Biliary Anomalies in Patients With HNF1B Diabetes

Context: The clinical spectrum of organogenetic anomalies associated with HNF1B mutations is heterogeneous. Besides cystic kidney disease, diabetes, and various other manifestations, odd cases of mainly neonatal and posttransplantation cholestasis have been described. The biliary phenotype is incompletely defined. Objective: To systematically characterize HNF1B-related anomalies in the bile ducts by imaging with magnetic resonance imaging (MRI) or magnetic resonance cholangiopancreatography (MRCP). Setting and Patients: Fourteen patients with HNF1B mutations in the catchment area of the Helsinki University Hospital were evaluated with upper abdominal MRI and MRCP. Blood samples and clinical history provided supplemental data on the individual phenotype. Main Outcome Measure(s): Structural anomalies in the biliary system, medical history of cholestasis, other findings in abdominal organs, diabetes and antihyperglycemic treatment, hypomagnesemia, and hyperuricemia. Results: Structural anomalies of the bile ducts were found in seven of 14 patients (50%). Six patients had choledochal cysts, which are generally considered premalignant. Conclusions: Structural anomalies of the biliary system were common in HNF1B mutation carriers. The malignant potential of HNF1B-associated choledochal cysts warrants further studies.Peer reviewe

The Impact of Overstocking and Negative Energy Balance on Quantitative Measurement of Non-typhoidal Salmonella in Periparturient Dairy Cattle

Stressful conditions in animal production facilities may exacerbate the fecal shedding and foodborne transmission of non-typhoidal Salmonella enterica subsp. enterica. Dairy cows are reservoirs of this zoonotic microorganism, and its prevalence has roughly doubled in the past decade on dairy farms in United States. Dairy cows are commonly overstocked at the feed bunk, and stressors placed on the animal prior to parturition may exacerbate Salmonella shedding. However, no studies have evaluated the impact of overstocking and metabolic stress on fecal concentrations of the pathogen. Therefore, we conducted a field trial with 120 multiparous dairy cows randomized into one of four treatment groups with different stocking densities at the feed bunk during the periparturient period as follows: US, understocked from -60 to -1 DRC; OS, overstocked from -60 to -1 DRC; USOS, understocked from -60 to -26 DRC/overstocked from -25 to -1 DRC; and OSUS, overstocked from -60 to -26 DRC/ understocked from -25 to -1 DRC. Fecal and blood samples were collected at four time points relative to calving. qPCR assays were used to quantify Salmonella invA gene and total bacterial community from fecal samples, and a subset of isolates recovered from fecal bacterial culture were characterized using pulsed field gel electrophoresis and serotyping. Serum non-esterified fatty acids (NEFA) were measured as a metabolic stress indicator using an immunoassay. Multivariable analyses were performed to test if changes in Salmonella concentrations were associated with stocking density, energy balance, or days relative to calving. From fecal isolates, three Salmonella serovars were identified, S. Cerro; Kentucky; Meleagridis. Concentrations of Salmonella increased as cows approached calving. Higher stocking densities at the feed bunk did not impact total bacterial community or NEFA; however, cows in the overstocked groups had higher Salmonella fecal concentrations. Further, cows with higher NEFA concentrations after calving had a higher likelihood of detection of Salmonella. Future farm interventions should aim to reduce environmental and metabolic stress during the periparturient period to decrease the dissemination of Salmonella to cattle, the environment, and humans.Peer reviewe

Psychiatric disorders, psychotropic medication use and falls among women: an observational study

BACKGROUND: Psychotropic agents known to cause sedation are associated with an increased risk of falls, but the role of psychiatric illness as an independent risk factor for falls is not clear. Thus, this study aimed to investigate the association between psychiatric disorders, psychotropic medication use and falls risk. METHODS: This study examined data collected from 1062 women aged 20-93 yr (median 50 yr) participating in the Geelong Osteoporosis Study, a large, ongoing, population-based study. Depressive and anxiety disorders for the preceding 12-month period were ascertained by clinical interview. Current medication use and falls history were self-reported. Participants were classified as fallers if they had fallen to the ground at least twice during the same 12-month period. Anthropometry, demographic, medical and lifestyle factors were determined. Logistic regression was used to test the associations, after adjusting for potential confounders. RESULTS: Fifty-six women (5.3%) were classified as fallers. Those meeting criteria for depression within the past 12 months had a 2.4-fold increased odds of falling (unadjusted OR = 2.4, 95% CI 1.2-4.5). Adjustment for age and mobility strengthened the relationship (adjusted OR = 2.7, 95% CI 1.4-5.2) between depression and falling, with results remaining unchanged following further adjustment for psychotropic medication use (adjusted OR = 2.7, 95% CI 1.3-5.6). In contrast, past (prior to 12-month) depression were not associated with falls. No association was observed between anxiety and falls risk. Falling was associated with psychotropic medication use (unadjusted OR = 2.8, 95% CI 1.5-5.2), as well as antidepressant (unadjusted OR = 2.4, 95% CI 1.2-4.8) and benzodiazepine use (unadjusted OR = 3.4, 95% CI 1.6-7.3); associations remained unchanged following adjustment for potential confounders. CONCLUSION: The likelihood of falls was increased among those with depression within the past 12 months, independent of psychotropic medication use and other recognised confounders, suggesting an independent effect of depression on falls risk. Psychotropic drug use was also confirmed as an independent risk factor for falls, but anxiety disorders were not. Further research into the underlying mechanisms is warranted

