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Background: Coronary artery disease (CAD) and its ultimate consequence - myocardial infarction (MI) - are major causes of sudden cardiac death (SCD). Previous studies have demonstrated the role of genetic polymorphisms in the risk of SCD and ventricular arrhythmia (VA) during MI., Objectives: To investigate the association between single nucleotide polymorphisms (SNPs) of genes implicated in congenital cardiac arrhythmias and the risk of developing VA in the context of MI., Material and Methods: We performed a case-control study in which we genotyped 4 SNPs (rs11708996, rs10428132, rs9388451, and rs2200733) in 469 subjects using amplification refractory mutation system (ARMS) and a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). These SNPs are located in the SCN5A, SCN10A, HEY2, and PITX2 genes, respectively. We first compared 70 patients who had developed VA in the context of MI with 141 healthy controls; next, we compared VA patients with 258 MI patients who did not develop VA during a 1-year follow up. The statistical analyses were adjusted for sex and age., Results: Compared to the controls, 2 polymorphisms were significantly associated with the development of VA during MI, located in SCN5A rs11708996 (p = 0.001) and SCN10A rs10428132 (p = 0.001). Similar results were found when comparing VA cases with patients without VA. No associations of HEY2 and PITX2 polymorphisms were observed., Conclusions: Our results suggest that the rs11708996 and rs10428132 polymorphisms of the SCN5A and SCN10A genes may contribute to an elevated risk of developing VA in the context of MI. The associated alleles or genotypes may be used to predict the risk, and thus prevent eventual SCD.

Brugada syndrome (BrS) is an autosomal-dominant genetic cardiac disorder caused in 18-30 % of the cases by SCN5A gene mutations and manifested by an atypical right bundle block pattern with ST segment elevation and T wave inversion in the right precordial leads. The syndrome is usually detected after puberty. The identification of BrS in pediatric patients is thus a rare occurrence, and most of the reported cases are unmasked after febrile episodes. Usually, having a family history of sudden death represents the first reason to perform an ECG in febrile children. However, this practice makes the sporadic cases of cardiac disease and specially the asymptomatic ones excluded from this diagnosis. Here, we report a sporadic case of a 2-month-old male patient presented with vaccination-related fever and ventricular tachycardia associated with short breathing, palpitation and cold sweating. ECG changes were consistent with type 1 BrS. SCN5A gene analysis of the proband and his family revealed a set of mutations and polymorphisms differentially distributed among family members, however, without any clear genotype-phenotype correlation. Based on our findings, we think that genetic testing should be pursued as a routine practice in symptomatic and asymptomatic pediatric cases of BrS, with or without family history of sudden cardiac death. Similarly, our study suggests that pediatrician should be encouraged to perform an ECG profiling in suspicious febrile children and quickly manage fever since it is the most important factor unmasking BrS in children.

Background: The human cardiac action potential in atrial and ventricular cells is initiated by a fast-activating, fast-inactivating sodium current generated by the SCN5A/Nav1.5 channel in association with its β1/SCN1B subunit. The role of Nav1.5 in the etiology of many cardiac diseases strongly suggests that proper regulation of cell biology and function of the channel is critical for normal cardiac function. Hence, numerous recent studies have focused on the regulatory mechanisms of Nav1.5 biosynthetic and degradation processes as well as its subcellular localization., Objective: The purpose of this study was to investigate the role of microRNAs in the Scn5a/Nav1.5 posttranscriptional regulation., Methods: Quantitative polymerase chain reaction, immunohistochemical and electrophysiological measurements of distinct microRNA gain-of-function experiments in cardiomyocytes for the assessment of Scn5a expression., Results: Functional studies of HL-1 cardiomyocytes and luciferase assays in fibroblasts demonstrate that Scn5a is directly (miR-98, miR-106, miR-200, and miR-219) and indirectly (miR-125 and miR-153) regulated by multiple microRNAs displaying distinct time-dependent profiles. Cotransfection experiments demonstrated that miR-219 and miR-200 have independent opposite effects on Scn5a expression modulation. Of all the microRNAs studied, only miR-219 increases Scn5a expression levels, leading to altered contraction rhythm of HL-1 cardiomyocytes. Electrophysiological analyses in HL-1 cells revealed that miR-219 increases the sodium current. In vivo administration of miR-219 does not alter normal cardiac rhythm, but abolishes some of the effects of flecainide intoxication in mice, particularly QRS prolongation., Conclusion: This study demonstrates the involvement of multiple microRNAs in the regulation of Scn5a. Particularly, miR-219 increases Scn5a/Nav1.5 transcript and protein expression. Our data suggest that microRNAs, such as miR-219, constitute a promising therapeutical tool to treat sodium cardiac arrhythmias., (Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Few data regarding molecular diagnosis of primary distal renal tubular acidosis (DRTA) in Tunisian population are available., Case Report: 25-day-old male patient from consanguineous parents of Tunisian origin diagnosed with DRTA and without hearing impairment observed later in life. ATP6V0A4 gene sequencing demonstrated a novel homozygous G deletion in exon 13 (c.1221delG, p.Met408CysfsX10), leading to a premature stop codon., Conclusion: A novel ATP6V0A4 gene mutation confirmed autosomal recessive DRTA with normal hearing in the patient. Molecular analysis may help to rapidly diagnose autosomal recessive DRTA in Tunisian population.

