[Abnormalities of white matter differentiate the Parkinson variant of multiple system atrophy from Parkinson's disease].

Objective: To identify objective markers between the Parkinson variant of multiple system atrophy (MSA-P) and Parkinson's disease (PD). Methods: Retrospective analysis was performed on 10 patients with MSA-P, 15 patients with PD, and 15 healthy control group during the period from August 2016 to February 2019 in Baoshan Branch of Shanghai First People's Hospital.We combined the novel tract based spatial statistics (TBSS) and region of interest (ROI) analyses for the first time to investigate three groups with diffusion tensor imaging. By TBSS, we performed pairwise comparisons of mean diffusivity and fractional anisotropy (FA) maps. The clusters with significant differences between MSA-P and PD were used as ROIs for further analyses. Results: FA values in the left anterior thalamic radiation(ATR) (ROI values were 0.371(0.287-0.535), 0.472(0.390-0.594), 0.473(0.388-0.555); P values were 0.008, 0.008) and left superior longitudinal fasciculus (SLF)(ROI values were 0.397(0.291-0.469), 0.456(0.338-0.560), 0.473(0.427-0.530); P values were 0.013,<0.001) were significantly decreased in MSA-P compared with PD or controls, and significantly correlated with clinical data((r =-0.807, P =0.005),(r =-0.455, P =0.022)). Conclusion: Our findings indicate the abnormalities of left ATR and left SLF as specific biomarkers for differential diagnosis.

Smallest critical region for microcephaly in a patient with mosaic ring chromosome 13.

A ring chromosome 13 or r(13) exhibits breakage and reunion at breakage points on the long and short arms of chromosome 13, with deletions of the chromosomal segments distal to the breakage points. The r(13) chromosome accounts for approximately 20% of ring chromosomes compatible with life. We describe a female patient with mental retardation, growth retardation, microcephaly, craniofacial dysmorphy, hearing impairment, and prolonged prothrombin time. Chromosomal analysis via GTG banding of peripheral blood lymphocytes revealed a karyotype of 46,XX,r(13)(p13q34)[71]/45,XX,-13[12]/ 46,XX,dic r(13;13)(p13q34;p13q34)[9]/46,XX,-13,+mar[5]/47, XX,+r(13) (p13q34)x2[2]/46,XX[1] at the age of 6 years and 46,XX,r(13)(p13q34)[82]/45,XX,-13[14]/46,XX,dic r(13;13)(p13q34; p13q34)[2]/46,XX, -13,+mar[2]. Array comparative genomic hybridization analysis of the blood demonstrated a 4.37-Mb deletion on chromosome 13q [arr cgh 13q34q34(109,743,729-144,110,721)]. A cytogenetic study of peripheral blood revealed a rare chromosomal abnormality associated with different cell lines that included structural and numerical abnormalities of chromosome 13. This case, along with 14 previously reported cases, indicate that the smallest critical region for chromosome 13 microcephaly is 109,743,729-144,110,721.

A whole genome methylation analysis of systemic lupus erythematosus: hypomethylation of the IL10 and IL1R2 promoters is associated with disease activity.

The etiology of systemic lupus erythematosus (SLE) involves a complex interaction of genetic and environmental factors. Investigations have shown that environmentally driven epigenetic changes contribute to the etiology of SLE. Here, we hypothesize that aberrant DNA methylation may contribute to the activation of the immune machinery and trigger lupus disease activity. A whole genome methylation array was applied to investigate the DNA methylation changes between 12 pairs of active SLE patients and healthy controls. The results were further confirmed in 66 SLE patients, 102 healthy controls. The methylation statuses of the IL10 and IL1R2 genes were significantly reduced in the SLE patient samples relative to the healthy controls (age-adjusted odds ratios, 64.2 and 16.9, respectively, P<0.0001). There was a trend toward SLE patients having hypomethylated IL10 and IL1R2 genes accompanied by greater disease activity. We observed that the methylation degree of IL10 and IL1R2 genes were reduced in the rheumatoid arthritis (RA) patients as well but the hypomethylation change was more significant in IL1R2 genes than in the IL10 genes in RA patients. This study demonstrated that DNA hypomethylation might be associated with SLE. Hypomethylated IL10 and IL1R2 genes may provide potential epigenetic markers as clinical predictors for autoimmune diseases.

