Rituximab, methotrexate, procarbazine, vincristine and intensified cytarabine consolidation for primary central nervous system lymphoma (PCNSL) in the elderly: a LOC network study.

Primary CNS lymphoma (PCNSL) is chemosensitive to high-dose methotrexate-based chemotherapy. However, responses in the elderly are short-lasting and outcome is poor. Given that radiotherapy and intensive chemotherapy expose elderly to severe toxicities, alternative consolidation approaches need to be evaluated. In this multicenter study, we retrospectively analyzed consecutive patients with newly-diagnosed PCNSL, aged >60, treated with a (R)-MPV-AAA regimen. The regimen consisted of three 28-day cycles of methotrexate (3.5 g/m2 D1, D15), procarbazine, vincristine, followed by three 28-day cycles of cytarabine consolidation (3 g/m2 D1-2). Addition of rituximab (375 mg/m2 D1) was optional. The results were compared with the historical MPV-A regimen. Ninety patients received the (R)-MPV-AAA regimen with (n = 39) or without (n = 51) rituximab. Median age was 68 and median KPS 60. 55% of patients achieved a complete response, 8% a partial response and 37% progressed. The median PFS was 10 months, the median OS 28.1 months. Toxicity was mainly hematological, with 54 and 51% of grade III-IV neutropenia and thrombopenia. The response rate was higher in patients receiving rituximab (77 vs. 53%; p = 0.03), whereas no difference was observed in terms of PFS or OS. When comparing the results to the historical MPV-A, there was no difference in terms of response rate, PFS or OS, but a higher rate of hematotoxicity. This study suggests that extending cytarabine consolidation after methotrexate-based chemotherapy does not improve the MPV-A efficacy but increases toxicity in the elderly. The addition of rituximab may improve the response rate, but its impact on final outcome remains unclear.

Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS or Ondine's curse; OMIM 209880) is a life-threatening disorder involving an impaired ventilatory response to hypercarbia and hypoxemia. This core phenotype is associated with lower-penetrance anomalies of the autonomic nervous system (ANS) including Hirschsprung disease and tumors of neural-crest derivatives such as ganglioneuromas and neuroblastomas. In mice, the development of ANS reflex circuits is dependent on the paired-like homeobox gene Phox2b. Thus, we regarded its human ortholog, PHOX2B, as a candidate gene in CCHS. We found heterozygous de novo mutations in PHOX2B in 18 of 29 individuals with CCHS. Most mutations consisted of 5-9 alanine expansions within a 20-residue polyalanine tract probably resulting from non-homologous recombination. We show that PHOX2B is expressed in both the central and the peripheral ANS during human embryonic development. Our data support an essential role of PHOX2B in the normal patterning of the autonomous ventilation system and, more generally, of the ANS in humans.

Early use of high efficacy therapies in pediatric forms of relapsing-remitting multiple sclerosis: A real-life observational study.

BACKGROUND: Pediatric forms of multiple sclerosis are more active than those in adults. Yet, the effectiveness of different therapeutic approaches is not well studied in this population. Our objective was to compare the effectiveness of the early use of high efficacy therapies (HETs) with the effectiveness of moderate efficacy therapies (METs) in children with MS. METHODS: This observational study included patients diagnosed with pediatric MS, at 4 hospital centers in France, during a 10-year period. METs included: interferon ß-1a, glatiramer acetate, dimethyl fumarate, teriflunomide; HETs included: fingolimod, natalizumab, ocrelizumab, alemtuzumab. The primary endpoint was the occurrence of a new relapse, the secondary endpoint was EDSS worsening. RESULTS: Sixty-four patients were included in the analysis (80% women; mean age 15.5 years, 81% treated with MET) with a median follow-up of 22.5 months. At baseline, 52 patients were on MET (interferon ß-1a, glatiramer acetate, dimethyl fumarate, teriflunomide) and 12 patients were on HET (natalizumab, ocrelizumab). The cumulative probability of being relapse-free at 6.5 years was 23.3% on MET, vs 90.9% on HET (p = 0.013). The cumulative probability of no EDSS worsening did not differ between the 2 groups. CONCLUSION: Patients starting with METs had much higher clinical disease activity than those starting early with HETs. Rapid initiation of more aggressive treatment may allow better disease control; however, the data on EDSS worsening are not conclusive.

Ocrelizumab versus fingolimod after natalizumab cessation in multiple sclerosis: an observational study.

