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Sample records for positive drug screens

  1. Psychometric validation of the POSIT for screening alcohol and other drugs risk consumption among adolescents.

    Science.gov (United States)

    Araujo, Manuel; Golpe, Sandra; Braña, Teresa; Varela, Jesús; Rial, Antonio

    2018-04-15

    Early detection of alcohol and drug abuse among adolescents is decisive not only for rapid referral and intervention in cases of risk, but also as an indicator for use in the evaluation of prevention programs and public policies to reduce consumption. One of the most widely-used screening instruments in the world is the Problem Oriented Screening Instrument for Teenagers (POSIT) (Rahdert, 1991), whose substance use and abuse subscale (POSITUAS) is a brief tool of enormous applied potential. However, there is still no empirical validation study that would ensure its good psychometric performance in Spain. The aim of this paper is to analyse the psychometric properties of POSITUAS among Spanish adolescents. For this purpose, 569 students aged between 12 and 18 years (M = 14.71; SD = 1.79) were personally interviewed. The study sample was selected through two-stage sampling. The results obtained, using the Adolescent Diagnostic Interview (Winters & Henly, 1993) as the gold criterion, allow us to inform that the Spanish version of the POSITUAS has excellent psychometric behaviour, both at the level of internal consistency (a  = .82) as well as regards sensitivity (94.3%) and specificity (83.9%), with an area under the ROC curve of .953. Also, the realisation of a Confirmatory Factor Analysis allows for verifying the one-dimensional character of the scale. As a result, POSITUAS is made available to researchers and professionals in the field of addictive behaviours for use with a minimum of psychometric guarantees.

  2. Urine drug screen

    Science.gov (United States)

    Drug screen - urine ... detect the presence of illegal and some prescription drugs in your urine. Their presence may indicate that you recently used these drugs. Some drugs may remain in your system for ...

  3. A trend analysis of laboratory positive propoxyphene workplace urine drug screens before and after the product recall.

    Science.gov (United States)

    Price, James

    2015-01-01

    Propoxyphene was withdrawn from the US market in November 2010. This drug is still tested for in the workplace as part of expanded panel nonregulated testing. A convenience sample of urine specimens (n = 7838) were provided by workers from various industries. The percentage of positive specimens with 95% confidence intervals was calculated for each year of the study. Logistic regression was used to assess the impact of the year upon the propoxyphene result. The prevalence of positive propoxyphene tests was much higher before the product's withdrawal from the market. Logistic regression provided evidence of a decreasing linear trend (P < 0.000; β = -0.71). The odds ratio signifies that for every additional year the urine specimens were 0.49 times less likely to be positive for propoxyphene. This favors the determination that the change in propoxyphene positive drug test over the years is not by chance. The conclusion supports no longer performing nonregulated workplace propoxyphene urine drug testing for this population.

  4. RAS - Screens & Assays - Drug Discovery

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    The RAS Drug Discovery group aims to develop assays that will reveal aspects of RAS biology upon which cancer cells depend. Successful assay formats are made available for high-throughput screening programs to yield potentially effective drug compounds.

  5. Advantages of analyzing postmortem brain samples in routine forensic drug screening-Case series of three non-natural deaths tested positive for lysergic acid diethylamide (LSD).

    Science.gov (United States)

    Mardal, Marie; Johansen, Sys Stybe; Thomsen, Ragnar; Linnet, Kristian

    2017-09-01

    Three case reports are presented, including autopsy findings and toxicological screening results, which were tested positive for the potent hallucinogenic drug lysergic acid diethylamide (LSD). LSD and its main metabolites were quantified in brain tissue and femoral blood, and furthermore hematoma and urine when available. LSD, its main metabolite 2-oxo-3-hydroxy-LSD (oxo-HO-LSD), and iso-LSD were quantified in biological samples according to a previously published procedure involving liquid-liquid extraction and ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). LSD was measured in the brain tissue of all presented cases at a concentration level from 0.34-10.8μg/kg. The concentration level in the target organ was higher than in peripheral blood. Additional psychoactive compounds were quantified in blood and brain tissue, though all below toxic concentration levels. The cause of death in case 1 was collision-induced brain injury, while it was drowning in case 2 and 3 and thus not drug intoxication. However, the toxicological findings could help explain the decedent's inability to cope with brain injury or drowning incidents. The presented findings could help establish reference concentrations in brain samples and assist in interpretation of results from forensic drug screening in brain tissue. This is to the author's knowledge the first report of LSD, iso-LSD, and oxo-HO-LSD measured in brain tissue samples. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. European position statement on lung cancer screening

    DEFF Research Database (Denmark)

    Oudkerk, Matthijs; Devaraj, Anand; Vliegenthart, Rozemarijn

    2017-01-01

    Lung cancer screening with low-dose CT can save lives. This European Union (EU) position statement presents the available evidence and the major issues that need to be addressed to ensure the successful implementation of low-dose CT lung cancer screening in Europe. This statement identified...... specific actions required by the European lung cancer screening community to adopt before the implementation of low-dose CT lung cancer screening. This position statement recommends the following actions: a risk stratification approach should be used for future lung cancer low-dose CT programmes...... need to set a timeline for implementing lung cancer screening....

  7. Amphetamine Positive Urine Toxicology Screen Secondary to Atomoxetine

    Directory of Open Access Journals (Sweden)

    Joshua L. Fenderson

    2013-01-01

    Full Text Available The aim of this paper is to report the first case of atomoxetine leading to false-positive urine drug screen. An otherwise healthy 27-year-old female with a history of attention deficit hyperactivity disorder (ADHD treated with atomoxetine had an acute onset tonic-clonic seizure. On arrival to the hospital, a urine toxicological drug screen with immunochemical cloned enzyme donor immunoassay (CEDIA was performed. Results were positive for amphetamines; however, the presence of these substances could not be confirmed with urine gas chromatography-mass spectrometry (GC-MS. She denied any illicit drug use, herbal medications, or supplements, and her other prescription medications have not been previously known to cause a false-positive result for amphetamines. While stimulant treatments for ADHD could certainly result in a positive result on urine screen for amphetamines, there have been no reports of false-positive results for amphetamines secondary to patients using atomoxetine. We implicate atomoxetine, and/or its metabolites, as a compound or compounds which may interfere with urine drug immunoassays leading to false-positive results for amphetamines CEDIA assays.

  8. Urine drug screening in the medical setting.

    Science.gov (United States)

    Hammett-Stabler, Catherine A; Pesce, Amadeo J; Cannon, Donald J

    2002-01-01

    The term drug screen is a misnomer since it implies screening for all drugs, which is not possible. Current practice is to limit the testing to the examination of serum for several drugs such as ethanol, acetaminophen, salicylate, and of urine for several specific drugs or classes of drugs. In the emergency setting the screen should be performed in less than one hour. Controversies continue to exist regarding the value of urine drug testing in the medical setting. The reasons for these include the drugs involved, the sample, the methods utilized to perform the tests, and the level of understanding of the physician using the data, all of which are closely related to the other. Current automated methods provide rapid results demanded in emergency situations, but are often designed for, or adapted from, workplace testing and are not necessarily optimized for clinical applications. Furthermore, the use of these methods without consideration of the frequency in which the drugs are found in a given area is not cost-effective. The laboratory must understand the limitations of the assays used and provide this information to the physician. Additionally, the laboratory and the physicians using the data must cooperate to determine which drugs are appropriate and necessary to measure for their institution and clinical setting. In doing so it should be remembered that for many drugs, the sample, urine, contains the end product(s) of drug metabolism, not the parent drug. Furthermore, it is necessary to understand the pharmacokinetic parameters of the drug of interest when interpreting data. Finally, while testing for some drugs may not appear cost-effective, the prevention or reduction of morbidity and mortality may offset any laboratory costs. While the literature is replete with studies concerning new methods and a few regarding physician understanding, there are none that we could find that thoroughly, objectively, and fully addressed the issues of utility and cost-effectiveness.

  9. Understanding drugs in breast cancer through drug sensitivity screening.

    Science.gov (United States)

    Uhr, Katharina; Prager-van der Smissen, Wendy J C; Heine, Anouk A J; Ozturk, Bahar; Smid, Marcel; Göhlmann, Hinrich W H; Jager, Agnes; Foekens, John A; Martens, John W M

    2015-01-01

    With substantial numbers of breast tumors showing or acquiring treatment resistance, it is of utmost importance to develop new agents for the treatment of the disease, to know their effectiveness against breast cancer and to understand their relationships with other drugs to best assign the right drug to the right patient. To achieve this goal drug screenings on breast cancer cell lines are a promising approach. In this study a large-scale drug screening of 37 compounds was performed on a panel of 42 breast cancer cell lines representing the main breast cancer subtypes. Clustering, correlation and pathway analyses were used for data analysis. We found that compounds with a related mechanism of action had correlated IC50 values and thus grouped together when the cell lines were hierarchically clustered based on IC50 values. In total we found six clusters of drugs of which five consisted of drugs with related mode of action and one cluster with two drugs not previously connected. In total, 25 correlated and four anti-correlated drug sensitivities were revealed of which only one drug, Sirolimus, showed significantly lower IC50 values in the luminal/ERBB2 breast cancer subtype. We found expected interactions but also discovered new relationships between drugs which might have implications for cancer treatment regimens.

  10. [Incretin mimetic drugs: therapeutic positioning].

    Science.gov (United States)

    López Simarro, F

    2014-07-01

    Type 2 diabetes is a chronic and complex disease, due to the differences among affected individuals, which affect choice of treatment. The number of drug families has increased in the last few years, and these families have widely differing mechanisms of action, which contributes greatly to the individualization of treatment according to the patient's characteristics and comorbidities. The present article discusses incretin mimetic drugs. Their development has been based on knowledge of the effects of natural incretin hormones: GLP-1 (glucagon-like peptide 1), GIP (glucose-dependent insulinotropic peptide) and dipeptidyl peptidase enzyme 4 (DPP4), which rapidly degrade them in the systemic circulation. This group is composed of 2 different types of molecules: GLP-1 analogs and DPP4 enzyme inhibitors. The benefits of these molecules include a reduction in plasma glucose without the risk of hypoglycemias or weight gain. There are a series of questions that require new studies to establish a possible association between the use of these drugs and notification of cases of pancreatitis, as well as their relationship with pancreatic and thyroid cancer. Also awaited is the publication of several studies that will provide information on the relationship between these drugs and cardiovascular risk in people with diabetes. All these questions will probably be progressively elucidated with greater experience in the use of these drugs. Copyright © 2014 Elsevier España, S.L.U. y Sociedad Española de Medicina Rural y Generalista (SEMERGEN). All rights reserved.

  11. Microfluidic Devices for Drug Delivery Systems and Drug Screening

    Science.gov (United States)

    Kompella, Uday B.; Damiati, Safa A.

    2018-01-01

    Microfluidic devices present unique advantages for the development of efficient drug carrier particles, cell-free protein synthesis systems, and rapid techniques for direct drug screening. Compared to bulk methods, by efficiently controlling the geometries of the fabricated chip and the flow rates of multiphase fluids, microfluidic technology enables the generation of highly stable, uniform, monodispersed particles with higher encapsulation efficiency. Since the existing preclinical models are inefficient drug screens for predicting clinical outcomes, microfluidic platforms might offer a more rapid and cost-effective alternative. Compared to 2D cell culture systems and in vivo animal models, microfluidic 3D platforms mimic the in vivo cell systems in a simple, inexpensive manner, which allows high throughput and multiplexed drug screening at the cell, organ, and whole-body levels. In this review, the generation of appropriate drug or gene carriers including different particle types using different configurations of microfluidic devices is highlighted. Additionally, this paper discusses the emergence of fabricated microfluidic cell-free protein synthesis systems for potential use at point of care as well as cell-, organ-, and human-on-a-chip models as smart, sensitive, and reproducible platforms, allowing the investigation of the effects of drugs under conditions imitating the biological system. PMID:29462948

  12. Comparative analysis of three drug-drug interaction screening systems against probable clinically relevant drug-drug interactions: a prospective cohort study.

    Science.gov (United States)

    Muhič, Neža; Mrhar, Ales; Brvar, Miran

    2017-07-01

    Drug-drug interaction (DDI) screening systems report potential DDIs. This study aimed to find the prevalence of probable DDI-related adverse drug reactions (ADRs) and compare the clinical usefulness of different DDI screening systems to prevent or warn against these ADRs. A prospective cohort study was conducted in patients urgently admitted to medical departments. Potential DDIs were checked using Complete Drug Interaction®, Lexicomp® Online™, and Drug Interaction Checker®. The study team identified the patients with probable clinically relevant DDI-related ADRs on admission, the causality of which was assessed using the Drug Interaction Probability Scale (DIPS). Sensitivity, specificity, and positive and negative predictive values of screening systems to prevent or warn against probable DDI-related ADRs were evaluated. Overall, 50 probable clinically relevant DDI-related ADRs were found in 37 out of 795 included patients taking at least two drugs, most common of them were bleeding, hyperkalemia, digitalis toxicity, and hypotension. Complete Drug Interaction showed the best sensitivity (0.76) for actual DDI-related ADRs, followed by Lexicomp Online (0.50), and Drug Interaction Checker (0.40). Complete Drug Interaction and Drug Interaction Checker had positive predictive values of 0.07; Lexicomp Online had 0.04. We found no difference in specificity and negative predictive values among these systems. DDI screening systems differ significantly in their ability to detect probable clinically relevant DDI-related ADRs in terms of sensitivity and positive predictive value.

  13. Lack of cross-reactivity of Ambien (zolpidem) with drugs in standard urine drug screens.

    Science.gov (United States)

    Piergies, A A; Sainati, S; Roth-Schechter, B

    1997-04-01

    To determine in healthy volunteers (men and women; 18 to 40 years old) the potential cross-reactivity of Ambien (zolpidem) and/or its metabolites with drugs that are screened by the Syva EMIT II and the Abbott ADx urine drug screens assays. Open-label, fixed-treatment sequence of 1 night each of treatment with zolpidem (10 mg) and temazepam (15 mg). Clinical Pharmacology Unit within a teaching hospital. Over a 24-hour period, presence or absence of positive results on the Syva EMIT II or the Abbott ADx urine drug assay system, each performed at two different laboratory assay sites. Following ingestion of zolpidem, no subject had any positive response in either laboratory to the Syva EMIT II or the Abbott ADx urine drug screen assays at 0, 4, 8, 12, and 24 hours postdose. During the same time period, all subjects had measurable zolpidem plasma concentrations at 1.5 and 8 hours postdose, with mean concentrations of 115.2 ng/mL and 30.1 ng/mL, respectively (in agreement with its half-life of 2.5 hours). The positive response rate at 10 hours after ingestion of Restoril (temazepam) among the four laboratory/assay combinations ranged from 36.8% to 73.7%, a range that is within the reported response rates for these tests. These data indicate that zolpidem will not cross-react in standard urine drug screens with benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines.

  14. Services Receipt Following Veteran Outpatients' Positive Screen for Homelessness.

    Science.gov (United States)

    Montgomery, Ann E; Dichter, Melissa E; Thomasson, Arwin M; Roberts, Christopher B

    2016-03-01

    The Veterans Health Administration seeks to reduce homelessness among Veterans by identifying, and providing prevention and supportive services to, patients with housing concerns. The objectives of this study were to assess the proportion of Veterans Health Administration patients who received homeless or social work services within 6 months of a positive screen for homelessness or risk in the Veterans Health Administration and the demographic and clinical characteristics that predicted services utilization. Data were from a cohort of 27,403 Veteran outpatients who screened positive for homelessness or risk between November 1, 2012 and January 31, 2013. During 2013, AORs were calculated using a mixed-effects logistic regression to estimate the likelihood of patients' receipt of VHA homeless or social work services based on demographic and clinical characteristics. The majority of patients received services within 6 months post-screening; predictors of services utilization varied by gender. Among women, diagnosis of drug abuse and psychosis predicted receipt of services, being unmarried increased the odds of using services among those screening positive for homelessness, and a diagnosis of post-traumatic stress disorder increased the odds of receiving services for at-risk women. Among men, being younger, unmarried, not service-connected/Medicaid-eligible, and having a medical or behavioral health condition predicted receipt of services. Receipt of housing support services among Veterans post-homelessness screening differs by patient demographic and clinical characteristics. Future research should investigate the role that primary and secondary prevention interventions play in Veterans' resolution of risk for homelessness and experience of homelessness. Published by Elsevier Inc.

  15. Implications of false-positive results for future cancer screenings.

    Science.gov (United States)

    Taksler, Glen B; Keating, Nancy L; Rothberg, Michael B

    2018-06-01

    False-positive cancer screening results may affect a patient's willingness to obtain future screening. The authors conducted logistic regression analysis of 450,484 person-years of electronic medical records (2006-2015) in 92,405 individuals aged 50 to 75 years. Exposures were false-positive breast, prostate, or colorectal cancer screening test results (repeat breast imaging or negative breast biopsy ≤3 months after screening mammography, repeat prostate-specific antigen [PSA] test ≤3 months after PSA test result ≥4.0 ng/mL or negative prostate biopsy ≤3 months after any PSA result, or negative colonoscopy [without biopsy/polypectomy] ≤6 months after a positive fecal occult blood test). Outcomes were up-to-date status with breast or colorectal cancer screening. Covariates included prior screening history, clinical information (eg, family history, obesity, and smoking status), comorbidity, and demographics. Women were more likely to be up to date with breast cancer screening if they previously had false-positive mammography findings (adjusted odds ratio [AOR], 1.43 [95% confidence interval, 1.34-1.51] without breast biopsy and AOR, 2.02 [95% confidence interval, 1.56-2.62] with breast biopsy; both Pfalse-positive PSA testing were more likely to be up to date with colorectal cancer screening (AOR, 1.22 [P = .039] without prostate imaging/biopsy and AOR, 1.60 [P = .028] with imaging/biopsy). Results were stronger for individuals with more false-positive results (all P≤.005). However, women with previous false-positive colorectal cancer fecal occult blood test screening results were found to be less likely to be up to date with breast cancer screening (AOR, 0.73; Pfalse-positive breast or prostate cancer screening test were more likely to engage in future screening. Cancer 2018;124:2390-8. © 2018 American Cancer Society. © 2018 American Cancer Society.

  16. Miniature short hairpin RNA screens to characterize antiproliferative drugs.

    Science.gov (United States)

    Kittanakom, Saranya; Arnoldo, Anthony; Brown, Kevin R; Wallace, Iain; Kunavisarut, Tada; Torti, Dax; Heisler, Lawrence E; Surendra, Anuradha; Moffat, Jason; Giaever, Guri; Nislow, Corey

    2013-08-07

    The application of new proteomics and genomics technologies support a view in which few drugs act solely by inhibiting a single cellular target. Indeed, drug activity is modulated by complex, often incompletely understood cellular mechanisms. Therefore, efforts to decipher mode of action through genetic perturbation such as RNAi typically yields "hits" that fall into several categories. Of particular interest to the present study, we aimed to characterize secondary activities of drugs on cells. Inhibiting a known target can result in clinically relevant synthetic phenotypes. In one scenario, drug perturbation could, for example, improperly activate a protein that normally inhibits a particular kinase. In other cases, additional, lower affinity targets can be inhibited as in the example of inhibition of c-Kit observed in Bcr-Abl-positive cells treated with Gleevec. Drug transport and metabolism also play an important role in the way any chemicals act within the cells. Finally, RNAi per se can also affect cell fitness by more general off-target effects, e.g., via the modulation of apoptosis or DNA damage repair. Regardless of the root cause of these unwanted effects, understanding the scope of a drug's activity and polypharmacology is essential for better understanding its mechanism(s) of action, and such information can guide development of improved therapies. We describe a rapid, cost-effective approach to characterize primary and secondary effects of small-molecules by using small-scale libraries of virally integrated short hairpin RNAs. We demonstrate this principle using a "minipool" composed of shRNAs that target the genes encoding the reported protein targets of approved drugs. Among the 28 known reported drug-target pairs, we successfully identify 40% of the targets described in the literature and uncover several unanticipated drug-target interactions based on drug-induced synthetic lethality. We provide a detailed protocol for performing such screens and for

  17. Reliability, Validity and Factor Structure of Drug Abuse Screening Test

    Directory of Open Access Journals (Sweden)

    Sayed Hadi Sayed Alitabar

    2016-05-01

    Full Text Available Background and Objective: According to the increasing of substance use in the country, more researches about this phenomenon are necessary. This Study Investigates the Validity, Reliability and Confirmatory Factor Structure of the Drug Abuse Screening test (DAST. Materials and Methods: The Sample Consisted of 381 Patients (143 Women and 238 Men with a Multi-Stage Cluster Sampling of Areas 2, 6 and 12 of Tehran Were Selected from Each Region, 6 Randomly Selected Drug Rehabilitation Center. The DAST Was Used as Instrument. Divergent & Convergent Validity of this Scale Was Assessed with Problems Assessment for Substance Using Psychiatric Patients (PASUPP and Relapse Prediction Scale (RPS.Results: The DAST after the First Time Factor Structure of Using Confirmatory Factor Analysis Was Confirmed. The DAST Had a Good Internal Consistency (Cranach’s Alpha, and the Reliability of the Test Within a Week, 0.9, 0.8. Also this Scale Had a Positive Correlation with Problems Assessment for Substance Using Psychiatric Patients and Relapse Prediction Scale (P<0.01.Conclusion: The Overall Results Showed that the Drug Abuse Screening Test in Iranian Society Is Valid. It Can Be Said that Self-Report Scale Tool Is Useful for Research Purposes and Addiction.

  18. High-throughput matrix screening identifies synergistic and antagonistic antimalarial drug combinations

    Science.gov (United States)

    Mott, Bryan T.; Eastman, Richard T.; Guha, Rajarshi; Sherlach, Katy S.; Siriwardana, Amila; Shinn, Paul; McKnight, Crystal; Michael, Sam; Lacerda-Queiroz, Norinne; Patel, Paresma R.; Khine, Pwint; Sun, Hongmao; Kasbekar, Monica; Aghdam, Nima; Fontaine, Shaun D.; Liu, Dongbo; Mierzwa, Tim; Mathews-Griner, Lesley A.; Ferrer, Marc; Renslo, Adam R.; Inglese, James; Yuan, Jing; Roepe, Paul D.; Su, Xin-zhuan; Thomas, Craig J.

    2015-01-01

    Drug resistance in Plasmodium parasites is a constant threat. Novel therapeutics, especially new drug combinations, must be identified at a faster rate. In response to the urgent need for new antimalarial drug combinations we screened a large collection of approved and investigational drugs, tested 13,910 drug pairs, and identified many promising antimalarial drug combinations. The activity of known antimalarial drug regimens was confirmed and a myriad of new classes of positively interacting drug pairings were discovered. Network and clustering analyses reinforced established mechanistic relationships for known drug combinations and identified several novel mechanistic hypotheses. From eleven screens comprising >4,600 combinations per parasite strain (including duplicates) we further investigated interactions between approved antimalarials, calcium homeostasis modulators, and inhibitors of phosphatidylinositide 3-kinases (PI3K) and the mammalian target of rapamycin (mTOR). These studies highlight important targets and pathways and provide promising leads for clinically actionable antimalarial therapy. PMID:26403635

  19. A single-question screening test for drug use in primary care.

    Science.gov (United States)

    Smith, Peter C; Schmidt, Susan M; Allensworth-Davies, Donald; Saitz, Richard

    2010-07-12

    Drug use (illicit drug use and nonmedical use of prescription drugs) is common but underrecognized in primary care settings. We validated a single-question screening test for drug use and drug use disorders in primary care. Adult patients recruited from primary care waiting rooms were asked the single screening question, "How many times in the past year have you used an illegal drug or used a prescription medication for nonmedical reasons?" A response of at least 1 time was considered positive for drug use. They were also asked the 10-item Drug Abuse Screening Test (DAST-10). The reference standard was the presence or absence of current (past year) drug use or a drug use disorder (abuse or dependence) as determined by a standardized diagnostic interview. Drug use was also determined by oral fluid testing for common drugs of abuse. Of 394 eligible primary care patients, 286 (73%) completed the interview. The single screening question was 100% sensitive (95% confidence interval [CI], 90.6%-100%) and 73.5% specific (95% CI, 67.7%-78.6%) for the detection of a drug use disorder. It was less sensitive for the detection of self-reported current drug use (92.9%; 95% CI, 86.1%-96.5%) and drug use detected by oral fluid testing or self-report (81.8%; 95% CI, 72.5%-88.5%). Test characteristics were similar to those of the DAST-10 and were affected very little by participant demographic characteristics. The single screening question accurately identified drug use in this sample of primary care patients, supporting the usefulness of this brief screen in primary care.

  20. Use of a single alcohol screening question to identify other drug use.

    Science.gov (United States)

    Smith, Peter C; Cheng, Debbie M; Allensworth-Davies, Donald; Winter, Michael R; Saitz, Richard

    2014-06-01

    People who consume unhealthy amounts of alcohol are more likely to use illicit drugs. We tested the ability of a screening test for unhealthy alcohol use to simultaneously detect drug use. Adult English speaking patients (n=286) were enrolled from a primary care waiting room. They were asked the screening question for unhealthy alcohol use "How many times in the past year have you had X or more drinks in a day?", where X is 5 for men and 4 for women, and a response of one or more is considered positive. A standard diagnostic interview was used to determine current (past year) drug use or a drug use disorder (abuse or dependence). Oral fluid testing was also used to detect recent use of common drugs of abuse. The single screening question for unhealthy alcohol use was 67.6% sensitive (95% confidence interval [CI], 50.2-82.0%) and 64.7% specific (95% CI, 58.4-70.6%) for the detection of a drug use disorder. It was similarly insensitive for drug use detected by oral fluid testing and/or self-report. Although a patient with a drug use disorder has twice the odds of screening positive for unhealthy alcohol use compared to one without a drug use disorder, suggesting patients who screen positive for alcohol should be asked about drug use, a single screening question for unhealthy alcohol use was not sensitive or specific for the detection of other drug use or drug use disorders in a sample of primary care patients. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  1. The cumulative risk of false-positive screening results across screening centres in the Norwegian Breast Cancer Screening Program

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    Roman, M., E-mail: Marta.Roman@kreftregisteret.no [Cancer Registry of Norway, Oslo (Norway); Department of Women and Children’s Health, Oslo University Hospital, Oslo (Norway); Skaane, P., E-mail: PERSK@ous-hf.no [Department of Radiology, Oslo University Hospital Ullevaal, University of Oslo, Oslo (Norway); Hofvind, S., E-mail: Solveig.Hofvind@kreftregisteret.no [Cancer Registry of Norway, Oslo (Norway); Oslo and Akershus University College of Applied Sciences, Faculty of Health Science, Oslo (Norway)

    2014-09-15

    Highlights: • We found variation in early performance measures across screening centres. • Radiologists’ performance may play a key role in the variability. • Potential to improve the effectiveness of breast cancer screening programs. • Continuous surveillance of screening centres and radiologists is essential. - Abstract: Background: Recall for assessment in mammographic screening entails an inevitable number of false-positive screening results. This study aimed to investigate the variation in the cumulative risk of a false positive screening result and the positive predictive value across the screening centres in the Norwegian Breast Cancer Screening Program. Methods: We studied 618,636 women aged 50–69 years who underwent 2,090,575 screening exams (1996–2010. Recall rate, positive predictive value, rate of screen-detected cancer, and the cumulative risk of a false positive screening result, without and with invasive procedures across the screening centres were calculated. Generalized linear models were used to estimate the probability of a false positive screening result and to compute the cumulative false-positive risk for up to ten biennial screening examinations. Results: The cumulative risk of a false-positive screening exam varied from 10.7% (95% CI: 9.4–12.0%) to 41.5% (95% CI: 34.1–48.9%) across screening centres, with a highest to lowest ratio of 3.9 (95% CI: 3.7–4.0). The highest to lowest ratio for the cumulative risk of undergoing an invasive procedure with a benign outcome was 4.3 (95% CI: 4.0–4.6). The positive predictive value of recall varied between 12.0% (95% CI: 11.0–12.9%) and 19.9% (95% CI: 18.3–21.5%), with a highest to lowest ratio of 1.7 (95% CI: 1.5–1.9). Conclusions: A substantial variation in the performance measures across the screening centres in the Norwegian Breast Cancer Screening Program was identified, despite of similar administration, procedures, and quality assurance requirements. Differences in the

  2. The cumulative risk of false-positive screening results across screening centres in the Norwegian Breast Cancer Screening Program

    International Nuclear Information System (INIS)

    Roman, M.; Skaane, P.; Hofvind, S.

    2014-01-01

    Highlights: • We found variation in early performance measures across screening centres. • Radiologists’ performance may play a key role in the variability. • Potential to improve the effectiveness of breast cancer screening programs. • Continuous surveillance of screening centres and radiologists is essential. - Abstract: Background: Recall for assessment in mammographic screening entails an inevitable number of false-positive screening results. This study aimed to investigate the variation in the cumulative risk of a false positive screening result and the positive predictive value across the screening centres in the Norwegian Breast Cancer Screening Program. Methods: We studied 618,636 women aged 50–69 years who underwent 2,090,575 screening exams (1996–2010. Recall rate, positive predictive value, rate of screen-detected cancer, and the cumulative risk of a false positive screening result, without and with invasive procedures across the screening centres were calculated. Generalized linear models were used to estimate the probability of a false positive screening result and to compute the cumulative false-positive risk for up to ten biennial screening examinations. Results: The cumulative risk of a false-positive screening exam varied from 10.7% (95% CI: 9.4–12.0%) to 41.5% (95% CI: 34.1–48.9%) across screening centres, with a highest to lowest ratio of 3.9 (95% CI: 3.7–4.0). The highest to lowest ratio for the cumulative risk of undergoing an invasive procedure with a benign outcome was 4.3 (95% CI: 4.0–4.6). The positive predictive value of recall varied between 12.0% (95% CI: 11.0–12.9%) and 19.9% (95% CI: 18.3–21.5%), with a highest to lowest ratio of 1.7 (95% CI: 1.5–1.9). Conclusions: A substantial variation in the performance measures across the screening centres in the Norwegian Breast Cancer Screening Program was identified, despite of similar administration, procedures, and quality assurance requirements. Differences in the

  3. False-positive Human Papillomavirus DNA tests in cervical screening

    DEFF Research Database (Denmark)

    Rebolj, Matejka; Pribac, Igor; Lynge, Elsebeth

    2011-01-01

    Based on data from randomised controlled trials (RCT) on primary cervical screening, it has been reported that the problem of more frequent false-positive tests in Human Papillomavirus (HPV) DNA screening compared to cytology could be overcome. However, these reports predominantly operated...

  4. USER S GUIDE FOR THE RANDOM DRUG SCREENING SYSTEM

    Energy Technology Data Exchange (ETDEWEB)

    McNeany, Karen I [ORNL

    2013-12-01

    The Random Drug Screening System (RDSS) is a desktop computing application designed to assign nongameable drug testing dates to each member in a population of employees, within a specific time line. The program includes reporting capabilities, test form generation, unique test ID number assignment, and the ability to flag high-risk employees for a higher frequency of drug testing than the general population.

  5. Work-related injuries in a state trauma registry: relationship between industry and drug screening.

    Science.gov (United States)

    Bunn, Terry L; Slavova, Svetla; Bernard, Andrew C

    2014-08-01

    Work-related injuries exert a great financial and economic burden on the US population. The study objectives were to identify the industries and occupations associated with worker injuries and to determine the predictors for injured worker drug screening in trauma centers. Work-related injury cases were selected using three criteria (expected payer source of workers' compensation, industry-related e-codes, and work-related indicator) from the Kentucky Trauma Registry data set for years 2008 to 2012. Descriptive analyses and multiple logistic regression were performed on the work-related injury cases. The "other services" and construction industry sectors accounted for the highest number of work-related cases. Drugs were detected in 55% of all drug-screened work-related trauma cases. Higher percentages of injured workers tested positive for drugs in the natural resources and mining, transportation and public utilities, and construction industries. In comparison, higher percentages of injured workers in the other services as well as transportation and public utilities industries were drug screened. Treatment at Level I trauma centers and Glasgow Coma Scale (GCS) scores indicating a coma or severe brain injury were both significant independent predictors for being screened for drugs; industry was not a significant predictor for being drug screened. The injured worker was more likely to be drug screened if the worker had a greater than mild injury, regardless of whether the worker was an interfacility transfer. These findings indicate that there may be elevated drug use or abuse in natural resources and mining, transportation and public utilities, as well as construction industry workers; improved identification of the specific drug types in positive drug screen results of injured workers is needed to better target prevention efforts. Epidemiologic study, level III.

  6. A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

    Science.gov (United States)

    Eleuteri, C.; Olla, S.; Veroni, C.; Umeton, R.; Mechelli, R.; Romano, S.; Buscarinu, Mc.; Ferrari, F.; Calò, G.; Ristori, G.; Salvetti, M.; Agresti, C.

    2017-04-01

    There is no treatment for the myelin loss in multiple sclerosis, ultimately resulting in the axonal degeneration that leads to the progressive phase of the disease. We established a multi-tiered platform for the sequential screening of drugs that could be repurposed as remyelinating agents. We screened a library of 2,000 compounds (mainly Food and Drug Administration (FDA)-approved compounds and natural products) for cellular metabolic activity on mouse oligodendrocyte precursors (OPC), identifying 42 molecules with significant stimulating effects. We then characterized the effects of these compounds on OPC proliferation and differentiation in mouse glial cultures, and on myelination and remyelination in organotypic cultures. Three molecules, edaravone, 5-methyl-7-methoxyisoflavone and lovastatin, gave positive results in all screening tiers. We validated the results by retesting independent stocks of the compounds, analyzing their purity, and performing dose-response curves. To identify the chemical features that may be modified to enhance the compounds’ activity, we tested chemical analogs and identified, for edaravone, the functional groups that may be essential for its activity. Among the selected remyelinating candidates, edaravone appears to be of strong interest, also considering that this drug has been approved as a neuroprotective agent for acute ischemic stroke and amyotrophic lateral sclerosis in Japan.

  7. A high content screening assay to predict human drug-induced liver injury during drug discovery.

    Science.gov (United States)

    Persson, Mikael; Løye, Anni F; Mow, Tomas; Hornberg, Jorrit J

    2013-01-01

    Adverse drug reactions are a major cause for failures of drug development programs, drug withdrawals and use restrictions. Early hazard identification and diligent risk avoidance strategies are therefore essential. For drug-induced liver injury (DILI), this is difficult using conventional safety testing. To reduce the risk for DILI, drug candidates with a high risk need to be identified and deselected. And, to produce drug candidates without that risk associated, risk factors need to be assessed early during drug discovery, such that lead series can be optimized on safety parameters. This requires methods that allow for medium-to-high throughput compound profiling and that generate quantitative results suitable to establish structure-activity-relationships during lead optimization programs. We present the validation of such a method, a novel high content screening assay based on six parameters (nuclei counts, nuclear area, plasma membrane integrity, lysosomal activity, mitochondrial membrane potential (MMP), and mitochondrial area) using ~100 drugs of which the clinical hepatotoxicity profile is known. We find that a 100-fold TI between the lowest toxic concentration and the therapeutic Cmax is optimal to classify compounds as hepatotoxic or non-hepatotoxic, based on the individual parameters. Most parameters have ~50% sensitivity and ~90% specificity. Drugs hitting ≥2 parameters at a concentration below 100-fold their Cmax are typically hepatotoxic, whereas non-hepatotoxic drugs typically hit based on nuclei count, MMP and human Cmax, we identified an area without a single false positive, while maintaining 45% sensitivity. Hierarchical clustering using the multi-parametric dataset roughly separates toxic from non-toxic compounds. We employ the assay in discovery projects to prioritize novel compound series during hit-to-lead, to steer away from a DILI risk during lead optimization, for risk assessment towards candidate selection and to provide guidance of safe

  8. Preformulation compatibility screening of dika fat-drug mixtures ...

    African Journals Online (AJOL)

    Differential scanning calorimetry (DSC) was used as screening technique for assessing compatibility between dika fat and drug substances. Dika fat was found to be compatible with aspirin, ascorbic acid, paracetamol, sulphanilamide, phenylpropanolamine hydrochloride, bromopheniramine maleate, chlorpheniramire ...

