Literature search from ms 29/4/2010

Manuel, D. G., J. J. Y. Lim, et al. (2007). "How many people have had a myocardial infarction? Prevalence estimated using historical hospital data." BMC Public Health 7: 174.

BACKGROUND: Health administrative data are increasingly used to examine disease occurrence. However, health administrative data are typically available for a limited number of years - posing challenges for estimating disease prevalence and incidence. The objective of this study is to estimate the prevalence of people previously hospitalized with an acute myocardial infarction (AMI) using 17 years of hospital data and to create a registry of people with myocardial infarction. METHODS: Myocardial infarction prevalence in Ontario 2004 was estimated using four methods: 1) observed hospital admissions from 1988 to 2004; 2) observed (1988 to 2004) and extrapolated unobserved events (prior to 1988) using a "back tracing" method using Poisson models; 3) DisMod incidence-prevalence-mortality model; 4) self-reported heart disease from the population-based Canadian Community Health Survey (CCHS) in 2000/2001. Individual respondents of the CCHS were individually linked to hospital discharge records to examine the agreement between self-report and hospital AMI admission. RESULTS: 170,061 Ontario residents who were alive on March 31, 2004, and over age 20 years survived an AMI hospital admission between 1988 to 2004 (cumulative incidence 1.8%). This estimate increased to 2.03% (95% CI 2.01 to 2.05) after adding extrapolated cases that likely occurred before 1988. The estimated prevalence appeared stable with 5 to 10 years of historic hospital data. All 17 years of data were needed to create a reasonably complete registry (90% of estimated prevalent cases). The estimated prevalence using both DisMod and self-reported "heart attack" was higher (2.5% and 2.7% respectively). There was poor agreement between self-reported "heart attack" and the likelihood of having an observed AMI admission (sensitivity = 63.5%, positive predictive value = 54.3%). CONCLUSION: Estimating myocardial infarction prevalence using a limited number of years of hospital data is feasible, and validity increases when unobserved events are added to observed events. The "back tracing" method is simple, reliable, and produces a myocardial infarction registry with high estimated "completeness" for jurisdictions with linked hospital data.

Manzanares, M., P. A. Trainor, et al. (1999). "The role of kreisler in segmentation during hindbrain development." DEVELOPMENTAL BIOLOGY 211(2): 220-237.

The mouse kreisler gene is expressed in rhombomeres (r) 5 and 6 during neural development and kreisler mutants have patterning defects in the hindbrain that are not fully understood. Here we analyzed this phenotype with a combination of genetic, molecular, and cellular marking techniques. Using Hox/lacZ transgenic mice as reporter lines and by analyzing Eph/ephrin expression, we have found that while r5 fails to form in these mice, r6 is present. This shows that kreisler has an early role in the formation of r5. We also observed patterning defects in r3 and r4 that are outside the normal domain of kreisler expression. In both heterozygous and homozygous kreisler embryos some r5 markers are induced in r3, suggesting that there is a partial change in r3 identity that is not dependent upon the loss of r5. To investigate the cellular character of r6 in kreisler embryos we performed heterotopic grafting experiments in the mouse hindbrain to monitor its mixing properties. Control experiments revealed that cells from even- or odd- numbered segments only mixed freely with themselves, but not with cells of opposite character. Transposition of cells from the r6 territory of kreisler mutants reveals that they adopt mature r6 characteristics, as they freely mix only with cells from even-numbered rhombomeres. Analysis of Phox2b expression shows that some aspects of later neurogenesis in r6 are altered, which may be associated with the additional roles of kreisler in regulating segmental identity. Together these results suggest that the formation of r6 has not been affected in kreisler mutants. This analysis has revealed phenotypic and mechanistic differences between kreisler and its zebrafish equivalent valentino. While valentino is believed to subdivide preexisting segmental units, in the mouse kreisler specifies a particular segment. The formation of r6 independent of r5 argues against a role of kreisler in prorhombomeric segmentation of the mouse hindbrain. We conclude that the mouse kreisler gene regulates multiple steps in segmental patterning involving both the formation of segments and their A-P identity.

Marazita, M. L., B. S. Maher, et al. (2001). "Genetic segregation analysis of autonomic nervous system dysfunction in families of probands with idiopathic congenital central hypoventilation syndrome." AMERICAN JOURNAL OF MEDICAL GENETICS 100(3): 229-36.

