Expression of Clock genes in the pineal glands of newborn rats with hypoxic-ischemic encephalopathy

Clock genes are involved in circadian rhythm regulation, and surviving newborns with hypoxic-ischemic encephalopathy may present with sleep-wake cycle reversal. This study aimed to determine the expression of the clock genes Clock and Bmall, in the pineal gland of rats with hypoxic-ischemic brain damage. Results showed that levels of Clock mRNA v^re not significantly changed within 48 hours after cerebral hypoxia and ischemia. Expression levels of CLOCK and BMAL1 protein were significantly higher after 48 hours. The levels of Bmall mRNA reached a peak at 36 hours, but were significantly reduced at 48 hours. Experimental findings indicate that Clock and Bmall genes were indeed expressed in the pineal glands of neonatal rats. At the initial stage （within 36 hours） of hypoxic-ischemic brain damage, only slight changes in the expression levels of these two genes were detected, followed by significant changes at 36-48 hours. These changes may be associated with circadian rhythm disorder induced by hypoxic-ischemic brain damage.

An Unusual and Previously Unreported Association between Tyrosinemia Type 1 and an Extremely Rare Variation of Congenital Cystic Dilatation: TODANI’s VI Cystic Duct Cyst: Report of a Case

Cystic duct cysts are rare lesions, and type VI of TODANI’s modified classification is the rarest subtype with only sporadic case reports in the literature. The following report describes the coexistence of this entity and type 1 tyrosinemia in a one month-old infant referred to our department for etiological investigations of prolonged neonatal cholestasis. To the best of our knowledge, we report herein the first case in the literature describing this association. Cystic duct abnormalities should be considered in the differential diagnosis of neonatal cholestases, however further investigations should be performed to exclude associated life-threatening conditions such as metabolic disorders including tyrosinemia.

Effectiveness of Rituximab Therapy on Severe Calcinosis in 4 Children with Juvenile Dermatomyositis

Background: Calcinosis is an important sequela of JDM which may cause significant morbidity and mortality. There is no standard curative treatment for calcinosis but different agents were used with variable efficacy. We report the favorable outcome of rituximab on severe calcinosis in 4 JDM patients and present their clinical data. Patients and Methods: A retrospective chart review of 4 children with JDM and severe calcinosis who received rituximab for relapsing or polycyclic JDM course. Diagnosis and follow up of calcinosis was clinically and by X-ray. Review data included: age of patients at onset of JDM symptoms and diagnosis, clinical and laboratory criteria at diagnosis, disease course and duration of follow up. Data about calcinosis onset, sites, severity and its progression were also included. Further data about rituximab therapy included: dosage, side effects, other treatment used before, during or after this drug and outcome and duration of follow up of calcinosis after therapy. Results: 4 patients (2 male, 2 female), interval between onset of symptoms and diagnosis was 6 - 12 months, course of JDM was polycyclic or relapsing, duration of follow up was 5 - 7 years. Calcinosis was severe causing ulceration, recurrent skin infections and joint limitation. It was not improving despite treatment with different DMARDs and/or bisphosphonates, colchicine and warfarin. Reason to start rituximab was inadequate disease control with conventional DMARDs. All patients received steroids and more than one DMARD before starting rituximab and were continued thereafter, follow up after rituximab was 3 to 5 years. All patients had improvement in disease activity and frequency of admission especially due to complications of calcinosis. One patient had complete clearance of calcinosis for the last 5 years. Others had significant improvement in calcinosis with no new lesions, decreased sites and density and decreased calcinosis related contractures. There were no serious side effects to rituximab. Conclusion: Our study showed the favorable effect of rituximab in treatment of calcinosis in 4 patients with JDM-associated severe calcinosis when it was used with other conventional DMARDs.

