Mast cells regulate homeostatic intestinal epithelial migration and barrier function by a chymase/Mcpt4-dependent mechanism

Altered intestinal barrier function is postulated to be a central predisposing factor to intestinal diseases, including inflammatory bowel diseases and food allergies. However, the mechanisms involved in maintaining homeostatic intestinal barrier integrity remain undefined. In this study, we demonstrate that mice deficient in mast cells (Kit^W-sh/W-sh [Wsh]) or mast cell chymase (Mcpt4^−/−) have significantly decreased basal small intestinal permeability compared with wild-type (WT) mice. Altered intestinal barrier function was linked to decreased intestinal epithelial cell migration along the villus/crypt axis, altered intestinal morphology, and dysregulated claudin-3 crypt expression. Remarkably, engraftment of Wsh mice with WT but not Mcpt4^−/− mast cells restored intestinal epithelial cell migration, morphology, and intestinal epithelial barrier function. Collectively, these findings identify a mechanism by which mast cells regulate homeostatic intestinal epithelial migration and barrier function.     

Impact of age on survival after intensive therapy for multiple myeloma: a population-based study by the Nordic Myeloma Study Group

The value of intensive therapy, including autologous stem cell transplantation, in newly diagnosed myeloma patients >60 years is not clear. We evaluated the impact of age (<60 years vs. 60-64 years) on survival in a prospective, population-based setting and compared survival with conventionally treated historic controls. The prospective population comprised 452 patients registered between 1998 and 2000. Of these, 414 received intensive therapy. The historic population, derived from our most recent population-based study on conventional therapy, comprised 281 patients. Of these, 243 fulfilled our eligibility criteria for intensive therapy. For patients undergoing intensive therapy it was found that two factors, beta-2-microglobulin and age <60 years vs. 60-64 years, had independent prognostic impact on survival. However, compared with the historic controls a survival advantage was found both for patients <60 (median 66 months vs. 43 months, P < 0.001) and 60-64 years (median 50 months vs. 27 months; P = 0.001). We conclude that in a population-based setting higher age adversely influences outcome after intensive therapy. Our results indicate that intensive therapy prolongs survival also at age 60-64 years but with less superiority than in younger patients.     

Accidental falls,health-related quality of life and life satisfaction: A prospective study of the general elderly population

As the physical consequences of accidental falls in the elderly are well-researched, the long-term associations between falls and quality of life and related concepts are less known. The aim of this study was to prospectively examine the long-term relations between falls and health-related quality of life (HRQoL) and life satisfaction (LS) over six years in the general elderly population.     

Vaskul?re Komplikationen der perkutanen transradialen Koronarangiographie und Koronarintervention

ZusammenfassungHintergrund und Ziel:  Vaskuläre Komplikationen nach transradialer Koronarangiographie und Koronarintervention können dramatische Folgen für die Durchblutung der Hand haben. Schwerwiegende Folgen (Handischämie mit Verschluss der Fingerarterien) nach Kanülierung der A. radialis sind bisher nur kasuistisch beschrieben. Die vorliegende Untersuchung soll klären, ob die perkutane transradiale Koronarangiographie/-intervention zu vaskulären Komplikationen führt.Patienten und Methodik:  93 Patienten wurden in einem Zeitraum von 4 Monaten konsekutiv in die vorliegende Studie eingeschlossen und sowohl vor als auch nach der Herzkatheteruntersuchung/-intervention untersucht. Gefäßweite, Blutfluss, Flussgeschwindigkeiten und Verschlussdruckwerte wurden mittels Duplexsonographie und Verschlussdruckplethysmographie registriert. Die Stenosegraduierung erfolgte mit der „peak velocity ratio“-Methode.Ergebnisse:  Bei 93 Patienten (75 Männer, mittleres Alter 62,5 Jahre) wurde bei unauffälligem Allen-Test eine transradiale Koronarangiographie oder -intervention durchgeführt. Die prozedurale Erfolgsrate lag bei 97,2%. Bei drei Patienten (2,8%) konnte die Untersuchung nicht erfolgreich durchgeführt werden. Der mittlere Gefäßdurchmesser nahm von 2,46 ± 1,7 mm (Standardabweichung [SD]) vor der Intervention auf 2,78 ± 0,69 mm (SD) nach der Intervention statistisch signifikant (p = 0,002) zu. Nicht signifikante Änderungen wurden bei Blutfluss, Flussgeschwindigkeiten und Verschlussdruckwerten registriert. Neun von 93 Patienten (10%) wiesen duplexsonographisch vaskuläre Komplikationen nach der transradialen Herzkatheteruntersuchung/-intervention auf. Kein Patient beklagte Beschwerden. Trotz vaskulärer Komplikationen traten bei keinem Patienten Perfusionsausfälle der Digitalarterien auf.Schlussfolgerung:  Die transradiale Koronarangiographie und Koronarintervention ist für die Patienten eine sichere Methode mit einer hohen prozeduralen Erfolgsrate.     

