Literature search from ms 29/4/2010

Onimaru, H., K. Ikeda, et al. (2010). "Phox2b expressing neurons in the most rostral medulla of newborn rats." ADVANCES IN EXPERIMENTAL MEDICINE & BIOLOGY 669: 87-90.

Phox2b expressing cells in the parafacial region of the ventral medulla are proposed to play a role in central chemoreception and postnatal survival. We have showed that pre-inspiratory (Pre-I) neurons in the parafacial region (pFRG/Pre-I) in neonatal rats express Phox2b and are postsynaptically CO(2) sensitive. Recent evidence examining Phox2b expression established more clearly the cell architecture of the pFRG, and that Phox2b expression is the most noticeable characteristic of pFRG/Pre-I neurons. Here, we briefly review these recent findings. We also show a unique distribution of Phox2b expressing cells in the most rostral medulla, which could be an interesting target for neurophysiological analysis.

Or, S.-F. J., M.-f. T. Tong, et al. (2006). "PHOX2B mutations in three Chinese patients with congenital central hypoventilation syndrome." CHINESE MEDICAL JOURNAL 119(20): 1749-52.

Oren, J., D. H. Kelly, et al. (1987). "Long-term follow-up of children with congenital central hypoventilation syndrome." PEDIATRICS 80(3): 375-80.

The long-term clinical course of six patients with congenital central hypoventilation syndrome is described. During the neonatal period, the patients had prolonged apneas and hypoventilation, in the absence of cardiac, pulmonary, or neuromuscular disease. After an initial period of respirator dependency, they became able to sustain normal gas exchange while awake. During sleep, however, profound hypoventilation developed, and tracheostomy and mechanical ventilation were required. Ventilatory responses to hypercapnia and hypoxia were depressed or absent and did not improve with time. One patient was able, at 2 years of age, to breathe spontaneously during sleep with only moderate hypoventilation. The others, now 4 to 14 years of age, still need ventilatory support during sleep. Complications, such as cardiac failure and hypoxic seizures, mostly occurred early in the course and resolved with correction of insufficient mechanical ventilation. Speech acquisition was possible with the use of a special stoma plug. All patients were managed at home, and with appropriate support, the parents were able to provide safe ventilatory care with low morbidity and no mortality.
Oren, J., C. J. Newth, et al. (1986). "Ventilatory effects of almitrine bismesylate in congenital central hypoventilation syndrome." American Review of Respiratory Disease 134(5): 917-9.

Patients with congenital central hypoventilation syndrome (CCHS) lack hypercapnic and hypoxic stimulation of ventilation but have demonstrated carotid body function in response to hyperoxia and to pharmacological stimulation with doxapram. This study investigated the ventilatory effects of almitrine bismesylate, a carotid body stimulant, in 12 patients with CCHS. Measurements of minute ventilation, tidal volume (VT), respiratory rate (RR) and transcutaneous PO2 (TCPO2) were taken before and after administration of 4.5 mg/kg and 6 mg/kg of almitrine. Twenty-four hour pharmacokinetic studies were performed in 7 patients who received 4.5 mg/kg and in 6 patients who received 6 mg/kg almitrine. There was no significant improvement in ventilatory and gas exchange parameters at either dose of almitrine despite appropriate peak serum concentration of the drug at the time of the studies. These results suggest that almitrine is not a useful ventilatory stimulant in children with CCHS.

O'Sullivan, J., A. J. Cottrell, et al. (1993). "Ondine's curse and neurally mediated syncope--a new and important association." EUROPEAN HEART JOURNAL 14(9): 1289-91.

A 6-year-old boy with congenital central hypoventilation syndrome (Ondine's curse) presented with presyncope. Investigation revealed a diagnosis of neurally mediated syncope. This previously unreported association provides strong evidence that autonomic dysfunction is implicated in both these conditions.

