are a common and unresolved problem. Antimicrobial susceptibility testing methods help to define the optimal treatment and identify antimicrobial resistance. This review discusses proven gold-standard techniques and recently developed models for antimicrobial susceptibility testing, while also providing a future outlook. Conventional, gold-standard methods, such as broth microdilution, are still widely applied in clinical settings. Although recently developed methods based on microfluidics and microdroplets have shown advantages over conventional methods in terms of testing speed, safety and the potential to provide a deeper insight into resistance mechanisms, extensive validation is required to translate this research to clinical practice. Recent optical and mechanical methods are complex and expensive and, therefore, not immediately clinically applicable. Novel osteoblast infection and tissue models best resemble infections in vivo. However, the integration of biomaterials into these models remains challenging and they require a long tissue culture, making their rapid clinical implementation unlikely. A method applicable for both clinical and research environments is difficult to realise. With a continuous increase in antimicrobial resistance, there is an urgent need for methods that analyse recurrent infections to identify the optimal treatment approaches. Graphical abstract Timeline of published and partly applied antimicrobial susceptibility testing methods, listed according to their underlying mechanism, complexity and application in research or clinics.


Hot-wire anemometry for superfluid turbulent coflows.
We report the first evidence of an enhancement of the heat transfer from a heated wire to an external turbulent coflow of superfluid helium. We used a standard Pt-Rh hot-wire anemometer and overheat it up to 21 K in a pressurized liquid helium turbulent round jet at temperatures between 1.9 K and 2.12 K. The null-velocity response of the sensor can be satisfactorily modeled by the counterflow mechanism, while the extra cooling produced by the forced convection is found to scale similarly as the corresponding extra cooling in classical fluids. We propose a preliminary analysis of the response of the sensor and show that-contrary to a common assumption-such sensor can be used to probe local velocity in turbulent superfluid helium.


Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association.
Kawasaki disease is an acute vasculitis of childhood that leads to coronary artery aneurysms in ≈25% of untreated cases. It has been reported worldwide and is the leading cause of acquired heart disease in children in developed countries. To revise the previous American Heart Association guidelines, a multidisciplinary writing group of experts was convened to review and appraise available evidence and practice-based opinion, as well as to provide updated recommendations for diagnosis, treatment of the acute illness, and long-term management. Although the cause remains unknown, discussion sections highlight new insights into the epidemiology, genetics, pathogenesis, pathology, natural history, and long-term outcomes. Prompt diagnosis is essential, and an updated algorithm defines supplemental information to be used to assist the diagnosis when classic clinical criteria are incomplete. Although intravenous immune globulin is the mainstay of initial treatment, the role for additional primary therapy in selected patients is discussed. Approximately 10% to 20% of patients do not respond to initial intravenous immune globulin, and recommendations for additional therapies are provided. Careful initial management of evolving coronary artery abnormalities is essential, necessitating an increased frequency of assessments and escalation of thromboprophylaxis. Risk stratification for long-term management is based primarily on maximal coronary artery luminal dimensions, normalized as Z scores, and is calibrated to both past and current involvement. Patients with aneurysms require life-long and uninterrupted cardiology follow-up. These recommendations provide updated and best evidence-based guidance to healthcare providers who diagnose and manage Kawasaki disease, but clinical decision making should be individualized to specific patient circumstances.


