Literature search from ms 29/4/2010

Gaultier, C., S. Dauger, et al. (2003). "Genes modulating chemical breathing control: lessons from mutant animals." Respiratory Physiology & Neurobiology 136(2-3): 105-14.

Genetic factors influence breathing control. Respiratory phenotypes of mutant mice may help to better understand these factors. Congenital central hypoventilation syndrome (CCHS) is a rare disorder defined as failure of chemical control of breathing causing central alveolar hypoventilation, especially during sleep. A genetic basis for CCHS is supported by several arguments, mainly the identification, in a few CCHS patients, of heterozygous mutations of genes contributing to neural crest cell development, namely, genes involved in the endothelin and c-ret pathways. Furthermore, plethysmography studies of the respiratory phenotypes of newborn heterozygous mutant mice have shown that genes in both pathways are involved in breathing control at birth. Nevertheless, no single gene mutation in newborn mice reproduces the human CCHS phenotype. Avenues for future research into the genetics of CCHS include (i) testing of mutant newborn mice for genes in other pathways and (ii) use of microarrays to identify gene clusters that should be associated with abnormal chemical breathing control. [References: 64]

Gaultier, C. and J. Gallego (2005). "Development of respiratory control: evolving concepts and perspectives." Respiratory Physiology & Neurobiology 149(1-3): 3-15.

The mechanisms underlying respiratory system immaturity in newborns have been investigated, both in vivo and in vitro, in humans and in animals. Immaturity affects breathing rhythmicity and its modulation by suprapontine influences and by afferents from central and peripheral chemoreceptors. Recent research has moved from bedside tools to sophisticated technologies, bringing new insights into the plasticity and genetics of respiratory control development. Genetic research has benefited from investigations of newborn mice having targeted deletions of genes involved in respiratory control. Genetic variability may govern the normal programming of development and the processes underlying adaptation to homeostasis disturbances induced by prenatal and postnatal insults. Studies of plasticity have emphasized the role of neurotrophic factors. Improvements in our understanding of the mechanistic effects of these factors should lead to new neuroprotective strategies for infants at risk for early respiratory control disturbances, such as apnoeas of prematurity, sudden infant death syndrome and congenital central hypoventilation syndrome. [References: 92]

Gaultier, C. and J. Gallego (2008). "Neural control of breathing: insights from genetic mouse models." JOURNAL OF APPLIED PHYSIOLOGY 104(5): 1522-30.

Recent studies described the in vivo ventilatory phenotype of mutant newborn mice with targeted deletions of genes involved in the organization and development of the respiratory-neuron network. Whole body flow barometric plethysmography is the noninvasive method of choice for studying unrestrained newborn mice. Breathing-pattern abnormalities with apneas occur in mutant newborn mice that lack genes involved in the development and modulation of rhythmogenesis. Studies of deficits in ventilatory responses to hypercapnia and/or hypoxia helped to identify genes involved in chemosensitivity to oxygen and carbon dioxide. Combined studies in mutant newborn mice and in humans have shed light on the pathogenesis of genetically determined respiratory-control abnormalities such as congenital central hypoventilation syndrome, Rett syndrome, and Prader-Willi syndrome. The development of mouse models has opened up the field of research into new treatments for respiratory-control disorders in humans. [References: 88]

Gaultier, C., M. Simonneau, et al. (2003). "Genetics and respiratory control: Studies in normal humans and genetically modified animals. [French]." REVUE DES MALADIES RESPIRATOIRES 20(1 I): 77-94.

Introduction: Studies into the contribution of genetic factors to respiratory control disorders are scarce, with impediments to their conduct including difficulties in characterizing these disorders, the large number of genes involved in respiratory control, and interactions between genetic and environmental factors. State of the art: The rare congenital central hypoventilation syndrome (CCHS) has opened up the field of respiratory control genetics. Heterozygous mutations of genes involved in neural crest development were discovered recently. Studies in mutant mice have identified respiratory control disturbances related to loss of function of genes involved in neural crest development, genes encoding transcription factors, diffusible factors, and proteins contributing to neurotransmission. Perspectives: Future genetic epidemiological studies in humans and new models of mutant mice should describe genes involved in respiratory control. Better knowledge of CCHS genetics should provide guideposts for investigating the genetics of other respiratory control disorders. Conclusions: Respiratory control genetics is opening up new paths for research into respiratory physiology and pathophysiology.

Gaultier, C., H. Trang, et al. (2005). "Pediatric disorders with autonomic dysfunction: what role for PHOX2B?" PEDIATRIC RESEARCH 58(1): 1-6.

