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Identification in Chinese patients with GLIALCAM mutations of megalencephalic leukoencephalopathy with subcortical cysts and brain pathological study on Glialcam knock-in mouse models
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Zhen Shi, Hui-Fang Yan, Bin-Bin Cao, Mang-Mang Guo, Han Xie, Kai Gao, Jiang-Xi Xiao, Yan-Ling Yang, Hui Xiong, Qiang Gu, Ming Li, Ye Wu, Yu-Wu Jiang, Jing-Min Wang |
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Background: Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare neurological degenerative disorder caused by the mutations of MLC1 or GLIALCAM with autosomal recessive or autosomal dominant inheritance and a different prognosis, characterized by macrocephaly, delayed motor and cognitive development, and bilateral abnormal signals in cerebral white matter (WM) with or without cysts on magnetic resonance imaging (MRI). This study aimed to reveal the clinical and genetic features of MLC patients with GLIALCAM mutations and to explore the brain pathological characteristics and prognosis of mouse models with different modes of inheritance.
Methods: Clinical information and peripheral venous blood were collected from six families. Genetic analysis was performed by Sanger sequencing of GLIALCAM. GlialcamArg92Trp/+ and GlialcamLys68Met/Thr132Asn mouse models were generated based on mutations from patients (c.274C>T(p.Arg92Trp) (c.203A>T(p.Lys68Met), and c.395C>A (p.Thr132Asn))). Brain pathologies of the mouse models at different time points were analyzed.
Results: Six patients were clinically diagnosed with MLC. Of the six patients, five (Pt1每Pt5) presented with a heterozygous mutation in GLIALCAM (c.274C>T(p.Arg92Trp) or c.275G>C(p.Arg92Pro)) and were diagnosed with MLC2B; the remaining patient (Pt6) with two compound heterozygous mutations in GLIALCAM (c.203A>T (p.Lys68Met) and c.395C>A (p.Thr132Asn)) was diagnosed with MLC2A. The mutation c.275C>G (p.Arg92Pro) has not been reported before. Clinical manifestations of the patient with MLC2A (Pt6) progressed with regression, whereas the course of the fi ve MLC2B patients remained stable or improved. The GlialcamArg92Trp/+ and GlialcamLys68Met/Thr132Asn mouse models showed vacuolization in the anterior commissural WM at 1 month of age and vacuolization in the cerebellar WM at 3 and 6 months, respectively. At 9 months, the vacuolization of the GlialcamLys68Met/Thr132Asn mouse model was heavier than that of the GlialcamArg92Trp/+ mouse model. Decreased expression of Glialcam in GlialcamArg92Trp/+ and GlialcamLys68Met/Thr132Asn mice may contribute to the vacuolization. Conclusions: Clinical and genetic characterization of patients with MLC and GLIALCAM mutations revealed a novel mutation, expanding the spectrum of GLIALCAM mutations. The first Glialcam mouse model with autosomal recessive inheritance and a new Glialcam mouse model with autosomal dominant inheritance were generated. The two mouse models with different modes of inheritance showed different degrees of brain pathological features, which were consistent with the patients* phenotype and further confirmed the pathogenicity of the corresponding mutations. |
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[Abstract] [Full Text] [PDF]
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Cardiovascular dysfunction and vitamin D status in childhood acute lymphoblastic leukemia survivors
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Paola Muggeo, Vito Michele Rosario Muggeo, Paola Giordano, Maurizio Delvecchio, Maria Altomare, Chiara Novielli, Marco Matteo Ciccone, Gabriele D*Amato, Maria Felicia Faienza, Nicola Santoro |
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Background: Vitamin D (25-OHD) has a role in bone health after treatment for cancer. 25-OHD deficiency has been associated with risk factors for cardiovascular disease, but no data focusing on this topic in childhood cancer survivors have been published. We investigated the 25-OHD status in children treated for acute lymphoblastic leukemia (ALL), and evaluated its influence on vascular function.
Methods: 25-OHD levels were evaluated in 52 ALL survivors and 40 matched healthy controls. Patients were grouped according to 25-OHD level (< 20 ng/m or ≡ 20 ng/mL). Auxological parameters, biochemical and hemostatic markers of endothelial function (AD, HMW-AD, ET-1, vWFAg, TAT, D-dimers, Fbg, and hs-CRP), ultrasound markers of vascular endothelial function (flow-mediated dilatation, FMD, common carotid intima-media thickness, C-IMT, and antero-posterior diameter of infra-renal abdominal aorta, APAO) were evaluated in the patients.
