Research Progress on the Prevention of Premature Infant Lung Injury and Neonatal Respiratory Support

In the past 40 years,advances in neonatal intensive care unit(NICU)technology have enabled premature infants with lower birth weight and younger gestational age to survive.But with it comes an increase in the incidence of long-term respiratory dysfunction,mainly in the form of bronchopulmonary dysplasia(BPD).Preventing lung injury is crucial for preventing BPD and improving the long-term prognosis of premature infants.Therefore,how to avoid ventilator-associated lung injury has become a focus of clinical and scientific research in premature infants in recent years.This article will elaborate on the susceptibility and pathophysiology of premature infant lung injury,ventilation strategies for preventing lung injury,and new advances in neonatal respiratory support.

History of the infantile hepatic hemangioma:From imaging to generating a differential diagnosis

We aim to provide an up-to-date summary of infantile hepatic hemangioma(IHH) and its misnomers and to dialectically present the differential diagnosis of these rare entities of the liver.Eligible peer-reviewed articles on hepatic infantile hemangiomas,published between 2000 and 2015,were reviewed for this study.IHH is the most common hepatic vascular tumor in children.Once a liver mass is identified in an infant,the differential diagnosis ranges from vascular malformations to benign and malignant tumors including mesenchymal hamartoma,hepatoblastoma,metastatic neuroblastoma,so careful physical examination,imaging studies,and,if indicated,tumor markers and biopsy,are of pivotal importance to ascertain the correct diagnosis.Despite the benign nature of IHHs,some of these lesions may demand medical and/or surgical intervention,especially for multiple and diffuse IHH.Complications can include hepatomegaly,hypothyroidism and cardiac failure.Therefore,a close follow-up is required until complete involution of the lesions.We propose an algorithm to guide the physicians towards the proper management of hepatic lesions.

CHOP THER APY INDUCED MITOCHONDRIAL REDOX STATE ALTERATION IN NON-HODGKIN'S LYMPHOMA XENOGRAFTS

We are interested in investigating whether cancer therapy may alter the mitochondrial redox state in cancer cells to inhibit their growth and survival.The redox state can be imaged by the redox scanner that collects the fuorescence signals from both the oxidized-fAavoproteins(Fp)and the reduced form of nicotinamide adenine dinucleotide(NADH)in snap frozen tissues and has been previously employed to study tumor aggressiveness and treatment responses.Here,with the redox scanner we investigated the effects of chemotherapy on mouse xenografts of a human diffuse large B.cell lymphoma cell line(DLCL2).The mice were treated with CHOP therapy,i.e,cyclophosphamide(C)+hydroxydoxorubicin(H)+Oncovin(O)+prednisone(P)with CHO administration on day 1 and prednisone administration on days 1-5.The Fp content of the treated group was significantly decreased(p=0.033)on day 5,and the mitochondrial redox state of the treated group was slightly more reduced than that of the control group(p=0.048).The decrease of the Fp heterogeneity(measured by the mean st andard deviation)had a border-line statistical significance(p=0.071).The result suggests that the mitochondrial metabolism of lymphoma cells was slightly suppressed and the lymphomas became less aggressive after the CHOP therapy.

对儿童用药和临床试验的思考

近年来,有高达79%的儿科药物在没有明确标识或者没有额外获得儿童使用许可的情况下使用[1]。2006年,我国医院对于4亿儿科患者使用的1 103种药品中仅有64种（占5.8%）是按说明书指导使用的[2]。另有数据显示,中国患病儿童占总患病人口的20%左右,但80%以上的已上市药品没有儿童使用标识,90%的药物没有儿童剂型[3]。

定量药理学:一个促进药物开发及转换型研究严谨思考的多学科领域

尽管从事定量药理学研究的科学工作者一再强调将定量分析的原则应用于促进新药研发的决策,定量药理学的发展还是超过了上述领域。普通研究和决策领域总是期望着常规和传统的研究范例发生进步,当与定量药理学相关的领域自身在发展并与其交互作用时,自然便产生对临床药理学的协同作用。创新性和可塑性训练计划和策略均是将来临床研究工作中必不可少的要素。掌握定量药理学领域的知识成为对药理科学家的要求,具有定量药理学背景的人员可望获得更高的薪水。目前定量药理学相关培训计划,教学资料,及学术权威均比较贫乏,学生们可以从企业化、调控性的背景的教师等多种机构的教职员那获得指导,此外也可以通过在线课程,可视化教学进修课程,与他们的导师保持联系。对课程和学位的管理可以采取灵活的态度,这样可在短期内培养更多的定量药理学工作者。

定量药理学与儿童药物研发和合理用药

This article provides a comprehensive overview of key issues related to pediatric drug development and rational dosing guidance in pediatrics with an emphasis on how pharmacometrics can improve the efficiency and productivity of pediatric trials.The pharmacokinetics(PK)and pharmacodynamics(PD)of drugs are often different between adult and pediatric populations which necessitate specific studies in children.The aims of this review are to discuss a number of recent methodological developments of modeling and simulation that facilitate the evaluation of drugs in pediatrics.Specific focus has been placed on addressing the key issues of PK/PD scaling,sparse sampling,colinearity,covariate evaluation,dose optimization for trial design and label,modeling strategies and validation approaches.The features and potential advantages of Bayesian hierarchical model,physiology-based PK models,and K-PD models are also presented.