Hirschsprung disease, neuroblastomas, and congenital central hypoventilation syndrome can occur in combination, and familial cases have been reported in all three conditions. This suggests variable expression of a single genetic abnormality as the common cause to these neural crest disorders. Because the PHOX2B gene is pivotal in the development of most relays of the autonomic nervous system, including all autonomic neural crest derivatives, it was considered a candidate gene for the above conditions. Recent studies have shown that 1) PHOX2B is the main disease-causing gene for congenital central hypoventilation syndrome, an autosomal dominant disorder with incomplete penetrance; 2) PHOX2B is the first gene for which germline mutations have been demonstrated to predispose to neuroblastoma; and 3) Hirschsprung disease was associated with an intronic single-nucleotide polymorphism of the PHOX2B gene in a case-control study. For clarifying the variable clinical expression of the autonomic nervous system dysfunction observed in neural crest disorders, international databases of clinical symptoms and molecular test results should be established. Furthermore, the development of genetic mouse models should help to improve our understanding of the molecular mechanisms underlying neural crest disorders. [References: 55]

Gaultier, C., H. Trang-Pham, et al. (1997). "Cardiorespiratory control during sleep in the congenital central hypoventilation syndrome." PEDIATRIC PULMONOLOGY 23(2): 140-142.

Geerling, J. C., P. C. Chimenti, et al. (2008). "Phox2b expression in the aldosterone-sensitive HSD2 neurons of the NTS." BRAIN RESEARCH 1226(C): 82-88.

The transcription factor Phox2b is necessary for the development of the nucleus of the solitary tract (NTS). In this brainstem nucleus, Phox2b is expressed exclusively within a subpopulation of glutamatergic neurons. The present experiments in the adult rat were designed to test whether this subpopulation includes the aldosterone-sensitive NTS neurons, which express the enzyme 11-beta-hydroxysteroid dehydrogenase type 2 (HSD2). Nuclear Phox2b was found in virtually all the HSD2 neurons (95-99%, n = 6 cases). Unlike the activity-related transcription factor c-Fos, Phox2b expression in the HSD2 neurons was not influenced by dietary sodium deprivation. The ubiquitous expression of Phox2b by the HSD2 neurons suggests that they are developmentally related to other Phox2b-dependent neurons of the NTS and that they release the excitatory neurotransmitter glutamate. This finding also suggests that human Phox2b mutations, which cause the central congenital hypoventilation syndrome (CCHS, also known as Ondine's curse), may also produce deficits in central aldosterone signaling and appetitive or autonomic responses to sodium deficiency. copyright 2008 Elsevier B.V. All rights reserved.
Geisen, M. J., T. Di Meglio, et al. (2008). "Hox paralog group 2 genes control the migration of mouse pontine neurons through slit-Robo signaling." PLoS Biology 6(6): 1178-1194.

The pontine neurons (PN) represent a major source of mossy fiber projections to the cerebellum. During mouse hindbrain development, PN migrate tangentially and sequentially along both the anteroposterior (AP) and dorsoventral (DV) axes. Unlike DV migration, which is controlled by the Netrin-1/Dcc attractive pathway, little is known about the molecular mechanisms guiding PN migration along the AP axis. Here, we show that Hoxa2 and Hoxb2 are required both intrinsically and extrinsically to maintain normal AP migration of subsets of PN, by preventing their premature ventral attraction towards the midline. Moreover, the migration defects observed in Hoxa2 and Hoxb2 mutant mice were phenocopied in compound Robo1;Robo2, Slit1;Slit2, and Robo2;Slit2 knockout animals, indicating that these guidance molecules act downstream of Hox genes to control PN migration. Indeed, using chromatin immunoprecipitation assays, we further demonstrated that Robo2 is a direct target of Hoxa2 in vivo and that maintenance of high Robo and Slit expression levels was impaired in Hoxa2 mutant mice. Lastly, the analysis of Phox2b-deficient mice indicated that the facial motor nucleus is a major Slit signaling source required to prevent premature ventral migration of PN. These findings provide novel insights into the molecular control of neuronal migration from transcription factor to regulation of guidance receptor and ligand expression. Specifically, they address the question of how exposure to multiple guidance cues along the AP and DV axes is regulated at the transcriptional level and in turn translated into stereotyped migratory responses during tangential migration of neurons in the developing mammalian brain. copyright 2008 Geisen et al.

Gerardy, R. and W. Gerardy (1984). "Observations on ECG, EEG and respiration in cases of chronic alveolar hypoventilation with normal respiratory tract. [German]." Therapiewoche 34(47): 6702-6710.