  9. Thermodynamic Studies for Drug Design and Screening

    Science.gov (United States)

    Garbett, Nichola C.; Chaires, Jonathan B.

    2012-01-01

    Introduction A key part of drug design and development is the optimization of molecular interactions between an engineered drug candidate and its binding target. Thermodynamic characterization provides information about the balance of energetic forces driving binding interactions and is essential for understanding and optimizing molecular interactions. Areas covered This review discusses the information that can be obtained from thermodynamic measurements and how this can be applied to the drug development process. Current approaches for the measurement and optimization of thermodynamic parameters are presented, specifically higher throughput and calorimetric methods. Relevant literature for this review was identified in part by bibliographic searches for the period 2004 – 2011 using the Science Citation Index and PUBMED and the keywords listed below. Expert opinion The most effective drug design and development platform comes from an integrated process utilizing all available information from structural, thermodynamic and biological studies. Continuing evolution in our understanding of the energetic basis of molecular interactions and advances in thermodynamic methods for widespread application are essential to realize the goal of thermodynamically-driven drug design. Comprehensive thermodynamic evaluation is vital early in the drug development process to speed drug development towards an optimal energetic interaction profile while retaining good pharmacological properties. Practical thermodynamic approaches, such as enthalpic optimization, thermodynamic optimization plots and the enthalpic efficiency index, have now matured to provide proven utility in design process. Improved throughput in calorimetric methods remains essential for even greater integration of thermodynamics into drug design. PMID:22458502

  10. Thermodynamic studies for drug design and screening.

    Science.gov (United States)

    Garbett, Nichola C; Chaires, Jonathan B

    2012-04-01

    A key part of drug design and development is the optimization of molecular interactions between an engineered drug candidate and its binding target. Thermodynamic characterization provides information about the balance of energetic forces driving binding interactions and is essential for understanding and optimizing molecular interactions. This review discusses the information that can be obtained from thermodynamic measurements and how this can be applied to the drug development process. Current approaches for the measurement and optimization of thermodynamic parameters are presented, specifically higher throughput and calorimetric methods. Relevant literature for this review was identified in part by bibliographic searches for the period 2004 - 2011 using the Science Citation Index and PUBMED and the keywords listed below. The most effective drug design and development platform comes from an integrated process utilizing all available information from structural, thermodynamic and biological studies. Continuing evolution in our understanding of the energetic basis of molecular interactions and advances in thermodynamic methods for widespread application are essential to realize the goal of thermodynamically driven drug design. Comprehensive thermodynamic evaluation is vital early in the drug development process to speed drug development toward an optimal energetic interaction profile while retaining good pharmacological properties. Practical thermodynamic approaches, such as enthalpic optimization, thermodynamic optimization plots and the enthalpic efficiency index, have now matured to provide proven utility in the design process. Improved throughput in calorimetric methods remains essential for even greater integration of thermodynamics into drug design. © 2012 Informa UK, Ltd.

  11. Socioeconomic position and participation in colorectal cancer screening

    DEFF Research Database (Denmark)

    Frederiksen, B L; Jørgensen, Torben; Brasso, K

    2010-01-01

    Colorectal cancer (CRC) screening with faecal occult blood test (FOBT) has the potential to reduce the incidence and mortality of CRC. Screening uptake is known to be inferior in people with low socioeconomic position (SEP) when compared with those with high position; however, the results of most...... information on education, employment, and income to encompass different but related aspects of socioeconomic stratification. Also, the impact of ethnicity and cohabiting status was analysed.......Colorectal cancer (CRC) screening with faecal occult blood test (FOBT) has the potential to reduce the incidence and mortality of CRC. Screening uptake is known to be inferior in people with low socioeconomic position (SEP) when compared with those with high position; however, the results of most...... previous studies have limited value because they are based on recall or area-based measures of socioeconomic position, and might thus be subject to selective participation and misclassification. In this study we investigated differences in CRC screening participation using register-based individual...

  12. Alcohol and drug screening of occupational drivers for preventing injury

    NARCIS (Netherlands)

    Cashman, Clodagh M.; Ruotsalainen, Jani H.; Greiner, Birgit A.; Beirne, Paul V.; Verbeek, Jos H.

    2009-01-01

    BACKGROUND: Workforce alcohol and drug testing is commonplace but its effect in reducing occupational injuries remains unclear. OBJECTIVES: To assess the effects of alcohol and drug screening of occupational drivers (operating a motorised vehicle) in preventing injury or work-related effects such as

  13. Microreactor for electrochemical conversion: in drug screening and proteomics

    NARCIS (Netherlands)

    van den Brink, Floris Teunis Gerardus

    2016-01-01

    The majority of marketed drugs are metabolized through oxidation by enzymes of the cytochrome P450 family, thereby producing phase I metabolites. For pharmaceutical companies it is essential to thoroughly screen candidate drugs for potentially toxic metabolites, in order to avoid high costs

  14. A multi-infrastructure gateway for virtual drug screening

    NARCIS (Netherlands)

    Jaghoori, Mohammad Mahdi; van Altena, Allard J.; Bleijlevens, Boris; Ramezani, Sara; Font, Juan Luis; Olabarriaga, Silvia D.

    2015-01-01

    In computer-aided drug design, software tools are used to narrow down possible drug candidates, thereby reducing the amount of expensive in vitro research, by a process called virtual screening. This process includes large computations that require advanced computing infrastructure; however, using

  15. Hierarchical virtual screening approaches in small molecule drug discovery.

    Science.gov (United States)

    Kumar, Ashutosh; Zhang, Kam Y J

    2015-01-01

    Virtual screening has played a significant role in the discovery of small molecule inhibitors of therapeutic targets in last two decades. Various ligand and structure-based virtual screening approaches are employed to identify small molecule ligands for proteins of interest. These approaches are often combined in either hierarchical or parallel manner to take advantage of the strength and avoid the limitations associated with individual methods. Hierarchical combination of ligand and structure-based virtual screening approaches has received noteworthy success in numerous drug discovery campaigns. In hierarchical virtual screening, several filters using ligand and structure-based approaches are sequentially applied to reduce a large screening library to a number small enough for experimental testing. In this review, we focus on different hierarchical virtual screening strategies and their application in the discovery of small molecule modulators of important drug targets. Several virtual screening studies are discussed to demonstrate the successful application of hierarchical virtual screening in small molecule drug discovery. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Prevalence of HIV positive blood donors among screened ...

    African Journals Online (AJOL)

    hope&shola

    2006-04-03

    Apr 3, 2006 ... Department of Physiology, Obafemi Awolowo College of Health Sciences, Olabisi Onabanjo University Teaching. Hospital ... screening volunteer donors by initial criteria alone does not fully eliminate all HIV positive donors. The prevalence of HIV ... HIV test criteria alone to qualify for blood donation in the.

  17. Bead-based screening in chemical biology and drug discovery

    DEFF Research Database (Denmark)

    Komnatnyy, Vitaly V.; Nielsen, Thomas Eiland; Qvortrup, Katrine

    2018-01-01

    libraries for early drug discovery. Among the various library forms, the one-bead-one-compound (OBOC) library, where each bead carries many copies of a single compound, holds the greatest potential for the rapid identification of novel hits against emerging drug targets. However, this potential has not yet...... been fully realized due to a number of technical obstacles. In this feature article, we review the progress that has been made towards bead-based library screening and applications to the discovery of bioactive compounds. We identify the key challenges of this approach and highlight key steps needed......High-throughput screening is an important component of the drug discovery process. The screening of libraries containing hundreds of thousands of compounds requires assays amanable to miniaturisation and automization. Combinatorial chemistry holds a unique promise to deliver structural diverse...

  18. Understanding drugs in breast cancer through drug sensitivity screening

    NARCIS (Netherlands)

    K. Uhr (Katharina); W.J.C. Prager-van der Smissen (Wendy); A.A.J. Heine (Anouk); B. Ozturk (Bahar); M. Smid (Marcel); H.W.H. Göhlmann (Hinrich W. H.); A. Jager (Agnes); J.A. Foekens (John); J.W.M. Martens (John)

    2015-01-01

    textabstractWith substantial numbers of breast tumors showing or acquiring treatment resistance, it is of utmost importance to develop new agents for the treatment of the disease, to know their effectiveness against breast cancer and to understand their relationships with other drugs to best assign

  19. Test equality between two binary screening tests with a confirmatory procedure restricted on screen positives.

    Science.gov (United States)

    Lui, Kung-Jong; Chang, Kuang-Chao

    2015-01-01

    In studies of screening accuracy, we may commonly encounter the data in which a confirmatory procedure is administered to only those subjects with screen positives for ethical concerns. We focus our discussion on simultaneously testing equality of sensitivity and specificity between two binary screening tests when only subjects with screen positives receive the confirmatory procedure. We develop four asymptotic test procedures and one exact test procedure. We derive sample size calculation formula for a desired power of detecting a difference at a given nominal [Formula: see text]-level. We employ Monte Carlo simulation to evaluate the performance of these test procedures and the accuracy of the sample size calculation formula developed here in a variety of situations. Finally, we use the data obtained from a study of the prostate-specific-antigen test and digital rectal examination test on 949 Black men to illustrate the practical use of these test procedures and the sample size calculation formula.

  20. Family Checkup: Positive Parenting Prevents Drug Abuse

    Science.gov (United States)

    ... Alcohol Club Drugs Cocaine Fentanyl Hallucinogens Inhalants Heroin Marijuana MDMA (Ecstasy/Molly) Methamphetamine Opioids Over-the-Counter Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/ ...

  1. Semiautomated radioimmunoassay for mass screening of drugs of abuse

    International Nuclear Information System (INIS)

    Sulkowski, T.S.; Lathrop, G.D.; Merritt, J.H.; Landez, J.H.; Noe, E.R.

    1975-01-01

    A rapid, semiautomated radioimmunoassay system for detection of morphine, barbiturates, and amphetamines is described. The assays are applicable to large drug abuse screening programs. The heart of the system is the automatic pipetting station which can accomplish 600 pipetting operations per hour. The method uses 15 to 30 μl for the amphetamine and combined morphine/barbiturate assays. A number of other drugs were tested for interference with the assays and the results are discussed

  2. Reliability, Validity and Factor Structure of Drug Abuse Screening Test

    OpenAIRE

    Sayed Hadi Sayed Alitabar; Mojtaba Habibi; Maryam Falahatpisheh; Musa Arvin

    2016-01-01

    Background and Objective: According to the increasing of substance use in the country, more researches about this phenomenon are necessary. This Study Investigates the Validity, Reliability and Confirmatory Factor Structure of the Drug Abuse Screening test (DAST). Materials and Methods: The Sample Consisted of 381 Patients (143 Women and 238 Men) with a Multi-Stage Cluster Sampling of Areas 2, 6 and 12 of Tehran Were Selected from Each Region, 6 Randomly Selected Drug Rehabilitation Center. T...

  3. Detection of drugs in 275 alcohol-positive blood samples of Korean drivers.

    Science.gov (United States)

    Kim, Eunmi; Choe, Sanggil; Lee, Juseon; Jang, Moonhee; Choi, Hyeyoung; Chung, Heesun

    2016-08-01

    Since driving under the influence of drugs (DUID) is as dangerous as drink-driving, many countries regulate DUID by law. However, laws against the use of drugs while driving are not yet established in Korea. In order to investigate the type and frequency of drugs used by drivers in Korea, we analyzed controlled and non-controlled drugs in alcohol-positive blood samples. Total 275 blood samples were taken from Korean drivers, which were positive in roadside alcohol testing. The following analyses were performed: blood alcohol concentrations by GC; screening for controlled drugs by immunoassay and confirmation for positive samples by GC-MS. For the detection of DUID related drugs in blood samples, a total of 49 drugs were selected and were examined by GC-MS. For a rapid detection of these drugs, an automated identification software called "DrugMan" was used. Concentrations of alcohol in 275 blood samples ranged from 0.011 to 0.249% (average 0.119%). Six specimens showed positive results by immunoassay: one methamphetamine and five benzodiazepines I. By GC-MS confirmation, only benzodiazepines in four cases were identified, while methamphetamine and benzodiazepine in two cases were not detected from the presumptive positive blood samples. Using DrugMan, four drugs were detected; chlorpheniramine (5)*, diazepam (4), dextromethorphan (1) and doxylamine (1). In addition, ibuprofen (1), lidocaine (1) and topiramate (1) were also detected as general drugs in blood samples ('*' indicates frequency). The frequency of drug abuse by Korean drivers was relatively low and a total 14 cases were positive in 275 blood samples with a ratio of 5%. However it is necessary to analyze more samples including alcohol negative blood, and to expand the range of drug lists to get the detailed information. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  4. Focused use of drug screening in overdose patients increases impact on management.

    Science.gov (United States)

    Erdmann, Andreas; Werner, Dominique; Hugli, Olivier; Yersin, Bertrand

    2015-01-01

    Drug poisoning is a common cause for attendance in the emergency department. Several toxicology centres suggest performing urinary drug screens, even though they rarely influence patient management. Measuring the impact on patient management, in a University Emergency Department with approximately 40 000 admissions annually, of a rapid urinary drug screening test using specifically focused indications. Drug screening was restricted to patients having a first psychotic episode or cases demonstrating respiratory failure, coma, seizures, a sympathomimetic toxidrome, severe opiate overdose necessitating naloxone, hypotension, ventricular arrhythmia, acquired long QT or QRS >100 ms, and high-degree heart block. Retrospective analysis of Triage® TOX drug screen tests performed between September 2009 and November 2011, and between January 2013 and March 2014. A total of 262 patients were included, mean age 35 ± 14.6 (standard deviation) years, 63% men; 29% poisoning with alcohol, and 2.3% deaths. Indications for testing were as follows: 34% were first psychotic episodes; 20% had acute respiratory failure; 16% coma; 8% seizures; 8% sympathomimetic toxidromes; 7% severe opioid toxidromes; 4% hypotension; 3% ventricular arrhythmias or acquired long QT intervals on electrocardiogram. A total of 78% of the tests were positive (median two substances, maximum five). The test resulted in drug-specific therapy in 6.1%, drug specific diagnostic tests in 13.3 %, prolonged monitoring in 10.7% of methadone-positive tests, and psychiatric admission in 4.2%. Overall, 34.3% tests influenced patient management. In contrast to previous studies showing modest effects of toxicological testing, restricted use of rapid urinary drug testing increases the impact on management of suspected overdose patients in the ED.

  5. High throughput miniature drug-screening platform using bioprinting technology

    International Nuclear Information System (INIS)

    Rodríguez-Dévora, Jorge I; Reyna, Daniel; Xu Tao; Zhang Bimeng; Shi Zhidong

    2012-01-01

    In the pharmaceutical industry, new drugs are tested to find appropriate compounds for therapeutic purposes for contemporary diseases. Unfortunately, novel compounds emerge at expensive prices and current target evaluation processes have limited throughput, thus leading to an increase of cost and time for drug development. This work shows the development of the novel inkjet-based deposition method for assembling a miniature drug-screening platform, which can realistically and inexpensively evaluate biochemical reactions in a picoliter-scale volume at a high speed rate. As proof of concept, applying a modified Hewlett Packard model 5360 compact disc printer, green fluorescent protein expressing Escherichia coli cells along with alginate gel solution have been arrayed on a coverslip chip under a repeatable volume of 180% ± 26% picoliters per droplet; subsequently, different antibiotic droplets were patterned on the spots of cells to evaluate the inhibition of bacteria for antibiotic screening. The proposed platform was compared to the current screening process, validating its effectiveness. The viability and basic function of the printed cells were evaluated, resulting in cell viability above 98% and insignificant or no DNA damage to human kidney cells transfected. Based on the reduction of investment and compound volume used by this platform, this technique has the potential to improve the actual drug discovery process at its target evaluation stage. (paper)

  6. Screening for drugs of abuse (II): Cannabinoids, lysergic acid diethylamide, buprenorphine, methadone, barbiturates, benzodiazepines and other drugs.

    Science.gov (United States)

    Simpson, D; Braithwaite, R A; Jarvie, D R; Stewart, M J; Walker, S; Watson, I W; Widdop, B

    1997-09-01

    Requirements for the provision of an efficient and reliable service for drugs of abuse screening in urine have been summarized in Part I of this review. The requirements included rapid turn-around times, good communications between requesting clinicians and the laboratory, and participation in quality assessment schemes. In addition, the need for checking/confirmation of positive results obtained for preliminary screening methods was stressed. This aspect of the service has assumed even greater importance with widespread use of dip-stick technology and the increasing number of reasons for which drug screening is performed. Many of these additional uses of drug screening have possible serious legal implications, for example, screening school pupils, professional footballers, parents involved in child custody cases, persons applying for renewal of a driving licence after disqualification for a drug-related offence, doctors seeking re-registration after removal for drug abuse, and checking for compliance with terms of probation orders; as well as pre-employment screening and work-place testing. In many cases these requests will be received from a general practitioner or drug clinic with no indication of the reason for which testing has been requested. This also raises the serious problems of a chain of custody, provision of two samples, stability of samples, and secure and lengthy storage of samples in the laboratory-samples may be requested by legal authorities several months after the initial testing. The need for confirmation of positive results is now widely accepted but it may be equally important to confirm unexpected negative results. Failure to detect the presence of maintenance drugs may lead to the patient being discharged from a drug treatment clinic and, if attendance at the clinic is one of the terms of continued employment, to dismissal. It seems likely that increasing abuse of drugs and the efforts of regulatory authorities to control this, will lead to

  7. Screening for Drug Abuse Among College Students: Modification of the Michigan Alcoholism Screening Test

    Science.gov (United States)

    Cannell, M. Barry; Favazza, Armando R.

    1978-01-01

    Modified version of the Michigan Alcoholism Screening Test was anonymously given to 245 college students on two Midwestern university campuses. Cutoff score for suspected drug abuse was set at five points. The percent of students scoring five or more points was 25 and 22 from campuses A and B respectively. (Author)

  8. New arylsparteine derivatives as positive inotropic drugs.

    Science.gov (United States)

    Boido, Vito; Ercoli, Marcella; Tonelli, Michele; Novelli, Federica; Tasso, Bruno; Sparatore, Fabio; Cichero, Elena; Fossa, Paola; Dorigo, Paola; Froldi, Guglielmina

    2017-12-01

    Positive inotropic agents are fundamental in the treatment of heart failure; however, their arrhythmogenic liability and the increased myocardial oxygen demand strongly limit their therapeutic utility. Pursuing our study on cardiovascular activities of lupin alkaloid derivatives, several 2-(4-substituted-phenyl)-2-dehydrosparteines and 2-(4-substituted-phenyl)sparteines were prepared and tested for inotropic and chronotropic activities on isolated guinea pig atria. Four compounds (6b, 6e, 7b, and 7f) exhibited significant inotropism that, at the higher concentrations, was followed by negative inotropism or toxicity. Compound 7e (2-(4-tolyl)sparteine) exhibited a steep dose-depending inotropic activity up to the highest concentration tested (300 µM) with an E max of 116.5 ± 3.4% of basal force, proving less potent but much more active in comparison to the highest concentrations tested of digoxin and milrinone having E max of 87.5 ± 3.1% and 52.2 ± 1.1%, respectively. Finally, docking studies suggested that the relevant sparteine derivatives could target the sigma-1 receptor, whose involvement in cardiac activity is well documented.

  9. False-positive results in mammographic screening for breast cancer in Europe

    DEFF Research Database (Denmark)

    Hofvind, Solveig; Ponti, Antonio; Patnick, Julietta

    2012-01-01

    To estimate the cumulative risk of a false-positive screening result in European mammographic screening programmes, and examine the rates and procedures of further assessment.......To estimate the cumulative risk of a false-positive screening result in European mammographic screening programmes, and examine the rates and procedures of further assessment....

  10. Drug abuse in the workplace: employee screening techniques

    International Nuclear Information System (INIS)

    Buzzeo, R.W.

    1984-01-01

    Recent studies show that as many as three to five percent of the employees of a medium- to large-sized plant may be dependent on drugs as a way of life. The detrimental effects of drug abuse in the workplace can be measured in lost productivity, poor quality control and other areas at an annual cost to the American economy of $30 billion. However, a price tag cannot be attached to the lives affected by this unrelenting problem. The purpose of this paper is to provide an overview of the employee screening and hiring techniques available to industry to detect and eliminate potentially dangerous or fatal situations involving drug abuse in the workplace. The techniques are universal and can be effectively applied by the nuclear industry as well as other businesses to ensure that its work force is a reputable and reliable one

  11. Congestion game scheduling for virtual drug screening optimization

    Science.gov (United States)

    Nikitina, Natalia; Ivashko, Evgeny; Tchernykh, Andrei

    2018-02-01

    In virtual drug screening, the chemical diversity of hits is an important factor, along with their predicted activity. Moreover, interim results are of interest for directing the further research, and their diversity is also desirable. In this paper, we consider a problem of obtaining a diverse set of virtual screening hits in a short time. To this end, we propose a mathematical model of task scheduling for virtual drug screening in high-performance computational systems as a congestion game between computational nodes to find the equilibrium solutions for best balancing the number of interim hits with their chemical diversity. The model considers the heterogeneous environment with workload uncertainty, processing time uncertainty, and limited knowledge about the input dataset structure. We perform computational experiments and evaluate the performance of the developed approach considering organic molecules database GDB-9. The used set of molecules is rich enough to demonstrate the feasibility and practicability of proposed solutions. We compare the algorithm with two known heuristics used in practice and observe that game-based scheduling outperforms them by the hit discovery rate and chemical diversity at earlier steps. Based on these results, we use a social utility metric for assessing the efficiency of our equilibrium solutions and show that they reach greatest values.

  12. Risk of breast cancer after false-positive test results in screening mammography

    DEFF Research Database (Denmark)

    von Euler-Chelpin, My Catarina; Risør, Louise Madeleine; Thorsted, Brian Larsen

    2012-01-01

    Screening for disease in healthy people inevitably leads to some false-positive tests in disease-free individuals. Normally, women with false-positive screening tests for breast cancer are referred back to routine screening. However, the long-term outcome for women with false-positive tests...

  13. Screening Drug, Alcohol and Substance Abuse the Psychometric Measures

    Directory of Open Access Journals (Sweden)

    Othman Mohamad Hashim

    2018-01-01

    Full Text Available Urinalysis was used in previous studies among higher institution students (n=16252 in Malaysia to answer the question of whether university students are involved in drug abuse. However, the use of urinalysis had faced some problems. The problems were related to human rights issues and the cost to perform the urinalysis was expensive and quite impossible to be implemented to a large population of university students. To overcome this problem, this study was conducted to examine the effectiveness of psychometric measures in screening drug, alcohol and substance abuse. The Substance Abuse Subtle Screening Inventory A2 (SASSI-A2 was used for this purpose. SASSI-A2 is a brief screening tool designed to identify individuals who have a high probability of having a substance use disorder, including both substance abuse and substance dependence. SASSI-A2 comprises of 72 items that are rated on a two point scale with response; true and false. SASSI-A2 was translated into Malay language and it was refined through a back-translation technique and focus group approach. Psychometric testing was undertaken on a sample of 750 university students from five public universities in Malaysia. All participants were aged between 19 and 20 years. Internal consistency coefficients were calculated for the total scale and its subscales. Chronbach's alpha obtained for SASSI-A2 was 0.72. This relatively high level of Chronbach's alpha showed relatively high level of reliability. The results demonstrated that the whole SASSI-A2 meets the fundamental measurement properties and can discriminate groups of higher institution students from high to low on the substance dependency variable. The accuracy of the test has been found to be unaffected by gender, ethnicity, age and years of education. Although more rigorous validation studies are needed, it is recommended that SASSI-A2 be considered for usage to higher institution students populations when a brief, objective, and

  14. Combinatorial Drug Screening Identifies Ewing Sarcoma-specific Sensitivities

    DEFF Research Database (Denmark)

    Radic-Sarikas, Branka; Tsafou, Kalliopi P; Emdal, Kristina B.

    2017-01-01

    Improvements in survival for Ewing sarcoma pediatric and adolescent patients have been modest over the past 20 years. Combinations of anticancer agents endure as an option to overcome resistance to single treatments caused by compensatory pathways. Moreover, combinations are thought to lessen any...... associated adverse side effects through reduced dosing, which is particularly important in childhood tumors. Using a parallel phenotypic combinatorial screening approach of cells derived from three pediatric tumor types, we identified Ewing sarcoma-specific interactions of a diverse set of targeted agents...... including approved drugs. We were able to retrieve highly synergistic drug combinations specific for Ewing sarcoma and identified signaling processes important for Ewing sarcoma cell proliferation determined by EWS-FLI1 We generated a molecular target profile of PKC412, a multikinase inhibitor with strong...

  15. Focused use of drug screening in overdose patients increases impact on management.

    OpenAIRE

    Erdmann, A.; Werner, D.; Hugli, O.; Yersin, B.

    2015-01-01

    UNLABELLED: Drug poisoning is a common cause for attendance in the emergency department. Several toxicology centres suggest performing urinary drug screens, even though they rarely influence patient management. STUDY OBJECTIVES: Measuring the impact on patient management, in a University Emergency Department with approximately 40 000 admissions annually, of a rapid urinary drug screening test using specifically focused indications. Drug screening was restricted to patients having a first p...

  16. Screening applications in drug discovery based on microfluidic technology.

    Science.gov (United States)

    Eribol, P; Uguz, A K; Ulgen, K O

    2016-01-01

    Microfluidics has been the focus of interest for the last two decades for all the advantages such as low chemical consumption, reduced analysis time, high throughput, better control of mass and heat transfer, downsizing a bench-top laboratory to a chip, i.e., lab-on-a-chip, and many others it has offered. Microfluidic technology quickly found applications in the pharmaceutical industry, which demands working with leading edge scientific and technological breakthroughs, as drug screening and commercialization are very long and expensive processes and require many tests due to unpredictable results. This review paper is on drug candidate screening methods with microfluidic technology and focuses specifically on fabrication techniques and materials for the microchip, types of flow such as continuous or discrete and their advantages, determination of kinetic parameters and their comparison with conventional systems, assessment of toxicities and cytotoxicities, concentration generations for high throughput, and the computational methods that were employed. An important conclusion of this review is that even though microfluidic technology has been in this field for around 20 years there is still room for research and development, as this cutting edge technology requires ingenuity to design and find solutions for each individual case. Recent extensions of these microsystems are microengineered organs-on-chips and organ arrays.

  17. Screening applications in drug discovery based on microfluidic technology

    Science.gov (United States)

    Eribol, P.; Uguz, A. K.; Ulgen, K. O.

    2016-01-01

    Microfluidics has been the focus of interest for the last two decades for all the advantages such as low chemical consumption, reduced analysis time, high throughput, better control of mass and heat transfer, downsizing a bench-top laboratory to a chip, i.e., lab-on-a-chip, and many others it has offered. Microfluidic technology quickly found applications in the pharmaceutical industry, which demands working with leading edge scientific and technological breakthroughs, as drug screening and commercialization are very long and expensive processes and require many tests due to unpredictable results. This review paper is on drug candidate screening methods with microfluidic technology and focuses specifically on fabrication techniques and materials for the microchip, types of flow such as continuous or discrete and their advantages, determination of kinetic parameters and their comparison with conventional systems, assessment of toxicities and cytotoxicities, concentration generations for high throughput, and the computational methods that were employed. An important conclusion of this review is that even though microfluidic technology has been in this field for around 20 years there is still room for research and development, as this cutting edge technology requires ingenuity to design and find solutions for each individual case. Recent extensions of these microsystems are microengineered organs-on-chips and organ arrays. PMID:26865904

  18. Orbitrap technology for comprehensive metabolite-based liquid chromatographic–high resolution-tandem mass spectrometric urine drug screening – Exemplified for cardiovascular drugs

    International Nuclear Information System (INIS)

    Helfer, Andreas G.; Michely, Julian A.; Weber, Armin A.; Meyer, Markus R.; Maurer, Hans H.

    2015-01-01

    LC–high resolution (HR)-MS well established in proteomics has become more and more important in bioanalysis of small molecules over the last few years. Its high selectivity and specificity provide best prerequisites for its use in broad screening approaches. Therefore, Orbitrap technology was tested for developing a general metabolite-based LC–HR-MS/MS screening approach for urinalysis of drugs necessary in clinical and forensic toxicology. After simple urine precipitation, the drugs and their metabolites were separated within 10 min and detected by a Q-Exactive mass spectrometer in full scan with positive/negative switching, and subsequent data dependent acquisition (DDA) mode. Identification criteria were the presence of accurate precursor ions, isotopic patterns, five most intense fragment ions, and comparison with full HR-MS/MS library spectra. The current library contains over 1900 parent drugs and 1200 metabolites. The method was validated for typical drug representatives and metabolites concerning recovery, matrix effects, process efficiency, and limits showed acceptable results. The applicability was tested first for cardiovascular drugs, which should be screened for in poisoning cases and for medication adherence of hypertension patients. The novel LC–HR-MS/MS method allowed fast, simple, and robust urine screening, particularly for cardiovascular drugs showing the usefulness of Orbitrap technology for drug testing. - Highlights: • First study on the application of Orbitrap technology for comprehensive drug screening in clinical and forensic toxicology. • Simple workup, sufficient separation, and powerful screening and identification using modern high resolution MS. • Validation of the assay according to guidelines for qualitative approaches. • Elucidation of the power of new data evaluation software in combination with a new reference drug and metabolite library. • Great relevance for science and practice in clinical and forensic

  19. Orbitrap technology for comprehensive metabolite-based liquid chromatographic–high resolution-tandem mass spectrometric urine drug screening – Exemplified for cardiovascular drugs

    Energy Technology Data Exchange (ETDEWEB)

    Helfer, Andreas G.; Michely, Julian A.; Weber, Armin A.; Meyer, Markus R.; Maurer, Hans H., E-mail: hans.maurer@uks.eu

    2015-09-03

    LC–high resolution (HR)-MS well established in proteomics has become more and more important in bioanalysis of small molecules over the last few years. Its high selectivity and specificity provide best prerequisites for its use in broad screening approaches. Therefore, Orbitrap technology was tested for developing a general metabolite-based LC–HR-MS/MS screening approach for urinalysis of drugs necessary in clinical and forensic toxicology. After simple urine precipitation, the drugs and their metabolites were separated within 10 min and detected by a Q-Exactive mass spectrometer in full scan with positive/negative switching, and subsequent data dependent acquisition (DDA) mode. Identification criteria were the presence of accurate precursor ions, isotopic patterns, five most intense fragment ions, and comparison with full HR-MS/MS library spectra. The current library contains over 1900 parent drugs and 1200 metabolites. The method was validated for typical drug representatives and metabolites concerning recovery, matrix effects, process efficiency, and limits showed acceptable results. The applicability was tested first for cardiovascular drugs, which should be screened for in poisoning cases and for medication adherence of hypertension patients. The novel LC–HR-MS/MS method allowed fast, simple, and robust urine screening, particularly for cardiovascular drugs showing the usefulness of Orbitrap technology for drug testing. - Highlights: • First study on the application of Orbitrap technology for comprehensive drug screening in clinical and forensic toxicology. • Simple workup, sufficient separation, and powerful screening and identification using modern high resolution MS. • Validation of the assay according to guidelines for qualitative approaches. • Elucidation of the power of new data evaluation software in combination with a new reference drug and metabolite library. • Great relevance for science and practice in clinical and forensic

  20. Evaluation of California's Alcohol and Drug Screening and Brief Intervention Project for Emergency Department Patients

    Directory of Open Access Journals (Sweden)

    Susan I Woodruff

    2013-05-01

    Full Text Available Introduction: Visits to settings such as emergency departments (EDs may present a “teachable moment” in that a patient may be more open to feedback and suggestions regarding their risky alcohol and illicit drug-use behaviors. Screening, Brief Intervention, and Referral to Treatment (SBIRT is an ’opportunistic’ public health approach that targets low-risk users, in addition to those already dependent on alcohol and/or drugs. SBIRT programs provide patients with comprehensive screening and assessments, and deliver interventions of appropriate intensity to reduce risks related to alcohol and drug use. Methods: This study used a single group pre-post test design to assess the effect of the California SBIRT service program (i.e., CASBIRT on 6 substance-use outcomes (past-month prevalence and number of days of binge drinking, illegal drug use, and marijuana use. Trained bilingual/bicultural Health Educators attempted to screen all adult patients in 12 EDs/trauma centers (regardless of the reason for the patient’s visit using a short instrument, and then delivered a brief motivational intervention matched to the patient’s risk level. A total of 2,436 randomly selected patients who screened positive for alcohol and/or drug use consented to be in a 6-month telephone follow-up interview. Because of the high loss to follow-up rate, we used an intention-to-treat approach for the data analysis. Results: Results of generalized linear mixed models showed modest reductions in all 6 drug- and alcohol-use outcomes. Men (versus women, those at relatively higher risk status (versus lower risk, and those with only one substance of misuse (versus both alcohol and illicit drug misuse tended to show more positive change. Conclusion: These results suggest that SBIRT services provided in acute care settings are associated with modest changes in self-reported recent alcohol and illicit drug use. [West J Emerg Med. 2013;14(3:263–270.

  1. Combinatorial Drug Screening Identifies Ewing Sarcoma-specific Sensitivities.

    Science.gov (United States)

    Radic-Sarikas, Branka; Tsafou, Kalliopi P; Emdal, Kristina B; Papamarkou, Theodore; Huber, Kilian V M; Mutz, Cornelia; Toretsky, Jeffrey A; Bennett, Keiryn L; Olsen, Jesper V; Brunak, Søren; Kovar, Heinrich; Superti-Furga, Giulio

    2017-01-01

    Improvements in survival for Ewing sarcoma pediatric and adolescent patients have been modest over the past 20 years. Combinations of anticancer agents endure as an option to overcome resistance to single treatments caused by compensatory pathways. Moreover, combinations are thought to lessen any associated adverse side effects through reduced dosing, which is particularly important in childhood tumors. Using a parallel phenotypic combinatorial screening approach of cells derived from three pediatric tumor types, we identified Ewing sarcoma-specific interactions of a diverse set of targeted agents including approved drugs. We were able to retrieve highly synergistic drug combinations specific for Ewing sarcoma and identified signaling processes important for Ewing sarcoma cell proliferation determined by EWS-FLI1 We generated a molecular target profile of PKC412, a multikinase inhibitor with strong synergistic propensity in Ewing sarcoma, revealing its targets in critical Ewing sarcoma signaling routes. Using a multilevel experimental approach including quantitative phosphoproteomics, we analyzed the molecular rationale behind the disease-specific synergistic effect of simultaneous application of PKC412 and IGF1R inhibitors. The mechanism of the drug synergy between these inhibitors is different from the sum of the mechanisms of the single agents. The combination effectively inhibited pathway crosstalk and averted feedback loop repression, in EWS-FLI1-dependent manner. Mol Cancer Ther; 16(1); 88-101. ©2016 AACR. ©2016 American Association for Cancer Research.

