Abstract
Introduction
Vitamin D–dependent rickets type 1A (VDDR1A) is a rare genetic disease associated with loss-of-function variations in the gene encoding the vitamin D–activating enzyme ...1α-hydroxylase (CYP27B1). Phenotype-genotype correlation is unclear. Long-term outcome data are lacking. The objective of this study was to describe characteristics and outcomes to search for a phenotype-genotype correlation.
Methods
We retrospectively collected clinical data, genetic features, and outcomes from 24 genetically confirmed cases from 10 French centers; results are presented as median (min–max).
Results
Clinical symptoms at diagnosis (age, 1.5 0.5-8.7 years) were mainly bone and neurological abnormalities, and laboratory data showed hypocalcemia (1.97 1.40-2.40 mmol/L), hypophosphatemia (−3.4 −13.4 to (−)0.2 SD score for age), low 25OHD and low 1,25(OH)2D3, secondary hyperparathyroidism with PTH at 6.6 (1.3-13.7) times the upper limit for normal (ULN; PTH expressed as ULN to homogenize data presentation), and increased alkaline phosphatase (1968 521-7000 IU/L). Bone radiographs were abnormal in 83% of patients. We identified 17 variations (11 missense, 3 frameshift, 2 truncating, and 1 acceptor splice site variations) in 19 families (homozygous state in 58% 11/19). The partial loss-of-function variation p.(Ala129Thr) was associated with a milder phenotype: older age at diagnosis, higher serum calcium (2.26 vs 1.85 mmol/L), lower PTH (4.7 vs 7.5 ULN), and lower alkaline phosphatase (759 vs 2082 IU/L). Patients were treated with alfacalcidol. Clinical (skeletal, neurological), biochemical, and radiological outcomes were satisfactory, and complications occurred if there was bad adherence.
Conclusion
Overall, our findings highlight good outcomes under substitutive treatment and the need of a closer follow-up of eyes, teeth, kidneys, and blood pressure in VDDR1A.
Summary
Childhood autoimmune haemolytic anaemia (AIHA) requires second‐line immunosuppressive therapy in 30–50% of cases. It appears that rituximab is indicated in such circumstances. This ...prospective national study reports the practice, efficacy and tolerance of rituximab in children with isolated AIHA and AIHA in the setting of Evans syndrome (ES). Sixty‐one children were given rituximab between 2000 and 2014. The median interval from diagnosis to rituximab was 9·9 interquartile range (IQR) 1·6–28·5 months. Forty‐six patients responded (75%) and the 6‐year relapse‐free survival (RFS) was 48%. Twenty patients relapsed at a median interval of 10·8 (IQR 3·9–18·7) months, rituximab allowed steroid withdrawal in 44/61 (72%) of children. In isolated AIHA, complete response and 6‐year RFS were significantly higher than in ES (P < 0·05). Ten out of 61 patients were infants, seven of who responded with a 6‐year RFS of 71%. Among patients without immunoglobulin substitution before rituximab, 4 are still receiving substitutions. Five patients died, including one potentially attributable to rituximab. This large observational series of childhood AIHA established the rituximab benefit‐risk ratio, allowing steroid withdrawal, with 37% of long‐term responders, mainly in isolated AIHA. All subgroups of patients drew benefit. Our long‐term results indicate the baseline to be challenged by new treatment approaches.
