Matrix Metalloproteinase Gene Polymorphisms and Bronchopulmonary Dysplasia: Identification of MMP16 as a New Player in Lung Development

International audienceBACKGOUND: Alveolarization requires coordinated extracellular matrix remodeling, a process in which matrix metalloproteinases (MMPs) play an important role. We postulated that polymorphisms in MMP genes might affect MMP function in preterm lungs and thus influence the risk of bronchopulmonary dysplasia (BPD). METHODS AND FINDINGS: Two hundred and eighty-four consecutive neonates with a gestational age of <28 weeks were included in this prospective study. Forty-five neonates developed BPD. Nine single-nucleotide polymorphisms (SNPs) were sought in the MMP2, MMP14 and MMP16 genes. After adjustment for birth weight and ethnic origin, the TT genotype of MMP16 C/T (rs2664352) and the GG genotype of MMP16 A/G (rs2664349) were found to protect from BPD. These genotypes were also associated with a smaller active fraction of MMP2 and with a 3-fold-lower MMP16 protein level in tracheal aspirates collected within 3 days after birth. Further evaluation of MMP16 expression during the course of normal human and rat lung development showed relatively low expression during the canalicular and saccular stages and a clear increase in both mRNA and protein levels during the alveolar stage. In two newborn rat models of arrested alveolarization the lung MMP16 mRNA level was less than 50% of normal. CONCLUSIONS: MMP16 may be involved in the development of lung alveoli. MMP16 polymorphisms appear to influence not only the pulmonary expression and function of MMP16 but also the risk of BPD in premature infants

Polymorphisme du gène de la métalloprotéinase de type 2 (MMP-2) et risque de dysplasie bronchopulmonaire chez le prématuré né à moins de 28 SA

LYON1-BU Santé (693882101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Children with Sickle Cell Anemia Experience Severe Oxygen Desaturation During Night and After Six-Minute Walk Distance Test

Abstract Abstract 4766 Background: Respiratory complications are the first causes of death among adult patients with sickle cell anemia (SCA). Finding risk factors for children is important. We study clinical, biological, respiratory and heart parameters, as well as exercise and sleep oxygen saturation in SCA children. Patients and Methods: We conducted a prospective study in homozygous SS or S/beta 0 thalassemic children. A chronic transfusion program was an exclusion criterion. We recorded the number of vaso-occlusive crises (VOC) the year before and after inclusion, past history of acute chest syndrome (ACS), hydroxyurea treatment, tonsils size, baseline heart rate and blood pressure, baseline hemoglobin (Hb), reticulocytes, fetal Hb levels, leukocytes and platelets counts, total bilirubin, aspartate aminotransferase (AST), lactate deshydrogenase (LDH). All patients underwent respiratory function testing (RFT), echocardiography assessing tricuspid regurgitation velocity jet (TRV). We measured daytime oxygen saturation using a Radical Masimo set ® pulse oximeter. All patients underwent a non-encouraged six-minute walk test (6MWT). Nocturnal pulse oximetry was recorded using a Nonin ® device during 3 consecutive nights for 30 patients. We considered the average night-time oxygen saturation and the percentage of sleep time with oxygen saturation less than 90%. Statistical analysis was conducted using the Fisher exact test for categorical variables and the Wilcoxon test for continuous variables. Results: Forty-two unselected SCA children were enrolled. Three patients were secondarily excluded because the echocardiography revealed asymptomatic cardiac anomalies (two pulmonary valve stenosis and one persistent arterial canal). In the remaining 39 patients, 38 were SS and one was S/beta 0 thalassemic. Median age was 10.8 years (range 5.7–17); 25 patients were females (64%). The median number of VOC was 0 the year before inclusion (range 0–6), and 0 the year after (range 0–7). Fifteen patients (38%) had displayed at least one ACS. Nine patients (23%) were receiving hydroxyurea treatment. Sixteen patients (43%) had tonsillitis enlargement. Median basal heart rate was 97 bpm (range 75–122). Mean systolic blood pressure was 107 ± 11.3 mm Hg and mean diastolic blood pressure was 64 ± 6.6 mm Hg. Mean Hb was 7.9 ± 1.2 g/dL, mean reticulocyte count was 236 ± 82 Giga/L, median HbF was 9.2 % (range 0.8–28), mean leukocyte count was 11.1 ± 3.2 Giga/L, mean platelet count was 407 ± 132 Giga/L. Median total bilirubin, AST, and LDH were, respectively, 41.5 mg/dL (range 13–163), 62 UI/l (range 35–132), and 1421 UI/l (range 618–1893) (normal range for LDH in our lab 125–243). Fifteen patients (38.5%) had abnormal RFT: 4 had obstructive pattern, 3 had restrictive pattern, and 3 had both. Left ventricular diastolic function was normal for all patients. Six patients had a TRV above 2.6 m/s. Median daytime oxygen saturation was 97 % (range 89–100). One patient had a daytime saturation below 92%. Median nocturnal oxygen saturation was 94.7 % (range 87.7–99.5). Ten patients (33%) displayed average night-time saturation below 92%. Eleven patients (37%) spent more than 10% of their sleep time with oxygen saturation below 90%. Mean six-minute walk distance (6MWD) was 547 ± 99 m. After the 6MWT, 14 patients (35%) had an oxygen saturation below 92%. Median difference in oxygen saturation before and after the test was 2% (range −57, +2). Nocturnal hypoxemia was not associated with age, gender, tonsils size, hydroxyurea treatment, past history of ACS, RFT pattern, number of VOC, leukocytes, platelets, LDH, bilirubin nor AST. It was associated with Hb level (7.2±1.2 g/dL if nocturnal hypoxemia vs 8.4±1.1, p=0.02), daytime oxygen saturation (94% [range 92–99] if nocturnal hypoxemia vs 98% [range 89–100], p=0.03), and oxygen saturation after 6MWT (91% [range 40–99] if nocturnal hypoxemia vs 96% [range 79–100], p=0.03). Children with a TRV above 2.6m/s had a significantly lower Hb level (7.4 g/dL [6.4–8.1] vs 8.5 [6.5–10.6]). Conclusions: Our study emphasizes the frequency of night-time oxygen desaturation in SCA children. It shows that a simple effort can induce a significant decrease in oxygen saturation. The consequences of hypoxemia are difficult to assess given the small sample size. One can hypothesize that hypoxemia and hypoxia/reoxygenation cycles both contribute to the pathophysiology of the disease through inflammation and vascular injury. Disclosures: No relevant conflicts of interest to declare. </jats:sec