Ectodysplasin/NF-kappa B Promotes Mammary Cell Fate via Wnt/beta-catenin Pathway

Mammary gland development commences during embryogenesis with the establishment of a species typical number of mammary primordia on each flank of the embryo. It is thought that mammary cell fate can only be induced along the mammary line, a narrow region of the ventro-lateral skin running from the axilla to the groin. Ectodysplasin (Eda) is a tumor necrosis factor family ligand that regulates morphogenesis of several ectodermal appendages. We have previously shown that transgenic overexpression of Eda (K14-Eda mice) induces formation of supernumerary mammary placodes along the mammary line. Here, we investigate in more detail the role of Eda and its downstream mediator transcription factor NF-kappa B in mammary cell fate specification. We report that K14-Eda mice harbor accessory mammary glands also in the neck region indicating wider epidermal cell plasticity that previously appreciated. We show that even though NF-kappa B is not required for formation of endogenous mammary placodes, it is indispensable for the ability of Eda to induce supernumerary placodes. A genome-wide profiling of Eda-induced genes in mammary buds identified several Wnt pathway components as potential transcriptional targets of Eda. Using an ex vivo culture system, we show that suppression of canonical Wnt signalling leads to a dose-dependent inhibition of supernumerary placodes in K14-Eda tissue explants.Peer reviewe

Pim-selective inhibitor DHPCC-9 reveals Pim kinases as potent stimulators of cancer cell migration and invasion

<p>Abstract</p> <p>Background</p> <p>Pim family kinases are small constitutively active serine/threonine-specific kinases, elevated levels of which have been detected in human hematopoietic malignancies as well as in solid tumours. While we and others have previously shown that the oncogenic Pim kinases stimulate survival of hematopoietic cells, we now examined their putative role in regulating motility of adherent cancer cells. For this purpose, we inhibited Pim kinase activity using a small molecule compound, 1,10-dihydropyrrolo[2,3-<it>a</it>]carbazole-3-carbaldehyde (DHPCC-9), which we had recently identified as a potent and selective inhibitor for all Pim family members.</p> <p>Results</p> <p>We now demonstrate that the Pim kinase inhibitor DHPCC-9 is very effective also in cell-based assays. DHPCC-9 impairs the anti-apoptotic effects of Pim-1 in cytokine-deprived myeloid cells and inhibits intracellular phosphorylation of Pim substrates such as Bad. Moreover, DHPCC-9 slows down migration and invasion of cancer cells derived from either prostate cancer or squamocellular carcinoma patients. Silencing of Pim expression reduces cell motility, while Pim overexpression enhances it, strongly suggesting that the observed effects of DHPCC-9 are dependent on Pim kinase activity. Interestingly, DHPCC-9 also abrogates NFATc-dependent migration of cancer cells, implying that NFATc factors mediate at least part of the pro-migratory effects of Pim kinases.</p> <p>Conclusions</p> <p>Altogether, our data indicate that DHPCC-9 is not only a powerful tool to investigate physiological effects of the oncogenic Pim family kinases, but also an attractive molecule for drug development to inhibit invasiveness of Pim-overexpressing cancer cells.</p

International perception of lung sounds : a comparison of classification across some European borders

Peer reviewe

Specifying computer-supported collaboration scripts

Collaboration scripts are activity programs which aim to foster collaborative learning by structuring interaction between learners. Computer-supported collaboration scripts generally suffer from the problem of being restrained to a specific learning platform and learning context. A standardization of collaboration scripts first requires a specification of collaboration scripts that integrates multiple perspectives from computer science, education and psychology. So far, only few and limited attempts at such specifications have been made. This paper aims to consolidate and expand these approaches in light of recent findings and to propose a generic framework for the specification of collaboration scripts. The framework enables a description of collaboration scripts using a small number of components (participants, activities, roles, resources and groups) and mechanisms (task distribution, group formation and sequencing)

Deep sequencing of blood and gut T-cell receptor beta-chains reveals gluten-induced immune signatures in celiac disease

Celiac disease (CD) patients mount an abnormal immune response to gluten. T-cell receptor (TCR) repertoires directed to some immunodominant gluten peptides have previously been described, but the global immune response to in vivo gluten exposure in CD has not been systematically investigated yet. Here, we characterized signatures associated with gluten directed immune activity and identified gluten-induced T-cell clonotypes from total blood and gut TCR repertoires in an unbiased manner using immunosequencing. CD patient total TCR repertoires showed increased overlap and substantially altered TRBV-gene usage in both blood and gut samples, and increased diversity in the gut during gluten exposure. Using differential abundance analysis, we identified gluten-induced clonotypes in each patient that were composed of a large private and an important public component. Hierarchical clustering of public clonotypes associated with dietary gluten exposure identified subsets of highly similar clonotypes, the most proliferative of which showing significant enrichment for the motif ASS[LF] R[SW][TD][DT][TE][QA][YF] in PBMC repertoires. These results show that CD-associated clonotypes can be identified and that common gluten associated immune response features can be characterized in vivo from total repertoires, with potential use in disease stratification and monitoring.Peer reviewe