Manifestations of COVID-19 infection in children with malignancy:A single-center experience in Jordan

BACKGROUND The coronavirus disease 2019(COVID-19)has been the cause of a global health crisis since the end of 2019.All countries are following the guidelines and recommendations released by the World Health Organization to decrease the spread of the disease.Children account for only 3%-5%of COVID-19 cases.Few data are available regarding the clinical course,disease severity,and mode of treatment in children with malignancy and COVID-19.AIM To evaluate the treatment plan and outcome of children with malignancy who contracted COVID-19.METHODS A retrospective study of the medical files of patients with malignancy who contracted COVID-19 between July 2020 and June 2021 was performed.The following data were reviewed for all patients:primary disease,laboratory data,admission ward,clinical status upon admission,disease course,treatment plan,and outcome.Eligible patients were those with malignancy who tested positive for COVID-19 by reverse transcription polymerase chain reaction.RESULTS A total of 40 patients who had malignancy contracted COVID-19 from July 1,2020 to June 1,2021.Their primary diseases were as follows:34 patients(85%)had hematological malignancies(30 had acute lymphoblastic leukemia,2 had acute myeloblastic leukemia,and 2 had Hodgkin lymphoma),whereas 6 patients(15%)had solid tumors(2 had neuroblastoma,2 had rhabdomyosarcoma,and 2 had central nervous system tumors).Twelve patients(30%)did not need hospitalization and underwent home isolation only,whereas twenty-eight patients(70%)required hospitalization(26 patients were admitted in the COVID-19 ward and 2 were admitted in the pediatric intensive care unit).CONCLUSION COVID-19 with malignancy in the pediatric age group has a benign course and does not increase the risk of having severe infection compared to other children.

Effect of vaccinations and school restrictions on the spread of COVID-19 in different age groups in Germany

With the emergence of SARS-CoV-2,various non-pharmaceutical interventions were adopted to control virus transmission,including school closures.Subsequently,the introduction of vaccines mitigated not only disease severity but also the spread of SARSCoV-2.This study leveraged an adapted SIR model and non-linear mixed-effects modeling to quantify the impact of remote learning,school holidays,the emergence of Variants of Concern(VOCs),and the role of vaccinations in controlling SARS-CoV-2 spread across 16 German federal states with an age-stratified approach.Findings highlight a significant inverse correlation(Spearman's ρ=0.92,p<0.001)between vaccination rates and peak incidence rates across all age groups.Model-parameter estimation using the observed number of cases stratified by federal state and age allowed to assess the effects of school closure and holidays,considering adjustments for vaccinations and spread of VOCs over time.Here,modeling revealed significant(p<0.001)differences in the virus's spread among pre-school children(0-4),children(5-11),adolescents(12-17),adults(18-59),and the elderly(60+).The transition to remote learning emerged as a critical measure in significantly reducing infection rates among children and adolescents(p<0.001),whereas an increased infection risk was noted among the elderly during these periods,suggesting a shift in infection networks due to altered caregiving roles.Conversely,during school holiday periods,infection rates among adolescents mirrored those observed when schools were open.Simulation exercises based on the model provided evidence that COVID-19 vaccinations might serve a dual purpose:they protect the vaccinated individuals and contribute to the broader community's safety.

Eosinophilic gastroenteritis with cytomegalovirus infection in an immunocompetent child

A 3-year-old boy developed transient protein-losing gastroenteropathy associated with cytomegalovirus (CMV) infection. Both IgG and IgM antibodies to CMV were positive in a serologic blood test. Upper gastrointestinal endoscopy showed multiple erosions throughout the body of the stomach, without enlarged gastric folds. Histological examination of the biopsy specimens indicated eosinophilic gastroenteritis and CMV infection. The patient had complete resolution without specific therapy for CMV in four weeks. An allergic reaction as well as CMV infection played important roles in the pathogenesis of this case.