The Ubiquitin-Proteasome 26s Pathway in Liver Cell Protein Turnover: Effect of Ethanol and Drugs

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Samuel W. French and R. J. Mayer. The presentations were (1) The ubiquitin-proteasome 26s pathway in liver cell protein turnover: Effect of alcohol and drugs, by Samuel W. French and F. Bardag-Gorce; (2) The role of CYP2E1 phosphorylation and degradation pathway in the induction of the enzyme, by Magnus Ingelman-Sundberg; (3) Role of proteasome in the proteolysis of oxidized proteins in experimental chronic alcoholism, by Helen Rouach; (4) Alcohol, proteolysis and liver cancer, by R. J. Mayer; (5) Effect of ethanol feeding on the ATP-ubiquitin-proteasome pathway in the liver cell, by F. Bardag-Gorce; (6) Novel mechanisms and targets for intracellular transport of CYP2E1, by E. Neve; and (7) Gankyrin, an oncoprotein commonly over expressed in hepatoma, by H. Higashitsuji.     

Worldwide genomic diversity of the human papillomaviruses-53, 56, and 66, a group of high-risk HPVs unrelated to HPV-16 and HPV-18

Among more than 200 human papillomavirus (HPV) types presumed to exist, 18 "high-risk" HPV types are frequently found in anogenital cancer. The best studied types are HPV-16 and 18, which are only distantly related to one another and form two separate phylogenetic branches, each including six closely related types. HPV-30, 53, 56, and 66 form a third phylogenetic branch unrelated to HPV-16 and 18. Worldwide comparison of HPV-16 and 18 isolates revealed a distribution of variant genomes that correlated with the geographic origin and the ethnicity of the infected cohort and led to the concept of unique African, European, Asian, and Native American HPV-16 and 18 variants. Here, we address the question whether similar phylogenies are found for HPV-53, 56, and 66 by determining the sequence of the long control regions (LCR) of these HPVs in samples from Europe, Asia, and Africa, and from immigrant societies in North and South America. Phylogenetic trees calculated from point mutations and a few insertions/deletions affecting 2-4.2% of the nucleotide sequences were distinct for each of the three HPVs and divergent from HPV-16 and 18. In contrast to the "star-phylogenies" formed by HPV-16 and 18 variants, 44 HPV-53 isolates represented nine variants, which formed two deep dichotomic branches reminiscent of the beginning split into two new taxa, as recently observed for subtypes of HPV-44 and 68. A total of 66 HPV-56 isolates represented 17 variants, which formed three branches preferentially containing European, Asian, and African variants. Variants of a fourth branch, deeply separated from the other three, were characterized by a 25 bp insertion and created a dichotomy rather than star-like phylogeny. As it contained isolates from cohorts in all continents, it may have evolved before the spread of humans into all continents. 18 of 31 HPV-66 isolates represented the prototype clone, which was found in all parts of the world, while the remaining 13 clones formed 11 branches without any geographic association. Our findings confirm the notion of a quantitatively limited genomic diversity of each HPV type with some correlation to the geographic origin of the sample. In addition, we observed in some variants of these three HPV types mutations that affect the amino acid sequence of the E6 oncoproteins and the L1 capsid protein, supporting the possibility of immunogenic and oncogenic diversity between variants of any HPV type.     

Unplanned discharges from a surgical intensive care unit: Readmissions and mortality

Purpose

There is great patient turnover every day on surgical intensive care units (SICUs). Surgical intensive care unit beds are provided for major elective surgery. Emergency admissions trigger unplanned discharges. Those patients are at risk for a worse outcome.

Materials and Methods

We retrospectively analyzed 2558 patients discharged from a 20-bed SICU within 1 year. They were followed up whether discharged electively or not. Patients readmitted to the SICU were stratified according to reason for readmission.

