Impact of early transcranial Doppler screening and intensive therapy on cerebral vasculopathy outcome in a newborn sickle cell anemia cohort.

Transcranial Doppler (TCD) is used to detect children with sickle cell anemia (SCA) who are at risk for stroke, and transfusion programs significantly reduce stroke risk in patients with abnormal TCD. We describe the predictive factors and outcomes of cerebral vasculopathy in the Créteil newborn SCA cohort (n = 217 SS/Sß(0)), who were early and yearly screened with TCD since 1992. Magnetic resonance imaging/magnetic resonance angiography was performed every 2 years after age 5 (or earlier in case of abnormal TCD). A transfusion program was recommended to patients with abnormal TCD and/or stenoses, hydroxyurea to symptomatic patients in absence of macrovasculopathy, and stem cell transplantation to those with human leukocyte antigen-genoidentical donor. Mean follow-up was 7.7 years (1609 patient-years). The cumulative risks by age 18 years were 1.9% (95% confidence interval [95% CI] 0.6%-5.9%) for overt stroke, 29.6% (95% CI 22.8%-38%) for abnormal TCD, which reached a plateau at age 9, whereas they were 22.6% (95% CI 15.0%-33.2%) for stenosis and 37.1% (95% CI 26.3%-50.7%) for silent stroke by age 14. Cumulating all events (stroke, abnormal TCD, stenoses, silent strokes), the cerebral risk by age 14 was 49.9% (95% CI 40.5%-59.3%); the independent predictive factors for cerebral risk were baseline reticulocytes count (hazard ratio 1.003/L × 10(9)/L increase, 95% CI 1.000-1.006; P = .04) and lactate dehydrogenase level (hazard ratio 2.78/1 IU/mL increase, 95% CI1.33-5.81; P = .007). Thus, early TCD screening and intensification therapy allowed the reduction of stroke-risk by age 18 from the previously reported 11% to 1.9%. In contrast, the 50% cumulative cerebral risk suggests the need for more preventive intervention.

[Recurrent upper respiratory tract infections and otitis in children]. / Rhinopharyngites et otites à répétition de l'enfant.

Recurrent upper respiratory tract infections should be considered as a normal process in infants who build immune defenses in an environment where they meet viruses. Nasal lavage with saline serum and the blowing when possible are the only treatment justified in all the cases. Antibiotic treatment is not justified. It does not shorten the course and does not prevent complications. Recurrent otitis media (three episodes in six months or four in one year) are the most common complication. Bacterial superinfections are due to bacteria who colonise nasopharynx. Facilitating factors for recurrent ENT infections in children are individual: age, sex, martial deficiency, gastro-oesophageal reflux, adenoid growths. Other facilitating factors are environmental: absence or short duration of breast-feading, pollution, passive smoking, day care center. In the great majority of cases, laboratory tests are unnecessary. The most important is to reassure because recurrent upper respiratory infections improve with time. Different facilitating factors previously described have to be taken into account and should allow to decrease the number of episodes.

In vitro prediction of stop-codon suppression by intravenous gentamicin in patients with cystic fibrosis: a pilot study.

BACKGROUND: Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which acts as a chloride channel activated by cyclic AMP (cAMP). The most frequent mutation found in 70% of CF patients is F508del, while premature stop mutations are found in about 10% of patients. In vitro aminoglycoside antibiotics (e.g. gentamicin) suppress nonsense mutations located in CFTR permitting translation to continue to the natural termination codon. Pharmacologic suppression of stop mutations within the CFTR may be of benefit to a significant number of patients. Our pilot study was conducted to determine whether intravenous gentamicin suppresses stop codons in CF patients and whether it has clinical benefits. METHODS: A dual gene reporter system was used to determine the gentamicin-induced readthrough level of the most frequent stop mutations within the CFTR in the French population. We investigated readthrough efficiency in response to 10 mg/kg once-daily intravenous gentamicin perfusions in patients with and without stop mutations. Respiratory function, sweat chloride concentration, nasal potential difference (NPD) and CFTR expression in nasal epithelial cells were measured at baseline and after 15 days of treatment. RESULTS: After in vitro gentamicin incubation, the readthrough efficiency for the Y122X mutation was at least five times higher than that for G542X, R1162X, and W1282X. In six of the nine patients with the Y122X mutation, CFTR immunodetection showed protein at the membrane of the nasal epithelial cells and the CFTR-dependent Cl- secretion in NPD measurements increased significantly. Respiratory status also improved in these patients, irrespective of the gentamicin sensitivity of the bacteria present in the sputum. Mean sweat chloride concentration decreased significantly and normalised in two patients. Clinical status, NPD and sweat Cl- values did not change in the Y122X patients with no protein expression, in patients with the other stop mutations investigated in vitro and those without stop mutations. CONCLUSION: Suppression of stop mutations in the CFTR gene with parenteral gentamicin can be predicted in vitro and is associated with clinical benefit and significant modification of the CFTR-mediated Cl- transport in nasal and sweat gland epithelium.