BACKGROUND: Exit strategy after natalizumab cessation in multiple sclerosis (MS) is a crucial point because the risk of disease reactivation is high during this period. The objective of this observational study was to compare ocrelizumab to fingolimod after natalizumab cessation in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: All RRMS patients starting fingolimod or ocrelizumab within 6 weeks after natalizumab cessation were included. The primary endpoint was the annualized relapse rate (ARR) at 1 year. RESULTS: We included 54 patients receiving fingolimod and 48 patients receiving ocrelizumab after natalizumab cessation. In multivariate analysis, ARR at 1 year was significantly lower in the ocrelizumab group than in the fingolimod group (0.12 ± 0.39 versus 0.41 ± 0.71, p = 0.026), i.e. a 70.7% lower relapse rate. The cumulative probability of relapses at 1 year was 31.5% (17/54 patients) with fingolimod and 10.4% (5/48 patients) with ocrelizumab, corresponding to a hazard ratio of 3.4 (95% confidence interval: 1.1-11, p = 0.04). CONCLUSIONS: Our results suggest ocrelizumab is potentially a better exit strategy than fingolimod after natalizumab cessation.

Characteristics, Patterns of Care and Predictive Geriatric Factors in Elderly Patients Treated for High-Grade IDH-Mutant Gliomas: A French POLA Network Study.

Background: Describe the characteristics, patterns of care, and predictive geriatric factors of elderly patients with IDHm high-grade glioma (HGG) included in the French POLA network. Material and Methods: The characteristics of elderly (≥70 years) patients IDHm HGG were compared to those of younger patients IDHm HGG (<70 years) and of elderly patients IDHwt HGG. Geriatric features were collected. Results: Out of 1433 HGG patients included, 119 (8.3%) were ≥70 years. Among them, 39 presented with IDHm HGG. The main characteristics of elderly IDHm HGG were different from those of elderly IDHwt HGG but similar to those of younger IDHm HGG. In contrast, their therapeutic management was different from those of younger IDHm HGG with less frequent gross total resection and radiotherapy. The median progression-free survival (PFS) and overall survival (OS) were longer for elderly patients IDHm HGG (29.3 months and 62.1 months) than elderly patients IDHwt HGG (8.3 months and 13.3 months) but shorter than those of younger patients IDHm HGG (69.1 months and not reached). Geriatric factors associated with PFS and OS were mobility, neuropsychological disorders, body mass index, and autonomy. Geriatric factors associated with PFS and OS were mobility, neuropsychological disorders, and body mass index, and autonomy. Conclusion: the outcome of IDHm HGG in elderly patients is better than that of IDHwt HGG. Geriatric assessment may be particularly important to optimally manage these patients.

CSF interleukin 6 is a useful marker to distinguish pseudotumoral CNS inflammatory diseases from primary CNS lymphoma.

BACKGROUND: Interleukin 6 (IL-6) is a pleomorphic cytokine that can be found in the cerebrospinal fluid (CSF) in a wide spectrum of inflammatory pathologies of the central nervous system (CNS). OBJECTIVE: Our aim was to characterize the diagnostic significance of CSF IL-6 among various CNS inflammatory diseases with pseudotumoral lesions (CNSID) and primary CNS lymphoma (PCNSL). METHODS: We retrospectively analyzed the CSF IL-6 concentrations in 43 consecutive patients with suspected PCNSL. A total of 28 patients were positively diagnosed with PCNSL and 15 with CNSID. We verified the results with CSF IL-10, an established biomarker for PCNSL. RESULTS: In the PCNSL group, the median CSF IL-6 concentration was 8 pg/ml, interquartile range (IQR) 5-18.5. For the patients with CNSID, the median concentration was 70 pg/ml, IQR 5-1368. A group comparison showed significantly higher CSF IL-6 levels in patients with CNSID than in those with PCNSL (p = 0.032). Moreover, IL-6 was correlated with CSF cell count in the CNSID group (r = 0.56, p = 0.028), but not in the PCNSL group (r = 0.3, p = 0.13). We found significantly higher CSF IL-10 levels in patients with PCNSL than in patients with CNS inflammatory lesions (p < 0.001). DISCUSSION AND CONCLUSIONS: Our study suggests that CSF IL-6 levels could represent, in addition to CSF IL-10, a useful biomarker in the differential diagnosis of CNSID and suspected PCNSL.