Analytical validation of GMEX rapid point- of care CYP2C19 genotyping system for the CHANCE-2 trial

Background and purpose Rapid genotyping is useful for guiding early antiplatelet therapy in patients with high-risk nondisabling ischaemic cerebrovascular events(HR-NICE).Conventional genetic testing methods used in CYP2C19 genotype-guided antiplatelet therapy for patients with HR-NICE did not satisfy the needs of the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events(CHANCE)-2 trial.Therefore,we developed the rapid-genotyping GMEX(point-of care)system to meet the needs of the CHANCE-2 trial.Methods Healthy individuals and patients with history of cardiovascular diseases(n=408)were enrolled from six centres of the CHANCE-2 trial.We compared the laboratory-based genomic test results with Sanger sequencing test results for accuracy verification.Next,we demonstrated the accuracy,timeliness and clinical operability of the GMEX system compared with laboratory-based technology(YZY Kit)to verify whether the GMEX system satisfies the needs of the CHANCE-2 trial.Results Genotypes reported by the GMEX system showed 100%agreement with those determined by using the YZY Kit and Sanger sequencing for all three CYP2C19 alleles(*2,*3 and*17)tested.The average result’s turnaround times for the GMEX and YZY Kit methods were 85.0(IQR:85.0-86.0)and 1630.0(IQR:354.0-7594.0)min(p<0.001),respectively.Conclusions Our data suggest that the GMEX system is a reliable and feasible point-of care system for rapid CYP2C19 genotyping for the CHANCE-2 trial or related clinical and research applications.

Surgical management of the tonsillectomy and adenoidectomy patient

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Mcll becomes ubiquitin-ous： new opportunities to antagonize a pro-survival protein

Cancer remains a major cause of human mortality. The greatest barrier to cure is resistance to conventional medi- cal treatments. Therapy resistance arises through clonal evolution driven by ge- nomic instability, fostered by selection as therapy-sensitive ceils are eradicated. Such resistance has been attributed to al- terations in numerous cellular pathways, yet many ultimately impact the process ofmitochondrial apoptosis. The critical gatekeepers for mitochondrial apoptosis initiation are the Bcl2-homology （BH） proteins, whose interactions integrate the varied stressors a cell encounters and provide a live-or-die decision （reviewed in [1]）. As such, BH proteins are the frequent target of alterations in cancer cells during oncogenesis and tumor progression [2].

Airway function throughout the lifespan: Pediatric origins of adult respiratory disease

Chronic obstructive pulmonary disease(COPD)is a leading cause of disability and death of adults in the USA and worldwide.While environmental factors such as smoking and air pollution are major contributors to COPD,pediatric respiratory disease and more specifically early childhood wheezing are frequent predisposing factors.It is therefore possible that aggressive prevention and treatment of childhood respiratory illness may modify adult COPD risk.This article reviews some of the physiological factors that may explain the pediatric origins of childhood lung disease.One such factor is the"tracking"of normal lung function which occurs with growth.The maximal expiratory flow volume(MEFV)curve is an ideally suited tool to monitor tracking of airway function over the lifespan,as its relative effort independence makes it highly reliable.Study of the MEFV curve has demonstrated that individuals with similar lung volumes can have large differences in maximal flows,reflecting a disconnection between airway and lung growth("dysanapsis").Less than average airway size due to dysanaptic airway growth or airway remodeling may be independent risk factors for the development of COPD and the asthma/COPD overlap syndrome in adult life.There are intriguing early data suggesting that perhaps at least some of this risk is modifiable by improving asthma control with inhaled corticosteroids and minimizing asthma exacerbations.