Idiopathic congenital central hypoventilation syndrome (CCHS) is a very rare syndrome with major respiratory complications. Hypothesizing that CCHS is the most severe manifestation of general autonomic nervous system dysfunction (ANSD), we applied a case-control family study design to investigate the genetics of ANSD. Fifty-two probands with CCHS were identified, as well as 52 age-, race-, and gender-matched controls. ANSD phenotypic features were characterized in the cases, controls, and their family members. Our earlier studies found that most ANSD symptoms were more likely in CCHS cases and their relatives than in controls and their relatives (P < 0.05). The goal of the current study was to determine if the familiality of ANSD was consistent with a genetic pattern. We performed major locus segregation analysis of ANSD utilizing regressive models. CCHS probands were assumed to be affected; controls and relatives were designated as affected if they had two or more relevant symptoms. The hypothesis of "no transmission and no familial effects" was rejected in both case and control families. Case families were consistent with transmission of a major effect; control families were not (the difference in the pattern of results was significant, P < 0.0001). In the total data set, the best-fitting model was codominant Mendelian inheritance of a major gene for ANSD. These case-control family studies support our hypothesis that CCHS is the most severe manifestation of a general ANSD, with a family pattern consistent with Mendelian transmission, and demonstrate the potential utility of the approach to studies of other, similarly intractable disorders. Copyright 2001 Wiley-Liss, Inc.

Marcus, C. L., D. B. Bautista, et al. (1991). "Hypercapneic arousal responses in children with congenital central hypoventilation syndrome." PEDIATRICS 88(5): 993-8.

Congenital central hypoventilation syndrome (CCHS, Ondine's curse) is generally thought to be due to insensitivity of the central chemoreceptors to carbon dioxide. Children with CCHS have absent ventilatory responses to both hypercapnea and hypoxia, suggesting either abnormal central and peripheral chemoreceptor function or abnormal central integration of chemoreceptor input. Because ventilatory and arousal responses to respiratory stimuli are distinct from each other, if children with CCHS have complete chemoreceptor dysfunction, one would predict that both ventilatory and arousal responses to respiratory stimuli would be abnormal. However, if they have abnormal central integration of chemoreceptor input for ventilation, they may still arouse to respiratory stimuli despite the absence of a ventilatory response. Hypercapneic arousal responses were tested in eight children with CCHS, aged 5.8 +/- 1.2 (SEM) years, and seven healthy control subjects, aged 4.4 +/- 1.1 years. Children were studied during sleep while normal ventilation was maintained using their home ventilators. Hypercapneic challenges were performed by rapidly increasing the inspired carbon dioxide tension to 60 mm Hg and maintaining this level until the child aroused or for a maximum of 3 minutes. Of children with CCHS, 87.5% aroused to hypercapnea, compared with 100% of control children. There was no significant difference in arousal between children with CCHS and normal control subjects. It is concluded that most children with CCHS arouse to hypercapnea, indicating the presence of some central chemoreceptor function. It is speculated that because these children do respond to hypercapnea, the most probable mechanism for CCHS is a brainstem lesion in the area where input from both chemoreceptors is integrated.

Marcus, C. L., M. T. Jansen, et al. (1991). "Medical and psychosocial outcome of children with congenital central hypoventilation syndrome." JOURNAL OF PEDIATRICS 119(6): 888-95.

We report the long-term medical and psychosocial outcome of 13 children with congenital central hypoventilation syndrome. One child (8%) died before initial hospital discharge. Of the remaining 12 children, 11 (92%) have been successfully cared for in their natural or foster parents' homes. Home ventilatory support was provided with positive-pressure ventilation, negative-pressure ventilation, or diaphragm pacers. After an initial lengthy hospitalization, children spent little time in the hospital. Severe medical complications were uncommon but included cor pulmonale (one child), poor growth (two children), and seizure disorder (three children). Most children functioned in the slow-learner range of mental processing, with a composite score (Kaufman Assessment Battery for Children) of 78 +/- 20 (SD); two were mentally retarded, and one functioned above the normal range. The children's care givers were assessed as having low levels of psychologic distress (Symptom Checklist 90--Revised) and good coping resources (Coping Resources Inventory) but a high level of marital discord. The children were able to attend school and partake in normal childhood activities. We conclude that with modern techniques for home ventilation, children with CCHS can have a good long-term medical and psychosocial outcome. We speculate that early diagnosis and the prevention of intermittent hypoxia will improve their physical and mental outcome.

Marcus, C. L., F. R. Livingston, et al. (1991). "Hypercapnic and hypoxic ventilatory responses in parents and siblings of children with congenital central hypoventilation syndrome." American Review of Respiratory Disease 144(1): 136-40.

