NXF1 and CRM1 nuclear export pathways orchestrate nuclear export, translation and packaging of murine leukaemia retrovirus unspliced RNA.

Cellular mRNAs are exported from the nucleus as fully spliced RNAs. Proofreading mechanisms eliminate unprocessed and irregular pre-mRNAs to control the quality of gene expression. Retroviruses need to export partially spliced and unspliced full-length RNAs to the cytoplasm where they serve as templates for protein synthesis and/or as encapsidated RNA in progeny viruses. Genetically complex retroviruses such as HIV-1 use Rev-equivalent proteins to export intron-retaining RNA from the nucleus using the cellular CRM1-driven nuclear export machinery. By contrast, genetically simpler retroviruses such as murine leukaemia virus (MLV) recruit the NXF1 RNA export machinery. In this study, we reveal for the first time that MLV hijacks both NXF1 and CRM1-dependent pathways to achieve optimal replication capacity. The CRM1-pathway marks the MLV full-length RNA (FL RNA) for packaging, while NXF1-driven nuclear export is coupled to translation. Thus, the cytoplasmic function of the viral RNA is determined early in the nucleus. Depending on the nature of ribonucleoprotein complex formed on FL RNA cargo in the nucleus, the FL RNA will be addressed to the translation machinery sites or to the virus-assembly sites at the plasma membrane.

Do microRNAs regulate bone marrow stem cell niche physiology?

The adult bone marrow, situated within the bone cavity, comprises three distinct stem cell populations: hematopoietic stem cells (HSCs), mesenchymal stromal/stem cells (MSCs) and endothelial progenitor/stem cells (EPCs). HSCs are a well-characterized population of self-renewing cells that give rise to all blood cells. The definition of MSCs is more complex due to the limited understanding of MSC properties. In general, MSCs are considered multipotent stromal cells that are able to differentiate into various cell types, including osteoblasts, chondrocytes and adipocytes. Compared to HSCs and MSCs, EPCs are a newly discovered population of stem/progenitor cells with the capacity to differentiate into endothelial cells, the cells forming the inner lining of a blood vessel. Although functionally different, HSCs, MSCs and EPCs, like stem cells in general, share the ability to self-renew and differentiate into one or more cell types. The homeostasis inside the bone marrow and within the entire body is sustained by an intricate network of growth factors and transcription factors that orchestrate the proliferation and differentiation of these multipotent stem/progenitor cells. Increasing evidence indicates that microRNAs (miRNAs), small non-coding RNAs, are among the key players of this concert. This review summarizes the current insights into miRNA-mediated regulation of bone marrow stem/progenitor cell maintenance and differentiation. Furthermore, the potential contribution of miRNAs in bone marrow stem cell niches is discussed.

Use of self-expandable metal stents for the treatment of esophageal perforations and anastomotic leaks.

BACKGROUND: Esophageal perforations and extensive anastomotic leaks after esophageal resection or gastrectomy are surgical emergencies with high mortality rates. In recent years, the use of self-expanding metallic stents (SEMS) has emerged as a promising treatment alternative for bridging and sealing the damage. This study aimed to evaluate the role of covered SEMS for the management of esophageal perforations and anastomotic leaks. METHODS: All esophageal stent placement procedures (174 procedures for 157 patients) at the authors' unit between January 1999 and April 2008 were assessed by a retrospective chart review. Of the 157 patients, 10 (6.4%) were treated with SEMS for sealing of an iatrogenic esophageal perforation (n = 4), a spontaneous esophageal rupture in Boerhaave's syndrome (n = 4), or an anastomotic leakage (n = 2). RESULTS: The median time from perforation or anastomotic leak to stent insertion was 13 days (range, 2 h to 48 days). The esophageal leak was totally sealed for 8 (80%) of 10 patients. The overall mortality rate was 50% (n = 5), and three (30%) of the five deaths were related to the perforation (n = 2) or leakage (n = 1). In both of the perforation cases, the diagnosis and treatment were substantially delayed. One patient with an anastomotic leak after gastrectomy died of the complication despite successful operative and SEMS treatment. Two of the deaths were unrelated to the perforation. In both cases, the cause of death was a disseminated malignant disease. CONCLUSIONS: Traumatic perforations and anastomotic leaks can be treated effectively with covered SEMS together with adequate drainage of the thoracic cavity even in cases of severely ill patients with inveterate esophageal perforations and leaks.

Job strain as a predictor of disability pension: the Finnish Public Sector Study.

OBJECTIVE: To examine whether high job strain (a combination of high job demands and low job control) is a risk factor for disability pension. SETTING: Ten municipalities and 21 hospitals in Finland. DESIGN AND PARTICIPANTS: A prospective cohort study of 20 386 female and 4 764 male Finnish public sector employees aged 19-50 using data from two surveys (baseline in 2000-2 and follow-up in 2005) and employers' registers. In addition to self-reported job strain, we computed work unit-aggregated job strain for each participant (the average of scores of all workers of participant's work unit except the participant him/herself). MAIN RESULTS: 93 employees (0.4%) retired because of disability during the follow-up. In multilevel logistic regression analysis adjusted for demographic characteristics and health risk behaviour, odds for disability pension was 2.60 (95% CI 1.26 to 5.34) times higher for employees with high self-assessed job strain than for those with low self-assessed job strain at baseline. The corresponding OR for passive job versus low job strain was 2.82 (95% CI 1.34 to 5.96). Analysis of work unit-aggregated scores replicated the association for high job strain, OR 2.25 (95% CI 1.17 to 4.35), but not that for passive job. The association between work unit job strain and disability pension remained significant after further adjustment for prevalent diseases, psychological distress and perceived health status. CONCLUSIONS: Job strain is associated with risk of subsequent disability pension. If causal, this association suggests that organisational interventions to reduce job strain may also reduce early exit from work.

