Literature search from ms 29/4/2010

Cross, S. H., J. E. Morgan, et al. (2004). "Haploinsufficiency for Phox2b in mice causes dilated pupils and atrophy of the ciliary ganglion: mechanistic insights into human congenital central hypoventilation syndrome." HUMAN MOLECULAR GENETICS 13(14): 1433-9.

Dilp1 is a semi-dominant mouse mutation that causes dilated pupils when heterozygous and is lethal when homozygous. We report here that it is caused by a point mutation that introduces a stop codon close to the start of the coding sequence of the paired-like homeobox transcription factor Phox2b. Mice carrying a targeted allele of Phox2b also have dilated pupils and the two alleles do not complement. Phox2b is necessary for the development of the autonomic nervous system and when absent one of the consequences is that all parasympathetic ganglia fail to form. Constriction of the pupil is a parasympathetic response mediated by the ciliary ganglion and we find that in Phox2b heterozygous mutants it is highly atrophic. The development of other parasympathetic and sympathetic ganglia appears to be largely unaffected indicating that the ciliary ganglion is exquisitely sensitive to a reduction in dose of this transcription factor. PHOX2B has been implicated in human disease. Mutations, principally leading to polyalanine expansions within the protein, have been found in patients with congenital central hypoventilation syndrome (CCHS), the cardinal feature of which is an inability to breathe unassisted when asleep. Additionally, some CCHS patients have ocular abnormalities, including pupillary defects, although they principally have constricted rather than dilated pupils. The apparent phenotypic differences observed between mice carrying a loss-of-function mutation of Phox2b and CCHS patients indicate that PHOX2B mutations found in CCHS patients, all of which can produce proteins with intact DNA-binding domains, are gain-of-function mutations that alter rather than abolish protein function.

Currie, S. R., S. B. Patten, et al. (2005). "Comorbidity of major depression with substance use disorders." Canadian Journal of Psychiatry - Revue Canadienne de Psychiatrie 50(10): 660-6.

OBJECTIVES: In the Canadian adult population, we aimed to 1) estimate the 12-month prevalence of major depressive disorder (MDD) in persons with a diagnosis of harmful alcohol use, alcohol dependence, and drug dependence; 2) estimate the 12-month prevalence of harmful alcohol use, alcohol dependence, and drug dependence in persons with a 12-month and lifetime diagnosis of MDD; 3) identify socioeconomic correlates of substance use disorder-major depression comorbidity; 4) determine how comorbidity impacts the prevalence of suicidal thoughts; and 5) determine how comorbidity affects mental health care used. METHODS: We examined data from the Canadian Community Health Survey: Mental Health and Well-Being (CCHS 1.2). RESULTS: The 12-month prevalences of MDD in persons with a substance use disorder (SUD) were 6.9% for harmful alcohol use (95% confidence interval [CI], 5.2 to 8.5), 8.8% for alcohol dependence (95%CI, 6.6 to 11.0), and 16.1% for drug dependence (95%CI, 10.3 to 21.9). Conversely, the 12-month prevalences of harmful alcohol use, alcohol dependence, and drug dependence in persons with a 12-month diagnosis of MDD were 12.3% (95%CI, 9.4 to 15.2), 5.8% (95%CI, 4.3 to 7.3), and 3.2% (95%CI, 2.0 to 4.4), respectively. Regression modelling did not identify any socioeconomic predictors of SUD-MDD comorbidity. Substance dependence and MDD independently predicted higher prevalence of suicidal thoughts and mental health treatment use. CONCLUSIONS: SUDs cooccur with a high frequency in cases of MDD. Clinicians and mental health services should consider routine assessment of SUDs in depression patients.

Cutz, E., T. K. Ma, et al. (1997). "Peripheral chemoreceptors in congenital central hypoventilation syndrome." AMERICAN JOURNAL OF RESPIRATORY & CRITICAL CARE MEDICINE 155(1): 358-63.

Congenital central hypoventilation syndrome (CCHS) is a rare disorder of unknown etiology, characterized by failure of the autonomic control of respiration. The primary defect is believed to involve central respiratory control; however, no specific lesion has been identified. We report two cases of CCHS (one female, 3 mo of age and one male 2 yr of age) in which there was detailed examination of the neural, muscular, and chemoreceptor components of respiratory control. Although no specific abnormalities were identified in the central nervous system (CNS) or muscles of respiration, striking changes were observed in arterial chemoreceptors, carotid bodies (CB), and airway chemoreceptors, neuroepithelial bodies (NEB). In both cases, CB were small (< 50% of control), with a marked decrease in the number of glomus cells identified by immunostaining for tyrosine hydroxylase and serotonin. Ultrastructural analysis of glomus cells in Case 1 showed a marked decrease in the frequency of dense core vesicles (< 20% of control), the storage site of amine and peptide neurotransmitters. Immunostaining for S100 protein, a marker of sustentacular or Type II cells, was increased up to twofold compared with controls. In the lung, the frequency and size of NEB immunostained for bombesin was increased twofold in both cases, suggesting compensatory hyperplasia of airway chemoreceptors. Since intact peripheral chemoreceptors are essential for respiratory control, especially the response to hypoxia, abnormalities in CB and NEB may contribute to the pathophysiology of CCHS and related conditions such as sudden infant death syndrome (SIDS).

