Efficacy of antiepileptic drugs in the era of pharmacogenomics: A focus on childhood

BackgroundIn recent years advances in the field of pharmacogenomics have expanded the concept for more individualized treatments. Our aim is to provide literature data about the relationship between genetic polymorphisms and efficacy of antiepileptic drugs in children.MethodsPubmed was used as the main medical database source. Only original research papers were considered. No year-of-publication restriction was placed. Quality of evidence was assessed according to American Academy of Neurology guidelines.ResultsA total of 12 cross-sectional and case–control studies fulfilled our selection criteria. ABCB1 gene was associated with drug responsiveness in 2 out of 6 studies and ABCC2 gene in 1 out of 1 studies. SCN1A gene was also associated with seizure control in 4 out of 5 studies. Cytochrome P450 genes were found to significantly affect drug responsiveness in 2 out of 4 studies, while polymorphisms of uridinediphosphateglucuronosyltransferaseUGT2B7 gene predisposed to drug-resistance in 1 out of 2 studies.ConclusionVariability in genes coding for sodium channels, drug transporters and cytochrome P450 enzymes can have a significant impact on response to antiepileptic drugs. Larger prospective studies with better stratification of samples are needed to shed light on these associations.     

Epigenetics and therapeutic targets in gastrointestinal malignancies

Gastrointestinal (GI) malignancies account for substantial mortality and morbidity worldwide. They are generally promoted by dysregulated signal transduction and epigenetic pathways, which are controlled by specific enzymes. Recent studies demonstrated that histone deacetylases (HDACs) together with DNA methyltransferases (DNMTs) have crucial roles in the signal transduction/epigenetic pathways in GI regulation. In this review, we discuss various enzyme targets and their functional mechanisms responsible for the regulatory processes of GI malignancies. We also discuss the epigenetic therapeutic targets that are mainly facilitated by DNMT and HDAC inhibitors, which have functional consequences and clinical outcomes for GI malignancies.     

Evaluation on the persistence of anti-HPV immune responses to the quadrivalent HPV vaccine in Chinese females and males: Up to 3.5 years of follow-up

BackgroundThis was an extension study of a randomized, double-blind, placebo-controlled immunogenicity and safety study of the quadrivalent human papillomavirus (qHPV) (HPV 6, 11, 16, and 18) vaccine conducted in Chinese female subjects aged 9–45 years and male subjects aged 9–15 years. To investigate the persistence of anti-HPV 6, -11, -16, and -18 responses among Chinese subjects, subjects enrolled in the base study were followed up at around month 42 (approximately 3.5 years after vaccination).MethodsAmong 600 subjects enrolled in the base study, a total of 468 subjects consented for participation in the extension study. Anti-HPV 6, -11, -16, and -18 antibodies were detected by the competitive Luminex immunoassay (cLIA) and total IgG Luminex immunoassay (IgG LIA).ResultsAmong the female subjects who received the qHPV vaccine, the proportions of subjects remained seropositive were high with both the cLIA and IgG LIA for HPV type 6, 11, and 16 through approximately 42 months following the first dose vaccination. For HPV 18, the seropositivity rate remained high as 82.0% with the IgG LIA, while it decreased to 53.6% with the cLIA, which was similar to the findings observed in other studies. The seropositivity rates remained high at month 42 for all qHPV types with both the cLIA and IgG LIA among the male subjects.ConclusionsAdministration of a 3-dose regimen of qHPV vaccine induces durable anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 responses among Chinese subjects for at least 3.5 years after vaccination.ClinicalTrials.gov registry: NCT01427777     

Scoring systems in acute pancreatitis: Which one to use in intensive care units?

Purpose

The aim of the study was to assess and compare the efficacy of various scoring systems in predicting the severity and outcome of patients with acute pancreatitis (AP) admitted in intensive care unit (ICU).

Methods

Prospective, single institution review of 55 consecutive AP patients admitted in ICU during a 2-year period. Disease severity scores and mortality predictions were calculated using the collected data in the first 48 hours of ICU admission for Ranson and Glasgow scores and in the first 24 hours for other scores.

Results

Forty-two patients (76.4%) developed severe pancreatitis. Intensive care unit and 30-day mortality was 18.2% and 27.3%, respectively. Use of mechanical ventilation (MV) was an independent predictor of outcome on multivariate analysis with lack of MV being protective (adjusted odds ratio, 0.003; 95% confidence interval [CI], 0.00001-0.67; P = .04). All scoring systems had comparable accuracy in predicting severity and 30-day mortality, but sequential organ failure assessment (SOFA) score had greater efficacy with its area under curve for predicting severity and 30-day mortality being 0.81 (95% CI, 0.69-0.92) and 0.93 (95% CI, 0.85-0.99), respectively. Sensitivity and specificity (SOFA score, >4) was 76.2% and 69.2%, respectively, for predicting severity, and sensitivity and specificity (SOFA score, >8) was 86.7% and 90%, respectively, for predicting 30-day mortality.

Conclusions

Use of MV is an independent predictor of outcome in AP patients admitted to ICU. Although all scoring systems had reliable accuracy in predicting severity and outcome, SOFA score performed better with additional advantages of easy applicability and timely assessment.     

Microsatellite mutation in the maternally/paternally transmitted D18S51 locus: two cases of allele mismatch in the child

BACKGROUND: We investigated 2 cases of paternity dispute with 17 autosomal short tandem repeats (STR), that indicated a mismatch to the maternally and paternally inherited allele at D18S51 locus in children under inquiry. METHODS: 17 autosomal and Y STR loci were analyzed using AmpFlSTR Identifiler, PowerPlex 16, AmpFlSTR(R)Y-filertrade mark kits. The mitochondrial DNA hypervariable regions HV1 and HV2 and 6 STR markers on X chromosome were amplified and sequenced. RESULTS: In case M1, allelic representation in the mother, questioned child and suspected father was 14/19, 12/20 and 12/14 respectively. A complete match with the mother at 6 X STR loci and mitochondrial hypervariable regions was observed. In case F1, allelic representation was 13/14, 14/20 and 16/18 respectively. A complete match with the father at 17 Y chromosome STR loci was observed. D18S51 sequence analysis indicates the expansion of 1 repeat in M1 and 2 repeats in F1 leading to allele mismatch in the child. CONCLUSION: The probability of maternity and paternity were 0.999999 and 0.999999 respectively. This is the first report of a maternally/paternally transmitted D18S51 mutations in the paternity DNA testing. These results conclusively determined that the mother and suspected father are the biological parents of the questioned children in both the cases.     

Synthesis, antimicrobial activity, and molecular modeling of novel 4-(3-(4-benzylpiperazin-1-yl)propoxy)-7-methoxy-3-substituted phenyl-2H-chromen-2-one

A series of novel 4-(3-(4-benzylpiperazin-1-yl)propoxy)-7-methoxy-3-substituted phenyl-2H-chromen-2-one (7a–7j) were synthesized by the reductive amination of 7-methoxy-3-phenyl-4-(3-piperizin-1-yl-propaxy)chromen-2-one (6) with different substituted aromatic aldehydes by using sodium cyanoborohydride in methanol. The newly synthesized compounds were purified and their structures were characterized by IR, ¹H NMR, ¹³C NMR, and mass spectroscopy. The representative analogs were screened for in vitro antimicrobial activity. The compounds exhibited significant antibacterial and antifungal activity as that of standards. The data was further compared with structure-based investigations using docking studies with the crystal structure of oxidoreductase (1XDQ and 3QLS) protein organisms. The estimated score by genetic algorithm was found to have a good correlation with the experimental inhibitory potency of the derivatives.