Severe and fatal complications after ERCP: analysis of 2555 procedures in a single experienced center.

BACKGROUND AND STUDY AIMS: The majority of recent large series on endoscopic retrograde cholangiopancreatography (ERCP) complications have been multicenter studies reflecting varying degrees of experience and ERCP volume; major ERCP complications are associated with low case volume. The aim of this study was to report and analyze the frequency of severe and fatal complications associated with ERCP at a single specialized surgical high-volume referral center (Turku University Central Hospital). METHODS: All scheduled ERCP procedures (n = 2788) at our unit between January 1997 and December 2005 were included and the procedure-related severe and fatal complications were assessed by retrospective chart review. Complications were classified as severe or fatal according to standardized guidelines. RESULTS: The number of ERCP procedures performed was 2555, of which 71% were therapeutic and 29% were diagnostic. Seventeen (0.8%) severe complications were identified in 16 patients, of whom 15 underwent a therapeutic endoscopic procedure. Of the 17 severe complications, perforation constituted five cases (0.2%), pancreatitis occurred in five patients (0.2%), bleeding in five cases (0.2%), and two patients suffered from purulent cholangitis (0.1%). Procedure-related mortality was 0.08% (n = 3). CONCLUSIONS: In our study the rate of severe or fatal complications of ERCP is low in experienced hands at a high-volume center, comparing favorably to corresponding complication rates of multicenter series, which further supports the importance of centralizing ERCP procedures in high-volume advanced centers.

Surgeons' experience with laparoscopic fundoplication after the early personal experience: does it have an impact on the outcome?

BACKGROUND: The adverse outcomes of laparoscopic fundoplication are more likely during the initial 20 cases performed by each individual surgeon. This study aimed to evaluate the impact of substantial surgical experience versus experience beyond the learning curve on the early and late objective and subjective results. METHODS: The patients were divided into two groups according to the surgeon. In group 1 (n = 230), all the patients underwent surgery by a surgeon with substantial experience in laparoscopic fundoplication. In group 2 (n = 118), the patients were treated by a total of seven surgeons whose personal experience exceeded the individual learning curve, but was distinctively less than that of the group 1 surgeon. RESULTS: The conversion rate was 2.2% in group 1 and 4.4% in group 2. The median operating time was 65 min in group 1 and 70 min in group 2 (p = 0.0020). The occurrence of immediate complications was 3.5% in group 1 and 7.6% in group 2 (p = 0.0892). At 6 months after surgery, 7.4% of the patients in group 1 and 16.1% of the patients in group 2 reported that dysphagia disturbed their daily lives (p = 0.0115). The late subjective results, including postoperative symptoms and evaluation of the surgical result, were similar in the two groups. CONCLUSIONS: Substantial experience with the procedure is associated with a shorter operating time and somewhat fewer complications, conversions, and early dysphagia episodes. This supports the provision of expert supervision even after the initial learning phase of 20 individual procedures. The patients' long-term subjective symptomatic outcome was similar in the two groups. Substantial experience does not provide better late results than surgical experience beyond the learning curve.

Duodenal diazepam-binding protein expression and plasma cholecystokinin after alcoholic pancreatitis.

OBJECTIVE: After the first acute alcohol-induced pancreatitis (AAIP) episode 46 % of patients will have a recurrent attack, but the pathophysiology is unclear. The hyperstimulation of the pancreas with cholecystokinin (CCK) induces acute pancreatitis. Alcohol induces temporary stimulation of the pancreas and CCK could be a mediator. CCK is regulated by releasing peptides - diazepam-binding protein (DBI) being a possible candidate. The aim of this study was to investigate the possible association between CCK plasma levels and DBI expression in patients with AAIP or its recurrence. MATERIAL AND METHODS: The study comprised 44 subjects (mean age 42 years): A) Patients with a first episode of AAIP (n = 9); B) patients with three or more episodes of AAIP (n = 11); C) patients with a heavy alcohol consumption, with no detected AAIP (n = 11) and D) healthy controls (n = 13). CCK levels were measured by radioimmunoassay (RIA). Duodenal biopsies were analyzed for DBI mRNA and histology. RESULTS: There was no significant difference in CCK plasma levels, DBI expression or CCK/DBI ratio between the groups. CONCLUSIONS: There were no changes in fasting CCK plasma levels or DBI expression. This may suggest that they do not play a major role as risk factors for alcohol-induced pancreatitis.

Needle-knife assisted ERCP.

BACKGROUND: During endoscopic retrograde cholangiopancreatography (ERCP), incising through the wall of the major papilla with an electrocautery needle-knife is a method for achieving access into the bile duct. This procedure, often referred to as a "precut," may be used when cannulation attempts via the orifice of the papilla are unsuccessful. Potential complications include hemorrhage, duodenal perforation, and acute pancreatitis. METHODS: The 172 patients who underwent an attempt of a needle-knife assisted ERCP during the years 1997-2003 at our institution were retrospectively evaluated. RESULTS: A selective bile duct cannulation was achieved after needle-knife incision in 148 out of 172 patients (86%) at the primary session. In 10 additional patients (6%), a repeated procedure proved successful for cannulation. In the remaining 14 patients (8%), the biliary cannulation failed and was not attempted again. Complications after needle-knife assisted ERCP occurred as follows: three patients (2%) presented with late bleeding after the ERCP and three patients (2%) developed acute pancreatitis. None of the patients required operative treatment for complications. There was no mortality. CONCLUSION: The use of the needle-knife markedly improves the success rate of selective biliary cannulation in ERCP without increasing the rate of complications.