Therapy-refractory gastrointestinal motility disorder in a child with c-kit mutations

Constipation and fecal impaction are frequent and distressing complaints in pediatric gastroenterology. Especially in neurologically handicapped children, treatment of severe forms of slow-transit constipation (STC) can be difficult. In the majority of cases, STC is of unknown etiology. However, in recent years, there is growing evidence that interstitial cells of Cajal (ICCs), which serve as electrical pacemakers and generate spontaneous electrical slow waves in the gastrointestinal tract, might play an important role in the pathophysiology of STC. It remains unclear whether morphological ICC alterations seen in affected patients are based on congenital developmental anomalies, or whether they are a consequence of long-term constipation with secondary damage of the gastrointestinal nervous system. To the best of our knowledge, we present the first case of a patient with histological alterations in ICC morphology who displayed multiple alterations of c-kit at the level of mRNA. The protein encoded by c-kit is the receptor tyrosine kinase Kit (CD117), which is crucial for development and function of ICCs. Therefore, these findings provide a new explanation for congenital alterations of ICC development that result in gastrointestinal motility disorders.

Differential diagnosis in patients with suspected bile acid synthesis defects

AIM: To investigate the clinical presentations associated with bile acid synthesis defects and to describe identification of individual disorders and diagnostic pitfalls. METHODS: We describe semiquantitative determination of 16 urinary bile acid metabolites by electrospray ionization-tandem mass spectrometry. Sample preparation was performed by solid-phase extraction. The total analysis time was 2 min per sample. We determined bile acid metabolites in 363 patients with suspected defects in bile acid metabolism. RESULTS: Abnormal bile acid metabolites were found in 36 patients. Two patients had bile acid synthesis defects but presented with atypical presentations. In 2 other patients who were later shown to be affected by biliary atresia and cystic fibrosis the profile of bile acid metabolites was initially suggestive of a bile acid synthesis defect. Three adult patients suffered from cerebrotendinous xanthomatosis. Nineteen patients had peroxisomal disorders, and 10 patients had cholestatic hepatopathy of other cause. CONCLUSION: Screening for urinary cholanoids should be done in every infant with cholestatic hepatopathy as well as in children with progressive neurological disease to provide specific therapy.

No Correlation between <i>AVPR</i>1A Promoter Polymorphisms and Prepulse Inhibition in Patients with Nocturnal Enuresis

Introduction: A correlation between AVPR1A promoter polymorphisms and prepulse inhibition (PPI) of startle reflexes has been described in healthy adults. Many children with nocturnal enuresis (NE) have a reduced PPI and treatment with desamino arginine vasopressin (dDAVP), a ligand of the arginine vasopressin receptor 1A (AVPR1A), and both improve clanical symptoms and significantly increase PPI. Methods: In 17 children (median 9.1 years, range 6.4-17.3) with NE, promoter repeats within the RS1 and RS3 regions of AVPR1A were quantified and correlated to PPI (native and age-adjusted). Results: No direct correlation was found between the number of promoter repeats at RS1 and PPI (correlation coefficient—0.240, p = 0.346) or RS3 and PPI (correlation coefficient—0.0192, p = 0.936), with no change through age-adjustment of PPI. The different RS3 length subgroups did not show differences in PPI, nor did differentiation of NE according to clinical subtype or treatment response to dDAVP show differences in the number of promoter repeats. Conclusion: The missing reproducibility of the correlation between AVPR1A promoter polymorphisms and PPI in a group with wide range of PPI suggests a more complex interaction. Therefore, further investigations are needed to analyze this very plausible interaction. Conditions with a reduced PPI, such as enuresis, schizophrenia or autism, are particularly interesting for this research.

1例具有神经系统症状和白三烯代谢异常患者:白三烯生物合成的新缺陷

A 15- year-old male patient presented with mental retardation, mild motor impairment, and partial deafness. Biochemical investigations showed an abnormal urinary profile of leukotrienes. Concentration of leukotriene D4 (LTD4), which is usually not detectable, was highly increased, whereas LTE4,the major urinary metabolite in humans, was completely absent. These data suggest membrane-bound dipeptidase deficiency, a new defect in leukotriene biosynthesis on the step of LTE4 synthesis, as underlying defect.