Children with congenital central hypoventilation syndrome (CCHS) have abnormal ventilatory responses to metabolic stimuli. As there is a genetically determined component of chemoreceptor sensitivity, parents and siblings of children with CCHS may also have blunted ventilatory responses to hypercapnea and hypoxia. To test this, we studied hypercapnic ventilatory responses and hypoxic ventilatory responses in six mothers, four fathers, and five siblings (6 to 49 yr of age) of seven children with CCHS and compared them with 15 age- and sex-matched control subjects (5 to 47 yr of age). Pulmonary function tests were not different between relatives of children with CCHS and control subjects. To measure hypercapnic ventilatory responses, subjects rebreathed 5% CO2/95% O2 until PACO2 reached 60 to 70 mm Hg. To measure hypoxic ventilatory responses (L/min/% SaO2), subjects rebreathed 14% O2/7% CO2/balance N2 at mixed venous PCO2 until SaO2 fell to 75%. All tests were completed in less than 4 min. Instantaneous minute ventilation, mean inspiratory flow (tidal volume/inspiratory time), and respiratory timing (inspiratory timing/total respiratory cycle timing) were calculated on a breath-by-breath basis. Hypercapnic ventilatory responses were 1.97 +/- 0.32 L/min/mm Hg PACO2 in children with CCHS relatives and 2.23 +/- 0.23 L/min/mm Hg PACO2 in control subjects. Hypoxic ventilatory responses were -1.99 +/- 0.37 L/min/% SaO2 in the relatives and -1.54 +/- 0.25 L/min/% SaO2 in the control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Marin-Sanabria, E. A., N. Kobayashi, et al. (2006). "Snoring associated with Ondine's curse in a patient with brainstem glioma." Journal of Clinical Neuroscience 13(3): 370-3.

Ondine's curse is an uncommon type of sleep apnea syndrome characterized by failure of automatic respiration. We present an adult patient with brainstem glioma who presented with snoring and Ondine's curse as the only symptoms. CASE REPORT: A 52-year-old female was brought to the hospital by a fellow resident due to exceptionally loud snoring. During the hospitalization, Ondine's curse was diagnosed after monitoring using Apnomonitor 5 (Chest Co., Tokyo), a cheap, non-invasive respiratory monitoring procedure. MRI and MR spectroscopy revealed a brainstem glioma. After radiation therapy, clinical response was documented using repeat apnomonitoring. CONCLUSION: Exceptionally loud snoring in non-obese adult patients with sleep apnea may be an early feature of a brainstem space-occupying lesion. Overnight sleep respiratory evaluation and neuroimaging should be considered in such instances.

Maris, J. M. (2005). "The biologic basis for neuroblastoma heterogeneity and risk stratification." CURRENT OPINION IN PEDIATRICS 17(1): 7-13.

PURPOSE OF REVIEW: Neuroblastoma serves as the paradigm for the clinical utility of tumor-specific biologic data for prognostication. This review will describe the genetic and biologic basis for the diverse clinical phenotypes observed in neuroblastoma patients. It will also discuss the current approach to risk classification and how this may change in the future. RECENT FINDINGS: The biologic basis of neuroblastoma has come into clearer focus. PHOX2B is the first bona fide neuroblastoma predisposition gene identified, but is mutated in only a small subset of cases. Somatically acquired alterations at chromosome arms 3p and 11q are highly correlated with acquisition of metastases in the absence of MYCN amplification and may be useful as prognostic markers. The Children's Oncology Group risk classification system has been validated, with current emphasis on further refinement such as reevaluation of the age cutoff used to stratify therapy, and incorporation of additional molecular genetic markers is being studied prospectively. High-throughput genome scale analyses of neuroblastomas are further clarifying the genetic basis of this heterogeneous disease. SUMMARY: Neuroblastoma remains a significant challenge as high-risk patients are treated with intensive multimodal therapies but cure rates remain suboptimal. There is remarkable heterogeneity observed in tumor phenotype, ranging from spontaneous regression to relentless progression. There are literally dozens of clinical and biologic markers that have been proposed as being predictive of disease outcome, but large clinical correlative studies are sharpening the focus of which markers can be used by the clinician to optimize therapy for an individual patient. [References: 70]

Mark, J. D. and J. G. Brooks (1984). "Sleep-associated airway problems in children." PEDIATRIC CLINICS OF NORTH AMERICA 31(4): 907-918.