Clinical utility of array comparative genomic hybridisation for prenatal diagnosis: a cohort study of 3171 pregnancies.

OBJECTIVE: To evaluate the clinical value of prenatal array comparative genomic hybridisation (CGH) in screening for submicroscopic genomic imbalances. DESIGN: Cross-sectional study. SETTING: Tertiary referral centre. POPULATION: From June 2008 to February 2011, 3171 fetuses underwent prenatal array CGH testing and karyotyping at the National Taiwan University Hospital. Indications for invasive prenatal diagnosis included abnormal karyotype, abnormal ultrasound, advanced maternal age and parental anxiety. METHODS: In all, 2497 fetuses were screened with 1-Mb resolution bacterial artificial chromosome array-based CGH, and 674 fetuses with 60-K oligonucleotide array-based CGH. Multiplex ligation-dependent probe amplification, fluorescence in situ hybridization, or 105-K oligonucleotide array CGH provided further confirmation. MAIN OUTCOME MEASURE: Copy number variations identified by array CGH. RESULTS: Array CGH detected numerical chromosome anomalies in 37 (1.2%) fetuses, microdeletion/duplication in 34 (1.1%) fetuses, large deletion/duplication in 13 (0.4%) fetuses, benign copy number changes in 13 (0.4%) fetuses and variation of unknown clinical significance in five (0.2%) fetuses. Array CGH was effective in identifying submicroscopic genomic imbalance in fetuses with de novo balance translocations (2/17, 1.8%), supernumerary marker chromosomes (3/6, 50%), and abnormal prenatal ultrasound findings (33/194, 17.0%). Array CGH detected microdeletions/duplications in 12 fetuses with normal karyotype. CONCLUSION: Prenatal array CGH is effective in screening for submicroscopic genomic imbalance. Array CGH may add 8.2% to the diagnostic field, compared with conventional karyotyping, for fetuses with abnormal ultrasound results, and is particularly useful in fetuses with karyotypic balanced translocation or marker chromosomes. There is a 0.52% baseline risk of submicroscopic genomic imbalance, even in women with an uneventful prenatal examination.

Partial monosomy 9p (9p22.2-->pter) and partial trisomy 18q (18q21.32-->qter) in a female infant with anorectal malformations.

We report a female infant with a karyotype of 46,XX,der(9)t(9;18)(p22.2;q21.32)pat and the phenotypic features of craniofacial dysmorphisms, developmental delay, hypotonia, horizontal nystagmus, strabismus, congenital heart defects, clubfoot, and anorectal malformations with an anterior ectopic anus and a stenosed anal opening. Array comparative genomic hybridization revealed a 16.93-Mb deletion at 9p24.3-p22.2 encompassing the FREM1 gene and a 20.43-Mb duplication at 18q21.32-q23 encompassing the PIGN gene. We speculate that dual genome imbalances in FREMI at 9p22.3 and in PIGN at 18q21.3 are most likely responsible for the abnormal development of anorectum in this patient.

Pure distal 9p deletion in a female infant with cerebral palsy.

We report cytogenetic and molecular characterization of a 15.63-Mb pure distal deletion of chromosome 9p (9p22.3-->pter) in a l 1/2-year-old female infant with cerebral palsy and diffuse cerebral dysfunction. The deletion is of paternal origin and encompasses the genes of ANKRDS15, DOCK8, FOXD4 and VLDLR. We discuss the genotype-phenotype correlation in this case with neurological dysfunction and a distal 9p deletion of paternal origin.

Partial trisomy 1q (1q42.13-->qter) and partial monosomy 6q (6q27-->qter) in a girl with single median maxillary central incisor, corpus callosum dysgenesis and developmental delay.