Paris-Trousseau syndrome : clinical, hematological, molecular data of ten new cases.

Paris-Trousseau syndrome (PTS) is an inherited disorder characterized by mild hemorragic tendency associated with 11q chromosome deletion. Here we report ten new patients (5 boys, 5 girls) with complete clinical history, biological data, ultra-structural and molecular investigations. Thrombocytopenia is chronic in all the patients except two boys in whom it disappeared during the two first years of life. On Romanovsky stained peripheral blood smears, abnormal platelets with giant granules were detected in all the children and confirmed by electron microscopy (EM). On bone marrow smears, dysmegakaryopoiesis with many micromegakaryocytes was constantly observed. Abnormal alpha-granules were virtually absent from bone marrow and cultured megakaryocytes, while EM detected numerous images of granule fusion within blood platelets. Molecular analyses evidenced that the fli-1 gene is deleted in all the patients except one confirming the crucial role of the transcription factor FLI-1 in megakaryopoiesis. In summary, this study documents ten new cases of PTS with characteristic alpha-granule abnormalities, and shows the putative pathogenic role of fli-1 gene in the pathophysiology of this syndrome.

The enlarging clinical, genetic, and population spectrum of tumor necrosis factor receptor-associated periodic syndrome.

OBJECTIVE: To characterize the frequency, clinical signs, and genotypic features of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in a series of 394 patients of various ethnic origins who have recurrent inflammatory syndromes. METHODS: Sequencing of the coding region of the TNFRSF1A gene was performed in 128 patients in whom there was a high suspicion of TRAPS, and denatured high-performance liquid chromatography was used to systematically screen for TNFRSF1A in 266 patients with recurrent inflammatory syndrome and no or only 1 Mediterranean fever gene (MEFV) mutation. RESULTS: TNFRSF1A mutations were found in 28 (7.1%) of 394 unrelated patients. Nine (32%) of the 28 patients had a family history of recurrent inflammatory syndromes. In 13 patients, the length of the attack of inflammation was fewer than 5 days. Three of the mutations (Y20H, L67P, and C96Y) were novel. Two mutations, R92Q and (mainly) P46L, found in 12 and 10 patients, respectively, had lower penetrance compared with other mutations. TNFRSF1A mutations were found in patients of various ethnic origins, including those at risk for familial Mediterranean fever (FMF): Armenians, Sephardic Jews, and especially Arabs from Maghreb. Only 3 (10.7%) of the 28 patients had amyloidosis. CONCLUSION: TRAPS is an underdiagnosed cause of recurrent inflammatory syndrome. Its presence in the population of persons of Mediterranean ancestry and the short duration of the attacks of inflammation can lead to a fallacious diagnosis of FMF. Because an accurate diagnosis in patients with recurrent inflammatory syndromes is crucial for proper clinical management and treatment, genetic screening for TNFRSF1A is warranted.

An 8-y-old boy with acute stroke and radiological signs of cerebral vasculitis after recent Mycoplasma pneumoniae infection.

A young boy was admitted to hospital for acute stroke. Cerebral angiography showed a pattern suggestive of vasculitis and a recent Mycoplasma pneumoniae infection was detected. The absence of microorganisms in cerebrospinal fluid, the pattern of vasculitis and previous reports supporting a post-infectious immunological mechanism for certain complications of M. pneumoniae infection suggest this mechanism as the cause of the stroke.