在1例携带新型NF1突变的患者身上出现的类似西拉综合征的症状

Mutations in the NF1 gene (17q11.2) cause neurofibromatosis type 1 (NF1), a pleiotropic and progressive autosomal dominant disorder with marked variability of clinical expression. Clinical diagnosis is usually readily achieved in most adult and adolescent patients due to the presence of at least two of the classic signs of NF1. However, the absence of many of the diseasedefining features in young children frequently renders definite diagnosis impossible in this age group. Particularly, clinical diagnosis is challenging in young patients whose phenotypical presentation does not lie within the common spectrum of “ typical” NF1 features. Sensitive and reliable molecular genetic testing can be of great help in these cases. Here, we report clinical and molecular findings in a 2- year- old boy with features of NF1. Severe growth retardation together with other dysmorphic features was also suggestive for Silver- Russell syndrome (SRS) in this patient. Molecular genetic testing identified a novel NF1 mutation and, thus, enabled a confident NF1 diagnosis despite the unusual phenotypical presentation in this patient.

血浆亮氨酸水平对典型MSUD患儿智力的影响

Maple syrup urine disease (MSUD) is an inherited deficiency of branched chain α-ketoacid dehydrogenase (BCKDH) activity impairing the degradation of the branched chain amino acids valine,leucine,and isoleucine. Classic MSUD may lead to severe neonatal encephalopathy including coma and impaired cognitive outcome in later life. Early start of dietary treatment and careful metabolic control may improve the outcome of patients with classic MSUD. The aim of this study was to investigate the impact of long-term metabolic control assessed by plasma leucine levels on cognitive outcome in patients with classic MSUD. Plasma leucine levels of 24 patients were obtained retrospectively for the first 6 y of life and yearly medians of mean plasma leucine levels were calculated. At the age of 6 y,IQ tests were performed. Yearly medians of mean plasma leucine levels yielded three homogeneous clusters (low,intermediate,high). Patients of the low cluster showed statistically significant higher IQ scores compared with those of those of intermediate and high clusters. Long-term plasma leucine levels are associated with impaired cognitive outcome in patients with classic MSUD. To achieve the best possible intellectual outcome for affected individuals,we recommend that in infants and preschool children the target range for plasma leucine should not exceed 200 μmol/L.

脾棘球蚴病儿童的手术治疗

Background/Purpose: Hydatid disease of the spleen is a rare disease, and it occurs in 1%to 8%of all children with hydatid disease. That difference in frequency depends on the social and economic status of the patients and the country. The aim of our study is to reveal its diagnosis and treatment. Methods:From 1985 to 2004, 152 children with hydatid disease have been operated on at the Surgical Department of General and Pediatric surgery at the Medical University in Stara Zagora and Medical University in Plovdiv, Bulgaria. Of the 152 children,15 (9.87%) had spleen localization: 6 males and 9 females,aged 10 to 18 years. A solitary cyst in the spleen was found in 10 patients, 8 children had an isolated cyst only in the spleen, 7 with involvement of other organs (5 in the liver, 2 in liver andlungs). All spleen cysts were “silent.”Abdominal sonography,computed tomography, and enzyme-linked immunosorbent assay tests proved the diagnosis. All children were operated on.Results: A splenectomy was performed in 14 cases, and a cystectomy was possible in only 1 case. Patients with combined forms successfully underwent different variations of cystectomy:6 omentoplasty, 5 capitonnages, and 4 invaginations.Conclusions: Splenic involvement of hydatid disease has no specific clinical manifestation, the diagnosis is late and often leads to splenectomy. Organ-preserving procedures are possible only in cases with early diagnosis. It has to be suspected in a patient with a splenic cyst and has to be confirmed by ultrasonography and/or computed tomography,magnetic resonance imaging, and immunologic tests. The early diagnosis is a good precondition for better results.

戊二基辅酶A去氢酶缺陷患者的迟发神经病变

Neurologic disease in glutaryl- CoA dehydrogenase (GC- DH)- deficiency usually presents with acute encephalopathic crises before 2 years of age. The authors report two previously asymptomatic patients with macro cephaly presenting with progressive neurologic deterioration and a severe leukoe ncephalopathy during adolescence or adulthood.