Results

Readmission rate to the SICU was 8.3% (139/1675) in elective discharges, and 25.1% (110/439) in unplanned discharges (P < .001); 50% (125/249) of all readmissions were for surgical complications. Hospital mortality was 2.28% (50/2,197) in patients not readmitted to the SICU and 13.3% (33/249) for those readmitted (P < .001). The mortality rate increased by 4% in readmissions for each year of age (P < .05, OR for death 1.04 for each year of age, 95% CI 1.010-1.071). Respiratory failure as a reason for readmission implied a 44% risk of death (P < .001, OR 11.85, 95% CI 5.11-27.45).

Conclusions

Earlier-than-planned discharge from a SICU leads to a substantially higher readmission rate. Readmission correlates with an elevated risk of death. Most readmissions in a surgical clinic are due to surgical complications. Readmission for respiratory failure accounts for most of the mortality.     

Gastric bypass alters the dynamics and metabolic effects of insulin and proinsulin secretion.

AIMS: Hyperproinsulinaemia is associated with obesity and is a risk factor for Type 2 diabetes. We explored the dynamics of proinsulin and insulin and postprandial effects on glucose and lipids in subjects who had undergone gastric bypass (GBP) surgery compared with morbidly obese (MO) subjects and normal weight control subjects (NW). METHODS: Subjects free from diabetes were recruited: 10 previously MO subjects [body mass index (BMI) +/- sd, 34.8 +/- 6.2 kg/m2] who had undergone GBP surgery, 10 MO subjects (BMI 44 +/- 3.1 kg/m2) and 12 NW control subjects (BMI 23.2 +/- 2.4 kg/m2). After an overnight fast, a standard meal (2400 kJ) was ingested and glucose, proinsulin, insulin free fatty acids and triglycerides were determined up to 180 min. RESULTS: Fasting proinsulin was similar in the GBP group and NW control subjects, but threefold increased in MO subjects (P < 0.05). Postprandial AUC for glucose was similar in the three groups and AUC for proinsulin was high in MO, intermediate in the GBP group and lowest in NW control subjects (P for trend = 0.020). Postprandial proinsulin at 60 min was similar in the GBP group and MO subjects and twofold higher than in NW control subjects. Postprandial proinsulin at 180 min was normal in the GBP group, but fivefold increased in MO subjects (P = 0.008). Insulin increased rapidly at 30 min in the GBP group and was normal at 90 min, whereas insulin was still increased at 90-180 min in the MO subjects (P < 0.001). CONCLUSIONS: MO subjects, free from diabetes, have elevated proinsulin concentrations in the fasting as well as the postprandial phase. After GBP surgery markedly lower fasting and postprandial proinsulin concentrations were observed, although BMI was higher compared with NW control subjects.     

Strong Signature of Natural Selection within an FHIT Intron Implicated in Prostate Cancer Risk

Previously, a candidate gene linkage approach on brother pairs affected with prostate cancer identified a locus of prostate cancer susceptibility at D3S1234 within the fragile histidine triad gene (FHIT), a tumor suppressor that induces apoptosis. Subsequent association tests on 16 SNPs spanning approximately 381 kb surrounding D3S1234 in Americans of European descent revealed significant evidence of association for a single SNP within intron 5 of FHIT. In the current study, re-sequencing and genotyping within a 28.5 kb region surrounding this SNP further delineated the association with prostate cancer risk to a 15 kb region. Multiple SNPs in sequences under evolutionary constraint within intron 5 of FHIT defined several related haplotypes with an increased risk of prostate cancer in European-Americans. Strong associations were detected for a risk haplotype defined by SNPs 138543, 142413, and 152494 in all cases (Pearson's χ²=12.34, df 1, P=0.00045) and for the homozygous risk haplotype defined by SNPs 144716, 142413, and 148444 in cases that shared 2 alleles identical by descent with their affected brothers (Pearson's χ²=11.50, df 1, P=0.00070). In addition to highly conserved sequences encompassing SNPs 148444 and 152413, population studies revealed strong signatures of natural selection for a 1 kb window covering the SNP 144716 in two human populations, the European American (π=0.0072, Tajima's D=3.31, 14 SNPs) and the Japanese (π=0.0049, Fay & Wu's H=8.05, 14 SNPs), as well as in chimpanzees (Fay & Wu's H=8.62, 12 SNPs). These results strongly support the involvement of the FHIT intronic region in an increased risk of prostate cancer.