Simian virus 40 large tumor antigen-immortalized normal human liver epithelial cells express hepatocyte characteristics and metabolize chemical carcinogens.

Normal human liver tissue and cultured human hepatocytes are valuable models to study xenobiotic metabolism and toxicity, but they only have a limited in vitro life-span and are not readily available. This report describes the establishment of replicative cultures of human adult liver epithelial cells in serum-free medium. The longevity of three of these cultures, derived from different donors, was extended by introduction of the simian virus 40 large T antigen gene. Two cell lines, THLE-2 and -3, established with a recombinant simian virus 40 large T antigen virus have undergone > 100 population doublings, are nontumorigenic when injected into athymic nude mice, have near-diploid karyotypes, and do not express alpha-fetoprotein. The cells express cytokeratin 18 and albumin in early passage, whereas higher-passage cells in logarithmic-phase growth also express cytokeratin 19. THLE-2 and -3 cells metabolize benzo[a]pyrene, N-nitrosodimethylamine, and aflatoxin B1 to their ultimate carcinogenic metabolites that adduct DNA, which indicates functional cytochrome P450 pathways. Other enzymes involved in metabolism of chemical carcinogens, such as epoxide hydrolase, NADPH cytochrome P450 reductase, superoxide dismutase, catalase, glutathione S-transferases, and glutathione peroxidase are also retained by THLE cells. Thus, these immortalized human liver cells constitute an in vitro model for pharmacotoxicological studies and for the investigation of etiology and pathogenesis of human hepatocellular carcinoma.     

Acute exacerbation of chronic obstructive pulmonary disease: Influence of social factors in determining length of hospital stay and readmission rates

BACKGROUND:

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is the leading reason for hospitalization in Canada and a significant financial burden on hospital resources. Identifying factors that influence the time a patient spends in the hospital and readmission rates will allow for better use of scarce hospital resources.

OBJECTIVES:

To determine the factors that influence length of stay (LOS) in the hospital and readmission for patients with AECOPD in an inner-city hospital.

METHODS:

Using the Providence Health Records, a retrospective review of patients admitted to St Paul’s Hospital (Vancouver, British Columbia) during the winter of 2006 to 2007 (six months) with a diagnosis of AECOPD, was conducted. Exacerbations were classified according to Anthonisen criteria to determine the severity of exacerbation on admission. Severity of COPD was scored using the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. For comparative analysis, severity of disease (GOLD criteria), age, sex and smoking history were matched.

RESULTS:

Of 109 admissions reviewed, 66 were single admissions (61%) and 43 were readmissions (39%). The number of readmissions ranged from two to nine (mean of 3.3 readmissions). More than 85% of admissions had the severity of COPD equal to or greater than GOLD stage 3. The significant indicators for readmission were GOLD status (P<0.001), number of related comorbidities (OR 1.47, 95% CI 1.10 to 1.97; P<0.009) and marital status (single) (OR 4.18, 95% CI 1.03 to 17.02; P<0.046). The requirement for social work involvement during hospital admission was associated with a prolonged LOS (P<0.05).

CONCLUSIONS:

The results of the present study show that disease severity (GOLD status) and number of comorbidities are associated with readmission rates of patients with AECOPD. Interestingly, social factors such as marital status and the need for social work intervention are also linked to readmission rates and LOS, respectively, in patients with AECOPD.     

Seasonality and daily weather conditions in relation to myocardial infarction and sudden cardiac death in Olmsted County, Minnesota, 1979 to 2002.

OBJECTIVES: We assessed the relationship of season and weather types with myocardial infarction (MI) and sudden cardiac death (SCD) in a geographically defined population, and tested the hypothesis that the increased risk in winter was related to weather. BACKGROUND: Winter peaks in coronary heart disease (CHD) have been documented. Yet, it is uncertain if seasonality exists for both incident events and deaths, and the role of weather conditions is not clear. METHODS: The daily occurrence of incident MI and SCD in Olmsted County was examined with data from the National Weather Service. Poisson regression models were used to assess the relative risks (RRs) associated with season and climatic variables. Subsequent analysis stratified SCD into those with and without antecedent CHD (unexpected SCD). RESULTS: Between 1979 and 2002, 2,676 MI and 2,066 SCD occurred. The age-, gender-, and year-adjusted RR of SCD, but not of MI, was increased in winter versus summer (1.17, 95% confidence interval [CI] 1.03 to 1.32) and in low temperatures (1.20, 95% CI 1.07 to 1.35, for temperatures below 0 degrees C vs. 18 degrees C to 30 degrees C). These associations were stronger for unexpected SCD than for SCD with prior CHD (p < 0.05). After adjustment for all climatic variables, low temperature was associated with a large increase in the risk of unexpected SCD (RR = 1.38, 95% CI 1.10 to 1.73), while the association with winter declined (RR = 1.06, 95% CI 0.83 to 1.35). CONCLUSIONS: These data suggest that the winter peak in SCD can be accounted for by daily weather.     

Further delineation of the KBG syndrome caused by ANKRD11 aberrations

Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.