Effect of mutations in LDLR and PCSK9 genes on phenotypic variability in Tunisian familial hypercholesterolemia patients

BackgroundAutosomal dominant hypercholesterolemia (ADH) is commonly caused by mutations in the low-density lipoprotein (LDL) receptor gene (LDLR), in the apolipoprotein B-100 gene (APOB), or in the proprotein convertase subtilisin kexine 9 gene (PCSK9). ADH subjects carrying a mutation in LDLR present highly variable plasma LDL-cholesterol (LDL-C). This variability might be due to environmental factors or the effect of some modifying genes such as PCSK9 and APOE.AimsWe investigated the molecular basis of thirteen Tunisian ADH families and attempted to determine the impact of PCSK9 and APOE gene variations on LDL-cholesterol levels and on the variable phenotypic expression of the disease.Methods and resultsFifty six subjects were screened for mutations in the LDLR gene through direct sequencing. The causative mutation was found to segregate with the disease in each family and a new frameshift mutation, p.Met767CysfsX21, was identified in one family. The distribution of total- and LDL-cholesterol levels, adjusted for age and gender, among homozygous and heterozygous ADH patients varied widely. Within seven families, nine subjects presented low LDL-cholesterol levels despite carrying a mutation in the LDLR gene. To identify the molecular actors underlying this phenotypic variability, the PCSK9 gene was screened using direct sequencing and/or enzymatic restriction analysis, and the apo E genotypes were determined. A new missense variation (p.Pro174Ser) in the PCSK9 gene was identified and characterized as a new putative loss-of-function mutation.ConclusionGenetic variations in PCSK9 and APOE genes could explain only part of the variability observed in the phenotypic expression in Tunisian ADH patients carrying mutations in the LDLR gene. Other genetic variants and environmental factors very probably act to fully explain this phenotypic variability.     

Role of Fetal Sex in the Outcome of Antenatal Glucocorticoid Treatment to Prevent Respiratory Distress Syndrome: Systematic Review and Meta-Analysis

BackgroundAntenatal glucocorticoid (AGC) therapy has been associated with a decrease in respiratory distress syndrome (RDS). While preterm males remain at greater risk of RDS than females, the role of fetal sex in AGC response is not well known.ObjectivesTo review the available evidence regarding the effect of fetal sex in the prevention of RDS using AGC.MethodWe conducted a systematic review and meta-analysis of RCTs to compare the effect of AGC in male and female infants with regard to the rates of RDS, intra-ventricular hemorrhage (IVH) grades III and IV, and neonatal mortality. Random effects with 95% confidence intervals were assessed in both groups and relative risks were compared using mixed regression.ResultsFrom 248 potentially eligible articles, we included eight in the analysis for a total of 1109 male and 968 female infants. Both male and female infants had a significant decrease in the risks, but no difference between the sexes was observed in terms of reduction in RDS (RR 0.50; 95% CI 0.33 to 0.77 for males, and RR 0.57; 95% CI 0.43 to 0.75 for females, P = 0.99), reduction in IVH (P = 0.98), and reduction in neonatal mortality (P = 0.43). In a sub-analysis, use of betamethasone was associated with a significant decrease in the rate of RDS in males (RR 0.29; 95% CI 0.15 to 0.57) but dexamethasone was not (RR 0.78; 95% CI 0.57 to 1.07). Conversely, dexamethasone use was significantly helpful in females (RR 0.51; 95% CI 0.32 to 0.81) but betamethasone was not (RR 0.62; 95% CI 0.38 to 1.00).ConclusionThe effect of AGC for prevention of RDS is similar in females and males. However, futures studies should investigate the type of AGC according to fetal/neonatal sex.     

Chemical composition and antibacterial activity of Pinus halepensis Miller growing in West Northern of Algeria

Objective

To find new bioactive natural products, the chemical composition and to sudy the antibacterial activity of essential oil components extracted from the aerial parts of the Algerian aromatic plant Pinus halepensis Miller (P. halepensis) (needles, twigs and buds).

Methods

The essential oil used in this study was isolated by hydrodistillation using a Clevenger-type apparatus according to the European Pharmacopoeia. The chemical composition was investigated using GC-retention indices (RI) and GC-MS.

