A TGFβ-ECM-Integrin signalling axis drives structural reconfiguration of the bile duct to promote polycystic liver disease

: The formation of multiple cysts in the liver occurs in a number of isolated monogenic diseases or multisystemic syndromes, during which bile ducts develop into fluid-filled biliary cysts. For patients with polycystic liver disease (PCLD), nonsurgical treatments are limited, and managing life-long abdominal swelling, pain, and increasing risk of cyst rupture and infection is common. We demonstrate here that loss of the primary cilium on postnatal biliary epithelial cells (via the deletion of the cilia gene Wdr35) drives ongoing pathological remodeling of the biliary tree, resulting in progressive cyst formation and growth. The development of cystic tissue requires the activation of transforming growth factor-β (TGFβ) signaling, which promotes the expression of a procystic, fibronectin-rich extracellular matrix and which itself is perceived by a changing profile of integrin receptors on the cystic epithelium. This signaling axis is conserved in liver cysts from patients with either autosomal dominant polycystic kidney disease or autosomal dominant polycystic liver disease, indicating that there are common cellular mechanisms for liver cyst growth regardless of the underlying genetic cause. Cyst number and size can be reduced by inhibiting TGFβ signaling or integrin signaling in vivo. We suggest that our findings represent a therapeutic route for patients with polycystic liver disease, most of whom would not be amenable to surgery

In vivo modeling of patient genetic heterogeneity identifies new ways to target cholangiocarcinoma.

L. Boulter was funded by The Wellcome Trust (207793/Z/17/Z), AMMF (2016/108, 2017/115), and Cancer Research UK (C52499/A27948). L. Boulter is also supported by an MRC university grant to the MRC Human Genetics Unit

Mortality in Dutch hospitals: Trends in time, place and cause of death after admission for myocardial infarction and stroke. An observational study

<p>Abstract</p> <p>Background</p> <p>Patterns in time, place and cause of death can have an important impact on calculated hospital mortality rates. Objective is to quantify these patterns following myocardial infarction and stroke admissions in Dutch hospitals during the period 1996–2003, and to compare trends in the commonly used 30-day in-hospital mortality rates with other types of mortality rates which use more extensive follow-up in time and place of death.</p> <p>Methods</p> <p>Discharge data for all Dutch admissions for index conditions (1996–2003) were linked to the death certification registry. Then, mortality rates within the first 30, 90 and 365 days following admissions were analyzed for deaths occurring within and outside hospitals.</p> <p>Results</p> <p>Most deaths within a year after admission occurred within 30 days (60–70%). No significant trends in this distribution of deaths over time were observed. Significant trends in the distribution over place of death were observed for both conditions. For myocardial infarction, the proportion of deaths after transfer to another hospital has doubled from 1996–2003. For stroke a significant rise of the proportion of deaths outside hospital was found. For MI the proportion of deaths attributed to a circulatory disease has significantly fallen ovtime. Seven types of hospital mortality indicators, different in scope and observation period, all show a drop of hospital mortality for both MI and stroke over the period 1996–2003. For stroke the observed absolute reduction in death rate increases for the first year after admission, for MI the observed drop in 365-day overall mortality almost equals the observed drop in 30-day in hospital mortality over 1996–2003.</p> <p>Conclusion</p> <p>Changes in the timing, place and causes of death following admissions for myocardial infarction and stroke have important implications for the definitions of in-hospital and post-admission mortality rates as measures of hospital performance. Although necessary for understanding mortality patterns over time, including within mortality rates deaths which occur outside hospitals and after longer periods following index admissions remain debatable and may not reflect actual hospital performance but probably mirrors transfer, efficiency, and other health care policies.</p

Availability and structure of primary medical care services and population health and health care indicators in England

BACKGROUND: It has been proposed that greater availability of primary medical care practitioners (GPs) contributes to better population health. We evaluated whether measures of the supply and structure of primary medical services are associated with health and health care indicators after adjusting for confounding. METHODS: Data for the supply and structure of primary medical services and the characteristics of registered patients were analysed for 99 health authorities in England in 1999. Health and health care indicators as dependent variables included standardised mortality ratios (SMR), standardised hospital admission rates, and conceptions under the age of 18 years. Linear regression analyses were adjusted for Townsend score, proportion of ethnic minorities and proportion of social class IV/ V. RESULTS: Higher proportions of registered rural patients and patients ≥ 75 years were associated with lower Townsend deprivation scores, with larger partnership sizes and with better health outcomes. A unit increase in partnership size was associated with a 4.2 (95% confidence interval 1.7 to 6.7) unit decrease in SMR for all-cause mortality at 15–64 years (P = 0.001). A 10% increase in single-handed practices was associated with a 1.5 (0.2 to 2.9) unit increase in SMR (P = 0.027). After additional adjustment for percent of rural and elderly patients, partnership size and proportion of single-handed practices, GP supply was not associated with SMR (-2.8, -6.9 to 1.3, P = 0.183). CONCLUSIONS: After adjusting for confounding with health needs of populations, mortality is weakly associated with the degree of organisation of practices as represented by the partnership size but not with the supply of GPs