It is generally agreed that the protease inhibitor (PI) alleles PI*S (Val264Glu) and PI*Z (Lys342Glu) are the most common alpha 1 antitrypsin deficiency variants worldwide, but the PI*Mmalton allele (ΔPhe52) prevails over these variants in some Mediterranean regions. In eastern Tunisia (Mahdia), we screened 100 subjects with chronic obstructive pulmonary disease for these variants. The PI*S and PI*Z alleles were genotyped by the previously described SexAI/Hpγ99I RFLP-PCR. We provide here a new method for PI*Mmalton genotyping using mismatched RFLP-PCR. These methods are suitable for routine clinical application and can easily be reproduced by several laboratories, since they do not require extensive optimization, unlike the previously described bidirectional allele-specific amplification PCR for PI*Mmalton genotyping. Our results were in agreement with previous reports from central Tunisia (Kairouan), suggesting that the PI*Mmalton mutation is the most frequent alpha 1 antitrypsin deficiency-related mutation in Tunisia.

Several polymorphisms in the complement components factor H and CFHR1 are associated with higher risk to develop atypical Haemolytic Uraemic Syndrome (aHUS) in Caucasians. We have determined the prevalence of these polymorphisms in Tunisian controls by using genetic and immunological techniques. No differences in the frequency of the factor H risk alleles c.-331C>T, c.2089A>G or c.2881G>T between Tunisian and Caucasians were found. On the contrary, the analysis of CFHR1 polymorphism revealed a higher frequency of Tunisian individuals homozygous for the CFHR1*Del (deleted) allele, and of individuals presenting the CFHR1*A phenotype. These results suggest distinct contributions of factor H and CFHR1 polymorphisms to aHUS in Tunisian and Caucasian populations., (© 2011 Blackwell Publishing Ltd.)

Chronic obstructive pulmonary disease (COPD) is characterized by systemic and local chronic inflammation and oxidative stress. The sources of the increased oxidative stress in COPD patients derive from the increased burden of inhaled oxidants such as cigarette smoke and other forms of particulate or gaseous air pollution and from the increase in reactive oxygen species (ROS) generated by several inflammatory, immune, and structural airways cells. There is increasing evidence that genetic factors may also contribute to the pathogenesis if COPD, particularly antioxidant genes, which may confer a susceptibility to environmental insults such as cigarette smoke and thereafter development of COPD. Consequently, heme oxygenase-1 (HO-1), superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), microsomal epoxide hydrolase (EPHX1), and cytochrome P450 (CYP) genetic polymorphisms may have an important role in COPD pathogenesis. In this review the authors summarized the most recent findings dealing with these antioxidant genes contributing to the free radical neutralization and xenobiotic enzymes playing a role in different phases of cell detoxification reactions related to the redox status imbalance in COPD, with an emphasis on their possible roles in disease progression.