因K_(ATP)通道突变所致的无亮氨酸敏感性高胰岛素血症患儿口服蛋白质可诱导低血糖症

Objective:Because children with congenital hyperinsulinism(HI) caused by recessive loss of function mutations in the adenosine triphosphate (ATP)-dependent potassium channel(KATP-HI) are not leucine sensitive,we evaluated for protein induced hypoglycemia with oral protein tolerance tests. Study design:Blood glucose and insulin concentrations were measure devery 15 minutes for 3 hours after an oral protein loadin children with KATP-HI (n=11) and compared with those of children with glutamate dehydrogenase HI (n=12) and control subjects (n=12). Results:Similar to children with glutamate dehydrogenase HI,patients with KATP-HI displayed protein-induced hypoglycemia (10/11)with blood glucose concentrations declining by 17 to 69 mg/dL. In contrast,oral proteinhad little effect on blood glucose concentrations in control subjects.Conclusions:Protein induced hypoglycemia is a feature of KATP-HI,despite the absence of leucine sensitivity. The results indicate that amino acids can stimulate insulin secretionvia a glutamate dehydrogenase and KATP channel-independent pathway.

转化型研究中的定量药理学(英文)

转化型研究一般是指将基础科学发现应用到治疗或预防疾病或损伤,其价值通常是基于探索或发展可产生有效疗法的可能性。当今的制药工业已发展成为一个从事转化型研究的高度专业化行业,在美国国立卫生研究院的倡议及激励下,医学科研队伍同样接受了这一模式。临床和转化型研究奖的设立可以为能从事此类研究机构所需的多学科环境创造机会。临床和转化型研究奖的一个关键组成部分以及美国国立卫生研究院的工作路线图和美国食品药物管理局的关键路径计划中的一个元素就是通过定量药理学研究桥接基础与临床科学。美国宾夕法尼亚大学/费城儿童医院临床和转化型研究相对突出,两项研究和教育目标均依赖于定量药理学。美国国立卫生研究院所赞助的一项旨在探索神经激肽1受体拮抗用于治疗神经性爱滋病的研究案例,正是用来说明运用定量药理进行转化型研究的范例。

An update to monocanalicular stent surgery

Dear Sir,I n their article, ＂A comparison between monocanalicular and pushed monocanalicular silicone intubation in the treatment of congenital nasolacrimal duct obstruction＂, Andalib et al present the results of a prospective study on congenital nasolacrimal duct obstruction treated either with a Monoka stent （using a Crawford hook for nasal retrieval） or a Masterka pushed technique for insertion of the Masterka stent. The success rates were respectively 90% and 50%.

对1例胆管闭锁患婴行肝门肠吻合修复术获成功

We present a case report of a boy with biliary atresia who,after hepatoportoenterostomy performed on day 21 of life, had immediate resolution of cholestasis and remained anicteric until 3.5 months of age. He then abruptly developed acholic stools.Nuclear medicine imaging study showed no excretion. Broadspectrum antibiotics and corticosteroids were administered but did not lead to clinical improvement; a surgical revision of the original anastomosis was undertaken at 4 months of age. At 14 months of age, the child is anicteric and growing well. In this case, successful revision of hepatoportoenterostomy averted the need for liver transplantation.

在儿科三级保健医院内囊性纤维病是复发性静脉血栓形成的危险因素

Objective:To evaluate risk factors for recurrent thrombosis in pediatric patients. Study design:This prospective observational cohort study enrolled 120 patients with acute venous thromboembolism from January 2003 to April 2005. Datacollection included medical and family history,radiologic and laboratory studies,therapy,and follow-up. Results:The overall prevalence of recurrent thrombosis in our cohort was 19/120(15.8%). Patients with recurrence were older,with a median age of 14.8 years (range 2 weeks-23.6 years),compared with 10.1years (range newborn 23.4 years) in patients without recurrence(P = 0.03). Six of the 19 patients with recurrent thrombosis had cystic fibrosis (CF),compared with 0/101without recurrence (P< 0.001). Five of these 6 patients were colonized with Burkholderia cepacia in their sputum. Central venous catheters were associated with most,but not all,of the thromboses in patients with CF. Conclusions:In this study,patients with CF had a high risk of recurrent venous thrombosis,as well as a high prevalence of colonization with B cepacia. The cause of this risk has not been defined. This observation may have important implications for thromboprophylaxis,particularly in the setting of central venous catheters.

青春前期Alagille综合征患儿的静息时能量消耗没有增加

Increased resting energy expenditure (REE) is a possible explanation for the negative energy balance seen in children with Alagille syndrome (AGS).We evaluated 16 subjects with AGS and 37 healthy controls and did not find a significant difference in REE (101%±12%,105%±13%,respectively).