DNA Microarrays for Identifying Fishes

In many cases marine organisms and especially their diverse developmental stages are difficult to identify by morphological characters. DNA-based identification methods offer an analytically powerful addition or even an alternative. In this study, a DNA microarray has been developed to be able to investigate its potential as a tool for the identification of fish species from European seas based on mitochondrial 16S rDNA sequences. Eleven commercially important fish species were selected for a first prototype. Oligonucleotide probes were designed based on the 16S rDNA sequences obtained from 230 individuals of 27 fish species. In addition, more than 1200 sequences of 380 species served as sequence background against which the specificity of the probes was tested in silico. Single target hybridisations with Cy5-labelled, PCR-amplified 16S rDNA fragments from each of the 11 species on microarrays containing the complete set of probes confirmed their suitability. True-positive, fluorescence signals obtained were at least one order of magnitude stronger than false-positive cross-hybridisations. Single nontarget hybridisations resulted in cross-hybridisation signals at approximately 27% of the cases tested, but all of them were at least one order of magnitude lower than true-positive signals. This study demonstrates that the 16S rDNA gene is suitable for designing oligonucleotide probes, which can be used to differentiate 11 fish species. These data are a solid basis for the second step to create a “Fish Chip” for approximately 50 fish species relevant in marine environmental and fisheries research, as well as control of fisheries products

"Nested" cryptic diversity in a widespread marine ecosystem engineer: a challenge for detecting biological invasions

<p>Abstract</p> <p>Background</p> <p>Ecosystem engineers facilitate habitat formation and enhance biodiversity, but when they become invasive, they present a critical threat to native communities because they can drastically alter the receiving habitat. Management of such species thus needs to be a priority, but the poorly resolved taxonomy of many ecosystem engineers represents a major obstacle to correctly identifying them as being either native or introduced. We address this dilemma by studying the sea squirt <it>Pyura stolonifera</it>, an important ecosystem engineer that dominates coastal communities particularly in the southern hemisphere. Using DNA sequence data from four independently evolving loci, we aimed to determine levels of cryptic diversity, the invasive or native status of each regional population, and the most appropriate sampling design for identifying the geographic ranges of each evolutionary unit.</p> <p>Results</p> <p>Extensive sampling in Africa, Australasia and South America revealed the existence of "nested" levels of cryptic diversity, in which at least five distinct species can be further subdivided into smaller-scale genetic lineages. The ranges of several evolutionary units are limited by well-documented biogeographic disjunctions. Evidence for both cryptic native diversity and the existence of invasive populations allows us to considerably refine our view of the native versus introduced status of the evolutionary units within <it>Pyura stolonifera </it>in the different coastal communities they dominate.</p> <p>Conclusions</p> <p>This study illustrates the degree of taxonomic complexity that can exist within widespread species for which there is little taxonomic expertise, and it highlights the challenges involved in distinguishing between indigenous and introduced populations. The fact that multiple genetic lineages can be native to a single geographic region indicates that it is imperative to obtain samples from as many different habitat types and biotic zones as possible when attempting to identify the source region of a putative invader. "Nested" cryptic diversity, and the difficulties in correctly identifying invasive species that arise from it, represent a major challenge for managing biodiversity.</p

Optimal foraging and community structure: implications for a guild of generalist grassland herbivores

A particular linear programming model is constructed to predict the diets of each of 14 species of generalist herbivores at the National Bison Range, Montana. The herbivores have body masses ranging over seven orders of magnitude and belonging to two major taxa: insects and mammals. The linear programming model has three feeding constraints: digestive capacity, feeding time and energy requirements. A foraging strategy that maximizes daily energy intake agrees very well with the observed diets. Body size appears to be an underlying determinant of the foraging parameters leading to diet selection. Species that possess digestive capacity and feeding time constraints which approach each other in magnitude have the most generalized diets. The degree that the linear programming models change their diet predictions with a given percent change in parameter values (sensitivity) may reflect the observed ability of the species to vary their diets. In particular, the species which show the most diet variability are those whose diets tend to be balanced between monocots and dicots. The community-ecological parameters of herbivore body-size ranges and species number can possibly be related to foraging behavior.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47765/1/442_2004_Article_BF00377109.pd