Dahan, A. (2005). "Consciousness. [Dutch]." Nederlands Tijdschrift voor Anesthesiologie 18(3): 73-80.

D'Alessandro, V., T. Mason, 2nd, et al. (2005). "Late-onset hypoventilation without PHOX2B mutation or hypothalamic abnormalities." Journal of Clinical Sleep Medicine 1(2): 169-72.

Most children with idiopathic central hypoventilation have symptoms at birth or shortly thereafter and have mutations of the PHOX2B gene. Those whose symptoms appear later usually have obesity and hypothalamic abnormalities. We describe a case of a boy who presented at 5 years of age with severe idiopathic central hypoventilation, but no obesity or hypothalamic abnormalities, and who tested negative for mutation of the PHOX2B gene. This case illustrates the heterogeneity of childhood idiopathic central hypoventilation syndromes and indicates the multifactorial etiology of these syndromes.
Dauger, S., A. Pattyn, et al. (2003). "Phox2b controls the development of peripheral chemoreceptors and afferent visceral pathways." DEVELOPMENT 130(26): 6635-6642.

We report that the afferent relays of visceral (cardiovascular, digestive and respiratory) reflexes, differentiate under the control of the paired-like homeobox gene Phox2b: the neural crest-derived carotid body, a chemosensor organ, degenerates in homozygous mutants, as do the three epibranchial placode-derived visceral sensory ganglia (geniculate, petrosal and nodose), while their central target, the nucleus of the solitary tract, which integrates all visceral information, never forms. These data establish Phox2b as an unusual 'circuit-specific' transcription factor devoted to the formation of autonomic reflex pathways. We also show that Phox2b heterozygous mutants have an altered response to hypoxia and hypercapnia at birth and a decreased tyrosine hydroxylase expression in the petrosal chemosensory neurons, thus providing mechanistic insight into congenital central hypoventilation syndrome, which is associated with heterozygous mutations in PHOX2B.

Dauger, S., S. Renolleau, et al. (1999). "Ventilatory responses to hypercapnia and hypoxia in Mash-1 heterozygous newborn and adult mice." PEDIATRIC RESEARCH 46(5): 535-542.

Normal control of breathing is characterized by maintenance of CO₂ and O₂ arterial pressures at constant levels by appropriate ventilatory responses to changes in CO₂ production and O₂ consumption. Abnormal development of this regulatory system during embryogenesis may produce early impairments in chemosensitivity, as in congenital central hypoventilation syndrome. The present study addresses the role of the mammalian achaete-scute homologous gene (Mash-1) in the development of respiratory control. We analyzed ventilatory responses to hypercapnia (8% CO₂, 21% O₂, 71% N₂) and hypoxia (10% O₂, 3% CO₂, 87% N₂) in newborn and adult Mash-1 heterozygous mice (Mash-1(+/-)) and their wild-type littermates (Mash-1(+/+)). Ventilation, breath duration, and tidal volume were measured using whole-body plethysmography. Ventilatory responses to hypercapnia were significantly weaker in newborn male Mash-1(+/-) compared with Mash-1(+/+) mice as a result of a weaker breath-duration response. No differences were observed between adult Mash-1(+/-) and Mash-1(+/+) mice. Our data suggest that Mash-1 may be involved in respiratory control development via mechanisms linked to the X chromosome.

David, M. and L. Cret (1975). "["Ondine's curse": primitive alveolar hypoventilations]." Pediatrie 30(3): 319-21.

de Pontual, L., V. Nepote, et al. (2003). "Noradrenergic neuronal development is impaired by mutation of the proneural HASH-1 gene in congenital central hypoventilation syndrome (Ondine's curse)." HUMAN MOLECULAR GENETICS 12(23): 3173-80.

