Nanbert Zhong

Preterm birth-associated neurodevelopmental impairment estimates at regional and global levels for 2010.

Background:In 2010, there were an estimated 15 million preterm births worldwide (<37 wk gestation). Survivors are at risk of adverse outcomes, and burden estimation at global and regional levels is critical for priority setting.Methods:Systematic reviews and meta-analyses were undertaken to estimate the risk of long-term neurodevelopmental impairment for surviving preterm babies according to the level of care. A compartmental model was used to estimate the number of impaired postneonatal survivors following preterm birth in 2010. A separate model (DisMod-MR) was used to estimate years lived with disability (YLDs) for the global burden of disease 2010 study. Disability adjusted life years (DALYs) were calculated as the sum of YLDs and years of life lost (YLLs).Results:In 2010, there were an estimated 13 million preterm births who survived beyond the first month. Of these, 345,000 (2.7%, uncertainty range: 269,000–420,000) were estimated to have moderate or severe neurodevelopmental impairment, and a further 567,000 (4.4%, (445,000–732,000)) were estimated to have mild neurodevelopmental impairment. Many more have specific learning or behavioral impairments or reduced physical or mental health. Fewest data are available where the burden is heaviest. Preterm birth was responsible for 77 million DALYs, 3.1% of the global total, of which only 3 million were YLDs.Conclusion:Most preterm births (>90%) survive without neurodevelopmental impairment. Developing effective means of prevention of preterm birth should be a longer term priority, but major burden reduction could be made immediately with improved coverage and quality of care. Improved newborn care would reduce mortality, especially in low-income countries and is likely to reduce impairment in survivors, particularly in middle-income settings.

Pheno/genotypic correlations of neuronal ceroid lipofuscinoses

The neuronal ceroid lipofuscinoses (NCL) are a large group of autosomal recessive lysosomal storage disorders with both enzymatic deficiency and structural protein dysfunction. Previously, diagnosis of NCL was based on age at onset and clinicopathologic (C-P) findings, classified as 1) infantile (INCL), 2) late infantile (LINCL), 3) juvenile (JNCL), and 4) adult (ANCL). Most patients with NCL have progressive ocular and cerebral dysfunction, including cognitive/motor dysfunction and uncontrolled seizures. After reviewing 319 patients with NCL, the authors found that 64 (20%) did not fit into this classification of NCL. With research progress, four additional forms have been recognized: 5) Finnish, 6) Gypsy/Indian, and 7) Turkish variants of LINCL and 8) northern epilepsy, also known as progressive epilepsy with mental retardation. These eight NCL forms resulted from 100 different mutations on genes CLN1to CLN8 causing different phenotypes (http://www.ucl.ac.uk/ncl). The genes CLN1 and CLN2 encode lysosomal palmitoyl protein thioesterase and tripeptidyl peptidase 1. The function of CLN3, CLN5, and CLN8 gene-encoded products is unknown, although their predicted amino acid sequences suggest they have a transmembrane topology. The diagnosis of NCL is based on C-P findings, enzymatic assay, and molecular genetic testing. Before biochemical and genetic tests are conducted, ultrastructural studies (i.e., blood [buffy coat] or punch biopsies [skin, conjunctiva]) must be performed to confirm the presence and nature of lysosomal storage material (fingerprint or curvilinear profiles or granular osmiophilic deposits). The recognition of variable onset from infancy to middle age supersedes the traditional emphasis on age-related NCL forms.

Association of genetic polymorphisms in the type II deiodinase gene with bipolar disorder in a subset of Chinese population.

OBJECTIVE Genetic factors play a critical role in the etiology of bipolar disorder (BPAD). Previous studies suggested an association between thyroid dysfunction and BPAD. We hypothesize that genetic variations in the type II deiodinase (DIO2) gene that possibly alter the bioactivity of thyroid hormones are associated with BPAD. METHOD A case-control association study was conducted in a subset of Chinese Han population. Two single nucleotide polymorphisms (SNP), open reading frame a (ORFa)-Gly3Asp (rs12885300) and Thr92Ala (rs225014) with potential functions on the activity of DIO2, were selected. The frequencies of allele, genotype and haplotype of the two SNPs were compared between the BPAD patients and the control group. RESULTS Statistical significance between the BPAD patients and the control group was observed for the allele (chi(2)=7.746, P=0.005, df=1) and genotype frequencies (chi(2)=8.158, P=0.017, df=2) at the locus of ORFa-Gly3Asp, and for the allele (chi(2)=15.838, P=7.00e-005, df=1) and genotype frequencies (chi(2)=17.236, P=0.0002, df=2) at Thr92Ala. Distribution of allele 3Gly and 92Ala were significantly higher in the BPAD patients, with odds ratios of 1.489 [95% confidence interval (CI)=1.124-1.973] and 1.616 [95% CI=1.275-2.048], respectively. Individuals with two copies of the variant 3Gly or 92Ala were at greater risk of BPAD than individuals with one copy (dose-response manner). Haplotypes ORFa-3Asp-92Ala and ORFa-3Gly-92Ala indicated higher susceptibility for BPAD with odds ratios of 3.759 (95% CI=2.013-7.020) and 1.292 (95% CI=1.017-1.642), respectively, while ORFa-3Asp-92Thr probably played a protective role with an odds ratio of 0.395 (95% CI=0.284-0.549). CONCLUSION Data generated from this study supported our hypothesis that genetic variations of the DIO2 gene were associated with BPAD and suggested further consideration on the possible involvement of these functionally active variants in the pathophysiology of BPAD.