Within 17 years we examined 30 patients with a Pickwick syndrome and 13 patients with an Undine syndrome. The polygraphic conductions with synchronic discription of the EEG, ECG and respiration on awake and sleeping patients show characteristic variations that permit correct diagnosis. Pathophysiological courses of both illnesses are discussed. Whereas the causal factor concerning the Pickwick syndrome is the extreme obesity primary cerebral damage must be assumed in the Undine syndrome.

Gestreau, C., D. Heitzmann, et al. (2010). "Task2 potassium channels set central respiratory CO2 and O2 sensitivity." PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 107(5): 2325-30.

Task2 K(+) channel expression in the central nervous system is surprisingly restricted to a few brainstem nuclei, including the retrotrapezoid (RTN) region. All Task2-positive RTN neurons were lost in mice bearing a Phox2b mutation that causes the human congenital central hypoventilation syndrome. In plethysmography, Task2(-/-) mice showed disturbed chemosensory function with hypersensitivity to low CO(2) concentrations, leading to hyperventilation. Task2 probably is needed to stabilize the membrane potential of chemoreceptive cells. In addition, Task2(-/-) mice lost the long-term hypoxia-induced respiratory decrease whereas the acute carotid-body-mediated increase was maintained. The lack of anoxia-induced respiratory depression in the isolated brainstem-spinal cord preparation suggested a central origin of the phenotype. Task2 activation by reactive oxygen species generated during hypoxia could silence RTN neurons, thus contributing to respiratory depression. These data identify Task2 as a determinant of central O(2) chemoreception and demonstrate that this phenomenon is due to the activity of a small number of neurons located at the ventral medullary surface.

Giangaspero, F., M. Schiavina, et al. (1988). "Failure of automatic control of ventilation (Ondine's curse) associated with viral encephalitis of the brainstem: a clinicopathologic study of one case." CLINICAL NEUROPATHOLOGY 7(5): 234-7.

A case of Ondine's curse associated with hypothalamic dysfunction in an 8-year-old boy is described. The neuropathological examination revealed a viral encephalitis affecting the hypothalamus and the brainstem. In the medulla the inflammatory process involved the reticular formation and the nuclei considered to control automatic respiration such as the dorsal motor nucleus of the vagus, the nucleus tractus solitarii and the nucleus ambiguous. Although Ondine's curse following viral infection of the central nervous system has been previously reported this represents the first case of viral encephalitis to be pathologically documentated.

Ginn, K. A., R. D. Herbert, et al. (1997). "A randomized, controlled clinical trial of a treatment for shoulder pain." PHYSICAL THERAPY(8): 802-9; discussion 810-1.

BACKGROUND AND PURPOSE: The aim of this study was to evaluate the efficacy of a physical therapy approach to the treatment of shoulder pain. Subjects. Sixty-six volunteers with shoulder pain believed to be of local mechanical origin were randomly allocated to either a treatment group or a control group. METHODS: Subjects in the treatment group received 1 month of physical therapy aimed at restoring function of their shoulder muscles. Subjects in the control group received no treatment. Outcome measurements of pain intensity, range of motion (ROM), isometric muscle force, functional impairment, and self-perception of improvement were obtained by blinded assessment. RESULTS: Subjects in the treatment group showed improvement in pain-free abduction and flexion ROM, functional impairment, and self-perception of improvement. The control group deteriorated slightly over the experimental period in ROM and functional impairment measures. CONCLUSION AND DISCUSSION: These results suggest that the physical therapy approach used in this study is effective in improving shoulder function in subjects experiencing pain of mechanical origin. The results also provide little evidence of spontaneous recovery over a 1-month period.

Giroud, M., R. Flandrois, et al. (1974). "[Primary alveolar hypoventilation, Ondine's curse. New aspects of functional exploration. Study of ventilatory regulation and disorders of wakefulness]." Poumon et le Coeur 30(2): 101-8.

Glas, J., J. Seiderer, et al. (2009). "rs224136 on chromosome 10q21.1 and variants in PHOX2B, NCF4, and FAM92B are not major genetic risk factors for susceptibility to Crohn's disease in the German population." AMERICAN JOURNAL OF GASTROENTEROLOGY 104(3): 665-72.