Severe nocturnal and postexercise hypoxia in children and adolescents with sickle cell disease.

Hypoxia is a common feature in children with sickle cell disease (SCD) that is inconsistently associated with painful crises and acute chest syndrome. To assess the prevalence and risk factors of hypoxia, we recorded daytime, nocturnal, and postexercise pulse oximetry (SpO2) values in 39 SCD patients with a median age of 10.8 years. Median daytime SpO2 was 97% (range, 89%-100%), and 36% of patients had daytime hypoxia defined as SpO2<96%. Median nocturnal SpO2 was 94.7% (range, 87.7%-99.5%), 50% of patients had nocturnal hypoxia defined as SpO2≤93%, and 11(37%) patients spent more than 10% of their total sleep time with SpO2<90%. Median postexercise SpO2 was 94% (range, 72%-100%) and 44.7% of patients had postexercise hypoxia defined as an SpO2 decrease ≥3% after a 6-minute walk test. Among patients with normal daytime SpO2, 35% had nocturnal and 42% postexercise hypoxia. Compared to 9 patients without daytime, nocturnal, or postexercise hypoxia, 25 patients with hypoxia under at least one of these three conditions had greater anemia severity (P = 0.01), lower HbF levels (P = 0.04), and higher aspartate aminotransferase levels (P = 0.03). Males predominated among patients with postexercise hypoxia (P = 0.004). Hypoxia correlated neither with painful crises nor with acute chest syndrome. Of 32 evaluable patients, 6 (18.8%) had a tricuspid regurgitation velocity ≥2.6 m/s, and this feature was associated with anemia (P = 0.044). Median percentage of the predicted distance covered during a 6-minute walk test was 86% [46-120]; the distance was negatively associated with LDH (P = 0.044) and with a past history of acute chest syndrome (P = 0.009). In conclusion, severe episodes of nocturnal and postexercise hypoxia are common in children with SCD, even those with normal daytime SpO2

Distribution of the patients according to distance walked during the 6-minute walking test, expressed as % of the expected value.

<p>Distribution of the patients according to distance walked during the 6-minute walking test, expressed as % of the expected value.</p

Main characteristics of the 39 children and adolescents with sickle cell disease (part 1).

<p>Main characteristics of the 39 children and adolescents with sickle cell disease (part 1).</p

Clinical and laboratory characteristics according to the SpO₂ decline induced by the 6-minute walking test.

<p>BMI, body mass index; VOC, vasoocclusive crisis; ACS, acute chest syndrome; 6 MWT, 6-minute walking test.</p

Thrombotic Microangiopathy and Purtscher-like Retinopathy as a Rare Presentation of Juvenile Dermatomyositis

Juvenile dermatomyositis is a rare systemic vasculopathy that may sometimes present with acute complications. We report here the case of a 7-year-old boy with severe dermatomyositis associated with thrombocytopenia and blurry vision. The presence of schistocytosis and the secondary occurrence of hemolytic anemia were consistent with a diagnosis of thrombotic thrombocytopenic purpura (TTP). Further investigations demonstrated the association of TTP with muscular microangiopathy and Purtscher-like retinopathy. Retinal and hematologic involvements dramatically improved after the initiation of plasma exchange in emergency. This report emphasizes that early recognition of TTP and prompt plasmapheresis are important in a child with severe juvenile dermatomyositis associated with thrombocytopenia.</jats:p