Reliable Field Assessment of Proliferative Kidney Disease in Wild Brown Trout, Salmo trutta, Populations: When Is the Optimal Sampling Period?

Proliferative kidney disease (PKD), caused by the myxozoan parasite Tetracapsuloides bryosalmonae, is suspected to contribute to the decline of wild brown trout Salmo trutta populations. Different factors need to be taken into consideration for PKD outbreaks. Among them, water temperature appears as a main driver of the disease. To understand the epidemiology and impact of the disease on wild fish populations, reliable sampling approaches to detect the presence of T. bryosalmonae-infected fish are needed. This study aimed to characterize the seasonal variation of the prevalence of T. bryosalmonae-infected fish in brown trout populations in two small streams with differing temperature regimes between upstream and downstream sites. As water temperature is known to influence PKD manifestation in brown trout, we hypothesized that the number of T. bryosalmonae-positive fish, as well as their seasonal distribution, will vary between upper and downstream parts of the two streams. Since, in field studies, results can strongly vary across years, we extended the study over a 3-year-period. The number of infected fish and the intensity of infection were assessed by histology. The results confirmed the hypothesis of pronounced temporal- and site-related differences in the percentage of PKD-positive fish and the intensity of the infection. Comparison of water temperatures (total degree days as well as the number of days with a daily mean temperature ≥15 °C) with PKD data indicated that temperature was the driving factor for the temporal development and the intensity of the infection. A mean of 1500 degree days or 30 days with a daily mean temperature ≥15 °C was required before the infection could be detected histologically. From our findings, recommendations are derived for a water temperature-driven sampling strategy campaigns that enables the detection of PKD infection and prevalence in wild brown trout populations

Do fish get wasted? Assessing the influence of effluents on parasitic infection of wild fish

Many ecosystems are influenced simultaneously by multiple stressors. One important environmental stressor is aquatic pollution via wastewater treatment plant (WWTP) effluents. WWTP effluents may contribute to eutrophication or contain anthropogenic contaminants that directly and/or indirectly influence aquatic wildlife. Both eutrophication and exposure to anthropogenic contaminants may affect the dynamics of fish-parasite systems. With this in mind, we studied the impact of WWTP effluents on infection of brown trout by the parasite Tetracapsuloides bryosalmonae, the causative agent of proliferative kidney disease (PKD). PKD is associated with the long-term decline of wild brown trout (Salmo trutta) populations in Switzerland. We investigated PKD infection of brown trout at two adjacent sites (≈400 m apart) of a Swiss river. The sites are similar in terms of ecology except that one site receives WWTP effluents. We evaluated the hypothesis that fish inhabiting the effluent site will show greater susceptibility to PKD in terms of prevalence and disease outcome. We assessed susceptibility by (i) infection prevalence, (ii) parasite intensity, (iii) host health in terms of pathology, and (iv) estimated apparent survival rate. At different time points during the study, significant differences between sites concerning all measured parameters were found, thus providing evidence of the influence of effluents on parasitic infection of fish in our study system. However, from these findings we cannot determine if the effluent has a direct influence on the fish host via altering its ability to manage the parasite, or indirectly on the parasite or the invertebrate host via increasing bryozoa (the invertebrate host) reproduction. On a final note, the WWTP adhered to all national guidelines and the effluent only resulted in a minor water quality reduction assessed via standardized methods in this study. Thus, we provide evidence that even a subtle decrease in water quality, resulting in small-scale pollution can have consequences for wildlife

Cdx2 homeoprotein inhibits non-homologous end joining in colon cancer but not in leukemia cells

Cdx2, a gene of the paraHox cluster, encodes a homeodomain transcription factor that plays numerous roles in embryonic development and in homeostasis of the adult intestine. Whereas Cdx2 exerts a tumor suppressor function in the gut, its abnormal ectopic expression in acute leukemia is associated to a pro-oncogenic function. To try to understand this duality, we have hypothesized that Cdx2 may interact with different protein partners in the two tissues and set up experiments to identify them by tandem affinity purification. We show here that Cdx2 interacts with the Ku heterodimer specifically in intestinal cells, but not in leukemia cells, via its homeodomain. Ku proteins do not affect Cdx2 transcriptional activity. However, Cdx2 inhibits in vivo and in vitro the DNA repair activity mediated by Ku proteins in intestinal cells. Whereas Cdx2 does not affect the recruitment of Ku proteins and DNA-PKcs into the DNA repair complex, it inhibits DNA-PKcs activity. Thus, we report here a new function of Cdx2, acting as an inhibitor of the DNA repair machinery, that may contribute to its tumor suppressor function specifically in the gut

Incidence and determinants of new AIDS-defining illnesses after HAART initiation in a Senegalese cohort