OBJECTIVES: Recently, a North American genome-wide association study identified three novel gene variants in PHOX2B, NCF4, and FAM92B as well as one single nucleotide polymorphisms (SNP; rs224136) in the intergenic region on chromosome 10q21.1 as being associated with Crohn's disease (CD). However, their influence on European CD patients as well as ulcerative colitis (UC) is unknown. Therefore we aimed to replicate these novel CD susceptibility variants in a large European cohort with inflammatory bowel disease and analyzed potential gene-gene interactions with variants in the NOD2/CARD15, IL23R, and ATG16L1 genes. METHODS: Genomic DNA from 2,833 Caucasian individuals including 854 patients with CD, 476 patients with UC, and 1,503 healthy unrelated controls was analyzed for SNPs in PHOX2B (rs16853571), NCF4 (rs4821544), and FAM92B (rs8050910), including rs224136 on chromosome 10q21.1. RESULTS: In our study population, no association of PHOX2B (P=0.563), NCF4 (P=0.506), FAM92B (P=0.401), and rs224136 (P=0.363) with CD was found. Similarly, none of these SNPs was associated with UC. In contrast, all analyzed SNPs in NOD2/CARD15, IL23R, and ATG16L1 were strongly associated with CD with P values ranging from 5.0x10(-3) to 1.6x10(-22), but there was no epistasis with polymorphisms in PHOX2B, NCF4, FAM92B, and rs224136. CONCLUSIONS: In contrast to the North American population, PHOX2B, NCF4, FAM92B, and rs224136 are not associated with CD in the European population, whereas NOD2/CARD15, IL23R, and ATG16L1 are strongly associated with CD in both the North American and European populations, confirming these three genes as major CD susceptibility genes in Caucasian populations.
Glazier, R. H., M. M. Agha, et al. (2009). "Universal health insurance and equity in primary care and specialist office visits: a population-based study." ANNALS OF FAMILY MEDICINE 7(5): 396-405.

PURPOSE: Universal coverage of physician services should serve to reduce socioeconomic disparities in care, but the degree to which a reduction occurs is unclear. We examined equity in use of physician services in Ontario, Canada, after controlling for health status using both self-reported and diagnosis-based measures. METHODS: Ontario respondents to the 2000-2001 Canadian Community Health Survey (CCHS) were linked with physician claim files in 2002-2003 and 2003-2004. Educational attainment and income were based on self-report. The CCHS was used for self-reported health status and Johns Hopkins Adjusted Clinical Groups was used for diagnosis-based health status. RESULTS: After adjustment, higher education was not associated with at least 1 primary care visit (odds ratio [OR] = 1.05; 95% confidence interval [CI], 0.87-1.24), but it was inversely associated with frequent visits (OR = 0.77; 95% CI, 0.65-0.88). Higher education was directly associated with at least 1 specialist visit (OR = 1.20; 95% CI, 1.07-1.34), with frequent specialist visits (OR = 1.21; 95% CI, 1.03-1.39), and with bypassing primary care to reach specialists (OR = 1.23, 95% CI 1.02-1.44). The largest inequities by education were found for dermatology and ophthalmology. Income was not independently associated with inequities in physician contact or frequency of visits. CONCLUSIONS: After adjusting for health status, we found equity in contact with primary care for educational attainment but inequity in specialist contact, frequent visits, and bypassing primary care. In this setting, universal health insurance appears to be successful in achieving income equity in physician visits. This strategy alone does not eliminate education-related gradients in specialist care.

Godtfredsen, N. S., P. Lange, et al. (2001). "Changes in smoking habits and risk of asthma: a longitudinal population based study." EUROPEAN RESPIRATORY JOURNAL 18(3): 549-54.

A common statement from exsmokers is that symptoms of asthma develop shortly after smoking cessation. This study, therefore, investigated the relationship between smoking cessation and development of asthma in a large cohort from the Copenhagen City Heart Study (CCHS). The CCHS is a longitudinal, epidemiological study of the general population from the capital of Denmark, conducted between 1976 and 1994. The study population involved the 10,200 subjects who provided information on self-reported asthma and smoking habits from the first two examinations (baseline and 5-yr follow-up), and the 6,814 subjects who also attended the third and last examination (10-yr follow-up). The point-prevalence of smoking cessation as well as the asthma incidence between examinations was estimated, and a multivariate logistic regression model was used to examine the relationship between changes in smoking habits and development of asthma. During the study period, asthma incidence increased from 1.2-4.2%. Between examinations 1,316 subjects quit smoking. Smoking cessation between examinations was significantly related to reported asthma at follow-up. With never-smokers as the reference group and following adjustment for sex, age, chronic bronchitis, level of forced expiratory volume in one second and pack-yrs of smoking, the odds ratio (OR) for developing asthma when quitting smoking between examinations was 3.9 (95% confidence interval (CI) 1.8-8.2) from baseline to first follow-up and 3.1 (95% CI 1.9-5.1) from first to second follow-up. Continuing smoking also increased the risk of asthma significantly (OR 2.6 and 2.0, respectively). The results indicate that exsmokers have a higher incidence of self-reported asthma than never-smokers. It is likely that subjects perceive chronic obstructive pulmonary disease as asthma, hence the relationship between smoking cessation and asthma might be due to misclassification rather than causality.

