Locally increased P-glycoprotein function in major depression: a PET study with [C-11]verapamil as a probe for P-glycoprotein function in the blood-brain barrier

The aetiology of depressive disorder remains unknown, although genetic susceptibility and exposure to neurotoxins are currently being discussed as possible contributors to this disorder. In normal circumstances, the brain is protected against bloodborne toxic influences by the blood-brain barrier, which includes the molecular efflux pump P-glycoprotein (P-gp) in the vessel wall of brain capillaries. We hypothesized that P-gp function in the blood-brain barrier is changed in patients with major depression. Positron emission tomography Was used to measure brain uptake of [C-11]verapamil, which is normally expelled from the brain by P-gp. Cerebral Volume of distribution (V-T) of [C-11]verapamil was used as a measure of P-gp function. Both region-of-interest (ROI) analysis and voxel analysis using statistical parametric mapping (SPM2) were performed to assess regional brain P-gp function. We found that patients with a major depressive episode, using antidepressants, compared to health), controls showed a significant decrease of [C-11]verapamil uptake in different areas throughout the brain, in particular in frontal and temporal regions. The decreased [C-11]verapamil uptake correlates with an increased function of the P-gp protein and may be related to chronic use of psychotropic drugs, Our results may explain why treatment-resistant depression can develop

The use of oral recombinant feline interferon omega in two cats with type II diabetes mellitus and concurrent feline chronic gingivostomatitis syndrome

Articles in International JournalsFeline Chronic Gingivostomatitis Syndrome (FCGS) is a common disease in clinical practice. Among the therapeutic options available, long-acting corticosteroids are frequently used due to their anti-inflammatory and immunosuppressive properties. Although they may improve the clinical symptoms, they can lead to a progressive form of the disease that becomes refractory to treatment. Furthermore, their direct relationship with type II diabetes mellitus (DM) is well known. Consequently, these drugs are controversial and not recommended for routine management of FCGS. Recombinant feline interferon-omega (rFeIFN-ω) is an immunomodulatory compound. Recently, its daily oral administration has been shown to be successful in treating refractory cases of FCGS. This case study describes two clinical cases of type II DM complicated by FCGS. Both animals were calicivirus positive and they had been previously treated with long-acting corticosteroids, which may have been the major cause of DM. The two cats were treated with glargine insulin (Lantus, starting dose 1 IU/cat twice daily (BID)), achieving remission 10 and 18 weeks later respectively. Considering the difficulty with control of FCGS in these animals, an oral daily dose of rFeIFN-ω was started as an alternative to long-acting corticosteroids. In both cats oral clinical signs gradually improved and 60 days after the start of therapy the owners reported a significant relief of pain during mastication. According to the authors’ knowledge, this is the first case report that describes the successful use of rFeIFN-ω in the management of FCGS in type II diabetic cats, in which long-acting corticosteroids are contraindicated

Comparative mapping of quantitative trait loci involved in heterosis for seedling and yield traits in oilseed rape (Brassica napus L.)

Little is known about the genetic control of heterosis in the complex polyploid crop species oilseed rape (Brassica napus L.). In this study, two large doubled-haploid (DH) mapping populations and two corresponding sets of backcrossed test hybrids (THs) were analysed in controlled greenhouse experiments and extensive field trials for seedling biomass and yield performance traits, respectively. Genetic maps from the two populations, aligned with the help of common simple sequence repeat markers, were used to localise and compare quantitative trait loci (QTL) related to the expression of heterosis for seedling developmental traits, plant height at flowering, thousand seed mass, seeds per silique, siliques per unit area and seed yield. QTL were mapped using data from the respective DH populations, their corresponding TH populations and from mid-parent heterosis (MPH) data, allowing additive and dominance effects along with digenic epistatic interactions to be estimated. A number of genome regions containing numerous heterosis-related QTL involved in different traits and at different developmental stages were identified at corresponding map positions in the two populations. The co-localisation of per se QTL from the DH population datasets with heterosis-related QTL from the MPH data could indicate regulatory loci that may also contribute to fixed heterosis in the highly duplicated B. napus genome. Given the key role of epistatic interactions in the expression of heterosis in oilseed rape, these QTL hotspots might harbour genes involved in regulation of heterosis (including fixed heterosis) for different traits throughout the plant life cycle, including a significant overall influence on heterosis for seed yield.German Research Foundation (DFG) [SPP 1149

The consequences of reservoir host eradication on disease epidemiology in animal communities.

Non-native species have often been linked with introduction of novel pathogens that spill over into native communities, and the amplification of the prevalence of native parasites. In the case of introduced generalist pathogens, their disease epidemiology in the extant communities remains poorly understood. Here, Sphaerothecum destruens, a generalist fungal-like fish pathogen with bi-modal transmission (direct and environmental) was used to characterise the biological drivers responsible for disease emergence in temperate fish communities. A range of biotic factors relating to both the pathogen and the surrounding host communities were used in a novel susceptible-exposed-infectious-recovered (SEIR) model to test how these factors affected disease epidemiology. These included: (i) pathogen prevalence in an introduced reservoir host (Pseudorasbora parva); (ii) the impact of reservoir host eradication and its timing and (iii) the density of potential hosts in surrounding communities and their connectedness. These were modelled across 23 combinations and indicated that the spill-over of pathogen propagules via environmental transmission resulted in rapid establishment in adjacent fish communities (<1 year). Although disease dynamics were initially driven by environmental transmission in these communities, once sufficient numbers of native hosts were infected, the disease dynamics were driven by intra-species transmission. Subsequent eradication of the introduced host, irrespective of its timing (after one, two or three years), had limited impact on the long-term disease dynamics among local fish communities. These outputs reinforced the importance of rapid detection and eradication of non-native species, in particular when such species are identified as healthy reservoirs of a generalist pathogen