Otabor, I. A., J. P. Balint, et al. (2009). "Myectomy-myotomy for long segment Hirschsprung's disease in a patient with Haddad syndrome." JOURNAL OF PEDIATRIC SURGERY 44(3): 620-2.

Hirschsprung's disease is a rare entity with an incidence of 1 in 5000 live born infants. Long segment Hirschsprung's disease occurs in approximately 5% to 10% of this patient population and is defined as a transition zone proximal to the sigmoid colon (Bodian M, Carter CO, Ward BC. Hirschsprung's disease. Lancet. 1951;1:302-309). The association of congenital central hypoventilation syndrome (also known as Ondine's curse) and Hirschsprung's disease is termed Haddad syndrome.

Ottonello, G., I. Ceccherini, et al. (2003). "Congenital and late onset central hypoventilation syndromes: Diagnostic pittfalls and therapeutic strategies." Italian Journal of Pediatrics 29(6): 433-436.

Three patients, two suffering from congenital central hypoventilation syndrome and one from late onset central hypoventilation are reported. In both conditions the diagnosis was based on exclusion of hypoventilation derived from either peripheral or central but not primitive causes and on polysomnographic evaluation. The three patients presented various degrees of hypoventilation severity requiring different respiratory supports. The difficulties encountered in arranging rapid and efficient discharge at home are discussed.

Ottonello, G., I. Ferrari, et al. (2007). "Home mechanical ventilation in children: retrospective survey of a pediatric population." Pediatrics International 49(6): 801-5.

BACKGROUND: Home care support is beneficial for children needing mechanical ventilation, when clinically stable. METHODS: A retrospective analysis was carried out of the long-term home ventilation management of a pediatric population with chronic respiratory failure composed of 20 ventilator-dependent children categorized according to age, diagnosis and ventilation support. Age groups consisted of 10% under 1 year, 30% between 2 and 5 years, 30% between 6 and 12 years, and 30% older than 12 years. Diagnostic categories included myopathic disorder, n = 5; congenital central hypoventilation syndrome, n = 6; chest wall disorder, n = 5; cystic fibrosis, n = 1; pulmonary hypertension, n = 1; and diaphragmatic paralysis, n = 2. RESULTS: Sixty-five percent were ventilated using non-invasive mode (NIMV): eight with nasal mask, five with full-face mask, and two children in NIMV also used negative pressure mode; 35% were ventilated using tracheostomy, one of them also used a diaphragmatic pacer. Seventy percent needed nocturnal ventilatory support, (20% 12-18 h, 10% full-day). A total of 18 children were included in the home care and follow-up program. Two children died: one because of worsening of his chronic disease and one because of septic shock. CONCLUSION: Although home care ventilation is not yet widely diffused, it represents a valid alternative to long hospitalization for children with stable chronic respiratory failure.

Ou-Yang, M.-C., S.-N. Yang, et al. (2007). "Concomitant existence of total bowel aganglionosis and congenital central hypoventilation syndrome in a neonate with PHOX2B gene mutation." JOURNAL OF PEDIATRIC SURGERY 42(2): e9-11.

Hirschsprung's disease (HSCR) is characterized by the absence of intramural ganglion cells in the distal gut, resulting in bowel obstruction shortly after birth. Congenital central hypoventilation syndrome (CCHS) results in hypoventilation, most pronounced during sleep, with relative insensitivity to hypercarbia and reduced insensitivity to hypoxia. Congenital central hypoventilation syndrome with HSCR is a rare condition with variable severity. Both CCHS and HSCR are uncommon and their co-occurrence may suggest a common etiology, probably involving a fault of neural crest development. Recent reports have identified the paired-like homeobox 2B (PHOX2B) gene as the major gene for CCHS and HSCR. We report here an identified PHOX2B gene in a newborn baby who had concurrence of CCHS and total colonic aganglionosis with proximal small bowel involvement. Management of this rare disorder is challenging not only because it presents in newborn stage but also because it has extensive HSCR. Considering the issue of medical futility, the therapeutic and ethical dilemma of this infant was discussed.

