DNA methylation in anal intraepithelial lesions and anal squamous cell carcinoma.

PURPOSE: Anal intraepithelial neoplasia is associated with human papillomavirus infection and may progress to invasive squamous cell carcinoma (SCC), which is increasing in immunocompromised patients. We hypothesize that anal intraepithelial neoplasia is associated with abnormal DNA methylation and that detection of these events may be used to improve screening programs. EXPERIMENTAL DESIGN: Seventy-six patients were identified who underwent anal cytology screening and subsequent biopsy at our institution between 1999 and 2004. The specimens from these patients included 184 anal biopsies [normal, n = 57; low-grade squamous intraepithelial lesion (LSIL), n = 74; high-grade squamous intraepithelial lesion (HSIL), n = 41; and invasive SCC, n = 12] and 37 residual liquid-based anal cytology specimens (normal, n = 11; LSIL, n = 12; HSIL, n = 14). The methylation status of the following genes was determined for each biopsy and cytology sample using real-time methylation-specific PCR: HIC1, RASSF1, RARB, CDKN2A, p14, TP73, APC, MLH1, MGMT, DAPK1, and IGSF4. RESULTS: Methylation-specific PCR analysis of biopsy samples revealed that DNA methylation was more common in SCC and HSIL than LSIL and normal mucosa. Specifically, methylation of IGSF4 and DAPK1 was prevalent in SCC (75% and 75% of cases, respectively) and HSIL (59% and 71%, respectively) but was absent in LSIL and normal biopsy samples. Methylation profiles of cytologic samples were similar to those found in the biopsy samples. CONCLUSIONS: Aberrant DNA methylation is a frequent event in anal HSIL and SCC. Methylation of IGSF4 and DAPK1 is specific for HSIL and SCC, and may serve as a useful molecular biomarker.     

Role of mouse CYP2E1 in the O-hydroxylation of p-nitrophenol: comparison of activities in hepatic microsomes from Cyp2e1(-/-) and wild-type mice.

Enzymatic activities are routinely used to identify the contribution of individual forms of cytochrome P450 in a particular biotransformation. p-Nitrophenol O-hydroxylation (PNPH) has been widely used as a measure of CYP2E1 catalytic activity. However, rat and human forms of CYP3A have also been shown to catalyze this activity. In mice, the contributions of CYP3A and CYP2E1 to PNPH activity are not known. Here we used hepatic microsomes from Cyp2e1(-/-) and wild-type mice to investigate the contributions of constitutively expressed and alcohol-induced murine CYP2E1 and CYP3A to PNPH activity. In liver microsomes from untreated mice, PNPH activity was much greater in wild-type mice compared with Cyp2e1(-/-) mice, suggesting a major role for CYP2E1 in catalyzing PNPH activity. Hepatic PNPH activities were not significantly different in microsomes from male and female mice, although the microsomes from females have dramatically higher levels of CYP3A. Treatment with a combination of ethanol and isopentanol resulted in induction of CYP3A proteins in wild-type and Cyp2e1(-/-) mice, as well as CYP2E1 protein in wild-type mice. The alcohol treatment increased PNPH activities in hepatic microsomes from wild-type mice but not from Cyp2e1(-/-) mice. Our findings suggest that in untreated and alcohol-treated mice, PNPH activity may be used as a specific probe for CYP2E1 and that constitutively expressed and alcohol-induced forms of mouse CYP3A have little to no role in catalyzing PNPH activity.     

Real-time clinical note monitoring to detect conditions for rapid follow-up: A case study of clinical trial enrollment in drug-induced torsades de pointes and Stevens-Johnson syndrome

Identifying acute events as they occur is challenging in large hospital systems. Here, we describe an automated method to detect 2 rare adverse drug events (ADEs), drug-induced torsades de pointes and Stevens-Johnson syndrome and toxic epidermal necrolysis, in near real time for participant recruitment into prospective clinical studies. A text processing system searched clinical notes from the electronic health record (EHR) for relevant keywords and alerted study personnel via email of potential patients for chart review or in-person evaluation. Between 2016 and 2018, the automated recruitment system resulted in capture of 138 true cases of drug-induced rare events, improving recall from 43% to 93%. Our focused electronic alert system maintained 2-year enrollment, including across an EHR migration from a bespoke system to Epic. Real-time monitoring of EHR notes may accelerate research for certain conditions less amenable to conventional study recruitment paradigms.     