  2. Outreach screening of drug users for cirrhosis with transient elastography

    DEFF Research Database (Denmark)

    Moessner, Belinda K; Jørgensen, Tina R; Skamling, Merete

    2011-01-01

    Aims  Transient elastography (TE) is a non-invasive sensitive tool for diagnosing cirrhosis in hospital-based cohorts. This study aimed to evaluate TE as a screening tool for cirrhosis among drug users. Design  Cross-sectional study. Setting  All treatment centres in the county of Funen, Denmark....... Participants  Drug users attending treatment centres during the presence of the study team. Measurements  Liver stiffness measurements (LSM) by transient elastography using the Fibroscan device; blood tests for viral hepatitis, HIV infection and hyaluronic acid (HA) levels; and routine liver tests. Individuals...... with LSM ≥ 8 kPa were referred to the hospital for treatment evaluation. Individuals with LSM ≥ 12 kPa were recommended a liver biopsy. Findings  Among 175 drug users negative for hepatitis C, 13% had LSM = 8-11.9 kPa and 4% had LSM ≥ 12 kPa; elevated LSM was associated with a body mass index (BMI) > 30...

  3. Rates of sexual history taking and screening in HIV-positive men who have sex with men.

    Science.gov (United States)

    MacRae, Alasdair; Lord, Emily; Forsythe, Annabel; Sherrard, Jackie

    2017-03-01

    A case note audit was undertaken of HIV-positive men who have sex with men (MSM) to ascertain whether national guidelines for taking sexual histories, including recreational drug use and sexually transmitted infection (STI) screening were being met. The notes of 142 HIV-positive men seen in 2015 were available, of whom 85 were MSM. Information was collected regarding sexual history, recreational drug use documentation, sexually transmitted infection screen offer and test results. Seventy-seven (91%) of the MSM had a sexual history documented, of whom 60 (78%) were sexually active. STI screens were offered to 58/60 (97%) of those who were sexually active and accepted by 53 (91%). Twelve (23%) of these had an STI. A recreational drug history was taken in 63 (74%) with 17 (27%) reporting use and 3 (5%) chemsex. The high rate of STIs highlights that regular screening in this group is essential. Additionally, the fact that over a quarter reported recreational drug use and given the increasing concern around chemsex, questions about this should be incorporated into the sexual history proforma.

  4. Prevalence of HIV positive blood donors among screened ...

    African Journals Online (AJOL)

    Two thousand five hundred and thirty two (2,532) males, aged 25 – 50 years potential blood donors were randomly selected from the total number of volunteer blood donors who satisfied the initial screening criteria for donating blood, and were screened for HIV using Immunocomb II (HIV 1 and 2 Bispot) and Recombigen ...

  5. Spirituality and adherence to antiretroviral drugs among HIV positive ...

    African Journals Online (AJOL)

    Method: It was an observational, longitudinal study in which 215 consenting HIV positive patients aged 18 to 65 years who were on antiretroviral drugs were recruited through systematic random sampling technique. Socio-demographic characteristics, clinical history and physical examination findings were documented for ...

  6. A Clinical Drug Library Screen Identifies Tosufloxacin as Being Highly Active against Staphylococcus aureus Persisters

    Directory of Open Access Journals (Sweden)

    Hongxia Niu

    2015-07-01

    Full Text Available To identify effective compounds that are active against Staphylococcus aureus (S. aureus persisters, we screened a clinical drug library consisting of 1524 compounds and identified six drug candidates that had anti-persister activity: tosufloxacin, clinafloxacin, sarafloxacin, doxycycline, thiostrepton, and chlorosalicylanilide. Among them, tosufloxacin had the highest anti-persister activity, which could completely eradicate S. aureus persisters within 2 days in vitro. Clinafloxacin ranked the second with very few persisters surviving the drug exposure. Interestingly, we found that both tosufloxacin and trovafloxacin that had high activity against persisters contained at the N-1 position the 2,4-difluorophenyl group, which is absent in other less active quinolones and may be associated with the high anti-persister activity. Further studies are needed to evaluate tosufloxacin in animal models and to explain its unique activity against bacterial persisters. Our findings may have implications for improved treatment of persistent bacterial infections.

  7. Chemical biology drug sensitivity screen identifies sunitinib as synergistic agent with disulfiram in prostate cancer cells.

    Directory of Open Access Journals (Sweden)

    Kirsi Ketola

    Full Text Available Current treatment options for castration- and treatment-resistant prostate cancer are limited and novel approaches are desperately needed. Our recent results from a systematic chemical biology sensitivity screen covering most known drugs and drug-like molecules indicated that aldehyde dehydrogenase inhibitor disulfiram is one of the most potent cancer-specific inhibitors of prostate cancer cell growth, including TMPRSS2-ERG fusion positive cancers. However, the results revealed that disulfiram alone does not block tumor growth in vivo nor induce apoptosis in vitro, indicating that combinatorial approaches may be required to enhance the anti-neoplastic effects.In this study, we utilized a chemical biology drug sensitivity screen to explore disulfiram mechanistic details and to identify compounds potentiating the effect of disulfiram in TMPRSS2-ERG fusion positive prostate cancer cells. In total, 3357 compounds including current chemotherapeutic agents as well as drug-like small molecular compounds were screened alone and in combination with disulfiram. Interestingly, the results indicated that androgenic and antioxidative compounds antagonized disulfiram effect whereas inhibitors of receptor tyrosine kinase, proteasome, topoisomerase II, glucosylceramide synthase or cell cycle were among compounds sensitizing prostate cancer cells to disulfiram. The combination of disulfiram and an antiangiogenic agent sunitinib was studied in more detail, since both are already in clinical use in humans. Disulfiram-sunitinib combination induced apoptosis and reduced androgen receptor protein expression more than either of the compounds alone. Moreover, combinatorial exposure reduced metastatic characteristics such as cell migration and 3D cell invasion as well as induced epithelial differentiation shown as elevated E-cadherin expression.Taken together, our results propose novel combinatorial approaches to inhibit prostate cancer cell growth. Disulfiram

  8. Comparison of cumulative false-positive risk of screening mammography in the United States and Denmark

    DEFF Research Database (Denmark)

    Jacobsen, Katja Kemp

    2015-01-01

    INTRODUCTION: In the United States (US), about one-half of women screened with annual mammography have at least one false-positive test after ten screens. The estimate for European women screened ten times biennially is much lower. We evaluate to what extent screening interval, mammogram type......=400,204), between 1991-2012 and 1993-2013, respectively. Model-based cumulative false-positive risks were computed for the entire sample, using two statistical methods (Hubbard Njor) previously used to estimate false-positive risks in the US and Europe. RESULTS: Empirical cumulative risk of at least...... one false-positive test after eight (annual or biennial) screens was 41.9% in BCSC, 16.1% in Copenhagen, and 7.4% in Funen. Variation in screening interval and mammogram type did not explain the differences by country. Using the Hubbard method, the model-based cumulative risks after eight screens...

  9. Evaluation of the on-site immunoassay drug-screening device Triage-TOX in routine forensic autopsy.

    Science.gov (United States)

    Tominaga, Mariko; Michiue, Tomomi; Maeda, Hitoshi

    2015-11-01

    Instrumental identification of drugs with quantification is essential in forensic toxicology, while on-site immunoassay urinalysis drug-screening devices conveniently provide preliminary information when adequately used. However, suitable or sufficient urine specimens are not always available. The present study evaluated the efficacy of a new on-site immunoassay drug-screening device Triage-TOX (Alere Inc., San Diego, CA, USA), which has recently been developed to provide objective data on the one-step automated processor, using 51 urine and 19 pericardial fluid samples from 66 forensic autopsy cases, compared with Triage-Drug of Abuse (DOA) and Monitect-9. For benzodiazepines, the positive predictive value and specificity of Triage-TOX were higher than those of Triage-DOA; however, sensitivity was higher with Monitect-9, despite frequent false-positives. The results for the other drugs with the three devices also included a few false-negatives and false-positives. These observations indicate the applicability of Triage-TOX in preliminary drug screening using urine or alternative materials in routine forensic autopsy, when a possible false-negative is considered, especially for benzodiazepines, providing objective information; however, the combined use of another device such as Monitect-9 can help minimize misinterpretation prior to instrumental analysis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  10. Positive predictive values by mammographic density and screening mode in the Norwegian Breast Cancer Screening Program.

    Science.gov (United States)

    Moshina, Nataliia; Ursin, Giske; Roman, Marta; Sebuødegård, Sofie; Hofvind, Solveig

    2016-01-01

    To investigate the probability of breast cancer among women recalled due to abnormal findings on the screening mammograms (PPV-1) and among women who underwent an invasive procedure (PPV-2) by mammographic density (MD), screening mode and age. We used information about 28,826 recall examinations from 26,951 subsequently screened women in the Norwegian Breast Cancer Screening Program, 1996-2010. The radiologists who performed the recall examinations subjectively classified MD on the mammograms into three categories: fatty (70%). Screening mode was defined as screen-film mammography (SFM) and full-field digital mammography (FFDM). We examined trends of PPVs by MD, screening mode and age. We used logistic regression to estimate odds ratio (OR) of screen-detected breast cancer associated with MD among women recalled, adjusting for screening mode and age. PPV-1 and PPV-2 decreased by increasing MD, regardless of screening mode (p for trend breasts. Among women recalled, the adjusted OR of breast cancer decreased with increasing MD. Compared with women with fatty breasts, the OR was 0.90 (95% CI: 0.84-0.96) for those with medium dense breasts and 0.85 (95% CI: 0.76-0.95) for those with dense breasts. PPVs decreased by increasing MD. Fewer women needed to be recalled or undergo an invasive procedure to detect one breast cancer among those with fatty versus dense breasts in the screening program in Norway, 1996-2010. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  11. Position-aware deep multi-task learning for drug-drug interaction extraction.

    Science.gov (United States)

    Zhou, Deyu; Miao, Lei; He, Yulan

    2018-05-01

    A drug-drug interaction (DDI) is a situation in which a drug affects the activity of another drug synergistically or antagonistically when being administered together. The information of DDIs is crucial for healthcare professionals to prevent adverse drug events. Although some known DDIs can be found in purposely-built databases such as DrugBank, most information is still buried in scientific publications. Therefore, automatically extracting DDIs from biomedical texts is sorely needed. In this paper, we propose a novel position-aware deep multi-task learning approach for extracting DDIs from biomedical texts. In particular, sentences are represented as a sequence of word embeddings and position embeddings. An attention-based bidirectional long short-term memory (BiLSTM) network is used to encode each sentence. The relative position information of words with the target drugs in text is combined with the hidden states of BiLSTM to generate the position-aware attention weights. Moreover, the tasks of predicting whether or not two drugs interact with each other and further distinguishing the types of interactions are learned jointly in multi-task learning framework. The proposed approach has been evaluated on the DDIExtraction challenge 2013 corpus and the results show that with the position-aware attention only, our proposed approach outperforms the state-of-the-art method by 0.99% for binary DDI classification, and with both position-aware attention and multi-task learning, our approach achieves a micro F-score of 72.99% on interaction type identification, outperforming the state-of-the-art approach by 1.51%, which demonstrates the effectiveness of the proposed approach. Copyright © 2018 Elsevier B.V. All rights reserved.

  12. Depression screening among older adults attending low-vision rehabilitation and eye-care services: Characteristics of those who screen positive and client acceptability of screening.

    Science.gov (United States)

    Holloway, Edith E; Sturrock, Bonnie A; Lamoureux, Ecosse L; Keeffe, Jill E; Rees, Gwyneth

    2015-12-01

    To investigate characteristics associated with screening positive for depressive symptoms among older adults accessing low-vision rehabilitation and eye-care services and to determine client acceptability of depression screening using the Patient Health Questionnaire-2 (PHQ-2) in these settings. One-hundred and twenty-four older adults (mean = 77.02 years, SD = 9.12) attending low-vision rehabilitation and eye-care services across Australia were screened for depression and invited to complete a telephone-administered questionnaire to determine characteristics associated with depressive symptoms and client acceptability of screening in these settings. Thirty-seven per cent (n = 46/124) of participants screened positive for depressive symptoms, and the majority considered the new depression screening method to be a 'good idea' in vision services (85%). Severe vision loss (<6/60 in the better eye) was associated with an increased odds of screening positive for depressive symptoms (odds ratio 2.37; 95% confidence interval 1.08-6.70) even after adjusting for potential confounders. Participants who screened positive had a preference for 'talking' therapy or a combination of medication and 'talking therapy' delivered within their own home (73%) or via telephone (67%). The PHQ-2 appears to be an acceptable method for depression screening in eye-care settings among older adults. Targeted interventions that incorporate home-based or telephone delivered therapy sessions may improve outcomes for depression in this group. © 2014 ACOTA.

  13. Timing of specimen collection is crucial in urine screening of drug dependent mothers and newborns.

    Science.gov (United States)

    Halstead, A C; Godolphin, W; Lockitch, G; Segal, S

    1988-01-01

    We compared results of urine drug analysis with clinical data and history to test the usefulness of peripartum drug screening and to establish guidelines for optimal testing. Urine from 28 mothers and 52 babies was analysed. Drugs not suspected by history were found in 10 mothers and six babies. Results assisted in the management of neonatal withdrawal in three babies. Drugs suspected by history were not found in 11/22 mothers and 23/35 babies. About half of these results were associated with delayed urine collection. In 12/28 mothers, drugs administered in hospital could have confused interpretation of screen results. We conclude that urine drug screening without strict protocols for specimen collection is of limited usefulness for management of drug abuse in pregnancy and neonatal drug withdrawal. We favour testing of maternal urine obtained before drugs are administered in hospital. Neonatal urine, if used, should be collected in the first day of life.

  14. Enhancing Reproducibility in Cancer Drug Screening: How Do We Move Forward?

    DEFF Research Database (Denmark)

    Shi, Leming; Haibe-Kains, Benjamin; Birkbak, Nicolai Juul

    2014-01-01

    Large-scale pharmacogenomic high-throughput screening (HTS) studies hold great potential for generating robust genomic predictors of drug response. Two recent large-scale HTS studies have reported results of such screens, revealing several known and novel drug sensitivities and biomarkers...

  15. Follow up Evaluation of Air Force Blood Donors Screening Positive for Chagas Disease

    Science.gov (United States)

    2017-10-05

    59 MDW/SGVU SUBJECT: Professional Presentation Approval 31 JULY2017 Your paper, entitled Follow-up Evaluation of Air Force Blood Donors Screening...PUBLISHED OR PRESENTED: Follow-up Evaluation of Air Force Blood Donors Screening Positive for Chagas Disease 7. FUNDING RECEIVED FOR THIS STUDY? 0...PREVIOUS EDITIONS ARE OBSOLETE 50. DATE Page 3 of 3 Pages Follow-up Evaluation of Air Force Blood Donors Screening Positive for Chagas Disease

  16. Desensitization in delayed drug hypersensitivity reactions -- an EAACI position paper of the Drug Allergy Interest Group.

    Science.gov (United States)

    Scherer, K; Brockow, K; Aberer, W; Gooi, J H C; Demoly, P; Romano, A; Schnyder, B; Whitaker, P; Cernadas, J S R; Bircher, A J

    2013-07-01

    Drug hypersensitivity may deprive patients of drug therapy, and occasionally no effective alternative treatment is available. Successful desensitization has been well documented in delayed drug hypersensitivity reactions. In certain situations, such as sulfonamide hypersensitivity in HIV-positive patients or hypersensitivity to antibiotics in patients with cystic fibrosis, published success rates reach 80%, and this procedure appears helpful for the patient management. A state of clinical tolerance may be achieved by the administration of increasing doses of the previously offending drug. However, in most cases, a pre-existent sensitization has not been proven by positive skin tests. Successful re-administration may have occurred in nonsensitized patients. A better understanding of the underlying mechanisms of desensitization is needed. Currently, desensitization in delayed hypersensitivity reactions is restricted to mild, uncomplicated exanthems and fixed drug eruptions. The published success rates vary depending on clinical manifestations, drugs, and applied protocols. Slower protocols tend to be more effective than rush protocols; however, underreporting of unsuccessful procedures is very probable. The decision to desensitize a patient must always be made on an individual basis, balancing risks and benefits. This paper reviews the literature and presents the expert experience of the Drug Hypersensitivity Interest Group of the European Academy of Allergy and Clinical Immunology. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. Risk of breast cancer after false-positive results in mammographic screening

    DEFF Research Database (Denmark)

    Roman, Marta; Castells, Xavier; Hofvind, Solveig

    2016-01-01

    risk (RR) of screen-detected cancer for women with false-positive versus negative results. We analyzed information from 1,935,093 women 50–69 years who underwent 6,094,515 screening exams. During an average 5.8 years of follow-up, 230,609 (11.9%) women received a false-positive result and 27,849 (1......Women with false-positive results are commonly referred back to routine screening. Questions remain regarding their long-term outcome of breast cancer. We assessed the risk of screen-detected breast cancer in women with false-positive results. We conducted a joint analysis using individual level.......4%) were diagnosed with screen-detected cancer. The adjusted RR of screen-detected cancer after a false-positive result was 2.01 (95% CI: 1.93–2.09). Women who tested false-positive at first screen had a RR of 1.86 (95% CI: 1.77–1.96), whereas those who tested false-positive at third screening had a RR...

  18. Risk of breast cancer after false-positive results in mammographic screening.

    Science.gov (United States)

    Román, Marta; Castells, Xavier; Hofvind, Solveig; von Euler-Chelpin, My

    2016-06-01

    Women with false-positive results are commonly referred back to routine screening. Questions remain regarding their long-term outcome of breast cancer. We assessed the risk of screen-detected breast cancer in women with false-positive results. We conducted a joint analysis using individual level data from the population-based screening programs in Copenhagen and Funen in Denmark, Norway, and Spain. Overall, 150,383 screened women from Denmark (1991-2008), 612,138 from Norway (1996-2010), and 1,172,572 from Spain (1990-2006) were included. Poisson regression was used to estimate the relative risk (RR) of screen-detected cancer for women with false-positive versus negative results. We analyzed information from 1,935,093 women 50-69 years who underwent 6,094,515 screening exams. During an average 5.8 years of follow-up, 230,609 (11.9%) women received a false-positive result and 27,849 (1.4%) were diagnosed with screen-detected cancer. The adjusted RR of screen-detected cancer after a false-positive result was 2.01 (95% CI: 1.93-2.09). Women who tested false-positive at first screen had a RR of 1.86 (95% CI: 1.77-1.96), whereas those who tested false-positive at third screening had a RR of 2.42 (95% CI: 2.21-2.64). The RR of breast cancer at the screening test after the false-positive result was 3.95 (95% CI: 3.71-4.21), whereas it decreased to 1.25 (95% CI: 1.17-1.34) three or more screens after the false-positive result. Women with false-positive results had a twofold risk of screen-detected breast cancer compared to women with negative tests. The risk remained significantly higher three or more screens after the false-positive result. The increased risk should be considered when discussing stratified screening strategies. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  19. Effects of screening and partner notification on Chlamydia positivity in the United States: a modeling study.

    Science.gov (United States)

    Kretzschmar, Mirjam; Satterwhite, Catherine; Leichliter, Jami; Berman, Stuart

    2012-05-01

    Model impact of increasing screening and partner notification (PN) on chlamydia positivity. We used a stochastic simulation model describing pair formation and dissolution in an age-structured heterosexual population. The model accounts for steady, casual, and concurrent partnerships and a highly sexually active core group. The model used existing sexual behavior data from the United States and was validated using chlamydia positivity data from Region X (Alaska, Idaho, Oregon, Washington). A screening program with a coverage rate of 20% was implemented among women aged 15 to 24 years. After 10 years, we increased screening coverage to 35%, 50%, and 65% and partner treatment rates from 20% to 40% and 55%. Finally, we included male screening (aged 15-24, screening coverage: 20% and 35%, partner treatment: 25% and 40%). We analyzed the effects on chlamydia positivity in women and the frequency of reinfection 6 months after treatment. The model described the decline in positivity observed from 1988 to 1997 in Region X, given screening coverage of 20% and a 25% partner treatment rate. Increasing screening coverage from 35% to 65% resulted in incremental decreases in positivity as did increasing the PN rate; a 23% reduction in positivity was achieved by either increasing screening by 3-fold or PN by 2-fold. Adding male screening to the program had less impact than increasing screening coverage or PN among women. Increased PN and treatment reduced reinfection rates considerably. Increasing efforts in PN may contribute at least as much to control of chlamydia infection as increasing screening coverage rates.

  20. Drug and bioactive molecule screening based on a bioelectrical impedance cell culture platform

    Directory of Open Access Journals (Sweden)

    Ramasamy S

    2014-12-01

    Full Text Available Sakthivel Ramasamy,1 Devasier Bennet,1 Sanghyo Kim1,2 1Department of Bionanotechnology, Gachon University, Gyeonggi-Do, Republic of Korea; 2Graduate Gachon Medical Research Institute, Gil Medical Center, Incheon, Republic of Korea Abstract: This review will present a brief discussion on the recent advancements of bioelectrical impedance cell-based biosensors, especially the electric cell-substrate impedance sensing (ECIS system for screening of various bioactive molecules. The different technical integrations of various chip types, working principles, measurement systems, and applications for drug targeting of molecules in cells are highlighted in this paper. Screening of bioactive molecules based on electric cell-substrate impedance sensing is a trial-and-error process toward the development of therapeutically active agents for drug discovery and therapeutics. In general, bioactive molecule screening can be used to identify active molecular targets for various diseases and toxicity at the cellular level with nanoscale resolution. In the innovation and screening of new drugs or bioactive molecules, the activeness, the efficacy of the compound, and safety in biological systems are the main concerns on which determination of drug candidates is based. Further, drug discovery and screening of compounds are often performed in cell-based test systems in order to reduce costs and save time. Moreover, this system can provide more relevant results in in vivo studies, as well as high-throughput drug screening for various diseases during the early stages of drug discovery. Recently, MEMS technologies and integration with image detection techniques have been employed successfully. These new technologies and their possible ongoing transformations are addressed. Select reports are outlined, and not all the work that has been performed in the field of drug screening and development is covered. Keywords: screening of bioactive agents, impedance-based cell

  1. Predicting Drug-Target Interactions Based on Small Positive Samples.

    Science.gov (United States)

    Hu, Pengwei; Chan, Keith C C; Hu, Yanxing

    2018-01-01

    A basic task in drug discovery is to find new medication in the form of candidate compounds that act on a target protein. In other words, a drug has to interact with a target and such drug-target interaction (DTI) is not expected to be random. Significant and interesting patterns are expected to be hidden in them. If these patterns can be discovered, new drugs are expected to be more easily discoverable. Currently, a number of computational methods have been proposed to predict DTIs based on their similarity. However, such as approach does not allow biochemical features to be directly considered. As a result, some methods have been proposed to try to discover patterns in physicochemical interactions. Since the number of potential negative DTIs are very high both in absolute terms and in comparison to that of the known ones, these methods are rather computationally expensive and they can only rely on subsets, rather than the full set, of negative DTIs for training and validation. As there is always a relatively high chance for negative DTIs to be falsely identified and as only partial subset of such DTIs is considered, existing approaches can be further improved to better predict DTIs. In this paper, we present a novel approach, called ODT (one class drug target interaction prediction), for such purpose. One main task of ODT is to discover association patterns between interacting drugs and proteins from the chemical structure of the former and the protein sequence network of the latter. ODT does so in two phases. First, the DTI-network is transformed to a representation by structural properties. Second, it applies a oneclass classification algorithm to build a prediction model based only on known positive interactions. We compared the best AUROC scores of the ODT with several state-of-art approaches on Gold standard data. The prediction accuracy of the ODT is superior in comparison with all the other methods at GPCRs dataset and Ion channels dataset. Performance

  2. Screening for substance abuse risk in cancer patients using the Opioid Risk Tool and urine drug screen.

    Science.gov (United States)

    Barclay, Joshua S; Owens, Justine E; Blackhall, Leslie J

    2014-07-01

    The use of opioids for management of cancer-related pain has increased significantly and has been associated with a substantial rise in rates of substance abuse and diversion. There is a paucity of data not only on the prevalence of substance abuse in cancer patients, but also for issues of drug use and diversion in family caregivers. This study aimed to evaluate the frequency of risk factors for substance abuse and diversion, and abnormal urine drug screens in cancer patients receiving palliative care. A retrospective chart review was performed for patients with cancer who were seen in the University of Virginia Palliative Care Clinic during the month of September 2012. We evaluated Opioid Risk Tool variables and total scores, insurance status, and urine drug screen results. Of the 114 cancer patients seen in September 2012, the mean Opioid Risk Tool score was 3.79, with 43% of patients defined as medium to high risk. Age (16-45 years old, 23%) and a personal history of alcohol (23%) or illicit drugs (21%) were the most common risk factors identified. We obtained a urine drug screen on 40% of patients, noting abnormal findings in 45.65%. Opioids are an effective treatment for cancer-related pain, yet substantial risk for substance abuse exits in the cancer population. Screening tools, such as the Opioid Risk Tool, should be used as part of a complete patient assessment to balance risk with appropriate relief of suffering.

  3. The problem of false-positive human papillomavirus DNA tests in cervical screening

    DEFF Research Database (Denmark)

    Rebolj, Matejka; Pribac, Igor; Frederiksen, Maria Eiholm

    2013-01-01

    Human Papillomavirus (HPV) testing has been extensively studied in randomized controlled trials of primary cervical screening. Based on encouraging results concerning its high detection rates and a high negative predictive value for high-grade cervical intraepithelial neoplasia (CIN), HPV testing...... will probably replace cytology in future primary cervical screening. However, HPV testing is associated with more frequent false-positive tests compared to cytology. False-positive tests are defined as positive screening tests which are not subsequently confirmed with high-grade CIN. Several authors have...

  4. An Algorithm of Calculating the Position in a Self-Capacitance Touch Screen

    Science.gov (United States)

    Zhang, Huan; Peng, Haiyan; Qian, Xiaoli; Ren, Can; Wang, Wentao; Li, Jianjun

    Touch screens have been widely used in many kinds of electronic products. For many capacitive touch sensing devices, they always suffer from a variety of electronic signal noises. So when a finger touches the screen, it is difficult to calculate the exact touch position on the screen. We proposed an algorithm of calculating the position in a self-capacitance touch screen to alleviate noise interference. We determined the touch region by calculating the differences between current data and reference data in every channel. In the touch region we divided it into different ranges to calculate the touch point. The simulation results show that the algorithm that we proposed can alleviate noise interference effectively and obtain the exact positioning on touch screen accurately.

  5. An update on the use of C. elegans for preclinical drug discovery: screening and identifying anti-infective drugs.

    Science.gov (United States)

    Kim, Wooseong; Hendricks, Gabriel Lambert; Lee, Kiho; Mylonakis, Eleftherios

    2017-06-01

    The emergence of antibiotic-resistant and -tolerant bacteria is a major threat to human health. Although efforts for drug discovery are ongoing, conventional bacteria-centered screening strategies have thus far failed to yield new classes of effective antibiotics. Therefore, new paradigms for discovering novel antibiotics are of critical importance. Caenorhabditis elegans, a model organism used for in vivo, offers a promising solution for identification of anti-infective compounds. Areas covered: This review examines the advantages of C. elegans-based high-throughput screening over conventional, bacteria-centered in vitro screens. It discusses major anti-infective compounds identified from large-scale C. elegans-based screens and presents the first clinically-approved drugs, then known bioactive compounds, and finally novel small molecules. Expert opinion: There are clear advantages of using a C. elegans-infection based screening method. A C. elegans-based screen produces an enriched pool of non-toxic, efficacious, potential anti-infectives, covering: conventional antimicrobial agents, immunomodulators, and anti-virulence agents. Although C. elegans-based screens do not denote the mode of action of hit compounds, this can be elucidated in secondary studies by comparing the results to target-based screens, or conducting subsequent target-based screens, including the genetic knock-down of host or bacterial genes.

  6. Generation of human pluripotent stem cell-derived hepatocyte-like cells for drug toxicity screening.

    Science.gov (United States)

    Takayama, Kazuo; Mizuguchi, Hiroyuki

    2017-02-01

    Because drug-induced liver injury is one of the main reasons for drug development failures, it is important to perform drug toxicity screening in the early phase of pharmaceutical development. Currently, primary human hepatocytes are most widely used for the prediction of drug-induced liver injury. However, the sources of primary human hepatocytes are limited, making it difficult to supply the abundant quantities required for large-scale drug toxicity screening. Therefore, there is an urgent need for a novel unlimited, efficient, inexpensive, and predictive model which can be applied for large-scale drug toxicity screening. Human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are able to replicate indefinitely and differentiate into most of the body's cell types, including hepatocytes. It is expected that hepatocyte-like cells generated from human ES/iPS cells (human ES/iPS-HLCs) will be a useful tool for drug toxicity screening. To apply human ES/iPS-HLCs to various applications including drug toxicity screening, homogenous and functional HLCs must be differentiated from human ES/iPS cells. In this review, we will introduce the current status of hepatocyte differentiation technology from human ES/iPS cells and a novel method to predict drug-induced liver injury using human ES/iPS-HLCs. Copyright © 2016 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

  7. A novel hanging spherical drop system for the generation of cellular spheroids and high throughput combinatorial drug screening.

    Science.gov (United States)

    Neto, A I; Correia, C R; Oliveira, M B; Rial-Hermida, M I; Alvarez-Lorenzo, C; Reis, R L; Mano, J F

    2015-04-01

    We propose a novel hanging spherical drop system for anchoring arrays of droplets of cell suspension based on the use of biomimetic superhydrophobic flat substrates, with controlled positional adhesion and minimum contact with a solid substrate. By facing down the platform, it was possible to generate independent spheroid bodies in a high throughput manner, in order to mimic in vivo tumour models on the lab-on-chip scale. To validate this system for drug screening purposes, the toxicity of the anti-cancer drug doxorubicin in cell spheroids was tested and compared to cells in 2D culture. The advantages presented by this platform, such as feasibility of the system and the ability to control the size uniformity of the spheroid, emphasize its potential to be used as a new low cost toolbox for high-throughput drug screening and in cell or tissue engineering.

  8. Evaluation of positive and false-positive results in syphilis screening of blood donors in Rio de Janeiro, Brazil.

    Science.gov (United States)

    Sandes, V S; Silva, S G C; Motta, I J F; Velarde, L G C; de Castilho, S R

    2017-06-01

    We propose to analyse the positive and false-positive results of treponemal and nontreponemal tests in blood donors from Brazil and to evaluate possible factors associated with the results of treponemal tests. Treponemal tests have been used widely for syphilis screening in blood banks. The introduction of these tests in donor screening has caused an impact and a loss of donors who need to be assessed. This was a retrospective cross-sectional study of syphilis screening and confirmatory test results of blood donors that were obtained before and after adopting a chemiluminescent immunoassay (CLIA). A comparative analysis was performed using a second sample drawn from positive donors. The possible factors associated with CLIA-positive or CLIA-false-positive results were investigated in a subgroup. Statistical tests were used to compare the proportions and adjusted estimates of association. The reactivity rate increased from 1·01% (N = 28 158) to 2·66% (N = 25 577) after introducing the new test. Among Venereal Disease Research Laboratory (VDRL)- and CLIA-confirmed results, the false-positive rates were 40·5% (N = 180) and 37·4% (N = 359), respectively (P = 0·5266). Older donors (OR = 1·04; P = 0·0010) and donors with lower education levels (OR = 6·59; P = 0·0029) were associated with a higher risk of positivity for syphilis. CLIA represents an improvement in blood bank serological screening. However, its use in a healthy population appears to result in high rates of false positives. Identifying which characteristics can predict false positives, however, remains a challenge. © 2017 British Blood Transfusion Society.

  9. Evaluation of three rapid oral fluid test devices on the screening of multiple drugs of abuse including ketamine.

    Science.gov (United States)

    Tang, Magdalene H Y; Ching, C K; Poon, Simon; Chan, Suzanne S S; Ng, W Y; Lam, M; Wong, C K; Pao, Ronnie; Lau, Angus; Mak, Tony W L

    2018-05-01

    Rapid oral fluid testing (ROFT) devices have been extensively evaluated for their ability to detect common drugs of abuse; however, the performance of such devices on simultaneous screening for ketamine has been scarcely investigated. The present study evaluated three ROFT devices (DrugWipe ® 6S, Ora-Check ® and SalivaScreen ® ) on the detection of ketamine, opiates, methamphetamine, cannabis, cocaine and MDMA. A liquid chromatography tandem mass spectrometry (LCMS) assay was firstly established and validated for confirmation analysis of the six types of drugs and/or their metabolites. In the field test, the three ROFT devices were tested on subjects recruited from substance abuse clinics/rehabilitation centre. Oral fluid was also collected using Quantisal ® for confirmation analysis. A total of 549 samples were collected in the study. LCMS analysis on 491 samples revealed the following drugs: codeine (55%), morphine (49%), heroin (40%), methamphetamine (35%), THC (8%), ketamine (4%) and cocaine (2%). No MDMA-positive cases were observed. Results showed that the overall specificity and accuracy were satisfactory and met the DRUID standard of >80% for all 3 devices. Ora-Check ® had poor sensitivities (ketamine 36%, methamphetamine 63%, opiates 53%, cocaine 60%, THC 0%). DrugWipe ® 6S showed good sensitivities in the methamphetamine (83%) and opiates (93%) tests but performed relatively poorly for ketamine (41%), cocaine (43%) and THC (22%). SalivaScreen ® also demonstrated good sensitivities in the methamphetamine (83%) and opiates (100%) tests, and had the highest sensitivity for ketamine (76%) and cocaine (71%); however, it failed to detect any of the 28 THC-positive cases. The test completion rate (proportion of tests completed with quality control passed) were: 52% (Ora-Check ® ), 78% (SalivaScreen ® ) and 99% (DrugWipe ® 6S). Copyright © 2018 Elsevier B.V. All rights reserved.

  10. Participation behaviour following a false positive test in the Copenhagen mammography screening programme

    DEFF Research Database (Denmark)

    Andersen, Sune Bangsbøll; Vejborg, Ilse; von Euler-Chelpin, My

    2008-01-01

    women experiencing a negative screening test, regardless of whether the false positive statement was given following assessment or following surgery. The benign to malignant biopsy ratio, comparing the type B false positives to the true positives, was by the fifth round well below the desirable level...