Ozawa, Y. and N. Okado (2002). "Alteration of serotonergic receptors in the brain stems of human patients with respiratory disorders." NEUROPEDIATRICS 33(3): 142-9.

We compared the developmental changes of 5-hydroxytryptamine (5-HT) 1 A and 5-HT2 A receptor immunoreactivity in the nuclei in relation to the cardiorespiratory or autonomic function in the human brain stem in sudden infant death syndrome (SIDS) and congenital central hypoventilation syndrome (CCHS) patients and age-matched controls by means of immunohistochemical methods. There were significant decreases in 5-HT1 A and 5-HT2 A receptor immunoreactivity in the dorsal nucleus of the vagus, solitary nucleus and ventrolateral medulla in the medulla oblongata, and significant increases in the periaqueductal gray matter (PAG) of the midbrain in SIDS victims, but there were no significant differences between those in CCHS patients and controls. The decreased immunoreactivity of the receptors in the medulla oblongata was accompanied by brain stem gliosis. Therefore, the decreases in the receptors may be secondary to chronic hypoxia or repeated ischemia, but may be causally related to some impairment of the developing cardiorespiratory neuronal system. As 5-HT1 A and 5-HT2 A receptors were the most abundant in the fetal period and then decreased with subsequent development, the increases in 5-HT1 A and 5-HT2 A receptor immunoreactivity in PAG may reflect delayed neuronal maturation, but may also reflect compensatory changes in response to hypofunctioning serotonergic neurons in the medulla oblongata in SIDS. There was no abnormal expression of 5-HT1 A and 5-HT2 A receptors in CCHS brain stems, and so the pathophysiology seems to be different between SIDS and CCHS patients.

Pabst, O., J. Rummelies, et al. (2003). "Targeted disruption of the homeobox gene Nkx2.9 reveals a role in development of the spinal accessory nerve." DEVELOPMENT 130(6): 1193-1202.

The homeodomain-containing transcription factor Nkx2.9 is expressed in the ventralmost neural progenitor domain of the neural tube together with the related protein Nkx2.2 during early mouse embryogenesis. Cells within this region give rise to V3 interneurons and visceral motoneurons in spinal cord and hindbrain, respectively. To investigate the role of the Nkx2.9 gene, we generated a mutant mouse by targeted gene disruption. Homozygous mutant animals lacking Nkx2.9 were viable and fertile with no apparent morphological or behavioral phenotype. The distribution of neuronal progenitor cells and differentiated neurons in spinal cord was unaffected in Nkx2.9-deficient animals. This finding is in contrast to Nkx2.2-null mutants, which have been shown to exhibit ventral to dorsal transformation of neuronal cell fates in spinal cord. Our results suggest that specification of V3 interneurons in the posterior CNS does not require Nkx2.9, most probably because of functional redundancy with the co-expressed Nkx2.2 protein. In hindbrain, however, absence of Nkx2.9 resulted in a significantly altered morphology of the spinal accessory nerve (XIth), which appeared considerably shorter and thinner than in wild-type animals. Consistent with this phenotype, immature branchial motoneurons of the spinal accessory nerve, which normally migrate from a ventromedial to a dorsolateral position within the neural tube, were markedly reduced in Nkx2.9-deficient embryos at E10.5, while ventromedial motor column cells were increased in numbers. In addition, the vagal and glossopharyngeal nerves appeared abnormal in approximately 50% of mutant embryos, which may be related to the observed reduction of Phox2b expression in the nucleus ambiguus of adult mutant mice. From these observations, we conclude that Nkx2.9 has a specific function in the hindbrain as determinant of the branchial motoneuron precursor cells for the spinal accessory nerve and possibly other nerves of the branchial-motor column. Like other Nkx genes expressed in the CNS, Nkx2.9 seems to be involved in converting positional information into cell fate decisions.

