Solubilization and assay of an hepatic receptor for the haptoglobin-hemoglobin complex

Hemoglobin released into the bloodstream is tightly bound by haptoglobin. The resulting complex (HpHb) is promptly cleared from the circulation and accumulates in the liver. A binding protein with a high affinity for HpHb has been solubilized from an acetone powder of rat liver and freed from an endogenous inhibitor by passage over a column of immobilized hemoglobin. An assay procedure has been developed whereby the bound HpHb is selectively precipitated by polyethylene glycol 6000. Employing this assay, the binding reaction was shown to be linear and saturable with respect to the ligand. In contrast to several previously described receptors for glycoproteins, the carbohydrate moiety of haptoglobin did not appear to participate in the binding of HpHb by the soluble receptor.     

Individual and population penalized regression splines for accelerated longitudinal designs

In an accelerated longitudinal design (ALD), individuals enter the study at different points of their growth trajectory and are observed over a short time span relative to the entire time span of interest. ALD data are combined across independent units to provide an estimate of an overall population curve and predictions of individual patterns of change. As a modest extension of the work of Ruppert et al. (2003, Semiparametric Regression, Cambridge University Press), we develop a computationally efficient procedure for the application of longitudinal semiparametric methods under ALD sampling schemes. We compare balanced and complete longitudinal designs to ALDs using the Berkeley Growth Study data and apply our method to longitudinal magnetic resonance imaging (MRI) brain structure size (volume) measurements from an ongoing developmental study. Potential applications extend beyond growth studies to many other fields in which cost and feasibility constraints impose restrictions on sample size and on the numbers and timings of repeated measurements across subjects.     

Quantification of the magnification and distortion effects of a pediatric flexible video-bronchoscope

Background

Flexible video bronchoscopes, in particular the Olympus BF Type 3C160, are commonly used in pediatric respiratory medicine. There is no data on the magnification and distortion effects of these bronchoscopes yet important clinical decisions are made from the images. The aim of this study was to systematically describe the magnification and distortion of flexible bronchoscope images taken at various distances from the object.

Methods

Using images of known objects and processing these by digital video and computer programs both magnification and distortion scales were derived.

Results

Magnification changes as a linear function between 100 mm (×1) and 10 mm (×9.55) and then as an exponential function between 10 mm and 3 mm (×40) from the object. Magnification depends on the axis of orientation of the object to the optic axis or geometrical axis of the bronchoscope. Magnification also varies across the field of view with the central magnification being 39% greater than at the periphery of the field of view at 15 mm from the object. However, in the paediatric situation the diameter of the orifices is usually less than 10 mm and thus this limits the exposure to these peripheral limits of magnification reduction. Intraclass correlations for measurements and repeatability studies between instruments are very high, r = 0.96. Distortion occurs as both barrel and geometric types but both types are heterogeneous across the field of view. Distortion of geometric type ranges up to 30% at 3 mm from the object but may be as low as 5% depending on the position of the object in relation to the optic axis.

Conclusion

We conclude that the optimal working distance range is between 40 and 10 mm from the object. However the clinician should be cognisant of both variations in magnification and distortion in clinical judgements.     

瑞芬太尼、芬太尼对小儿扁桃体切除术中应激反应和苏醒期躁动的影响

目的：探讨瑞芬太尼、芬太尼对小儿扁桃体切除术中应激反应以及苏醒期躁动的影响。方法：选择2012年1月至2012年12月期间择期行扁桃体切除手术的患儿80例为研究对象,将其分随机为瑞芬太尼组（40例）和芬太尼组（40例）,比较两组患者不同时间应激反应指标（ACTH、COR、IL-6）、苏醒时间、躁动评分、躁动发生率以及RamSay镇静评分,探讨两种麻醉药物的临床应用价值。结果：两组术前ACTH、COR、IL-6的基础应激指标比较,差别无统计学意义（P〉0．05）。瑞芬太尼组及芬太尼组术毕该三项指标较术前升高,术后1d较术毕有回落,差别有统计学意义（P〈0．05）;瑞芬太尼组术毕睐后1d的各项指标均远远低于芬太尼组,差别有统计学意义（P〈0．05）。瑞芬太尼组苏醒时间明显少于芬太尼组,躁动评分明显低于芬太尼组,躁动发生率明显低于芬太尼组,RamSay镇静评分明显高于芬太尼组,差别有统计学意义（P〈0．05）。结论：瑞芬太尼引起的应激反应明显弱于芬太尼组,且其苏醒期躁动情况明显优于芬太尼组,值得进一步推广应用。     