Smoking is considered as the major causal factor of chronic obstructive pulmonary disease (COPD). Nevertheless, a minority of chronic heavy cigarette smokers develops COPD. This suggests important contribution of other factors such as genetic predisposing. Our objective was to investigate combined role of EPHX1, GSTP1, M1 and T1 gene polymorphisms in COPD risk, its phenotypes and lung function impairment. Prevalence of EPHX1, GSTP1, M1 and T1 gene polymorphisms were assessed in 234 COPD patients and 182 healthy controls from Tunisia. Genotypes of EPHX1 (Tyr113His; His139Arg) and GSTP1 (Ile105Val; Ala114Val) polymorphisms were performed by PCR-RFLP, while the deletion in GSTM1 and GSTT1 genes was determined using multiplex PCR. Analysis of combinations showed a significant association of 113His/His EPHX1/null-GSTM1 (OR=4.07) and null-GSTM1/105Val/Val GSTP1 (OR =3.56) genotypes with increased risk of COPD (respectively P=0.0094 and P=0.0153). The null-GSTM1/ null-GSTT1, 105Val/Val GSTP1/null GSTT1, 113His/His EPHX1/null-GSTM1 and null-GSTM1/105Val/Val GSTP1 genotypes were related to emphysema (respectively P=0.01; P=0.009; P=0.008 and P=0.001). Combination of 113His/His EPHX1/null-GSTM1 genotypes showed a significant association with the decrease of Δ FEV1 in patients (P =0.028).In conclusion, our results suggest combined EPHX1, GSTP1, GSTM1 and GSTT1 genetic polymorphisms may play a significant role in the development of COPD, emphysema and decline of the lung function.

It is well known that cigarette smoking is the major risk factor for chronic obstructive pulmonary disease (COPD). However, only 10%-20% of chronic heavy cigarette smokers develop symptomatic disease, which suggests the presence of genetic susceptibility. Microsomal epoxide hydrolase (EPHX1) is an enzyme involved in the protective mechanism against oxidative stress. It has been reported that gene polymorphisms of this enzyme may be associated with variations in EPHX1 activity. In this study, we aimed at investigating the relationship between EPHX1 polymorphisms and susceptibility to COPD in the Tunisian population. EPHX1 exon 3 (rs1051740, Tyr113His) and exon 4 (rs2234922, His139Arg) polymorphisms were genotyped by polymerase chain reaction followed by restriction fragment length polymorphism analysis. These techniques were used to examine a total of 416 Tunisian individuals, including 182 blood donors and a group of 234 COPD patients. All subjects were not related. An increased risk for COPD was observed in subjects with EPHX1 His113-His113 genotype (odds ratio = 2.168; confidence interval 1.098-4.283; p = 0.02386). However, multivariate logistic regression analysis showed no significant relationship between the mutant genotype and the disease after adjustment for sex, age, body mass index, smoking status, and pack-year smoking (odds ratio = 1.524; confidence interval, 0.991-6.058; p = 0.06137). Regarding the two subtypes of COPD, our investigations demonstrated that there is no significant correlation between exon 3 polymorphism and the chronic bronchitis subgroup (p = 0.09034). The relation between exon 3 polymorphism and emphysema was significant in the univariate analysis (p = 0.02257), but no association was found after controlling for classic risk factors (p = 0.06273). In conclusion, our results showed that there is a weak relation between 113His genotype and COPD, and no apparent relation between 139Arg and COPD in the studied Tunisian population.

Alpha1-antitrypsin (AAT) is a highly polymorphic protein with more than 120 variants that are classified as normal (normal protein secretion), deficient (reduced circulating AAT level caused by defective secretion) or null (no protein secretion). Alpha1-antitrypsin deficiency, one of the most common genetic disorders, predisposes adults to pulmonary emphysema and, to a lesser extent, chronic liver disease and cirrhosis. In this report, we provide additional sequence data for alpha1-antitrypsin based on the characterization of a novel variant detected in a 53-year-old heterozygous patient with chronic obstructive pulmonary disease. The mutation occurred on a PI*M2 base allele and was characterized by a T → C transition at nt 97 in exon II that led to the replacement of phenylalanine by leucine (F33L). Since the mutation was found in the heterozygous state with the expression of a normally secreted variant (PI*M1) it was not possible to assess the pattern of F33L secretion. However, computational analyses based on evolutionary, structural and functional information indicated a reduction of 23 Å (3) in the side chain volume and the creation of a cavity in the protein hydrophobic core that likely disturbed the tridimensional structure and folding of AAT. The accuracy of the in silico prediction was confirmed by testing known mutations.