Airway problems during sleep are often difficult to document and may be overlooked if the child appears normal when awake. The primary and secondary symptoms of these disorders vary widely in children and may range from behavioral changes to hypoxemia with secondary right heart failure (cor pulmonale), pulmonary edema, and even death. Several of the most common and important sleep-associated airway problems are the topic of this review. Other sleep-related respiratory disorders in children, such as obesity hypoventilation syndrome, failure of autonomic ventilation (Ondine's curse), apnea of prematurity, apnea of infancy, and sudden infant death syndrome (SIDS), although important, will not be discussed.

Masumoto, K., T. Arima, et al. (2002). "Ondine's curse associated with Hirschsprung disease and ganglioneuroblastoma." Journal of Pediatric Gastroenterology & Nutrition 34(1): 83-6.

Masuyama, S., K. Hirata, et al. (1989). "'Ondine's curse': side effect of acetazolamide?" AMERICAN JOURNAL OF MEDICINE 86(5): 637.

Matera, I., T. Bachetti, et al. (2002). "Mutational analysis of the RNX gene in congenital central hypoventilation syndrome." AMERICAN JOURNAL OF MEDICAL GENETICS 113(2): 178-82.

Congenital central hypoventilation syndrome (CCHS) is a rare syndrome characterized by failure of autonomic respiratory control, often presenting with other dysfunctions of the autonomic nervous system. Segregation analysis suggested a complex model of inheritance with a major locus involved. Disruption of the Rnx gene, a member of the Hox11 family of homeobox genes, in embryonic stem cells produced mice showing a phenotype similar to CCHS. Based on this observation, we have carried out mutation screening of the RNX gene in a set of 13 patients affected with CCHS, 2 of whom showing association with Hirschsprung disease. Single-strand conformational polymorphism analysis and direct sequencing of the whole coding portion of the RNX gene and of 1,311 bp of 5' flanking region were performed. No sequence variant was identified, with the exception of a private nucleotide change at position -874 bp from the ATG codon in two siblings affected with isolated CCHS. A functional test, performed by using the luciferase gene reporter system, has not shown any significant difference in the activity of the promoter region carrying this latter nucleotide change with respect to the wild-type allele. We conclude that RNX, and presumably its expression, are not altered in our index cases of CCHS. Copyright 2002 Wiley-Liss, Inc.

Matera, I., T. Bachetti, et al. (2004). "PHOX2B mutations and polyalanine expansions correlate with the severity of the respiratory phenotype and associated symptoms in both congenital and late onset Central Hypoventilation syndrome." JOURNAL OF MEDICAL GENETICS 41(5): 373-80.

Mather, S. J. (1987). "Ondine's curse and the anaesthetist." ANAESTHESIA 42(4): 394-403.

The central hypoventilation syndrome (Ondine's curse) is reviewed and discussed with emphasis on the clinical features and treatment of the disorder. It is a rare syndrome, but the anaesthetist working in a paediatric centre or in intensive care should be aware of its existence since advice and assistance in management may be required. [References: 49]
Matschke, J. and R. Laas (2007). "Sudden death due to central alveolar hypoventilation syndrome (Ondine's curse) in a 39-year-old woman with heterotopia of the inferior olive." American Journal of Forensic Medicine & Pathology 28(2): 141-4.

Failure of automatic involuntary respiration with preservation of voluntary respiratory drive (Ondine's curse) is a rare occurrence which has been reported following a variety of morphologic lesions near respiratory centers in the lower brainstem. We report the case of a 39-year-old woman with a syndrome of fulminant respiratory failure with features of Ondine's curse in whom neuropathologic examination disclosed a preexisting malformation of the lower brainstem, as well as acute local subarachnoid bleeding. Mechanisms in the present case are discussed and a review of similar cases published so far is given. The necessity of sound investigation, including neuropathologic studies in cases of sudden unexplained death, is underlined.

McAfee, P. C., J. R. Cassidy, et al. (1991). "Fusion of the occiput to the upper cervical spine. A review of 37 cases." SPINE 16(10 Suppl): S490-4.