A 3-year-old girl presented with mental retardation, developmental delay, seizures, hypotonia, brachycephaly, a triangular face, single median maxillary central incisor (SMMCI), prominent forehead, down-slanting palpebral fissures, hypertelorism, a high-arched palate, micrognathia and low-set ears. Computed tomographic scans revealed corpus callosum dysgenesis and hypoplasia of bilateral frontal sinuses. Oligonucleotide-based array comparative genomic hybridization analysis revealed a -20.7-Mb duplication of 1q42.13-->qter and a -3.6-Mb deletion of 6q27-->qter. The karyotype of the girl was 46,XX,der(6)t(1;6)(q42.13;q27)pat. Mutational analysis of the patient revealed no mutation in the genes of SHH, SIX3 and TGIF. The present case adds unbalanced chromosome aberration of partial trisomy 1q and partial monosomy 6q to the list of genetic conditions associated with SMMCI.

Partial monosomy 3p (3p26.2 --> pter) and partial trisomy 5q (5q34 --> qter) in a girl with coarctation of the aorta, congenital heart defects, short stature, microcephaly and developmental delay.

A 1-year-and-3-month-old girl presented with psychomotor retardation, developmental delay, clinodactyly of the thumb, coarctation of the aorta, patent ductus arteriosus, peripheral pulmonary stenosis, atrial septal defect, microcephaly, brachycephaly, a small oval face, almond-shaped eyes, a down-turned mouth, a widened nasal bridge, hypertelorism, epicanthic folds, long philtrum, low-set large ears and but no craniosynostosis. Oligonucleotide-based array comparative genomic hybridization revealed a -4.79-Mb deletion of 3p26.2 --> pter encompassing CHL1 and CNTN4, and a -19.56-Mb duplication of 5q34 --> qter encompassing MSX2, NKX2-5 and NSD1. The karyotype of the girl was 46,XX,der(3)t(3;5)(p26.2;q34) pat. The present case adds distal 5q duplication to the list of chromosome aberrations associated with coarctation of the aorta.

A 24.2-Mb deletion of 4q12 --> q21.21 characterized by array CGH in a 131/2-year-old girl with short stature, mental retardation, developmental delay, hyperopia, exotropia, enamel defects, delayed tooth eruption and delayed puberty.

We report molecular and cytogenetic characterization of proximal deletion of chromosome 4q, del(4)(q12 --> q21.21) in a 131/2-year-old girl with short stature, mental retardation, developmental delay, hyperopia, exotropia, enamel defects, delayed tooth eruption and delayed puberty. We speculate that haploinsufficiency of the AMTN, ENAM and AMBN genes is most likely responsible for dental disorders, haploinsufficiency of the BMP2K genes is most likely responsible for ocular disorders, and haploinsufficiency of the EREG, AREG and BTC genes is most likely responsible for delayed puberty in this patient.

Mosaic supernumerary r(1)(p13.2q23.3) in a 10-year-old girl with epilepsy facial asymmetry psychomotor retardation kyphoscoliosis dermatofibrosarcoma and multiple exostoses.

We report molecular cytogenetic characterization of mosaic supernumerary r(1)(p13.2q23.3) in a 10-year-old girl with epilepsy, facial asymmetry, psychomotor retardation, kyphoscoliosis, dermatofibrosarcoma and multiple exostoses. The supernumerary r(1) is associated with gene dosage increase of CHRNB2, ADAR and KCNJ10 in the pericentromeric area of 1q, and a breakpoint within CTTNBP2NL at 1p13.2. We speculate that the gene dosage increase of CHRNB2, ADAR and KCNJ10 is most likely responsible for epilepsy, and the breakpoint at 1p13.2 in the supernumerary r(1) is most likely responsible for the development of multiple exostoses and osteochondroma in this patient.

Human opioid µ-receptor A118G polymorphism may protect against central pruritus by epidural morphine for post-cesarean analgesia.