Congenital central hypoventilation syndrome (CCHS, Ondine's curse) is a rare disorder of the chemical control of breathing. It is frequently associated with a broad spectrum of dysautonomic symptoms, suggesting the involvement of genes widely expressed in the autonomic nervous system. In particular, the HASH-1-PHOX2A-PHOX2B developmental cascade was proposed as a candidate pathway because it controls the development of neurons with a definitive or transient noradrenergic phenotype, upstream from the RET receptor tyrosine kinase and tyrosine hydroxylase. We recently showed that PHOX2B is the major CCHS locus, whose mutation accounts for 60% of cases. We also studied the proneural HASH-1 gene and identified a heterozygous nucleotide substitution in three CCHS patients. To analyze the functional consequences of HASH-1 mutations, we developed an in vitro model of noradrenergic differentiation in neuronal progenitors derived from the mouse vagal neural crest, reproducing in vitro the HASH-PHOX-RET pathway. All HASH-1 mutant alleles impaired noradrenergic neuronal development, when overexpressed from adenoviral constructs. Thus, HASH-1 mutations may contribute to the CCHS phenotype in rare cases, consistent with the view that the abnormal chemical control of breathing observed in CCHS patients is due to the impairment of noradrenergic neurons during early steps of brainstem development.
de Pontual, L., A. Pelet, et al. (2007). "Epistatic interactions with a common hypomorphic RET allele in syndromic Hirschsprung disease." HUMAN MUTATION 28(8): 790-6.

Hirschsprung disease (HSCR) stands as a model for genetic dissection of complex diseases. In this model, a major gene, RET, is involved in most if not all cases of isolated (i.e., nonsyndromic) HSCR, in conjunction with other autosomal susceptibility loci under a multiplicative model. HSCR susceptibility alleles can harbor either heterozygous coding sequence mutations or, more frequently, a polymorphism within intron 1, leading to a hypomorphic RET allele. On the other hand, about 30% of HSCR are syndromic. Hitherto, the disease causing gene has been identified for eight Mendelian syndromes with HSCR: congenital central hypoventilation (CCHS), Mowat-Wilson (MWS), Bardet-Biedl (BBS), Shah-Waardenburg (WS4), cartilage-hair-hypoplasia (CHH), Smith-Lemli-Opitz (SLO), Goldberg-Sprintzsen (GSS), and hydrocephalus due to congenital stenosis of the aqueduct of sylvius (HSAS). According to the HSCR syndrome, the penetrance of HSCR trait varies from 5 to 70%. Trisomy 21 (T21) also predisposes to HSCR. We were able to collect a series of 393 patients affected by CCHS (n = 173), WS4 (n = 24), BBS (n = 51), MWS (n = 71), T21 (n = 46), and mental retardation (MR) with HSCR (n = 28). For each syndrome, we studied the RET locus in two subgroups of patients; i.e., with or without HSCR. We genotyped the RET locus in 393 patients among whom 195 had HSCR, and compared the distribution of alleles and genotypes within the two groups for each syndrome. RET acts as a modifier gene for the HSCR phenotype in patients with CCHS, BBS, and Down syndrome, but not in patients with MWS and WS4. The frequent, low penetrant, predisposing allele of the RET gene can be regarded as a risk factor for the HSCR phenotype in CCHS, BBS, and Down syndrome, while its role is not significant in MWS and WS4. These data highlight the pivotal role of the RET gene in both isolated and syndromic HSCR. (c) 2007 Wiley-Liss, Inc.

de Pontual, L., A. Pelet, et al. (2006). "Mutations of the RET gene in isolated and syndromic Hirschsprung's disease in human disclose major and modifier alleles at a single locus." JOURNAL OF MEDICAL GENETICS 43(5): 419-23.

BACKGROUND: In Hirschsprung's disease (HSCR), a hypomorphic allele of a major gene, RET, accounts for most isolated (non-syndromic) cases, along with other autosomal susceptibility loci under a multiplicative model. However, some syndromic forms of HSCR are monogenic entities, for which the disease causing gene is known. OBJECTIVE: To determine whether RET could be considered a modifier gene for the enteric phenotype on the background of a monogenic trait. METHODS: The syndromic HSCR entities studied were congenital central hypoventilation (CCHS) and Mowat-Wilson syndrome (MWS), caused by PHOX2B and ZFHX1B gene mutations, respectively. The RET locus was genotyped in 143 CCHS patients, among whom 44 had HSCR, and in 30 MWS patients, among whom 20 had HSCR. The distribution of alleles, genotypes, and haplotypes was compared within the different groups. To test the interaction in vivo, heterozygous mice were bred for a null allele of Phox2b and Ret genes. RESULTS: RET was shown to act as a modifier gene for the HSCR phenotype in patients with CCHS but not with MWS. The intestine of double heterozygote mice was indistinguishable from their littermates. A loss of over 50% of each gene function seemed necessary in the mouse model for an enteric phenotype to occur. CONCLUSIONS: In CCHS patients, the weak predisposing haplotype of the RET gene can be regarded as a quantitative trait, being a risk factor for the HSCR phenotype, while in MWS, for which the HSCR penetrance is high, the role of the RET predisposing haplotype is not significant. It seems likely that there are both RET dependent and RET independent HSCR cases.

de Pontual, L., D. Trochet, et al. (2007). "Methylation-associated PHOX2B gene silencing is a rare event in human neuroblastoma." EUROPEAN JOURNAL OF CANCER 43(16): 2366-72.