PHOX2B germline and somatic mutations in late-onset central hypoventilation syndrome.

RATIONALE: Late-onset central hypoventilation syndrome (LO-CHS) is a rare disorder that may manifest as early as infancy or as late as during adulthood. The potential overlap of LO-CHS with congenital CHS is under debate, even though both disorders can result from heterozygous PHOX2B gene mutations. OBJECTIVES: To characterize the PHOX2B status in a series of 25 patients with LO-CHS referred from 3 months of age to adulthood. Whenever a PHOX2B mutation was identified, we ascertained its germline or somatic origin in both patients with LO-CHS and in 15 parents of probands with congenital CHS found to harbor a PHOX2B mutation. METHODS: The PHOX2B gene was analyzed by direct DNA sequencing and origin of the mutation evaluated by fluorescent PCR. MEASUREMENTS AND MAIN RESULTS: We have identified a heterozygous PHOX2B gene mutation in 17 of 25 patients with LO-CHS. The far most frequent mutation results in a germline +5 alanine expansion in the series of 20 alanines (15 cases) that show incomplete penetrance and variable expressivity, possibly resulting from combined environmental and genetic factors. PHOX2B frameshift and missense mutations have also been identified in patients with LO-CHS. Importantly, one parent found to harbor a somatic mosaic for a +8 alanine expansion developed alveolar hypoventilation in his 40s. CONCLUSIONS: These data indicate that PHOX2B gene mutations should be systematically examined in any adult with unexplained central hypoventilation and raise the question of follow-up for apparently healthy parents found to harbor a somatic mosaic for the PHOX2B mutation identified in their child.

Noninvitation of eligible individuals to participate in pediatric studies: a qualitative study.

OBJECTIVE: To identify subjective factors that lead investigators not to invite eligible individuals to participate in pediatric studies. DESIGN: Qualitative study with semistructured interviews. SETTING: Four pediatric teaching hospitals in Paris. PARTICIPANTS: Pediatric investigators (n=24). MAIN OUTCOME MEASURE: Report by investigator that eligible patients were not invited by him or her to participate in a clinical research study. RESULTS: Sixty-three percent of investigators (15 of 24) reported not inviting eligible patients. The noninvitation patterns were global (ie, investigators did not invite anyone) (37.5% [9/24]) or targeted specific patient subgroups (37.5% [9/24]). Noninvitation was often described as driven by ethical concerns related to the study design or patients or by anticipated patient refusal (58.3% [14/24]). None of the investigators kept records of noninvitation rates or refusal rates. Investigators estimated refusal rates of 1% to 10%, and none remembered a study that had failed because of potential subjects' refusals (including healthy participants). CONCLUSIONS: Noninvitation to participate in studies is not an absence of action but rather is an organized practice that reflects investigators' perceptions. Consequences are practical (eg, recruitment bias and study failure) and ethical (eg, unequal access to trials and failure to respect the autonomy of eligible patients). Our data suggest an urgent need for quantitative studies aimed at documenting and understanding noninvitation of eligible patients to participate in research studies in pediatrics and in other medical specialties.

Optic Nerve Infiltration in Primary Central Nervous System Lymphoma.

Importance: Visual impairment in primary central nervous system lymphoma (PCNSL) is caused mostly by intraocular lymphomatous involvement (vitritis and retinal infiltration), whereas optic nerve infiltration (ONI) is a rare condition. Objective: To describe the clinical presentation of ONI, its imaging characteristics, and outcome. Design, Setting and Participants: A total of 752 patients diagnosed with PCNSL were retrospectively identified from the databases of 3 French hospitals from January 1, 1998, through December 31, 2014. Of these, 7 patients had documented ONI. Exclusion criteria were intraocular involvement, orbital lymphoma, or other systemic lymphoma. Clinical presentation, neuroimaging, biological features, treatment, and outcomes were assessed. Main Outcomes and Measures: Treatment response was evaluated clinically and radiologically on follow-up magnetic resonance imaging (MRI) according to the International PCNSL Collaborative Group response criteria. Results: The 7 patients included 5 women and 2 men. Median age at diagnosis was 65 years (range, 49-78 years). Two patients had initial ONI at diagnosis, and 5 had ONI at relapse. Clinical presentation was marked by rapidly progressive and severe visual impairment for all patients. The MRI findings showed optic nerve enlargement in 3 patients and contrast enhancement of the optic nerve in all patients. Additional CNS lesions were seen in 4 patients. Examination of cerebrospinal fluid samples detected lymphomatous meningitis in 2 patients. Clinical outcome was poor and marked by partial recovery for 2 patients and persistent severe low visual acuity or blindness for 5 patients. Median progression-free survival after optic nerve infiltration was 11 months (95% CI, 9-13 months), and median overall survival was 18 months (95% CI, 9-27 months). Conclusions and Relevance: Optic nerve infiltration is an atypical and challenging presentation of PCNSL. Its visual and systemic prognosis is particularly poor compared with vitreoretinal lymphomas even in response to chemotherapy. Although intraocular involvement is frequent in PCNSL and clinically marked by slowly progressive visual deterioration, lymphomatous ONI is rare and characterized by rapidly progressive severe visual impairment.

