Adrenergic Innervation of Bowel in Hirschsprung's Disease

The adrenergic innervation of normal and aganglionic regions of bowel from patients with Hirschsprung''s disease was investigated by a fluorescent histochemical technique. In normal bowel the adrenergic nerves end about intramural ganglion cells. In aganglionic bowel the adrenergic nerves form a dense varicose plexus in both muscularis externa and muscularis mucosae. It is suggested that the cause of megacolon in Hirschsprung''s disease is due to a lack of nervous pathways controlling the intrinsic reflexes, which is probably congenital in origin.     

Hirschsprung's disease prevalence in Europe: A register based study

Background: Hirschsprung's disease is a congenital gut motility disorder, characterised by the absence of the enteric ganglion cells along the distal gut. The aim of this study was to describe the epidemiology of Hirschsprung's disease, including additional congenital anomalies, total prevalence, trends, and association with maternal age. Methods: Cases of Hirschsprung's disease delivered during 1980 to 2009 notified to 31 European Surveillance of Congenital Anomaly registers formed the population‐based case‐series. Prevalence rates and 95% confidence intervals were calculated as the number of cases per 10,000 births. Multilevel Poisson regression was performed to investigate trends in prevalence, geographical variation and the association with maternal age. Results: There were 1,322 cases of Hirschsprung's disease among 12,146,210 births. The total prevalence was 1.09 (95% confidence interval, 1.03–1.15) per 10,000 births and there was a small but significant increase in prevalence over time (relative risk = 1.01; 95% credible interval, 1.00–1.02; p = 0.004). There was evidence of geographical heterogeneity in prevalence (p < 0.001). Excluding 146 (11.0%) cases with chromosomal anomalies or genetic syndromes, there were 1,176 cases (prevalence = 0.97; 95% confidence interval, 0.91–1.03 per 10,000 births), of which 137 (11.6%) had major structural anomalies. There was no evidence of a significant increased risk of Hirschsprung's disease in cases born to women aged ≥35 years compared with those aged 25 to 29 (relative risk = 1.09; 95% credible interval, 0.91–1.31; p = 0.355). Conclusion: This large population‐based study found evidence of a small increasing trend in Hirschsprung's disease and differences in prevalence by geographic location. There was also no evidence of an association with maternal age. Birth Defects Research (Part A), 100:695–702, 2014. © 2014 Wiley Periodicals, Inc.     

HIRSCHSPRUNG'S DISEASE—The Clinical Differentiation and Treatment of Children with Hirschsprung's Disease and Pseudo-Hirschsprung's Disease

Hirschsprung''s disease is marked by constipation from the time of birth, with the development, if uncorrected, of a protuberant abdomen and flared costal margins. The rectal ampulla is empty and the abdomen is filled with fecal masses. Pain is not prominent. Flatus is passed in large amounts. Encopresis does not occur. Barium enema shows the characteristic narrowed distal rectal segment and biopsy of the rectum shows absence of the ganglion cells of the myenteric plexus.Treatment is operative resection of the distal narrow segment and a primary anastomosis.Hirschsprung''s disease may be mimicked in children with:1. Psychogenic constipation—pseudo-Hirschsprung''s disease. Unlike Hirschsprung''s disease, symptoms do not appear at birth, encopresis is common, and the barium enema shows no narrow distal segment.2. Mental retardation and cerebral defect.3. Corrected imperforate anus—on the basis of stenosis, imperfect innervation or poor habit training.4. Cretinism—with severe constipation and intestinal dilatation perhaps the presenting symptoms.Treatment of these four groups of children with severe constipation not due to Hirschsprung''s disease is:For Group 1, open discussion with parent and child. Assumption by the physician of full control of the details of treatment, and relegation of parent to the role of the physician''s agent in following the prescribed regimen.For Group 2, an enema regimen. Whereas fairly rapid restoration (and then persistence) of normal bowel habit can be expected in Group 1, the basic defects in Group 2 may require indefinite continuation of treatment.For Group 3, regular enema regimen, in the less severe cases—one identical with that used in Group 1, and dilatation of strictures or anoplasty.In Group 4, thyroid hormone therapy relieves the constipation of hypothyroidism and causes reversion of radiographic changes in the colon and rectum.     

Genetic Background of Hirschsprung Disease: A Bridge Between Basic Science and Clinical Application

Hirschsprung's disease (HSCR) is a congenital disorder, defined by partial or complete loss of the neuronal ganglion cells in the intestinal tract, which is caused by the failure of neural crest cells to migrate completely during intestinal development during fetal life. HSCR has a multifactorial etiology, and genetic factors play a key role in its pathogenesis; these include mutations within several gene loci. These have been identified by screening candidate genes, or by conducting genome wide association (GWAS) studies. However, only a small portion of them have been proposed as major genetic risk factors for the HSCR. In this review, we focus on those genes that have been identified as either low penetrant or high penetrant variants that determine the risk of Hirschsprung's disease. J. Cell. Biochem. 119: 28–33, 2018. © 2017 Wiley Periodicals, Inc.     

加速康复外科理念辅助治疗小婴儿先天性巨结肠的有效性和安全性研究

目的:探讨加速康复外科(Enhanced recovery after surgery,ERAS)理念用于治疗小婴儿先天性巨结肠(Hirschsprung's,HSCR)的临床疗效和安全性。方法:选择2016年01月至2017年12月在我院新生儿外科接受手术治疗并临床病理确诊的79例HSCR患儿并将其分为对照组和ERAS组。对照组26例给予经腹巨结肠根治术,ERAS组44例入院后据患儿病情进行宣教ERAS,再采用腹腔镜巨结肠根治术。比较两组手术时间、术后肠功能恢复时间、留置管道情况、平均住院日、住院费用、血清C反应蛋白(C-reactive protein,CRP)、降钙素原、白介素-6(Interleukin,IL-6)、皮质醇水平的变化及围手术期并发症的发生情况。结果:ERAS组手术时间、术中出血量、肠功能恢复时间、术前平均住院天数、术后平均住院天数、平均住院天数、平均费用、留置胃管时间、留置尿管时间均显著短于对照组。术后,ERAS组血清CRP、降钙素原、IL-6、皮质醇水平均明显低于对照组。ERAS组术中并发症发生率显著低于对照组(2.27%vs. 23.08,P0.05)。结论:加速康复外科理念辅助治疗小婴儿先天性巨结肠可促进患者术后病情恢复,减少患者医疗费用并提高治疗安全性。     

IGF2‐derived miR‐483‐3p associated with Hirschsprung's disease by targeting FHL1

HSCR (Hirschsprung's disease) is a serious congenital defect, and the aetiology of it remains unclear. Many studies have highlighted the significant roles of intronic miRNAs and their host genes in various disease, few was mentioned in HSCR although. In this study, miR‐483‐3p along with its host gene IGF2 (Insulin‐like growth factor 2) was found down‐regulated in 60 HSCR aganglionic colon tissues compared with 60 normal controls. FHL1 (Four and a half LIM domains 1) was determined as a target gene of miR‐483‐3p via dual‐luciferase reporter assay, and its expression was at a higher level in HSCR tissues. Here, we study cell migration and proliferation in human 293T and SH‐SY5Y cell lines by performing Transwell and CCK8 assays. In conclusion, the knockdown of miR‐483‐3p and IGF2 both suppressed cell migration and proliferation, while the loss of FHL1 leads to opposite outcome. Furthermore, miR‐483‐3p mimics could rescue the negative effects on cell proliferation and migration caused by silencing IGF2, while the FHL1 siRNA may inverse the function of miR‐483‐3p inhibitor. This study revealed that miR‐483‐3p derived from IGF2 was associated with Hirschsprung's disease by targeting FHL1 and may provide a new pathway to understand the aetiology of HSCR.     

Long non-coding RNA LOC100507600 functions as a competitive endogenous RNA to regulate BMI1 expression by sponging miR128-1-3p in Hirschsprung's disease

Recently studies reported that long non-coding RNAs (lncRNAs) may take part in a lot of congenital diseases, meanwhile, Hirschsprung's disease (HSCR) is a major congenital digestive tract malformation. Nevertheless whether lncRNAs participate in the occurrence of HSCR and how it contributes to this disease are still unknown. LOC100507600 was selected from our gene expression microarray data obtained from bowel tissues from HSCR patients and negative controls. Subsequently, we used qRT-PCR to prove the result in 64 pairs of HSCR disease bowel stenosis tissues and negative controls. Transwell assay, CCK-8 assay and flow cytometry were employed to explore whether cellular functions change after knocking down the LOC100507600 in SH-SY5Y cell and human 293T cell. Dual-luciferase reporter assay was used to confirm the competitive relationship between BMI1 and LOC100507600 through their association with hsa-miR128–1-3p. Protein extraction and Western blotting were used to further confirm the relationship between LOC100507600 and BMI1. We found that LOC100507600 was obvious reduced in tissues from HSCR patients with noteworthy correlation with BMI1. Furthermore, Downregulation of LOC100507600 repressed cell migration and proliferation and didn't affect cell apoptosis or cycle. Dual-luciferase reporter assay, qRT-PCR and Western blotting assay verified that LOC100507600 serves as a competitive endogenous RNA of miR128–1-3p and down-regulates BMI1 expression by sponging miR128–1-3p in HSCR. In sum, our study researches the potential diagnostic value of LOC100507600 in HSCR and deduces that LOC100507600 can contributes to HSCR as a competitive endogenous RNA to regulate BMI1 expression by sponging miR128–1-3p.     

Implantation of Total Artificial Heart in Congenital Heart Disease

In patients with end-stage heart failure (HF), a total artificial heart (TAH) may be implanted as a bridge to cardiac transplant. However, in congenital heart disease (CHD), the malformed heart presents a challenge to TAH implantation. In the case presented here, a 17 year-old patient with congenital transposition of the great arteries (CCTGA) experienced progressively worsening HF due to his congenital condition. He was hospitalized multiple times and received an implantable cardioverter defibrillator (ICD). However, his condition soon deteriorated to end-stage HF with multisystem organ failure. Due to the patient''s grave clinical condition and the presence of complex cardiac lesions, the decision was made to proceed with a TAH. The abnormal arrangement of the patient''s ventricles and great arteries required modifications to the TAH during implantation.With the TAH in place, the patient was able to return home and regain strength and physical well-being while awaiting a donor heart. He was successfully bridged to heart transplantation 5 months after receiving the device. This report highlights the TAH is feasible even in patients with structurally abnormal hearts, with technical modification.     

The Meconium-Plug Syndrome and Hirschsprung's Disease

A mass of inspissated meconium in the distal colon or rectum is a relatively common cause of neonatal intestinal obstruction. The meconium-plug syndrome is unrelated to cystic fibrosis and meconium ileus. The clinical picture is frequently indistinguishable, without contrast study of the colon, from other forms of mechanical intestinal obstruction requiring laparotomy. A barium enema examination is almost always diagnostic, and use of this procedure usually results in dislodgement and passage of the plug.No single cause for the excessive viscosity and tenaciousness of the obstructive meconium mass has been identified. Previous reports have generally emphasized the normal ganglion-cell content of the colon in affected patients.Two infants are described who fulfilled all criteria for this syndrome but who were not rendered asymptomatic, as normally anticipated, by removal of the plug. Subsequent studies revealed the presence of Hirschsprung''s disease in both patients. This diagnosis should be considered when an infant with meconium-plug obstruction of the colon fails to follow the usual satisfactory clinical course after the plug has been passed.     

腹腔镜下改良Soave术对先天性巨结肠患儿肛门功能、肠道菌群及生活质量的影响

摘要 目的：探讨腹腔镜下改良Soave术对先天性巨结肠患儿肛门功能、肠道菌群及生活质量的影响。方法：选取2019年5月~2022年3月期间本院接收的先天性巨结肠患儿68例,根据手术方案的不同将患儿分为常规组（常规经腹腔镜辅助下Soave术,32例）和改良组（腹腔镜下改良Soave术,36例）,比较两组临床指标、肛门功能、肠道菌群、生活质量的变化及并发症发生情况。结果：与常规组比较,改良组手术时间、术后肠蠕动时间、住院时间较短,术中出血量较少（P<0.05）。改良组的优良率高于常规组（P<0.05）。改良组术后3个月健康生活量表简表（SF-36）各维度评分高于常规组（P<0.05）。改良组术后3个月双歧杆菌、乳酸杆菌、粪肠球菌高于常规组（P<0.05）,大肠杆菌低于常规组（P<0.05）。改良组的中期并发症发生率、短期并发症发生率低于常规组（P<0.05）。结论：与常规经腹腔镜辅助下Soave术相比,先天性巨结肠患儿采用腹腔镜下改良Soave术治疗,在改善肛门功能、肠道菌群、生活质量、临床指标、降低并发症发生率等方面效果显著,临床应用价值较高。     

Treatment of Aganglionic Megacolon Mice via Neural Stem Cell Transplantation

To explore a potential methodology for treating aganglionic megacolon, neural stem cells (NSCs) expressing engineered endothelin receptor type B (EDNRB) and glial cell-derived neurotrophic factor (GDNF) genes were transplanted into the aganglionic megacolon mice. After transplantation, the regeneration of neurons in the colon tissue was observed, and expression levels of differentiation-related genes were determined. Primary culture of NSCs was obtained from the cortex of postnatal mouse brain and infected with recombinant adenovirus expressing EDNRB and GDNF genes. The mouse model of aganglionic megacolon was developed by treating the colon tissue with 0.5 % benzalkonium chloride (BAC) to selectively remove the myenteric nerve plexus that resembles the pathological changes in the human congenital megacolon. The NSCs stably expressing the EDNRB and GDNF genes were transplanted into the benzalkonium chloride-induced mouse aganglionic colon. Survival and differentiation of the implanted stem cells were assessed after transplantation. Results showed that the EDNRB and GDNF genes were able to be expressed in primary culture of NSCs by adenovirus infection. One week after implantation, grafted NSCs survived and differentiated into neurons. Compared to the controls, elevated expression of EDNRB and GDNF was determined in BAC-induced aganglionic megacolon mice with partially improved intestinal function. Those founding indicated that the genes transfected into NSCs were expressed in vivo after transplantation. Also, this study provided favorable support for the therapeutic potential of multiple gene-modified NSC transplantation to treat Hirschsprung’s disease, a congenital disorder of the colon in which ganglion cells are absent.     

Unexplained left ventricular hypertrophy: consider a diagnosis of Fabry's disease

Lysosomal storage disorders are a group of disorders characterised by the deficiency of a specific lysosomal hydrolase. These diseases are rare, with only a few hundred patients in the Netherlands. Fabry''s disease, an X-linked lysosomal storage disorder, is caused by a deficiency of the lysosomal enzyme α-galactosidase A which results in, among other things, left ventricular hypertrophy, renal failure and cerebrovascular events. Patients with Fabry''s disease, especially males, have a decreased life expectancy. Recent studies have shown that Fabry''s disease may be much more common among patients with left ventricular hypertrophy (LVH) than previously thought. Up to 7% of male patients with left ventricular hypertrophy and up to 12% of female patients with unexplained LVH were found to suffer from Fabry''s disease. Thus, Fabry''s disease should be considered in patients with unexplained LVH. This case report summarises the main features of the disease. In addition recent developments concerning prevalence, diagnosis and the current available treatments are discussed and an algorithm on who and how to screen for Fabry''s disease is presented.     

Hodgkin's disease and leukemia

Four cases of acute leukemia occurring in patients with Hodgkin''s disease are described. The literature on the association of these two diseases is reviewed. Acute myeloid or undifferentiated leukemias appear to be, at least in part, a complication affecting long-term survivors of Hodgkin''s disease. Reed Sternberg cell leukemia is an unusual form of Hodgkin''s disease and may be associated with a poor prognosis. The cytology and cytochemistry of Reed Sternberg cells are briefly discussed.     

Decreased tuftsin concentrations in patients who have undergone splenectomy.

Serum tuftsin concentrations were measured, using a radioimmunoassay developed in Israel, in normal subjects and in patients who had undergone splenectomy. Concentrations in those who had undergone traumatic and elective splenectomy were much lower. The tuftsin concentration in 38 patients with Hodgkin''s disease who had undergone splenectomy during staging laparotomy was not significantly different from the mean concentration in other patients who had had elective splenectomy. In four patients who underwent splenectomy for non-malignant haematological disorders measurements made before and after operation showed that tuftsin concentrations fell significantly in the days after operation. The increased susceptibility to overwhelming infections of patients with Hodgkin''s disease and others who have undergone splenectomy may be related to the low tuftsin concentrations. As pre-splenectomy tuftsin concentrations in patients with Hodgkin''s disease were normal, the practice of performing staging laparotomy and splenectomy in patients with Hodgkin''s disease should perhaps be reconsidered.     

Evolutionary Signatures amongst Disease Genes Permit Novel Methods for Gene Prioritization and Construction of Informative Gene-Based Networks

Genes involved in the same function tend to have similar evolutionary histories, in that their rates of evolution covary over time. This coevolutionary signature, termed Evolutionary Rate Covariation (ERC), is calculated using only gene sequences from a set of closely related species and has demonstrated potential as a computational tool for inferring functional relationships between genes. To further define applications of ERC, we first established that roughly 55% of genetic diseases posses an ERC signature between their contributing genes. At a false discovery rate of 5% we report 40 such diseases including cancers, developmental disorders and mitochondrial diseases. Given these coevolutionary signatures between disease genes, we then assessed ERC''s ability to prioritize known disease genes out of a list of unrelated candidates. We found that in the presence of an ERC signature, the true disease gene is effectively prioritized to the top 6% of candidates on average. We then apply this strategy to a melanoma-associated region on chromosome 1 and identify MCL1 as a potential causative gene. Furthermore, to gain global insight into disease mechanisms, we used ERC to predict molecular connections between 310 nominally distinct diseases. The resulting “disease map” network associates several diseases with related pathogenic mechanisms and unveils many novel relationships between clinically distinct diseases, such as between Hirschsprung''s disease and melanoma. Taken together, these results demonstrate the utility of molecular evolution as a gene discovery platform and show that evolutionary signatures can be used to build informative gene-based networks.     

Autoimmunity as a Candidate for the Etiopathogenesis of Meniere's Disease: Detection of Autoimmune Reactions and Diagnostic Biomarker Candidate

Meniere''s disease is an inner ear disorder that can manifest as fluctuating vertigo, sensorineural hearing loss, tinnitus, and aural fullness. However, the pathologic mechanism of Meniere''s disease is still unclear. In this study, we evaluated autoimmunity as a potential cause of Meniere''s disease. In addition we tried to find useful biomarker candidates for diagnosis. We investigated the protein composition of human inner ear fluid using liquid column mass spectrometry, the autoimmune reaction between circulating autoantibodies in patient serum and multiple antigens using the Protoarray system, the immune reaction between patient serum and mouse inner ear tissues using western blot analysis. Nine proteins, including immunoglobulin and its variants and interferon regulatory factor 7, were found only in the inner ear fluid of patients with Meniere''s disease. Enhanced immune reactions with 18 candidate antigens were detected in patients with Meniere''s disease in Protoarray analysis; levels of 8 of these antigens were more than 10-fold higher in patients than in controls. Antigen-antibody reactions between mouse inner ear proteins with molecular weights of 23–48 kDa and 63–75 kDa and patient sera were detected in 8 patients. These findings suggest that autoimmunity could be one of the pathologic mechanisms behind Meniere''s disease. Multiple autoantibodies and antigens may be involved in the autoimmune reaction. Specific antigens that caused immune reactions with patient''s serum in Protoarray analysis can be candidates for the diagnostic biomarkers of Meniere''s disease.     

Unusual clustering of diseases in a Canadian Old Colony (Chortitza) Mennonite kindred and community.

We investigated a large Old Colony (Chortitza) Mennonite kindred with branches across Canada. Six generations of the kindred were traced. There was intermarriage among numerous family members. Insulin-dependent diabetes mellitus (IDDM) was identified in 10 members; all 7 living patients were found to carry the immunogenetic marker HLA-DR4. Nine other close relatives had disorders of carbohydrate metabolism, including gestational diabetes mellitus and non-insulin-dependent diabetes mellitus progressing to insulin use. Ten other relatives had autoimmune diseases, including rheumatoid arthritis, hyperthyroidism, hypothyroidism and multiple sclerosis. Cases of Alport''s syndrome, congenital malformations, inborn errors of metabolism and unusual malignant diseases were also found in the kindred. In the small Alberta community in which the kindred was ascertained there were people of Old Colony Mennonite descent with genetic conditions such as Gilles de la Tourette''s syndrome and congenital malformations, including congenital heart disease. This kindred represents the largest reported familial aggregation of IDDM. This disease and other disorders of carbohydrate metabolism occur in the context of a strong familial predisposition to autoimmune disease. Study of this family may permit empiric testing of proposed models of inheritance of diseases of complex origin such as IDDM. We report this Old Colony (Chortitza) Mennonite community because it is one of the settlements populated by this religious and genetic isolate, which extends across Canada and Central and South America and affords opportunities for the study of both common and rare inherited diseases.     

Relation between nicotine intake and Alzheimer's disease.

OBJECTIVE--To study the association between Alzheimer''s disease and nicotine intake through smoking. DESIGN--Population based case-control study. SETTING--City of Rotterdam and four northern provinces of The Netherlands. SUBJECTS--198 patients with early onset Alzheimer''s disease, 198 controls matched for age and sex, and families of 17 patients in whom Alzheimer''s disease was apparently inherited as an autosomal dominant disorder. MAIN OUTCOME MEASURES--Age of onset of dementia, relative risk of Alzheimer''s disease. RESULTS--89 of 193 patients with Alzheimer''s disease had a history of smoking compared with 102 of 195 controls. Among the patients and controls with a family history of dementia, smoking was significantly less common in those with dementia (40/95 with dementia v 55/96 controls; relative risk 0.35; 95% confidence interval 0.16 to 0.78). The risk of Alzheimer''s disease decreased with increasing daily number of cigarettes smoked before onset of disease (relative risk 0.3 in those smoking greater than 21/day v 1 in non-smokers). In six families in which the disease was apparently inherited as an autosomal dominant disorder, the mean age of onset was 4.17 years later in smoking patients than in non-smoking patients from the same family (p = 0.03). CONCLUSIONS--These findings suggest an inverse association between smoking and Alzheimer''s disease, although smoking cannot be advocated for other health reasons. We speculate that nicotine may have a role in the aetiology of both Alzheimer''s disease and Parkinson''s disease.     

Crohn's Disease and Pregnancy

This paper reports the outcome of 60 pregnancies in 40 women, all of whom had concomitant Crohn''s disease. Detailed analysis of pregnancy rates in Crohn''s disease supports in outline the hypothesis that some patients with bowel symptoms may be rendered temporarily subfertile by the activity of their bowel complaints. In contrast there is little or no evidence of any adverse effect during pregnancy on mother or child. Most pregnancies went normally to term and, if anything, Crohn''s disease tended to improve during the period of confinement.After delivery, however, over 40% of patients suffered a relapse of Crohn''s disease. Such a situation might well constitute a logical indication for the administration of corticosteroid therapy.