STRN-ALK rearranged pediatric malignant peritoneal mesothelioma – Functional testing of 527 cancer drugs in patient-derived cancer cells

Genetic rearrangements involving the anaplastic lymphoma kinase (ALK) gene create oncogenic drivers for several cancers, including malignant peritoneal mesothelioma (MPeM). Here, we report genomic and functional precision oncology profiling on a rare case of a 5-year old patient diagnosed with wide-spread and aggressive MPeM, driven by STRN-ALK rearrangement. We established genomically representative patient-derived cancer cells (PDCs) from the tumor sample and performed high-throughput drug sensitivity testing with 527 oncology compounds to identify potent inhibitors. As expected, the PDCs were overall sensitive to the ALK inhibitors, although the eight different inhibitors tested had variable efficacy. We also discovered other effective inhibitors, such as MEK/ERK inhibitors and those targeting pathways downstream of ALK as well as Bcl-xl inhibitors. In contrast, most cytotoxic drugs were not very effective. ALK inhibitors synergized with MEK and PI3K/mTOR inhibitors, highlighting potential combinatorial strategies to enhance drug efficacy and tackle drug resistance. Based on genomic data and associated functional validation, the patient was treated with the ALK inhibitor crizotinib in combination with conventional chemotherapy (cisplatin and gemcitabine). A complete disease remission was reached, lasting now for over 3 years. Our results illustrate a rare pediatric cancer case, and highlight the potential of functional precision oncology to discover pathogenetic drivers, validate dependency on driver signals, compare different inhibitors against each other and potentially enhance targeted treatments by drug combinations. Such real-time implementation of functional precision oncology could pave the way towards safer and more effective personalized cancer therapies for individual pediatric cancer patients with rare tumors.     

Typical values for pediatric interventional cardiology catheterizations: A standardized approach towards Diagnostic Reference Level establishment

PurposeTo define weight-stratified Diagnostic Reference Levels (DRL) typical values for pediatric interventional cardiology (IC) procedures adopting standardized methodologies proposed by ICRP135 and RP185.MethodsProcedures performed at the pediatric catheterization room of the University-Hospital of Padua were analysed. Patients were stratified into body weight (BW) classes and DRL quantities were analysed for the most performed procedures. Typical values are defined as median P_KA and K_a,r. For database consistency, sampling and exclusion methods were precisely defined. The DRL-curve methodology by means of quantile regression median curves was investigated to assess the relationship between P_KA and weight. A like-to-like comparison with literature was made.Results385 procedures were analysed. A large P_KA variability was observed in each weight group. P_KA differences across BW groups were not always statistically significant. When stratifying by procedure, P_KA variability decreased while correlations of P_KA and P_KA/FT with weight increased. The established typical values are generally lower than DRLs published data, whatever stratification method adopted. The highest P_KA median values were observed for Angioplasty (4.9 and 11.6 Gycm² for 5-<15 kg and 15-<30 kg, respectively). The DRL-curve approach shows promising results for Valvuloplasty and Angioplasty.ConclusionsTypical values for pediatric IC DRL quantities were determined according to ICRP135 and RP185 methodologies. Stratification by BW classification does not reduce the variability of the P_KA values, unlike what happens when stratifying by procedure type. Results seem to corroborate that variability and exposure are more affected by procedure type and complexity than by patient weight. DRL-curve is a feasible approach.     

Pediatric psychopharmacology: too much or too little?