Neuroblastoma (NB), an embryonic tumour originating from neural crest cells, is one of the most common solid tumours in childhood. Although NB is characterised by numerous recurrent, large-scale chromosome rearrangements, the genes targeted by these imbalances have remained elusive. We recently identified the paired-like homeobox 2B (PHOX2B, MIM 603851) gene as disease-causing in dysautonomic disorders including Congenital Central Hypoventilation Syndrome (CCHS), Hirschsprung disease (HSCR) and NB in various combinations. Most patients with NB due to a germline heterozygous PHOX2B gene mutation are familial and/or syndromic. PHOX2B, at chromosome 4p12, does not lie in a commonly rearranged locus in NB. To evaluate the role of PHOX2B in sporadic, isolated NB, we analysed 13 NB cell lines and 45 tumours for expression, mutations of coding and promoter sequences, loss of heterozygosity (LOH), or aberrant hypermethylation of PHOX2B (13 cell lines and 18 tumours). We didn't identify any mutation but LOH in about 10% of the cases and aberrant CpG dinucleotide methylation of the 500 bp PHOX2B promoter region in 4/31 tumours and cell lines (12.9%). Altogether, both germinal and somatic anomalies at the PHOX2B locus are found in NB.

De Pontual, L., D. Trochet, et al. (2008). "Delineation of late onset hypoventilation associated with hypothalamic dysfunction syndrome." PEDIATRIC RESEARCH 64(6): 689-94.

Late Onset Central Hypoventilation Syndrome associated with Hypothalamic Dysfunction (LO-CHS/HD) is a distinct entity among the clinical and genetic heterogeneous group of patients with late onset central hypoventilation. Here we report a series of 13 patients with LO-CHS/HD. Rapid onset obesity is the first symptom of HD followed by hypoventilation with a mean delay of 18 mos. The outcome remains poor for this group of patients and would benefit from early diagnosis to anticipate ventilation and possible metabolic disorders. Tumor predisposition is more frequent than initially suspected and as high as 40% in this series. These tumors of the sympathetic nervous system (TSNS) are usually differentiated and do not significantly worsen the prognosis. We report a familial case with recurrence in siblings. The cause underlying LO-CHS/HD remains poorly understood although recurrence in siblings argues for a monogenic disorder. We ruled out PHOX2B, ASCL1, and NECDIN as disease-causing genes by direct sequencing in our series of patients and discuss possible disease-causing mechanisms.

Dean, C. M. and R. B. Shepherd (1997). "Task-related training improves performance of seated reaching tasks after stroke. A randomized controlled trial." Stroke; a journal of cerebral circulation(4): 722-8.

BACKGROUND AND PURPOSE: After stroke, the ability to balance in sitting is critical to independence. Although impairments in sitting balance are common, little is known about the effectiveness of rehabilitation strategies designed to improve it. The purpose of this randomized placebo-controlled study was to evaluate the effect of a 2-week task-related training program aimed at increasing distance reached and the contribution of the affected lower leg to support and balance. METHODS: Twenty subjects at least 1 year after stroke were randomized into an experimental or control group. The experimental group participated in a standardized training program involving practice of reaching beyond arm's length. The control group received sham training involving completion of cognitive-manipulative tasks within arm's length. Performance of reaching in sitting was measured before and after training using electromyography, videotaping, and two force plates. Variables tested were movement time, distance reached, vertical ground reaction forces through the feet, and muscle activity. Subjects were also tested on sit-to-stand, walking, and cognitive tasks. Nineteen subjects completed the study. RESULTS: After training, experimental subjects were able to reach faster and further, increase load through the affected foot, and increase activation of affected leg muscles compared with the control group (P < .01). The experimental group also improved in sit-to-stand. The control group did not improve in reaching or sit-to-stand. Neither group improved in walking. CONCLUSIONS: This study provides strong evidence of the efficacy of task-related motor training in improving the ability to balance during seated reaching activities after stroke.

