High incidence of EDNRB gene mutation in seven southern Chinese familial cases with Hirschsprung's disease.

PURPOSE: Hirschsprung's disease (HSCR) is the leading cause of neonatal functional intestinal obstruction, which has been identified in many familial cases. HSCR, a multifactorial disorder of enteric nervous system (ENS) development, is associated with at least 24 genes and seven chromosomal loci, with RET and EDNRB as its major genes. We present a genetic investigation of familial HSCR to clarify the genotype-phenotype relationship. METHODS: We performed whole exome sequencing (WES) on Illumina HiSeq X Ten platform to investigate genetic backgrounds of core family members, and identified the possibly harmful mutation genes. Mutation carriers and pedigree relatives were validated by Sanger sequencing for evaluating the gene penetrance. RESULTS: Four familial cases showed potential disease-relative variants in EDNRB and RET gene, accounting for all detection rate of 57.1%. Three familial cases exhibited strong pathogenic variants as frameshift or missense mutations in EDNRB gene. A novel c.367delinsTT mutation of EDNRB was identified in one family member. The other two EDNRB mutations, c.553G>A in family 2 and c.877delinsTT in family 5, have been reported in previous literatures. The penetrance of EDNRB variants was 33-50% according mutation carries. In family 6, the RET c.1858T>C (C620R) point mutation has previously been reported to cause HSCR, with 28.5% penetrance. CONCLUSION: We identified a novel EDNRB (deleted C and inserted TT) mutation in this study using WES. Heterozygote variations in EDNRB gene were significantly enriched in three families and RET mutations were identified in one family. EDNRB variants showed an overall higher incidence and penetrance than RET in southern Chinese families cases.

Enhanced recovery after surgery for the treatment of congenital duodenal obstruction.

BACKGROUND: Enhanced recovery after surgery (ERAS) has been widely used in adult surgery. However, ERAS has not been reported in neonatal surgery. The present prospective study explored the application value of ERAS in treating congenital duodenal obstruction (CDO). METHODS: A total of 68 cases of CDO were collected from October 1, 2017 to July 31, 2019. We divided patients with a prenatal diagnosis of congenital duodenal obstruction into the ERAS group and those who were diagnosed the disease after birth into the control group. The ERAS group adopted ERAS-related measures, and the control group followed the usual measures. The study compared the differences in the gestational age, birth weight, length of hospital stay (LOS), complications, feeding intolerance, and weight one month after surgery between the two groups. RESULTS: A total of 49 patients were included in the analysis, including 23 who were allocated to the ERAS group and 26 to the control group. The LOS was 9.696±1.222 days in the ERAS group and 12.654±1.686 days in the control group, resulting in a significantly shorter LOS in the ERAS group than in the control group (p<0.001). One month after surgery, the neonates in the ERAS group weighted significantly more than those in the control group. No differences were observed in birth weight, gestational age, and the incidence of complications or feeding intolerance between the two groups. CONCLUSION: In this single-center study, the implementation of neonate-specific ERAS for CDO surgery was feasible and safe and led to a shorter LOS without increasing the incidence of complications or feeding intolerance. TYPE OF STUDY: Treatment Study LEVEL OF EVIDENCE: Level III.

Gene expression profiling coupled with Connectivity Map database mining reveals potential therapeutic drugs for Hirschsprung disease.

BACKGROUND: Hirschsprung disease (HD) is a congenital intestinal anomaly resulting from a failure to form enteric ganglia in the lower bowel. Surgery is the main therapeutic strategy, although neural stem cell transplantation has recently shown promise. However, HD remains a challenging disorder to treat. Our aim was to identify drugs that could counteract the dysregulated pathways in HD and could thus be potential novel therapies. METHODS: We used microarray analysis to identify genes differentially expressed in ganglionic and aganglionic bowel samples from eight children with HD. The signature of differentially expressed genes was then used as a search query to explore the Connectivity Map (cMAP), a transcriptional expression database that catalogs gene signatures elicited by chemical perturbagens. RESULTS: We uncovered several dysregulated signaling pathways, and in particular regulation of neuron development, in HD. The cMAP search identified some compounds with the potential to counteract the effects of the dysregulated molecular signature in this disease. One of these, pepstatin A, was recently shown to rescue the migration defects observed in a mouse model of HD, providing strong support for our findings. CONCLUSIONS: This study advances our understanding of the molecular changes in HD and identifies several potential pharmacological interventions. Further testing of the identified compounds is warranted.

Diagnostic Value of Semiquantitative Analysis of 99mTechnetium-Methoxyisobutylisonitrile (99mTc-MIBI) Imaging in Predicting Early-Stage Cervical Lymph Node Metastasis of Thyroid Carcinoma.