This is the first report of a large series of patients undergoing preoperative traction to reduce spinomedullary compression from cranial settling. In all cases, an attempt was made to reduce the malalignment with Gardner-Wells or halo traction before posterior fusion. One patient required an anterior retropharyngeal decompression of the odontoid performed as a one-stage procedure at the time of the posterior operation, and two required subsequent anterior transoral-transpharyngeal resection of the odontoid. From 1974 to 1989, 37 patients underwent posterior occipital cervical arthrodesis. All cases presented with neurologic deficit, and most had signs of brain stem compression, such as L'hermitte's sign or Ondine's curse. The most common cause of basilar impression was rheumatoid arthritis, neoplastic destruction, previously failed C1-C2 fusion, or Down's syndrome. Mean postoperative follow-up was 2 years and 10 months; the patients with less than 2 years' follow-up were followed until successful fusion. Eight of 9 patients with L'hermitte's sign or Ondine's curse and 10 of 12 patients with intractable occipital pain were relieved of their symptoms after reduction and triple-wire stabilization-fusion. Eighteen of 25 patients with long tract signs improved after surgery. Interestingly, 14 (93.3%) of 15 patients with myelopathy improved when successful preoperative reduction of their deformity occurred, whereas only 4 (40%) of 10 patients with fixed basilar impression improved (chi 2 = 8.57, P = .014). Symptoms such as Ondine's curse, L'hermitte's sign, intractable occipital headache, and myelopathy are usually relieved by skeletal traction and posterior fusion without need of an additional transmucosal anterior procedure.(ABSTRACT TRUNCATED AT 250 WORDS)

McConville, C., S. Reid, et al. (2006). "PHOX2B analysis in non-syndromic neuroblastoma cases shows novel mutations and genotype-phenotype associations." AMERICAN JOURNAL OF MEDICAL GENETICS Part A. 140(12): 1297-301.

Neuroblastoma (NB) is an embryonal tumor originating from neural crest cells and is one of the most common solid tumors of childhood. Recently, constitutional mutations in PHOX2B have been shown to confer an increased risk of NB. To date, mutations predisposing to neural crest tumors have been reported in 20 individuals from 16 families. These families included additional clinical features such as Hirschsprung (HSCR) disease or congenital central hypoventilation syndrome, either in the index case or relatives. The contribution of PHOX2B mutations to NB cases without additional features is unclear. To address this we sequenced PHOX2B in constitutional DNA from 86 individuals with non-syndromic NB (4 cases had a family history of NB). We identified two mutations, 600delC, a frameshift mutation in an individual with isolated, unifocal NB and G197D, a missense mutation that was present in a family with multiple individuals with NB but no evidence of autonomic dysfunction. These data demonstrate that PHOX2B mutations are a rare cause of non-syndromic NB. The mutations we identified are outside the domains typically mutated in PHOX2B syndromes. This provides further evidence that the underlying PHOX2B mutational mechanism influences tumor risk and suggests that the position of missense mutations may influence the resulting phenotype. Copyright 2006 Wiley-Liss, Inc.

McGaughey, D. M., Z. E. Stine, et al. (2009). "Asymmetrical distribution of non-conserved regulatory sequences at PHOX2B is reflected at the ENCODE loci and illuminates a possible genome-wide trend." BMC Genomics 10: 8.

BACKGROUND: Transcriptional regulatory elements are central to development and interspecific phenotypic variation. Current regulatory element prediction tools rely heavily upon conservation for prediction of putative elements. Recent in vitro observations from the ENCODE project combined with in vivo analyses at the zebrafish phox2b locus suggests that a significant fraction of regulatory elements may fall below commonly applied metrics of conservation. We propose to explore these observations in vivo at the human PHOX2B locus, and also evaluate the potential evidence for genome-wide applicability of these observations through a novel analysis of extant data. RESULTS: Transposon-based transgenic analysis utilizing a tiling path proximal to human PHOX2B in zebrafish recapitulates the observations at the zebrafish phox2b locus of both conserved and non-conserved regulatory elements. Analysis of human sequences conserved with previously identified zebrafish phox2b regulatory elements demonstrates that the orthologous sequences exhibit overlapping regulatory control. Additionally, analysis of non-conserved sequences scattered over 135 kb 5' to PHOX2B, provides evidence of non-conserved regulatory elements positively biased with close proximity to the gene. Furthermore, we provide a novel analysis of data from the ENCODE project, finding a non-uniform distribution of regulatory elements consistent with our in vivo observations at PHOX2B. These observations remain largely unchanged when one accounts for the sequence repeat content of the assayed intervals, when the intervals are sub-classified by biological role (developmental versus non-developmental), or by gene density (gene desert versus non-gene desert). CONCLUSION: While regulatory elements frequently display evidence of evolutionary conservation, a fraction appears to be undetected by current metrics of conservation. In vivo observations at the PHOX2B locus, supported by our analyses of in vitro data from the ENCODE project, suggest that the risk of excluding non-conserved sequences in a search for regulatory elements may decrease as distance from the gene increases. Our data combined with the ENCODE data suggests that this may represent a genome wide trend.