To evaluate the nutritional consequences of acute lymphoblastic leukemia and its treatment, 15 children with leukemia were studied. Anthropometric data, fat-free mass by impedance, energy intake, and ...resting energy expenditure (REE) were determined at diagnosis and on days 22, 36, and 71 of the treatment. Interleukin (IL)-1 beta, IL-6, interferon-gamma, and tumor necrosis factor were also measured. Fifteen healthy control subjects were matched for age and sex. Body weight and height and body composition were comparable at all times of the study, although three children were underweight at diagnosis (weight-for-height < 85% of French standards). Although two different methods were used for dietary recall in the two groups, energy intake expressed as a percentage of normal recommended values for age and sex was lower in patients than in control subjects (104 +/- 19%) on day 1 (47 +/- 32.1%) and day 22 (58 +/- 24%), but was comparable on day 36 (85 +/- 71%) and day 71 (85 +/- 48%). This low energy intake involved both carbohydrates and fats. Energy and carbohydrate intakes improved significantly during the study in patients. The nonprotein respiratory quotient (RQ) in patients was significantly lower than in control subjects (0.84 +/- 0.04) on day 1 (0.79 +/- 0.02) but was comparable on day 71. The REE of the patients on day 1 (5057.8 +/- 1588.4 kJ/24 h) and day 71 (4844.7 +/- 116.1 kJ/24 h) and of the control subjects (4313.8 +/- 823.5 kJ/24 h) was not significantly different. Cytokines remained undetectable on days 1, 36, and 71. The results showed that at the time of diagnosis and during this period of chemotherapy there was no evidence of raised REE. The poor intakes during the first month of chemotherapy were recent as shown by the parents' questionnaire responses and the absence of consequences in body composition. The transient decrease in RQ seemed to be an adaptative mechanism to the poor carbohydrate intake. No indication of undernutrition in the patients as a group was evident during the first 71 d of treatment although further long-term nutritional assessment is needed.
Autologous stem cell transplantation (ASCT) and chimeric antigen receptor (CAR) T-cells are two therapeutic options for relapsed/refractory diffuse large B-cell lymphoma. Both are intensive and ...potentially curative therapies but differ in their efficacy and toxicity. ASCT may be offered to ‘fit’ patients (i.e. usually young with limited comorbidities) with chemosensitive disease. On the other hand, real world studies have shown that CAR T-cells may be safely administered to less fit and older patients. Thus, there is a potentially significant population of patients who may be offered CAR T-cell therapy despite not being eligible for ASCT. As the relative role of ASCT and CAR T-cells evolves, recognising and defining this population may be increasingly relevant. Here, we review criteria which may help identify this ‘ASCT-ineligible but CAR T-cells eligible’ population of patients.
•ASCT and chimeric antigen receptor (CAR) T-cells are two therapeutic options for relapsed/refractory diffuse large B-cell lymphoma.•ASCT is offered to fit patients with a chemosensitive disease.•CAR-T cells may be safely administered to less fit and older patients.•This population of ASCT-ineligible but CAR T-cells eligible should be defined.
Territoires Boutier, Jean; Boutry, Philippe; Brun, Jacques ...
2016
eBook, Book
Odprti dostop
Depuis vingt ans, le territoire s’est imposé comme catégorie de pensée des sciences sociales et comme catégorie d’action des politiques publiques. Les uns annoncent « la fin des territoires », ...bousculés par la mondialisation et le développement inexorable des réseaux. Les autres montrent la vitalité des frontières et des identités territoriales, l’acuité des conflits géopolitiques et le goût renouvelé des terroirs et du local. Face à la banalisation et à la polysémie du terme territoire, il importe d’examiner de manière critique son contenu et d’envisager ses applications les plus pertinentes au regard de la réalité sociale. Cet ouvrage, tiré d’une réflexion collective contemporaine des débuts de la vogue territoriale, propose des définitions, suggère des questions et illustre quelques usages d’une notion aux multiples facettes.
To assess the 9-month HIV-free survival of children with two strategies to prevent HIV mother-to-child transmission.
Nonrandomized interventional cohort study.
Four public health centres in Rwanda.
...Between May 2005 and January 2007, all consenting HIV-infected pregnant women were included.
Women could choose the mode of feeding for their infant: breastfeeding with maternal HAART for 6 months or formula feeding. All received HAART from 28 weeks of gestation. Nine-month cumulative probabilities of HIV transmission and HIV-free survival were determined using the Kaplan-Meier method and compared using the log-rank test. Determinants were analysed using a Cox model analysis.
