Developmental programming of O2 sensing by neonatal intermittent hypoxia via epigenetic mechanisms

Recurrent apnea with intermittent hypoxia (IH) is a major clinical problem in infants born preterm. Carotid body chemo-reflex and catecholamine secretion from adrenal medullary chromaffin cells (AMC) are important for maintenance of cardio-respiratory homeostasis during hypoxia. This article highlights studies on the effects of IH on O₂ sensing by the carotid body and AMC in neonatal rodents. Neonatal IH augments hypoxia-evoked carotid body sensory excitation and catecholamine secretion from AMC which are mediated by reactive oxygen species (ROS)-dependent recruitment of endothelin-1 and Ca²⁺ signaling, respectively. The effects of neonatal IH persist into adulthood. Evidence is emerging that neonatal IH initiates epigenetic mechanisms involving DNA hypermethylation contributing to long-lasting increase in ROS levels. Since adult human subjects born preterm exhibit higher incidence of sleep-disordered breathing and hypertension, DNA hypomethylating agents might offer a novel therapeutic intervention to decrease long-term cardio-respiratory morbidity caused by neonatal IH.     

Diagnostic omission errors in acute paediatric practice: impact of a reminder system on decision-making

Background

Computerized decision support systems (DSS) have mainly focused on improving clinicians' diagnostic accuracy in unusual and challenging cases. However, since diagnostic omission errors may predominantly result from incomplete workup in routine clinical practice, the provision of appropriate patient- and context-specific reminders may result in greater impact on patient safety. In this experimental study, a mix of easy and difficult simulated cases were used to assess the impact of a novel diagnostic reminder system (ISABEL) on the quality of clinical decisions made by various grades of clinicians during acute assessment.

Methods

Subjects of different grades (consultants, registrars, senior house officers and medical students), assessed a balanced set of 24 simulated cases on a trial website. Subjects recorded their clinical decisions for the cases (differential diagnosis, test-ordering and treatment), before and after system consultation. A panel of two pediatric consultants independently provided gold standard responses for each case, against which subjects' quality of decisions was measured. The primary outcome measure was change in the count of diagnostic errors of omission (DEO). A more sensitive assessment of the system's impact was achieved using specific quality scores; additional consultation time resulting from DSS use was also calculated.

Results

76 subjects (18 consultants, 24 registrars, 19 senior house officers and 15 students) completed a total of 751 case episodes. The mean count of DEO fell from 5.5 to 5.0 across all subjects (repeated measures ANOVA, p < 0.001); no significant interaction was seen with subject grade. Mean diagnostic quality score increased after system consultation (0.044; 95% confidence interval 0.032, 0.054). ISABEL reminded subjects to consider at least one clinically important diagnosis in 1 in 8 case episodes, and prompted them to order an important test in 1 in 10 case episodes. Median extra time taken for DSS consultation was 1 min (IQR: 30 sec to 2 min).

Conclusion

The provision of patient- and context-specific reminders has the potential to reduce diagnostic omissions across all subject grades for a range of cases. This study suggests a promising role for the use of future reminder-based DSS in the reduction of diagnostic error.     

机体和细胞对间歇性低氧的反应与呼吸暂停综合征的关系

 睡眠障碍伴反复性呼吸暂停的患者表现为交感神经活动（sympathetic nerve activity,SNA）增强的自主神经系统功能失调和高血压。动物实验表明反复呼吸暂停引起的慢性间歇性低氧(chronic intermittent hypoxia,CIH)是激发自主神经系统功能失调的主要因素。在啮齿类动物模型中,CIH使动脉化学感受性反射功能增强的部分原因在于增加了颈动脉体对低氧的敏感性,因而导致SNA增强。最近研究表明,缺氧诱导因子-1和2(hyproxia-inducible factor,HIF)转录的变化及随之而来的活性氧类介导的信号,是CIH时化学感受性反射引起的交感神经系统兴奋的重要细胞机制。     

The angiogenins: An emerging family of ribonuclease related proteins with diverse cellular functions

Angiogenin is a member of the ribonuclease superfamily, which shows an ever expanding collection of molecules being identified and cloned. It was initially isolated from the conditioned medium of cultured tumour cells. Its angiogenic activity appears to be critical for the maintenance and support of tumour growth. Angiogenin also plays a role in a number of non-malignant vasculoproliferative pathological conditions. Along with other related molecules, it has been identified in a wide variety of somatic tissues in adult and embryonic stages of vertebrate development. This suggests that angiogenin and related molecules are likely to play a vital role in normal physiology. Angiogenin is detectable in serum and to date has been implicated as a mitogen for vascular endothelial cells, an immune modulator with suppressive effects on polymorphonuclear leukocytes, an activator of certain protease cascades such as matrix metalloproteases and plasminogen-activated plasmin pathways, as well as an adhesion molecule. However, the role of the angiogenin family in both normal and abnormal physiology and in development will only fully be realised by genetic approaches involving gene deletion. This revised version was published online in June 2006 with corrections to the Cover Date.     

Management of severe pulmonary Langerhans cell histiocytosis in children

Patients with pulmonary Langerhans cell histiocytosis (LCH) typically have a benign course but may have extensive cystic lung disease with rare life‐threatening complications including multiple and recurrent pneumothoraces and respiratory failure. We report seven severely affected pediatric patients treated with chemotherapy, aggressive chest tube management, and pleurodesis of whom five survived. Patients with extraordinary amounts of pulmonary cystic disease and multiple pneumothoraces due to LCH can have remarkable, curative outcomes with early recognition, optimal LCH‐directed therapy, and supportive care.