Parental behaviors and sleep/wake patterns of infants and toddlers in Hong Kong, China

Background:To describe the sleep patterns of children below 36 months in Hong Kong,and evaluate the associations between parental behaviors and childhood sleep/wake patterns.Methods:Parents of 1049 infants and toddlers completed an internet-based expanded version of the Brief Infant Sleep Questionnaire.Results:Total sleep duration (P<0.001),frequency (P<0.001) and duration (P<0.001) of nocturnal awakenings decreased with age,whereas the longest sleep duration (P<0.001) and nocturnal sleep duration (P<0.001) increased with age.Children who room-or bed-shared with parents had later bedtimes (P<0.001),but similar sleep duration compared with those who had a separate sleep location.Falling asleep independently was associated with longer nocturnal sleep duration (P<0.001) and less sleep awakenings (P<0.001).Full-time employment of parents was associated with shorter total sleep duration of children (P<0.001).Although breastfeeding was associated with more nocturnal awakenings (P<0.001),no association was detected between breastfeeding and shorter sleep duration in children.Conclusions:As infants and toddlers develop,their sleep consolidates.Falling asleep independently was associated with longer nocturnal sleep duration and fewer sleep awakenings,whereas sleep location was not.This is an important finding,especially for families with limited living space where parent/ child room-or bed-sharing cannot be avoided.

Autophagy receptor CCDC50 tunes the STING-mediated interferon response in viral infections and autoimmune diseases

DNA sensing and timely activation of interferon(IFN)-mediated innate immunity are crucial for the defense against DNA virus infections and the clearance of abnormal cells.However,overactivation of immune responses may lead to tissue damage and autoimmune diseases;therefore,these processes must be intricately regulated.STING is the key adaptor protein,which is activated by cyclic GMP-AMP,the second messenger derived from cGAS-mediated DNA sensing.Here,we report that CCDC50,a newly identified autophagy receptor,tunes STING-directed type I IFN signaling activity by delivering K63-polyubiquitinated STING to autolysosomes for degradation.Knockout of CCDC50 significantly increases herpes simplex virus 1(HSV-1)-or DNA ligand-induced production of type I IFN and proinflammatory cytokines.Ccdc50-deficient mice show increased production of IFN,decreased viral replication,reduced cell infiltration,and improved survival rates compared with their wild-type littermates when challenged with HSV-1.Remarkably,the expression of CCDC50 is downregulated in systemic lupus erythematosus(SLE),a chronic autoimmune disease.CCDC50 levels are negatively correlated with IFN signaling pathway activation and disease severity in human SLE patients.CCDC50 deficiency potentiates the cGAS-STING-mediated immune response triggered by SLE serum.Thus,our findings reveal the critical role of CCDC50 in the immune regulation of viral infections and autoimmune diseases and provide insights into the therapeutic implications of CCDC50 manipulation.

Input oscillometry and the forced oscillation technique for assessing lung function in preschool children with asthma

Preschool children with asthma present a challenge in lung function testing, as they cannot readily cooperate with spirometry. The forced oscillation technique (FOT) measures passive pressures and flows delivered by a loudspeaker to a facemask, at frequencies much higher than those occurring physiologically. This in turn allows for rapid collection of data from a spontaneously breathing child in a timespan of seconds. However, at very rapid oscillatory flow rates, the mechanical properties opposing flows into and out of the respiratory system (collectively termed the respiratory system impedance, and comprised of elastic, resistive and inertial components) are very different from at normal breathing frequencies, with elastic properties being less important and inertial properties being more important. An understanding of how the respiratory system behaves at high frequencies is essential to understanding the physiological basis of this technique. This article presents a way to understand these oscillatory mechanics of the respiratory system. It then describes studies of the FOT in normal preschool children and in children with asthma. The technique can also measure the separate contributions of the central and peripheral airways, as well as assess for changes after bronchodilator administration. The FOT holds promise for the objective measurement of lung function in children who are too young to reliably perform spirometry.

"Reactance inversion" at low frequencies in a child undergoing treatment of a cystic fibrosis exacerbation

Introduction:Impulse oscillometry(IOS)employs high frequency sinusoidal or impulse pressure and flow waveforms to interrogate the mechanical properties of the respiratory system.It has special applications to preschool and younger children who may have difficulty performing the repetitive forced expiratory maneuvers required for spirometry.Case presentation:We present a case illustrating improvements of respiratory system mechanics measured by IOS in a 6-year-old child with cystic fibrosis(CF)who demonstrated clinical and radiological improvement after a course of therapy with hospitalization and intravenous antibiotics,and initiation of a cystic fibrosis transmembrane regulator(CFTR)protein corrector/potentiator agent.We also report a new finding:observed lower than expected reactance at low compared to high frequencies("reactance inversion").Conclusion:Reactance inversion may reflect parallel pathway inhomogeneities in resistance and elastance or intrabreath airway inertance changes in young children with CF.Further study is needed in children with airway obstruction due to asthma,cystic fibrosis,and chronic lung disease of infancy to demonstrate the prevalence of this finding and whether it is specific to a measurement device.