Clinical Predictors of Emergency Department Revisits within 48 Hours of Discharge; a Case Control Study.
Emergency department (ED) revisits increase overcrowding and predicting which patients may need to revisit could increase patient safety. This study aimed to identify clinical variables that could be used to predict the probability of revisiting ED within 48 hours of discharge. A retrospective case-control study was conducted between July 2018 and January 2019 at the Emergency Medicine Department in Ramathibodi Hospital, Bangkok, Thailand. Patients who revisited the ED within 48 hours of discharge (case group) and patients who did not (control group) participated. The predictive factors for ED revisit were identified through multivariate logistic regression analysis. The case group consisted of 372 patients, who revisited the ED within 48 hours, and the control group consisted of 1488 patients. The most common reason for revisiting the ED was recurring gastrointestinal illness, in 107 patients (28.76%). According to the multivariate data analysis , five factors influenced the probability of revisiting the ED: age of more than 60 years (p < 0.001, OR = 2.04, 95%CI: 1.51-2.77), initial Emergency Severity Index (ESI) triage level of 2 (p = 0.007, OR = 1.20, 95%CI: 0.93-1.56), ED stay duration of 4 hours or longer (p = 0.013, OR = 1.12, 95%CI: 0.87-1.44), body temperature of ≥37.5ºC on discharge (p = 0.034, OR = 1.34, 95%CI: 1.00-1.80), and pulse rate of less than 60 (OR = 1.55, 95%CI: 0.87-2.77) or more than 100 beats/minute (OR = 1.53, 95%CI: 1.10-2.11) (p = 0.011). According to the findings, the most important and independent predictive factor of ED revisit within 48 hours of discharge were, age ≥ 60 years, ESI triage level 2, ED length of stay ≥ 4 hours, temperature ≥ 37.5 C, and 60 > pulse rate ≥ 100 beats/minute.


Hepatitis B Virus Infection among Health Care Workers in Indonesia.
Hepatitis B virus (HBV) infection is a global health problem with an estimated 257 million chronically infected people. Indonesia is a moderately hepatitis B-endemic country with 7.1% prevalence of hepatitis surface antigen (HBsAg). This infection is considered as an important occupational hazard among health care workers (HCWs), who may become further transmitters of this infection. The extent of hepatitis B among HCWs and specific control strategy are not available in Indonesia. A study was done on 644 HCWs, who were categorized into administration, nonintervention, and intervention groups. The prevalence of HBsAg, antibody to HBV core antigen (anti-HBc), and antibody to HBsAg (anti-HBs) was 4.7, 18.5, and 36.7% respectively, while 57.3% were negative for all seromarkers, indicating susceptibility to this infection. Increasing trend with age was observed in the exposure to infection (anti-HBc) (p <0.001) and the marker of resolved infection (HBsAg-, anti-HBc+, anti-HBs+) (p = 0.004), suggesting accumulated exposure to HBV infection by increasing age. Rising trend of exposure rate was also observed across the administration, nonintervention, and intervention groups (p < 0.001). By length of service period, significant escalation of exposure (p = 0.010) and resolved infection (p < 0.001) were also observed, suggesting increasing occupational risk to HBV infection. There is an urgent need to safeguard the HCWs with hepatitis B vaccination and provide continuing education at various health care setups. The establishment of a national policy and a roadmap for effective and efficient intervention is required for the prevention, diagnosis, postexposure management, and treatment of HBV infection in this special population. How to cite this article: Muljono DH, Wijayadi T, Sjahril R. Hepatitis B Virus Infection among Health Care Workers in Indonesia. Euroasian J Hepato-Gastroenterol 2018;8(1):88-92.


[Over the counter medication in pregnant women].
A prospective survey is conducted in a population of pregnant women in order to evaluate the prevalence of pregnant women using over the counter medication, to define their profile and to evaluate the information received about prenatal drug exposure and teratogen risk. During the study period, 223 women were interviewed, 23.3% of them use over the counter medication. In most cases, the drugs are "comfort drug". One woman, only, had taken anti-inflammatory during the first trimester. Only 51% had received information on drug and teratogen risk. Self medication is not frequently used by the pregnant women. The information provided by health professionals, about the risk and OTC medications during pregnancy, is insufficient.