Transgenic models to study disorders of respiratory control in newborn mice.

Recent studies described the in vivo respiratory phenotype of mutant newborn mice with targeted deletions of genes involved in respiratory control development. Whole-body flow barometric plethysmography is the noninvasive method of choice for studying unrestrained newborn mice. The main characteristics of the early postnatal development of respiratory control in mice are reviewed, including available data on breathing patterns and on hypoxic and hypercapnic ventilatory responses. Mice are very immature at birth, and their instable breathing is similar to that of preterm infants. Breathing pattern abnormalities with prolonged apneas occur in newborn mice that lack genes involved in the development of rhythmogenesis. Some mutant newborn mice have blunted hypoxic and hypercapnic ventilatory responses whereas others exhibit impairments in responses to hypoxia or hypercapnia. Furthermore, combined studies in mutant newborn mice and in humans have helped to provide pathogenic information on genetically determined developmental disorders of respiratory control in humans.

The French Congenital Central Hypoventilation Syndrome Registry: general data, phenotype, and genotype.

OBJECTIVE: To analyze the main clinical features, genetic mutations, and outcomes of patients of the French Congenital Central Hypoventilation Syndrome (CCHS) Registry. DESIGN: A country-wide cohort established throughout a long-term multicenter effort. PATIENTS: Seventy French patients with CCHS (29 male patients and 41 female patients). METHODS: The following items were analyzed: the most important moments of the disease course; the main clinical characteristics; associated pathologic conditions; management; clinical outcome; and genetic mutations. RESULTS: An average of four new cases of CCHS per year was observed in the last 5 years. Thus, the incidence may be estimated to be 1 per 200,000 live births in France. The median age at diagnosis was 3.5 months (range, 0.5 to 15 months) before 1995 and < 2 weeks in the last 5 years (p = 0.01). CCHS occurred in isolation in 58 of 70 patients. In the remainder, it was associated with Hirschsprung disease (HSCR) [nine patients], Hirschsprung and neural crest tumor (two patients), and growth hormone deficiency (one patient). Among the 50 patients who lived beyond 1 year of age, all but one received nighttime ventilation, with 10 of them (20%) receiving it noninvasively. Three patients (6%) required daytime ventilatory support in addition to nighttime ventilation. The overall mortality rate was 38% (95% confidence interval [CI], 27 to 49%). The median age at death was 3 months (range, 0.4 months to 21 years). The 2-year mortality rate was greater in male patients than in female patients (p = 0.02; relative risk [RR], 2.71; 95% CI, 1.14 to 6.47) but was not affected by HSCR (p = 0.93; RR, 0.95; 95% CI, 0.28 to 3.2). The 43 patients who are currently alive (11 men; sex ratio, 0.4) have a mean age of 9 years (range, 2 months to 27 years). Among the 34 patients tested thus far, heterozygous mutations of the paired-like homeobox gene 2B (PHOX2B) gene were found in 31 patients (91%). CONCLUSION: Our four major findings are the extreme rarity of CCHS, the improved recognition over time, the lack of effect of HSCR on the mortality rate, and the high frequency of PHOX2B mutations.

Development of respiratory control: evolving concepts and perspectives.

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.

Allelic loss of 9p21.3 is a prognostic factor in 1p/19q codeleted anaplastic gliomas.