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Molecular characterization of old local grapevine varieties from South East European countries

South East European (SEE) viticulture partially relies on native grapevine varieties, previously scarcely described. In order to characterize old local grapevine varieties and assess the level of synonymy and genetic diversity from SEE countries, we described and genotyped 122 accessions from Albania, Federation of Bosnia and Herzegovina (B&amp;H), Croatia, Macedonia, Moldova, Montenegro, Republika Srpska (Bosnia and Herzegovina) and Romania on nine most commonly used microsatellite loci. As a result of the study a total of 86 different genotypes were identified. All loci were very polymorphic and a total of 96 alleles were detected, ranging from 8 to 14 alleles per locus, with an average allele number of 10.67. Overall observed heterozygosity was 0.759 and slightly lower than expected (0.789) while gene diversity per locus varied between 0.600 (VVMD27) and 0.906 (VVMD28). Eleven cases of synonymy and three of homonymy have been recorded for samples harvested from different countries. Cultivars with identical genotypes were mostly detected between neighboring countries. No clear differentiation between countries was detected although several specific alleles were detected. The integration of the obtained genetic data with ampelographic ones is very important for accurate identification of the SEE cultivars and provides a significant tool in cultivar preservation and utilization.

Estimating Exposome Score for Schizophrenia Using Predictive Modeling Approach in Two Independent Samples: The Results From the EUGEI Study

Exposures constitute a dense network of the environment: exposome. Here, we argue for embracing the exposome paradigm to investigate the sum of nongenetic "risk" and show how predictive modeling approaches can be used to construct an exposome score (ES; an aggregated score of exposures) for schizophrenia. The training dataset consisted of patients with schizophrenia and controls, whereas the independent validation dataset consisted of patients, their unaffected siblings, and controls. Binary exposures were cannabis use, hearing impairment, winter birth, bullying, and emotional, physical, and sexual abuse along with physical and emotional neglect. We applied logistic regression (LR), Gaussian Naive Bayes (GNB), the least absolute shrinkage and selection operator (LASSO), and Ridge penalized classification models to the training dataset. ESs, the sum of weighted exposures based on coefficients from each model, were calculated in the validation dataset. In addition, we estimated ES based on meta-analyses and a simple sum score of exposures. Accuracy, sensitivity, specificity, area under the receiver operating characteristic, and Nagelkerke's R2 were compared. The ESMeta-analyses performed the worst, whereas the sum score and the ESGNB were worse than the ESLR that performed similar to the ESLASSO and ESRIDGE. The ESLR distinguished patients from controls (odds ratio [OR] = 1.94, P < .001), patients from siblings (OR = 1.58, P < .001), and siblings from controls (OR = 1.21, P = .001). An increase in ESLR was associated with a gradient increase of schizophrenia risk. In reference to the remaining fractions, the ESLR at top 30%, 20%, and 10% of the control distribution yielded ORs of 3.72, 3.74, and 4.77, respectively. Our findings demonstrate that predictive modeling approaches can be harnessed to evaluate the exposome

Prospective multicentre cohort study of patient-reported outcomes and complications following major abdominal neoplastic surgery (PATRONUS) – study protocol for a CHIR-Net student-initiated German medical audit study (CHIR-Net SIGMA study)

Background: One of the most important aspects of designing a clinical trial is selecting appropriate outcomes. Patient-reported outcomes (PROs) can provide a personal assessment of the burden and impact of a malignant disease and its treatment. PROs comprise a wide range of outcomes including basic clinical symptom scores and complex metrics such as health-related quality of life (HRQoL). There is limited data on how postoperative complications following cancer surgery affect symptoms and HRQoL. For this reason the primary aim of the PATRONUS study is to investigate how perioperative complications affect cancer-related symptoms and HRQoL in patients undergoing abdominal cancer surgery. The PATRONUS study is designed and will be initiated and conducted by medical students under the direct supervision of clinician scientists based on the concept of inquiry-based learning. Methods: PATRONUS is a non-interventional prospective multicentre cohort study. Patients undergoing elective oncological abdominal surgery will be recruited at regional centres of the clinical network of the German Surgical Society (CHIR-Net) and associated hospitals. A core set of 12 cancer associated symptoms will be assessed via the PRO version of the Common Terminology Criteria for Adverse Events. The cancer-specific HRQoL will be measured via the computerised adaptive testing version of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30. PROs will be measured eight times over a period of six months. The short-term clinical outcome measure is the rate of postoperative complications (grade II to V) within 30 days according to the Clavien-Dindo classification. The long-term clinical outcome is overall survival within six months postoperative. Discussion: PATRONUS will provide essential insights into the patients’ assessment of their well-being and quality of life in direct relation to clinical outcome parameters following abdominal cancer surgery. Furthermore, PATRONUS will investigate the feasibility of multicentre student-led clinical research. Trial registration German Clinical Trials Register: DRKS00013035 (registered on October 26, 2017). Universal Trial Number (UTN): U1111–1202-8863

Examining the independent and joint effects of genomic and exposomic liabilities for schizophrenia across the psychosis spectrum

Psychosis spectrum disorder has a complex pathoetiology characterised by interacting environmental and genetic vulnerabilities. The present study aims to investigate the role of gene-environment interaction using aggregate scores of genetic (polygenic risk score for schizophrenia (PRS-SCZ)) and environment liability for schizophrenia (exposome score for schizophrenia (ES-SCZ)) across the psychosis continuum