Prolonged superficial local cryotherapy attenuates microcirculatory impairment, regional inflammation, and muscle necrosis after closed soft tissue injury in rats.
Closed soft tissue injury induces progressive microvascular dysfunction and regional inflammation. The authors tested the hypothesis that adverse trauma-induced effects can be reduced by local cooling. While superficial cooling reduces swelling, pain, and cellular oxygen demand, the effects of cryotherapy on posttraumatic microcirculation are incompletely understood. Controlled laboratory study. After a standardized closed soft tissue injury to the left tibial compartment, male rats were randomly subjected to percutaneous perfusion for 6 hours with 0.9% NaCL (controls; room temperature) or cold NaCL (cryotherapy; 8 degrees C) (n = 7 per group). Uninjured rats served as shams (n = 7). Microcirculatory changes and leukocyte adherence were determined by intravital microscopy. Intramuscular pressure was measured, and invasion of granulocytes and macrophages was assessed by immunohistochemistry. Edema and tissue damage was quantified by gravimetry and decreased desmin staining. Closed soft tissue injury significantly decreased functional capillary density (240 +/- 12 cm(-1)); increased microvascular permeability (0.75 +/- 0.03), endothelial leukocyte adherence (995 +/- 77/cm(2)), granulocyte (182.0 +/- 25.5/mm(2)) and macrophage infiltration, edema formation, and myonecrosis (ratio: 2.95 +/- 0.45) within the left extensor digitorum longus muscle. Cryotherapy for 6 hours significantly restored diminished functional capillary density (393 +/- 35), markedly decreased elevated intramuscular pressure, reduced the number of adhering (462 +/- 188/cm(2)) and invading granulocytes (119 +/- 28), and attenuated tissue damage (ratio: 1.7 +/- 0.17). The hypothesis that prolonged cooling reduces posttraumatic microvascular dysfunction, inflammation, and structural impairment was confirmed. These results may have therapeutic implications as cryotherapy after closed soft tissue injury is a valuable therapeutic approach to improve nutritive perfusion and attenuate leukocyte-mediated tissue destruction. The risk for evolving compartment syndrome may be reduced, thereby preventing further irreversible aggravation.


Genotyping of Campylobacter jejuni using seven single-nucleotide polymorphisms in combination with flaA short variable region sequencing.
This investigation describes the development of a generally applicable, bioinformatics-driven, single-nucleotide polymorphism (SNP) genotyping assay for the common bacterial gastrointestinal pathogen Campylobacter jejuni. SNPs were identified in silico using the program 'Minimum SNPs', which selects for polymorphisms providing the greatest resolution of bacterial populations based on Simpson's index of diversity (D). The high-D SNPs identified in this study were derived from the combined C. jejuni/Campylobacter coli multilocus sequence typing (MLST) database. Seven SNPs were found that provided a D of 0.98 compared with full MLST characterization, based on 959 sequence types (STs). The seven high-D SNPs were interrogated using allele-specific real-time PCR (AS kinetic PCR), which negates the need for expensive labelled primers or probes and requires minimal assay optimization. The total turnaround time of the SNP typing assay was approximately 2 h. Concurrently, 69 C. jejuni isolates were subjected to MLST and flagellin A short variable region (flaA SVR) sequencing and combined with a population of 84 C. jejuni and C. coli isolates previously characterized by these methods. Within this collection of 153 isolates, 19 flaA SVR types (D=0.857) were identified, compared with 40 different STs (D=0.939). When MLST and flaA SVR sequencing were used in combination, the discriminatory power was increased to 0.959. In comparison, SNP typing of the 153 isolates alone provided a D of 0.920 and was unable to resolve a small number of unrelated isolates. However, addition of the flaA SVR locus to the SNP typing procedure increased the resolving power to 0.952 and clustered isolates similarly to MLST/flaA SVR. This investigation has shown that a seven-member C. jejuni SNP typing assay, used in combination with sequencing of the flaA SVR, efficiently discriminates C. jejuni isolates.