Of the 532 first-liveborn infants, 227 (43%) were breastfeeding and 305 (57%) were formula feeding. Overall, seven (1.3%) children were HIV-infected of whom six were infected in utero. Only one child in the breastfeeding group became infected between months 3 and 7, corresponding to a 9-month cumulative risk of postnatal infection of 0.5% 95% confidence interval (CI) 0.1-3.4%; P = 0.24 with breastfeeding. Nine-month cumulative mortality was 3.3% (95% CI 1.6-6.9%) in the breastfeeding arm group and 5.7% (95% CI 3.6-9.2%) for the formula feeding group (P = 0.20). HIV-free survival by 9 months was 95% (95% CI 91-97%) in the breastfeeding group and 94% (95% CI 91-96%) for the formula feeding group (P = 0.66), with no significant difference in the adjusted analysis (adjusted hazard ratio for breastfeeding: 1.2 (95% CI 0.5-2.9%).
: Maternal HAART while breastfeeding could be a promising alternative strategy in resource-limited countries.
Although asthma and rhinitis often coexist, it is still unknown whether they are characterized by a similar inflammatory profile. We studied eosinophilic infiltration, epithelial shedding and ...reticular basement membrane thickness in nasal and bronchial biopsies of six control subjects, 15 untreated allergic asthmatics with perennial rhinitis, and six corticosteroid-dependent (CSD) asthmatics. In nasal and bronchial biopsies, eosinophils were greater in untreated asthmatics than in control subjects and CSD asthmatics (p = 0.001). In untreated asthmatics, eosinophils were higher in bronchial than in nasal biopsies (p = 0.002). In nasal and bronchial biopsies, reticular basement membrane thickness was greater in untreated and CSD asthmatics than in control subjects (nasal: p < 0.008 and p < 0. 004; bronchial: p < 0.001 and p < 0.008). In untreated and CSD asthmatics, reticular basement membrane thickness was greater in bronchial than in nasal biopsies (p = 0.001; Wilcoxon's W test). Nasal epithelium was not shed in all the study groups. In untreated asthmatics, bronchial epithelium shedding was greater than in control subjects or CSD asthmatics (p < 0.005), and it was greater than nasal epithelium shedding (p < 0.006). This study has shown that, although concomitant, the extent of eosinophilic inflammation of reticular basement membrane thickness and of the epithelium shedding is greater in bronchial than in nasal mucosa of asthmatic patients with perennial rhinitis.
Introduction
The World Health Organization (WHO) 2010 guidelines recommended to treat all HIV‐infected children less than two years of age. We described the inclusion process and its correlates of ...HIV‐infected children initiated on early antiretroviral therapy (EART) at less than two years of age in Abidjan, Côte d'Ivoire, and Ouagadougou, Burkina Faso.
Methods
All children with HIV‐1 infection confirmed with a DNA PCR test of a blood sample, aged less than two years, living at a distance less than two hours from the centres and whose parents (or mother if she was the only legal guardian or the legal caregiver if parents were not alive) agreed to participate in the MONOD ANRS 12206 project were included in a cohort to receive EART based on lopinavir/r. We used logistic regression to identify correlates of inclusion.
Results
Among the 217 children screened and referred to the MONOD centres, 161 (74%) were included and initiated on EART. The main reasons of non‐inclusion were fear of father's refusal (48%), mortality (24%), false‐positive HIV infection test (16%) and other ineligibility reasons (12%). Having previously disclosed the child's and mother's HIV status to the father (adjusted odds ratio (aOR): 3.20; 95% confidence interval (95% CI): 1.55 to 6.69) and being older than 12 months (aOR: 2.05; 95% CI: 1.02 to 4.12) were correlates of EART initiation. At EART initiation, the median age was 13.5 months, 70% had reached WHO Stage 3/4 and 57% had a severe immune deficiency.