  11. poolHiTS: A Shifted Transversal Design based pooling strategy for high-throughput drug screening

    Directory of Open Access Journals (Sweden)

    Woolf Peter J

    2008-05-01

    Full Text Available Abstract Background A key goal of drug discovery is to increase the throughput of small molecule screens without sacrificing screening accuracy. High-throughput screening (HTS in drug discovery involves testing a large number of compounds in a biological assay to identify active compounds. Normally, molecules from a large compound library are tested individually to identify the activity of each molecule. Usually a small number of compounds are found to be active, however the presence of false positive and negative testing errors suggests that this one-drug one-assay screening strategy can be significantly improved. Pooling designs are testing schemes that test mixtures of compounds in each assay, thereby generating a screen of the whole compound library in fewer tests. By repeatedly testing compounds in different combinations, pooling designs also allow for error-correction. These pooled designs, for specific experiment parameters, can be simply and efficiently created using the Shifted Transversal Design (STD pooling algorithm. However, drug screening contains a number of key constraints that require specific modifications if this pooling approach is to be useful for practical screen designs. Results In this paper, we introduce a pooling strategy called poolHiTS (Pooled High-Throughput Screening which is based on the STD algorithm. In poolHiTS, we implement a limit on the number of compounds that can be mixed in a single assay. In addition, we show that the STD-based pooling strategy is limited in the error-correction that it can achieve. Due to the mixing constraint, we show that it is more efficient to split a large library into smaller blocks of compounds, which are then tested using an optimized strategy repeated for each block. We package the optimal block selection algorithm into poolHiTS. The MATLAB codes for the poolHiTS algorithm and the corresponding decoding strategy are also provided. Conclusion We have produced a practical version

  12. Follow-up Evaluation of Air Force Blood Donors Screening Positive for Chagas Disease

    Science.gov (United States)

    2017-08-27

    Blood Donors Screening Positive for Cbagas Disease presented at/published to Military Health System Research Symposium (Florida, 27-30 Aug 2017) in...disease upon blood donation at JBSA -Lackland 6. TITLE OF MATERIAL TO BE PUBLISHED OR PRESENTED: Follow-up evaluation of Air Force blood donors ...Designated Exempt Reviewer Follow-up evaluation of Air Force blood donors screening positive for Chagas disease Joseph Marcus1, Bryant Webber2, Leo Cropper2

  13. Psychological effects of false-positive results in expanded newborn screening in China.

    Directory of Open Access Journals (Sweden)

    Wen-Jun Tu

    Full Text Available OBJECTIVES: As more families participate expanded newborn screening for metabolic disorders in China, the overall number of false positives increases. Our goal was to assess the potential impact on parental stress, perceptions of the child's health, and family relationships. METHODS: Parents of 49 infants with false-positive screening results for metabolic disorders in the expanded newborn screening panel were compared with parents of 42 children with normal screening results. Parents first completed structured interview using likert scales, closed and open questions. Parents also completed the parenting stress index. RESULTS: A total of 88 mothers and 41 fathers were interviewed. More mothers in the false-positive group reported that their children required extra parental care (21%, compared with 5% of mothers in the normal-screened group (P<0.001. 39% of mothers in the false-positive group reported that they worry about their child's future development, compared with 10% of mothers in the normal-screened group (P<0.001. Fathers in the false-positive group did not differ from fathers in the normal-screened group in reporting worry about their child's extra care requirements, and their child's future development. Children with false-positive results compared with children with normal results were triple as likely to experience hospitalization (27%vs 9%, respectively; P<0.001. CONCLUSIONS: The results showing false-positive screening results may affect parental stress and the parent-child relationship. Parental stress and anxiety can be reduced with improved education and communication to parents about false-positive results.

  14. Identification of Multiple Cryptococcal Fungicidal Drug Targets by Combined Gene Dosing and Drug Affinity Responsive Target Stability Screening

    Directory of Open Access Journals (Sweden)

    Yoon-Dong Park

    2016-08-01

    Full Text Available Cryptococcus neoformans is a pathogenic fungus that is responsible for up to half a million cases of meningitis globally, especially in immunocompromised individuals. Common fungistatic drugs, such as fluconazole, are less toxic for patients but have low efficacy for initial therapy of the disease. Effective therapy against the disease is provided by the fungicidal drug amphotericin B; however, due to its high toxicity and the difficulty in administering its intravenous formulation, it is imperative to find new therapies targeting the fungus. The antiparasitic drug bithionol has been recently identified as having potent fungicidal activity. In this study, we used a combined gene dosing and drug affinity responsive target stability (GD-DARTS screen as well as protein modeling to identify a common drug binding site of bithionol within multiple NAD-dependent dehydrogenase drug targets. This combination genetic and proteomic method thus provides a powerful method for identifying novel fungicidal drug targets for further development.

  15. Computer-delivered indirect screening and brief intervention for drug use in the perinatal period: A randomized trial.

    Science.gov (United States)

    Ondersma, Steven J; Svikis, Dace S; Thacker, Casey; Resnicow, Ken; Beatty, Jessica R; Janisse, James; Puder, Karoline

    2018-04-01

    Under-reporting of drug use in the perinatal period is well-documented, and significantly limits the reach of proactive intervention approaches. The Wayne Indirect Drug Use Screener (WIDUS) focuses on correlates of drug use rather than use itself. This trial tested a computer-delivered, brief intervention designed for use with indirect screen-positive cases, seeking to motivate reductions in drug use without presuming its presence. Randomized clinical trial with 500 WIDUS-positive postpartum women recruited between August 14, 2012 and November 19, 2014. Participants were randomly assigned to either a time control condition or a single-session, tailored, indirect brief intervention. The primary outcome was days of drug use over the 6-month follow-up period; secondary outcomes included urine and hair analyses results at 3- and 6-month follow-up. All outcomes were measured by blinded evaluators. Of the 500 participants (252 intervention and 248 control), 36.1% of participants acknowledged drug use in the 3 months prior to pregnancy, but 89% tested positive at the 6-month follow-up. Participants rated the intervention as easy to use (4.9/5) and helpful (4.4/5). Analyses revealed no between-group differences in drug use (52% in the intervention group, vs. 53% among controls; OR 1.03). Exploratory analyses also showed that intervention effects were not moderated by baseline severity, WIDUS score, or readiness to change. The present trial showed no evidence of efficacy for an indirect, single-session, computer-delivered, brief intervention designed as a complement to indirect screening. More direct approaches that still do not presume active drug use may be possible and appropriate. Copyright © 2018 Elsevier B.V. All rights reserved.

  16. Virtual screening methods as tools for drug lead discovery from large chemical libraries.

    Science.gov (United States)

    Ma, X H; Zhu, F; Liu, X; Shi, Z; Zhang, J X; Yang, S Y; Wei, Y Q; Chen, Y Z

    2012-01-01

    Virtual screening methods have been developed and explored as useful tools for searching drug lead compounds from chemical libraries, including large libraries that have become publically available. In this review, we discussed the new developments in exploring virtual screening methods for enhanced performance in searching large chemical libraries, their applications in screening libraries of ~ 1 million or more compounds in the last five years, the difficulties in their applications, and the strategies for further improving these methods.

  17. Screening and brief intervention for unhealthy drug use: little or no efficacy

    Directory of Open Access Journals (Sweden)

    Richard eSaitz

    2014-09-01

    Full Text Available Unhealthy drug use ranges from use that risks health harms through severe drug use disorders. This narrative review addresses whether screening and brief intervention, efficacious for risky alcohol use, has efficacy for reducing other drug use and consequences. Brief intervention among those seeking help shows some promise. Screening tools have been validated though most are neither brief nor simple enough for use in general health settings. Several randomized trials have tested the efficacy of brief intervention for unhealthy drug use identified by screening in general health settings (i.e. in people not seeking help for their drug use. Substantial evidence now suggests efficacy is limited or non-existent. Reasons likely include a range of actual and perceived severity (or lack of severity, concomitant unhealthy alcohol use and comorbid mental health conditions, and the wide range of types of unhealthy drug use (e.g. from marijuana, to prescription drugs, to heroin. Although brief intervention may have some efficacy for unhealthy drug users seeking help, the model of screening and brief intervention that has effects in primary care settings on risky alcohol use may not be efficacious for other drug use.

  18. Distinguishing Binders from False Positives by Free Energy Calculations: Fragment Screening Against the Flap Site of HIV Protease

    Science.gov (United States)

    2015-01-01

    Molecular docking is a powerful tool used in drug discovery and structural biology for predicting the structures of ligand–receptor complexes. However, the accuracy of docking calculations can be limited by factors such as the neglect of protein reorganization in the scoring function; as a result, ligand screening can produce a high rate of false positive hits. Although absolute binding free energy methods still have difficulty in accurately rank-ordering binders, we believe that they can be fruitfully employed to distinguish binders from nonbinders and reduce the false positive rate. Here we study a set of ligands that dock favorably to a newly discovered, potentially allosteric site on the flap of HIV-1 protease. Fragment binding to this site stabilizes a closed form of protease, which could be exploited for the design of allosteric inhibitors. Twenty-three top-ranked protein–ligand complexes from AutoDock were subject to the free energy screening using two methods, the recently developed binding energy analysis method (BEDAM) and the standard double decoupling method (DDM). Free energy calculations correctly identified most of the false positives (≥83%) and recovered all the confirmed binders. The results show a gap averaging ≥3.7 kcal/mol, separating the binders and the false positives. We present a formula that decomposes the binding free energy into contributions from the receptor conformational macrostates, which provides insights into the roles of different binding modes. Our binding free energy component analysis further suggests that improving the treatment for the desolvation penalty associated with the unfulfilled polar groups could reduce the rate of false positive hits in docking. The current study demonstrates that the combination of docking with free energy methods can be very useful for more accurate ligand screening against valuable drug targets. PMID:25189630

  19. High-Throughput Screening of Ototoxic and Otoprotective Pharmacological Drugs

    Science.gov (United States)

    Kalinec, Federico

    2005-01-01

    Drug ototoxicity research has relied traditionally on animal models for the discovery and development of therapeutic interventions. More than 50 years of research, however, has delivered few--if any--successful clinical strategies for preventing or ameliorating the ototoxic effects of common pharmacological drugs such as aminoglycoside…

  20. Development and Validation of a POSIT-Short Form: Screening for Problem Behaviors among Adolescents at Risk for Substance Use.

    Science.gov (United States)

    Danseco, Evangeline R.; Marques, Paul R.

    2002-01-01

    The Problem-Oriented Screening Instrument for Teenagers (POSIT) screens for multiple problems among adolescents at risk for substance use. A shortened version of the POSIT was developed, using factor analysis, and correlational and reliability analyses. The POSIT-SF shows potential for a reliable and cost-efficient screen for youth with substance…

  1. New approach for high-throughput screening of drug activity on Plasmodium liver stages.

    NARCIS (Netherlands)

    Gego, A.; Silvie, O.; Franetich, J.F.; Farhati, K.; Hannoun, L.; Luty, A.J.F.; Sauerwein, R.W.; Boucheix, C.; Rubinstein, E.; Mazier, D.

    2006-01-01

    Plasmodium liver stages represent potential targets for antimalarial prophylactic drugs. Nevertheless, there is a lack of molecules active on these stages. We have now developed a new approach for the high-throughput screening of drug activity on Plasmodium liver stages in vitro, based on an

  2. Comprehensive screening and quantification of veterinary drugs in milk using UPLC-ToF-MS

    NARCIS (Netherlands)

    Stolker, A.A.M.; Rutgers, P.; Oosterink, J.E.; Lasaroms, J.J.P.; Peters, R.J.B.; Rhijn, van J.A.; Nielen, M.W.F.

    2008-01-01

    Ultra-performance liquid chromatography combined with time-of-flight mass spectrometry (UPLC¿ToF-MS) has been used for screening and quantification of more than 100 veterinary drugs in milk. The veterinary drugs represent different classes including benzimidazoles, macrolides, penicillins,

  3. Associations of Parental Rules and Socioeconomic Position With Preschool Children's Sedentary Behaviour and Screen Time.

    Science.gov (United States)

    Downing, Katherine L; Hinkley, Trina; Hesketh, Kylie D

    2015-04-01

    There is little current understanding of the influences on sedentary behavior and screen time in preschool children. This study investigated socioeconomic position (SEP) and parental rules as potential correlates of preschool children's sedentary behavior and screen time. Data from the Healthy Active Preschool Years (HAPPY) Study were used. Participating parents reported their child's usual weekly screen time and their rules to regulate their child's screen time. Children wore accelerometers for 8 days to objectively measure sedentary time. Children whose parents limited television viewing spent significantly less time in that behavior and in total screen time; however, overall sedentary behavior was unaffected. An association between parents limiting computer/electronic game use and time spent on the computer was found for girls only. SEP was inversely associated with girls', but not boys', total screen time and television viewing. As parental rules were generally associated with lower levels of screen time, intervention strategies could potentially encourage parents to set limits on, and switch off, screen devices. Intervention strategies should target preschool children across all SEP areas, as there was no difference by SEP in overall sedentary behavior or screen time for boys.

  4. Screening the Drug Sensitivity Genes Related to GEM and CDDP in the Lung Cancer Cell-lines

    Directory of Open Access Journals (Sweden)

    Chunyu YANG

    2009-10-01

    Full Text Available Background and objective Screening of small-cell lung cancer (SCLC and non-small cell lung cancer (NSCLC cell lines with gemcitabine hydrochloride (GEM and cisplatin (CDDP related to drug sensitivity gene might clarify the action mechanism of anti-cancer drugs and provide a new clue for overcoming drug resistance and the development of new anti-cancer drugs, and also provide theoretical basis for the clinical treatment of individual. Methods The drug sensitivity of CDDP and GEM in 4 SCLC cell lines and 6 NSCLC cell lines was determined using MTT colorimetric assay, while the cDNA macroarray was applied to detect the gene expression state related to drug sensitivity of 10 lung cancer cell line in 1 291, and the correlation between the two was analysized. Results There were 6 genes showing significant positive correlation (r≥0.632, P < 0.05 with GEM sensitivity; 45 genes positively related to CDDP; another 41 genes related to both GEM and CDDP (r≥± 0.4. Lung cancer with GEM and CDDP sensitivity of two types of drugs significantly related genes were Metallothinein (Signal transduction molecules, Cathepsin B (Organization protease B and TIMP1 (Growth factor; the GEM, CDDP sensitivity associated genes of lung cancer cell lines mainly distributed in Metallothinein, Cathepsin B, growth factor TIMP1 categories. Conclusion There existed drug-related sensitive genes of GEM, CDDP in SCLC and NSCLC cell lines; of these genes, Metallothinein, Cathepsin B and TIMP1 genes presented a significant positive correlation with GEM drug sensitivity, a significant negative correlation with CDDP drug sensitivity.

  5. Drug-drug cocrystals of antituberculous 4-aminosalicylic acid: Screening, crystal structures, thermochemical and solubility studies.

    Science.gov (United States)

    Drozd, Ksenia V; Manin, Alex N; Churakov, Andrei V; Perlovich, German L

    2017-03-01

    Experimental multistage cocrystal screening of the antituberculous drug 4-aminosalicylic acid (PASA) has been conducted with a number of coformers (pyrazinamide (PYR), nicotinamide (NAM), isonicotinamide (iNAM), isoniazid (INH), caffeine (CAF) and theophylline (TPH)). The crystal structures of 4-aminosalicylic acid cocrystals with isonicotinamide ([PASA+iNAM] (2:1)) and methanol solvate with caffeine ([PASA+CAF+MeOH] (1:1:1)) have been determined by single X-ray diffraction experiments. For the first time for PASA cocrystals it has been found that the structural unit of the [PASA+iNAM] cocrystal (2:1) is formed by 2 types of heterosynthons: acid-pyridine and acid-amide. The desolvation study of the [PASA+CAF+MeOH] cocrystal solvate (1:1:1) has been conducted. The correlation models linking the melting points of the cocrystals with the melting points of the coformers used in this paper have been developed. The thermochemical and solubility properties for all the obtained cocrystals have been studied. Cocrystallization has been shown to lead not only to PASA solubility improving but also to its higher stability against the chemical decomposition. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Advantages of crystallographic fragment screening: functional and mechanistic insights from a powerful platform for efficient drug discovery.

    Science.gov (United States)

    Patel, Disha; Bauman, Joseph D; Arnold, Eddy

    2014-01-01

    X-ray crystallography has been an under-appreciated screening tool for fragment-based drug discovery due to the perception of low throughput and technical difficulty. Investigators in industry and academia have overcome these challenges by taking advantage of key factors that contribute to a successful crystallographic screening campaign. Efficient cocktail design and soaking methodologies have evolved to maximize throughput while minimizing false positives/negatives. In addition, technical improvements at synchrotron beamlines have dramatically increased data collection rates thus enabling screening on a timescale comparable to other techniques. The combination of available resources and efficient experimental design has resulted in many successful crystallographic screening campaigns. The three-dimensional crystal structure of the bound fragment complexed to its target, a direct result of the screening effort, enables structure-based drug design while revealing insights regarding protein dynamics and function not readily obtained through other experimental approaches. Furthermore, this "chemical interrogation" of the target protein crystals can lead to the identification of useful reagents for improving diffraction resolution or compound solubility. Copyright © 2014. Published by Elsevier Ltd.

  7. Advantages of Crystallographic Fragment Screening: Functional and Mechanistic Insights from a Powerful Platform for Efficient Drug Discovery

    Science.gov (United States)

    Patel, Disha; Bauman, Joseph D.; Arnold, Eddy

    2015-01-01

    X-ray crystallography has been an under-appreciated screening tool for fragment-based drug discovery due to the perception of low throughput and technical difficulty. Investigators in industry and academia have overcome these challenges by taking advantage of key factors that contribute to a successful crystallographic screening campaign. Efficient cocktail design and soaking methodologies have evolved to maximize throughput while minimizing false positives/negatives. In addition, technical improvements at synchrotron beamlines have dramatically increased data collection rates thus enabling screening on a timescale comparable to other techniques. The combination of available resources and efficient experimental design has resulted in many successful crystallographic screening campaigns. The three-dimensional crystal structure of the bound fragment complexed to its target, a direct result of the screening effort, enables structure-based drug design while revealing insights regarding protein dynamics and function not readily obtained through other experimental approaches. Furthermore, this “chemical interrogation” of the target protein crystals can lead to the identification of useful reagents for improving diffraction resolution or compound solubility. PMID:25117499

  8. DISIS: prediction of drug response through an iterative sure independence screening.

    Directory of Open Access Journals (Sweden)

    Yun Fang

    Full Text Available Prediction of drug response based on genomic alterations is an important task in the research of personalized medicine. Current elastic net model utilized a sure independence screening to select relevant genomic features with drug response, but it may neglect the combination effect of some marginally weak features. In this work, we applied an iterative sure independence screening scheme to select drug response relevant features from the Cancer Cell Line Encyclopedia (CCLE dataset. For each drug in CCLE, we selected up to 40 features including gene expressions, mutation and copy number alterations of cancer-related genes, and some of them are significantly strong features but showing weak marginal correlation with drug response vector. Lasso regression based on the selected features showed that our prediction accuracies are higher than those by elastic net regression for most drugs.

  9. Legal Position of School Personnel -- Drugs and Narcotics.

    Science.gov (United States)

    Shannon, Thomas A.

    California educators have been given broad discretionary powers to control students who misuse drugs or narcotics, and to develop drug education programs. This paper outlines and discusses legislation dealing with disciplinary actions against drug offenders, and delineates school responsibilities for developing and implementing effective drug…

  10. Screening of potent anticancer drug taxol from Entophytic fungus ...

    African Journals Online (AJOL)

    Muthumary

    2011-02-21

    Feb 21, 2011 ... Isolation and detection of taxol, an anticancer drug produced from ... cancer cell line, taxol produced by the test fungus in MID culture medium was isolated for its .... then plotted on a graph. RESULTS AND ... Wavelength (nm).

  11. How Phenotypic Screening Influenced Drug Discovery: Lessons from Five Years of Practice.

    Science.gov (United States)

    Haasen, Dorothea; Schopfer, Ulrich; Antczak, Christophe; Guy, Chantale; Fuchs, Florian; Selzer, Paul

    Since 2011, phenotypic screening has been a trend in the pharmaceutical industry as well as in academia. This renaissance was triggered by analyses that suggested that phenotypic screening is a superior strategy to discover first-in-class drugs. Despite these promises and considerable investments, pharmaceutical research organizations have encountered considerable challenges with the approach. Few success stories have emerged in the past 5 years and companies are questioning their investment in this area. In this contribution, we outline what we have learned about success factors and challenges of phenotypic screening. We then describe how our efforts in phenotypic screening have influenced our approach to drug discovery in general. We predict that concepts from phenotypic screening will be incorporated into target-based approaches and will thus remain influential beyond the current trend.

  12. Stem cells: a model for screening, discovery and development of drugs.

    Science.gov (United States)

    Kitambi, Satish Srinivas; Chandrasekar, Gayathri

    2011-01-01

    The identification of normal and cancerous stem cells and the recent advances made in isolation and culture of stem cells have rapidly gained attention in the field of drug discovery and regenerative medicine. The prospect of performing screens aimed at proliferation, directed differentiation, and toxicity and efficacy studies using stem cells offers a reliable platform for the drug discovery process. Advances made in the generation of induced pluripotent stem cells from normal or diseased tissue serves as a platform to perform drug screens aimed at developing cell-based therapies against conditions like Parkinson's disease and diabetes. This review discusses the application of stem cells and cancer stem cells in drug screening and their role in complementing, reducing, and replacing animal testing. In addition to this, target identification and major advances in the field of personalized medicine using induced pluripotent cells are also discussed.

  13. Influence of Ceiling Suspended Screen Positioning to the Scatter Radiation Levels in Interventional Cardiology

    International Nuclear Information System (INIS)

    Arandjic, D.; Bozovic, P.; Ciraj-Bjelac, O.; Antic, V.

    2013-01-01

    The objective of this paper is to identify the effects of the ceiling suspended screen position to the scatter radiation levels in the interventional cardiology. The scatter radiation in terms of ambient dose equivalent H * (10) was measured for various positions of protective screen in the positions of the first operator, nurse and radiographer, at elevations 100-190 cm and in four different angulations of the x-ray tube. To assess the effectiveness of the protective screen, the scattered dose was also measured in the absence of any protection in all four angulations and elevations. To simulate real clinical situation the measurements were performed in the presence of 30 cm PMMA phantom using standard clinical protocol. The utility of protective screen varied for different positions and angulations. Scatter radiation levels varied in the range 70 - 3400 μSv/h for the first operator, 140 - 3200 μSv/h for the nurse and 50 - 560 μSv/h for radiographer. Ceiling suspended screens can provide a substantial level of protection (up to factor 18) in interventional cardiology, but they have to be properly managed and positioned to achieve sufficient level of protection. The guidance for optimal protection is provided in the paper.(author)

  14. The ligase chain reaction as a primary screening tool for the detection of culture positive tuberculosis.

    LENUS (Irish Health Repository)

    O'Connor, T M

    2012-02-03

    BACKGROUND: The ligase chain reaction Mycobacterium tuberculosis assay uses ligase chain reaction technology to detect tuberculous DNA sequences in clinical specimens. A study was undertaken to determine its sensitivity and specificity as a primary screening tool for the detection of culture positive tuberculosis. METHODS: The study was conducted on 2420 clinical specimens (sputum, bronchoalveolar lavage fluid, pleural fluid, urine) submitted for primary screening for Mycobacterium tuberculosis to a regional medical microbiology laboratory. Specimens were tested in parallel with smear, ligase chain reaction, and culture. RESULTS: Thirty nine patients had specimens testing positive by the ligase chain reaction assay. Thirty two patients had newly diagnosed tuberculosis, one had a tuberculosis relapse, three had tuberculosis (on antituberculous therapy when tested), and three had healed tuberculosis. In the newly diagnosed group specimens were smear positive in 21 cases (66%), ligase chain reaction positive in 30 cases (94%), and culture positive in 32 cases (100%). Using a positive culture to diagnose active tuberculosis, the ligase chain reaction assay had a sensitivity of 93.9%, a specificity of 99.8%, a positive predictive value of 83.8%, and a negative predictive value of 99.9%. CONCLUSIONS: This study is the largest clinical trial to date to report the efficacy of the ligase chain reaction as a primary screening tool to detect Mycobacterium tuberculosis infection. The authors conclude that ligase chain reaction is a useful primary screening test for tuberculosis, offering speed and discrimination in the early stages of diagnosis and complementing traditional smear and culture techniques.

  15. Long-term psychosocial consequences of false-positive screening mammography

    DEFF Research Database (Denmark)

    Brodersen, John; Siersma, Volkert Dirk

    2013-01-01

    Cancer screening programs have the potential of intended beneficial effects, but they also inevitably have unintended harmful effects. In the case of screening mammography, the most frequent harm is a false-positive result. Prior efforts to measure their psychosocial consequences have been limite...... by short-term follow-up, the use of generic survey instruments, and the lack of a relevant benchmark-women with breast cancer....

  16. Drug screening in clinical or forensic toxicology: are there differences?

    Science.gov (United States)

    Gerostamoulos, Dimitri; Beyer, Jochen

    2010-09-01

    Legal and medical practitioners need to remember that, with respect to drug analysis, there are two distinct disciplines in analytical toxicology concerned with human biological matrices, namely clinical and forensic toxicology. Both fields use similar analytical techniques designed to detect and quantify drugs, chemicals and poisons in fluids or tissues. In clinical toxicology, analytical results help to specify the appropriate treatment of a poisoned or intoxicated patient. In forensic toxicology, the results often play a vital role in determining the possible impairment or behavioural changes in an individual, or the contribution of drugs or poisons to death in a medico-legal investigation. This column provides an overview of the similarities and differences inherent in clinical and forensic toxicology.

  17. Combinatorial drug screening identifies Ewing sarcoma-specific sensitivities

    OpenAIRE

    Radic-Sarikas, Branka; Tsafou, Kalliopi P.; Emdal, Kristina B.; Papamarkou, Theodore; Huber, Kilian V.M.; Mutz, Cornelia; Toretsky, Jeffrey A.; Bennett, Keiryn L.; Olsen, Jesper V.; Brunak, Søren; Kovar, Heinrich; Superti-Furga, Giulio

    2017-01-01

    Improvements in survival for Ewing sarcoma pediatric and adolescent patients have been modest over the past 20 years. Combinations of anticancer agents endure as an option to overcome resistance to single treatments caused by compensatory pathways. Moreover, combinations are thought to lessen any associated adverse side effects through reduced dosing, which is particularly important in childhood tumors. Using a parallel phenotypic combinatorial screening approach of cells derived from three p...

  18. Combinatorial Drug Screening Identifies Ewing Sarcoma-specific Sensitivities

    DEFF Research Database (Denmark)

    Radic-Sarikas, Branka; Tsafou, Kalliopi P; Emdal, Kristina B.

    2017-01-01

    Improvements in survival for Ewing sarcoma pediatric and adolescent patients have been modest over the past 20 years. Combinations of anticancer agents endure as an option to overcome resistance to single treatments caused by compensatory pathways. Moreover, combinations are thought to lessen any...... including approved drugs. We were able to retrieve highly synergistic drug combinations specific for Ewing sarcoma and identified signaling processes important for Ewing sarcoma cell proliferation determined by EWS-FLI1 We generated a molecular target profile of PKC412, a multikinase inhibitor with strong...

  19. Screening for alcohol and drug use disorders among adults in primary care: a review

    Directory of Open Access Journals (Sweden)

    Pilowsky DJ

    2012-04-01

    Full Text Available Daniel J Pilowsky1, Li-Tzy Wu21Departments of Epidemiology and Psychiatry, Columbia University, and the New York State Psychiatric Institute, New York City, NY, 2Department of Psychiatry and Behavioral Sciences, School of Medicine, Duke University Medical Center, Durham, NC, USABackground: The Patient Protection and Affordable Care Act of 2010 supports integration of substance abuse interventions and treatments into the mainstream health care system. Thus, effective screening and intervention for substance use disorders in health care settings is a priority.Objective: This paper reviews the prevalence of alcohol and drug use disorders (abuse or dependence in primary care settings and emergency departments, as well as current screening tools and brief interventions.Methods: MEDLINE was searched using the following keywords: alcohol use, alcohol use disorder, drug use, drug use disorder, screening, primary care, and emergency departments. Using the related-articles link, additional articles were screened for inclusion. This review focuses on alcohol and drug use and related disorders among adults in primary care settings.Conclusion: Screening, brief intervention, and referral for treatment are feasible and effective in primary care settings, provided that funding for screening is available, along with brief interventions and treatment facilities to which patients can be referred and treated promptly.Keywords: brief intervention, emergency departments

  20. Teen options for change: an intervention for young emergency patients who screen positive for suicide risk.

    Science.gov (United States)

    King, Cheryl A; Gipson, Polly Y; Horwitz, Adam G; Opperman, Kiel J

    2015-01-01

    Previous research has documented the feasibility of screening in emergency departments for adolescent suicide risk. This randomized trial examined the effectiveness of Teen Options for Change (TOC), an intervention for adolescents seeking general medical emergency services who screen positive for suicide risk. Participants were 49 youths, ages 14 to 19, seeking services for nonpsychiatric emergencies. They screened positive for suicide risk because of recent suicidal ideation, suicide attempt, or depression plus substance abuse. Youths were randomly assigned to the TOC intervention or to enhanced treatment as usual. Depression, hopelessness, and suicidal ideation were assessed at baseline and two months later. Adolescents assigned to TOC showed greater reductions in depression than adolescents assigned to the comparison group (Cohen's d=1.07, a large effect size). Hopelessness, suicidal ideation, and substance abuse outcomes trended positively (nonsignificantly), with small to moderate effect sizes. TOC may be a promising, brief intervention for adolescents seeking emergency services and at risk of suicide.

  1. SEMIAUTOMATED SOLID-PHASE EXTRACTION PROCEDURE FOR DRUG SCREENING IN BIOLOGICAL-FLUIDS USING THE ASPEC SYSTEM IN COMBINATION WITH CLEAN SCREEN DAU COLUMNS

    NARCIS (Netherlands)

    CHEN, XH; FRANKE, JP; ENSING, K; WIJSBEEK, J; DEZEEUW, RA

    1993-01-01

    The use of a semi-automated solid-phase extraction system (ASPEC) for the screening of drugs in plasma and urine on a single mixed-mode column (Clean Screen DAU) is described. The processes of column preconditioning, sample application, column wash, pH adjustment and elution of the drugs were

  2. Stem cells: a model for screening, discovery and development of drugs

    Directory of Open Access Journals (Sweden)

    Kitambi SS

    2011-09-01

    Full Text Available Satish Srinivas Kitambi1, Gayathri Chandrasekar21Department of Medical Biochemistry and Biophysics; 2Department of Biosciences, Karolinska Institutet, Stockholm, SwedenAbstract: The identification of normal and cancerous stem cells and the recent advances made in isolation and culture of stem cells have rapidly gained attention in the field of drug discovery and regenerative medicine. The prospect of performing screens aimed at proliferation, directed differentiation, and toxicity and efficacy studies using stem cells offers a reliable platform for the drug discovery process. Advances made in the generation of induced pluripotent stem cells from normal or diseased tissue serves as a platform to perform drug screens aimed at developing cell-based therapies against conditions like Parkinson's disease and diabetes. This review discusses the application of stem cells and cancer stem cells in drug screening and their role in complementing, reducing, and replacing animal testing. In addition to this, target identification and major advances in the field of personalized medicine using induced pluripotent cells are also discussed.Keywords: therapeutics, stem cells, cancer stem cells, screening models, drug development, high throughput screening

  3. Screening for the drug-phospholipid interaction: correlation to phospholipidosis

    DEFF Research Database (Denmark)

    Alakoskela, Juha-Matti; Vitovic, Pavol; Kinnunen, Paavo K J

    2009-01-01

    Phospholipid bilayers represent a complex, anisotropic environment fundamentally different from bulk oil or octanol, for instance. Even "simple" drug association to phospholipid bilayers can only be fully understood if the slab-of-hydrocarbon approach is abandoned and the complex, anisotropic...

  4. A comparison of the impact of screen-positive results obtained from ultrasound and biochemical screening for Down syndrome in the first trimester : a pilot study

    NARCIS (Netherlands)

    Weinans, M.J.; Kooij, L.; Muller, M.A.; Bilardo, K.M.; van Lith, J.M.; Tymstra, T.

    2004-01-01

    OBJECTIVE: To compare the experiences of women who received a screen-positive test result for Down syndrome after nuchal translucency screening or after biochemical screening in the first trimester of pregnancy in the Netherlands. METHOD: Semi-quantitative questionnaires were sent to 40 women with a

  5. Parental knowledge reduces long term anxiety induced by false-positive test results after newborn screening for cystic fibrosis

    NARCIS (Netherlands)

    Vernooij-van Langen, A.M.M.; Pal, S.M. van der; Reijntjens, A.J.T.; Loeber, J.G.; Dompeling, E.; Dankert-Roelse, J.E.

    2014-01-01

    Background: False-positive screening results in newborn screening for cystic fibrosis may lead to parental stress, family relationship problems and a changed perception of the child's health. Aim of the study: To evaluate whether parental anxiety induced by a false positive screening result

  6. Selective anti-proliferation of HER2-positive breast cancer cells by anthocyanins identified by high-throughput screening.

    Directory of Open Access Journals (Sweden)

    Weihua Liu

    Full Text Available Overexpressed Human epidermal growth factor receptor 2 (HER2 drives the biology of 20% breast cancer and is a prediction of a poor prognosis for patients. HER2-targeted therapies significantly improve outcomes for HER2-positive patients. Traditional Chinese herbs/medicines have been used to treat breast cancer patients including HER2-positive patients in Asia for decades. Although the traditional medicines demonstrate efficacy in clinics for HER2-positive patients, the mechanism is largely unknown. In this article, we screened a 10,000 natural product library in 6 different cell lines representing breast cancer, and assessed the ability of each drug to cause cytotoxicity through a high-throughput screening approach. We have identified eight natural compounds that selectively inhibit the proliferation of HER2-positive cells. Two of the hit compounds, peonidin-3-glucoside and cyaniding-3-glucoside, are both extracts from black rice. They inhibit the phospho-HER2 and phospho-AKT and were confirmed to induce HER2-psotive breast cancer cells apoptosis both in vitro and in vivo. Peonidin-3-glucoside and cyaniding-3-glucoside treatments significantly reduced the tumor size and volume in vivo compared to the control group. There is no significant difference of antitumorgenic effects between peonidin-3-glucoside and cyaniding-3-glucoside treatments.

  7. Cervical Screening within HIV Care: Findings from an HIV-Positive Cohort in Ukraine

    Science.gov (United States)

    Bailey, Heather; Thorne, Claire; Semenenko, Igor; Malyuta, Ruslan; Tereschenko, Rostislav; Adeyanova, Irina; Kulakovskaya, Elena; Ostrovskaya, Lyudmila; Kvasha, Liliana; Cortina-Borja, Mario; Townsend, Claire L.