Deering, K. N., L. M. Lix, et al. (2009). "Chronic diseases and risk factors in Canada's northern populations: longitudinal and geographic comparisons." Canadian Journal of Public Health Revue Canadienne de Sante Publique. 100(1): 14-7.

OBJECTIVE: Chronic diseases are the leading cause of death and disability worldwide and place considerable burden on the Canadian health care system. This research investigates the self-reported prevalence of major chronic diseases and risk factors in northern Canadian populations and compares their prevalence to southern Canadian populations over time. METHODS: Canadian Community Health Survey (CCHS) cycle 1.1 (2000/01) and 3.1 (2005) data were used for the analyses. Respondents 20 years old or greater in the Yukon, Northwest Territories, and Nunavut comprised the northern Canadian sample. Respondents in the same age group in the rest of Canada comprised the southern Canadian sample. Unadjusted and adjusted weighted prevalence estimates and confidence intervals were calculated and tested for significance using z-tests. RESULTS: Northern Canadian respondents had significantly lower crude prevalence of self-reported hypertension, arthritis/rheumatism, diabetes, heart disease and stroke than southern Canadian respondents, although these associations did not remain significant after adjusting for age and sex. Northern Canadian respondents had significantly lower adjusted prevalence of any chronic disease. However, northern Canadian respondents had significantly higher adjusted prevalence of obesity and smoking than southern Canadian respondents at both time periods. The prevalence of any chronic disease increased significantly from 2000/01-2005 for both northern and southern Canadian respondents. DISCUSSION: The higher prevalence of key chronic disease risk factors in northern Canadian populations and the increasing prevalence for many chronic diseases in both southern and northern populations signal a need for continual monitoring of chronic diseases and the development of appropriate prevention and management strategies.

Dejhalla, M., P. Parton, et al. (2006). "Case report of Haddad syndrome in a newborn: congenital central hypoventilation syndrome and Hirschsprung's disease." JOURNAL OF PERINATOLOGY 26(4): 259-60.

Congenital central hypoventilation syndrome (CCHS) is a rare disorder characterized by failure of automatic control of breathing. Diagnosis is made by exclusion of other causes of hypoventilation. Genetic etiology is strongly suspected. Other autonomic nervous system dysfunctions, tumors of neural crest origin and Hirschsprung's disease are often found in affected children. Association with Hirschsprung's disease is known as Haddad syndrome. We present a newborn with respiratory distress since birth and Hirschprung's disease subsequently diagnosed with Haddad syndrome.

Deonna, T., W. Arczynska, et al. (1974). "Congenital failure of automatic ventilation (Ondine's curse). A case report." JOURNAL OF PEDIATRICS 84(5): 710-4.

Deonna, T., W. Arczynska, et al. (1974). "Letter: Congenital failure of automatic ventilation (Ondine's curse)." JOURNAL OF PEDIATRICS 85(5): 736.

Dhalla, S. and G. Poole (2009). "Determinants of condom use: results of the Canadian Community Health Survey 3.1." Canadian Journal of Public Health Revue Canadienne de Sante Publique. 100(4): 299-303.

OBJECTIVES: To examine the independent effects of mood disorder, age, race/ethnicity, personal income, being a current student, having a regular medical doctor and substance use in relationship to condom use at last intercourse in a Canadian population stratified by sex. METHODS: We used Cycle 3.1 of the 2006 Canadian Community Health Survey (CCHS 3.1), a population-based, voluntary, cross-sectional survey of subjects ages 12-85 years. Data collection took place between January and December 2005. From the survey, a study sample of 20,975 people was drawn, consisting of individuals providing valid responses (yes/no) to mood disorder and last-time condom use. The question of sexual behaviours was asked only of those ages 15-49 years. Logistic regression was used to examine individual variables as potential determinants of last-time condom use stratified by sex. RESULTS: The relationship between mood disorder and condom use was non-significant in both males (AOR = 0.85, 95% CI = 0.70-1.04) and females (AOR = 0.90, 95% CI = 0.78-1.03). Increasing age was found to be inversely associated with last-time condom use in both males and females. Male factors significantly associated with last-time condom use were being of white ethnicity (AOR = 0.71, 95% CI = 0.64-0.79) and being a current student (AOR = 1.28, 95% CI =1.16-1.42). Female factors associated with last-time condom use were being of white ethnicity (AOR = 0.71, 95% CI = 0.63-0.79) and being a former drinker (AOR = 2.25, 95% CI = 1.63-3.11). CONCLUSION: Our results identify important determinants of last-time condom use in both males and females in the CCHS 3.1. These findings may have important implications for the devising and implementation of safe sex programs in a Canadian population ages 15-49 years.