Pache, H. D., C. Forster, et al. (1978). "[Chronic central alveolar hypoventilation (Undine syndrome)]." MMW - Munchener Medizinische Wochenschrift 120(32-33): 1049-52.

Parodi, S., T. Bachetti, et al. (2008). "Parental origin and somatic mosaicism of PHOX2B mutations in Congenital Central Hypoventilation Syndrome." HUMAN MUTATION 29(1): 206.

Heterozygous polyalanine repeat expansions of PHOX2B have been associated with Congenital Central Hypoventilation Syndrome, a rare neurocristopathy characterized by absence of adequate control of respiration during sleep. Here we report a PHOX2B mutational screening in 63 CCHS patients, 58 of whom presenting with poly-A expansions or frameshift, missense and nonsense mutations. To assess a somatic or germline occurrence of poly-A length variations, the relative amounts of mutant and wild type alleles have been quantified in 20 selected CCHS patients presenting with an expansion, and in their parents. Somatic mosaicism was shown in four parents, while no mosaic was found among CCHS patients. Moreover, while co-segregation analysis of the PHOX2B poly-A expansions with selected marker alleles in the same 20 CCHS trios has not demonstrated any parent-of-origin effect of the mutations, it has provided further clues to clarify the molecular mechanism underlying the expansion occurrence. Finally, the segregation of PHOX2B poly-A anomalous tracts within family members has allowed us to exclude tendency of polymorphic variations towards expansion. This strengthens the notion that expanded polyalanine tracts, identified as frequent disease-causing mutations also in other human diseases, are mitotically and meiotically stable. Published 2007 Wiley-Liss, Inc.
Parodi, S., M. P. Baglietto, et al. (2008). "A novel missense mutation in the PHOX2B gene is associated with late onset central hypoventilation syndrome." PEDIATRIC PULMONOLOGY 43(10): 1036-9.

We report the case of a 15-month-old male suffering from Late Onset Congenital Central Hypoventilation Syndrome and recto-sigmoid Hirschsprung's disease, an association that has not been reported thus far. Nevertheless, our patient showed a missense mutation of the PHOX2B gene already known in isolated late onset central hypoventilation, resulting in a substitution of the Ala140 residue with a Glu residue (p.A140E). The present association of LO-CHS and HSCR in a patient harboring a rare and atypical PHOX2B mutation allows to refine the mutational spectrum of this disease and suggests individualized ventilatory care along with specific surgical and oncological approaches. (c) 2008 Wiley-Liss, Inc.

Paton, J. Y., S. Swaminathan, et al. (1993). "Ventilatory response to exercise in children with congenital central hypoventilation syndrome." American Review of Respiratory Disease 147(5): 1185-91.

The role of the central and peripheral chemoreceptors in the hyperpnea of exercise has been controversial. We studied five children, age 6 to 11 yr, with absent hypercapneic and hypoxic ventilatory responses during wakefulness (congenital central hypoventilation syndrome, CCHS). Each child performed an incremental treadmill exercise test. Maximal oxygen consumption (VO2) and minute ventilation (VE) at maximal exercise were lower than but not significantly different from these values in a group of nine normal control children of similar age, height, and weight (VO2/kg, 33.7 +/- 5.0 versus 45.4 +/- 2.9 ml/kg/min, mean +/- SEM, NS; VE 28.3 +/- 7.3 versus 43.8 +/- 3.9 L/min, NS). Oxygen tension and saturation fell and CO2 tension rose significantly at maximal exercise in CCHS but not in control subjects. In contrast to control subjects, CCHS subjects increased VE largely by increasing respiratory frequency (f) rather than tidal volume (VT). In the oldest child, submaximal exercise tests at 50% VO2, with varying pacing rate, showed a significant positive relation between pacing rate and f, but not VT. Thus, VE was higher at the faster pacing rate. Further incremental testing in the two oldest subjects with recording of the pacing rate showed positive linear relations between pacing frequency and breathing frequency and between pacing frequency and VE up to a maximum pacing rate of 48 to 50 paces per 15 s. VE beyond this level varied randomly around the maximum level. We conclude that exercise-induced hyperpnea can occur in the absence of chemoreceptor function. In the CCHS children, limb movement is an important determinant of the ventilatory response to exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Paton, J. Y., S. Swaminathan, et al. (1989). "Hypoxic and hypercapnic ventilatory responses in awake children with congenital central hypoventilation syndrome." American Review of Respiratory Disease 140(2): 368-72.

