Differences in phenotype and disease course in adult and paediatric inflammatory bowel disease--a population-based study

Aliment Pharmacol Ther 2011; 34: 1217–1224

Summary

Background Few studies have compared phenotype and disease course in children and adults with inflammatory bowel disease (IBD). Aim To compare phenotype, treatment and disease course in children (<15 years) and adults (≥18 years) with IBD. Methods Two population‐based cohorts comprising paediatric (2001–2006) and adult (2003–2004) patients from Copenhagen County and City were studied. Results Twenty children and 106 adults with ulcerative colitis (UC), and 29 children and 67 adults with Crohn′s disease (CD) were included. Median follow‐up time was 4.8 years (children) and 5.2 years (adults). Children with UC had more extensive disease compared to adult patients [14 (70%) vs. 20 (19%), P < 0.001]. The risks of starting systemic steroid treatment and AZA/MP were higher for paediatric UC patients compared to adult UC patients; hazard ratio (HR): 3.1 (95% CI: 1.8–5.3) and HR: 2.5 (1.3‐5‐9), respectively. Steroid dependency was more frequent in paediatric than in adult UC patients [9 (45%) vs. 9 (8%), P < 0.001]. Mild disease course was less frequent in children with UC compared to adult patients [7 (35%) vs. 76 (72%), P = 0.002]. Paediatric and adult CD patients did not differ regarding treatment or disease course. Cumulative 5‐year surgery rates for paediatric and adult patients were 5% and 9% for UC (N.S.) and 18% and 21% for CD (N.S.), respectively. Conclusions Paediatric UC patients had more extensive disease, were more often treated with systemic steroids and AZA, had a higher frequency of steroid dependency and a more severe disease course compared to adult UC patients. No differences were found when comparing paediatric and adult CD patients.     

Pertussis toxin permeabilization enhances the traversal of Escherichia coli K1, macrophages, and monocytes in a cerebral endothelial barrier model in vitro

The occasionally severe neurological complications following the human respiratory tract infection 'whooping cough' have been attributed to pertussis toxin (PT) expressed by the causative agent Bordetella pertussis. Disruption of the endothelial blood-brain barrier (BBB) by PT might facilitate the translocation of immune cells and of hematogenous microbial pathogens. To test this hypothesis, we investigated whether PT enhances the traversal of bacteria employing human brain microvascular endothelial cells (HBMEC) as an in vitro endothelial barrier model. PT incubation significantly increased the translocation of Escherichia coli K1 across the HBMEC barrier. Only intercellular E. coli K1 bacteria could be identified by electron microscopy suggesting paracellular translocation. In addition, the migration of differentiated HL60-derived macrophages and of human monocytic U937 cells through PT-treated HBMEC barriers was also enhanced. In comparison to E. coli C600, E. coli K1 showed prolonged survival in translocated HL60-derived and J774 macrophages as well as in U937 monocytes which suggested a contribution of the 'Trojan horse' mechanism. In summary, our findings demonstrate that the PT-induced permeabilization of endothelial barriers enhances the paracellular transmigration of microbes and immune cells. In vivo, this activity might lower the threshold of bacteremia facilitating secondary cerebral infections and the subsequent development of brain pathologies.     

Incontinence,bladder neck mobility,and sphincter ruptures in primiparous women

Objective

To compare the function of the pelvic floor in primiparae before and during pregnancy with the status post partum concerning symptoms of incontinence, sphincter ruptures, bladder-neck mobility and the influence of the different modes of deliveries.

Methods

Questionnaire evaluating symptoms of urinary and anal incontinence in nulliparous women before and after delivery and correlating these symptoms with functional changes of the pelvic floor based on a careful gynaecologic examination as well as perineal and endoanal ultrasound.

Results

112 women were included in our study and came for the first visit, 99 women returned for follow-up 6 months after childbirth. Stress and flatus incontinence significantly increased from before pregnancy (3 and 12%) to after childbirth (21 and 28%) in women with spontaneous delivery or vacuum extraction. No new symptoms occurred after c-section. There was no significant difference between the bladder neck position before and after delivery. The mobility of the bladder neck was significantly higher after vaginal delivery using a vacuum extraction compared to spontaneous delivery or c-section.The bladder neck in women with post partum urinary stress incontinence was significantly more mobile than in continent controls. The endoanal ultrasound detected seven occult sphincter defects without any correlation to symptoms of anal incontinence.