This paper provides a selective overview of the past, present and future of pediatric psychopharmacology. The acceptance of medication use in child psychiatry was based on the results of double‐blind, placebo‐controlled trials documenting the efficacy of drug treatments for attention‐deficit/hyperactivity disorder, enuresis, depression, anxiety disorders, obsessive‐compulsive disorder and psychoses. This period of success was followed by a series of challenges, including a growing awareness of the long‐term adverse effects of medications and of the inadequacy of long‐term drug surveillance. There is great concern today that children are being overtreated with medication, especially in the US. Further advances in pediatric psychopharmacology may come from examination of large medical data sets including both pharmacological and psychiatric information, which could lead to drug repurposing, as well as from preclinical translational studies such as those using human induced pluripotent stem cells.     

穴位按摩联合高压氧对急性脑卒中后吞咽功能障碍临床效果

目的:研究穴位按摩联合高压氧对急性脑卒中后吞咽功能障碍的临床效果。方法:选择2016年1月～2018年12月我院收治的80例急性脑卒中后吞咽功能障碍患者,将其随机分为两组。对照组采取高压氧治疗,观察组采取穴位按摩联合高压氧治疗。观察和比较两组吞咽功能障碍的改善效果。结果:观察组的吞咽功能障碍改善有效率明显高于对照组(P0.05);两组治疗15 d和30 d的洼田饮水试验评分均明显低于治疗前1 d(P0.05),且观察组明显低于对照组(P0.05);两组治疗后的吞咽障碍特异性生活质量量表(Swallowing quality-of-life questionnaire,SWAL-QOL)评分均明显低于治疗前(P0.05),且观察组明显低于对照组(P0.05);观察组吸入性肺炎的发生率为7.50%(3/40),明显低于对照组[25.00%(10/40)](P0.05)。结论:穴位按摩联合高压氧可促进急性脑卒中后吞咽功能障碍患者吞咽功能的恢复,防止吸入性肺炎的发生,提高患者生活质量。     

High parental occupational social contact and risk of childhood hematopoietic,brain and bone cancers

BackgroundThe etiology of childhood cancer is largely unknown, though some research suggests an infectious origin of hematopoietic, central nervous system (CNS) and bone cancers.MethodsWe examined parental occupational social contact as a proxy for exposure to infectious agents and risk of childhood cancer. This population-based case-control study utilized a linkage of four Danish data-registries, and included 3581 cases (<17 years, diagnosed 1973–2012) and 358,100 age-matched controls. We examined the risks of leukemia, lymphoma, CNS and bone cancer related to high occupational social contact from (1) conception to birth and (2) birth to diagnosis.ResultsAcute lymphoblastic leukemia (ALL) and bone cancer were inversely associated with high maternal social contact from conception to birth (OR: 0.86, 95% CI: 0.67–1.10) and birth to diagnosis (OR: 0.54, 95% CI: 0.34–0.86). Children of fathers with high social contact from birth to diagnosis had an increased risk of bone cancers, particularly in rural areas (OR: 1.65, 95% CI: 1.03–2.63). Parental social contact was associated with increased risk of astrocytoma, with strongest associations found in first-born children (maternal: OR: 1.54, 95% CI: 1.02–2.32; paternal: OR: 1.82, 95% CI: 1.05–3.17).ConclusionOur results support the notion of a role of infections for some cancer types.     

Label-free mass spectrometric profiling of urinary proteins and metabolites from paediatric idiopathic nephrotic syndrome

Idiopathic nephrotic syndrome (INS) is caused by renal diseases that increase the permeability of the glomerular filtration barrier without evidence of a specific systemic cause. The aim of the present work was to reveal inherent molecular features of INS in children using combined urinary proteomics and metabolomics profiling. In this study, label-free mass spectrometric analysis of urinary proteins and small molecule metabolites was carried out in 12 patients with INS versus 12 sex- and age-matched control subjects with normal renal function. Integration and biological interpretation of obtained results were carried out by Ingenuity IPA software. Validation of obtained proteomics data was carried out by Western blot method. Proteomics data have been deposited to the ProteomeXchange Consortium with the data set identifier PXD000765. This study indicates for the first time that paediatric INS is associated with up-regulation of afamin, hydroxyphenylacetate and uridine, and concomitant down-regulation in glutamine and phenylalanine levels, and many of these molecular species were previously shown to be involved in oxidative stress. Further studies in larger patient population are underway to investigate the role of oxidative stress in renal injury in paediatric INS.