    2012-01-01

    Introduction HIV-positive women have an increased risk of invasive cervical cancer but cytologic screening is effective in reducing incidence. Little is known about cervical screening coverage or the prevalence of abnormal cytology among HIV-positive women in Ukraine, which has the most severe HIV epidemic in Europe. Methods Poisson regression models were fitted to data from 1120 women enrolled at three sites of the Ukraine Cohort Study of HIV-infected Childbearing Women to investigate factors associated with receiving cervical screening as part of HIV care. All women had been diagnosed as HIV-positive before or during their most recent pregnancy. Prevalence of cervical abnormalities (high/low grade squamous intraepithelial lesions) among women who had been screened was estimated, and associated factors explored. Results Overall, 30% (337/1120) of women had received a cervical screening test as part of HIV care at study enrolment (median 10 months postpartum), a third (115/334) of whom had been tested >12 months previously. In adjusted analyses, women diagnosed as HIV-positive during (vs before) their most recent pregnancy were significantly less likely to have a screening test reported, on adjusting for other potential risk factors (adjusted prevalence ratio (APR) 0.62, 95% CI 0.51–0.75 p<0.01 for 1st/2nd trimester diagnosis and APR 0.42, 95% CI 0.28–0.63 p<0.01 for 3rd trimester/intrapartum diagnosis). Among those with a cervical screening result reported at any time (including follow-up), 21% (68/325) had a finding of cervical abnormality. In adjusted analyses, Herpes simplex virus 2 seropositivity and a recent diagnosis of bacterial vaginosis were associated with an increased risk of abnormal cervical cytology (APR 1.83 95% CI 1.07–3.11 and APR 3.49 95% CI 2.11–5.76 respectively). Conclusions In this high risk population, cervical screening coverage as part of HIV care was low and could be improved by an organised cervical screening programme for HIV-positive

  8. Design, development, and validation of a high-throughput drug-screening assay for targeting of human leukemia

    Science.gov (United States)

    Karjalainen, Katja; Pasqualini, Renata; Cortes, Jorge E.; Kornblau, Steven M.; Lichtiger, Benjamin; O'Brien, Susan; Kantarjian, Hagop M.; Sidman, Richard L.; Arap, Wadih; Koivunen, Erkki

    2015-01-01

    Background We introduce an ex vivo methodology to perform drug library screening against human leukemia. Method Our strategy relies on human blood or bone marrow cultures under hypoxia; under these conditions, leukemia cells deplete oxygen faster than normal cells, causing a hemoglobin oxygenation shift. We demonstrate several advantages: (I) partial recapitulation of the leukemia microenvironment, (ii) use of native hemoglobin oxygenation as real-time sensor/reporter, (iii) cost-effectiveness, (iv) species-specificity, and (v) format that enables high-throughput screening. Results As a proof-of-concept, we screened a chemical library (size ∼20,000) against human leukemia cells. We identified 70 compounds (“hit” rate=0.35%; Z-factor=0.71) with activity; we examined 20 to find 18 true-positives (90%). Finally, we show that carbonohydraxonic diamide group-containing compounds are potent anti-leukemia agents that induce cell death in leukemia cells and patient-derived samples. Conclusions This unique functional assay can identify novel drug candidates as well as find future applications in personalized drug selection for leukemia patients. PMID:24496871

  9. False-positive findings in mammography screening induces short-term distress - breast cancer-specific concern prevails longer

    DEFF Research Database (Denmark)

    Aro, A R; Pilvikki Absetz, S; van Elderen, T M

    2000-01-01

    The aim of this study was to examine psychological distress in a mammography screening process as a consequence of screening after adjusting for background, personality and prescreening distress. Subjects, aged 50 years, were invitees at their first screening. There were three groups; normal find...... perceived breast cancer risk and susceptibility. Distress related to screening and false-positive findings seems to be moderate, but prevailing cancer-specific concerns call for improvements in screening programmes....

  10. Diagnostic accuracy of a two-item Drug Abuse Screening Test (DAST-2).

    Science.gov (United States)

    Tiet, Quyen Q; Leyva, Yani E; Moos, Rudolf H; Smith, Brandy

    2017-11-01

    Drug use is prevalent and costly to society, but individuals with drug use disorders (DUDs) are under-diagnosed and under-treated, particularly in primary care (PC) settings. Drug screening instruments have been developed to identify patients with DUDs and facilitate treatment. The Drug Abuse Screening Test (DAST) is one of the most well-known drug screening instruments. However, similar to many such instruments, it is too long for routine use in busy PC settings. This study developed and validated a briefer and more practical DAST for busy PC settings. We recruited 1300 PC patients in two Department of Veterans Affairs (VA) clinics. Participants responded to a structured diagnostic interview. We randomly selected half of the sample to develop and the other half to validate the new instrument. We employed signal detection techniques to select the best DAST items to identify DUDs (based on the MINI) and negative consequences of drug use (measured by the Inventory of Drug Use Consequences). Performance indicators were calculated. The two-item DAST (DAST-2) was 97% sensitive and 91% specific for DUDs in the development sample and 95% sensitive and 89% specific in the validation sample. It was highly sensitive and specific for DUD and negative consequences of drug use in subgroups of patients, including gender, age, race/ethnicity, marital status, educational level, and posttraumatic stress disorder status. The DAST-2 is an appropriate drug screening instrument for routine use in PC settings in the VA and may be applicable in broader range of PC clinics. Published by Elsevier Ltd.

  11. Risk factors for VIA positivity and determinants of screening attendances in Dar es Salaam, Tanzania

    DEFF Research Database (Denmark)

    Kahesa, Crispin; Kjaer, Susanne Kruger; Ngoma, Twalib

    2012-01-01

    . CONCLUSION: Women who are widowed/separated, of high parity, of low education and married at a young age are more likely to be VIA positive and thus at risk of developing cervical cancer. The study further documents that a referral linkage between the HIV care and treatment program and the cervical cancer...... screening program is in place in the setting studied, where HIV positive were more likely to participate in the cervical cancer screening program than HIV negative women.......ABSTRACT: BACKGROUND: Tanzania is among the countries in the world where the cervical cancer incidence is estimated to be highest. Acknowledging an increase in the burden of cervical cancer, VIA was implemented as a regional cervical cancer screening strategy in Tanzania in 2002. With the aim...

  12. Drug discovery for Duchenne muscular dystrophy via utrophin promoter activation screening.

    Directory of Open Access Journals (Sweden)

    Catherine Moorwood

    Full Text Available Duchenne muscular dystrophy (DMD is a devastating muscle wasting disease caused by mutations in dystrophin, a muscle cytoskeletal protein. Utrophin is a homologue of dystrophin that can functionally compensate for its absence when expressed at increased levels in the myofibre, as shown by studies in dystrophin-deficient mice. Utrophin upregulation is therefore a promising therapeutic approach for DMD. The use of a small, drug-like molecule to achieve utrophin upregulation offers obvious advantages in terms of delivery and bioavailability. Furthermore, much of the time and expense involved in the development of a new drug can be eliminated by screening molecules that are already approved for clinical use.We developed and validated a cell-based, high-throughput screening assay for utrophin promoter activation, and used it to screen the Prestwick Chemical Library of marketed drugs and natural compounds. Initial screening produced 20 hit molecules, 14 of which exhibited dose-dependent activation of the utrophin promoter and were confirmed as hits. Independent validation demonstrated that one of these compounds, nabumetone, is able to upregulate endogenous utrophin mRNA and protein, in C2C12 muscle cells.We have developed a cell-based, high-throughput screening utrophin promoter assay. Using this assay, we identified and validated a utrophin promoter-activating drug, nabumetone, for which pharmacokinetics and safety in humans are already well described, and which represents a lead compound for utrophin upregulation as a therapy for DMD.

  13. A Fully Automated High-Throughput Flow Cytometry Screening System Enabling Phenotypic Drug Discovery.

    Science.gov (United States)

    Joslin, John; Gilligan, James; Anderson, Paul; Garcia, Catherine; Sharif, Orzala; Hampton, Janice; Cohen, Steven; King, Miranda; Zhou, Bin; Jiang, Shumei; Trussell, Christopher; Dunn, Robert; Fathman, John W; Snead, Jennifer L; Boitano, Anthony E; Nguyen, Tommy; Conner, Michael; Cooke, Mike; Harris, Jennifer; Ainscow, Ed; Zhou, Yingyao; Shaw, Chris; Sipes, Dan; Mainquist, James; Lesley, Scott

    2018-05-01

    The goal of high-throughput screening is to enable screening of compound libraries in an automated manner to identify quality starting points for optimization. This often involves screening a large diversity of compounds in an assay that preserves a connection to the disease pathology. Phenotypic screening is a powerful tool for drug identification, in that assays can be run without prior understanding of the target and with primary cells that closely mimic the therapeutic setting. Advanced automation and high-content imaging have enabled many complex assays, but these are still relatively slow and low throughput. To address this limitation, we have developed an automated workflow that is dedicated to processing complex phenotypic assays for flow cytometry. The system can achieve a throughput of 50,000 wells per day, resulting in a fully automated platform that enables robust phenotypic drug discovery. Over the past 5 years, this screening system has been used for a variety of drug discovery programs, across many disease areas, with many molecules advancing quickly into preclinical development and into the clinic. This report will highlight a diversity of approaches that automated flow cytometry has enabled for phenotypic drug discovery.

  14. GENIUS In Silico Screening Technology for HCV Drug Discovery.

    Science.gov (United States)

    Patil, Vaishali M; Masand, Neeraj; Gupta, Satya P

    2016-01-01

    The various reported in silico screening protocols such as molecular docking are associated with various drawbacks as well as benefits. In molecular docking, on interaction with ligand, the protein or receptor molecule gets activated by adopting conformational changes. These conformational changes cannot be utilized to predict the 3D structure of a protein-ligand complex from unbound protein conformations rigid docking, which necessitates the demand for understanding protein flexibility. Therefore, efficiency and accuracy of docking should be achieved and various available/developed protocols may be adopted. One such protocol is GENIUS induced-fit docking and it is used effectively for the development of anti-HCV NS3-4A serine protease inhibitors. The present review elaborates the GENIUS docking protocol along with its benefits and drawbacks.

  15. Improved detection of breast cancer on FDG-PET cancer screening using breast positioning device

    International Nuclear Information System (INIS)

    Kaida, Hayato; Ishibashi, Masatoshi; Fujii, Teruhiko; Kurata, Seiji; Ogo, Etsuyo; Hayabuchi, Naofumi; Tanaka, Maki

    2008-01-01

    The aim of this study was to investigate the detection rate of breast cancer by positron emission tomography cancer screening using a breast positioning device. Between January 2004 and January 2006, 1,498 healthy asymptomatic individuals underwent cancer screening by fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) at our institution; 660 of 1498 asymptomatic healthy women underwent breast PET imaging in the prone position using the breast positioning device to examine the mammary glands in addition to whole-body PET imaging. All subjects that showed abnormal 18 F-FDG uptake in the mammary glands were referred for further examination or surgery at our institution or a local hospital. Our data were compared with the histopathological findings or findings of other imaging modalities in our institution and replies from the doctors at another hospital. Of the 660 participants, 7 (1.06%) were found to have breast cancers at a curable stage. All the seven cancers were detected by breast PET imaging, but only five of these were detected by whole-body PET imaging; the other two were detected by breast PET imaging using the breast positioning device. In cancer screening, prone breast imaging using a positioning device may help to improve the detection rate of breast cancer. However, overall cancer including mammography and ultrasonography screening should be performed to investigate the false-negative cases and reduce false-positive cases. The effectiveness of prone breast PET imaging in cancer screening should be investigated using a much larger number of cases in the near future. (author)

  16. Grid Based Technologies for in silico Screening and Drug Design.

    Science.gov (United States)

    Potemkin, Vladimir; Grishina, Maria

    2018-03-08

    Various techniques for rational drug design are presented in the paper. The methods are based on a substitution of antipharmacophore atoms of the molecules of training dataset by new atoms and/or group of atoms increasing the atomic bioactivity increments obtained at a SAR study. Furthermore, a design methodology based on the genetic algorithm DesPot for discrete optimization and generation of new drug candidate structures is described. Additionally, wide spectra of SAR approaches (3D/4D QSAR interior and exterior-based methods - BiS, CiS, ConGO, CoMIn, high-quality docking method - ReDock) using MERA force field and/or AlteQ quantum chemical method for correct prognosis of bioactivity and bioactive probability is described. The design methods are implemented now at www.chemosophia.com web-site for online computational services. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  17. In silico structure-based drug screening of novel antimycobacterial pharmacophores by DOCK-GOLD tandem screening

    Directory of Open Access Journals (Sweden)

    Junichi Taira

    2017-01-01

    Full Text Available Background: Enzymes responsible for cell wall development in Mycobacterium tuberculosis are considered as potential targets of anti-tuberculosis (TB agents. Mycobacterial cyclopropane mycolic acid synthase 1 (CmaA1 is essential for mycobacterial survival because of its critical role in synthesizing mycolic acids. Materials and Methods: We screened compounds that were capable of interacting with the mycobacterial CmaA1 active site using a virtual compound library with an in silico structure-based drug screening (SBDS. Following the selection of such compounds, their antimycobacterial activity was examined. Results: With the in silico SBDS, for which we also used DOCK-GOLD programs and screening methods that utilized the structural similarity between the selected active compounds, we identified two compounds with potent inhibitory effects on mycobacterial growth. The antimycobacterial effect of the compounds was comparable to that of isoniazid, which is used as a first-line anti-TB drug. Conclusion: The compounds identified through SBDS were expected to be a novel class of anti-TB pharmacophores.

  18. Neurotoxicity screening of (illicit) drugs using novel methods for analysis of microelectrode array (MEA) recordings.

    Science.gov (United States)

    Hondebrink, L; Verboven, A H A; Drega, W S; Schmeink, S; de Groot, M W G D M; van Kleef, R G D M; Wijnolts, F M J; de Groot, A; Meulenbelt, J; Westerink, R H S

    2016-07-01

    Annual prevalence of the use of common illicit drugs and new psychoactive substances (NPS) is high, despite the often limited knowledge on the health risks of these substances. Recently, cortical cultures grown on multi-well microelectrode arrays (mwMEAs) have been used for neurotoxicity screening of chemicals, pharmaceuticals, and toxins with a high sensitivity and specificity. However, the use of mwMEAs to investigate the effects of illicit drugs on neuronal activity is largely unexplored. We therefore first characterised the cortical cultures using immunocytochemistry and show the presence of astrocytes, glutamatergic and GABAergic neurons. Neuronal activity is concentration-dependently affected following exposure to six neurotransmitters (glutamate, GABA, serotonin, dopamine, acetylcholine and nicotine). Most neurotransmitters inhibit neuronal activity, although glutamate and acetylcholine transiently increase activity at specific concentrations. These transient effects are not detected when activity is determined during the entire 30min exposure window, potentially resulting in false-negative results. As expected, exposure to the GABAA-receptor antagonist bicuculline increases neuronal activity. Exposure to a positive allosteric modulator of the GABAA-receptor (diazepam) or to glutamate receptor antagonists (CNQX and MK-801) reduces neuronal activity. Further, we demonstrate that exposure to common drugs (3,4-methylenedioxymethamphetamine (MDMA) and amphetamine) and NPS (1-(3-chlorophenyl)piperazine (mCPP), 4-fluoroamphetamine (4-FA) and methoxetamine (MXE)) decreases neuronal activity. MXE most potently inhibits neuronal activity with an IC50 of 0.5μM, whereas 4-FA is least potent with an IC50 of 113μM. Our data demonstrate the importance of analysing neuronal activity within different time windows during exposure to prevent false-negative results. We also show that cortical cultures grown on mwMEAs can successfully be applied to investigate the effects of

  19. Fertility drug use and mammographic breast density in a mammography screening cohort of premenopausal women

    OpenAIRE

    Sprague, Brian L.; Trentham-Dietz, Amy; Terry, Mary Beth; Nichols, Hazel B.; Bersch, Andy J.; Buist, Diana S. M.

    2008-01-01

    The widespread use of ovulation-inducing drugs to enhance fertility has raised concerns regarding potential effects on breast cancer risk, as ovarian stimulation is associated with increases in estrogen and progesterone levels. We investigated the short-term relation between fertility drug use and mammographic breast density, a strong marker of breast cancer risk, among participants in the Group Health Breast Cancer Screening Program. Data linkage with Group Health’s automated pharmacy record...

  20. Using a 3-d model system to screen for drugs effective on solid tumors

    OpenAIRE

    Fayad, Walid

    2011-01-01

    There is a large medical need for the development of effective anticancer agents with minimal side effects. The present thesis represents an attempt to identify potent drugs for treatment of solid tumors. We used a strategy where 3-D multicellular tumor spheroids (cancer cells grown in three dimensional culture) were utilized as in vitro models for solid tumors. Drug libraries were screened using spheroids as targets and using apoptosis induction and loss of cell viability as endpoints. The h...

  1. iScreen: world's first cloud-computing web server for virtual screening and de novo drug design based on TCM database@Taiwan.

    Science.gov (United States)

    Tsai, Tsung-Ying; Chang, Kai-Wei; Chen, Calvin Yu-Chian

    2011-06-01

    The rapidly advancing researches on traditional Chinese medicine (TCM) have greatly intrigued pharmaceutical industries worldwide. To take initiative in the next generation of drug development, we constructed a cloud-computing system for TCM intelligent screening system (iScreen) based on TCM Database@Taiwan. iScreen is compacted web server for TCM docking and followed by customized de novo drug design. We further implemented a protein preparation tool that both extract protein of interest from a raw input file and estimate the size of ligand bind site. In addition, iScreen is designed in user-friendly graphic interface for users who have less experience with the command line systems. For customized docking, multiple docking services, including standard, in-water, pH environment, and flexible docking modes are implemented. Users can download first 200 TCM compounds of best docking results. For TCM de novo drug design, iScreen provides multiple molecular descriptors for a user's interest. iScreen is the world's first web server that employs world's largest TCM database for virtual screening and de novo drug design. We believe our web server can lead TCM research to a new era of drug development. The TCM docking and screening server is available at http://iScreen.cmu.edu.tw/.

  2. iScreen: world's first cloud-computing web server for virtual screening and de novo drug design based on TCM database@Taiwan

    Science.gov (United States)

    Tsai, Tsung-Ying; Chang, Kai-Wei; Chen, Calvin Yu-Chian

    2011-06-01

    The rapidly advancing researches on traditional Chinese medicine (TCM) have greatly intrigued pharmaceutical industries worldwide. To take initiative in the next generation of drug development, we constructed a cloud-computing system for TCM intelligent screening system (iScreen) based on TCM Database@Taiwan. iScreen is compacted web server for TCM docking and followed by customized de novo drug design. We further implemented a protein preparation tool that both extract protein of interest from a raw input file and estimate the size of ligand bind site. In addition, iScreen is designed in user-friendly graphic interface for users who have less experience with the command line systems. For customized docking, multiple docking services, including standard, in-water, pH environment, and flexible docking modes are implemented. Users can download first 200 TCM compounds of best docking results. For TCM de novo drug design, iScreen provides multiple molecular descriptors for a user's interest. iScreen is the world's first web server that employs world's largest TCM database for virtual screening and de novo drug design. We believe our web server can lead TCM research to a new era of drug development. The TCM docking and screening server is available at http://iScreen.cmu.edu.tw/.

  3. Validation of LC–TOF-MS Screening for Drugs, Metabolites, and Collateral Compounds in Forensic Toxicology Specimens

    Science.gov (United States)

    Guale, Fessessework; Shahreza, Shahriar; Walterscheid, Jeffrey P.; Chen, Hsin-Hung; Arndt, Crystal; Kelly, Anna T.; Mozayani, Ashraf

    2013-01-01

    Liquid chromatography time-of-flight mass spectrometry (LC–TOF-MS) analysis provides an expansive technique for identifying many known and unknown analytes. This study developed a screening method that utilizes automated solid-phase extraction to purify a wide array of analytes involving stimulants, benzodiazepines, opiates, muscle relaxants, hypnotics, antihistamines, antidepressants and newer synthetic “Spice/K2” cannabinoids and cathinone “bath salt” designer drugs. The extract was applied to LC–TOF-MS analysis, implementing a 13 min chromatography gradient with mobile phases of ammonium formate and methanol using positive mode electrospray. Several common drugs and metabolites can share the same mass and chemical formula among unrelated compounds, but they are structurally different. In this method, the LC–TOF-MS was able to resolve many isobaric compounds by accurate mass correlation within 15 ppm mass units and a narrow retention time interval of less than 10 s of separation. Drug recovery yields varied among spiked compounds, but resulted in overall robust area counts to deliver an average match score of 86 when compared to the retention time and mass of authentic standards. In summary, this method represents a rapid, enhanced screen for blood and urine specimens in postmortem, driving under the influence, and drug facilitated sexual assault forensic toxicology casework. PMID:23118149

  4. Validation of LC-TOF-MS screening for drugs, metabolites, and collateral compounds in forensic toxicology specimens.

    Science.gov (United States)

    Guale, Fessessework; Shahreza, Shahriar; Walterscheid, Jeffrey P; Chen, Hsin-Hung; Arndt, Crystal; Kelly, Anna T; Mozayani, Ashraf

    2013-01-01

    Liquid chromatography time-of-flight mass spectrometry (LC-TOF-MS) analysis provides an expansive technique for identifying many known and unknown analytes. This study developed a screening method that utilizes automated solid-phase extraction to purify a wide array of analytes involving stimulants, benzodiazepines, opiates, muscle relaxants, hypnotics, antihistamines, antidepressants and newer synthetic "Spice/K2" cannabinoids and cathinone "bath salt" designer drugs. The extract was applied to LC-TOF-MS analysis, implementing a 13 min chromatography gradient with mobile phases of ammonium formate and methanol using positive mode electrospray. Several common drugs and metabolites can share the same mass and chemical formula among unrelated compounds, but they are structurally different. In this method, the LC-TOF-MS was able to resolve many isobaric compounds by accurate mass correlation within 15 ppm mass units and a narrow retention time interval of less than 10 s of separation. Drug recovery yields varied among spiked compounds, but resulted in overall robust area counts to deliver an average match score of 86 when compared to the retention time and mass of authentic standards. In summary, this method represents a rapid, enhanced screen for blood and urine specimens in postmortem, driving under the influence, and drug facilitated sexual assault forensic toxicology casework.

  5. High-Throughput Screening Using Mass Spectrometry within Drug Discovery.

    Science.gov (United States)

    Rohman, Mattias; Wingfield, Jonathan

    2016-01-01

    In order to detect a biochemical analyte with a mass spectrometer (MS) it is necessary to ionize the analyte of interest. The analyte can be ionized by a number of different mechanisms, however, one common method is electrospray ionization (ESI). Droplets of analyte are sprayed through a highly charged field, the droplets pick up charge, and this is transferred to the analyte. High levels of salt in the assay buffer will potentially steal charge from the analyte and suppress the MS signal. In order to avoid this suppression of signal, salt is often removed from the sample prior to injection into the MS. Traditional ESI MS relies on liquid chromatography (LC) to remove the salt and reduce matrix effects, however, this is a lengthy process. Here we describe the use of RapidFire™ coupled to a triple-quadrupole MS for high-throughput screening. This system uses solid-phase extraction to de-salt samples prior to injection, reducing processing time such that a sample is injected into the MS ~every 10 s.

  6. The development of high-content screening (HCS) technology and its importance to drug discovery.

    Science.gov (United States)

    Fraietta, Ivan; Gasparri, Fabio

    2016-01-01

    High-content screening (HCS) was introduced about twenty years ago as a promising analytical approach to facilitate some critical aspects of drug discovery. Its application has spread progressively within the pharmaceutical industry and academia to the point that it today represents a fundamental tool in supporting drug discovery and development. Here, the authors review some of significant progress in the HCS field in terms of biological models and assay readouts. They highlight the importance of high-content screening in drug discovery, as testified by its numerous applications in a variety of therapeutic areas: oncology, infective diseases, cardiovascular and neurodegenerative diseases. They also dissect the role of HCS technology in different phases of the drug discovery pipeline: target identification, primary compound screening, secondary assays, mechanism of action studies and in vitro toxicology. Recent advances in cellular assay technologies, such as the introduction of three-dimensional (3D) cultures, induced pluripotent stem cells (iPSCs) and genome editing technologies (e.g., CRISPR/Cas9), have tremendously expanded the potential of high-content assays to contribute to the drug discovery process. Increasingly predictive cellular models and readouts, together with the development of more sophisticated and affordable HCS readers, will further consolidate the role of HCS technology in drug discovery.

  7. A rapid in vitro screening system for the identification and evaluation of anticancer drugs

    International Nuclear Information System (INIS)

    Kao, J.W.; Collins, J.L.

    1989-01-01

    We report the development of an in vitro screening system that can be used to identify new anticancer drugs that are specifically cytotoxic for dividing cells. The screening system takes advantage of the potential of many cell lines, including tumor cells, to stop dividing when they are plated at high cell density. The cytotoxic effects of anticancer drugs on dividing (i.e., cells plated at low cell density) and nondividing cells (i.e., cells plated at high cell density) is measured by the incorporation of 51Cr. This in vitro system was evaluated by measuring the cytotoxic effects of the anticancer drugs cisplatin, thiotepa, doxorubicin, methotrexate, and vinblastine on the cell lines B/C-N, ME-180, and MCF-7. In this in vitro system the concentrations of the anticancer drugs that produced significant cytotoxicity on only dividing cells are similar to the concentrations that are used clinically. The fact that this in vitro system is rapid, simple, applicable to many cell types, and able to predict effective concentrations of anticancer drugs should make it useful for the screening of new anticancer drugs and for the design of preclinical studies

  8. Willingness and acceptability of cervical cancer screening among HIV positive Nigerian women

    Directory of Open Access Journals (Sweden)

    Ezechi Oliver C

    2013-01-01

    Full Text Available Abstract Background The proven benefit of integrating cervical cancer screening programme into HIV care has led to its adoption as a standard of care. However this is not operational in most HIV clinics in Nigeria. Of the various reasons given for non-implementation, none is backed by scientific evidence. This study was conducted to assess the willingness and acceptability of cervical cancer screening among HIV positive Nigerian women. Methods A cross sectional study of HIV positive women attending a large HIV treatment centre in Lagos, Nigeria. Respondents were identified using stratified sampling method. A pretested questionnaire was used to obtain information by trained research assistants. Obtained information were coded and managed using SPSS for windows version 19. Multivariate logistic regression model was used to determine independent predictor for acceptance of cervical cancer screening. Results Of the 1517 respondents that returned completed questionnaires, 853 (56.2% were aware of cervical cancer. Though previous cervical cancer screening was low at 9.4%, 79.8% (1210 accepted to take the test. Cost of the test (35.2% and religious denial (14.0% were the most common reasons given for refusal to take the test. After controlling for confounding variables in a multivariate logistic regression model, having a tertiary education (OR = 1.4; 95% CI: 1.03-1.84, no living child (OR: 1.5; 95% CI: 1.1-2.0, recent HIV diagnosis (OR: 1.5; 95% CI: 1.1-2.0 and being aware of cervical cancer (OR: 1.5; 95% CI: 1.2-2.0 retained independent association with acceptance to screen for cervical cancer. Conclusions The study shows that HIV positive women in our environment are willing to screen for cervical cancer and that the integration of reproductive health service into existing HIV programmes will strengthen rather than disrupt the services.

  9. Beyond reverse pharmacology: Mechanism-based screening of Ayurvedic drugs.

    Science.gov (United States)

    Lele, R D

    2010-10-01

    This paper reviews the pharmacology of Indian medicinal plants, starting with the historical background of European work on the subject beginning as early as the 17th century, and tracing its history through the work of Sen and Bose in the 1930's, and Vakhil's historic 1949 paper on Sarpaghanda. The often crucial role of patient feedback in early discoveries is highlighted, as is the time lag between proof of pharmacological action and identification of the active principle, and subsequent elucidation of mechanism of action. In the case of Indian plants in the 20th century this process sometimes took almost 50 years. Reserpine and its mechanisms are given in detail, and its current relevance to public health discussed. The foundation of present day methods of pharmacology is briefly presented so the complexity of methods used to identify properties of Ayurveda derived drugs like forskolin and baicalein, and their bioavailability, may be better appreciated. Ayurveda derived anti-oxidants and their levels of action, immuno-modulators, particularly with respect to the NF-kB pathway and its implications for cancer control, are all considered. The example of curcumin derived from turmeric is explained in more detail, because of its role in cancer prevention. Finally, the paper emphasizes the importance of Ayurveda's concepts of rasayana as a form of dietary chemo-prevention; the significance of ahar, diet, in Ayurveda's aspiration to prevent disease and restore health thus becomes clear. Understood in this light, Ayurveda may transcend pharmacology as a treatment paradigm.

  10. Human Vascular Microphysiological System for in vitro Drug Screening.

    Science.gov (United States)

    Fernandez, C E; Yen, R W; Perez, S M; Bedell, H W; Povsic, T J; Reichert, W M; Truskey, G A

    2016-02-18

    In vitro human tissue engineered human blood vessels (TEBV) that exhibit vasoactivity can be used to test human toxicity of pharmaceutical drug candidates prior to pre-clinical animal studies. TEBVs with 400-800 μM diameters were made by embedding human neonatal dermal fibroblasts or human bone marrow-derived mesenchymal stem cells in dense collagen gel. TEBVs were mechanically strong enough to allow endothelialization and perfusion at physiological shear stresses within 3 hours after fabrication. After 1 week of perfusion, TEBVs exhibited endothelial release of nitric oxide, phenylephrine-induced vasoconstriction, and acetylcholine-induced vasodilation, all of which were maintained up to 5 weeks in culture. Vasodilation was blocked with the addition of the nitric oxide synthase inhibitor L-N(G)-Nitroarginine methyl ester (L-NAME). TEBVs elicited reversible activation to acute inflammatory stimulation by TNF-α which had a transient effect upon acetylcholine-induced relaxation, and exhibited dose-dependent vasodilation in response to caffeine and theophylline. Treatment of TEBVs with 1 μM lovastatin for three days prior to addition of Tumor necrosis factor - α (TNF-α) blocked the injury response and maintained vasodilation. These results indicate the potential to develop a rapidly-producible, endothelialized TEBV for microphysiological systems capable of producing physiological responses to both pharmaceutical and immunological stimuli.

  11. Toxicological screening of basic drugs in whole blood using UPLC-TOF-MS

    DEFF Research Database (Denmark)

    Dalsgaard, Petur Weihe; Rasmussen, Brian Schou; Müller, Irene Breum

    2012-01-01

    Ultra performance liquid chromatography (UPLC) coupled with time-of-flight (TOF) mass spectrometry (MS) was established for toxicological screening of basic drugs in whole blood and tested on authentic samples. Whole blood samples (0.2 ml) were extracted using a Gilson apparatus equipped with Bond...

  12. Microengineering methods for cell-based microarrays and high-throughput drug-screening applications

    International Nuclear Information System (INIS)

    Xu Feng; Wu Jinhui; Wang Shuqi; Gurkan, Umut Atakan; Demirci, Utkan; Durmus, Naside Gozde

    2011-01-01

    Screening for effective therapeutic agents from millions of drug candidates is costly, time consuming, and often faces concerns due to the extensive use of animals. To improve cost effectiveness, and to minimize animal testing in pharmaceutical research, in vitro monolayer cell microarrays with multiwell plate assays have been developed. Integration of cell microarrays with microfluidic systems has facilitated automated and controlled component loading, significantly reducing the consumption of the candidate compounds and the target cells. Even though these methods significantly increased the throughput compared to conventional in vitro testing systems and in vivo animal models, the cost associated with these platforms remains prohibitively high. Besides, there is a need for three-dimensional (3D) cell-based drug-screening models which can mimic the in vivo microenvironment and the functionality of the native tissues. Here, we present the state-of-the-art microengineering approaches that can be used to develop 3D cell-based drug-screening assays. We highlight the 3D in vitro cell culture systems with live cell-based arrays, microfluidic cell culture systems, and their application to high-throughput drug screening. We conclude that among the emerging microengineering approaches, bioprinting holds great potential to provide repeatable 3D cell-based constructs with high temporal, spatial control and versatility.

  13. Microengineering methods for cell-based microarrays and high-throughput drug-screening applications

    Energy Technology Data Exchange (ETDEWEB)

    Xu Feng; Wu Jinhui; Wang Shuqi; Gurkan, Umut Atakan; Demirci, Utkan [Department of Medicine, Demirci Bio-Acoustic-MEMS in Medicine (BAMM) Laboratory, Center for Biomedical Engineering, Brigham and Women' s Hospital, Harvard Medical School, Boston, MA (United States); Durmus, Naside Gozde, E-mail: udemirci@rics.bwh.harvard.edu [School of Engineering and Division of Biology and Medicine, Brown University, Providence, RI (United States)

    2011-09-15

    Screening for effective therapeutic agents from millions of drug candidates is costly, time consuming, and often faces concerns due to the extensive use of animals. To improve cost effectiveness, and to minimize animal testing in pharmaceutical research, in vitro monolayer cell microarrays with multiwell plate assays have been developed. Integration of cell microarrays with microfluidic systems has facilitated automated and controlled component loading, significantly reducing the consumption of the candidate compounds and the target cells. Even though these methods significantly increased the throughput compared to conventional in vitro testing systems and in vivo animal models, the cost associated with these platforms remains prohibitively high. Besides, there is a need for three-dimensional (3D) cell-based drug-screening models which can mimic the in vivo microenvironment and the functionality of the native tissues. Here, we present the state-of-the-art microengineering approaches that can be used to develop 3D cell-based drug-screening assays. We highlight the 3D in vitro cell culture systems with live cell-based arrays, microfluidic cell culture systems, and their application to high-throughput drug screening. We conclude that among the emerging microengineering approaches, bioprinting holds great potential to provide repeatable 3D cell-based constructs with high temporal, spatial control and versatility.

  14. A Plasmodium falciparum screening assay for anti-gametocyte drugs based on parasite lactate dehydrogenase detection

    NARCIS (Netherlands)

    D'Alessandro, S.; Silvestrini, F.; Dechering, K.; Corbett, Y.; Parapini, S.; Timmerman, M.; Galastri, L.; Basilico, N.; Sauerwein, R.; Alano, P.; Taramelli, D.

    2013-01-01

    OBJECTIVES: Plasmodium gametocytes, responsible for malaria parasite transmission from humans to mosquitoes, represent a crucial target for new antimalarial drugs to achieve malaria elimination/eradication. We developed a novel colorimetric screening method for anti-gametocyte compounds based on the

  15. Screening for mental illness: the merger of eugenics and the drug industry.

    Science.gov (United States)

    Sharav, Vera Hassner

    2005-01-01

    The implementation of a recommendation by the President's New Freedom Commission (NFC) to screen the entire United States population--children first--for presumed, undetected, mental illness is an ill-conceived policy destined for disastrous consequences. The "pseudoscientific" methods used to screen for mental and behavioral abnormalities are a legacy from the discredited ideology of eugenics. Both eugenics and psychiatry suffer from a common philosophical fallacy that undermines the validity of their theories and prescriptions. Both are wed to a faith-based ideological assumption that mental and behavioral manifestations are biologically determined, and are, therefore, ameliorated by biological interventions. NFC promoted the Texas Medication Algorithm Project (TMAP) as a "model" medication treatment plan. The impact of TMAP is evident in the skyrocketing increase in psychotropic drug prescriptions for children and adults, and in the disproportionate expenditure for psychotropic drugs. The New Freedom Commission's screening for mental illness initiative is, therefore, but the first step toward prescribing drugs. The escalating expenditure for psychotropic drugs since TMAP leaves little doubt about who the beneficiaries of TMAP are. Screening for mental illness will increase their use.

  16. Drug screening in biological fluids - The need for a systematic approach

    NARCIS (Netherlands)

    de Zeeuw, R.A

    1997-01-01

    In this paper the key steps towards drug screening in biological fluids are considered: (i) sample work up-isolation-concentration: (ii) differentiation-detection; (iii) identification. For (i) solid-phase extraction has very good potential; for (ii) thin-layer chromatography, gas chromatography and

  17. A Drug Combination Screen Identifies Drugs Active against Amoxicillin-Induced Round Bodies of In Vitro Borrelia burgdorferi Persisters from an FDA Drug Library.