Congenital central hypoventilation syndrome (CCHS) has been thought to be a disorder of central chemoreceptor responsiveness. Previous studies in CCHS have shown decreased or absent ventilatory responsiveness to both hypercarbia and hypoxia. However, hypoxic responsiveness during wakefulness has not been systematically studied. We studied hypoxic and hypercapnic ventilatory responses during wakefulness in five children with CCHS (6 to 11 yr of age). To measure the hypercapnic response, the children rebreathed a hyperoxic hypercapnic mixture until PaCO2 reached 56 to 69 mm Hg. For the hypoxic response, the children rebreathed a hypoxic gas mixture, at mixed venous PCO2, until SaO2 had fallen to less than 78%. We found that the ventilatory responses to hypercapnia and hypoxia were very variable (linear correlation coefficients ranging from -0.44 to +0.63 for hypercapnic responses and from -0.15 to +0.77 for hypoxic responses), with no significant change from baseline in response to either stimulus. There was no evidence of progressive ventilatory stimulation despite increasing stimulus. Additionally, these children had no subjective sensation of dyspnea or discomfort. This establishes that hypoxic and hypercapnic ventilatory control is absent during wakefulness. Chemoreceptor control (peripheral and central) is, therefore, defective in all states in children with CCHS. We speculate that the defect in CCHS lies in central integration of the central and peripheral chemoreceptor signals.

Patten, S. B. (2004). "The impact of antidepressant treatment on population health: Synthesis of data from two national data sources in Canada." Population Health Metrics 2(9).

Background: In randomized, controlled trials, antidepressant medications have been shown to reduce the duration of major depressive episodes and to reduce the frequency of relapse during long-term treatment. The epidemiological impact of antidepressant use on episode duration and relapse frequency, however, has not been described. Methods: Data from two Canadian general health surveys were used in this analysis: the National Population Health Survey (NPHS) and the Canadian Community Health Survey (CCHS). The NPHS is a longitudinal study that collected data between 1994 and 2000. These longitudinal data allowed an approximation of episode incidence to be calculated. The cross-sectional CCHS allowed estimation of episode duration. The surveys used the same sampling frame and both incorporated a Short Form version of the Composite International Diagnostic Interview. Results: Episodes occurring in antidepressant users lasted longer than those in non-users. The apparent incidence of major depressive episodes among those taking antidepressants was higher than that among respondents not taking antidepressants. Changes in duration and incidence over the data collection interval were not observed. Conclusions: The most probable explanation for these results is confounding by indication and/or severity: members of the general population who are taking antidepressants probably have more highly recurrent and more severe mood disorders. In part, this may have been due to the use of a brief predictive diagnostic interview, which may be prone to detection of sub-clinical cases. Whereas antidepressant use increased considerably over the data-collection period, differences in episode incidence and duration over time were not observed. This suggests that the impact of antidepressant medications on population health may have been less than expected. copyright 2004 Patten; licensee BioMed Central Ltd.

Patten, S. B., C. A. Beck, et al. (2005). "Long-term medical conditions and major depression: strength of association for specific conditions in the general population." Canadian Journal of Psychiatry - Revue Canadienne de Psychiatrie 50(4): 195-202.