Alpha-1-antitrypsin (AAT) plays an important role in the pathogenesis of emphysema, the pathological lesion underlying the majority of the manifestations of Chronic Obstructive Pulmonary Disease (COPD). In this study we tested the hypothesis that common AAT polymorphisms influence the risk of developing COPDs. We investigated PiM1 (Ala213Val), PiM2 (Arg101His), PiM3 (Glu376Asp), PiS (Glu264Val) and PiZ (Glu342Lys) SERPINA1 alleles in 100 COPD patients and 200 healthy controls. No significant differences were observed in allele frequencies between COPD patients and controls, neither did haplotype analysis show significant differences between the two groups. A cross-sectional study revealed no significant relationship between common SERPINA1 polymorphisms (PiM1, PiM2, PiM3) and the emphysematous type of COPD. In addition, FEV(1) annual decline, determined during a two-year follow up period, revealed no difference among carriers of the tested polymorphisms.

Background: AATD is one of the most common inherited disorders in the World. However, it is generally accepted that AATD in North African populations is not a risk factor for lung and/or liver disease, based on a number of small studies. We therefore planned a screening study for detection of AATD in patients with OLD in a cohort of patients from Kairouan in central Tunisia., Methods: One hundred twenty patients with OLD (asthma, emphysema, COPD) were enrolled in the screening programme. Laboratory diagnosis for AATD was performed according to current diagnostic standards., Results: We found that 6/120 OLD patients carried an AAT deficient allele, 1 PI*MZ, 1 PI*MPlowel, 3 PI*MMmalton, 1 PI*MMwurzburg., Conclusion: this pilot study demonstrated that alleles related to deficiency of AAT are not absent in the Tunisian population, and that rare AATD variants prevailed over commonest PI*Z variant. These results would support a larger scale screening for AATD in Tunisia.

The effect of extracts obtained from Acacia salicina on genotoxicity and SOS response induced by Benzo(a)pyrene (B[a]P) as well as nifuroxazide was investigated in a bacterial assay system, i.e., the SOS chromotest with Escherichia coli PQ37. Preparations obtained from the leaves of A. salicina exhibited no genotoxicity either with or without the external S9 activation mixture. However, all extracts significantly decreased the genotoxicity induced by (B[a]P) and nifuroxazide. Ethyl acetate, methanol and TOF extracts exhibited the highest inhibition level of the SOS response induced by the direct mutagen nifuroxazide. Whereas, aqueous, ethyl acetate and methanol extracts displayed the greatest level of protection towards the indirect mutagen, (B[a]P), induced response. In addition to their antigenotoxic activity, TOF, aqueous, methanol and chloroform extracts showed an important free radical scavenging activity towards the 1,1-diphenyl 2-picrylhydrazyl (DPPH) free radical. These extracts showed IC(50) value of 36, 73, 65, and 87μg/ml respectively. Taken together, our finding showed that A. salicina exhibits significant antioxidant and antigenotoxic activities., (Copyright © 2006 Elsevier B.V. All rights reserved.)

For centuries, plants have been used in traditional medicines and there has been recent interest in the chemopreventive properties of compounds derived from plants. In the present study, we investigated the effects of extracts of Acacia salicina leaves on the genotoxicity of benzo[a]pyrene (B(a)P) and nifuroxazide in the SOS Chromotest. Aqueous, total oligomers flavonoids (TOF)-enriched, petroleum ether, chloroform, ethyl acetate, and methanol extracts were prepared from powdered Acacia leaves, and characterized qualitatively for the presence of tannins, flavonoids, and sterols. All the extracts significantly decreased the genotoxicity induced by 1 microg B(a)P (+S9) and 10 microg nifuroxazide (-S9). The TOF-enriched and methanol extracts decreased the SOS response induced by B(a)P to a greater extent, whereas the TOF-enriched and the ethyl acetate extracts exhibited increased activity against the SOS response produced by nifuroxazide. In addition, the aqueous, ethyl acetate, and methanol extracts showed increased activity in scavenging the 1,1-diphenyl- 2-picrylhydrazyl (DPPH) free radical, while 100-300 microg/ml of all the test extracts were active in inhibiting O2-production in a xanthine/xanthine oxidase system. In contrast, only the petroleum ether extract was effective at inhibiting nitroblue tetrazolium reduction by the superoxide radical in a nonenzymatic O2- -generating system. The present study indicates that extracts of A. salicina leaves are a significant source of compounds with antigenotoxic and antioxidant activity (most likely phenolic compounds and sterols), and thus may be useful for chemoprevention.