Mutation Spectrum of Familial Adenomatous Polyposis Patients in Turkish Population: Identification of 3 Novel APC Mutations

BackgroundFamilial adenomatous polyposis (OMIM #175100) and MUTYH-associated polyposis (OMIM #608456) are rare cancer-prone disorders characterized by hundreds of adenomatous polyps in the colon and rectum, which have a high probability of malignant transformation. Attenuated familial adenomatous polyposis is a variant of familial adenomatous polyposis, which is a term used for the condition in which patients have less than 100 colorectal polyps. Germline heterozygous Adenomatous polyposis coli (APC) and biallelic MUTYH (mutY DNA glycosylase) pathogenic variations are responsible for familial adenomatous polyposis and MUTYH-associated polyposis respectively. The aim of this study is to discuss the clinical manifestations of patients having pathogenic APC and MUTYH variations.MethodsWe included 27 probands who have more than 10 colonic polyps in this study. After evaluation of their clinical and family histories, the probands were screened for APC and MUTYH variations via next generation sequencing. The family members of the probands carrying pathogenic variations were screened via Sanger sequencing. ResultsAmong 27 probands, pathogenic APC and MUTYH variations were detected in 3 and 6 probands respectively. In the APC gene, 3 novel truncating variations (p.Leu360*, p.Leu1489Phefs*23, and p.Leu912*) were detected in 3 unrelated probands. In the MUTYH gene, only 2 distinct pathogenic variations were detected (p.Pro295Leu and p.Glu480del) in the homozygous or compound heterozygous state.ConclusionIn this study, molecular etiology was clarified in 9 familial polyposis patients. The p.Pro295Leu and p.Glu480del variations seem to be common in the Turkish population and may be considered as a first-step genetic test in Turkish familial polyposis patients showing autosomal recessive inheritance. However more studies are needed to reveal the exact frequency of these variations.     

A Combined Pharmacodynamic Quantitative and Qualitative Model Reveals the Potent Activity of Daptomycin and Delafloxacin against Staphylococcus aureus Biofilms

Biofilms are associated with persistence of Staphylococcus aureus infections and therapeutic failures. Our aim was to set up a pharmacodynamic model comparing antibiotic activities against biofilms and examining in parallel their effects on viability and biofilm mass. Biofilms of S. aureus ATCC 25923 (methicillin-sensitive S. aureus [MSSA]) or ATCC 33591 (methicillin-resistant S. aureus [MRSA]) were obtained by culture in 96-well plates for 6 h/24 h. Antibiotic activities were assessed after 24/48 h of exposure to concentrations ranging from 0.5 to 512 times the MIC. Biofilm mass and bacterial viability were quantified using crystal violet and the redox indicator resazurin. Biofilms stained with Live/Dead probes were observed by using confocal microscopy. Concentration-effect curves fitted sigmoidal regressions, with a 50% reduction toward both matrix and viability obtained at sub-MIC or low multiples of MICs against young biofilms for all antibiotics tested. Against mature biofilms, maximal efficacies and potencies were reduced, with none of the antibiotics being able to completely destroy the matrix. Delafloxacin and daptomycin were the most potent, reducing viability by more than 50% at clinically achievable concentrations against both strains, as well as reducing biofilm depth, as observed in confocal microscopy. Rifampin, tigecycline, and moxifloxacin were effective against mature MRSA biofilms, while oxacillin demonstrated activity against MSSA. Fusidic acid, vancomycin, and linezolid were less potent overall. Antibiotic activity depends on biofilm maturity and bacterial strain. The pharmacodynamic model developed allows ranking of antibiotics with respect to efficacy and potency at clinically achievable concentrations and highlights the potential utility of daptomycin and delafloxacin for the treatment of biofilm-related infections.     

Diagnosis and management of rabies encephalitis in two patients in northwest Africa: A case series

In persons bitten by a stray dog, prompt administration of post‐exposure rabies vaccination, anti‐rabies immunoglobulin, and wound care can save lives. However, rabies is often fatal once the patient develops signs and symptoms. Here, we describe two fatal cases of rabies following a long delay after dog bites.     

A case of a retinitis pigmentosa and asteroid hyalosis

Asteroid hyalosis is a rare degenerative condition of the vitreous. No causal relationship between retinitis pigmentosa and asteroid hyalosis has been established. We report a case of a 65-year-old male admitted for progressive hemeralopia. Visual acuities were 2/10e in the right eye and 4/10e in the left eye. Ophthalmic examination revealed a large number of asteroid and refringent bodies, a typical retinitis pigmentosa with a cystoid macular oedema confirmed by fluorescein angiography. Electrodiagnostic testing revealed an altered electroretinogram. Visual fields showed a typical generalized constriction. We discuss the clinical aspects and physiopathogenic mechanisms of this rare association through this case and other cases found in the literature.     

The neuropathologic effects in rats and neurometabolic effects in humans of large-dose remifentanil

Given in clinically relevant large doses to rats, mu-opioids produce limbic system hypermetabolism and histopathology. This investigation extends these observations, in both rats and humans, for the short-acting drug remifentanil, which allows more precise control and assessment of the effects of duration of opioid exposure. We performed two series of experiments: one in rats for neuropathologic effects and the second in humans for neurometabolic effects. Fifty mechanically ventilated rats received saline solution or remifentanil 20-160 microg x kg(-1) x min(-1) for 3 h, followed by neuropathologic evaluation 7 days later. Four volunteers underwent induction of anesthesia and endotracheal intubation with propofol and rocuronium administration followed by remifentanil infusion at 1-3 microg x kg(-1) x min(-1) with positron emission tomography evaluation of cerebral metabolic rate for glucose. In rats, dose-related electroencephalogram activation was evident and 19 of 40 remifentanil-treated rats showed brain damage, primarily in the limbic system (P < 0.01). In humans, cerebral metabolic rate for glucose in the temporal lobe increased from 6.29 +/- 0.32 to 7.68 +/- 1.05 mg x 100 g(-1) x min(-1) (P < 0.05). These data indicate that prolonged large-dose remifentanil infusion is neurotoxic in rats with congruent metabolic effects with brief infusion in humans and suggest that some adverse effects reported in rats may be clinically relevant. IMPLICATIONS: This study demonstrates dose-related remifentanil neurotoxicity in physiologically controlled rats with congruent brain metabolic effects in four humans undergoing positron emission tomography evaluation during brief large-dose remifentanil anesthesia. These data suggest that some adverse effects reported in rats may be clinically relevant.     

Detection and genotyping of GBV-C virus in the United Arab Emirates

GB virus-C/Hepatitis G virus (GBV-C/HGV), collectively known as GBV-C, is spread widely and has been reported to be associated with non A-E hepatitis. The aim of the current project was to determine the rate of infection and genotypic characteristics of GBV-C in the United Arab Emirates (UAE). A total of 379 plasma/serum samples representing different populations in the UAE and comprising healthy as well as patients positive for HBV and HCV were screened using RT-PCR/nested PCR of the 5'-untranslated region (UTR). National subjects (n=168) and non-nationals residing in the UAE (n=211) were tested. The results obtained showed that the rate of GBV-C infection in healthy nationals, and those positive for HCV or HBV were 11.1%, 14.3%, and 5.7%, respectively, compared to 8.3%, 33.3%, and 8.6%, respectively, in non-nationals. No statistically significant correlation between infection with GBV-C and HCV or HBV (P>0.05) was found. Sequence analysis of the 5'-UTR using 37 and 46 clones from 8 and 6 healthy nationals and non-nationals, respectively, revealed the prevalence of the European/North American genotype 2 when compared to the five reference genotypes in GenBank.