High Prevalence of Subclinical Atherosclerosis by Carotid Ultrasound among Mexican Americans: Discordance with 10‐Year Risk Assessment using the Framingham Risk Score

Background: Framingham risk scores (FRS) were validated in a mostly Caucasian population. Evaluation of subclinical atherosclerosis by carotid ultrasound may improve ascertainment of risk in nonwhite populations. This study aimed to evaluate carotid intima‐media thickness (cIMT) and carotid plaquing among Mexican Americans, and to correlate these markers with coronary risk factors and the FRS. Methods/Results: Participants (n = 141) were drawn from the Cameron County Hispanic Cohort. Carotid artery ultrasound was performed and cIMT measured. Carotid plaque was defined as areas of thickening >50% of the thickness of the surrounding walls. Mean age was 53.1 ± 11.7 years (73.8% female). Most were overweight or obese (88.7%) and more than half (53.2%) had the metabolic syndrome. One third (34.8%) had abnormal carotid ultrasound findings (either cIMT ≥75th percentile for gender and age or presence of plaque). Among those with abnormal carotid ultrasound, the majority were classified as being at low 10‐year risk for cardiovascular events. Carotid ultrasound reclassified nearly a third of the cohort as being at high risk. This discordance between 10‐year FRS and carotid ultrasound was noted whether risk was assessed for hard coronary events or global risk. Concordance between FRS and carotid ultrasound findings was best when long‐term (30‐year) risk was assessed and no subject with an abnormal carotid ultrasound was categorized as low risk by the 30‐year FRS algorithm. Conclusions: Integration of carotid ultrasound findings to coronary risk assessments and use of longer term prediction models may provide better risk assessment in this minority population, with earlier initiation of appropriate therapies.     

Role of Nurse Practitioners in the Management of Cirrhotic Patients

Patients with end-stage liver disease (ESLD) often suffer from complications that require ongoing management with outpatient providers. Complications include ascites, hepatic encephalopathy, hyponatremia, pulmonary vascular complications, and esophageal varices. Patients with cirrhosis need to be referred to a hepatologist to establish care and potential evaluation for liver transplantation. Nurse practitioners (NPs) involved in the care of cirrhotic patients are well positioned to provide supportive care, improve symptom management, and prevent complications associated with further decompensation. This article discusses the role of NPs in the management of patients with cirrhosis.     

Psychotic Experiences,Childhood Trauma,and Alcohol-Related Self-Efficacy in a Nonpsychiatric Sample of Individuals in Alcohol Dependence Treatment: A Pilot Study

There is a substantial co-occurrence between alcohol dependence and psychiatric symptoms. Moreover, research suggests that such symptoms, including psychotic experiences, are continuously distributed in the population. There is a lack of research concerning psychotic symptoms in otherwise non-psychiatric populations with alcohol dependence. The aim of this study was to investigate the prevalence of psychotic symptoms in this population, and to relate this to childhood trauma and management of alcohol dependence. From a population with alcohol dependence two sub-groups were extracted, with low and high levels of psychotic experiences respectively. These were compared concerning childhood trauma and management of dependence using ANOVA, and the resulting model was examined using binary logistic regression. There was a sub-group of 14,3% of the population with elevated levels of psychotic experiences. This group displayed higher degree of self-reported childhood trauma as well as difficulties in managing alcohol dependence, when compared to a sub-group with low levels of psychotic experiences. There may be a substantial sub-group in the otherwise non-psychiatric population with alcohol dependence, with significant difficulties concerning psychotic symptoms, trauma and management of dependence, where anxiety may have a mediating function. If so, this group calls for broader assessment and treatment than standard alcohol interventions.