BACKGROUND: Intrathecal or epidural morphine used for post-operative analgesia frequently induces central type pruritus. The purpose of this study was to investigate the association between the severity of central type pruritus induced by epidural morphine for post-cesarean analgesia and the A118G polymorphism of the human µ-opioid receptor gene (OPRM1). METHODS: Pregnant women (212) received pure epidural morphine (2 mg) twice per day for post-cesarean analgesia. Blood samples were collected and sequenced with high-resolution melting analysis to detect three different genotypes of OPRM1 (AA, AG and GG). We interviewed all candidates 24 h post-operatively to record the clinical phenotype with subjective complaints and objective observations. RESULTS: The genotyping revealed that 99 women (46.7%) were AA, 88 (41.5%) were AG and 25 (11.8%) were GG. Sixty-two of 212 women suffered from significant pruritus (29.2%), and 150 of 212 women had non-significant pruritus (70.8%). In genotype AA, 33 patients (53.2%) experienced significant pruritus, 26 (41.9%) in genotype AG and 3 (4.8%) in genotype GG. The G allele was a statistically independent protective factor for individuals developing pruritus, and the multivariate-adjusted odds ratio was 0.27. There was a trend for progressively decreasing severity scores among the three groups, with the lowest severity score (0.72) for pruritus in the GG group. CONCLUSIONS: The incidence of significant pruritus in the recessive type (GG) was significantly lower compared with the dominant types (AA+AG). The recessive G allele in the A118G polymorphism may have protective effects against significant pruritus after epidural morphine for post-cesarean analgesia.

LncRNA SNHG1 attenuates neuropathic pain following spinal cord injury by regulating CDK4 level.

OBJECTIVE: Neuropathic pain (NP) is one of the most intractable complications of spinal cord injury (SCI). This study aims to explore the role of long non-coding RNA (lncRNA) SNHG1 in influencing SCI-induced NP. MATERIALS AND METHODS: After establishment of the spinal nerve ligation (SNL) model in rats, spinal tissues were extracted. SNHG1 level in rat spinal tissues was determined by quantitative real-time polymerase chain reaction (qRT-PCR). The role of SNHG1 in the development of NP was explored by assessing paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) in model rats. The interaction between SNHG1 and CDK4 was explored by Luciferase assay and RIP (RNA-Binding Protein Immunoprecipitation). Enzyme-linked immunosorbent assay (ELISA) and qRT-PCR were conducted to determine inflammatory factor levels in rat spinal tissues. RESULTS: SNHG1 was upregulated in rats undergoing SNL. Knockdown of SNHG1 alleviated the development of NP and overexpression of SNHG1 was capable of inducing NP symptoms in uninjured rats. SNHG1 induced NP by directly regulating CDK4 level. CONCLUSIONS: SNHG1 is a novel target in the treatment of NP associated with neuroinflammation.

Role of three-dimensional power Doppler in the antenatal diagnosis of placenta accreta: comparison with gray-scale and color Doppler techniques.

OBJECTIVE: To assess the role of three-dimensional (3D) power Doppler in the antenatal diagnosis of placenta accreta and compare its diagnostic performance with gray-scale and color Doppler ultrasonography. METHODS: One hundred and seventy pregnant women with persistent placenta previa totalis (after 28 weeks' gestation) were prospectively enrolled into this study. Gray-scale transabdominal ultrasound examination was performed to detect loss of the subendometrial echolucent zone and other abnormalities suggestive of placenta accreta. Color flow mapping was used to scan the whole placenta to detect any newly formed vessels at the serosa-bladder border or the presence of abnormal lacunae. Finally a targeted examination of angioarchitecture in the basal and lateral views of the placenta was carried out using 3D power Doppler. The ultrasound findings were analyzed with reference to the final diagnosis made during Cesarean delivery. RESULTS: Placenta accreta and its variants (including increta and percreta) were confirmed in 39 patients at the time of Cesarean delivery. Based on receiver-operating characteristics analysis, 'numerous coherent vessels' visualized using 3D power Doppler in the basal view was the best single criterion for the diagnosis of placenta accreta, with a sensitivity of 97% and a specificity of 92%. If we considered the presence of at least one criterion to be diagnostic when using each ultrasound technique, then 3D power Doppler would have the best positive predictive value (76%), followed by gray-scale (51%) and color Doppler (47%). The majority of patients with placenta accreta showed multiple characteristic features on ultrasound imaging. In contrast, those patients with a false-positive diagnosis (i.e. the final diagnosis was placenta previa alone) tended to show isolated ultrasound markers of the condition. CONCLUSION: 3D power Doppler may be useful as a complementary technique for the antenatal diagnosis or exclusion of placenta accreta.