Enhanced 3D spatial resolution in quantitative phase microscopy using spatially incoherent illumination.
We describe the use of spatially incoherent illumination to make quantitative phase imaging of a semi-transparent sample, even out of the paraxial approximation. The image volume electromagnetic field is collected by scanning the image planes with a quadriwave lateral shearing interferometer, while the sample is spatially incoherently illuminated. In comparison to coherent quantitative phase measurements, incoherent illumination enriches the 3D collected spatial frequencies leading to 3D resolution increase (up to a factor 2). The image contrast loss introduced by the incoherent illumination is simulated and used to compensate the measurements. This restores the quantitative value of phase and intensity. Experimental contrast loss compensation and 3D resolution increase is presented using polystyrene and TiO(2) micro-beads. Our approach will be useful to make diffraction tomography reconstruction with a simplified setup.


Cathepsin B: a potential prognostic marker for inflammatory breast cancer.
Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer. In non-IBC, the cysteine protease cathepsin B (CTSB) is known to be involved in cancer progression and invasion; however, very little is known about its role in IBC. In this study, we enrolled 23 IBC and 27 non-IBC patients. All patient tissues used for analysis were from untreated patients. Using immunohistochemistry and immunoblotting, we assessed the levels of expression of CTSB in IBC versus non-IBC patient tissues. Previously, we found that CTSB is localized to caveolar membrane microdomains in cancer cell lines including IBC, and therefore, we also examined the expression of caveolin-1 (cav-1), a structural protein of caveolae in IBC versus non-IBC tissues. In addition, we tested the correlation between the expression of CTSB and cav-1 and the number of positive metastatic lymph nodes in both patient groups. Our results revealed that CTSB and cav-1 were overexpressed in IBC as compared to non-IBC tissues. Moreover, there was a significant positive correlation between the expression of CTSB and the number of positive metastatic lymph nodes in IBC. CTSB may initiate proteolytic pathways crucial for IBC invasion. Thus, our data demonstrate that CTSB may be a potential prognostic marker for lymph node metastasis in IBC.


Escherichia coli Strains Producing Selected Bacteriocins Inhibit Porcine Enterotoxigenic Escherichia coli (ETEC) under both In Vitro and In Vivo Conditions.
Enterotoxigenic Escherichia coli (ETEC) and Shiga toxin-producing E. coli (STEC) strains are the causative agents of severe foodborne diseases in both humans and animals. In this study, porcine pathogenic E. coli strains (n = 277) as well as porcine commensal strains (n = 188) were tested for their susceptibilities to 34 bacteriocin monoproducers to identify the most suitable bacteriocin types inhibiting porcine pathogens. Under in vitro conditions, the set of pathogenic E. coli strains was found to be significantly more susceptible to the majority of tested bacteriocins than commensal E. coli. Based on the production of bacteriocins with specific activity against pathogens, three potentially probiotic commensal E. coli strains of human origin were selected. These strains were found to be able to outcompete ETEC strains expressing F4 or F18 fimbriae in liquid culture and also decreased the severity and duration of diarrhea in piglets during experimental ETEC infection as well as pathogen numbers on the last day of in vivo experimentation. While the extents of the probiotic effect were different for each strain, the cocktail of all three strains showed the most pronounced beneficial effects, suggesting synergy between the tested E. coli strains. IMPORTANCE Increasing levels of antibiotic resistance among bacteria also increase the need for alternatives to conventional antibiotic treatment. Pathogenic Escherichia coli represents a major diarrheic infectious agent of piglets in their postweaning period; however, available measures to control these infections are limited. This study describes three novel E. coli strains producing antimicrobial compounds (bacteriocins) that actively inhibit a majority of toxigenic E. coli strains. The beneficial effect of three potentially probiotic E. coli strains was demonstrated under both in vitro and in vivo conditions. The novel probiotic candidates may be used as prophylaxis during piglets' postweaning period to overcome common infections caused by E. coli.


