Patients with cholestatic liver disease, including those with primary biliary cholangitis, can experience symptoms of impaired cognition or brain fog. This phenomenon remains unexplained and is ...currently untreatable. Bile duct ligation (BDL) is an established rodent model of cholestasis. In addition to liver changes, BDL animals develop cognitive symptoms early in the disease process (before development of cirrhosis and/or liver failure). The cellular mechanisms underpinning these cognitive symptoms are poorly understood. Herein, the study explored the neurocognitive symptom manifestations, and tested potential therapies, in BDL mice, and used human neuronal cell cultures to explore translatability to humans. BDL animals exhibited short-term memory loss and showed reduced astrocyte coverage of the blood-brain barrier, destabilized hippocampal network activity, and neuronal senescence. Ursodeoxycholic acid (first-line therapy for most human cholestatic diseases) did not reverse symptomatic or mechanistic aspects. In contrast, obeticholic acid (OCA), a farnesoid X receptor agonist and second-line anti-cholestatic agent, normalized memory function, suppressed blood-brain barrier changes, prevented hippocampal network deficits, and reversed neuronal senescence. Co-culture of human neuronal cells with either BDL or human cholestatic patient serum induced cellular senescence and increased mitochondrial respiration, changes that were limited again by OCA. These findings provide new insights into the mechanism of cognitive symptoms in BDL animals, suggesting that OCA therapy or farnesoid X receptor agonism could be used to limit cholestasis-induced neuronal senescence.
Display omitted
Childhood onset uveitis comprises a group of rare inflammatory disorders characterized by clinical heterogeneity, chronicity, and uncertainties around long term outcomes. Standardized, detailed ...datasets with harmonized clinical definitions and terminology are needed to enable the clinical research necessary to stratify disease phenotype and interrogate the putative determinants of health outcomes. We aimed to develop a core routine clinical collection dataset for clinicians managing children with uveitis, suitable for multicenter and national clinical and experimental research initiatives.
Development of the dataset was undertaken in three phases: phase 1, a rapid review of published datasets used in clinical research studies; phase 2, a scoping review of disease or drug registries, national cohort studies and core outcome sets; and phase 3, a survey of members of a multicenter clinical network of specialists. Phases 1 and 2 provided candidates for a long list of variables for the dataset. In Phase 3, members of the UK's national network of stakeholder clinicians who manage childhood uveitis (the Pediatric Ocular Inflammation Group) were invited to select from this long-list their essential items for the core clinical dataset, to identify any omissions, and to support or revise the clinical definitions. Variables which met a threshold of at least 95% agreement were selected for inclusion in the core clinical dataset.
The reviews identified 42 relevant studies, and 9 disease or drug registries. In total, 138 discrete items were identified as candidates for the long-list. Of the 41 specialists invited to take part in the survey, 31 responded (response rate 78%). The survey resulted in inclusion of 89 data items within the final core dataset: 81 items to be collected at the first visit, and 64 items at follow up visits.
We report development of a novel consensus core clinical dataset for the routine collection of clinical data for children diagnosed with non-infectious uveitis. The development of the dataset will provide a standardized approach to data capture able to support observational clinical studies embedded within routine clinical care and electronic patient record capture. It will be validated through a national prospective cohort study, the Uveitis in childhood prospective national cohort study (UNICORNS).
Because it is not possible to monitor skin cancer accurately using routine methods, special surveys have been undertaken in Nambour, a typical subtropical community in Queensland, Australia. ...Estimates of incidence reported here are based on skin cancers medically treated between 1985 and 1992 and new cases diagnosed by dermatologists in two examination clinics in 1986 and 1992. Among men and women aged 18–69 years in 1986, age-adjusted incidence rates of basal cell carcinoma were 2,074 and 1,579 per 100,000 per year, respectively—the highest incidence rates of a specific cancer ever reported. Squamous cell carcinoma occurred at half the rate of basal cell carcinoma among men and at about one third the rate among women. Although as expected, fair skin, a history of repeated sunburns, and nonmalignant solar skin damage diagnosed by dermatologists were strongly associated with both types of skin cancer, outdoor occupation was not. Significant self-selection was observed among outdoor workers, whereby people with fair or medium complexions and a tendency to sunburn were systematically underrepresented among those in long-term outdoor occupations although they accounted for more than 80 percent of the community study sample. The mitigating effect of this selection bias may partly explain the paradox of the lack of quantitative evidence of a causal link between sun exposure and skin cancer in humans. Am J Epidemiol 1996;144:1034–40.
PDF