Results

Forty-nine compounds, representing 97.9% of the total collective oil, were identified. Essential oil was dominated by hydrocarbon compounds (80.6%) especially monoterpenes (65.5%). The major compounds from ten oils stations were: myrcene (15.2%-32.0%), α-pinene (12.2%-24.5%), E-β-caryophyllene (7.0%-17.1%), terpinolene (1.8%-13.3%), 2-phenyl ethyl isovalerate (4.8%-10.9%), terpinene-4-ol (1.0%-8.2 %) and sabinene (1.5%-6.3%). The intra-species variations of the chemical compositions of P. halepensis aerial parts essential oils from ten Algerian sample locations were investigated using statistical analysis. Essential oil samples were clustered in 2 groups by hierarchical cluster analysis, according to their chemical composition. The essential oil revealed an interesting antimicrobial effect against Lysteria monocytogenes, Enterococcus faecalis, Pseudomonas aeruginosa, Acinetobacter baumanii, Citrobacter freundii and Klebsiella pneumoniae.

Conclusions

These results suggest that the essential oil from P. halepensis may be a new potential source as natural antimicrobial applied in pharmaceutical and food industries.     

N-terminal proB-type natriuretic peptide levels aid the diagnosis of left ventricular dysfunction in patients with severe acute exacerbations of chronic obstructive pulmonary disease and renal dysfunction

Background and objective: The aim of this study was to assess the performance of N‐terminal proB‐type natriuretic peptide (NT‐proBNP) levels for the diagnosis of left ventricular dysfunction in patients with severe acute exacerbations of chronic obstructive pulmonary disease (COPD) and renal dysfunction. Methods: NT‐proBNP levels at admission were measured in consecutive patients admitted to two participating intensive care units with acute exacerbations of COPD. Left ventricular dysfunction was assessed on the basis of clinical and echocardiographic criteria. The performance of NT‐proBNP levels was evaluated in patients with or without renal dysfunction. Results: Among the 120 patients included in the study, 70 had impaired renal function, defined as a glomerular filtration rate of <90 mL/min/1.73 m². NT‐proBNP levels were inversely correlated with glomerular filtration rate (Spearman's correlation coefficient = ?0.457, P < 0.001). Overall, left ventricular dysfunction was diagnosed in 58 patients (48.3%). Median NT‐proBNP levels were significantly higher in these patients, irrespective of whether their renal function was normal (3313 (interquartile range (IQR) 4603) vs 337 (IQR 695) pg/mL, P < 0.001) or impaired (5692 (IQR 10714) vs 887 (IQR 1165) pg/mL, P < 0.001). The areas under the receiver operating characteristic curves were 0.87 and 0.78, respectively. The threshold NT‐proBNP value with the highest diagnostic accuracy was greater in the setting of renal dysfunction (2000 pg/mL; sensitivity 71%, specificity 82%, compared with 1000 pg/mL in patients with normal renal function; sensitivity 94%, specificity 82%). Multivariate analysis showed that left ventricular dysfunction and glomerular filtration rate were independently associated with elevated NT‐proBNP levels. Conclusions: NT‐proBNP remains an accurate biomarker for the diagnosis of left ventricular dysfunction associated with acute exacerbations of COPD. Threshold values of NT‐proBNP were higher in patients with impaired renal function than in those with normal renal function.     

Childhood leishmaniasis: report of 106 cases

In Tunisia there are three epidemic clinical forms of cutaneous leishmaniasis. They are associated with three different species of Leishmania and are observed in different geographical areas. We undertook a single-center retrospective analysis of childhood leishmaniasis in order to describe epidemio-clinical profile, therapeutic characteristics and clinical outcomes of affected patients. The study comprises 166 children with 132 lesions of cutaneous leishmaniasis. The subjects ages range from 5 months to 15 years (average 8.75 years). The F:M sex ratio is 1.3. Leishmaniasis affects grown-up children in 74.5 percent of the cases. All of our patients live in an endemic area. The face is affected in 76.5 percent of cases. Mucosal leishmaniasis is present in 9 children (6.8 %). Clinical diagnosis confirmed by the parasitologic smear or histopathological examination in 89.6 percent of the cases. Treatment with intralesional meglumine antimoniate is done for 67 patients; the treatment regimen is one local injection (1 ml/cm(2)) per week until recovery. Systemic meglumine antimoniate is the initial therapy for 25 patients. Meglumine antimoniate treatment is well tolerated with no side-effects. All leishmaniasis lesions heal within an average period of 2.18 months. Childhood cutaneous leishmaniais is common in Tunisia. It has the characteristics of sporadic leishmaniasis. Mucosal leishmaniasis has a favorable outcome with no destruction, nor scaring deformity. The standard treatment remains intralesional meglumine antimoniate.