Progenitor cells in liver regeneration: molecular responses controlling their activation and expansion

Although normally quiescent, the adult mammalian liver possesses a great capacity to regenerate after different types of injuries in order to restore the lost liver mass and ensure maintenance of the multiple liver functions. Major players in the regeneration process are mature residual cells, including hepatocytes, cholangiocytes and stromal cells. However, if the regenerative capacity of mature cells is impaired by liver-damaging agents, hepatic progenitor cells are activated and expand into the liver parenchyma. Upon transit amplification, the progenitor cells may generate new hepatocytes and biliary cells to restore liver homeostasis. In recent years, hepatic progenitor cells have been the subject of increasing interest due to their therapeutic potential in numerous liver diseases as alternative or supportive/complementary tools to liver transplantation. While the first investigations on hepatic progenitor cells have focused on their origin and phenotypic characterization, recent attention has focused on the influence of the hepatic microenvironment on their activation and proliferation. This microenvironment comprises the extracellular matrix, epithelial and non-epithelial resident liver cells, and recruited inflammatory cells as well as the variety of growth-modulating molecules produced and/or harboured by these elements. The cellular and molecular responses to different regenerative stimuli seem to depend on the injury inflicted and consequently on the molecular microenvironment created in the liver by a certain insult. This review will focus on molecular responses controlling activation and expansion of the hepatic progenitor cell niche, emphasizing similarities and differences in the microenvironments orchestrating regeneration by recruitment of progenitor cell populations or by replication of mature cells.     

P.A. Schleisner: a pioneer in epidemiology.

In 1847 Schleisner (b. 1818) was sent from Copenhagen to the Vestmanna Islands in Iceland to study the epidemic of tetanus neonatorum. The neonatal mortality in those islands at that time was 600-740 per 1000 children. He built a small hospital and introduced treatment with Peru balsam of the umbilicus. Schleisner probably assumed that the infection was caused by airborne infection, contact infection or poor hygiene. The neonatal mortality fell to about 50 per 1000. Schleisner published his results in 1849. Semmelweiss published his observations in 1850 and Snow successfully fought the cholera epidemic in London in 1854. Schleisner deserves recognition as a pioneer in the field of epidemiology.     

Spiramycin is comparable to oxytetracycline in eradicating H. pylori when given with ranitidine bismuth citrate and metronidazole

BACKGROUND: We have consistently achieved about 90% eradication of H. pylori with liquid bismuth, metronidazole and oxytetracycline. AIM: To test eradication and adverse events of ranitidine bismuth citrate (RBC) when given with metronidazole and either oxytetracycline or spiramycin. METHODS: One hundred and eighty-three patients were randomized to one of four 10-day regimens: RBC400OM: RBC 400 mg b.d., oxytetracycline 500 mg q.d.s.; RBC400SM: RBC 400 mg b.d., spiramycin 1 g q.d.s.; RBC200OM: RBC 200 mg q.d.s., oxytetracycline 500 mg q.d.s.; RBC200SM: RBC 200 mg q.d.s., spiramycin 1 g q.d.s. Additionally, all patients received metronidazole 400 mg q.d.s. A 14C-urea breath test was performed at 8 weeks. RESULTS: Intention-to-treat eradication rates were 94%, 91%, 94% and 89% with RBC400OM, RBC400SM, RBC200OM and RBC200SM, respectively (P = 0.81). Eradication was significantly higher in ulcer patients (97%) than in those with diagnoses other than ulcer (86%) (P = 0.009). There was a strong tendency to better eradication among those who had never smoked (100%) compared with ex-smokers (93%) and smokers (89%) (P = 0.06). Fifty-three per cent experienced at least one moderate or severe adverse event, and women had more adverse events than men (P = 0.0002). CONCLUSIONS: All four regimens had comparable efficacy and adverse events. Eradication was significantly better in ulcer patients but there was a trend to better eradication in those who smoked less, used less alcohol and exercised more. Adverse events were frequent, perhaps because of the large dose of metronidazole used, but few patients stopped treatment.     