Results: Cases showed higher prevalence of 25-OHD deficiency than controls (P = 0.002). In univariate analysis via mean comparisons, 25-OHD deficient (< 20 ng/mL) patients showed higher C-IMT values compared to the 25-OHD non-deficient (≡ 20 ng/mL) group (P = 0.023). Significant differences were also found for ET-1 (P = 0.035) and AD-HMW (P = 0.015). In the multiple regression models controlling for some confounders, 25-OHD still was associated with C-IMT (P = 0.0163), ET-1 (P = 0.0077), and AD-HMW (P = 0.0008). Conclusions: Childhood ALL survivors show higher prevalence of 25-OHD deficiency as compared to controls. The 25-OHD levels appear to be linked to indicators of endothelial and vascular dysfunction. Careful monitoring of 25-OHD balance may help to prevent cardiovascular diseases in childhood ALL survivors, characterized by high cardiovascular risk. |
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[Abstract] [Full Text] [PDF]
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Impact of dyslipidemia on estimated glomerular filtration rate in apparently healthy children and adolescents: the CASPIAN-V study
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Mohammad Moafi, Farahnak Assadi, Ramin Heshmat, Mehri Khoshhali, Mostafa Qorbani, Mohammad E. Motlagh, Razieh Dashti, Majzoubeh Taheri, Roya Kelishadi |
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Background: Chronic kidney disease (CKD) is a leading risk factor for development of cardiovascular disease (CVD). Dyslipidemia is also known as risk factor for CVD development. However, the association of dyslipidemia with glomerular injury among healthy children and adolescents remains controversial. We aimed to investigate the relationship between estimated glomerular filtration rate (eGFR) and lipid profile risk factors among healthy children and adolescents.
Methods: In this nationwide survey, 3808 participants (1992 males, 1816 females), aged 7每18 years, were selected by cluster random sampling method from 30 provinces in Iran. Body mass index (BMI) and systolic and diastolic blood pressures were measured. Blood samples were obtained for serum creatinine, fasting blood glucose, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) determinations. GFR was estimated using Schwartz equation.
Results: Girls had higher eGFR than boys (P = 0.04). In a multiple regression analysis, eGFR demonstrated a positive correlation with systolic blood pressure, BMI, fasting glucose, TC, HDL-C, and TG. By the analysis of covariance, TC, HDLC, and TG showed a negative correlation with eGFR after adjustments for BMI, systolic and diastolic blood pressures, and fasting glucose (OR = 0.56, 95% CI = 0.29每0.89). Conclusion: The study showed that dyslipidemia is associated with reduced eGFR among the healthy children and adolescents. |
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[Abstract] [Full Text] [PDF]
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Management of Wilms tumor with intravenous thrombus in children: a single center experience
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Shuai Xu, Ning Sun, Wei-Ping Zhang, Hong-Cheng Song, Cheng-Ru Huang |
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Background: Wilms tumor tends to grow into vena cava, even invade atrium, which increased operating difficulty and frequency of surgical complications.
Methods: Forty-two patients of Wilms tumor with intravenous thrombus were retrospective studied. The diagnosis and therapy were discussed according to the medical records and interrelated literatures.
Results: Forty-two children with thrombus were diagnosed by computed tomography and 41 cases by ultrasound simultaneously. 36 children had received preoperative chemotherapy. Surgical resection was performed in all patients. Cardiopulmonary bypass was used for the removal of the intra-atrial thrombus in 5 patients. There were no surgical complications occurred. The patients received chemotherapy and radiotherapy according to clinical staging by National Wilms* Tumor Study (NWTS)-4 or NWTS-5. 34 patients were successfully followed up, 32 patients survive at present, including one who has been followed up more than 20 years since operation. Conclusion: Standardized sequential treatment, including preoperative chemotherapy and radiotherapy, nephrectomy combining resection of thrombus, postoperative adjuvant therapy, is the mainstay of treatment of Wilms tumor with intravenous thrombus. |
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[Abstract] [Full Text] [PDF]
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Family socioeconomic position and abnormal birth weight: evidence from a Chinese birth cohort
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Si Tu, Ao-Lin Wang, Mei-Zhen Tan, Jin-Hua Lu, Jian-Rong He, Song-Ying Shen, Dong-Mei Wei, Min-Shan Lu, Shiu Lun Au Yeung, Hui-Min Xia, Xiu Qiu |
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Background: Birth weight is a strong determinant of infant short- and long-term health outcomes. Family socioeconomic position (SEP) is usually positively associated with birth weight. Whether this association extends to abnormal birth weight or there exists potential mediator is unclear.
Methods: We analyzed data from 14,984 mother-infant dyads from the Born in Guangzhou Cohort Study. We used multivariable logistic regression to assess the associations of a composite family SEP score quartile with macrosomia and low birth weight (LBW), and examined the potential mediation effect of maternal pre-pregnancy body mass index (BMI) using causal mediation analysis.