BACKGROUND: The prevalence of major depression (MD) in persons with nonpsychiatric medical conditions is an indicator of clinical need in those groups, an indicator of the feasibility of screening and case-finding efforts, and a source of etiologic hypotheses. This analysis explores the prevalence of MD in the general population in relation to various long-term medical conditions. METHODS: We used a dataset from a large-scale Canadian national health survey, the Canadian Community Health Survey (CCHS). The sample consisted of 115 071 subjects aged 18 years and over, randomly sampled from the Canadian population. The survey interview recorded self-reported diagnoses of various long-term medical conditions and employed a brief predictive interview for MD, the Composite International Diagnostic Interview Short Form for Major Depression. Logistic regression was used to adjust estimates of association for age and sex. RESULTS: The conditions most strongly associated with MD were chronic fatigue syndrome (adjusted odds ratio [AOR] 7.2) and fibromyalgia (AOR 3.4). The conditions least strongly associated were hypertension (AOR 1.2), diabetes, heart disease, and thyroid disease (AOR 1.4 in each case). We found associations with various gastrointestinal, neurologic, and respiratory conditions. CONCLUSIONS: A diverse set of long-term medical conditions are associated with MD, although previous studies might have lacked power to detect some of these associations. The strength of association in prevalence data, however, varies across specific conditions.

Patten, S. B., C. A. Beck, et al. (2003). "Major depression in multiple sclerosis: a population-based perspective." NEUROLOGY 61(11): 1524-7.

OBJECTIVE: To determine the prevalence of major depression in multiple sclerosis (MS) in a population-based sample controlling for nonspecific illness effects. METHODS: This study used data from a large-scale national survey conducted in Canada: the Canadian Community Health Survey (CCHS). The analysis included 115,071 CCHS subjects who were 18 years or older at the time of data collection. The CCHS interview obtained self-reported diagnoses of MS and employed a brief predictive interview for major depression: the Composite International Diagnostic Interview Short Form for Major Depression. The 12-month period prevalence of major depression was estimated in subjects with and without MS and with and without other long-term medical conditions. RESULTS: The prevalence of major depression was elevated in persons with MS relative to those without MS and those reporting other conditions. The association persisted after adjustment for age and sex (adjusted odds ratio = 2.3, 95% CI 1.6 to 3.3). Major depression prevalence in MS for those in the 18- to 45-year age range was high at 25.7% (95% CI 15.6 to 35.7). CONCLUSIONS: The prevalence of major depression in the population with MS is elevated. This elevation is not an artifact of selection bias and exceeds that associated with having one or more other long-term conditions.

Patten, S. B., J. L. Wang, et al. (2006). "Descriptive epidemiology of major depression in Canada." Canadian Journal of Psychiatry - Revue Canadienne de Psychiatrie 51(2): 84-90.

OBJECTIVE: The Canadian Community Health Survey: Mental Health and Well-Being (CCHS 1.2) is the first national study to use a full version of the Composite International Diagnostic Interview. For this reason, and because of its large sample size, the CCHS 1.2 is capable of providing the best currently available description of major depression epidemiology in Canada. Using the CCHS 1.2 data, our study aimed to describe the epidemiology of major depression in Canada. METHOD: All estimates used appropriate sampling weights and bootstrap variance estimation procedures. The analysis consisted of estimating proportions supplemented by logistic regression modelling. RESULTS: The lifetime prevalence of major depressive episode was 12.2%. Past-year episodes were reported by 4.8% of the sample; 1.8% reported an episode in the past 30 days. As expected, major depression was more common in women than in men, but the difference became smaller with advancing age. The peak annual prevalence occurred in the group aged 15 to 25 years. The prevalence of major depression was not related to level of education but was related to having a chronic medical condition, to unemployment, and to income. Married people had the lowest prevalence, but the effect of marital status changed with age. Logistic regression analysis suggested that the annual prevalence may increase with age in men who never married. CONCLUSIONS: The prevalence of major depression in the CCHS 1.2 was slightly lower than that reported in the US and comparable to pan-European estimates. The pattern of association with demographic and clinical variables, however, is broadly similar. An increasing prevalence with age in single (never-married) men was an unexpected finding.