    Science.gov (United States)

    Feng, Jie; Shi, Wanliang; Zhang, Shuo; Sullivan, David; Auwaerter, Paul G; Zhang, Ying

    2016-01-01

    Although currently recommended antibiotics for Lyme disease such as doxycycline or amoxicillin cure the majority of the patients, about 10-20% of patients treated for Lyme disease may experience lingering symptoms including fatigue, pain, or joint and muscle aches. Under experimental stress conditions such as starvation or antibiotic exposure, Borrelia burgdorferi can develop round body forms, which are a type of persister bacteria that appear resistant in vitro to customary first-line antibiotics for Lyme disease. To identify more effective drugs with activity against the round body form of B. burgdorferi, we established a round body persister model induced by exposure to amoxicillin (50 μg/ml) and then screened the Food and Drug Administration drug library consisting of 1581 drug compounds and also 22 drug combinations using the SYBR Green I/propidium iodide viability assay. We identified 23 drug candidates that have higher activity against the round bodies of B. burgdorferi than either amoxicillin or doxycycline. Eleven individual drugs scored better than metronidazole and tinidazole which have been previously described to be active against round bodies. In this amoxicillin-induced round body model, some drug candidates such as daptomycin and clofazimine also displayed enhanced activity which was similar to a previous screen against stationary phase B. burgdorferi persisters not exposure to amoxicillin. Additional candidate drugs active against round bodies identified include artemisinin, ciprofloxacin, nifuroxime, fosfomycin, chlortetracycline, sulfacetamide, sulfamethoxypyridazine and sulfathiozole. Two triple drug combinations had the highest activity against amoxicillin-induced round bodies and stationary phase B. burgdorferi persisters: artemisinin/cefoperazone/doxycycline and sulfachlorpyridazine/daptomycin/doxycycline. These findings confirm and extend previous findings that certain drug combinations have superior activity against B. burgdorferi

  18. Smart polymer platforms for in vitro drug screening assays based on drug-loaded nanoparticles

    DEFF Research Database (Denmark)

    Faralli, Adele

    -electrodes for co-localization of drug-loaded nanoparticles (liposomes) and cancer cells. PEGDA hydrogels are widely used in different fields including tissue engineering and in vivo drug delivery. A home-made setup for the fabrication of PEGDA hydrogels through visible-light photopolymerization is described...

  19. Depressive symptoms and depression in people screened positive for dementia in primary care - results of the DelpHi-study.

    Science.gov (United States)

    Thyrian, Jochen René; Eichler, Tilly; Reimann, Melanie; Wucherer, Diana; Dreier, Adina; Michalowsky, Bernhard; Hoffmann, Wolfgang

    2016-06-01

    Dementia and depression are common syndromes in the elderly. There is lack of knowledge concerning the frequency of depressive symptoms in people with dementia (PWD) and factors associated with depression. The aim of this analysis is to (a) describe the frequency of depressive symptoms in people screened positive for dementia, (b) describe differences between PWD with and without depressive symptoms, and (c) analyze associations between depressive symptoms and other dementia-related variables. Analyses are based on data of the GP-based intervention trial DelpHi-MV. A sample of 430 (6.29%) people screened positive for dementia in primary care was analyzed regarding depression according to the German version of the Geriatric Depression Scale (GDS, 15-items), demographic variables, and dementia/depression-related variables. Multivariate analyses were conducted to identify factors associated with depressive symptoms. The mean GDS-score of depressive symptoms in n = 430 PWD was m = 3.21 (SD 2.45) with 67 PWD (15.55%) showing clinically relevant depression (GDS depression and n = 62 (14.42%) received antidepressive drug treatment. Depressive symptoms are significantly associated with age (OR = 0.93), functional impairment (OR = 1.36), and quality of life (OR = 0.01, CI: 0.00-0.06). Our results support previous findings that clinically relevant depressive symptoms are more common in people screened positive for dementia than in the general population and are often missed or mismanaged. Our findings underline the importance of managing quality of life, functional status, or depressive symptoms. Also, the results highlight the benefit of including the partner (and probably other carers) for adequate treatment of PWD.

  20. Beyond reverse pharmacology: Mechanism-based screening of Ayurvedic drugs

    Directory of Open Access Journals (Sweden)

    R D Lele

    2010-01-01

    Full Text Available This paper reviews the pharmacology of Indian medicinal plants, starting with the historical background of European work on the subject beginning as early as the 17th century, and tracing its history through the work of Sen and Bose in the 1930′s, and Vakhil′s historic 1949 paper on Sarpaghanda. The often crucial role of patient feedback in early discoveries is highlighted, as is the time lag between proof of pharmacological action and identification of the active principle, and subsequent elucidation of mechanism of action. In the case of Indian plants in the 20th century this process sometimes took almost 50 years. Reserpine and its mechanisms are given in detail, and its current relevance to public health discussed. The foundation of present day methods of pharmacology is briefly presented so the complexity of methods used to identify properties of Ayurveda derived drugs like forskolin and baicalein, and their bioavailability, may be better appreciated. Ayurveda derived anti-oxidants and their levels of action, immuno-modulators, particularly with respect to the NF-kB pathway and its implications for cancer control, are all considered. The example of curcumin derived from turmeric is explained in more detail, because of its role in cancer prevention. Finally, the paper emphasizes the importance of Ayurveda′s concepts of rasayana as a form of dietary chemo-prevention; the significance of ahar, diet, in Ayurveda′s aspiration to prevent disease and restore health thus becomes clear. Understood in this light, Ayurveda may transcend pharmacology as a treatment paradigm.

  1. Advantages of analyzing postmortem brain samples in routine forensic drug screening—case series of three non-natural deaths tested positive for lysergic acid diethylamide (LSD)

    DEFF Research Database (Denmark)

    Mardal, Marie; Johansen, Sys Stybe; Thomsen, Ragnar

    2017-01-01

    Three case reports are presented, including autopsy findings and toxicological screening results, which were tested positive for the potent hallucinogenic drug lysergic acid diethylamide (LSD). LSD and its main metabolites were quantified in brain tissue and femoral blood, and furthermore hematoma...

  2. Position of anticholinergic drugs in the treatment of childhood asthma

    Directory of Open Access Journals (Sweden)

    Stojković-Anđelković Anđelka

    2010-01-01

    Full Text Available Anticholinergic drugs block muscarinic effect of acetylcholine on the receptors of postjunctional membranes and so inhibit the answer of the postganglionic parasympathetic nerve. The loss of M2 muscarinic receptors function occurs in asthmatics and it contributes to bronchial hyperresponsiveness and it is not a chronic feature of asthma, instead it characterizes asthma exacerbation. The loss of M2 muscarinic receptor function in children and adults happens during antigen bronchoprovocation or during exposition of asthmatics to ozone. After inhalation, ipratropium bromide (IB can be found in a small quantity in circulation and it links less readily to muscarinic receptors on airway smooth muscles as related to its absorption after intravenous application. In the stepwise approach of asthma inhaled anticholinergics is recommended if the symptoms of the disease cannot be adequately controlled by a regular inhalation of antiinflammatory drugs with β2-agonist and oral steroids. The improvement of the airway inspiratory capacity is more elevated than the improvement of FEV1 after inhalation of IB. IB has similar effect as salbutamol and it is recommended to control a stable chronic obstructive disease. During our numerous investigations and up-to-date experience in the usage of 5-7 μg/kg/body mass of IB repeated every 4-6 hours in combination with salbutamol, we did not notice adverse effects of the drug in infants. IB is recommended for hospital treatment of children. .

  3. Cardiac Arrhythmia: In vivo screening in the zebrafish to overcome complexity in drug discovery.

    Science.gov (United States)

    Macrae, Calum A

    2010-07-01

    IMPORTANCE OF THE FIELD: Cardiac arrhythmias remain a major challenge for modern drug discovery. Clinical events are paroxysmal, often rare and may be asymptomatic until a highly morbid complication. Target selection is often based on limited information and though highly specific agents are identified in screening, the final efficacy is often compromised by unanticipated systemic responses, a narrow therapeutic index and substantial toxicities. AREAS COVERED IN THIS REVIEW: Our understanding of complexity of arrhythmogenesis has grown dramatically over the last two decades, and the range of potential disease mechanisms now includes pathways previously thought only tangentially involved in arrhythmia. This review surveys the literature on arrhythmia mechanisms from 1965 to the present day, outlines the complex biology underlying potentially each and every rhythm disturbance, and highlights the problems for rational target identification. The rationale for in vivo screening is described and the utility of the zebrafish for this approach and for complementary work in functional genomics is discussed. Current limitations of the model in this setting and the need for careful validation in new disease areas are also described. WHAT THE READER WILL GAIN: An overview of the complex mechanisms underlying most clinical arrhythmias, and insight into the limits of ion channel conductances as drug targets. An introduction to the zebrafish as a model organism, in particular for cardiovascular biology. Potential approaches to overcoming the hurdles to drug discovery in the face of complex biology including in vivo screening of zebrafish genetic disease models. TAKE HOME MESSAGE: In vivo screening in faithful disease models allows the effects of drugs on integrative physiology and disease biology to be captured during the screening process, in a manner agnostic to potential drug target or targets. This systematic strategy bypasses current gaps in our understanding of disease

  4. HAMS: High-Affinity Mass Spectrometry Screening. A High-Throughput Screening Method for Identifying the Tightest-Binding Lead Compounds for Target Proteins with No False Positive Identifications.

    Science.gov (United States)

    Imaduwage, Kasun P; Go, Eden P; Zhu, Zhikai; Desaire, Heather

    2016-11-01

    A major challenge in drug discovery is the identification of high affinity lead compounds that bind a particular target protein; these leads are typically identified by high throughput screens. Mass spectrometry has become a detection method of choice in drug screening assays because the target and the ligand need not be modified. Label-free assays are advantageous because they can be developed more rapidly than assays requiring labels, and they eliminate the risk of the label interfering with the binding event. However, in commonly used MS-based screening methods, detection of false positives is a major challenge. Here, we describe a detection strategy designed to eliminate false positives. In this approach, the protein and the ligands are incubated together, and the non-binders are separated for detection. Hits (protein binders) are not detectable by MS after incubation with the protein, but readily identifiable by MS when the target protein is not present in the incubation media. The assay was demonstrated using three different proteins and hundreds of non-inhibitors; no false positive hits were identified in any experiment. The assay can be tuned to select for ligands of a particular binding affinity by varying the quantity of protein used and the immobilization method. As examples, the method selectively detected inhibitors that have K i values of 0.2 μM, 50 pM, and 700 pM. These findings demonstrate that the approach described here compares favorably with traditional MS-based screening methods. Graphical Abstract ᅟ.

  5. Validation of the direct analysis in real time source for use in forensic drug screening.

    Science.gov (United States)

    Steiner, Robert R; Larson, Robyn L

    2009-05-01

    The Direct Analysis in Real Time (DART) ion source is a relatively new mass spectrometry technique that is seeing widespread use in chemical analyses world-wide. DART studies include such diverse topics as analysis of flavors and fragrances, melamine in contaminated dog food, differentiation of writing inks, characterization of solid counterfeit drugs, and as a detector for planar chromatography. Validation of this new technique for the rapid screening of forensic evidence for drugs of abuse, utilizing the DART source coupled to an accurate mass time-of-flight mass spectrometer, was conducted. The study consisted of the determination of the lower limit of detection for the method, determination of selectivity and a comparison of this technique to established analytical protocols. Examples of DART spectra are included. The results of this study have allowed the Virginia Department of Forensic Science to incorporate this new technique into their analysis scheme for the screening of solid dosage forms of drugs of abuse.

  6. A screen to identify drug resistant variants to target-directed anti-cancer agents

    Directory of Open Access Journals (Sweden)

    Azam Mohammad

    2003-01-01

    Full Text Available The discovery of oncogenes and signal transduction pathways important for mitogenesis has triggered the development of target-specific small molecule anti-cancer compounds. As exemplified by imatinib (Gleevec, a specific inhibitor of the Chronic Myeloid Leukemia (CML-associated Bcr-Abl kinase, these agents promise impressive activity in clinical trials, with low levels of clinical toxicity. However, such therapy is susceptible to the emergence of drug resistance due to amino acid substitutions in the target protein. Defining the spectrum of such mutations is important for patient monitoring and the design of next-generation inhibitors. Using imatinib and BCR/ABL as a paradigm for a drug-target pair, we recently reported a retroviral vector-based screening strategy to identify the spectrum of resistance-conferring mutations. Here we provide a detailed methodology for the screen, which can be generally applied to any drug-target pair.

  7. Exploiting pluripotent stem cell technology for drug discovery, screening, safety, and toxicology assessments.

    Science.gov (United States)

    McGivern, Jered V; Ebert, Allison D

    2014-04-01

    In order for the pharmaceutical industry to maintain a constant flow of novel drugs and therapeutics into the clinic, compounds must be thoroughly validated for safety and efficacy in multiple biological and biochemical systems. Pluripotent stem cells, because of their ability to develop into any cell type in the body and recapitulate human disease, may be an important cellular system to add to the drug development repertoire. This review will discuss some of the benefits of using pluripotent stem cells for drug discovery and safety studies as well as some of the recent applications of stem cells in drug screening studies. We will also address some of the hurdles that need to be overcome in order to make stem cell-based approaches an efficient and effective tool in the quest to produce clinically successful drug compounds. Copyright © 2013 Elsevier B.V. All rights reserved.

  8. A Drug Combination Screen Identifies Drugs Active against Amoxicillin-induced Round Bodies of Borrelia burgdorferi Persisters from an FDA Drug Library

    Directory of Open Access Journals (Sweden)

    Jie eFeng

    2016-05-01

    Full Text Available Although currently recommended antibiotics for Lyme disease such as doxycycline or amoxicillin cure the majority of the patients, about 10-20% of patients treated for Lyme disease may experience lingering symptoms including fatigue, pain, or joint and muscle aches. Under stress conditions such as starvation or antibiotic exposure, Borrelia burgdorferi can develop round body forms, which are a type of persister bacteria that are not killed by current Lyme antibiotics. To identify more effective drugs that are active against the round bodies of B. burgdorferi, we established a round body persister model induced by amoxicillin and screened the Food and Drug Administration (FDA drug library consisting of 1581 drug compounds and also 22 drug combinations using the SYBR Green I/propidium iodide (PI viability assay. We identified 23 drug candidates that have higher activity against the round bodies of B. burgdorferi than either amoxicillin or doxycycline. Eleven of these scored better than metronidazole and tinidazole which have been previously described to be active against round bodies. While some drug candidates such as daptomycin and clofazimine overlapped with a previous screen against stationary phase B. burgdorferi persisters, additional drug candidates active against round bodies we identified include artemisinin, ciprofloxacin, nifuroxime, fosfomycin, chlortetracycline, sulfacetamide, sulfamethoxypyridazine and sulfathiozole. Two triple drug combinations had the highest activity against round bodies and stationary phase B. burgdorferi persisters: artemisinin/cefoperazone/doxycycline and sulfachlorpyridazine/daptomycin/doxycycline. These findings confirm and extend previous findings that certain drug combinations have superior activity against B. burgdorferi persisters in vitro, even if pre-treated with amoxicillin. These findings may have implications for improved treatment of Lyme disease.

  9. The effect of screening for cardio-renal risk factors on drug use in the general population

    NARCIS (Netherlands)

    Atthobari, J.; Gansevoort, R.T.; Visser, S.T.; De Jong, P.E.; de Jong-van den Berg, L.T.

    2007-01-01

    Aims To evaluate the effect of a cardio-renal screening programme on desired and undue drug use. Methods Data from the PREVEND cohort (Prevention of REnal and Vascular ENd-stage Disease) were used. The drug use of screened (randomly) selected subjects (n = 2650) was compared with unscreened

  10. Ultrasound as a Screening Tool for Central Venous Catheter Positioning and Exclusion of Pneumothorax.

    Science.gov (United States)

    Amir, Rabia; Knio, Ziyad O; Mahmood, Feroze; Oren-Grinberg, Achikam; Leibowitz, Akiva; Bose, Ruma; Shaefi, Shahzad; Mitchell, John D; Ahmed, Muneeb; Bardia, Amit; Talmor, Daniel; Matyal, Robina

    2017-07-01

    Although real-time ultrasound guidance during central venous catheter insertion has become a standard of care, postinsertion chest radiograph remains the gold standard to confirm central venous catheter tip position and rule out associated lung complications like pneumothorax. We hypothesize that a combination of transthoracic echocardiography and lung ultrasound is noninferior to chest radiograph when used to accurately assess central venous catheter positioning and screen for pneumothorax. All operating rooms and surgical and trauma ICUs at the institution. Single-center, prospective noninferiority study. Patients receiving ultrasound-guided subclavian or internal jugular central venous catheters. During ultrasound-guided central venous catheter placement, correct positioning of central venous catheter was accomplished by real-time visualization of the guide wire and positive right atrial swirl sign using the subcostal four-chamber view. After insertion, pneumothorax was ruled out by the presence of lung sliding and seashore sign on M-mode. Data analysis was done for 137 patients. Chest radiograph ruled out pneumothorax in 137 of 137 patients (100%). Lung ultrasound was performed in 123 of 137 patients and successfully screened for pneumothorax in 123 of 123 (100%). Chest radiograph approximated accurate catheter tip position in 136 of 137 patients (99.3%). Adequate subcostal four-chamber views could not be obtained in 13 patients. Accurate positioning of central venous catheter with ultrasound was then confirmed in 121 of 124 patients (97.6%) as described previously. Transthoracic echocardiography and lung ultrasound are noninferior to chest x-ray for screening of pneumothorax and accurate central venous catheter positioning. Thus, the point of care use of ultrasound can reduce central venous catheter insertion to use time, exposure to radiation, and improve patient safety.

  11. Highly sensitive capillary electrophoresis-mass spectrometry for rapid screening and accurate quantitation of drugs of abuse in urine.

    Science.gov (United States)

    Kohler, Isabelle; Schappler, Julie; Rudaz, Serge

    2013-05-30

    The combination of capillary electrophoresis (CE) and mass spectrometry (MS) is particularly well adapted to bioanalysis due to its high separation efficiency, selectivity, and sensitivity; its short analytical time; and its low solvent and sample consumption. For clinical and forensic toxicology, a two-step analysis is usually performed: first, a screening step for compound identification, and second, confirmation and/or accurate quantitation in cases of presumed positive results. In this study, a fast and sensitive CE-MS workflow was developed for the screening and quantitation of drugs of abuse in urine samples. A CE with a time-of-flight MS (CE-TOF/MS) screening method was developed using a simple urine dilution and on-line sample preconcentration with pH-mediated stacking. The sample stacking allowed for a high loading capacity (20.5% of the capillary length), leading to limits of detection as low as 2 ng mL(-1) for drugs of abuse. Compound quantitation of positive samples was performed by CE-MS/MS with a triple quadrupole MS equipped with an adapted triple-tube sprayer and an electrospray ionization (ESI) source. The CE-ESI-MS/MS method was validated for two model compounds, cocaine (COC) and methadone (MTD), according to the Guidance of the Food and Drug Administration. The quantitative performance was evaluated for selectivity, response function, the lower limit of quantitation, trueness, precision, and accuracy. COC and MTD detection in urine samples was determined to be accurate over the range of 10-1000 ng mL(-1) and 21-1000 ng mL(-1), respectively. Copyright © 2013 Elsevier B.V. All rights reserved.

  12. Pharmacogenetic screening for polymorphisms in drug-metabolizing enzymes and drug transporters in a Dutch population.

    Science.gov (United States)

    Bosch, T M; Doodeman, V D; Smits, P H M; Meijerman, I; Schellens, J H M; Beijnen, J H

    2006-01-01

    A possible explanation for the wide interindividual variability in toxicity and efficacy of drug therapy is variation in genes encoding drug-metabolizing enzymes and drug transporters. The allelic frequency of these genetic variants, linkage disequilibrium (LD), and haplotype of these polymorphisms are important parameters in determining the genetic differences between patients. The aim of this study was to explore the frequencies of polymorphisms in drug-metabolizing enzymes (CYP1A1, CYP2C9, CYP2C19, CYP3A4, CYP2D6, CYP3A5, DPYD, UGT1A1, GSTM1, GSTP1, GSTT1) and drug transporters (ABCB1[MDR1] and ABCC2[MRP2]), and to investigate the LD and perform haplotype analysis of these polymorphisms in a Dutch population. Blood samples were obtained from 100 healthy volunteers and genomic DNA was isolated and amplified by PCR. The amplification products were sequenced and analyzed for the presence of polymorphisms by sequence alignment. In the study population, we identified 13 new single nucleotide polymorphisms (SNPs) in Caucasians and three new SNPs in non-Caucasians, in addition to previously recognized SNPs. Three of the new SNPs were found within exons, of which two resulted in amino acid changes (A428T in CYP2C9 resulting in the amino acid substitution D143V; and C4461T in ABCC2 in a non-Caucasian producing the amino acid change T1476M). Several LDs and haplotypes were found in the Caucasian individuals. In this Dutch population, the frequencies of 16 new SNPs and those of previously recognized SNPs were determined in genes coding for drug-metabolizing enzymes and drug transporters. Several LDs and haplotypes were also inferred. These data are important for further research to help explain the interindividual pharmacokinetic and pharmacodynamic variability in response to drug therapy.

  13. Desorption electrospray ionisation mass spectrometry: A rapid screening tool for veterinary drug preparations and forensic samples from hormone crime investigations

    International Nuclear Information System (INIS)

    Nielen, M.W.F.; Hooijerink, H.; Claassen, F.C.; Engelen, M.C. van; Beek, T.A. van

    2009-01-01

    Hormone and veterinary drug screening and forensics can benefit from the recent developments in desorption electrospray ionisation (DESI) mass spectrometry (MS). In this work the feasibility of DESI application has been studied. Using a linear ion trap or quadrupole time-of-flight (TOF) MS instrument both full-scan and data-dependent collision-induced dissociation MS n spectra were acquired in seconds without sample preparation. Preliminary data are presented for the rapid screening of (pro)hormone supplement samples, an illegal steroid cocktail and forensic samples from veterinary drug investigations. The potential of this DESI approach is clearly demonstrated since compounds observed could be independently confirmed by liquid chromatography/TOFMS with accurate mass measurement, and/or proton nuclear magnetic resonance spectroscopy. Specific concerns related to false-positive and false-negative findings due to limitations in quantification and memory-effects are briefly discussed. It is envisaged that DESI will achieve a prominent role in hormone and veterinary drug analysis in the near future

  14. Desorption electrospray ionisation mass spectrometry: A rapid screening tool for veterinary drug preparations and forensic samples from hormone crime investigations

    Energy Technology Data Exchange (ETDEWEB)

    Nielen, M.W.F. [RIKILT Institute of Food Safety, P.O. Box 230, 6700 AE Wageningen (Netherlands); Wageningen University, Laboratory of Organic Chemistry, Dreijenplein 8, 6703 HB Wageningen (Netherlands)], E-mail: michel.nielen@wur.nl; Hooijerink, H. [RIKILT Institute of Food Safety, P.O. Box 230, 6700 AE Wageningen (Netherlands); Claassen, F.C. [Wageningen University, Laboratory of Organic Chemistry, Dreijenplein 8, 6703 HB Wageningen (Netherlands); Engelen, M.C. van [RIKILT Institute of Food Safety, P.O. Box 230, 6700 AE Wageningen (Netherlands); Beek, T.A. van [Wageningen University, Laboratory of Organic Chemistry, Dreijenplein 8, 6703 HB Wageningen (Netherlands)

    2009-04-01

    Hormone and veterinary drug screening and forensics can benefit from the recent developments in desorption electrospray ionisation (DESI) mass spectrometry (MS). In this work the feasibility of DESI application has been studied. Using a linear ion trap or quadrupole time-of-flight (TOF) MS instrument both full-scan and data-dependent collision-induced dissociation MS{sup n} spectra were acquired in seconds without sample preparation. Preliminary data are presented for the rapid screening of (pro)hormone supplement samples, an illegal steroid cocktail and forensic samples from veterinary drug investigations. The potential of this DESI approach is clearly demonstrated since compounds observed could be independently confirmed by liquid chromatography/TOFMS with accurate mass measurement, and/or proton nuclear magnetic resonance spectroscopy. Specific concerns related to false-positive and false-negative findings due to limitations in quantification and memory-effects are briefly discussed. It is envisaged that DESI will achieve a prominent role in hormone and veterinary drug analysis in the near future.

  15. Primary care visit use after positive fecal immunochemical test for colorectal cancer screening.

    Science.gov (United States)

    Hillyer, Grace Clarke; Jensen, Christopher D; Zhao, Wei K; Neugut, Alfred I; Lebwohl, Benjamin; Tiro, Jasmin A; Kushi, Lawrence H; Corley, Douglas A

    2017-10-01

    For some patients, positive cancer screening test results can be a stressful experience that can affect future screening compliance and increase the use of health care services unrelated to medically indicated follow-up. Among 483,216 individuals aged 50 to 75 years who completed a fecal immunochemical test to screen for colorectal cancer at a large integrated health care setting between 2007 and 2011, the authors evaluated whether a positive test was associated with a net change in outpatient primary care visit use within the year after screening. Multivariable regression models were used to evaluate the relationship between test result group and net changes in primary care visits after fecal immunochemical testing. In the year after the fecal immunochemical test, use increased by 0.60 clinic visits for patients with true-positive results. The absolute change in visits was largest (3.00) among individuals with positive test results who were diagnosed with colorectal cancer, but significant small increases also were found for patients treated with polypectomy and who had no neoplasia (0.36) and those with a normal examination and no polypectomy performed (0.17). Groups of patients who demonstrated an increase in net visit use compared with the true-negative group included patients with true-positive results (odds ratio [OR], 1.60; 95% confidence interval [95% CI], 1.54-1.66), and positive groups with a colorectal cancer diagnosis (OR, 7.19; 95% CI, 6.12-8.44), polypectomy/no neoplasia (OR, 1.37; 95% CI, 1.27-1.48), and normal examination/no polypectomy (OR, 1.24; 95% CI, 1.18-1.30). Given the large size of outreach programs, these small changes can cumulatively generate thousands of excess visits and have a substantial impact on total health care use. Therefore, these changes should be included in colorectal cancer screening cost models and their causes investigated further. Cancer 2017;123:3744-3753. © 2017 American Cancer Society. © 2017 American Cancer Society.

  16. Phenotypic Screening Approaches to Develop Aurora Kinase Inhibitors: Drug Discovery Perspectives.

    Science.gov (United States)

    Marugán, Carlos; Torres, Raquel; Lallena, María José

    2015-01-01

    Targeting mitotic regulators as a strategy to fight cancer implies the development of drugs against key proteins, such as Aurora-A and -B. Current drugs, which target mitosis through a general mechanism of action (stabilization/destabilization of microtubules), have several side effects (neutropenia, alopecia, and emesis). Pharmaceutical companies aim at avoiding these unwanted effects by generating improved and selective drugs that increase the quality of life of the patients. However, the development of these drugs is an ambitious task that involves testing thousands of compounds through biochemical and cell-based assays. In addition, molecules usually target complex biological processes, involving several proteins and different molecular pathways, further emphasizing the need for high-throughput screening techniques and multiplexing technologies in order to identify drugs with the desired phenotype. We will briefly describe two multiplexing technologies [high-content imaging (HCI) and flow cytometry] and two key processes for drug discovery research (assay development and validation) following our own published industry quality standards. We will further focus on HCI as a useful tool for phenotypic screening and will provide a concrete example of HCI assay to detect Aurora-A or -B selective inhibitors discriminating the off-target effects related to the inhibition of other cell cycle or non-cell cycle key regulators. Finally, we will describe other assays that can help to characterize the in vitro pharmacology of the inhibitors.

  17. Phenotypic screening approaches to develop Aurora kinase inhibitors: Drug Discovery perspectives

    Directory of Open Access Journals (Sweden)

    Carlos eMarugán

    2016-01-01

    Full Text Available Targeting mitotic regulators as a strategy to fight cancer implies the development of drugs against key proteins such as Aurora A and B. Current drugs which target mitosis through a general mechanism of action (stabilization/destabilization of microtubules, have several side effects (neutropenia, alopecia, emesis. Pharmaceutical companies aim at avoiding these unwanted effects by generating improved and selective drugs that increase the quality of life of the patients. However, the development of these drugs is an ambitious task that involves testing thousands of compounds through biochemical and cell-based assays. In addition, molecules usually target complex biological processes, involving several proteins and different molecular pathways, further emphasizing the need for high-throughput screening techniques and multiplexing technologies in order to identify drugs with the desired phenotype.We will briefly describe two multiplexing technologies (high-content imaging, microarrays and flow cytometry and two key processes for drug discovery research (assay development and validation following our own published industry quality standards. We will further focus on high-content imaging as a useful tool for phenotypic screening and will provide a concrete example of high-content imaging assay to detect Aurora A or B selective inhibitors discriminating the off-target effects related to inhibition of other cell cycle or non-cell cycle key regulators. Finally, we will describe other assays that can help to characterize the in vitro pharmacology of the inhibitors.

  18. Identifying Relationships between High-Risk Sexual Behaviors and Screening Positive for Chlamydia and Gonorrhea in School-Wide Screening Events

    Science.gov (United States)

    Salerno, Jennifer; Darling-Fisher, Cindy; Hawkins, Nicole M.; Fraker, Elizabeth

    2013-01-01

    Background: This article describes a school-wide sexually transmitted infection (STI) screening to identify adolescent high-risk sexual behaviors, STI history/incidence, and presence of chlamydia and gonorrhea, and examines relationships between high-risk behaviors and screening positive for chlamydia and gonorrhea in an alternative high school…

  19. Validation of cervical cancer screening methods in HIV positive women from Johannesburg South Africa.

    Directory of Open Access Journals (Sweden)

    Cynthia Firnhaber

    Full Text Available HIV-infected women are at increased risk for developing cervical cancer. Women living in resource-limited countries are especially at risk due to poor access to cervical cancer screening and treatment. We evaluated three cervical cancer screening methods to detect cervical intraepithelial neoplasia grade 2 and above (CIN 2+ in HIV-infected women in South Africa; Pap smear, visual inspection with 5% acetic acid (VIA and human papillomavirus detection (HPV.HIV-infected women aged 18-65 were recruited in Johannesburg. A cross-sectional study evaluating three screening methods for the detection of the histologically-defined gold standard CIN-2 + was performed. Women were screened for cervical abnormalities with the Digene HC2 assay (HPV, Pap smear and VIA. VIA was performed by clinic nurses, digital photographs taken and then later reviewed by specialist physicians. The sensitivity, specificity and predictive valves for CIN-2 + were calculated using maximum likelihood estimators.1,202 HIV-infected women participated, with a median age of 38 years and CD4 counts of 394 cells/mm(3. One third of women had a high grade lesion on cytology. VIA and HPV were positive in 45% and 61% of women respectively. Estimated sensitivity/specificity for HPV, Pap smear and VIA for CIN 2+ was 92%/51.4%, 75.8%/83.4% and 65.4/68.5% (nurse reading, respectively. Sensitivities were similar, and specificities appeared significantly lower for the HPV test, cytology and VIA among women with CD4 counts ≤200 cells/mm(3 as compared to CD4 counts >350 cells/mm(3.Although HPV was the most sensitive screening method for detecting CIN 2+, it was less specific than conventional cytology and VIA with digital imaging review. Screening programs may need to be individualized in context of the resources and capacity in each area.

  20. Transgenic Plants as Low-Cost Platform for Chemotherapeutic Drugs Screening

    Directory of Open Access Journals (Sweden)

    Daniele Vergara

    2015-01-01

    Full Text Available In this work we explored the possibility of using genetically modified Arabidopsis thaliana plants as a rapid and low-cost screening tool for evaluating human anticancer drugs action and efficacy. Here, four different inhibitors with a validated anticancer effect in humans and distinct mechanism of action were screened in the plant model for their ability to interfere with the cytoskeletal and endomembrane networks. We used plants expressing a green fluorescent protein (GFP tagged microtubule-protein (TUA6-GFP, and three soluble GFPs differently sorted to reside in the endoplasmic reticulum (GFPKDEL or to accumulate in the vacuole through a COPII dependent (AleuGFP or independent (GFPChi mechanism. Our results demonstrated that drugs tested alone or in combination differentially influenced the monitored cellular processes including cytoskeletal organization and endomembrane trafficking. In conclusion, we demonstrated that A. thaliana plants are sensitive to the action of human chemotherapeutics and can be used for preliminary screening of drugs efficacy. The cost-effective subcellular imaging in plant cell may contribute to better clarify drugs subcellular targets and their anticancer effects.

  1. An audit to investigate the impact of false positive breast screening results and diagnostic work-up on re-engagement with subsequent routine screening

    International Nuclear Information System (INIS)

    Nightingale, Julie M.; Borgen, Rita; Porter-Bennett, Lisa; Szczepura, Katy

    2015-01-01

    Introduction: Women attending breast screening may have suspicious mammographic findings that are subsequently found at assessment clinic to be normal (false positive, FP). A false positive diagnosis is not harmless, with short and long term negative psychosocial consequences reported. Women are at increased relative risk of breast cancer therefore their attendance at subsequent screening is essential. Aims: To assess the impact of FP breast screening diagnosis and diagnostic work-up on re-attendance rates across four consecutive screening rounds at a typical breast screening centre. Method: Diagnostic interventions and screening re-attendance rates at one prior and two consecutive rounds were analysed for women receiving an FP diagnosis between 2004 and 2006. Results: 397 women (5.57%) were referred for further assessment, including 228 (57.43%) false positives. 34 eligible women failed to re-attend routine screening (+3 years), with 17 failing to re-attend subsequently (+6 years). 70.6% (24/34) of non-attenders had attended at least two screening rounds prior to FP assessment. 75% of FP women had an imaging-only assessment with 17.5% (30/171) failing to re-attend, and 25% received a biopsy, with 7% (4/57) failing to re-attend subsequently. Conclusion: This study is unique as it follows FP women through four consecutive screening rounds. FP non-attendance rates were considerably lower compared to the general screening population, with diagnostic work-up having limited influence. FP non-attendance may appear insignificant in comparison to total screened population, but these women are at greater risk of subsequent cancer so should be actively encouraged to re-engage with the screening programme

  2. Drug Repurposing Screening Identifies Novel Compounds That Effectively Inhibit Toxoplasma gondii Growth

    Science.gov (United States)

    Dittmar, Ashley J.; Drozda, Allison A.

    2016-01-01

    ABSTRACT The urgent need to develop new antimicrobial therapies has spawned the development of repurposing screens in which well-studied drugs and other types of compounds are tested for potential off-label uses. As a proof-of-principle screen to identify compounds effective against Toxoplasma gondii, we screened a collection of 1,120 compounds for the ability to significantly reduce Toxoplasma replication. A total of 94 compounds blocked parasite replication with 50% inhibitory concentrations of parasite invasion and replication but did so independently of inhibition of dopamine or other neurotransmitter receptor signaling. Tamoxifen, which is an established inhibitor of the estrogen receptor, also reduced parasite invasion and replication. Even though Toxoplasma can activate the estrogen receptor, tamoxifen inhibits parasite growth independently of this transcription factor. Tamoxifen is also a potent inducer of autophagy, and we find that the drug stimulates recruitment of the autophagy marker light chain 3-green fluorescent protein onto the membrane of the vacuolar compartment in which the parasite resides and replicates. In contrast to other antiparasitic drugs, including pimozide, tamoxifen treatment of infected cells leads to a time-dependent elimination of intracellular parasites. Taken together, these data suggest that tamoxifen restricts Toxoplasma growth by inducing xenophagy or autophagic destruction of this obligate intracellular parasite. IMPORTANCE There is an urgent need to develop new therapies to treat microbial infections, and the repurposing of well-characterized compounds is emerging as one approach to achieving this goal. Using the protozoan parasite Toxoplasma gondii, we screened a library of 1,120 compounds and identified several compounds with significant antiparasitic activities. Among these were pimozide and tamoxifen, which are well-characterized drugs prescribed to treat patients with psychiatric disorders and breast cancer

  3. Chemogenomics profiling of drug targets of peptidoglycan biosynthesis pathway in Leptospira interrogans by virtual screening approaches.