Conclusion

Several statistically significant changes of the pelvic floor after delivery were demonstrated. Spontaneous vaginal delivery or vacuum extraction increases the risk for stress or anal incontinence, delivery with vacuum extraction leads to higher bladder neck mobility and stress incontinent women have more mobile bladder necks than continent women.     

Defective muscle basement membrane and lack of M-laminin in the dystrophic dy/dy mouse.

M-laminin is a major member of the laminin family of basement membrane proteins. It is prominently expressed in striated muscle and peripheral nerve. M-laminin is deficient in patients with the autosomal recessive Fukuyama congenital muscular dystrophy but is normal in patients with the sex-linked Duchenne and Becker muscular dystrophies. We have examined M-laminin expression in mice with autosomal recessive muscular dystrophy caused by the mutation dy. The heavy chain of M-laminin was undetectable in skeletal muscle, heart muscle, and peripheral nerve by immunofluorescence and immunoblotting in homozygous dystrophic dy/dy mice but was normal in heterozygous and wild-type nondystrophic mice. Immunofluorescence confirmed the presence of other major basement membrane proteins in the dystrophic mice. Very low levels of M-laminin heavy chain mRNA were detected by Northern blotting of muscle and heart tissue from dy/dy mice, suggesting that M-laminin heavy-chain mRNA may be produced at very low levels or is unstable. Information about the chromosomal localization of the M heavy-chain in human and mouse suggests that a mutation in the M-chain gene causes the muscular dystrophy in dy/dy mice. The dy mouse may provide a model for autosomal muscular dystrophies in humans and facilitate studies of functions of M-laminin.     

胸腔镜治疗贲门失弛症

胸腔镜治疗贲门失弛症何启才ＢｒｙｎｅｒＵＭ王永清郦志军章文晓何正富作者单位：３１００１６浙江医科大学附属邵逸夫医院心胸外科（何启才、王永清、郦志军、章文晓、何正富）；美国罗马琳达大学医学中心外科（ＢｒｙｎｅｒＵＭ）１９９６年２月至４月我们应用胸腔镜行...     

Altered levels of laminin receptor mRNA in various human carcinoma cells that have different abilities to bind laminin.

The human laminin receptor was purified and molecularly cloned to investigate its biosynthetic regulation. Laminin receptor from normal and neoplastic tissue was preparatively affinity purified to homogeneity based on the high affinity of the receptor for laminin. The apparent molecular weight of the receptor from different carcinoma sources and from normal placental tissue is in the range of 68-72 kDa. Isoelectric focusing and two-dimensional gel electrophoresis indicated that the receptor protein consists of one major polypeptide chain with a pI value of 6.4 +/- 0.2. Laminin receptor cDNA clones were isolated after screening a human endothelial lambda gt11 cDNA library with a monoclonal antibody directed against a domain of the laminin receptor involved in ligand binding. Definitive identification of the cDNA clones was based on comparison of cDNA sequence with the amino acid sequence of a cyanogen bromide-generated octapeptide of purified placental laminin receptor. The laminin receptor mRNA is approximately 1700 bases long. The level of laminin receptor mRNA in a variety of human carcinoma-derived cell lines correlated with the number of laminin receptors on the cell surfaces of those cells. This suggests that the amount of laminin receptor mRNA may be a rate-limiting control step in the biosynthesis of the laminin receptor, and hence in the regulation of cellular attachment to basement membranes via laminin.     

Evidence of a liver–alpha cell axis in humans: hepatic insulin resistance attenuates relationship between fasting plasma glucagon and glucagonotropic amino acids

Aims/hypothesis

The secretion of glucagon is controlled by blood glucose and inappropriate secretion of glucagon contributes to hyperglycaemia in diabetes. Besides its role in glucose regulation, glucagon regulates amino acid metabolism in hepatocytes by increasing ureagenesis. Disruption of this mechanism causes hyperaminoacidaemia, which in turn increases glucagon secretion. We hypothesised that hepatic insulin resistance (secondary to hepatic steatosis) via defective glucagon signalling/glucagon resistance would lead to impaired ureagenesis and, hence, increased plasma concentrations of glucagonotropic amino acids and, subsequently, glucagon.