BACKGROUND The aim of this study was to evaluate the value of semiquantitative analysis (SQA) of 99mTc-MIBI imaging in predicting early-stage cervical lymph node metastasis (CLNM) in thyroid carcinoma (TC). MATERIAL AND METHODS TC patients (n =106) undergoing surgical resection and histopathological examination were enrolled. All patients received 99mTc-MIBI imaging prior to surgery. P-glycoprotein (P-gp) expression was detected by PT-PCR and immunohistochemistry. With pathological results as the criterion standard, the diagnostic efficiency of 99mTc-MIBI imaging in predicting early-stage CLNM was evaluated. The correlation of P-gp with 99mTc-MIBI imaging was investigated. Logistic regression analysis was applied for analyzing the factors affecting early-stage CLNM. RESULTS The detection rate and misdiagnosis rate of 99mTc-MIBI imaging for early-stage CLNM diagnosis were 87.3% and 12.7%, respectively. Receiver operating characteristic (ROC) curve analysis showed an accuracy of 99mTc-MIBI imaging of 85.85%. Preoperative 99mTc-MIBI scan showed statistical differences between metastasis and non-metastasis groups in early and delayed T/NT and washout rate (all P<0.05). The percentage of P-gp-expressing cells and the expression rate of P-gp gene both exhibited statistical differences between metastasis and no-metastasis groups (both P<0.05). Tumor diameter, lesion distribution, the percentage of P-gp-expressing cells, and the expression rate of P-gp gene were risk factors for CLNM (all P<0.05). CONCLUSIONS 99mTc-MIBI imaging has value in qualitative diagnosis of early-stage CLNM in TC. Tumor diameter, lesion distribution, the percentage of P-gp-expressing cells, and the expression rate of P-gp gene were risk factors for CLNM.

Fanconi syndrome due to prolonged use of low-dose adefovir.

Fanconi syndrome results from a generalized abnormality of the proximal tubules of the kidney and owing to phosphate depletion can cause hypophosphatemic osteomalacia. Adefovir dipivoxyl (ADV) effectively suppresses hepatitis B virus replication but exhibits nephrotoxicity when administered at a low dosage. We report two cases of Fanconi syndrome induced by ADV at 10 mg/day to call for regular screening for evidence of proximal tubular dysfunction and detailed bone metabolic investigations for prompt detection of ADV nephrotoxicity is critically important to ensure timely drug withdrawal before the development of irreversible tubulointerstitial injury.

Communicating bronchopulmonary foregut malformation type IA: radiologic anatomy and clinical dilemmas.

BACKGROUND: Communicating bronchopulmonary foregut malformation (CBPFM) type IA is extremely rare and is associated with a high mortality rate. This malformation manifests with communication between the lung and the foregut, and this can lead to esophageal atresia and tracheoesophageal fistula (EA-TEF) to the distal pouch. PURPOSE: To detail radiographic findings of CBPFM type IA cases and to summarize an appropriate therapeutic strategy for the management of this disorder. METHODS: Medical data for two patients with CBPFM type IA were retrospectively reviewed with regard to radiographic characteristics, therapy, and outcome. RESULTS: Both cases were initially misdiagnosed due to the presence of EA-TEF. Unusual atelectasis of the lateral lung was observed in chest radiographs, while non-aerated hypoplastic right lung and agenesis of the right main bronchus were detected by computed tomography. A final diagnosis was made by esophagogram. Only one patient survived following surgery. CONCLUSION: CBPFM type IA is a rare condition and is extremely difficult to diagnose. However, CBPFM type IA should be suspected in patients manifesting EA and atelectasis of a unilateral lung on a chest radiograph. The decision to perform a pneumonectomy or bronchoplasty depends on the degree of exiting permitted due to pulmonary damage assessed by computed tomography.

Deceased expression of prostatic acid phosphatase in primary sensory neurons after peripheral nerve injury.

Prostatic acid phosphatase (PAP) is expressed in nociceptive dorsal root ganglion (DRG) neurons and functions as an ectonucleotidase that dephosphorylates extracellular adenosine monophosphate (AMP) to adenosine to suppress pain via activating A1-adenosine receptor (A1R) in dorsal spinal cord. However, the effect of peripheral nerve injury on the expression of PAP has not been reported until now. In the present study we found that PAP expression in DRG neurons is significantly decreased from the 2nd day after peripheral nerve injury and reaches the bottom at the 14th. In addition, intrathecal PAP injection can reduce mechanical allodynia induced by spared nerve injury. Our findings suggest that the decrease of PAP is involved in pathophysiological mechanisms of neuropathic pain.

The research on screening differentially expressed genes in Hirschsprung's disease by using Microarray.

OBJECTIVE: To study the differential expression of genes between Hirschsprung's disease (HSCR) and normal tissue by using microarray for exploring the mechanism of HSCR development and establishing the gene expression profiles of HSCR. METHODS: Colon tissues (aganglionic and normal segments) of 4 patients with HSCR were detected by the Agilent SurePrint G3 Human GE 8x60K Microarrays. RT-PCR was used to verify the results of Microarray test. Then, immunohistochemistry was used to demonstrate the expression of HAND2 in the myenteric plexus of the colon from 46 patients with HSCR to further explore the relationship between HAND2 and development of HSCR. RESULTS: A total of 12,125 meaningful expressed genes were screened out. 4 pairs of specimens had 622 differentially expressed genes, 584 (93.89%) of which were up-regulated while 38(6.11%) were down-regulated. 6 of the 622 genes were tested by RT-PCR, which were consistent with the results detected by Microarray. The average optical density of positive expression of HAND2 in myenteric plexus was compared between the aganglionic, transitional, dilated, normal segments and control group. The average optical density in the aganglionic segments was obviously reduced. Statistical analyzed data showed that it has significant deviation (P<0.01). CONCLUSION: 1. A set of differentially expressed genes between aganglionic and normal segments of HSCR was obtained. Our data may provide significant information to research the pathogenesis of HSCR. 2. Reduced protein expression of HAND2 in the myenteric plexus of the aganglionic would suggest that HAND2 was involved in the pathogenesis of HSCR.