    Science.gov (United States)

    Bhattacharjee, Biplab; Simon, Rose Mary; Gangadharaiah, Chaithra; Karunakar, Prashantha

    2013-06-28

    Leptospirosis is a worldwide zoonosis of global concern caused by Leptospira interrogans. The availability of ligand libraries has facilitated the search for novel drug targets using chemogenomics approaches, compared with the traditional method of drug discovery, which is time consuming and yields few leads with little intracellular information for guiding target selection. Recent subtractive genomics studies have revealed the putative drug targets in peptidoglycan biosynthesis pathways in Leptospira interrogans. Aligand library for the murD ligase enzyme in the peptidoglycan pathway has also been identified. Our approach in this research involves screening of the pre-existing ligand library of murD with related protein family members in the putative drug target assembly in the peptidoglycan biosynthesis pathway. A chemogenomics approach has been implemented here, which involves screening of known ligands of a protein family having analogous domain architecture for identification of leads for existing druggable protein family members. By means of this approach, one murC and one murF inhibitor were identified, providing a platform for developing an antileptospirosis drug targeting the peptidoglycan biosynthesis pathway. Given that the peptidoglycan biosynthesis pathway is exclusive to bacteria, the in silico identified mur ligase inhibitors are expected to be broad-spectrum Gram-negative inhibitors if synthesized and tested in in vitro and in vivo assays.

  4. Repositioning FDA Drugs as Potential Cruzain Inhibitors from Trypanosoma cruzi: Virtual Screening, In Vitro and In Vivo Studies

    Directory of Open Access Journals (Sweden)

    Isidro Palos

    2017-06-01

    Full Text Available Chagas disease (CD is a neglected disease caused by the parasite Trypanosoma cruzi, which affects underdeveloped countries. The current drugs of choice are nifurtimox and benznidazole, but both have severe adverse effects and less effectivity in chronic infections; therefore, the need to discover new drugs is essential. A computer-guided drug repositioning method was applied to identify potential FDA drugs (approved and withdrawn as cruzain (Cz inhibitors and trypanocidal effects were confirmed by in vitro and in vivo studies. 3180 FDA drugs were virtually screened using a structure-based approach. From a first molecular docking analysis, a set of 33 compounds with the best binding energies were selected. Subsequent consensus affinity binding, ligand amino acid contact clustering analysis, and ranked position were used to choose four known pharmacological compounds to be tested in vitro. Mouse blood samples infected with trypomastigotes from INC-5 and NINOA strains were used to test the trypanocidal effect of four selected compounds. Among these drugs, one fibrate antilipemic (etofyllin clofibrate and three β-lactam antibiotics (piperacillin, cefoperazone, and flucloxacillin showed better trypanocidal effects (LC50 range 15.8–26.1 μg/mL in comparison with benznidazole and nifurtimox (LC50 range 33.1–46.7 μg/mL. A short-term in vivo evaluation of these compounds showed a reduction of parasitemia in infected mice (range 90–60% at 6 h, but this was low compared to benznidazole (50%. This work suggests that four known FDA drugs could be used to design and obtain new trypanocidal agents.

  5. Impact of Cell-Free Fetal DNA Screening on Patients’ Choice of Invasive Procedures after a Positive California Prenatal Screen Result

    Directory of Open Access Journals (Sweden)

    Forum T. Shah

    2014-07-01

    Full Text Available Until recently, maternal serum analyte levels paired with sonographic fetal nuchal translucency measurement was the most accurate prenatal screen available for Trisomies 18 and 21, (91% and 94% detection and false positive rates of 0.31% and 4.5% respectively. Women with positive California Prenatal Screening Program (CPSP results have the option of diagnostic testing to determine definitively if the fetus has a chromosomal abnormality. Cell-free fetal (cff- DNA screening for Trisomies 13, 18, and 21 was first offered in 2012, allowing women with positive screens to choose additional screening before diagnostic testing. Cff-DNA sensitivity rates are as high as 99.9% and 99.1%, with false positive rates of 0.4% and 0.1%, for Trisomies 18 and 21, respectively. A retrospective chart review was performed in 2012 on 500 CPSP referrals at the University of California, San Diego Thornton Hospital. Data were collected prior to and after the introduction of cff-DNA. There was a significant increase in the number of participants who chose to pursue additional testing and a decrease in the number of invasive procedures performed after cff-DNA screening was available. We conclude that as fetal aneuploidy screening improves, the number of invasive procedures will continue to decrease.

  6. Rapid screening of pharmaceutical drugs using thermal desorption – SALDI mass spectrometry

    International Nuclear Information System (INIS)

    Grechnikov, A A; Kubasov, A E; Borodkov, A S; Georgieva, V B; Nikiforov, S M; Simanovsky, Ya O; Alimpiev, S S

    2012-01-01

    A novel approach to the rapid screening of pharmaceutical drugs by surface assisted laser desorption-ionization (SALDI) mass spectrometry with the rotating ball interface coupled with temperature programmed thermal desorption has been developed. Analytes were thermally desorbed and deposited onto the surface of amorphous silicon substrate attached to the rotating ball. The ball was rotated and the deposited analytes were analyzed using SALDI. The effectiveness of coupling SALDI mass spectrometry with thermal desorption was evaluated by the direct and rapid analysis of tablets containing lidocaine, diphenhydramine and propranolol without any sample pretreatment. The overall duration of the screening procedure was 30÷40 sec. Real urine samples were studied for drug analysis. It is shown that with simple preparation steps, urine samples can be quantitatively analyzed using the proposed technique with the detection limits in the range of 0.2÷0.5 ng/ml.

  7. Alcohol screening and brief intervention among drug users in primary care: a discussion paper.

    LENUS (Irish Health Repository)

    Field, C A

    2011-08-24

    BACKGROUND: Problem alcohol use is common among problem drug users (PDU) and associated with adverse health outcomes. Primary care has an important role in the overall stepped approach to alcohol treatment, especially screening and brief intervention (SBI). AIM: To discuss three themes that emerged from an exploration of the literature on SBI for problem alcohol use in drug users attending primary care. METHODS: Material for this discussion paper was gathered from three biomedical databases (PubMed, PsycINFO and Cochrane library), conference proceedings and online resources of professional organisations or national health agencies. RESULTS: Themes discussed in this paper are: (a) the potential of primary care for delivery of alcohol SBIs to PDUs, (b) screening methods and (c) application of brief interventions to PDUs. CONCLUSIONS: Although SBI improves health outcomes associated with problem alcohol use in the general population, further research is needed among high-risk patient groups, especially PDUs.

  8. Data mining a small molecule drug screening representative subset from NIH PubChem.

    Science.gov (United States)

    Xie, Xiang-Qun; Chen, Jian-Zhong

    2008-03-01

    PubChem is a scientific showcase of the NIH Roadmap Initiatives. It is a compound repository created to facilitate information exchange and data sharing among the NIH Roadmap-funded Molecular Library Screening Center Network (MLSCN) and the scientific community. However, PubChem has more than 10 million records of compound information. It will be challenging to conduct a drug screening of the whole database of millions of compounds. Thus, the purpose of the present study was to develop a data mining cheminformatics approach in order to construct a representative and structure-diverse sublibrary from the large PubChem database. In this study, a new chemical diverse representative subset, rePubChem, was selected by whole-molecule chemistry-space matrix calculation using the cell-based partition algorithm. The representative subset was generated and was then subjected to evaluations by compound property analyses based on 1D and 2D molecular descriptors. The new subset was also examined and assessed for self-similarity analysis based on 2D molecular fingerprints in comparing with the source compound library. The new subset has a much smaller library size (540K compounds) with minimum similarity and redundancy without loss of the structural diversity and basic molecular properties of its parent library (5.3 million compounds). The new representative subset library generated could be a valuable structure-diverse compound resource for in silico virtual screening and in vitro HTS drug screening. In addition, the established subset generation method of using the combined cell-based chemistry-space partition metrics with pairwised 2D fingerprint-based similarity search approaches will also be important to a broad scientific community interested in acquiring structurally diverse compounds for efficient drug screening, building representative virtual combinatorial chemistry libraries for syntheses, and data mining large compound databases like the PubChem library in general.

  9. The Quebec Association of Gastroenterology Position Paper on Colorectal Cancer Screening - 2003

    Directory of Open Access Journals (Sweden)

    AN Barkun

    2004-01-01

    Full Text Available Colorectal cancer is a leading cause of death and the third most common cancer in Canada. Evidence suggests that screening can reduce mortality rates and the cost effectiveness of a program compares favourably with initiatives for breast and cervical cancer. The objectives of the Association des gastro-entérologues du Québec Task Force were to determine the need for a policy on screening for colorectal cancer in Quebec, to evaluate the testing methods available and to propose one or more of these alternatives as part of a formal screening program, if indicated. Fecal occult blood testing (FOBT, endoscopy (including sigmoidoscopy and colonoscopy, barium enema and virtual colonoscopy were considered. Although most clinical efficacy data are available for FOBT and sigmoidoscopy, there are limitations to programs based on these strategies. FOBT has a high false positive rate and a low detection yield, and even a combination of these strategies will miss 24% of cancers. Colonoscopy is the best strategy to both detect and remove polyps and to diagnose colorectal cancer, with double contrast barium enema also being a sensitive detection method. The Task Force recommended the establishment, in Quebec, of a screening program with five- to 10-yearly double contrast barium enema or 10-yearly colonoscopy for individuals aged 50 years or older at low risk. The program should include outcome monitoring, public and professional education to increase awareness and promote compliance, and central coordination with other provincial programs. The program should be evaluated; specific billing codes for screening for colorectal cancer would help facilitate this. Formal feasibility, effectiveness and cost-effectiveness studies in Quebec are now warranted.

  10. Breast cancer risk is increased in the years following false-positive breast cancer screening.

    Science.gov (United States)

    Goossens, Mathijs C; De Brabander, Isabel; De Greve, Jacques; Vaes, Evelien; Van Ongeval, Chantal; Van Herck, Koen; Kellen, Eliane

    2017-09-01

    A small number of studies have investigated breast cancer (BC) risk among women with a history of false-positive recall (FPR) in BC screening, but none of them has used time-to-event analysis while at the same time quantifying the effect of false-negative diagnostic assessment (FNDA). FNDA occurs when screening detects BC, but this BC is missed on diagnostic assessment (DA). As a result of FNDA, screenings that detected cancer are incorrectly classified as FPR. Our study linked data recorded in the Flemish BC screening program (women aged 50-69 years) to data from the national cancer registry. We used Cox proportional hazards models on a retrospective cohort of 298 738 women to assess the association between FPR and subsequent BC, while adjusting for potential confounders. The mean follow-up was 6.9 years. Compared with women without recall, women with a history of FPR were at an increased risk of developing BC [hazard ratio=2.10 (95% confidence interval: 1.92-2.31)]. However, 22% of BC after FPR was due to FNDA. The hazard ratio dropped to 1.69 (95% confidence interval: 1.52-1.87) when FNDA was excluded. Women with FPR have a subsequently increased BC risk compared with women without recall. The risk is higher for women who have a FPR BI-RADS 4 or 5 compared with FPR BI-RADS 3. There is room for improvement of diagnostic assessment: 41% of the excess risk is explained by FNDA after baseline screening.

  11. High Throughput Screening in Duchenne Muscular Dystrophy: From Drug Discovery to Functional Genomics

    OpenAIRE

    Thomas J.J. Gintjee; Alvin S.H. Magh; Carmen Bertoni

    2014-01-01

    Centers for the screening of biologically active compounds and genomic libraries are becoming common in the academic setting and have enabled researchers devoted to developing strategies for the treatment of diseases or interested in studying a biological phenomenon to have unprecedented access to libraries that, until few years ago, were accessible only by pharmaceutical companies. As a result, new drugs and genetic targets have now been identified for the treatment of Duchenne muscular dyst...

  12. Stem cells: a model for screening, discovery and development of drugs

    OpenAIRE

    Kitambi, Satish Srinivas; Chandrasekar, Gayathri

    2011-01-01

    Satish Srinivas Kitambi1, Gayathri Chandrasekar21Department of Medical Biochemistry and Biophysics; 2Department of Biosciences, Karolinska Institutet, Stockholm, SwedenAbstract: The identification of normal and cancerous stem cells and the recent advances made in isolation and culture of stem cells have rapidly gained attention in the field of drug discovery and regenerative medicine. The prospect of performing screens aimed at proliferation, directed differentiation, and toxicity and efficac...

  13. NMR screening in fragment-based drug design: a practical guide.

    Science.gov (United States)

    Kim, Hai-Young; Wyss, Daniel F

    2015-01-01

    Fragment-based drug design (FBDD) comprises both fragment-based screening (FBS) to find hits and elaboration of these hits to lead compounds. Typical fragment hits have lower molecular weight (FBDD since it identifies and localizes the binding site of weakly interacting hits on the target protein. Here we describe ligand-based NMR methods for hit identification from fragment libraries and for functional cross-validation of primary hits.

  14. Fatty acid ethyl esters (FAEEs) as markers for alcohol in meconium: method validation and implementation of a screening program for prenatal drug exposure.

    Science.gov (United States)

    Hastedt, Martin; Krumbiegel, Franziska; Gapert, René; Tsokos, Michael; Hartwig, Sven

    2013-09-01

    Alcohol consumption during pregnancy is a widespread problem and can cause severe fetal damage. As the diagnosis of fetal alcohol syndrome is difficult, the implementation of a reliable marker for alcohol consumption during pregnancy into meconium drug screening programs would be invaluable. A previously published gas chromatography mass spectrometry method for the detection of fatty acid ethyl esters (FAEEs) as alcohol markers in meconium was optimized and newly validated for a sample size of 50 mg. This method was applied to 122 cases from a drug-using population. The meconium samples were also tested for common drugs of abuse. In 73 % of the cases, one or more drugs were found. Twenty percent of the samples tested positive for FAEEs at levels indicating significant alcohol exposure. Consequently, alcohol was found to be the third most frequently abused substance within the study group. This re-validated method provides an increase in testing sensitivity, is reliable and easily applicable as part of a drug screening program. It can be used as a non-invasive tool to detect high alcohol consumption in the last trimester of pregnancy. The introduction of FAEEs testing in meconium screening was found to be of particular use in a drug-using population.

  15. Leveraging structure determination with fragment screening for infectious disease drug targets: MECP synthase from Burkholderia pseudomallei

    Energy Technology Data Exchange (ETDEWEB)

    Begley, Darren W.; Hartley, Robert C.; Davies, Douglas R.; Edwards, Thomas E.; Leonard, Jess T.; Abendroth, Jan; Burris, Courtney A.; Bhandari, Janhavi; Myler, Peter J.; Staker, Bart L.; Stewart, Lance J. (UWASH); (Emerald)

    2011-09-28

    As part of the Seattle Structural Genomics Center for Infectious Disease, we seek to enhance structural genomics with ligand-bound structure data which can serve as a blueprint for structure-based drug design. We have adapted fragment-based screening methods to our structural genomics pipeline to generate multiple ligand-bound structures of high priority drug targets from pathogenic organisms. In this study, we report fragment screening methods and structure determination results for 2C-methyl-D-erythritol-2,4-cyclo-diphosphate (MECP) synthase from Burkholderia pseudomallei, the gram-negative bacterium which causes melioidosis. Screening by nuclear magnetic resonance spectroscopy as well as crystal soaking followed by X-ray diffraction led to the identification of several small molecules which bind this enzyme in a critical metabolic pathway. A series of complex structures obtained with screening hits reveal distinct binding pockets and a range of small molecules which form complexes with the target. Additional soaks with these compounds further demonstrate a subset of fragments to only bind the protein when present in specific combinations. This ensemble of fragment-bound complexes illuminates several characteristics of MECP synthase, including a previously unknown binding surface external to the catalytic active site. These ligand-bound structures now serve to guide medicinal chemists and structural biologists in rational design of novel inhibitors for this enzyme.

  16. Resolution V fractional factorial Design for Screening of factors affecting weakly basic drugs liposomal systems.

    Science.gov (United States)

    El-Helaly, Sara Nageeb; Habib, Basant A; Abd El-Rahman, Mohamed K

    2018-04-21

    This study aims to investigate factors affecting weakly basic drugs liposomal systems. Resolution V fractional factorial design (2 V 5-1 ) is used as an example of screening designs that would better be used as a wise step before proceeding with detailed factors effects or optimization studies. Five factors probable to affect liposomal systems of weakly basic drugs were investigated using Amisulpride as a model drug. Factors studied were; A: Preparation technique B: Phosphatidyl choline (PhC) amount (mg) C: Cholesterol: PhC molar ratio, D: Hydration volume (ml) and E: Sonication type. Levels investigated were; Ammonium sulphate-pH gradient technique or Transmembrane zinc chelation-pH gradient technique, 200 or 400 mg, 0 or 0.5, 10 or 20 ml and bath or probe sonication for A, B, C, D and E respectively. Responses measured were Particle size (PS) (nm), Zeta potential (ZP) (mV) and Entrapment efficiency percent (EE%). Ion selective electrode was used as a novel method for measuring unentrapped drug concentration and calculating entrapment efficiency without the need for liposomal separation. Factors mainly affecting the studied responses were Cholesterol: PhC ratio and hydration volume for PS, preparation technique for ZP and preparation technique and hydration volume for EE%. The applied 2 V 5-1 design enabled the use of only 16 trial combinations for screening the influence of five factors on weakly basic drugs liposomal systems. This clarifies the value of the use of screening experiments before extensive investigation of certain factors in detailed optimization studies. Copyright © 2017. Published by Elsevier B.V.

  17. Stem cells as a novel tool for drug screening and treatment of degenerative diseases.

    Science.gov (United States)

    Zuba-Surma, Ewa K; Wojakowski, Wojciech; Madeja, Zbigniew; Ratajczak, Mariusz Z

    2012-01-01

    Degenerative diseases similarly as acute tissue injuries lead to massive cell loss and may cause organ failure of vital organs (e.g., heart, central nervous system). Therefore, they belong to a group of disorders that may significantly benefit from stem cells (SCs)-based therapies. Several stem and progenitor cell populations have already been described as valuable tools for developing therapeutic strategies in regenerative medicine. In particular, pluripotent stem cells (PSCs), including adult-tissue-derived PSCs, neonatal-tissue-derived SCs, embryonic stem cells (ESCs), and recently described induced pluripotent stem cells (iPSCs), are the focus of particular attention because of their capacity to differentiate into all the cell lineages. Although PSCs are predominantly envisioned to be applied for organ regeneration, they may be also successfully employed in drug screening and disease modeling. In particular, adult PSCs and iPSCs derived from patient tissues may not only be a source of cells for autologous therapies but also for individual customized in vitro drug testing and studies on the molecular mechanisms of disease. In this review, we will focus on the potential applications of SCs, especially PSCs i) in regenerative medicine therapies, ii) in studying mechanisms of disease, as well as iii) in drug screening and toxicology tests that are crucial in new drug development. In particular, we will discuss the application of SCs in developing new therapeutic approaches to treat degenerative diseases of the neural system and heart. The advantage of adult PSCs in all the above-mentioned settings is that they can be directly harvested from patient tissues and used not only as a safe non-immunogenic source of cells for therapy but also as tools for personalized drug screening and pharmacological therapies.

  18. Radioimmunoassay screening and GC/MS confirmation of whole blood samples for drugs of abuse

    Energy Technology Data Exchange (ETDEWEB)

    Spiehler, V.R.; Sedgwick, P.

    From 1981 to 1984, an average of 300 radioimmunoassay screens on whole blood were performed each week in the authors laboratory. Most samples were screened for opiates phencyclidine and its analogs, barbiturates, and cocaine or its metabolite benzoylecgonine. A commercially available radioimmunoassay was used with modifications to facilitate screening of whole blood. Increasing sample size increased the sensitivity of the assay. Changing reagent concentration (1:1 dilution), incubation time, sample matrix (water, urine, or blood), or fraction counted (precipitate or supernatant) did not affect the utility of the standard curve or the sensitivity of the assay. All positive results for phencyclidine, opiates, cocaine, and related compounds were confirmed by GC/MA. Barbiturate positives were confirmed by UV spectrophotometry.

  19. The influence of the negative-positive ratio and screening database size on the performance of machine learning-based virtual screening.

    Science.gov (United States)

    Kurczab, Rafał; Bojarski, Andrzej J

    2017-01-01

    The machine learning-based virtual screening of molecular databases is a commonly used approach to identify hits. However, many aspects associated with training predictive models can influence the final performance and, consequently, the number of hits found. Thus, we performed a systematic study of the simultaneous influence of the proportion of negatives to positives in the testing set, the size of screening databases and the type of molecular representations on the effectiveness of classification. The results obtained for eight protein targets, five machine learning algorithms (SMO, Naïve Bayes, Ibk, J48 and Random Forest), two types of molecular fingerprints (MACCS and CDK FP) and eight screening databases with different numbers of molecules confirmed our previous findings that increases in the ratio of negative to positive training instances greatly influenced most of the investigated parameters of the ML methods in simulated virtual screening experiments. However, the performance of screening was shown to also be highly dependent on the molecular library dimension. Generally, with the increasing size of the screened database, the optimal training ratio also increased, and this ratio can be rationalized using the proposed cost-effectiveness threshold approach. To increase the performance of machine learning-based virtual screening, the training set should be constructed in a way that considers the size of the screening database.

  20. Prenatal ultrasound screening: false positive soft markers may alter maternal representations and mother-infant interaction.

    Directory of Open Access Journals (Sweden)

    Sylvie Viaux-Savelon

    Full Text Available In up to 5% of pregnancies, ultrasound screening detects a "soft marker" (SM that places the foetus at risk for a severe abnormality. In most cases, prenatal diagnostic work-up rules out a severe defect. We aimed to study the effects of false positive SM on maternal emotional status, maternal representations of the infant, and mother-infant interaction.Utilizing an extreme-case prospective case control design, we selected from a group of 244 women undergoing ultrasound, 19 pregnant women whose foetus had a positive SM screening and a reassuring diagnostic work up, and 19 controls without SM matched for age and education. In the third trimester of pregnancy, within one week after delivery, and 2 months postpartum, we assessed anxiety, depression, and maternal representations. Mother-infant interactions were videotaped during feeding within one week after delivery and again at 2 months postpartum and coded blindly using the Coding Interactive Behavior (CIB scales. Anxiety and depression scores were significantly higher at all assessment points in the SM group. Maternal representations were also different between SM and control groups at all study time. Perturbations to early mother-infant interactions were observed in the SM group. These dyads showed greater dysregulation, lower maternal sensitivity, higher maternal intrusive behaviour and higher infant avoidance. Multivariate analysis showed that maternal representation and depression at third trimester predicted mother-infant interaction.False positive ultrasound screenings for SM are not benign and negatively affect the developing maternal-infant attachment. Medical efforts should be directed to minimize as much as possible such false diagnoses, and to limit their psychological adverse consequences.

  1. 'False-positive' and 'false-negative' test results in clinical urine drug testing.

    Science.gov (United States)

    Reisfield, Gary M; Goldberger, Bruce A; Bertholf, Roger L

    2009-08-01

    The terms 'false-positive' and 'false-negative' are widely used in discussions of urine drug test (UDT) results. These terms are inadequate because they are used in different ways by physicians and laboratory professionals and they are too narrow to encompass the larger universe of potentially misleading, inappropriate and unexpected drug test results. This larger universe, while not solely comprised of technically 'true' or 'false' positive or negative test results, presents comparable interpretive challenges with corresponding clinical implications. In this review, we propose the terms 'potentially inappropriate' positive or negative test results in reference to UDT results that are ambiguous or unexpected and subject to misinterpretation. Causes of potentially inappropriate positive UDT results include in vivo metabolic conversions of a drug, exposure to nonillicit sources of a drug and laboratory error. Causes of potentially inappropriate negative UDT results include limited assay specificity, absence of drug in the urine, presence of drug in the urine, but below established assay cutoff, specimen manipulation and laboratory error. Clinical UDT interpretation is a complicated task requiring knowledge of recent prescription, over-the-counter and herbal drug administration, drug metabolism and analytical sensitivities and specificities.

  2. TOXICOLOGICAL DRUG SCREENING BY GC-MS VERSUS HPLC-DAD USING A COMMON EFFICIENT EXTRACTION PROCEDURE SCREENING TOXICOLOGIQUE DES MEDICAMENTS PAR HPLC-DAD ET GC-MS: PROTOCOLE D’EXTRACTION UNIQUE

    Directory of Open Access Journals (Sweden)

    SELOUA ELMRABEH

    2015-05-01

    Full Text Available This paper presents a common extraction method for toxicological drug screening by gas chromatography-mass spectrometry (GC-MS and high-performance liquid chromatography with diode-array detection (HPLC-DAD. Liquid-liquid extraction was performed using plasma of 104 samples at the Laboratory of Moroccan Poison Control and Pharmacovigilance Center during a period of 12 months. The results obtained by HPLC-DAD are compared with those determined with GC-MS. 76 cases (73.08 % were found positive for at least by one of these two techniques. HPLC-DAD identified 59.87 % of all positive results, and 10 molecules were identified only by HPLC-DAD. GC/MS identified 40.13 % of all positives, and 4 molecules were identified only by GC/MS. In order to evaluate the performance of this extraction method, an extraction yield was calculated for three classes of drugs. All the analyzed molecules were obtained in satisfactory yields (higher than 50 % except for carbamazepine, amitriptyline and nortriptyline. Overall, the results indicate that the extraction method is well adapted for toxicological drug screening. The use of common extraction simultaneously for the two techniques can reduce workload and costs of screening, while increasing the validity and reliability of the results.

  3. A comprehensive screening platform for aerosolizable protein formulations for intranasal and pulmonary drug delivery.

    Science.gov (United States)

    Röhm, Martina; Carle, Stefan; Maigler, Frank; Flamm, Johannes; Kramer, Viktoria; Mavoungou, Chrystelle; Schmid, Otmar; Schindowski, Katharina

    2017-10-30

    Aerosolized administration of biopharmaceuticals to the airways is a promising route for nasal and pulmonary drug delivery, but - in contrast to small molecules - little is known about the effects of aerosolization on safety and efficacy of biopharmaceuticals. Proteins are sensitive against aerosolization-associated shear stress. Tailored formulations can shield proteins and enhance permeation, but formulation development requires extensive screening approaches. Thus, the aim of this study was to develop a cell-based in vitro technology platform that includes screening of protein quality after aerosolization and transepithelial permeation. For efficient screening, a previously published aerosolization-surrogate assay was used in a design of experiments approach to screen suitable formulations for an IgG and its antigen-binding fragment (Fab) as exemplary biopharmaceuticals. Efficient, dose-controlled aerosol-cell delivery was performed with the ALICE-CLOUD system containing RPMI 2650 epithelial cells at the air-liquid interface. We could demonstrate that our technology platform allows for rapid and efficient screening of formulations consisting of different excipients (here: arginine, cyclodextrin, polysorbate, sorbitol, and trehalose) to minimize aerosolization-induced protein aggregation and maximize permeation through an in vitro epithelial cell barrier. Formulations reduced aggregation of native Fab and IgG relative to vehicle up to 50% and enhanced transepithelial permeation rate up to 2.8-fold. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

  4. A multilayer microdevice for cell-based high-throughput drug screening

    International Nuclear Information System (INIS)

    Liu, Chong; Wang, Lei; Li, Jingmin; Ding, Xiping; Chunyu, Li; Xu, Zheng; Wang, Qi

    2012-01-01

    A multilayer polydimethylsiloxane microdevice for cell-based high-throughput drug screening is described in this paper. This established microdevice was based on a modularization method and it integrated a drug/medium concentration gradient generator (CGG), pneumatic microvalves and a cell culture microchamber array. The CGG was able to generate five steps of linear concentrations with the same outlet flow rate. The medium/drug flowed through CGG and then into the pear-shaped cell culture microchambers vertically. This vertical perfusion mode was used to reduce the impact of the shear stress on the physiology of cells induced by the fluid flow in the microchambers. Pear-shaped microchambers with two arrays of miropillars at each outlet were adopted in this microdevice, which were beneficial to cell distribution. The chemotherapeutics Cisplatin (DDP)-induced Cisplatin-resistant cell line A549/DDP apoptotic experiments were performed well on this platform. The results showed that this novel microdevice could not only provide well-defined and stable conditions for cell culture, but was also useful for cell-based high-throughput drug screening with less reagents and time consumption. (paper)

  5. Toxicophore exploration as a screening technology for drug design and discovery: techniques, scope and limitations.

    Science.gov (United States)

    Singh, Pankaj Kumar; Negi, Arvind; Gupta, Pawan Kumar; Chauhan, Monika; Kumar, Raj

    2016-08-01

    Toxicity is a common drawback of newly designed chemotherapeutic agents. With the exception of pharmacophore-induced toxicity (lack of selectivity at higher concentrations of a drug), the toxicity due to chemotherapeutic agents is based on the toxicophore moiety present in the drug. To date, methodologies implemented to determine toxicophores may be broadly classified into biological, bioanalytical and computational approaches. The biological approach involves analysis of bioactivated metabolites, whereas the computational approach involves a QSAR-based method, mapping techniques, an inverse docking technique and a few toxicophore identification/estimation tools. Being one of the major steps in drug discovery process, toxicophore identification has proven to be an essential screening step in drug design and development. The paper is first of its kind, attempting to cover and compare different methodologies employed in predicting and determining toxicophores with an emphasis on their scope and limitations. Such information may prove vital in the appropriate selection of methodology and can be used as screening technology by researchers to discover the toxicophoric potentials of their designed and synthesized moieties. Additionally, it can be utilized in the manipulation of molecules containing toxicophores in such a manner that their toxicities might be eliminated or removed.

  6. Validation of a modified fluorimetric assay for the screening of trichomonacidal drugs

    Directory of Open Access Journals (Sweden)

    Alexandra Ibáñez Escribano

    2012-08-01

    Full Text Available A fluorimetric microassay that uses a redox dye to determine the viability of the flagellate Trichomonas vaginalis has been optimised to provide a more sensitive method to evaluate potential trichomonacidal compounds. Resazurin has been used in recent years to test drugs against different parasites, including trichomonadid protozoa; however, the reproducibility of these resazurin-based methods in our laboratory has been limited because the flagellate culture medium spontaneously reduces the resazurin. The objective of this work was to refine the fluorimetric microassay method previously developed by other research groups to reduce the fluorescence background generated by the media and increase the sensitivity of the screening assay. The experimental conditions, time of incubation, resazurin concentration and media used in the microtitre plates were adjusted. Different drug sensitivity studies against T. vaginalis were developed using the 5-nitroimidazole reference drugs, new 5-nitroindazolinones and 5-nitroindazole synthetic derivatives. Haemocytometer count results were compared with the resazurin assay using a 10% solution of 3 mM resazurin dissolved in phosphate buffered saline with glucose (1 mg/mL. The fluorimetric assay and the haemocytometer counts resulted in similar percentages of trichomonacidal activity in all the experiments, demonstrating that the fluorimetric microtitre assay has the necessary accuracy for high-throughput screening of new drugs against T. vaginalis.

  7. Screens

    OpenAIRE

    2016-01-01

    This Sixth volume in the series The Key Debates. Mutations and Appropriations in European Film Studies investigates the question of screens in the context both of the dematerialization due to digitalization and the multiplication of media screens. Scholars offer various infomations and theories of topics such as the archeology of screen, film and media theories, contemporary art, pragmatics of new ways of screening (from home video to street screening).

  8. Early Pancreatic Ductal Adenocarcinoma Survival Is Dependent on Size: Positive Implications for Future Targeted Screening.

    Science.gov (United States)

    Hur, Chin; Tramontano, Angela C; Dowling, Emily C; Brooks, Gabriel A; Jeon, Alvin; Brugge, William R; Gazelle, G Scott; Kong, Chung Yin; Pandharipande, Pari V

    2016-08-01

    Pancreatic ductal adenocarcinoma (PDAC) has not experienced a meaningful mortality improvement for the past few decades. Successful screening is difficult to accomplish because most PDACs present late in their natural history, and current interventions have not provided significant benefit. Our goal was to identify determinants of survival for early PDAC to help inform future screening strategies. Early PDACs from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program database (2000-2010) were analyzed. We stratified by size and included carcinomas in situ (Tis). Overall cancer-specific survival was calculated. A Cox proportional hazards model was developed and the significance of key covariates for survival prediction was evaluated. A Kaplan-Meier plot demonstrated significant differences in survival by size at diagnosis; these survival benefits persisted after adjustment for key covariates in the Cox proportional hazards analysis. In addition, relatively weaker predictors of worse survival included older age, male sex, black race, nodal involvement, tumor location within the head of the pancreas, and no surgery or radiotherapy. For early PDAC, we found tumor size to be the strongest predictor of survival, even after adjustment for other patient characteristics. Our findings suggest that early PDAC detection can have clinical benefit, which has positive implications for future screening strategies.

  9. Towards novel therapeutics for HIV through fragment-based screening and drug design.

    Science.gov (United States)

    Tiefendbrunn, Theresa; Stout, C David

    2014-01-01

    Fragment-based drug discovery has been applied with varying levels of success to a number of proteins involved in the HIV (Human Immunodeficiency Virus) life cycle. Fragment-based approaches have led to the discovery of novel binding sites within protease, reverse transcriptase, integrase, and gp41. Novel compounds that bind to known pockets within CCR5 have also been identified via fragment screening, and a fragment-based approach to target the TAR-Tat interaction was explored. In the context of HIV-1 reverse transcriptase (RT), fragment-based approaches have yielded fragment hits with mid-μM activity in an in vitro activity assay, as well as fragment hits that are active against drug-resistant variants of RT. Fragment-based drug discovery is a powerful method to elucidate novel binding sites within proteins, and the method has had significant success in the context of HIV proteins.

  10. Comparison of the Substance Use Brief Screen (SUBS) to the AUDIT-C and ASSIST for detecting unhealthy alcohol and drug use in a population of hospitalized smokers.

