Phenylethanolamine N-methyltransferase gene expression in PC12 cells exposed to intermittent hypoxia.

Epidemiological studies show a strong correlation between Obstructive Sleep Apnea (OSA) and cardiovascular disorders. OSA patients experience intermittent hypoxia (IH), characterized by brief, but recurring episodes of cessation in breathing. These patients have higher levels of circulating catecholamines and an increased incidence of hypertension; however the mechanisms defining this association are not clearly established. Genetic linkage studies have associated the phenylethanolamine N-methyltransferase (PNMT) gene to the development of hypertension. PNMT, the terminal enzyme in the catecholamine biosynthetic pathway, directly responsible for adrenaline synthesis, is elevated in hypertensive animals. Recent studies utilizing PC12 cells show an increase in the expression of PNMT and its regulatory transcription factors when exposed to continuous hypoxia. The current study examined the regulation of PNMT under conditions of IH. The mRNA of PNMT was analyzed to assess if the regulation of PNMT expression entails alternative splicing. The mRNA and protein of transcription factors HIF1α, Egr-1, GR, and Sp1, were analyzed to assess the cellular pathways involved in regulating PNMT expression. A PNMT promoter-driven luciferase assay was performed to evaluate promoter activity under IH. Preliminary results lay an antecedent for the regulation of PNMT by IH conceivably via an altered regulation of its transcription factors and establish a possible role for PNMT in IH mediated hypertension in OSA patients.

Incidence, causes, and consequences of preventable adverse drug events: protocol for an overview of reviews.

BACKGROUND: Medication errors represent a noteworthy source of harm to patients. In recent years, several systematic reviews have assessed the frequency and causes of these events, as well as other factors such as commonly associated drugs, their incidence in different specialties, and their consequences to patients. Despite this past literature, there remains a need to study discrepancies between these reviews and establish the current state of the evidence. The planned review will bring together, compare, and contract existing evidence related to the occurrence of medication errors in acute and continuing/long-term care settings. METHODS: A systematic review of reviews will be performed. A literature search designed by an experienced information specialist will be carried out in Medline, Embase, and the Cochrane Library. We will seek systematic reviews and meta-analyses of primary research studies that evaluate one or more of the following aspects of the occurrence of preventable adverse drug events in hospitals and long-term care centers: the incidence of preventable adverse drug events, either overall or within subgroups of interest related to setting; drug or patient characteristics; cited consequences of these events to patients, including death, emergency room visits, or other outcomes; and established causes of the preventable adverse drug events. Two researchers will independently screen all abstracts and full texts for study selection and subsequently perform data extraction from all included studies. Quality of the reviews will be assessed using the assessing the methodological quality of systematic reviews (AMSTAR) tool. Where objectives from two or more reviews overlap, we will employ the Jadad framework to assess the causes of any noted discrepancies between reviews. An overall summary of results will be performed using tabular and graphical approaches and will be supplemented by narrative description. DISCUSSION: This overview will help synthesize the broad degree of information available on this important topic. This review is being performed by members of the Drug Safety and Effectiveness Network along with collaboration from Health Canada, and its findings will be published in a peer-reviewed journal. The results may also inform future research in this area. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016043220.