Disruption of beta-catenin pathway or genomic instability define two distinct categories of liver cancer in transgenic mice

BACKGROUND & AIMS: Human liver cancer can be divided into 2 categories that are characterized by activation of beta-catenin and genomic instability. Here we investigate whether similar categories exist among 5 transgenic models of liver cancer, including c-myc, transforming growth factor-alpha, E2F-1, c-myc/transforming growth factor-alpha, and c-myc/E2F-1 mice. METHODS: The random amplified polymorphic DNA method was used to assess the overall genomic instability, and chromosomal loci affected by genomic alterations were determined by microsatellite analysis. beta-Catenin mutations and deletions were analyzed by polymerase chain reaction and sequencing screening. Cellular localization of beta-catenin and expression of alpha-fetoprotein, a prognostic marker of hepatocellular carcinoma, were investigated by immunohistochemistry. RESULTS: Liver tumors from the transgenic mice could be divided into 2 broad categories characterized by extensive genomic instability (exemplified by the c-myc/transforming growth factor-alpha mouse) and activation of beta-catenin (exemplified by the c-myc/E2F-1 mouse). The c-myc/transforming growth factor-alpha tumors displayed extensive genomic instability with recurrent loss of heterozygosity at chromosomes 1, 2, 4, 6, 7, 9, 12, 14, and X and a low rate of beta-catenin activation. The genomic instability was evident from the early dysplastic stage and occurred concomitantly with increased expression of alpha-fetoprotein. The c-myc/E2F-1 tumors were characterized by a high frequency of beta-catenin activation in the presence of a relatively stable genome and low alpha-fetoprotein levels. CONCLUSIONS: We have identified 2 prototype experimental models, i.e., c-myc/transforming growth factor-alpha and c-myc/E2F-1 mice, for the 2 categories of human hepatocellular carcinoma characterized by genomic instability and beta-catenin activation, respectively. These mouse models will assist in the elucidation of the molecular basis of human hepatocellular carcinoma.     

Sixty-five gene-based risk score classifier predicts overall survival in hepatocellular carcinoma

Clinical application of the prognostic gene expression signature has been delayed due to the large number of genes and complexity of prediction algorithms. In the current study we aimed to develop an easy-to-use risk score with a limited number of genes that can robustly predict prognosis of patients with hepatocellular carcinoma (HCC). The risk score was developed using Cox coefficient values of 65 genes in the training set (n = 139) and its robustness was validated in test sets (n = 292). The risk score was a highly significant predictor of overall survival (OS) in the first test cohort (P = 5.6 × 10(-5), n = 100) and the second test cohort (P = 5.0 × 10(-5) , n = 192). In multivariate analysis, the risk score was a significant risk factor among clinical variables examined together (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.13-1.64; P = 0.001 for OS). CONCLUSION: The risk score classifier we have developed can identify two clinically distinct HCC subtypes at early and late stages of the disease in a simple and highly reproducible manner across multiple datasets.     

Urinary tract infections, antibiotic resistance and sales of antimicrobial drugs--an observational study of uncomplicated urinary tract infections in Icelandic women

OBJECTIVES: To analyse the antimicrobial susceptibility pattern of bacteria causing symptomatic but otherwise uncomplicated lower urinary tract infections (UTI) in primary health care and the sales of antimicrobial drugs. SETTING: Primary health care in Akureyri District, Northern Iceland, with about 17400 inhabitants. PATIENTS: A total of 516 episodes of symptomatic but otherwise uncomplicated lower UTI in women 10 to 69 years of age. MAIN OUTCOME MEASURES: Number of verified UTI, bacterial species, antimicrobial susceptibility pattern, and total sales of antimicrobial drugs. RESULTS: Escherichia coli was by far the most common cause of UTI (83%), followed by Staphylococcus saprophyticus (7%). Infections caused by E. coli resistant to ampicillin accounted for 36% of cases, with the corresponding figures for sulfafurazol being 37%, cephalothin 45%, trimethoprim 13% and mecillinam 14%. Only 1% of the strains were resistant to nitrofurantoin. The total use of antimicrobial drugs was 17.4 DDD/1000 inhabitants/day. CONCLUSIONS: The resistance of bacteria causing uncomplicated UTI to common antimicrobials is high and must be taken into account when selecting treatment strategies. High consumption of antibiotics in the community indicates possible association.