Insulin‐like growth factor‐II is produced by,signals to and is an important survival factor for the mature podocyte in man and mouse

Podocytes are crucial for preventing the passage of albumin into the urine and, when lost, are associated with the development of albuminuria, renal failure and cardiovascular disease. Podocytes have limited capacity to regenerate, therefore pro‐survival mechanisms are critically important. Insulin‐like growth factor‐II (IGF‐II) is a potent survival and growth factor; however, its major function is thought to be in prenatal development, when circulating levels are high. IGF‐II has only previously been reported to continue to be expressed in discrete regions of the brain into adulthood in rodents, with systemic levels being undetectable. Using conditionally immortalized human and ex vivo adult mouse cells of the glomerulus, we demonstrated the podocyte to be the major glomerular source and target of IGF‐II; it signals to this cell via the IGF‐I receptor via the PI3 kinase and MAPK pathways. Functionally, a reduction in IGF signalling causes podocyte cell death in vitro and glomerular disease in vivo in an aged IGF‐II transgenic mouse that produces approximately 60% of IGF‐II due to a lack of the P2 promoter of this gene. Collectively, this work reveals the fundamental importance of IGF‐II in the mature podocyte for glomerular health across mammalian species. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Endoscopic sclerotherapy compared with no specific treatment for the primary prevention of bleeding from esophageal varices. A randomized controlled multicentre trial [ISRCTN03215899]

Background

Since esophageal variceal bleeding is associated with a high mortality rate, prevention of bleeding might be expected to result in improved survival. The first trials to evaluate prophylactic sclerotherapy found a marked beneficial effect of prophylactic treatment. These results, however, were not generally accepted because of methodological aspects and because the reported incidence of bleeding in control subjects was considered unusually high. The objective of this study was to compare endoscopic sclerotherapy (ES) with nonactive treatment for the primary prophylaxis of esophageal variceal bleeding in patients with cirrhosis.

Methods

166 patients with esophageal varices grade II, III of IV according to Paquet's classification, with evidence of active or progressive liver disease and without prior variceal bleeding, were randomized to groups receiving ES (n = 84) or no specific treatment (n = 82). Primary end-points were incidence of bleeding and mortality; secondary end-points were complications and costs.

Results

During a mean follow-up of 32 months variceal bleeding occurred in 25% of the patients of the ES group and in 28% of the control group. The incidence of variceal bleeding for the ES and control group was 16% and 16% at 1 year and 33% and 29% at 3 years, respectively. The 1-year survival rate was 87% for the ES group and 84% for the control group; the 3-year survival rate was 62% for each group. In the ES group one death occurred as a direct consequence of variceal bleeding compared to 9 in the other group (p = 0.01, log-rank test). Complications were comparable for the two groups. Health care costs for patients assigned to ES were estimated to be higher. Meta-analysis of a large number of trials showed that the effect of prophylactic sclerotherapy is significantly related to the baseline bleeding risk.

Conclusion

In the present trial, prophylactic sclerotherapy did not reduce the incidence of bleeding from varices in patients with liver cirrhosis and a low to moderate bleeding risk. Although sclerotherapy lowered mortality attributable to variceal bleeding, overall survival was not affected. The effect of prophylactic sclerotherapy seems dependent on the underlying bleeding risk. A beneficial effect can only be expected for patients with a high risk for bleeding.     

慢性阻塞性肺疾病合并阻塞性睡眠呼吸暂停患者的随访结果

背景和目的:COPD合并阻塞性睡眠呼吸暂停(OSA)的患者,较单独患有其中1种疾病的患者更容易罹患肺动脉高压.本研究旨在评价COPD合并OSA患者的病死率及因COPD急性加重而首次住院的关系,以及持续气道正压通气(CPAP)对患者主要临床结局的影响.     

An abnormal screening ultrasound: concordance with a tertiary obstetrical ultrasound unit

Objective: To determine concordance of ultrasound diagnosis in referrals to a tertiary obstetrical ultrasound unit (TOU) for suspected abnormalities.

Study design: Consecutive referrals for ‘abnormal outside ultrasound’ during a 6-month period were compared with the TOU ultrasound diagnosis. Concordance of diagnosis was compared on the basis of organ system involved and referral for single or multiple suspected abnormalities. χ² analysis was used; p?<?0.05 was considered significant.

