Attitudes about genetic testing and genetic testing intentions in African American women at increased risk for hereditary breast cancer.

PURPOSE: To evaluate attitudes about the benefits, limitations, and risks of genetic testing for BRCA1 and BRCA2 (BRCA1/2) mutations and explore testing intentions in African American women at increased risk for hereditary breast cancer. METHODS: Attitudes and intentions were evaluated by telephone in African American women (n = 74) at moderate and high risk for having a BRCA1/2 mutation. RESULTS: Attitudes about the benefits of genetic testing were endorsed at a higher rate relative to limitations and risks; however, only 30% of respondents indicated that they would definitely have testing. In regression analysis, women most likely to be considering testing were those with fatalistic beliefs about cancer and those who believed they had a BRCA1/2 mutation. Women who had two or more affected relatives were also most likely to be considering testing. Women who had a personal history of cancer and those who believed they were at high risk for developing breast cancer were most likely to report greater limitations and risks. Pros scores were higher among women older than age 50 and those who were unemployed. CONCLUSION: Although African American women at moderate and high risk for BRCA1/2 mutations report favorable attitudes about genetic testing, interest in testing may be limited. Women affected with cancer and those who believe they are at a higher risk for developing breast cancer may be most concerned about the negative consequences of testing. Increased attention may need to be given to beliefs about genetic testing and testing motivations during genetic counseling with African American women.     

Non-systemic delivery of topical brimonidine to the brain: A neuro-ocular tissue distribution study

To date, the risks of central nervous system (CNS) side effects of topically administered ophthalmic therapeutic agents are thought to be the consequence of systemic absorption of these drugs. This paper envisions the possibility of drug delivery to the CNS following ocular application through non-systemic routes. After single instillation of 50 μl of ³H-radiolabeled Alphagan® solution (0.2%) in the cul de sac of the right eye, three male albino rabbits (2–2.5 kg) were sacrificed at each time point (5, 15, 30 and 60 min). Both sides (eyes) specimens of aqueous humor, cornea, iris, lens, vitreous, conjunctiva, sclera, ciliary body, choroid, retina, optic nerve, optic tract and olfactory bulb were weighed, and blood samples were measured, before combustion in tissue oxidizer and radioactive liquid scintillation counting. Significant ³H-brimonidine levels were found in right and left optic nerves and tracts with extremely low corresponding drug levels in blood. Uveal tract (ciliary body, iris and choroid tissues) brimonidine levels were relatively high in the treated eye, and the highest among contralateral eye tissues. Our data provide the first case of good CNS availability after ocular application of conventional ophthalmic therapeutic agent, through non-systemic routes. Similar neuro-ocular pharmacokinetic studies should be adopted as a routine ocular therapeutics evaluation study.     

Ethanol feeding potentiates the pro-inflammatory response of Kupffer cells to cellular fibronectin

Background: Excessive alcohol consumption leads to the increased extracellular matrix deposition of cellular fibronectin (cFn) in the liver, which is also implicated as an initiating event in the fibrogenic process. We propose that cFn directly stimulates Kupffer cells (KCs), which are involved in the early response to tissue damage, to produce factors that enhance the progression of alcohol‐induced liver injury toward inflammation and fibrosis. Method: KCs were isolated from rats fed a control or ethanol liquid diet for 4 to 6 weeks. The effect of exogenous cFn on KC viability and the secretion of the cytokines, TNF‐α and IL‐6, as well as of matrix remodeling factors, MMP‐2 and TIMP‐2, was determined after 20 hours of cell culture. Results: For KCs from both control‐ and ethanol‐fed rats, viability remained unaffected by treatment with cFn. TNF‐α and IL‐6 production were increased in KCs exposed to cFn, with cells treated with 1, 2.5, and 5 μg/ml cFn secreting significantly higher levels of both cytokines compared with untreated cells (p < 0.05). Chronic ethanol administration resulted in a significantly enhanced secretion of IL‐6 by KCs regardless of treatment with cFn. When MMP‐2 protein and activity levels were measured by western blot analysis and gelatin zymography, respectively, we found that cFn stimulated a dramatic increase in both cells from ethanol‐ and control‐fed rats, with the KCs from ethanol animals being more responsive to cFn at higher concentrations (p < 0.05). Significantly higher levels of TIMP‐2, which inhibits both the activation and activity of MMP‐2, were secreted by KCs treated with 5 μg/ml cFn. Correspondingly, more pro‐MMP‐2 than active‐MMP‐2 was detected. Conclusion: Altogether, these results show that cFn stimulates KCs to produce factors that may enhance the promotion of tissue damage and that ethanol administration increases these responses.     