Godtfredsen, N. S., E. Prescott, et al. (2006). "Smoking reduction and biomarkers in two longitudinal studies." ADDICTION 101(10): 1516-22.

AIMS: To measure reduction in exposure to smoke in two population-based studies of self-reported smoking reduction not using nicotine replacement. DESIGN: Cross-sectional analyses of biomarkers and smoking. SETTING: Data from two time-points in the Copenhagen City Heart Study (CCHS), 1981/83 and 1991/94, and the Copenhagen Male Study (CMS) in 1976 and 1985/86, respectively. PARTICIPANTS: There were 3026 adults who were smokers at both time-points in the CCHS and 1319 men smoking at both time-points in the CMS. MEASUREMENTS: Smoking status and tobacco consumption were assessed by self-completion questionnaire. Measurements of biomarkers of smoke intake were taken at the second time-point in the two studies: expired-air carbon monoxide (CO) in the CCHS and serum cotinine in the CMS. Biomarker levels in medium (15-29 g tobacco/day) and heavy (> 30 g/day) smokers at the first time-point who later reported a reduction in cigarettes per day of 50% or more without quitting were compared with continuing medium, heavy and light smokers (1-14 g/day) using linear regression. Sex (CCHS only), age, self-reported inhalation of smoke, duration of smoking, type of tobacco and amount smoked were included as covariates in multivariate models. FINDINGS: Heavy smokers who reduced did not show lower levels of biomarkers at follow-up. Medium smokers who reduced showed a reduction in cotinine but not CO. The reduction in cotinine was not commensurate with the reported reduction in consumption. CONCLUSIONS: Long-term reductions in self-reported tobacco smoking are probably associated with, at best, modest reductions in smoke exposure.

Goldberg, D. S. and I. H. Ludwig (1996). "Congenital central hypoventilation syndrome: ocular findings in 37 children." Journal of Pediatric Ophthalmology & Strabismus 33(3): 175-80.

BACKGROUND: Congenital central hypoventilation syndrome (CCHS) is a rare cause of central sleep apnea. Although ophthalmic abnormalities have been reported, the ocular findings have not been discussed in detail. METHODS: We examined or obtained the records of 37 children with CCHS. RESULTS: Twenty-seven patients were found to have abnormal pupils, most of which were miotic and reacted poorly to light. In 18 cases, the anterior surface of the iris was unusually smooth. Ten of the children with abnormal pupils also demonstrated light-near dissociation. Twenty had strabismus of various types, and 18 showed evidence of convergence insufficiency. CONCLUSIONS: The high incidence of strabismus, pupillary abnormalities, and convergence insufficiency may be a result of neurologic defects in the midbrain.

Goldberg, D. S. and I. H. Ludwig (1997). "Ocular signs in children with congenital central hypoventilation syndrome." PEDIATRIC PULMONOLOGY 23(2): 150-151.

Gootman, P. M. and M. I. Cohen (1981). "Sympathetic rhythms in spinal cats." JOURNAL OF THE AUTONOMIC NERVOUS SYSTEM 3(2-4): 379-387.

Simultaneous recordings from preganglionic sympathetic nerves at different spinal levels, cervical sympathetic and greater splanchnic, reveal the presence of common periodicities as shown by cross-correlation and power spectral analysis; the major types of periodicities are cardiac, respiratory and 10/sec rhythm. These common periodicities could be explained in two ways: there are common periodic inputs to the two types of preganglionic neurons; and there are feedback connections in the spinal cord between the two groups of neurons. To distinguish between these two possibilities, spinal cord transections at C2-C3 were performed on decerebrate unanesthetized cats; recordings were then taken at hourly intervals for more than 12 h, during which time activity gradually increased but still remained small compared to pre-section levels. This low level activity showed no sign of periodicity. Asphyxia of sufficient duration produced increased activity in sympathetic nerves. Splanchnic activity during asphyxia had 2-3/sec oscillations; but the cross-correlation histograms (CCHs) of cervical sympathetic and splanchnic activity were almost flat. Strychnine excited spinal cord neurons more effectively than asphyxia; the CCHs showed locking of activity in phrenic, cervical sympathetic and splanchnic nerves on a slow time-scale (1-5 sec), but not appreciable locking of cervical sympathetic and splanchnic activity on a faster time-scale (100-500 msec) such as occurs in the intact animal. Thus, while there can be oscillation of sympathetic activity at the spinal cord level, the normally occurring synchrony of oscillations between different segmental levels is dependent on inputs from the brain stem.