A reduced-scaling density matrix-based method for the computation of the vibrational Hessian matrix at the self-consistent field level.
An analytical method to calculate the molecular vibrational Hessian matrix at the self-consistent field level is presented. By analysis of the multipole expansions of the relevant derivatives of Coulomb-type two-electron integral contractions, we show that the effect of the perturbation on the electronic structure due to the displacement of nuclei decays at least as r(-2) instead of r(-1). The perturbation is asymptotically local, and the computation of the Hessian matrix can, in principle, be performed with O(N) complexity. Our implementation exhibits linear scaling in all time-determining steps, with some rapid but quadratic-complexity steps remaining. Sample calculations illustrate linear or near-linear scaling in the construction of the complete nuclear Hessian matrix for sparse systems. For more demanding systems, scaling is still considerably sub-quadratic to quadratic, depending on the density of the underlying electronic structure.


Evaluation of septic complications in patients undergoing biliary surgery for gall stones in a tertiary care teaching hospital of South India.
One of the etiologies of formation of gall stones is infection and bile is a good media for microorganisms to grow. Acute cholecystitis and spillage of bile intraoperatively can lead to sepsis and postoperative complications. An attempt to study the nature of organisms and their antibiotic sensitivity is important to take appropriate steps. Present study was done to assess the rate of infected bile in patients undergoing cholecystectomy for gallstones and to study its influence on postoperative infective complications. This prospective study was conducted over a period of two years (from July 2003 to July 2005) in a tertiary care teaching institute in South India. Bile samples of 100 patients undergoing biliary tract surgery were collected and cultured for aerobic and anaerobic bacteria. Patients were divided into two groups which included 84 cases who underwent laparoscopic cholecystectomy and 16, open cholecystectomy. All the patients received prophylactic antibiotic. Bile culture was positive in 8 cases. Two cases developed postoperative wound infection; however in these bile culture was sterile. No significant postoperative complications were observed in any of the group apart from 1 case that developed intra abdominal abscess along with wound infection requiring re-exploration. Six cases developed postoperative fever that subsided on its own. The overall rate of septic complications following biliary surgery was extremely low. Present study does not show any correlation between infected bile and septic complications that is in accordance with the published literature. Present study also highlights the fact that good surgical techniques and judicious use of prophylactic antibiotics are two major factors for lower incidence of septic complications, if any, after biliary tract surgery.


Binding of phage Phi29 architectural protein p6 to the viral genome: evidence for topological restriction of the phage linear DNA.
Bacillus subtilis phage Phi29 protein p6 is required for DNA replication and promotes the switch from early to late transcription. In vivo it binds all along the viral linear DNA, which suggests a global role as an architectural protein; in contrast, binding to bacterial DNA is negligible. This specificity could be due to the p6 binding preference for less negatively supercoiled DNA, as is presumably the case with viral (with respect to bacterial) DNA. Here we demonstrate that p6 binding to Phi29 DNA is greatly increased when negative supercoiling is decreased by novobiocin; in addition, gyrase is required for DNA replication. This indicates that, although non-covalently closed, the viral genome is topologically constrained in vivo. We also show that the p6 binding to different Phi29 DNA regions is modulated by the structural properties of their nucleotide sequences. The higher affinity for DNA ends is possibly related to the presence of sequences in which their bendability properties favor the formation of the p6-DNA complex, whereas the lower affinity for the transcription control region is most probably due to the presence of a rigid intrinsic DNA curvature.


The loss of endoglin promotes the invasion of extravillous trophoblasts.
Endoglin is a coreceptor for TGF-β, which is expressed in syncytiotrophoblasts. The soluble form of endoglin (sEng) has been observed to increase in the serum of preeclamptic patients. Several studies have shown that endoglin is involved in cancer invasion. However, the role of endoglin in extravillous trophoblasts (EVT), which have an invasive phenotype, remains unknown. The present study was designed to investigate the expression and role of endoglin in human EVT. We found that endoglin was mainly expressed on cytotrophoblasts within the cell column during the first trimester and its expression decreased in the EVT by immunohistochemistry and immunocytochemistry. The expression of endoglin significantly increased after treatment with TGF-β1 and TGF-β3 in the human EVT cell line, HTR-8/SVneo, as detected by semiquantitative RT-PCR. To investigate the role of endoglin in EVT, the stable knockdown of endoglin was performed by lentiviral short hairpin RNA transfection into the HTR-8/SVneo cells. Although proliferation was not affected, the motility and invasiveness of the HTR-8/SVneo cells significantly increased by the knockdown of endoglin. Both the mRNA expression and secretion of urokinase-type plasminogen activator significantly increased in endoglin knockdown cells. The secretion of sEng was very low in HTR-8/SVneo, and the treatment of endoglin knockdown cells with 10 ng/ml sEng had no effect on their invasiveness. Therefore, the suppression of sEng was not involved in the increased invasiveness of endoglin knockdown cells. These results suggested that EVT increased their invasive function as a result of decreasing expression of transmembrane endoglin.


