ATPase and Multidrug Transport Activities of the Overexpressed Yeast ABC Protein Yor1p

The Saccharomyces cerevisiae genome encodes 15 full-size ATP binding cassette transporters (ABC), of which PDR5, SNQ2, and YOR1 are known to be regulated by the transcription factors Pdr1p and Pdr3p (pleiotropic drug resistance). We have identified two new ABC transporter-encoding genes, PDR10 and PDR15, which were up-regulated by the PDR1-3 mutation. These genes, as well as four other ABC transporter-encoding genes, were deleted in order to study the properties of Yor1p. The PDR1-3 gain-of-function mutant was then used to overproduce Yor1p up to 10% of the total plasma membrane proteins. Overexpressed Yor1p was photolabeled by [gamma-32P]2', 3'-O-(2,4,6-trinitrophenyl)-8-azido-ATP (K0.5 = 45 microM) and inhibited by ATP (KD = 0.3 mM) in plasma membranes. Solubilization and partial purification on sucrose gradient allowed to detect significant Yor1p ATP hydrolysis activity (approximately 100 nmol of Pi.min-1.mg-1). This activity was phospholipid-dependent and sensitive to low concentrations of vanadate (I50 = 0.3 microM) and oligomycin (I50 = 8.5 microg/ml). In vivo, we observed a correlation between the amount of Yor1p in the plasma membrane and the level of resistance to oligomycin. We also demonstrated that Yor1p drives an energy-dependent, proton uncoupler-insensitive, cellular extrusion of rhodamine B. Furthermore, cells lacking both Yor1p and Pdr5p (but not Snq2p) showed increased accumulation of the fluorescent derivative of 1-myristoyl-2-[6-(NBD)aminocaproyl]phosphatidylethanolamine. Despite their different topologies, both Yor1p and Pdr5p mediated the ATP-dependent translocation of similar drugs and phospholipids across the yeast cell membrane. Both ABC transporters exhibit ATP hydrolysis in vitro, but Pdr5p ATPase activity is about 15 times higher than that of Yor1p, which may indicate mechanistic or regulatory differences between the two enzymes

Characteristics of abdominal vein thrombosis in children and adults

The demographic and clinical characteristics of adults and children with lower extremity deep-vein thrombosis and/or pulmonary embolism (LE DVT/PE) may differ from those with abdominal vein thrombosis (abdominal VT). Abdominal VT can be a presenting sign of an underlying prothrombotic state, and its presence in the setting of known disease might have prognostic implications different from LE DVT/PE. This study describes clinical presentations of abdominal VT compared to LE DVT/PE in adults and children. We analysed prospec-tively-collected data from consecutive consenting patients enrolled in one of seven Centers for Disease Control and Prevention (CDC) funded Thrombosis and Hemostasis Network Centers from August 2003 to April 2011 to compare the demographic and clinical characteristics of adults and children with abdominal VT. Both adults and children with abdominal VT tended to be younger and have a lower body mass index (BMI) than those with LE DVT/PE. Of patients with abdominal V T, children were more likely to have inferior vena cava (IVC) thrombosis than adults. For adults with venous thromboembolism (VTE), relatively more women had abdominal VT than LE DVT/PE, while the proportions with LE DVT/PE and abdominal VT by sex were similar in children. Children with abdominal VT were more likely to have diagnosed inherited thrombophilia, while trauma was more common in children with LE DVT/PE. In conclusion, both children and adults with abdominal VT were younger with a lower BMI than those with LE DVT/ PE. Significant differences exist between children and adults in respect to abdominal VT compared to LE DVT/PE

Whole blood gene expression profiles distinguish clinical phenotypes of venous thromboembolism

Recurrent venous thromboembolism (VTE) occurs infrequently following a provoked event but occurs in up to 30% of individuals following an initial unprovoked event. There is limited understanding of the biological mechanisms that predispose patients to recurrent VTE

Predictive accuracy of 29-comorbidity index for in-hospital deaths in US adult hospitalizations with a diagnosis of venous thromboembolism.

BACKGROUND: Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a significant source of mortality and morbidity worldwide. By analyzing data of the 2010 Nationwide Inpatient Sample from the Agency for Healthcare Research and Quality (AHRQ), we evaluated the predictive accuracy of the AHRQ's 29-comorbidity index with in-hospital death among US adult hospitalizations with a diagnosis of VTE. METHODS: We assessed the case-fatality and prevalence of comorbidities among a sample of 153,518 adult hospitalizations with a diagnosis of VTE that comprised 87,605 DVTs and 65,913 PEs (with and without DVT). We estimated adjusted odds ratios and 95% confidence intervals with multivariable logistic regression models by using comorbidities as predictors and status of in-hospital death as an outcome variable. We assessed the c-statistics for the predictive accuracy of the logistic regression models. RESULTS: In 2010, approximately 41,944 in-hospital deaths (20,212 with DVT and 21,732 with PE) occurred among 770,137 hospitalizations with a diagnosis of VTE. When compared separately to hospitalizations with VTE, DVT, or PE that had no corresponding comorbidities, congestive heart failure, chronic pulmonary disease, coagulopathy, liver disease, lymphoma, fluid and electrolyte disorders, metastatic cancer, other neurological disorders, peripheral vascular disorders, pulmonary circulation disorders, renal failure, solid tumor without metastasis, and weight loss were positively and independently associated with 10%-125% increased likelihoods of in-hospital death. The c-statistic values ranged from 0.776 to 0.802. CONCLUSION: The results of this study indicated that comorbidity was associated independently with risk of death among hospitalizations with VTE and among hospitalizations with DVT or PE. The AHRQ 29-comorbidity index provides acceptable to excellent predictive accuracy for in-hospital deaths among adult hospitalizations with VTE and among those with DVT or PE