Conclusions
Fear of stigmatization by the father and early competing mortality were the major reasons for missed opportunities of EART initiation. There is an urgent need to involve fathers in the care of their HIV‐exposed children and to promote early infant diagnosis to improve their future access to EART and survival.
Coronary artery bypass graft (CABG) surgery is frequently performed and effective; however, perioperative complications related to ischemia-reperfusion injury, including myocardial infarction (MI), ...remain common and result in significant morbidity and mortality. MC-1, a naturally occurring pyridoxine metabolite and purinergic receptor antagonist, prevents cellular calcium overload and may reduce ischemia-reperfusion injury. Phase 2 trial data suggest that MC-1 may reduce death or MI in high-risk patients undergoing CABG surgery.
To assess the efficacy and safety of MC-1 administered immediately before and for 30 days after surgery in patients undergoing CABG surgery.
The MC-1 to Eliminate Necrosis and Damage in Coronary Artery Bypass Graft Surgery II Trial, a phase 3, multicenter, randomized, double-blind, placebo-controlled trial, with 3023 intermediate- to high-risk patients undergoing CABG surgery with cardiopulmonary bypass enrolled between October 2006 and September 2007 at 130 sites in Canada, the United States, and Germany.
Patients received either MC-1, 250 mg/d (n = 1519), or matching placebo (n = 1504) immediately before and for 30 days after CABG surgery.
The primary efficacy outcome was cardiovascular death or nonfatal MI, defined as a creatine kinase (CK) MB fraction of at least 100 ng/mL or new Q waves through postoperative day 30.
The primary efficacy outcome occurred in 140 of 1510 patients (9.3%) in the MC-1 group and 133 of 1486 patients (9.0%) in the placebo group (risk ratio, 1.04; 95% confidence interval, 0.83-1.30; P = .76). All-cause mortality was higher among patients assigned to MC-1 than placebo at 4 days (1.0% vs 0.3%; P = .03) but was similar at 30 days (1.9% vs 1.5%; P = .44). There was no difference in the 8- to 24-hour CK-MB area under the curve between the MC-1 and placebo groups (median, 270 interquartile range, 175-492 vs 268 interquartile range, 170-456 hours x ng/mL; P = .11).
In this population of intermediate- to high-risk patients undergoing CABG surgery, MC-1 did not reduce the composite of cardiovascular death or nonfatal MI.
clinicaltrials.gov Identifier: NCT00402506
Eosinophils but not neutrophils may play a role in the airway inflammation of asthma. In chronic bronchitis (CB) and chronic obstructive pulmonary disease (COPD), neutrophils are present in the ...airways. To differentiate among the pathology of asthma, CB, and COPD eosinophils and neutrophils were studied in peripheral blood, bronchial biopsy specimens, and bronchoalveolar lavage fluid (BALF).
We studied nine nonsmoking healthy subjects, 20 nonsmoking patients with asthma, 10 nonatopic smoking patients with CB (forced expiratory volume in 1 second: 98.4% +/- 11.3%) and 17 patients with COPD (forced expiratory volume in 1 second: 51.2% +/- 14.3%). Eosinophils were characterized by their enumeration in biopsy specimens (EG2 monoclonal antibody), peripheral blood, and BALF and by measurement of eosinophil cationic protein in BALF. Neutrophils were characterized by their enumeration in biopsy specimens (anti-elastase monoclonal antibody) and BALF and by measurement of neutrophil-specific myeloperoxidase in BALF.
In patients with asthma we found degranulated eosinophils in biopsy specimens and significantly increased eosinophil cationic protein levels in BALF. In patients with CB or COPD, eosinophil numbers in biopsy specimens were not significantly different from those of patients with asthma, but cells were not degranulated and eosinophil cationic protein levels in BALF were similar to those of normal subjects. In patients with CB or COPD neutrophils were not increased in the mucosa, but neutrophil numbers and myeloperoxidase levels in BALF were significantly increased.
The percentages of neutrophils in BALF were greater in patients with COPD than in those with CB, suggesting a role in the chronic airflow limitation.
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