Melatonin with 1,25-dihydroxyvitamin D3 protects against apoptotic ischemia-reperfusion injury in the rat kidney.
This study was designed to evaluate the preventive role of melatonin (Mel) and 1,25-dihydroxyvitamin D3 (VD3) in biochemical and apoptotic events leading to tissue injury and renal dysfunction after ischemia-reperfusion (I/R). Thirty male Wistar rats were divided into five groups: sham-operated, I/R, Mel + I/R, VD3 + I/R, and Mel + VD3 + I/R. The rats were intraperitoneally administered with Mel (10 mg/kg), VD3 (0.5 μg/kg), or Mel (10 mg/kg) plus VD3 (0.5 μg/kg) each day at 1 week prior to ischemia. Right nephrectomy was initially performed and left renal I/R injury was induced by 45 min of bilateral renal ischemia followed by 45 min of reperfusion. After reperfusion, kidneys and blood were obtained for histopathologic and biochemical evaluation. Mel and VD3 had an ameliorative effect on biochemical parameters such as serum creatinine, blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase, and apoptosis (caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining) in the kidneys against renal I/R injury in rats. Additionally, VD3 combined with Mel significantly reduced apoptotic and histological alterations when compared with Mel or VD3 alone. This preventive effect on renal tubular apoptosis was remarkable when Mel was combined with VD3.


A fast and effective method to assess myocardial necrosis by means of contrast magnetic resonance imaging.
Contrast magnetic resonance (CMR) can identify myocardial necrosis after gadolinium administration as a hyperenhanced (HE) area. Yet there are no software tools that can effectively quantify such an area. The aim of this study is to develop a robust and effective algorithmic method for defining the extent of myocardial necrosis evidenced through CMR. Fifteen patients with previous myocardial infarction underwent nitrate Tetrofosmin G-SPECT and CMR. A software tool was developed, allowing semiautomatic detection of endocardial and epicardial borders and the automatic detection of HE regions. The accuracy of the proposed quantitative method of analysis has been tested with G-SPECT analysis that it is less than an ideal method for assessing myocardial viability, but at present is accepted and widely used in the clinical arena. Segmental (SEHE) and global extension of HE were evaluated. HE was present in 161 of the 255 analyzed segments. Of the 161 HE segments, the mean SEHE was 36 +/- 30%. The operator independence (intraobserver: r = 0.97, p < 0.0001, interobserver: r = 0.95, p < 0.0001) was good and significant, with noticeable time savings with respect to manual analysis. There was strong and inverse correlation between SEHE and scintigraphic regional uptake reduction (r = -0.66, p < 0.0001), and also a positive correlation between SEHE and SPECT defect extension (r = 0.75, p < 0.0001). When assessing the global extent of necrosis, the correlation between the two techniques was strong (r = 0.79, p = 0.0004). The proposed method of quantifying myocardial necrosis by CMR is highly reliable, reproducible, and operator-independent for quantifying.