OBJECTIVES: We aimed to study the potential clinical relevance of 9p allelic loss, with or without copy number variation, in 1p/19q codeleted anaplastic oligodendroglial tumors (AOTs). METHODS: This study enrolled 216 patients with 1p/19q codeleted AOT. The prognostic value of 9p allelic loss was investigated using a French nation-wide prospective registry, POLA (prise en charge des tumeurs oligodendrogliales anaplasiques) and high-density single nucleotide polymorphism arrays. We validated our results using the Repository of Molecular Brain Neoplasia Data (REMBRANDT) dataset. RESULTS: The minimal common region of allelic loss in chromosome arm 9p was 9p21.3. Allelic loss of 9p21.3, detected in 41.7% of tumors, was associated with shorter progression-free and overall survival rates in univariate (p = 0.008 and p < 0.001, respectively) and multivariate analyses (p = 0.009 and p = 0.009, respectively). This finding was validated in the REMBRANDT dataset in univariate and multivariate analysis (p = 0.01 and p = 0.01, respectively). CONCLUSION: Our study highlights a novel potential prognostic biomarker in 1p/19q codeleted AOT. Further prospective studies are warranted to investigate our finding.

Neonatal exposure to 65% oxygen durably impairs lung architecture and breathing pattern in adult mice.

STUDY OBJECTIVE: To test the hypothesis that exposure to hyperoxia during the postnatal period of rapid alveolar multiplication by septation would cause permanent impairments, even with moderate levels of hyperoxia. DESIGN: We exposed mouse pups to 65% O(2) (hyperoxic mice) or normoxia (normoxic mice) during their first postnatal month, and we analyzed lung histology, pulmonary mechanics, blood gas, and breathing pattern during normoxia or in response to chemical stimuli in adulthood, when they reached 7 to 8 months of postnatal age. RESULTS: Hyperoxic mice had fewer and larger alveoli than normoxic mice (number of alveoli per unit surface area of parenchyma, 266 +/- 62/mm(2) vs 578 +/- 77/mm(2), p < 0.0001) [mean +/- SD], the cause being impaired alveolarization (radial alveolar count, 5.8 +/- 0.2 in hyperoxic mice vs 10.5 +/- 0.5 in normoxic mice, p < 0.0001). Respiratory system compliance was higher in hyperoxic mice (0.098 +/- 0.006 mL/cm H(2)O) than in normoxic mice (0.064 +/- 0.006 mL/cm H(2)O, p < 0.016). Baseline tidal volume (VT) and breath duration (TTOT]) measured noninvasively by whole-body plethysmography were larger in hyperoxic mice than in normoxic mice (VT, + 15%, p < 0.01; TTOT, + 12%, p < 0.01). Despite these impairments, blood gas, baseline minute ventilation E, and E responses to hypoxia and hypercapnia were normal in hyperoxic mice, compared with normoxic mice. CONCLUSION: Hyperoxic exposure during lung septation in mice may cause irreversible lung injury and breathing pattern abnormalities in adulthood at O(2) concentrations lower than previously thought. However, ventilatory function and body growth were preserved, and ventilatory function showed no major abnormalities, at least at rest, despite early oxygen-induced injuries.

PHOX2B gene mutation in a patient with late-onset central hypoventilation.

Congenital central hypoventilation syndrome, which is related to abnormal autonomic control of breathing and typically manifests at birth, was recently associated with PHOX2B gene mutations. In contrast, central hypoventilation with later onset constitutes a poorly defined group of unknown etiology. Here, we report on the identification of a de novo heterozygous PHOX2B mutation in a patient with central hypoventilation manifesting in childhood. This finding suggests that some of these cases may be genetically determined and allelic to congenital central hypoventilation syndrome.

Ventilatory control in newborn mice prenatally exposed to cocaine.

Infants born to mothers who used cocaine during pregnancy are at increased risk for neonatal death and respiratory impairments. Confounding factors such as multiple substance abuse make it difficult to isolate the effects of cocaine. We used a murine model to test the hypothesis that prenatal cocaine exposure may impair ventilatory responses to chemical stimuli in newborns. Seventy-two pregnant mice were randomly assigned to three groups: cocaine (COC), saline (SAL), and untreated (UNT). COC and SAL mice received subcutaneous injections of either 20 mg/kg of cocaine or a saline solution twice a day from gestational days 8-17. Ventilation (V'(E)) and tidal volume (V(T)), both divided by body weight, and breath duration (T(TOT)) were measured using whole-body plethysmography in freely moving COC (n = 47), SAL (n = 123), and UNT (n = 93) pups on postnatal day 2.The comparison between SAL and UNT pups showed significant differences in baseline breathing and in V'(E) responses to hypoxia, suggesting that maternal stress caused by injections affected the development of ventilatory control in pups. Baseline T(TOT) was significantly longer in COC than in SAL pups. V'(E) responses to hypoxia were significantly smaller in COC than in SAL pups (+27 +/- 35% vs. +38 +/- 25%), but V'(E) responses to hypercapnia were similar (29 +/- 15% vs. 25 +/- 23%).Thus, breathing control was impaired by prenatal cocaine exposure, possibly because of abnormal development of neurotransmitter systems, such as the dopamine and serotonin systems.