Heterogeneity of late-infantile neuronal ceroid lipofuscinosis.

Purpose: Late-infantile neuronal ceroid lipofuscinosis (LINCL), an autosomal recessively inherited lysosomal storage disorder characterized by autofluorescent inclusions and rapid progression of neurodegeneration, is due to CLN2 gene mutations. However, CLN2 mutation analysis has failed to identify some clinically diagnosed “late-infantile” NCL cases. This study was conducted to further characterize genetic heterogeneity in families affected by LINCL.Methods: DNA mutations in the CLN1, CLN2, and CLN3 genes that underlie INCL (infantile NCL), LINCL, and JNCL (juvenile NCL), respectively, were studied with molecular analyses.Results: A total of 252 families affected by childhood NCL were studied. Of 109 families clinically diagnosed as having LINCL, 3 were determined to have either INCL or JNCL by identification of mutation(s) in CLN1 or CLN3. Six families diagnosed initially as having JNCL were found to have LINCL based on the finding of mutations in the CLN2 gene. In addition, several novel mutations were identified.Conclusions: Clinical and genetic heterogeneity of LINCL was demonstrated in nine LINCL families studied.

Similarity of DMD gene deletion and duplication in the Chinese patients compared to global populations.

BackgroundDNA deletion and duplication were determined as the major mutation underlying Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD).MethodApplying multiplex ligation-dependent probe amplification (MLPA), we have analyzed 179 unrelated DMD/BMD subjects from northern China.ResultsSeventy-three percent of the subjects were found having a deletion (66.25%) or duplication (6.25%). Exons 51–52 were detected as the most common fragment deleted in single-exon deletion, and the region of exons 45–50 was the most common exons deleted in multi-exon deletions. About 90% of DMD/BMD cases carry a small size deletion that involves 10 exons or less, 26.67% of which carry a single-exon deletion. Most of the smaller deletions resulted in an out-of-frame mutation. The most common exons deleted were determined to be between exon 48 and exon 52, with exon 50 was the model allele. Verifying single-exon deletion, one sample with a deletion of exon 53 that was initially observed from MLPA showed that there was a single base deletion that abolished the ligation site in MLPA. Confirmation of single-exon deletion is recommended to exclude single base deletion or mutation at the MLPA ligation site.ConclusionThe frequency of deletion and duplication in northern China is similar to global ethnic populations.

LncRNA Pathway Involved in Premature Preterm Rupture of Membrane (PPROM): An Epigenomic Approach to Study the Pathogenesis of Reproductive Disorders

Preterm birth (PTB) is a live birth delivered before 37 weeks of gestation (GW). About one-third of PTBs result from the preterm premature rupture of membranes (PPROM). Up to the present, the pathogenic mechanisms underlying PPROM are not clearly understood. Here, we investigated the differential expression of long chain non-coding RNAs (lncRNAs) in placentas of PTBs with PPROM, and their possible involvement in the pathogenic pathways leading to PPROM. A total number of 1954, 776, and 1050 lncRNAs were identified with a microarray from placentas of PPROM (group A), which were compared to full-term birth (FTB) (group B), PTB (group C), and premature rupture of membrane (PROM) (group D) at full-term, respectively. Instead of investigating the individual pathogenic role of each lncRNA involved in the molecular mechanism underlying PPROM, we have focused on investigating the metabolic pathways and their functions to explore what is the likely association and how they are possibly involved in the development of PPROM. Six groups, including up-regulation and down-regulation in the comparisons of A vs. B, A vs. C, and A vs. D, of pathways were analyzed. Our results showed that 22 pathways were characterized as up-regulated 7 down-regulated in A vs. C, 18 up-regulated and 15 down-regulated in A vs. D, and 33 up-regulated and 7 down-regulated in A vs. B. Functional analysis showed pathways of infection and inflammatory response, ECM-receptor interactions, apoptosis, actin cytoskeleton, and smooth muscle contraction are the major pathogenic mechanisms involved in the development of PPROM. Characterization of these pathways through identification of lncRNAs opened new avenues for further investigating the epigenomic mechanisms of lncRNAs in PPROM as well as PTB.