High incidence of maternal vitamin B12 deficiency detected by newborn screening: first results from a study for the evaluation of 26 additional target disorders for the German newborn screening panel

Background Newborn screening (NBS) in Germany currently includes 15 target disorders. Recent diagnostic improvements suggest an extension of the screening panel. Methods Since August 2016, a prospective study evaluating 26 additional target disorders (25 metabolic disorders and vitamin B12-deficiency) in addition to the German screening panel is performed at the Newborn Screening Center Heidel-berg. First-tier results from tandem-MS screening are complemented by second-tier strategies for 15 of the additional target disorders. NBS results of seven patients diagnosed symptomatically with one of the additional target disorders by selective screening since August 2016 are retrospectively evaluated. Results Over a 13-month period, 68,418 children participated in the study. Second-tier analyses were performed in 5.4%of samples. Only 59 (0.1%) of study participants had abnormal screening results for one of the additional target disorders. Target disorders from the study panel were confirmed in 12 children: 13-hydroxy-3-methylglutaryl coenzyme A (CoA)-lyase deficiency, 1 citrullinemia type I, 1 multiple acyl-CoA dehydrogenase-deficiency, 1 methylenetetrahydrofolate reductase-deficiency, and 8 children with maternal vitamin B12-deficiency. In addition, six of seven patients diagnosed symptomatically outside the study with one of the target disorders would have been identified by the study strategy in their NBS sample. Conclusions Within 13 months, the study 'Newborn Screening 2020' identified additional 12 children with treatable con-ditions while only marginally increasing the recall rate by 0.1%. Maternal vitamin B12-deficiency was the most frequent finding. Even more children could benefit from screening for the additional target disorders by extending the NBS panel for Germany and/or other countries.

Association of tumor differentiation and prognosis in patients with rectal cancer undergoing neoadjuvant chemoradiation therapy

Background and objective:Neoadjuvant chemoradiation therapy(NCRT)followed by radical resection has been a common practice for patients with locally advanced rectal cancer.This study aimed to analyse the association of tumor differentiation and prognosis in rectal-cancer patients undergoing NCRT.Methods:Patients with locally advanced,non-mucinous rectal cancer who underwent NCRT followed by radical resection between 2007 and 2017 were identified from an electronic health record system at the Sixth Affiliated Hospital of Sun Yatsen University(Guangzhou,China).Multivariable logistic regression and multivariate Cox regression were performed to analyse the association of response to NCRT and survival with clinicopathological characteristics of all these patients.Results:We identified 325 patients(241 males and 84 females;mean age,54.4611.2 years)who underwent NCRT followed by radical resection,including 26(8.0%)with poorly-differentiated rectal cancer,182(56.0%)with moderately-differentiated cancer and 117(36.0%)with well differentiated cancer.Propensity score matching analysis and multivariable logistic regression analysis results showed that tumor differentiation was significantly associated with response to NCRT.In the poor differentiation and non-poor differentiation groups,the 3-year overall survival(OS)rates were 74.6 and 93.5%,respectively,whereas the 3-year local recurrence rates were 18.6 and 3.7%,respectively.Multivariable Cox regression analyses revealed that poor differentiation was an independent risk factor for local recurrence and OS.Conclusions:Among the patients with locally advanced,non-mucinous rectal cancer,the patients with poorlydifferentiated cancer who underwent NCRT had a worse response to NCRT and poorer prognosis than those with moderately-and well-differentiated diseases.

Efficacy of live attenuated vaccines after two doses of intravenous immunoglobulin for Kawasaki disease

Kawasaki disease(KD)is a vasculitis of unknown etiology occurring predominantly in children under five years old[1].Coronary artery aneurysm,its most serious complica-tion,occurs in about 25%of untreated patients[2].High-dose intravenous immunoglobulin(IVIG)2 g/kg is used to prevent coronary artery aneurysms[1,3,4],but about 20%of patients are nonresponsive and require a second dose for a total of 4 g/kg.The appropriate timing of live attenuated vaccine(LAV)administration in such cases is unclear.