Results: The prevalence of macrosomia and LBW was 2.62% (n = 392) and 4.26% (n = 638). Higher family SEP was associated with a higher risk of macrosomia (OR 1.30, 95% CI 0.93每1.82; OR 1.53, 95% CI 1.11每2.11; and OR 1.59, 95% CI 1.15每2.20 for the 2nd, 3rd, and 4th SEP quartile respectively) and a lower risk of LBW (OR 0.69, 95% CI 0.55每0.86; OR 0.76, 95% CI 0.61每0.94; and OR 0.61, 95% CI 0.48每0.77 for the 2nd, 3rd, and 4th SEP quartile respectively), compared to the 1st SEP quartile. We found that pre-pregnancy BMI did not mediate the associations of SEP with macrosomia and LBW. Conclusions: Socioeconomic disparities in fetal macrosomia and LBW exist in Southern China. Whether the results can be applied to other populations should be further investigated. |
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[Abstract] [Full Text] [PDF]
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Impact of HIV on the health-related quality of life in youth with perinatally acquired HIV
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Isabel Cu谷llar-Flores, Tal赤a Sa赤nz, Carlos Velo, Mar赤a Isabel Gonz芍lez-Tom谷, Cristina Garc赤a-Navarro, Carolina Fern芍ndez-Mcphee, Sara Guill谷n, Jos谷 Tom芍s Ramos, Pilar Miralles, Rafael Rubio, Jos谷 Ignacio Bernardino, Luis Prieto, Pablo Rojo, Santiago Jim谷nez de Ory, Maria Luisa Navarro, on behalf of CoRiSpe (FARO and NeuroCoRISpeS projects, RITIP-Traslational Research Network in Pediatric Infectious Diseases) |
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Background: Studies investigating health-related quality of life (HRQoL) in youth with perinatally acquired HIV (PHIV+) are scarce. This study aimed to compare HRQoL of PHIV+ to sociodemographic-matched youth not living with HIV (HIV−), Spanish general youth population, and to explore associations between sociodemographic variables, drug consumption, and HRQoL.
Methods: PHIV+ youth were randomly selected from CoRISpe database (Cohort of the Spanish Pediatric HIV Network). HRQoL was evaluated by SF-12v2.
Results: Thirty-nine PHIV+ youth (mean age: 23.36 years, SD = 3.83) and thirty-nine HIV− youth (mean age: 22.97 years, SD = 3.80) participated in this study. PHIV+ obtained lower scores in SF-12 physical health subscale (PCS) than HIV − ( P = 0.001) and Spanish general youth population ( P = 0.006). PHIV+ had lower scores on the mental health subscale (MCS) than the Spanish general youth population ( P < 0.001). PHIV+ who were at school obtained better scores than those were not at school. PHIV+ youth who had used cocaine and cannabis had lower scores in MCS ( P = 0.002). Conclusion: There is a need for HRQoL management in the associated medical follow-up. |
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[Abstract] [Full Text] [PDF]
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Establishment of an efficient reverse genetic system of Mumps virus S79 from cloned DNA
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Duo Zhou, Meng-Ying Zhu, Yi-Long Wang, Xiao-Qiang Hao, Dong-Ming Zhou, Rong-Xian Liu, Chu-Di Zhang, Chu-Fan Qu, Zheng-Yan Zhao |
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Background: Mumps is a common type of respiratory infectious disease caused by mumps virus (MuV), and can be effectively prevented by vaccination. In this study, a reverse genetic system of MuV that can facilitate the rational design of safer, more efficient mumps vaccine candidates is established.
Methods: MuV-S79 cDNA clone was assembled into a full-length plasmid by means of the GeneArt™ High-Order Genetic Assembly System, and was rescued via reverse genetic technology. RT-PCR, sequencing, and immunofluorescence assays were used for rMuV-S79 authentication. Viral replication kinetics and in vivo experimental models were used to evaluate the replication, safety, and immunogenicity of rMuV-S79.
Results: A full-length cDNA clone of MuV-S79 in the assembly process was generated by a novel plasmid assemble strategy, and a robust reverse genetic system of MuV-S79 was successfully established. The established rMuV-S79 strain could reach a high virus titer in vitro. The average viral titer of rMuV-S79 in the lung tissues was 2.68 ㊣ 0.14 log 10 PFU/g lung tissue, and rMuV-S79 group did not induce inflammation in the lung tissues in cotton rats. Neutralizing antibody titers induced by rMuV-S79 were high, long-lasting and could provide complete protection against MuV wild strain challenge. Conclusions: We have established a robust reverse genetic system of MuV-S79 which can facilitate the optimization of mumps vaccines. rMuV-S79 rescued could reach a high virus titer and the safety was proven in vivo. It could also provide complete protection against MuV wild strain challenge. |
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[Abstract] [Full Text] [PDF]
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