Genes modulating chemical breathing control: lessons from mutant animals.

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.

Effects of warm and cool thermal conditions on ventilatory responses to hyperoxic test in neonates.

Body temperature interacts with respiratory control, but it is unclear what sites or mechanisms mediate those interactions. We hypothesized that warm and cool thermal conditions affect the decrease in ventilation (VE) seen during the hyperoxic test (HT), a breathing response believed to reflect the strength of the peripheral chemoreceptor drive. A breath-by-breath analysis during a 30 s HT was performed in eight premature neonates (postconceptional age: 36 +/- 1 weeks) under neutral, warm, and cool thermal conditions. Quiet sleep (QS) and active sleep (AS) were scored by neurophysiological criteria. The VE fall was higher in AS than in QS, and warm and cool conditions significantly enhanced the response only in AS (-24.2 +/- 6.0, -39.1 +/- 9.1, and -37.5 +/- 14.1% in neutral, warm, and cool conditions, respectively). Central control mechanisms of the respiratory chemoreflex may explain the increase in peripheral chemoreceptor drive during AS in response to thermal challenges, which may produce increased breathing instability leading to apnea in early life.

Ventilatory responses to hypercapnia and hypoxia in heterozygous c-ret newborn mice.

The c-ret proto-oncogene encodes a tyrosine-kinase receptor involved in survival and differentiation of neural crest cell lineages. Previous studies have shown that homozygous c-ret-/- mice die soon after birth and have impaired ventilatory responses to hypercapnia. Heterozygous c-ret +/- mice develop normally, but their respiratory phenotype has not been described in detail. We used whole-body flow plethysmography to compare baseline breathing and ventilatory and arousal responses to chemical stimuli in unrestrained heterozygous c-ret +/- newborn mice and their wild-type c-ret +/+ littermates at 10-12 h of postnatal age. The hyperpnoeic and arousal responses to hypoxia and hypercapnia were not significantly different in these two groups. However, the number and total duration of apnoeas and periodic breathing episodes were significantly higher in c-ret +/- than in c-ret +/+ pups during hypoxia and post-hypoxic normoxia. These results are further evidence that respiratory control at birth is heavily dependent on genes involved in the neural determination of neural crest cells.

Recruitment in pediatric clinical research was influenced by study characteristics and pediatricians' perceptions: a multicenter survey.

OBJECTIVES: The aim of this survey was to quantify refusal rates and identify factors of refusal pertaining to studies and recruiting pediatricians in the research recruitment process. STUDY DESIGN AND SETTING: We performed a cross-sectional survey on all clinical studies conducted in six pediatric Clinical Investigation Centers in France over an 18-month period. Data were retrieved using a data collection form for the characteristics of each of the studies included in the survey and a questionnaire addressed to recruiting pediatricians. Multilevel models were used for the statistical analysis. RESULTS: Overall, 145 pediatricians approached the families of 999 children and adolescents for participation in 44 studies. In the 36 of the 44 studies that enrolled subjects, median refusal rate was 12.5% (Q1-Q3, 0-28%). Lower refusal rates were associated with therapeutic drug use as the focus of the study [odds ratio (OR), 0.51; 95% CI: 0.25, 1.05], additional hospital stays required for the study (OR, 0.53; 95% CI: 0.28, 0.99), longer duration of the inclusion visit (OR, 0.93/10 min; 95% CI: 0.87, 1), and recruitment by a pediatrician with university teaching responsibilities (OR, 0.26; 95% CI: 0.10, 0.68). Refusal rate was higher when the recruiting pediatrician perceived the study as generating heavy practical burden for the subject and/or its family (OR, 1.3; 95% CI: 1.17, 1.45). CONCLUSION: Refusal to participate in clinical research was low and was influenced by factors associated to the objectives and conduct of the studies and factors related to the characteristics and perceptions of the recruiting pediatricians.