Constitutive STAT3 phosphorylation and IL-6/IL-10 co-expression are associated with impaired T-cell function in tuberculosis patients

T-cells critically contribute to protection against Mycobacterium tuberculosis infection,and impaired T-cell responses can lead to disease progression.Pro-inflammatory and immunosuppressive cytokines affect T-cells,and fine-tuned regulation of cytokine signaling via the Jak/STAT signaling pathways is crucial for appropriate T-cell function.Constitutive STAT3 phosphorylation as a consequence of aberrant cytokine signaling has been described to occur in pathognomonic T-cell responses in inflammatory and autoimmune diseases.We characterized blood samples from tuberculosis patients(n=28)and healthy contacts(n=28)from Ghana for M.tuberculosis-specific T-cell responses,constitutive cytokine production,and SOCS3 and pSTAT3 expression.Lentiviral modulation of primary CD4+T-cells was performed to determine the effects of SOCS3 on T-cell functions.T-cells from tuberculosis patients expressed higher levels of IL-10 and IL-6 and lower levels of T helper type(TH)17 cytokines after M.tuberculosis-specific stimulation compared to healthy contacts.In addition,tuberculosis patients had higher IL-10 and IL-6 levels in the supernatants of non-stimulated immune cells and plasma samples compared to healthy contacts.Notably,aberrant cytokine expression was accompanied by high constitutive pSTAT3 levels and SOCS3 expression in T-cells.Multivariate analysis identified an IL-6/IL-10 co-expression-based principal component in tuberculosis patients that correlated with high pSTAT3 levels.SOCS3 contributed to a regulatory component,and tuberculosis patients with high SOCS3 expression showed decreased TH1 cytokine expression and impaired IL-2-induced STAT5 phosphorylation.SOCS3 over-expression in primary CD4+T-cells confirmed the SOCS3 inhibitory function on IL-2-induced STAT5 phosphorylation.We conclude that constitutive pSTAT3 and high SOCS3 expression are influential factors that indicate impaired T-cell functions in tuberculosis patients.

Decreased hemoglobin after initial treatment is associated with treatment resistance in Kawasaki disease in Kobayashi risk stratification

Background Although Kawasaki disease(KD)is known to cause anemia,the relationship between its prognosis and hemoglobin level is less well known.Methods We herein performed a secondary analysis of data from a previous study(Post-RAISE).Children aged 6 months to 2 years at the time of KD diagnosis were enrolled.Decreased hemoglobin was defined as a decrease>10%on post-treatment day 2 compared with the level prior to the initial therapy.Results Of 1253 KD cases,treatment resistance was observed in 209(17%)and was significantly more frequent in the decreased hemoglobin group(37/167 vs.172/1086,P=0.041).Multivariable logistic regression analysis revealed that decreased hemoglobin was associated with resistance to the initial treatment(odds ratio 1.53;95%confidence interval 1.00-2.33;P=0.048).Conclusions Decreased hemoglobin was significantly associated with resistance to initial treatment in patients with KD.

Aberrant cytokine milieu and signaling affect immune cell phenotypes and functions in tuberculosis pathology:What can we learn from this phenomenon for application to inflammatory syndromes?

Our previous study published in Cellular&Molecular Immunology(Harling et al.1)described aberrant immunological features in the pathogenesis of tuberculosis.Overall,we provided evidence supporting an impact chain regarding aberrant high interleukin(IL)-6 and IL-10 cytokine expression and respective receptor signaling affecting T-cell functions in acute tuberculosis.Constitutive STAT3 phosphorylation,high expression of its key regulator suppressor of cytokine signaling(SOCS)3 and spontaneous IL-6/IL-10 secretion characterized CD4^(+)T cells from tuberculosis patients.