Impact of comorbid conditions on disease-specific quality of life in older men and women with atrial fibrillation

Quality of Life Research - Older persons with atrial fibrillation (AF) experience significant impairment in quality of life (QoL), which may be partly attributable to their comorbid diseases. A...     

Erratum to: investigation of metabolites for estimating blood deposition time

International Journal of Legal Medicine - Erratum to: Int J Legal Med (2017) https://doi.org/10.1007/s00414-017-1638-y     

Interaction of a Self-Emulsifying Lipid Drug Delivery System with the Everted Rat Intestinal Mucosa as a Function of Droplet Size and Surface Charge

Purpose. To investigate the interaction of positively charged self-emulsifying oil formulations (SEOF) following aqueous dilution as a function of resulting emulsion droplet charge and size with rat everted intestinal mucosa, adherent mucus layer and Peyer's patches, using cyclosporine A (CsA) as a lipophilic model drug. Methods. Droplet size determination (TEM technique) and -potential measurements were used to characterize the resulting emulsions. For the ex vivo interaction study, the well-known rat intestine everted sac technique was used in combination with confocal microscopy. Results. The positively charged oil droplets formed by SEOF dilutions at ratios of 1/50 and 1/10 elicited the stronger interaction with the mucosal surface. The positive charge of the smaller droplets was more readily neutralized, and even reversed in aqueous solutions containing moderate subphysiological mucin concentrations. Parameters such as droplet size, negativity of the epithelial mucosa potential and presence of the mucus layer on the epithelial surface affected drug mucosa uptake and the adhesion of the positively charged droplets to the rat intestinal mucosa. Conclusions. The enhanced electrostatic interactions of positively charged droplets with the mucosal surface are mostly responsible for the preferential uptake of CsA from the positively charged droplets as compared to negatively charged droplets irrespective of the experimental conditions used. The increased uptake of the CsA from the negatively charged oil droplets was consistent with the dilution extent, as expected, whereas in the positively charged droplets, an intermediate droplet size range was identified resulting in optimum drug uptake and clearly suggesting that drug uptake was not consistent with either dilution extent or droplet size.     

Repeat expansion and methylation-sensitive triplet-primed polymerase chain reaction for fragile X mental retardation 1 gene screening in institutionalised intellectually disabled individuals

INTRODUCTIONFragile X syndrome (FXS) is the most prevalent X-linked intellectual disability (ID) and a leading genetic cause of autism, characterised by cognitive and behavioural impairments. The hyperexpansion of a CGG repeat in the fragile X mental retardation 1 (FMR1) gene leads to abnormal hypermethylation, resulting in the lack or absence of its protein. Tools for establishing the diagnosis of FXS have been extensively developed, including assays based on triplet-primed polymerase chain reaction (TP-PCR) for detection and quantification of the CGG trinucleotide repeat expansion, as well as determination of the methylation status of the alleles. This study aimed to utilise a simple, quick and affordable method for high sensitivity and specificity screening and diagnosis of FXS in institutionalised individuals with ID.METHODSA total of 109 institutionalised individuals at the Center for Social Rehabilitation of Intellectual Disability Kartini, Temanggung, Central Java, Indonesia, were screened in a three-step process using FastFrax™ Identification, Sizing and Methylation Status Kits.RESULTSTwo samples that were classified as indeterminate with respect to the 41-repeat control at the identification step were subsequently determined to be non-expanded by both sizing and methylation status analyses. Two samples classified as expanded at the identification step were determined to carry full mutation expansions > 200 repeats that were fully methylated using sizing and methylation status analyses, respectively, yielding a disease prevalence of 1.83%.CONCLUSIONRepeat expansion and methylation-specific TP-PCR is practical, effective and inexpensive for the diagnosis of FXS, especially in high-risk populations of individuals with ID of undetermined aetiology.