Genotypic characterization of Staphylococcus aureus strains isolated from rabbit lesions.
Since staphylococcal infections are the main pathological problem in rabbit does, the objective of this study was to characterize epidemiologically Staphylococcus aureus isolates from different lesion types in rabbits. Using 3 genetic markers (coagulase, staphylococcal protein A and clumping factor B genes), 22 different genotypes were identified among 301 isolates recovered from 259 rabbit does with 10 different kinds of chronic purulent lesions. These infected rabbits were obtained from 30 herds located in the Valencia province on the Spanish Mediterranean coast. The most frequent genotype was designated A1/II1/delta (coa/spa/clfB combination genotype) and represented 70.76% of the isolates. Although most genotypes were previously identified in other countries, novel types were also documented. No specificity between genotypes and nature of the pathologic process could be identified. After genetic comparison between strains from different origins, the results may suggest that rabbit, bovine and human S. aureus isolates are not clonally related, suggesting that specific host-dependent pathogenic factors may have evolved independently in these species. These differences indicate that a rational and effective strategy to control infections caused by rabbit-specific isolates may be advantageous.


Xanthine oxidase interaction with vascular endothelial growth factor in human endothelial cell angiogenesis.
Reduced capillary density occurs early in cardiovascular diseases. Oxidant stress is implicated in endothelial apoptosis. We investigated the effects of xanthine oxidase (XO) on endothelial survival signaling: protein kinase B/Akt, its cross-talk with p38 MAPK and apoptosis pathways, and its effect on vascular tube formation in vascular endothelial growth factor (VEGF)-simulated human umbilical vein cells. We studied primary cultured human endothelial cells from the umbilical cord. Reactive oxygen species (ROS) production was detected by dihydroethidium staining, cell-signaling pathways by western blots, cell survival by western blots, and nuclear chromatin and angiogenesis response by MTT proliferation assay and three-dimensional Matrigel cultures. Exogenous XO increased cellular ROS production and caused superoxide-dependent inhibition of Akt phosphorylation and enhancement of p38 MAPK phosphorylation in a time-and dose-dependent manner. In contrast, application of the XO inhibitor oxypurinol or allopurinol inhibited VEGF-stimulated Akt phosphorylation, indicating that endogenous XO promotes VEGF-induced endothelial cell (EC) survival signaling. Exogenous XO induced activation of caspase-3 and reduced expression of the anti-apoptosis protein Bcl-2. Exogenous XO also reduced EC viability, proliferation, and vascular tube formation by p38 MAPK-dependent, phosphoinositide 3-kinase (PI3-K) reversible mechanisms; whereas VEGF promoted EC survival by PI3-K-dependent, p38 MAPK-independent effects. Exogenous XO activity is an important contributor to endothelial mechanisms for microvascular rarefaction, by modulation of cell survival signaling pathways; however, endogenous XO is necessary for maintaining EC survival.


The relevance of contact-independent cell-to-cell transfer of TDP-43 and SOD1 in amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving the formation of cytoplasmic aggregates by proteins including TDP-43 and SOD1, in affected cells in the central nervous system (CNS). Pathology spreads from an initial site of onset to contiguous anatomical regions. There is evidence that for disease-associated proteins, including TDP-43 and SOD1, non-native protein conformers can promote misfolding of the natively folded counterparts, and cell-to-cell transfer of pathological aggregates may underlie the spread of the disease throughout the CNS. A variety of studies have demonstrated that SOD1 is released by neuron-like cells into the surrounding culture medium, either in their free state or encapsulated in extracellular vesicles such as exosomes. Extracellular SOD1 can then be internalised by naïve cells incubated in this conditioned medium, leading to the misfolding and aggregation of endogenous intracellular SOD1; an effect that propagates over serial passages. A similar phenomenon has also been observed with other proteins associated with protein misfolding and progressive neurological disorders, including tau, α-synuclein and both mammalian and yeast prions. Conditioned media experiments using TDP-43 have been less conclusive, with evidence for this protein undergoing intercellular transfer being less straightforward. In this review, we describe the properties of TDP-43 and SOD1 and look at the evidence for their respective abilities to participate in cell-to-cell transfer via conditioned medium, and discuss how variations in the nature of cell-to-cell transfer suggests that a number of different mechanisms are involved in the spreading of pathology in ALS.