Connective tissue growth factor linked to the E7 tumor antigen generates potent antitumor immune responses mediated by an antiapoptotic mechanism.

A novel method for generating an antigen-specific cancer vaccine and immunotherapy has emerged using a DNA vaccine. However, antigen-presenting cells (APCs) have a limited life span, which hinders their long-term ability to prime antigen-specific T cells. Connective tissue growth factor (CTGF) has a role in cell survival. This study explored the intradermal administration of DNA encoding CTGF with a model tumor antigen, human papilloma virus type 16 E7. Mice vaccinated with CTGF/E7 DNA exhibited a dramatic increase in E7-specific CD4(+) and CD8(+) T-cell precursors. They also showed an impressive antitumor effect against E7-expressing tumors compared with mice vaccinated with the wild-type E7 DNA. The delivery of DNA encoding CTGF and E7 or CTGF alone could prolong the survival of transduced dendritic cells (DCs) in vivo. In addition, CTGF/E7-transduced DCs could enhance a higher number of E7-specific CD8(+) T cells than E7-transduced DCs. By prolonging the survival of APCs, DNA vaccine encoding CTGF linked to a tumor antigen represents an innovative approach to enhance DNA vaccine potency and holds promise for cancer prophylaxis and immunotherapy.

'Big-eyed frog' sign on spatiotemporal image correlation (STIC) in the antenatal diagnosis of transposition of the great arteries.

OBJECTIVE: To determine the value of simultaneous visualization of the cross-sectional view of both atrioventricular (AV) valves, the pulmonary artery and the aorta (en-face view of the AV valves and great vessels) in the identification of fetuses with transposition of the great arteries (TGA). METHODS: This was a retrospective analysis of volume datasets obtained with the spatiotemporal image correlation (STIC) technique from 56 fetuses with and 30 fetuses without congenital heart defects. Volume datasets were reviewed offline to compare the en-face view of the AV valves and great vessels between fetuses with normal echocardiography and those with TGA. RESULTS: The en-face view of both AV valves and great vessels in fetuses with TGA displayed the main pulmonary artery situated side-by-side with the aorta ('big-eyed frog' sign). In contrast, fetuses with normal hearts did not have this characteristic sonographic sign. This novel sonographic sign also helped to identify additional cases of TGA in 17 fetuses with complex heart defects. CONCLUSION: The big-eyed frog sign may prove helpful in the prenatal diagnosis of TGA.

Craniosynostosis and congenital tracheal anomalies in an infant with Pfeiffer syndrome carrying the W290C FGFR2 mutation.

Pfeiffer syndrome (OMIM 101600) is an autosomal dominant disorder characterized by craniosynostosis, midface hypoplasia, ocular proptosis and digital malformations. We report on a type II Pfeiffer female infant with craniosynostosis, hydrocephalus, and characteristic craniofacial and digital abnormalities. The patient had a history of airway difficulty. Bronchoscopy at age four months revealed low tracheal stenosis and fibrous cartilaginous rings. She underwent tracheostomy for the treatment of cyanotic episodes. Molecular analysis revealed a de novo missense mutation c.870 G>T (TGG>TGT) in the FGFR2 gene that predicts a substitution of cysteine for tryptophan at the codon 290, (W290C). There is phenotypic heterogeneity of tracheal anomalies due to FGFR2 mutations. A review of the literature shows that Pfeiffer patients with the similar tracheal abnormalities can be caused by different FGFR2 mutations and, likewise, the patients with the same FGFR2 mutation may manifest different kinds of tracheal anomalies. Tracheal anomalies may occur in Pfeiffer patients and cause morbidity and mortality because of airway obstruction. Recognition and detailed evaluation of tracheal anomalies should be included in the early diagnostic workup for severe Pfeiffer patients.