Production of Amidinyl Radicals via UV-Vis-Light Promoted Reduction of N-Arylthiophene-2-carboxamidoximes and Application to the Preparation of Some New N-Arylthiophene-2-carboxamidines.

A modern method for the preparation of some new N-arylthiophene-2-carboxamidines via amidinyl radicals generated using UV-vis-light promoting the reduction of N-arylthiophene-2-carboxamidoximes without any catalyst in a short amount of time, highly straight forward, and in an efficient manner is described. This method defeats the flaws of the conventional methods for the reduction of amidoxime derivatives to amidine derivatives, which require harsh conditions such as using a strong acid, high temperature, and expensive catalysts. Benzo[d]imidazoles, benzo[d]oxazoles, and amides can also be synthesized by applying this method. The photoproducts were analyzed by various spectroscopic and analytical techniques, including thin-layer chromatography, column chromatography, high-performance liquid chromatography, gas chromatography/mass spectrometry, IR, 1H NMR, 13C NMR, and MS. Notably, the chromatographic analyses proved that the best time for the production of N-arylthiophene-2-carboxamidines is 20 min. The reaction mechanism comprising pathways and intermediates was also suggested via the homolysis of N-O and C-N bonds.

A novel homozygous TPM1 mutation in familial pediatric hypertrophic cardiomyopathy and in silico screening of potential targeting drugs.

OBJECTIVE: Familial hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease. While sarcomeric gene mutations explain many HCM cases, the genetic basis of about half of HCM cases remains elusive. Here we aimed to identify the gene causing HCM in a non-consanguineous Saudi Arabian family with affected family members and a history of sudden death. The impact of the identified mutation on protein structure and potential drug targets were evaluated in silico. MATERIALS AND METHODS: Triplets (two HCM subjects and one patent ductus arteriosus (PDA) case) and unaffected parents were screened by targeted next-generation sequencing (NGS) for 181 candidate cardiomyopathy genes. In silico structural and functional analyses, including protein modeling, structure prediction, drug screening, drug binding, and dynamic simulations were performed to explore the potential pathogenicity of the variant and to identify candidate drugs. RESULTS: A homozygous missense mutation in exon 1 of TMP1 (assembly GRCh37-chr15: 63340781; G>A) was identified in the triplets [two HCM and one patent ductus arteriosus (PDA)] that substituted glycine for arginine at codon 3 (p.Gly3Arg). The parents were heterozygous for the variant. The mutation was predicted to cause a significant and deleterious change in the TPM1 protein structure that slightly affected drug binding, stability, and conformation. In addition, we identified several putative TPM1-targeting drugs through structure-based in silico screening. CONCLUSIONS: TPM1 mutations are a common cause of HCM and other congenital heart defects. To date, TPM1 has not been associated with isolated PDA; to our knowledge, this is the first report of the homozygous missense variation p.Gly3Arg in TPM1 associated with familial autosomal recessive pediatric HCM and PDA. The identified candidate TPM1 inhibitors warrant further prospective investigation.

Comparison of laparoscopic and open pyeloplasty in 100 patients with pelvi-ureteric junction obstruction.

BACKGROUND: This study aimed to determine whether the morbidity and outcome rates for laparoscopic transperitoneal dismembered pyeloplasty are different from those for dismembered pyeloplasty, to analyze the learning curve of laparoscopic pyeloplasty, and to determine whether preoperative stent placement affects outcome. METHODS: For this study, 49 laparoscopic pyeloplasties (period 2000-2005) and 51 open pyeloplasties (period 1992-2003) were reviewed. RESULTS: Compared with open procedures, laparoscopic procedures were associated with a longer mean operating time (159 vs 91 min; p < 0.001), a shorter mean time to normal diet (38 vs 72 h; p < 0.001), and a similar mean hospital stay (5 days; p = 0.6). The operative complication rates were 17% for primary laparoscopic pyeloplasties and 24% for primary open pyeloplasties. The rates were higher for secondary procedures. The success rates for primary and secondary procedures were, respectively, 98% (41/42) and 57% (4/7) for laparoscopy and 96% (46/48) and 67% (2/3) for open surgery. Failed procedures showed no improvement in loin pain or obstruction. At the 6-month follow-up evaluation, 29% of the open surgery patients but none of the laparoscopic surgery patients reported wound pain. CONCLUSIONS: The efficacy of laparoscopic pyeloplasty is equivalent to that of open pyeloplasty, with less wound pain at 6 months. The outcome for secondary procedures is inferior. There was a trend toward a reduction in complications and the conversion rates with time, suggesting that there may be a learning curve of approximately 30 laparoscopic pyeloplasty cases. Preoperative stent insertion did not seem to affect any objective measures of outcome for laparoscopic pyeloplasty.

The MTHFR C677T polymorphism is associated with mitral valve rheumatic heart disease.

OBJECTIVE: Rheumatic heart disease (RHD) is a serious complication of rheumatic fever (RF). Plasma homocysteine (Hcy) levels are increased in RHD patients. MTHFR catalyzes the irreversible conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate and plays a vital role in Hcy metabolism. We hypothesize that the MTHFR C677T polymorphism is associated with a risk of RHD. PATIENTS AND METHODS: Eighty-six patients with RHD and 130 matched controls without a history of RHD were eligible for the study. The diagnosis of RHD was made according to modified Jones' criteria and echocardiography. Using echocardiography, RHD patients were further divided into mitral valve lesion (MVL) and combined valve lesion (CVL) groups. MTHFR C677T polymorphisms were genotyped by DNA sequencing. The chi-squared test was used to evaluate differences in genotypes. RESULTS: Control genotypes were in Hardy-Weinberg equilibrium. The C677T homozygous genotype (OR = 4.09; 95% CIs 1.16-14.44; p = 0.020) and recessive model (TT vs. CC+CT; OR = 4.05; 95% CIs 1.17-14.04; p = 0.019) were significantly associated with MVL RHD. CONCLUSIONS: This is the first study to investigate the association between the MTHFR C677T polymorphism and risk of RHD. The MTHFR C677T polymorphism is associated with RHD in patients with MVLs, perhaps via an Hcy-mediated cytokine effect.

Angiotensin-converting enzyme gene insertion deletion (ACE I/D) polymorphism in Saudi children with congenital heart disease.

OBJECTIVE: Congenital heart diseases (CHDs) are the leading cause of infant deaths worldwide. Angiotensin-converting enzyme (ACE) gene I/D polymorphism is associated with many cardiovascular diseases. The precise relationship between this polymorphism and CHDs is not clear. The aim of this work is to determine the normal distribution of I/D polymorphism in Saudi citizens and to test for any association between this polymorphism and CHDs in Saudi children. PATIENTS AND METHODS: Ninety-six CHD cases and 145 controls were included in this study. DNA was isolated from their peripheral blood, and then ACE I/D gene polymorphism was assayed by polymerase chain reaction (PCR). RESULTS: There was no significant difference among the frequencies of the DD, DI and II genotypes in patients and controls [39 (41%), 64 (44%), 48 (51%) and 62 (43%), 7 (7%), 19 (13%)] respectively (p-value = 0.3 and OR (95% CI) = 0.3). There was no significant difference between D allele (DD+DI) and II genotype distribution among patients and controls [p-value = 0.2 & OR (95% CI) = 1.9 (0.8-4.7)]. Moreover, there was no difference between I allele (II+DI) and DD frequency [p-value = 0.8 & OR = 0.9, CI = 0.5-1.5]. CONCLUSIONS: ACE I/D gene polymorphism is not associated with CHDs in Saudi children. Further large-scale studies are necessary to establish our findings.