Results: Of 104 consecutive referrals reviewed, 42 (40.4%) had no abnormality documented at the TOU. Of the 62 abnormal ultrasound scans at the TOU, 78.3% were concordant. Concordance based on organ system involvement was central nervous system, 30.3%; cardiothoracic, 66.7%; gastrointestinal, 63.6%; genitourinary, 50%. Referrals for a single suspected anomaly were statistically no more likely to have a normal TOU ultrasound scan (40.4%) than those referred for multiple suspected anomalies (36.4%, p?>?0.05).

Conclusions: Most referrals to a tertiary center for ‘abnormal outside ultrasound’ will be diagnosed with an abnormality.     

Central or local incident reporting? A comparative study in Dutch GP out-of-hours services

Background

Centralised incident reporting in a Dutch collaboration of nine out-of-hours services yielded very few incident reports. To improve incident reporting and the awareness of primary caregivers about patient safety issues, a local incident-reporting procedure was implemented.

Aim

To compare the number and nature of incident reports collected in a local incident-reporting procedure (intervention) versus the currently used centralised incident-reporting procedure.

Design of study

Quasi experiment.

Setting

Three GPs'' out-of-hours services (OHSs) in the centre of the Netherlands participated over 2 years before and 2 years after the intervention.

Method

A local incident-reporting procedure was implemented in OHS1, in which participants were encouraged to report all occurring incidents. A local committee with peers analysed the reported incidents fortnightly in order to initiate improvements if necessary. In OHS2 and OHS3, the current centralised incident-reporting procedure was continued, where incidents were reported to an advisory committee of the board of directors of the OHSs collaboration and were assessed every 2 months. The main outcome measures were the number and nature of incidents reported.

Results

At baseline, participants reported fewer than 10 incidents per year each. In the follow-up period, the number of incidents reported in OHS1 increased 16-fold compared with the controls. The type of incidents reported did not alter. In the local incident-reporting procedure, improvements were implemented in a shorter time frame, but reports in the centralised incident-reporting procedure led to a more systematic addressing of general and recurring safety problems.

Conclusion

It is likely that a local incident-reporting procedure increases the willingness to report and facilitates faster implementation of improvements. In contrast, the central procedure, by collating reports from many settings, seems better at addressing generic and recurring safety issues. The advantages of both approaches should be combined.     

Serotonin receptor 3A polymorphism c.-42C &gt; T is associated with severe dyspepsia

Background

The association between anxiety and depression related traits and dyspepsia may reflect a common genetic predisposition. Furthermore, genetic factors may contribute to the risk of having increased visceral sensitivity, which has been implicated in dyspeptic symptom generation. Serotonin (5-HT) modulates visceral sensitivity by its action on 5-HT₃ receptors. Interestingly, a functional polymorphism in HTR3A, encoding the 5-HT₃ receptor A subunit, has been reported to be associated with depression and anxiety related traits. A functional polymorphism in the serotonin transporter (5-HTT), which terminates serotonergic signalling, was also found associated with these psychiatric comorbidities and increased visceral sensitivity in irritable bowel syndrome, which coexistence is associated with higher dyspeptic symptom severity. We investigated the association between these functional polymorphisms and dyspeptic symptom severity.

Methods

Data from 592 unrelated, Caucasian, primary care patients with dyspepsia participating in a randomised clinical trial comparing step-up and step-down antacid drug treatment (The DIAMOND trial) were analysed. Patients were genotyped for HTR3A c.-42C > T SNP and the 44 bp insertion/deletion polymorphism in the 5-HTT promoter (5-HTTLPR). Intensity of 8 dyspeptic symptoms at baseline was assessed using a validated questionnaire (0 = none; 6 = very severe). Sum score ≥20 was defined severe dyspepsia.

Results

HTR3A c.-42T allele carriers were more prevalent in patients with severe dyspepsia (OR 1.50, 95% CI 1.06-2.20). This association appeared to be stronger in females (OR 2.05, 95% CI 1.25-3.39) and patients homozygous for the long (L) variant of the 5-HTTLPR genotype (OR 2.00, 95% CI 1.01-3.94). Females with 5-HTTLPR LL genotype showed the strongest association (OR = 3.50, 95% CI = 1.37-8.90).

Conclusions

The HTR3A c.-42T allele is associated with severe dyspeptic symptoms. The stronger association among patients carrying the 5-HTTLPR L allele suggests an additive effect of the two polymorphisms. These results support the hypothesis that diminished 5-HT₃ mediated antinociception predisposes to increased visceral sensitivity of the gastrointestinal tract. Moreover, the HTR3A c.-42C > T and 5-HTTLPR polymorphisms likely represent predisposing genetic variants in common to psychiatric morbidity and dyspepsia.