Setting research priorities to improve global newborn health and prevent stillbirths by 2025

Background In 2013, an estimated 2.8 million newborns died and 2.7 million were stillborn. A much greater number suffer from long term impairment associated with preterm birth, intrauterine growth restriction, congenital anomalies, and perinatal or infectious causes. With the approaching deadline for the achievement of the Millennium Development Goals (MDGs) in 2015, there was a need to set the new research priorities on newborns and stillbirth with a focus not only on survival but also on health, growth and development. We therefore carried out a systematic exercise to set newborn health research priorities for 2013–2025. Methods We used adapted Child Health and Nutrition Research Initiative (CHNRI) methods for this prioritization exercise. We identified and approached the 200 most productive researchers and 400 program experts, and 132 of them submitted research questions online. These were collated into a set of 205 research questions, sent for scoring to the 600 identified experts, and were assessed and scored by 91 experts. Results Nine out of top ten identified priorities were in the domain of research on improving delivery of known interventions, with simplified neonatal resuscitation program and clinical algorithms and improved skills of community health workers leading the list. The top 10 priorities in the domain of development were led by ideas on improved Kangaroo Mother Care at community level, how to improve the accuracy of diagnosis by community health workers, and perinatal audits. The 10 leading priorities for discovery research focused on stable surfactant with novel modes of administration for preterm babies, ability to diagnose fetal distress and novel tocolytic agents to delay or stop preterm labour. Conclusion These findings will assist both donors and researchers in supporting and conducting research to close the knowledge gaps for reducing neonatal mortality, morbidity and long term impairment. WHO, SNL and other partners will work to generate interest among key national stakeholders, governments, NGOs, and research institutes in these priorities, while encouraging research funders to support them. We will track research funding, relevant requests for proposals and trial registers to monitor if the priorities identified by this exercise are being addressed.

LncRNA-regulated Infection and Inflammation Pathways Associated with Pregnancy Loss: Genome Wide Differential Expression of lncRNAs in Early Spontaneous Abortion

Spontaneous abortion (SA) occurs before 20 gestational weeks. Approximately, half of recurrent SA has no identifiable cause. No report has yet been investigated the possible involvement of lncRNA in pregnancy loss.

Identification of FMRP-associated mRNAs using yeast three-hybrid system.

Fragile X syndrome, one of the most common forms of inherited mental retardation, results from the absence of the fragile X mental retardation protein (FMRP), which is encoded by the fragile X mental retardation gene 1 (FMR1). FMRP is an RNA‐binding protein involved in translational regulation of targeted mRNAs. Identification of targeted mRNAs associated with FMRP is important to understand the function of FMRP and the pathogenic basis of the fragile X syndrome. Employing a yeast three‐hybrid system and a human fetal hippocampus cDNA library, we identified 22 candidate target mRNAs, and 18 of them were confirmed to be associated with FMRP in vitro by gel retardation. Some of these mRNAs code for structural proteins, enzymes or proteins involved in cellular processes, especially in the development and function of neural system. To further investigate the role of FMRP in regulating targeted gene expression, we analyzed the expression profile of TXNRD1, one of the candidate mRNAs, after knocking down the expression of endogenous FMRP by siRNA. The results showed that endogenous TXNRD1 translation increased along with depletion of FMRP, which suggested FMRP negatively regulates TXNRD1 translation.

Identification of transcripts and translatants targeted by overexpressed PCBP1

PCBP1 is a member of the hnRNP family that functions as a RNA-binding, as well as DNA-binding, protein. The detailed transcripts and translatants targeted by PCBP1 at a global level are not yet known. We undertook an investigation of transcriptional and translational profiles after overexpressing exogenous PCBP1 in SH-SY5Y cells. Our results in two independent studies showed that 601 transcripts, including 26 down-regulated transcripts and 575 up-regulated transcripts, were impacted by overexpression of exogenous PCBP1. However, 138 and 144 transcripts showed non-overlapped differential expression in each study. These altered transcripts are clustered mainly in metabolic and transcriptional regulations. Proteomic profiles detected with a two-dimensional chromatographic PF2D showed a global change of translations, mainly in a range of pI=4.96-5.76 and pI=7.96-8.36. Three predominant proteins, which were differentially less expressed in PCBP1 overexpression cells and were detected at pI=7.96-8.16, were identified as histone proteins, indicating that histone proteins are among the targets regulated by PCBP1. Our investigation has opened a new avenue for further studying the biological functions of PCBP1.