Screening U.S. College Athletes for Their Sickle Cell Disease Carrier Status

There are many issues surrounding the screening of collegiate athletes for their sickle cell disease carrier status (or sickle cell trait), a genetic condition. This paper summarizes the establishment of expert advice given to the Secretary's Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC) on the issue. The SACHDNC has developed a report to advise the Secretary of the USDHHS about the 2010 rule of the National Collegiate Athletic Association (NCAA) requiring testing for sickle cell trait in all incoming Division I student athletes. The SACHDNC does not support the NCAA's rule to screen collegiate athletes for sickle cell trait

Correlates of in-hospital deaths among hospitalizations with pulmonary embolism: findings from the 2001-2008 National Hospital Discharge Survey.

BACKGROUND: Deep vein thrombosis and pulmonary embolism (PE) are responsible for substantial mortality, morbidity, and impaired health-related quality of life. The aim of this study was to evaluate the correlates of in-hospital deaths among hospitalizations with a diagnosis of PE in the United States. METHODS: By using data from the 2001-2008 National Hospital Discharge Survey, we assessed the correlates of in-hospital deaths among 14,721 hospitalizations with a diagnosis of PE and among subgroups stratified by age, sex, race, days of hospital stay, type of admission, cancer, pneumonia, and fractures. We produced adjusted rate ratios (aRR) and 95% confidence intervals using log-linear multivariate regression models. RESULTS: Regardless of the listing position of diagnostic codes, we observed an increased likelihood of in-hospital death in subgroups of hospitalizations with ages 50 years and older (aRR = 1.82-8.48), less than 7 days of hospital stay (aRR = 1.43-1.57), cancer (aRR = 2.10-2.28), pneumonia (aRR = 1.79-2.20), or fractures (aRR = 2.18) (except for first-listed PE), when compared to the reference groups with ages 1-49 years, 7 days or more of hospital stay, without cancer, pneumonia, or fractures while adjusting for covariates. In addition, we observed an increased likelihood of in-hospital death for first-listed PE in hospitalizations of women, when compared to those of men (aRR = 1.45). CONCLUSIONS: The results of this study provide support for identifying, developing, and implementing effective, evidence-based clinical assessment and management strategies to reduce PE-related morbidity and mortality among hospitalized PE patients who may have concurrent health conditions including cancer, pneumonia, and fractures

Characteristics of marijuana use during pregnancy - eight states, Pregnancy Risk Assessment Monitoring System, 2017.

Marijuana is the most commonly used illicit substance under federal law in the United States (1); however, many states have legalized medical and adult nonmedical use. Evidence regarding the safety and health effects of cannabis use during pregnancy is largely inconclusive (2). Potential adverse health effects to exposed infants (e.g., lower birthweight) have been documented (2). To provide population-based estimates of use surrounding pregnancy, identify reasons for and mode of use, and understand characteristics of women who continue versus cease marijuana use during pregnancy, CDC analyzed data from eight states participating in the 2017 Pregnancy Risk Assessment Monitoring System (PRAMS) marijuana supplement. Overall, 9.8% of women self-reported marijuana use before pregnancy, 4.2% during pregnancy, and 5.5% after pregnancy. The most common reasons for use during pregnancy were to relieve stress or anxiety, nausea or vomiting, and pain. Smoking was the most common mode of use. In multivariable models that included age, race/ethnicity, marital status, education, insurance status, parity, trimester of entry into prenatal care, and cigarette and e-cigarette use during pregnancy, women who continued versus ceased marijuana use during pregnancy were more likely to be non-Hispanic white or other race/ethnicity than non-Hispanic black, be unmarried, have ≤12 years of education, and use cigarettes during pregnancy. The American College of Obstetricians and Gynecologists (ACOG) and the American Academy of Pediatrics (AAP) recommend refraining from marijuana use during pregnancy and lactation (3,4). Given the increasing number of states legalizing medical and adult nonmedical marijuana use, surveillance of perinatal marijuana use can inform clinical guidance, provider and patient education, and public health programs to support evidence-based approaches to addressing substance use