Methods

To examine the association between glucagon and amino acids, and to explore whether this relationship was modified by hepatic insulin resistance, we studied a well-characterised cohort of 1408 individuals with normal and impaired glucose regulation. In this cohort, we have previously reported insulin resistance to be accompanied by increased plasma concentrations of glucagon. We now measure plasma levels of amino acids in the same cohort. HOMA-IR was calculated as a marker of hepatic insulin resistance.

Results

Fasting levels of glucagonotropic amino acids and glucagon were significantly and inversely associated in linear regression models (persisting after adjustment for age, sex and BMI). Increasing levels of hepatic, but not peripheral insulin resistance (p?>?0.166) attenuated the association between glucagon and circulating levels of alanine, glutamine and tyrosine, and was significantly associated with hyperaminoacidaemia and hyperglucagonaemia. A doubling of the calculated glucagon–alanine index was significantly associated with a 30% increase in hepatic insulin resistance, a 7% increase in plasma alanine aminotransferase levels, and a 14% increase in plasma γ-glutamyltransferase levels.

Conclusions/interpretation

This cross-sectional study supports the existence of a liver–alpha cell axis in humans: glucagon regulates plasma levels of amino acids, which in turn feedback to regulate the secretion of glucagon. With hepatic insulin resistance, reflecting hepatic steatosis, the feedback cycle is disrupted, leading to hyperaminoacidaemia and hyperglucagonaemia. The glucagon–alanine index is suggested as a relevant marker for hepatic glucagon signalling.

     

Initiation of therapy for obstructive sleep apnea syndrome: a randomized comparison of outcomes of telemetry-supported home-based vs. sleep lab-based therapy initiation

Purpose

Diagnosis and treatment of obstructive sleep apnea are traditionally performed in sleep laboratories with polysomnography (PSG) and are associated with significant waiting times for patients and high cost. We investigated if initiation of auto-titrating CPAP (APAP) treatment at home in patients with obstructive sleep apnea (OSA) and subsequent telemonitoring by a homecare provider would be non-inferior to in-lab management with diagnostic PSG, subsequent in-lab APAP initiation, and standard follow-up regarding compliance and disease-specific quality of life.

Methods

This randomized, open-label, single-center study was conducted in Germany. Screening occurred between December 2013 and November 2015. Eligible patients with moderate-to-severe OSA documented by polygraphy (PG) were randomized to home management or standard care. All patients were managed by certified sleep physicians. The home management group received APAP therapy at home, followed by telemonitoring. The control group received a diagnostic PSG, followed by therapy initiation in the sleep laboratory. The primary endpoint was therapy compliance, measured as average APAP usage after 6 months.

Results

The intention-to-treat population (ITT) included 224 patients (110 home therapy, 114 controls); the per-protocol population (PP) included 182 patients with 6-month device usage data (89 home therapy, 93 controls). In the PP analysis, mean APAP usage at 6 months was not different in the home therapy and control groups (4.38 ± 2.04 vs. 4.32 ± 2.28, p = 0.845). The pre-specified non-inferiority margin (NIM) of 0.3 h/day was not achieved (p = 0.130); statistical significance was achieved in a post hoc analysis when NIM was set at 0.5 h/day (p < 0.05). Time to APAP initiation was significantly shorter in the home therapy group (7.6 ± 7.2 vs. 46.1 ± 23.8 days; p < 0.0001).

Conclusion

Use of a home-based telemonitoring strategy for initiation of APAP in selected patients with OSA managed by sleep physicians is feasible, appears to be non-inferior to standard sleep laboratory procedures, and facilitates faster access to therapy.

     

Merosin/laminin-2 and muscular dystrophy

The laminins are a family of structural basement membrane components with major influences on cells. They are high molecular weight glycoproteins composed of three different but homologous chains, , β and γ. At present 10 different chains have been identified. Each chain has a distinct structural organization of domains, some of which have been assigned biological activities, including self-assembly and interactions with other proteins. The particular importance of laminins for the formation and stability of cell adhesion complexes is highlighted in severe inherited diseases of muscle and skin. Merosin is the collective name for laminins that share a common subunit, the laminin 2 chain. Merosin-deficient congenital muscular dystrophy (CMD) is caused by mutations in the laminin 2 chain gene. The skin disease Herlitz junctional epidermolysis bullosa is caused by mutations in any of the laminin 3, β3 or γ2 chain genes. The medical importance of laminins provides a further impetus to study the basic structure-function relationships in laminins in order to understand genotype-phenotype relationships and to design prenatal diagnostic tests and therapies aimed at compensating for specific defects.