<p>Abstract</p> <p>Background</p> <p>Although a dramatic decrease in AIDS progression has been observed after Highly Active Anti Retroviral Therapy (HAART) in both low- and high-resource settings, few data support that fact in low-resource settings.</p> <p>This study describes the incidence of AIDS-defining illnesses (ADI) after HAART initiation and analyzes their risk factors in a low-resource setting. A focus was put on CD4 cell counts and viral load measurements.</p> <p>Methods</p> <p>404 HIV-1-infected Senegalese adult patients were enrolled in a prospective observational cohort and data censored as of April 2008. A Poisson regression was used to model the incidence of ADIs over two periods and to assess its association with baseline variables, current CD4, current viral load, CD4 response, and virological response.</p> <p>Results</p> <p>ADI incidence declined from 20.5 ADIs per 100 person-years, 95% CI = [16.3;25.8] during the first year to 4.3, 95% CI = [2.3;8.1] during the fourth year but increased afterwards. Before 42 months, the decrease was greater in patients with clinical stage CDC-C at baseline and with a viral load remaining below 1000 cp/mL but was uniform across CD4 strata (p = 0.1). After 42 months, 293 patients were still at risk. The current CD4 and viral load were associated with ADI incidence (decrease of 21% per 50 CD4/mm³and of 61% for patients with a viral load < 1000 cp/mL).</p> <p>Conclusions</p> <p>During the first four years, a uniform decline of ADI incidence was observed even in patients with low CD4-cell counts at HAART initiation as long as the viral load remained undetectable. An increase was noted later in patients with immunologic and virological failures but also in patients with only virological failure.</p

Acute bacterial prostatitis: heterogeneity in diagnostic criteria and management. Retrospective multicentric analysis of 371 patients diagnosed with acute prostatitis

<p>Abstract</p> <p>Background</p> <p>There is currently a lack of consensus for the diagnosis, investigations and treatments of acute bacterial prostatitis (AP).</p> <p>Methods</p> <p>The symptoms, investigations and treatments of 371 inpatients diagnosed with AP were analyzed through a retrospective study conducted in four departments – Urology (U), Infectious Diseases (ID), Internal Medicine (IM), Geriatrics (G) – of two French university hospitals.</p> <p>Results</p> <p>The cause of admission, symptoms, investigations and treatments depended markedly on the department of admission but not on the hospital. In U, patients commonly presented with a bladder outlet obstruction, they had a large imaging and functional check-up, and received alpha-blockers and anti-inflammatory drugs. In ID, patients were febrile and received longer and more appropriate antibiotic treatments. In G, patients presented with cognitive disorders and commonly had post-void urine volume measurements. In IM, patients presented with a wide range of symptoms, and had very diverse investigations and antibiotic regimen.</p> <p>Overall, a 3:1 ratio of community-acquired AP (CA-AP) to nosocomial AP (N-AP) was observed. Urine culture isolated mainly <it>E. coli </it>(58% of AP, 68% of CA-AP), with venereal agents constituting less than 1%. The probabilistic antibiotic treatments were similar for N-AP and CA-AP (58% bi-therapy; 63% fluoroquinolone-based regimen). For N-AP, these treatments were more likely to be inadequate (42% <it>vs. </it>8%, p < 0.001) and had a higher rate of bacteriological failure (48% <it>vs. </it>19%, p < 0.001).</p> <p>Clinical failure at follow-up was more common than bacteriological failure (75% versus 24%, p < 0.001). Patients older than 49 had more underlying urinary tract disorders and a higher rate of clinical failure (30% versus 10%, p < 0.0001).</p> <p>Conclusion</p> <p>This study highlights the difficulties encountered on a daily basis by the physicians regarding the diagnosis and management of acute prostatitis.</p

A simplified interventional mapping system (SIMS) for the selection of combinations of targeted treatments in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is a leading cause of death worldwide. Targeted monotherapies produce high regression rates, albeit for limited patient subgroups, who inevitably succumb. We present a novel strategy for identifying customized combinations of triplets of targeted agents, utilizing a simplified interventional mapping system (SIMS) that merges knowledge about existent drugs and their impact on the hallmarks of cancer. Based on interrogation of matched lung tumor and normal tissue using targeted genomic sequencing, copy number variation, transcriptomics, and miRNA expression, the activation status of 24 interventional nodes was elucidated. An algorithm was developed to create a scoring system that enables ranking of the activated interventional nodes for each patient. Based on the trends of co-activation at interventional points, combinations of drug triplets were defined in order to overcome resistance. This methodology will inform a prospective trial to be conducted by the WIN consortium, aiming to significantly impact survival in metastatic NSCLC and other malignancies

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms