Literature search from ms 29/4/2010

Reiff, T., K. Tsarovina, et al. (2010). "Neuroblastoma Phox2b variants stimulate proliferation and dedifferentiation of immature sympathetic neurons." JOURNAL OF NEUROSCIENCE 30(3): 905-915.

Neuroblastoma is a pediatric tumor that is thought to arise from autonomic precursors in the neural crest. Mutations in thePHOX2B gene have been observed in familial and sporadic forms of neuroblastoma and represent the first defined genetic predisposition for neuroblastoma. Here, we address the mechanisms that may underlie this predisposition, comparing the function of wild-type and mutant Phox2b proteins ectopically expressed in proliferating, embryonic sympathetic neurons. Phox2b displays a strong antiproliferative effect, which is lost in all Phox2b neuroblastoma variants analyzed. In contrast, an increase in sympathetic neuron proliferation is elicited by Phox2b variants with mutations in the homeodomain when endogenous Phox2b levels are lowered by siRNA-mediated knockdown to mimic the situation of heterozygous PHOX2B mutations in neuroblastoma. The increased proliferation is blocked by Hand2 knockdown and the antiproliferative Phox2b effects are rescued by Hand2 overexpression, implying Hand2 in Phox2b-mediated proliferation control. APhox2b variant with a nonsense mutation in the homeodomain elicits, in addition, a decreased expression of characteristic marker genes. Together, these results suggest that PHOX2B mutations predispose to neuroblastoma by increasing proliferation and promoting dedifferentiation of cells in the sympathoadrenergic lineage. Copyright copyright 2010 the authors.

Renoncourt, Y., P. Carroll, et al. (1998). "Neurons derived in vitro from ES cells express homeoproteins characteristic of motoneurons and interneurons." MECHANISMS OF DEVELOPMENT 79(1-2): 185-197.

We have characterized different neuronal subpopulations derived from in vitro differentiation of embryonic stem (ES) cells using as markers the expression of several homeodomain transcription factors. Following treatment of embryo-like aggregates with retinoic acid (RA), Pax-6, a protein expressed by ventral central nervous system (CNS) progenitors is induced. In contrast, Pax-7 expressed in vivo by dorsal CNS progenitors, and erbB3, a gene expressed by neural crest cells and its derivatives, are almost undetectable. CNS neuronal subpopulations generated expressed combinations of markers characteristic of somatic motoneurons (Islet- 1/2 , Lim-3, and HB-9), cranial motoneurons (Islet- 1/2 and Phox2b) and interneurons (Lira- 1/2 or EN1). Molecular characterization of neuron subtypes generated from ES cells should considerably facilitate the identification of new genes expressed by restricted neuronal cell lineages.

Repetto, G. M., R. J. Corrales, et al. (2009). "Later-onset congenital central hypoventilation syndrome due to a heterozygous 24-polyalanine repeat expansion mutation in the PHOX2B gene." ACTA PAEDIATRICA 98(1): 192-5.

AIM: to describe a family with later onset congenital central hypoventilation syndrome (LO-CCHS) and heterozygosity for a 24-polyalanine repeat expansion mutation in the PHOX2B gene, rendered phenotypically apparent with exposure to anesthetics. CASE SUMMARY: An otherwise healthy 2.75-year-old boy presented with alveolar hypoventilation after adenoidectomy and tonsillectomy for obstructive sleep apnea, requiring invasive ventilatory support during sleep. He had a heterozygous 24-polyalanine repeat expansion in the PHOX2B gene (20/24 genotype), a genotype that has not been previously described in association with CCHS or LO-CCHS symptoms. Clinical findings in members of the family with the same 20/24 genotype ranged from asymptomatic to prolonged sedation after benzodiazepines. CONCLUSION: CCHS should be suspected in individuals presenting with unexplained hypoventilation and/or seizures after anesthetics or sedatives. This is the first report of LO-CCHS in a kindred with the PHOX2B 20/24 genotype. The incomplete penetrance observed in this family suggests a gene-environment interaction.

Revet, I., G. Huizenga, et al. (2008). "The MSX1 homeobox transcription factor is a downstream target of PHOX2B and activates the Delta-Notch pathway in neuroblastoma." EXPERIMENTAL CELL RESEARCH 314(4): 707-19.

Neuroblastoma is an embryonal tumour of the peripheral sympathetic nervous system (SNS). One of the master regulator genes for peripheral SNS differentiation, the homeobox transcription factor PHOX2B, is mutated in familiar and sporadic neuroblastomas. Here we report that inducible expression of PHOX2B in the neuroblastoma cell line SJNB-8 down-regulates MSX1, a homeobox gene important for embryonic neural crest development. Inducible expression of MSX1 in SJNB-8 caused inhibition of both cell proliferation and colony formation in soft agar. Affymetrix micro-array and Northern blot analysis demonstrated that MSX1 strongly up-regulated the Delta-Notch pathway genes DLK1, NOTCH3, and HEY1. In addition, the proneural gene NEUROD1 was down-regulated. Western blot analysis showed that MSX1 induction caused cleavage of the NOTCH3 protein to its activated form, further confirming activation of the Delta-Notch pathway. These experiments describe for the first time regulation of the Delta-Notch pathway by MSX1, and connect these genes to the PHOX2B oncogene, indicative of a role in neuroblastoma biology. Affymetrix micro-array analysis of a neuroblastic tumour series consisting of neuroblastomas and the more benign ganglioneuromas showed that MSX1, NOTCH3 and HEY1 are more highly expressed in ganglioneuromas. This suggests a block in differentiation of these tumours at distinct developmental stages or lineages.

Rhee, J. W., A. Arata, et al. (2004). "Pbx3 deficiency results in central hypoventilation." AMERICAN JOURNAL OF PATHOLOGY 165(4): 1343-1350.

Pbx proteins comprise a family of TALE (three amino acid toop extension) class homeodomain transcription factors that are implicated in developmental gene expression through their abilities to form hetero-oligomeric DNA-binding complexes and function as transcriptional regulators in numerous cell types. We demonstrate here that one member of this family, Pbx3, is expressed at high levels predominantly in the developing central nervous system, including a region of the medulla oblongata that is implicated in the control of respiration. Pbx3-deficient mice develop to term but die within a few hours of birth from central respiratory failure due to abnormal activity of hispiratory neurons in the medulla. This partially phenocopies the defect in mice deficient for Rnx, a metaHox homeodomain transcription factor, that we demonstrate here is capable of forming a DNA-binding complex with Pbx3. Rnx expression is unperturbed in Pbx3-deficient mice, but its ability to enhance transcription in vitro as a complex with TALE proteins is compromised in the absence of Pbx3-Thus, Pbx3 is essential for respiration and, like its DNA-binding partner Rnx, is critical for proper development of medullary respiratory control mechanisms. Pbx3-deficient mice provide a model for congenital central hypoventilation syndrome and suggest that Pbx3 mutations may promote the pathogenesis of this disorder.

Rhodes, A. E. and J. Bethell (2008). "Suicidal ideators without major depression--whom are we not reaching?" Canadian Journal of Psychiatry - Revue Canadienne de Psychiatrie 53(2): 125-30.

OBJECTIVES: To describe individuals who reported suicidal ideation but neither met the criteria for major depression (MD) nor were in contact with mental health services in the previous year. METHOD: Data were drawn from the Canadian Community Health Survey: Mental Health and Well-Being (CCHS 1.2). Conducted in 2002, the CCHS 1.2 was a cross-sectional population-based survey of 36 984 Canadian household residents aged 15 years or more. First, we described the individuals who reported suicidal ideation, were without MD, and were not in contact with mental health services (n = 584) as well as their nonsuicidal counterparts (n = 31 382) based on various demographic and health status variables. Second, to analyse whether these same variables are associated with mental health service contact(s) among suicidal individuals without MD, we compared those who were in contact with mental health services (n = 209) to those who were not (n = 584). RESULTS: Almost one-half (47.9%) of the suicidal ideators were without both MD and a mental health service contact in the previous year. Individuals in this group were younger and exhibited greater morbidity than their nonsuicidal counterparts (without MD or mental health service contact) but did not differ by sex. Although male and female respondents were equally represented among the suicidal ideators without MD, male respondents were less likely to contact mental health services. Such contact was more likely among female respondents and individuals with an anxiety disorder. CONCLUSIONS: These findings underscore the need for further research evaluating early intervention programs that succeed in capturing suicidal youths, particularly male youths.

Riegler, R., G. Pauser, et al. (1981). "[3-years' domiciliary respirator therapy in idiopathic hypoventilation syndrome (ondine's curse syndrome) (author's transl)]." Anasthesie, Intensivtherapie, Notfallmedizin 16(5): 247-50.

A 67 years old patient with a tracheostomy and cribral cannula on account of severe idiopathic hypoventilation syndrome was discharged from the intensive care unit having been supplied with a respirator (MK 8-Bird) and compressor by his health insurance. The domiciliary respirator therapy was continued for more than 3 years. The disorder manifested itself initially in severe hypoventilation during sleep, acute hypoxaemia, hypercapnia and respiratory acidosis. The patient himself and his family took on the adjustment and maintenance of the respirator, having being appropriately trained before his discharge from hospital. The treatment succeeded for over 3 years in maintaining an acceptable quality of life for the patient.

Rintala, R. J. (2003). "Transanal coloanal pull-through with a short muscular cuff for classic Hirschsprung's disease." EUROPEAN JOURNAL OF PEDIATRIC SURGERY 13(3): 181-6.

INTRODUCTION: A totally transanal operation for classic Hirschsprung's disease has become increasingly popular during the last few years. The procedure leaves no scars, is associated with less postoperative pain and discomfort and shortens hospital stay. The most commonly used technique for transanal pull-through is long endorectal dissection leaving a long muscular cuff, which is usually split posteriorly. We present our preliminary results following transanal endorectal operations with a short unsplit muscular cuff. MATERIALS AND METHODS: Twenty-six patients underwent short-cuff transanal endorectal operation for Hirschsprung's disease between years 2000 and 2002. Patients' hospital records were analysed retrospectively. The collected data included age at operation, associated conditions, hospital stay and time to full enteral feeding, occurrence of pre- and postoperative enterocolitis and preoperative stoma, operative complications, need for postoperative anal dilatations, postoperative perianal skin problems and preliminary data on bowel function. RESULTS: The median age at operation was 1 month (range 0 - 60 months), 13 patients were operated on in the neonatal period. Four patients had Down's syndrome, 1 had cartilage-hair hypoplasia and one Ondine's syndrome. Five patients had preoperative enterocolitis. Four patients had undergone levelling stoma formation for unremitting constipation or enterocolitis. The proximal ganglionic stoma was concomitantly pulled-through and anastomosed to the anus in all 4 patients with a stoma. One patient with aganglionosis extending to the proximal sigmoid required additional laparoscopic colonic mobilisation. Complications related to surgery did not occur in the present series. Median postoperative hospital stay was 3 days (range 2 - 21 days) and median time to full enteral feeding was 3 days (range 1 - 14). Six patients required anal dilatations, two of those for a period of 3 weeks. The median follow-up time was 6 months (range 1 - 22 months). Fourteen patients had perianal skin rash, which usually resolved within 6 weeks. Postoperative enterocolitis requiring hospitalisation occurred in 1 patient, another patient had mild symptoms suggesting enterocolitis; these responded to oral antibiotic treatment. Early postoperative bowel function was characterised by frequent bowel movements in most patients. This usually resolved within a few months; of the 15 patients with a follow-up of longer than 6 months only 2 have more than 3 bowel movements per day. At the last follow-up frank soiling occurred in 1 patient with Down's syndrome, one patient requires oral laxatives for constipation. CONCLUSIONS: Transanal endorectal pull-through with a short cuff is a safe operation with a low incidence of operative and postoperative complications. Hospital stay and time to full enteral feeds is significantly shorter than after conventional procedures; this is associated with lower hospital costs. Long-term functional outcome is unclear but short-term function is very similar to that after procedures where transanal mucosectomy is combined with open rectosigmoid dissection.
Rintala, R. J. and T. Wester (2003). "[Transanal endorectal pull-through with short muscular cuff in the treatment of Hirschsprung disease. Preliminary study with 37 patients]." CIRUGIA PEDIATRICA 16(4): 161-5.

INTRODUCTION: Totally transanal operation for classic Hirschsprung's disease has gained increasing popularity during the last few years. The procedure leaves no scars, is associated with less postoperative pain and discomfort and shortens hospital stay. The most commonly used technique for transanal pull-through is long endorectal dissection leaving a long muscular cuff, which is usually split posteriorly. We present our preliminary results following transanal endorectal operation with a short unsplit muscular cuff. MATERIALS AND METHODS: Thirty-seven patients underwent short-cuff transanal endorectal operation for Hirchsprung's disease between years 2000 and 2002. Patients' hospital records were analysed retrospectively. The collected data included age at the operation, associated conditions, hospital stay and time to full enteral feeds, occurrence of pre- and postoperative enterocolitis and preoperative stoma, operative complications, need for postoperative anal dilatations, postoperative perianal skin problems and preliminary data on bowel function. RESULTS: The median age at operation was 5 months (range 0-60 months), 13 patients were operated in the neonatal period. Six patients had Down's syndrome, 1 had cartilage-hair hypoplasia and one Ondine's syndrome. Six patients had preoperative enterocolitis. Thirteen patients had undergone levelling stoma formation for unremitting obstruction or enterocolitis, two of these had a long segment aganglionosis. The proximal ganglionic stoma was concomitantly pulled-through and anastomosed to the anus in all 13 patients with a stoma. Complications related to surgery occurred in 3 patients, 2 had prolapse of the pulled-through bowel (reduced immediately without later sequels) and 1 infection in the stoma closure wound. Median postoperative hospital stay was 4 days (range 2-21 days) and median time to full enteral feeds 3 (range 1-14) days. The median follow-up time was 6 months (range 1-22 months). Postoperative enterocolitis occurred in 1 patient, further 3 patients had symptoms suggesting mild enterocolitis. Nine patients required anal dilatations, two of those for a period of 3 weeks. Twenty-two patients had perianal skin rash, which resolved usually within 6 weeks. Early postoperative bowel function was characterised by frequent bowel movements in most patients. These usually resolved within few months; of the 17 patients with a follow-up for longer than 6 months only 2 have more than 3 bowel movements per day. At last follow-up frank soiling occurred in 2 patients, one patient needs oral laxatives for constipation. CONCLUSIONS: Transanal endorectal pull-through with a short cuff is a safe operation with low incidence of operative and postoperative complications. Hospital stay and time to full enteral feeds is significantly shorter than following conventional procedures; this associates with lower hospital costs. Long-term functional outcome of patients having totally transanal pull-through is unclear but short tern function is very similar than after procedures where transanal mucosectomy is combined with rectosigmoid dissection through laparotomy.
Rioux, J. D., R. J. Xavier, et al. (2007). "Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis." NATURE GENETICS 39(5): 596-604.

We present a genome-wide association study of ileal Crohn disease and two independent replication studies that identify several new regions of association to Crohn disease. Specifically, in addition to the previously established CARD15 and IL23R associations, we identified strong and significantly replicated associations (combined P < 10(-10)) with an intergenic region on 10q21.1 and a coding variant in ATG16L1, the latter of which was also recently reported by another group. We also report strong associations with independent replication to variation in the genomic regions encoding PHOX2B, NCF4 and a predicted gene on 16q24.1 (FAM92B). Finally, we demonstrate that ATG16L1 is expressed in intestinal epithelial cell lines and that functional knockdown of this gene abrogates autophagy of Salmonella typhimurium. Together, these findings suggest that autophagy and host cell responses to intracellular microbes are involved in the pathogenesis of Crohn disease.

Roberts, R. L., J. E. Hollis-Moffatt, et al. (2008). "Confirmation of association of IRGM and NCF4 with ileal Crohn's disease in a population-based cohort." Genes & Immunity 9(6): 561-5.

Genome-wide association studies have identified PHOX2B, FAM92B, IRGM and NCF4 as candidate susceptibility factors for ileal Crohn's disease (CD). Here we sought to determine whether these genes were also associated with ileal CD in New Zealand Caucasians, as well as with ileocolonic CD, colonic CD and ulcerative colitis (UC). A total of 507 CD patients, 475 UC patients and 576 controls were genotyped for the single nucleotide polymorphisms rs16853571 (PHOX2B), rs4821544 (NCF4), rs13361189 and rs4958847 (IRGM), and rs8050910 (FAM92B). NCF4 and IRGM were significantly associated with ileal CD (P-value(rs4821544)=0.0090, odds ratio (OR)=1.425, 95% confidence interval (CI): 1.092-1.859; P-value(rs13361189)=0.0017, OR=1.942, 95% CI: 1.274-2.959; P-value(rs4958847)=0.0022, OR=1.767, 95% CI: 1.224-2.558), but not with other forms of inflammatory bowel disease (IBD). No association of PHOX2B or FAM92B with IBD was detected. Our study has demonstrated that IRGM and NCF4 are ileal-specific CD susceptibility factors in New Zealand Caucasians.

Rogala, L., N. Miller, et al. (2008). "Population-based controlled study of social support, self-perceived stress, activity and work issues, and access to health care in inflammatory bowel disease." Inflammatory Bowel Diseases 14(4): 526-35.

BACKGROUND: The Manitoba IBD Cohort Study is a longitudinal, population-based study of multiple determinants of health outcomes in persons with inflammatory bowel disease (IBD) diagnosed within 7 years at enrollment. In this cross-sectional substudy we compared IBD participants' levels of social support, self-perceived stress, disability, and access to healthcare with those of a matched community sample. METHODS: IBD participants (n = 388) were interviewed using the Canadian Community Health Surveys (CCHS) 1.1 and 1.2 to assess psychosocial variables. The national CCHS data were accessed to extract a community comparison group, matched on age, sex, and geographic residence. RESULTS: Compared to the community sample, IBD participants received more tangible, affective, or emotional support in the past year and were more likely to have experienced a positive social interaction. Those with IBD were as likely to be employed as those in the community sample, although they reported greater rates of reduced activity and days missed. Work was not identified as a significant source of stress, but physical health was more likely to be identified as a main stressor by those with active IBD compared to the non-IBD sample. Individuals with IBD were twice as likely to report unmet healthcare needs than the community sample; however, there was agreement across both groups regarding common barriers, including long waits and availability. CONCLUSIONS: While the disease may contribute to greater interference with work quality and daily activities, IBD patients have similar levels of stress and appear to have enhanced social supports relative to those in the community without IBD.

Rohrer, T., D. Trachsel, et al. (2002). "Congenital central hypoventilation syndrome associated with Hirschsprung's disease and neuroblastoma: case of multiple neurocristopathies." PEDIATRIC PULMONOLOGY 33(1): 71-6.

We report on a male infant with the rare combined occurrence of congenital central hypoventilation syndrome (CCHS or Ondine's curse), Hirschsprung's disease (HD), and neuroblastoma. Current therapeutical options leave no doubt that children with isolated forms of CCHS, HD, or neuroblastoma must be treated, but management decisions and the ethical dilemma become more difficult with the presence of multiple neurocristopathies. Our patient was dependent on mechanical ventilation and total parenteral nutrition, when a neuroblastoma was diagnosed at age 5 months. We initiated an attempt at curative chemotherapy. The tumor failed to respond to recommended chemotherapeutic regimens, and the patient died at 11 months of age. We emphasize the importance of screening CCHS patients for associated illnesses such as neuroblastoma and ganglioneuroblastoma at time of diagnosis. Copyright 2002 Wiley-Liss, Inc.

Romanczuk, B. J., W. P. Potsic, et al. (1978). "Hypersomnia with periodic breathing (an acromegalic Pickwickian)." Otolaryngology 86(6 Pt 1): ORL-897-903.

The syndromes of Pickwickian, Ondine's curse, and primary alveolar hypoventilation are respiratory disorders manifesting increased sleepiness and irregular respiratory rhythms. These disorders are currently grouped as hypersomnia with periodic breathing (HPB). Polygraphic techniques have lead to a reasonable hypothesis as to the pathophysiology of the multiple variants of HPB. Discernible causes of HPB have been attributed to both central and peripheral factors. Peripheral factors encompass those conditions relating to upper airway obstruction. An acromegalic person suffering the HPB syndrome secondary to laryngeal stenosis is described.

Rosa, G., P. Ciappetta, et al. (1982). "'Ondine's curse'. [Italian]." Acta Anaesthesiologica Italica 33(4): 587-595.

'Ondine's Curse' is a rare syndrome consisting of chronic alveolar hypoventilation related to disturbances of brain system respiratory nuclei. Its clinical presentation is a sort of sleep induced apnea, eventually leading to chronic progressive involvement of cardiorespiratory apparatus. This paper reports a case of such a disease occurring without apparent cause in a 60-year-old woman. The pathogenesis and pathophysiology are discussed as well as the clinical-therapeutic implications.

Rose, M. F., J. Ren, et al. (2009). "Math1 Is Essential for the Development of Hindbrain Neurons Critical for Perinatal Breathing." NEURON 64(3): 341-354.

Mice lacking the proneural transcription factor Math1 (Atoh1) lack multiple neurons of the proprioceptive and arousal systems and die shortly after birth from an apparent inability to initiate respiration. We sought to determine whether Math1 was necessary for the development of hindbrain nuclei involved in respiratory rhythm generation, such as the parafacial respiratory group/retrotrapezoid nucleus (pFRG/RTN), defects in which are associated with congenital central hypoventilation syndrome (CCHS). We generated a Math1-GFP fusion allele to trace the development of Math1-expressing pFRG/RTN and paratrigeminal neurons and found that loss of Math1 did indeed disrupt their migration and differentiation. We also identified Math1-dependent neurons and their projections near the pre-Botzinger complex, a structure critical for respiratory rhythmogenesis, and found that glutamatergic modulation reestablished a rhythm in the absence of Math1. This study identifies Math1-dependent neurons that are critical for perinatal breathing that may link proprioception and arousal with respiration. copyright 2009 Elsevier Inc. All rights reserved.