    Science.gov (United States)

    Han, Benjamin H; Sherman, Scott E; Link, Alissa R; Wang, Binhuan; McNeely, Jennifer

    2017-08-01

    Hospitalized patients have high rates of unhealthy substance use, which has important impacts on health both during and after hospitalization, but is infrequently identified in the absence of screening. The Substance Use Brief Screen (SUBS) was developed as a brief, self-administered instrument to identify use of tobacco, alcohol, illicit drugs, and non-medical use of prescription drugs, and was previously validated in primary care patients. This study assessed the diagnostic accuracy of the SUBS in comparison to longer screening instruments to identify unhealthy and high-risk alcohol and drug use in hospitalized current smokers. Participants were 439 patients, aged 18 and older, who were admitted to either two urban safety-net hospitals in New York City and enrolled in a smoking cessation trial. We measured the performance of the SUBS for identifying illicit drug and non-medical use of prescription drugs in comparison to a modified Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) and its performance for identifying excessive alcohol use in comparison to the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C). At the standard cutoff (response other than 'never' indicates a positive screen), the SUBS had a sensitivity of 98% (95% CI 95-100%) and specificity of 61% (95% CI 55-67%) for unhealthy alcohol use, a sensitivity of 85% (95% CI 80-90%) and specificity of 75% (95% CI 78-87%) for illicit drug use, and a sensitivity of 73% (95% CI 61-83%) and specificity of 83% (95% CI 78-87%) for prescription drug non-medical use. For identifying high-risk use, a higher cutoff (response of '3 or more days' of use indicates a positive screen), the SUBS retained high sensitivity (77-90%), and specificity was 62-88%. The SUBS can be considered as an alternative to longer screening instruments, which may fit more easily into busy inpatient settings. Further study is needed to evaluate its validity using gold standard measures in hospitalized

  11. [Phenotype-based primary screening for drugs promoting neuronal subtype differentiation in embryonic stem cells with light microscope].

    Science.gov (United States)

    Gao, Yi-ning; Wang, Dan-ying; Pan, Zong-fu; Mei, Yu-qin; Wang, Zhi-qiang; Zhu, Dan-yan; Lou, Yi-jia

    2012-07-01

    To set up a platform for phenotype-based primary screening of drug candidates promoting neuronal subtype differentiation in embryonic stem cells (ES) with light microscope. Hanging drop culture 4-/4+ method was employed to harvest the cells around embryoid body (EB) at differentiation endpoint. Morphological evaluation for neuron-like cells was performed with light microscope. Axons for more than three times of the length of the cell body were considered as neuron-like cells. The compound(s) that promote neuron-like cells was further evaluated. Icariin (ICA, 10(-6)mol/L) and Isobavachin (IBA, 10(-7)mol/L) were selected to screen the differentiation-promoting activity on ES cells. Immunofluorescence staining with specific antibodies (ChAT, GABA) was used to evaluate the neuron subtypes. The cells treated with IBA showed neuron-like phenotype, but the cells treated with ICA did not exhibit the morphological changes. ES cells treated with IBA was further confirmed to be cholinergic and GABAergic neurons. Phenotypic screening with light microscope for molecules promoting neuronal differentiation is an effective method with advantages of less labor and material consuming and time saving, and false-positive results derived from immunofluorescence can be avoided. The method confirms that IBA is able to facilitate ES cells differentiating into neuronal cells, including cholinergic neurons and GABAergic neurons.

  12. Machine Learning-based Virtual Screening and Its Applications to Alzheimer's Drug Discovery: A Review.

    Science.gov (United States)

    Carpenter, Kristy A; Huang, Xudong

    2018-06-07

    Virtual Screening (VS) has emerged as an important tool in the drug development process, as it conducts efficient in silico searches over millions of compounds, ultimately increasing yields of potential drug leads. As a subset of Artificial Intelligence (AI), Machine Learning (ML) is a powerful way of conducting VS for drug leads. ML for VS generally involves assembling a filtered training set of compounds, comprised of known actives and inactives. After training the model, it is validated and, if sufficiently accurate, used on previously unseen databases to screen for novel compounds with desired drug target binding activity. The study aims to review ML-based methods used for VS and applications to Alzheimer's disease (AD) drug discovery. To update the current knowledge on ML for VS, we review thorough backgrounds, explanations, and VS applications of the following ML techniques: Naïve Bayes (NB), k-Nearest Neighbors (kNN), Support Vector Machines (SVM), Random Forests (RF), and Artificial Neural Networks (ANN). All techniques have found success in VS, but the future of VS is likely to lean more heavily toward the use of neural networks - and more specifically, Convolutional Neural Networks (CNN), which are a subset of ANN that utilize convolution. We additionally conceptualize a work flow for conducting ML-based VS for potential therapeutics of for AD, a complex neurodegenerative disease with no known cure and prevention. This both serves as an example of how to apply the concepts introduced earlier in the review and as a potential workflow for future implementation. Different ML techniques are powerful tools for VS, and they have advantages and disadvantages albeit. ML-based VS can be applied to AD drug development. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  13. Could chiropractors screen for adverse drug events in the community? Survey of US chiropractors

    Directory of Open Access Journals (Sweden)

    Bero Lisa

    2010-11-01

    Full Text Available Abstract Background The "Put Prevention into Practice" campaign of the US Public Health Service (USPHS was launched with the dissemination of the Clinician's Handbook of Preventive Services that recommended standards of clinical care for various prevention activities, including preventive clinical strategies to reduce the risk of adverse drug events. We explored whether nonprescribing clinicians such as chiropractors may contribute to advancing drug safety initiatives by identifying potential adverse drug events in their chiropractic patients, and by bringing suspected adverse drug events to the attention of the prescribing clinicians. Methods Mail survey of US chiropractors about their detection of potential adverse drug events in their chiropractic patients. Results Over half of responding chiropractors (62% reported having identified a suspected adverse drug event occurring in one of their chiropractic patients. The severity of suspected drug-related events detected ranged from mild to severe. Conclusions Chiropractors or other nonprescribing clinicians may be in a position to detect potential adverse drug events in the community. These detection and reporting mechanisms should be standardized and policies related to clinical case management of suspected adverse drug events occurring in their patients should be developed.

  14. High-throughput screen of drug repurposing library identifies inhibitors of Sarcocystis neurona growth

    Directory of Open Access Journals (Sweden)

    Gregory D. Bowden

    2018-04-01

    Full Text Available The apicomplexan parasite Sarcocystis neurona is the primary etiologic agent of equine protozoal myeloencephalitis (EPM, a serious neurologic disease of horses. Many horses in the U.S. are at risk of developing EPM; approximately 50% of all horses in the U.S. have been exposed to S. neurona and treatments for EPM are 60–70% effective. Advancement of treatment requires new technology to identify new drugs for EPM. To address this critical need, we developed, validated, and implemented a high-throughput screen to test 725 FDA-approved compounds from the NIH clinical collections library for anti-S. neurona activity. Our screen identified 18 compounds with confirmed inhibitory activity against S. neurona growth, including compounds active in the nM concentration range. Many identified inhibitory compounds have well-defined mechanisms of action, making them useful tools to study parasite biology in addition to being potential therapeutic agents. In comparing the activity of inhibitory compounds identified by our screen to that of other screens against other apicomplexan parasites, we found that most compounds (15/18; 83% have activity against one or more related apicomplexans. Interestingly, nearly half (44%; 8/18 of the inhibitory compounds have reported activity against dopamine receptors. We also found that dantrolene, a compound already formulated for horses with a peak plasma concentration of 37.8 ± 12.8 ng/ml after 500 mg dose, inhibits S. neurona parasites at low concentrations (0.065 μM [0.036–0.12; 95% CI] or 21.9 ng/ml [12.1–40.3; 95% CI]. These studies demonstrate the use of a new tool for discovering new chemotherapeutic agents for EPM and potentially providing new reagents to elucidate biologic pathways required for successful S. neurona infection. Keywords: Drug repurposing, High-throughput screen, Sarcocystis neurona, Equine protozoal myeloencephalitis

  15. Mammography Clinical Image Quality and the False Positive Rate in a Canadian Breast Cancer Screening Program.

    Science.gov (United States)

    Guertin, Marie-Hélène; Théberge, Isabelle; Zomahoun, Hervé Tchala Vignon; Dufresne, Michel-Pierre; Pelletier, Éric; Brisson, Jacques

    2018-05-01

    The study sought to determine if mammography quality is associated with the false positive (FP) rate in the Quebec breast cancer screening program in 2004 and 2005. Mammography quality of a random sample of screen-film mammograms was evaluated by an expert radiologist following the criteria of the Canadian Association of Radiologists. For each screening examination, scores ranging from 1 (poor quality) to 5 (excellent quality) were attributed for positioning, compression, contrast, exposure level, sharpness, and artifacts. A final overall quality score (lower or higher) was also given. Poisson regression models with robust estimation of variance and adjusted for potential confounding factors were used to assess associations of mammography quality with the FP rate. Among 1,209 women without cancer, there were 104 (8.6%) FPs. Lower overall mammography quality is associated with an increase in the FP rate (risk ratio [RR], 1.4; 95% confidence interval [CI], 1.0-2.1; P = .07) but this increase was not statistically significant. Artifacts were associated with an increase in the FP rate (RR, 2.1; 95% CI, 1.3-3.3; P = .01) whereas lower quality of exposure level was related to a reduction of the FP rate (RR, 0.4; 95% CI, 0.1-1.0; P = .01). Lower quality scores for all other quality attributes were related to a nonstatistically significant increase in the FP rate of 10%-30%. Artifacts can have a substantial effect on the FP rate. The effect of overall mammography quality on the FP rate may also be substantial and needs to be clarified. Copyright © 2017 Canadian Association of Radiologists. Published by Elsevier Inc. All rights reserved.

  16. Targeted and non-targeted drug screening in whole blood by UHPLC-TOF-MS with data-independent acquisition

    DEFF Research Database (Denmark)

    Mollerup, Christian Brinch; Dalsgaard, Petur Weihe; Mardal, Marie

    2017-01-01

    of peaks to inspect by three orders of magnitude, down to four peaks per DUID sample. The screening allowed for tentative identification of metabolites and drugs not included in the initial screening, and three drugs and thirteen metabolites were tentatively identified in the authentic DUID samples......High-resolution mass spectrometry (HRMS) is widely used for the drug screening of biological samples in clinical and forensic laboratories. With the continuous addition of new psychoactive substances (NPS), keeping such methods updated is challenging. HRMS allows for combined targeted and non......-targeted screening; first, peaks are identified by software algorithms, and identifications are based on reference standard data. Remaining unknown peaks are attempted identified with in silico and literature data. However, several thousand peaks remain where most are unidentifiable or uninteresting in drug...

  17. Virtual drug screen schema based on multiview similarity integration and ranking aggregation.

    Science.gov (United States)

    Kang, Hong; Sheng, Zhen; Zhu, Ruixin; Huang, Qi; Liu, Qi; Cao, Zhiwei

    2012-03-26

    The current drug virtual screen (VS) methods mainly include two categories. i.e., ligand/target structure-based virtual screen and that, utilizing protein-ligand interaction fingerprint information based on the large number of complex structures. Since the former one focuses on the one-side information while the later one focuses on the whole complex structure, they are thus complementary and can be boosted by each other. However, a common problem faced here is how to present a comprehensive understanding and evaluation of the various virtual screen results derived from various VS methods. Furthermore, there is still an urgent need for developing an efficient approach to fully integrate various VS methods from a comprehensive multiview perspective. In this study, our virtual screen schema based on multiview similarity integration and ranking aggregation was tested comprehensively with statistical evaluations, providing several novel and useful clues on how to perform drug VS from multiple heterogeneous data sources. (1) 18 complex structures of HIV-1 protease with ligands from the PDB were curated as a test data set and the VS was performed with five different drug representations. Ritonavir ( 1HXW ) was selected as the query in VS and the weighted ranks of the query results were aggregated from multiple views through four similarity integration approaches. (2) Further, one of the ranking aggregation methods was used to integrate the similarity ranks calculated by gene ontology (GO) fingerprint and structural fingerprint on the data set from connectivity map, and two typical HDAC and HSP90 inhibitors were chosen as the queries. The results show that rank aggregation can enhance the result of similarity searching in VS when two or more descriptions are involved and provide a more reasonable similarity rank result. Our study shows that integrated VS based on multiple data fusion can achieve a remarkable better performance compared to that from individual ones and

  18. Improving computer-aided detection assistance in breast cancer screening by removal of obviously false-positive findings

    NARCIS (Netherlands)

    Mordang, Jan-Jurre; Gubern-Merida, Albert; Bria, Alessandro; Tortorella, Francesco; den Heeten, Gerard; Karssemeijer, Nico

    2017-01-01

    Purpose: Computer-aided detection (CADe) systems for mammography screening still mark many false positives. This can cause radiologists to lose confidence in CADe, especially when many false positives are obviously not suspicious to them. In this study, we focus on obvious false positives generated

  19. Improving computer-aided detection assistance in breast cancer screening by removal of obviously false-positive findings

    NARCIS (Netherlands)

    Mordang, J.J.; Gubern Merida, A.; Bria, A.; Tortorella, F.; Heeten, G.; Karssemeijer, N.

    2017-01-01

    PURPOSE: Computer-aided detection (CADe) systems for mammography screening still mark many false positives. This can cause radiologists to lose confidence in CADe, especially when many false positives are obviously not suspicious to them. In this study, we focus on obvious false positives generated

  20. Feasibility evaluation of 3 automated cellular drug screening assays on a robotic workstation.

    Science.gov (United States)

    Soikkeli, Anne; Sempio, Cristina; Kaukonen, Ann Marie; Urtti, Arto; Hirvonen, Jouni; Yliperttula, Marjo

    2010-01-01

    This study presents the implementation and optimization of 3 cell-based assays on a TECAN Genesis workstation-the Caspase-Glo 3/7 and sulforhodamine B (SRB) screening assays and the mechanistic Caco-2 permeability protocol-and evaluates their feasibility for automation. During implementation, the dispensing speed to add drug solutions and fixative trichloroacetic acid and the aspiration speed to remove the supernatant immediately after fixation were optimized. Decontamination steps for cleaning the tips and pipetting tubing were also added. The automated Caspase-Glo 3/7 screen was successfully optimized with Caco-2 cells (Z' 0.7, signal-to-base ratio [S/B] 1.7) but not with DU-145 cells. In contrast, the automated SRB screen was successfully optimized with the DU-145 cells (Z' 0.8, S/B 2.4) but not with the Caco-2 cells (Z' -0.8, S/B 1.4). The automated bidirectional Caco-2 permeability experiments separated successfully low- and high-permeability compounds (Z' 0.8, S/B 84.2) and passive drug permeation from efflux-mediated transport (Z' 0.5, S/B 8.6). Of the assays, the homogeneous Caspase-Glo 3/7 assay benefits the most from automation, but also the heterogeneous SRB assay and Caco-2 permeability experiments gain advantages from automation.

  1. Virtual target screening to rapidly identify potential protein targets of natural products in drug discovery

    Directory of Open Access Journals (Sweden)

    Yuri Pevzner

    2014-05-01

    Full Text Available Inherent biological viability and diversity of natural products make them a potentially rich source for new therapeutics. However, identification of bioactive compounds with desired therapeutic effects and identification of their protein targets is a laborious, expensive process. Extracts from organism samples may show desired activity in phenotypic assays but specific bioactive compounds must be isolated through further separation methods and protein targets must be identified by more specific phenotypic and in vitro experimental assays. Still, questions remain as to whether all relevant protein targets for a compound have been identified. The desire is to understand breadth of purposing for the compound to maximize its use and intellectual property, and to avoid further development of compounds with insurmountable adverse effects. Previously we developed a Virtual Target Screening system that computationally screens one or more compounds against a collection of virtual protein structures. By scoring each compound-protein interaction, we can compare against averaged scores of synthetic drug-like compounds to determine if a particular protein would be a potential target of a compound of interest. Here we provide examples of natural products screened through our system as we assess advantages and shortcomings of our current system in regards to natural product drug discovery.

  2. Virtual target screening to rapidly identify potential protein targets of natural products in drug discovery

    Directory of Open Access Journals (Sweden)

    Yuri Pevzner

    2015-08-01

    Full Text Available Inherent biological viability and diversity of natural products make them a potentially rich source for new therapeutics. However, identification of bioactive compounds with desired therapeutic effects and identification of their protein targets is a laborious, expensive process. Extracts from organism samples may show desired activity in phenotypic assays but specific bioactive compounds must be isolated through further separation methods and protein targets must be identified by more specific phenotypic and in vitro experimental assays. Still, questions remain as to whether all relevant protein targets for a compound have been identified. The desire is to understand breadth of purposing for the compound to maximize its use and intellectual property, and to avoid further development of compounds with insurmountable adverse effects. Previously we developed a Virtual Target Screening system that computationally screens one or more compounds against a collection of virtual protein structures. By scoring each compound-protein interaction, we can compare against averaged scores of synthetic drug-like compounds to determine if a particular protein would be a potential target of a compound of interest. Here we provide examples of natural products screened through our system as we assess advantages and shortcomings of our current system in regards to natural product drug discovery.

  3. Measuring psychosocial consequences of false-positive screening results - breast cancer as an example

    DEFF Research Database (Denmark)

    Brodersen, John

    Screening, mammografiscreening, psykosociale konsekvenser, falsk positiv screeningssvar, psykometri, differentiel item funktion......Screening, mammografiscreening, psykosociale konsekvenser, falsk positiv screeningssvar, psykometri, differentiel item funktion...

  4. Curcumin Based Drug Screening for Inhibitors of NF kappa B in a Cell Model of Prostate Cancer Progression

    Science.gov (United States)

    2008-02-01

    identify new and structurally diverse chemical analogs of the polyphenolic phytochemical Curcumin from the Indian herb Curcuma longa (family...AD_________________ Award Number: W81XWH-07-1-0081 TITLE: Curcumin Based Drug Screening for... Curcumin Based Drug Screening for Inhibitors of NF kappa B in a Cell Model of Prostate Cancer Progression 5b. GRANT NUMBER W81XWH-07-1-0081 5c

  5. Estimated glomerular filtration rate, chronic kidney disease and antiretroviral drug use in HIV-positive patients

    NARCIS (Netherlands)

    Mocroft, Amanda; Kirk, Ole; Reiss, Peter; de Wit, Stephane; Sedlacek, Dalibor; Beniowski, Marek; Gatell, Jose; Phillips, Andrew N.; Ledergerber, Bruno; Lundgren, Jens D.; Losso, M.; Elias, C.; Vetter, N.; Zangerle, R.; Karpov, I.; Vassilenko, A.; Mitsura, V. M.; Suetnov, O.; Clumeck, N.; Poll, B.; Colebunders, R.; Vandekerckhove, L.; Hadziosmanovic, V.; Kostov, K.; Begovac, J.; Machala, L.; Rozsypal, H.; Sedlacek, D.; Nielsen, J.; Kronborg, G.; Benfield, T.; Larsen, M.; Gerstoft, J.; Katzenstein, T.; Hansen, A.-B. E.; Skinhøj, P.; Pedersen, C.; Oestergaard, L.; Zilmer, K.; Smidt, Jelena; Ristola, M.; Katlama, C.; Viard, J.-P.; Girard, P.-M.; Livrozet, J. M.; Vanhems, P.; Pradier, C.; Dabis, F.; Neau, D.; Rockstroh, J.

    2010-01-01

    Objectives: Chronic kidney disease (CKD) in HIV-positive persons might be caused by both HIV and traditional or non-HIV-related factors. Our objective was to investigate long-term exposure to specific antiretroviral drugs and CKD. Design: A cohort study including 6843 HIV-positive persons with at

  6. Confidence from uncertainty - A multi-target drug screening method from robust control theory

    Directory of Open Access Journals (Sweden)

    Petzold Linda R

    2010-11-01

    Full Text Available Abstract Background Robustness is a recognized feature of biological systems that evolved as a defence to environmental variability. Complex diseases such as diabetes, cancer, bacterial and viral infections, exploit the same mechanisms that allow for robust behaviour in healthy conditions to ensure their own continuance. Single drug therapies, while generally potent regulators of their specific protein/gene targets, often fail to counter the robustness of the disease in question. Multi-drug therapies offer a powerful means to restore disrupted biological networks, by targeting the subsystem of interest while preventing the diseased network from reconciling through available, redundant mechanisms. Modelling techniques are needed to manage the high number of combinatorial possibilities arising in multi-drug therapeutic design, and identify synergistic targets that are robust to system uncertainty. Results We present the application of a method from robust control theory, Structured Singular Value or μ- analysis, to identify highly effective multi-drug therapies by using robustness in the face of uncertainty as a new means of target discrimination. We illustrate the method by means of a case study of a negative feedback network motif subject to parametric uncertainty. Conclusions The paper contributes to the development of effective methods for drug screening in the context of network modelling affected by parametric uncertainty. The results have wide applicability for the analysis of different sources of uncertainty like noise experienced in the data, neglected dynamics, or intrinsic biological variability.

  7. Trauma activation patients: evidence for routine alcohol and illicit drug screening.

    Directory of Open Access Journals (Sweden)

    C Michael Dunham

    Full Text Available BACKGROUND: Statistics from the National Trauma Data Bank imply that discretionary blood alcohol and urine drug testing is common. However, there is little evidence to determine which patients are appropriate for routine testing, based on information available at trauma center arrival. In 2002, Langdorf reported alcohol and illicit drug rates in Trauma Activation Patients. METHODOLOGY/PRINCIPAL FINDINGS: This is a retrospective investigation of alcohol and illicit drug rates in consecutive St. Elizabeth Health Center (SEHC trauma patients. SEHC Trauma Activation Patients are compared with the Langdorf Activation Patients and with the SEHC Trauma Nonactivation Patients. Minimum Rates are positive tests divided by total patients (tested and not tested. Activation patients: The minimum alcohol rates were: SEHC 23.1%, Langdorf 28.2%, combined 24.8%. The minimum illicit drug rates were: SEHC 15.7%, Langdorf 23.5, combined 18.3%. The minimum alcohol and/or illicit drug rates were: SEHC 33.4%, Langdorf 41.8%, combined 36.2%. Nonactivation patients: The SEHC minimum alcohol rate was 4.7% and the minimum illicit drug rate was 6.0%. CONCLUSIONS: Alcohol and illicit drug rates were significantly greater for Trauma Activation Patients, when compared to Nonactivation Patients. At minimum, Trauma Activation Patients are likely to have a 1-in-3 positive test for alcohol and/or an illicit drug. This substantial rate suggests that Trauma Activation Patients, a readily discernible group at trauma center arrival, are appropriate for routine alcohol and illicit drug testing. However, discretionary testing is more reasonable for Trauma Nonactivation Patients, because minimum rates are low.

  8. Screening and brief intervention for alcohol and other drug use in primary care: associations between organizational climate and practice.

    Science.gov (United States)

    Cruvinel, Erica; Richter, Kimber P; Bastos, Ronaldo Rocha; Ronzani, Telmo Mota

    2013-02-11

    Numerous studies have demonstrated that positive organizational climates contribute to better work performance. Screening and brief intervention (SBI) for alcohol, tobacco, and other drug use has the potential to reach a broad population of hazardous drug users but has not yet been widely adopted in Brazil's health care system. We surveyed 149 primary health care professionals in 30 clinics in Brazil who were trained to conduct SBI among their patients. We prospectively measured how often they delivered SBI to evaluate the association between organizational climate and adoption/performance of SBI. Organizational climate was measured by the 2009 Organizational Climate Scale for Health Organizations, a scale validated in Brazil that assesses leadership, professional development, team spirit, relationship with the community, safety, strategy, and remuneration. Performance of SBI was measured prospectively by weekly assessments during the three months following training. We also assessed self-reported SBI and self-efficacy for performing SBI at three months post-training. We used inferential statistics to depict and test for the significance of associations. Teams with better organizational climates implemented SBI more frequently. Organizational climate factors most closely associated with SBI implementation included professional development and relationship with the community. The dimensions of leadership and remuneration were also significantly associated with SBI. Organizational climate may influence implementation of SBI and ultimately may affect the ability of organizations to identify and address drug use.

  9. Factors associated with a clinician's offer of screening HIV-positive patients for sexually transmitted infections, including syphilis.

    Science.gov (United States)

    Heller, R; Fernando, I; MacDougall, M

    2011-06-01

    This retrospective study assessed whether Quality Improvement Scotland national standards for the sexual health care offered to HIV-positive individuals are being met by the Edinburgh genitourinary (GU) medicine clinic; specifically whether HIV-positive patients are offered: (a) sexually transmitted infection (STI) screening annually and (b) syphilis testing six-monthly. The study also reviewed what factors were associated with a clinician's offer of STI screening and syphilis testing. Of the 509 patients seen within the study period, case notes documented that 64% were offered STI screens, and 69% were offered syphilis testing, results consistent with audits of services elsewhere. Sexual orientation (P offer of STI screening, while gender (P offer of syphilis testing. Our results suggest that one explanation for clinicians failing to offer STI screens and syphilis serology testing is their (implicit) risk assessment that STI testing is not required in individual patients.

  10. Acid-fast bacilli culture positivity and drug resistance in abdominal tuberculosis in Mumbai, India.

    Science.gov (United States)

    Samant, Hrishikesh; Desai, Devendra; Abraham, Philip; Joshi, Anand; Gupta, Tarun; Rodrigues, Camilla; George, Siji

    2014-09-01

    Culture positivity for Mycobacterium tuberculosis complex (MTB) in abdominal tuberculosis (TB) using Lowenstein Jensen medium and Bactec system varies from 25 % to 36 %. Data on the prevalence of drug resistance in primary abdominal TB is scant. Our aim was to study the acid-fast bacilli (AFB) culture positivity rate in primary abdominal TB using Bactec Mycobacterial Growth Indicator Tubes (MGIT) system and the prevalence of drug resistance in these patients. Records of patients with abdominal TB (diagnosed on clinical features, endoscopy, histology, microbiology) seen during the period 2008 to 2013 were retrieved from the Gastroenterology and Microbiology departments. Patients with extra-abdominal TB (five pulmonary, two nodal), adnexal (one), and HIV (one) were excluded from analysis. Of 61 patients, 31 (50.8 %) had a positive AFB culture. In the 30 culture-negative patients, histology showed non-caseating granulomas in 25 patients. Drug sensitivity pattern was analyzed in 18 patients; resistance was detected in eight (14.3 % of all patients and 44.4 % of patients in whom drug sensitivity was done) including three (5.4 % of all subjects and 16.6 % in whom drug sensitivity was available) who were multidrug-resistant. The rate of AFB culture positivity in primary abdominal TB was 50.8 % using Bactec MGIT. Likelihood of drug resistance was seen in 14.3 %, of whom 5.4 % were multidrug-resistant.

  11. In vitro microfluidic models of tumor microenvironment to screen transport of drugs and nanoparticles.

    Science.gov (United States)

    Ozcelikkale, Altug; Moon, Hye-Ran; Linnes, Michael; Han, Bumsoo

    2017-09-01

    Advances in nanotechnology have enabled numerous types of nanoparticles (NPs) to improve drug delivery to tumors. While many NP systems have been proposed, their clinical translation has been less than anticipated primarily due to failure of current preclinical evaluation techniques to adequately model the complex interactions between the NP and physiological barriers of tumor microenvironment. This review focuses on microfluidic tumor models for characterization of delivery efficacy and toxicity of cancer nanomedicine. Microfluidics offer significant advantages over traditional macroscale cell cultures by enabling recapitulation of tumor microenvironment through precise control of physiological cues such as hydrostatic pressure, shear stress, oxygen, and nutrient gradients. Microfluidic systems have recently started to be adapted for screening of drugs and NPs under physiologically relevant settings. So far the two primary application areas of microfluidics in this area have been high-throughput screening using traditional culture settings such as single cells or multicellular tumor spheroids, and mimicry of tumor microenvironment for study of cancer-related cell-cell and cell-matrix interactions. These microfluidic technologies are also useful in modeling specific steps in NP delivery to tumor and characterize NP transport properties and outcomes by systematic variation of physiological conditions. Ultimately, it will be possible to design drug-screening platforms uniquely tailored for individual patient physiology using microfluidics. These in vitro models can contribute to development of precision medicine by enabling rapid and patient-specific evaluation of cancer nanomedicine. WIREs Nanomed Nanobiotechnol 2017, 9:e1460. doi: 10.1002/wnan.1460 For further resources related to this article, please visit the WIREs website. © 2017 Wiley Periodicals, Inc.

  12. False-positive ethyl glucuronide immunoassay screening caused by a propyl alcohol-based hand sanitizer.

    Science.gov (United States)

    Arndt, Torsten; Grüner, Joachim; Schröfel, Stefanie; Stemmerich, Karsten

    2012-11-30

    Urine ethyl glucuronide (EtG) is considered as a specific marker of recent ethanol consumption. We describe false-positive DRI(®) EIA EtG enzyme immunoassay results caused by propyl glucuronides in urine after using a propanol-based hand sanitizer. EtG screening was done with the DRI(®) EIA EtG assay (Microgenics), using a cut-off of 0.5 mg/L as recommended by the manufacturer and of 0.1 mg/L as demanded by the German Regulations for Reissuing Drivers Licenses. Confirmatory EtG analysis was done with the ClinMass(®) EtG LC-MS/MS testkit (Recipe), extended by the mass transitions 235.1→75.1, 235.1→85.1, and 235.1→113.1 for the detection of the 1- and 2-propyl glucuronides. Self-experiments were done by staff members of our lab (n=7), using 3 mL Sterillium(®) Classic Pure (30 g/100 g 1-propanol and 45 g/100 g 2-propanol) for hand sanitation every quarter of an hour for 8 h according to DIN EN 1500:2011-05 with and without an exhauster and by passive inhalation of the sanitizer vapor. Spot urine samples were taken immediately before and up to 24 h after the first sanitizer use. False-positive immunoassay results of up to 4 mg/L or 2.3 mg/g creatinine were obtained after normal use of the sanitizer and also after passive inhalation of the sanitizer vapor (up to 0.89 mg/L or 0.61 mg/g). Immunoassay results were positive even after 4-fold use of the sanitizer (up to 0.14 mg/L or 0.38 mg/g) and up to 6 h after the last sanitizer contact (maximum 0.63 mg/L and 0.33 mg/g for sanitizer users and 0.25 mg/g after passive inhalation). Spiking of EtG-free urine with 1-propyl glucuronide (Athena Environmental Sciences) between 0.05 and 10 mg/L clearly demonstrated a cross reaction of the immunoassay of approx. 10% as compared to EtG. LC-MS/MS of urines with a positive immunoassay EtG result did not show EtG signals, but distinct signals of 1-propyl glucuronide (n-propyl glucuronide) and 2-propyl glucuronide (iso-propyl glucuronide). An exhauster effectively prevented

  13. False-positive findings in mammography screening induces short-term distress - breast cancer-specific concern prevails longer

    DEFF Research Database (Denmark)

    Aro, A R; Pilvikki Absetz, S; van Elderen, T M

    2000-01-01

    -ups at 2 and 12 months postscreening. At 2 months, there was a moderate multivariate effect of group on distress; and intrusive thinking and worry about breast cancer, in particular, were most frequent amongst the false positives. Intrusive thinking still prevailed at 12 months, in addition to a higher...... findings (n=1407), false-positive findings (n=492) and referents from outside the screening programme (n=1718, age 48-49 years). Distress was measured as illness worry, anxiety, depression, cancer beliefs and early detection behaviour. Measurements were one month before screening invitation with follow...... perceived breast cancer risk and susceptibility. Distress related to screening and false-positive findings seems to be moderate, but prevailing cancer-specific concerns call for improvements in screening programmes....

  14. Screening of a Drug Library Identifies Inhibitors of Cell Intoxication by CNF1.

    Science.gov (United States)

    Mahtal, Nassim; Brewee, Clémence; Pichard, Sylvain; Visvikis, Orane; Cintrat, Jean-Christophe; Barbier, Julien; Lemichez, Emmanuel; Gillet, Daniel

    2018-04-06

    Cytotoxic necrotizing factor 1 (CNF1) is a toxin produced by pathogenic strains of Escherichia coli responsible for extra-intestinal infections. CNF1 deamidates Rac1, thereby triggering its permanent activation and worsening inflammatory reactions. Activated Rac1 is prone to proteasomal degradation. There is no targeted therapy against CNF1, despite its clinical relevance. In this work we developed a fluorescent cell-based immunoassay to screen for inhibitors of CNF1-induced Rac1 degradation among 1120 mostly approved drugs. Eleven compounds were found to prevent CNF1-induced Rac1 degradation, and five also showed a protective effect against CNF1-induced multinucleation. Finally, lasalocid, monensin, bepridil, and amodiaquine protected cells from both diphtheria toxin and CNF1 challenges. These data highlight the potential for drug repurposing to fight several bacterial infections and Rac1-based diseases. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Faculty buy-in to teach alcohol and drug use screening.

    Science.gov (United States)

    Puskar, Kathy; Mitchell, Ann M; Kane, Irene; Hagle, Holly; Talcott, Kimberly S

    2014-09-01

    Educating nursing faculty about the use of an evidence-based practice to screen and intervene earlier along the continuum of alcohol and other drug use, misuse, and dependence is essential in today's health care arena. Misuse of alcohol and other drugs is a significant problem for both individual health and societal economic welfare. The purpose of this article is to describe nursing faculty buy-in for the implementation of an evidence-based addiction training program at a university-based school of nursing. Derived from an academic-community partnership, the training program results suggest implications for continuing education and curriculum innovation in schools of nursing and clinical practice. The training content presented can be used in continuing education for nursing faculty across all types of nursing school programs and professional nursing staff employed in multiple settings. The training program was funded by the Health Resources and Services Administration.

  16. The Relations Between False Positive and Negative Screens and Smoking Cessation and Relapse in the National Lung Screening Trial: Implications for Public Health.

    Science.gov (United States)

    Clark, Melissa A; Gorelick, Jeremy J; Sicks, JoRean D; Park, Elyse R; Graham, Amanda L; Abrams, David B; Gareen, Ilana F

    2016-01-01

    Lung screening is an opportunity for smoking cessation and relapse prevention, but smoking behaviors may differ across screening results. Changes in smoking were evaluated among 18 840 current and former smokers aged 55-74 scheduled to receive three annual lung screenings. Participants were randomized to low-dose computed tomography or single-view chest radiography in the American College of Radiology/National Lung Screening Trial. Outcome measures included point and sustained (6-month) abstinence and motivation to quit among smokers; and relapse among smokers who quit during follow-up, recent quitters (quit < 6 months), and long-term former smokers (quit ≥ 6 months). During five years of follow-up, annual point prevalence quit rates ranged from 11.6%-13.4%; 48% of current smokers reported a quit attempt and 7% of long-term former smokers relapsed. Any false positive screening result was associated with subsequent increased point (multivariable hazard ratio HR = 1.23, 95% CI = 1.13, 1.35) and sustained (HR = 1.28, 95% CI = 1.15, 1.43) abstinence among smokers. Recent quitters with ≥1 false positive screen were less likely to relapse (HR = 0.72, 95% CI = 0.54, 0.96). Screening result was not associated with relapse among long-term former smokers or among baseline smokers who quit during follow-up. A false positive screen was associated with increased smoking cessation and less relapse among recent quitters. Consistently negative screens were not associated with greater relapse among long-term former smokers. Given the Affordable Care Act requires most health plans to cover smoking cessation and lung screening, the impact and cost-effectiveness of lung screening could be further enhanced with the addition of smoking cessation interventions. © The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  17. Changes in depression in a cohort of Danish HIV-positive individuals: time for routine screening

    DEFF Research Database (Denmark)

    Rodkjaer, Lotte; Laursen, Tinne; Christensen, Nils B

    2011-01-01

    demonstrated a decline in depression scores over time and an association between the risk of depression and low medication adherence, stress and unsafe sex. We recommend routine screening for depression to be conducted regularly to provide full evaluations and relevant psychiatric treatment.......Background: The aim of this study was to follow a cohort of HIV-positive individuals for 3 years in order to assess changes in depression, adherence, unsafe sex and emotional strains from living with HIV. Methods: Participants were assessed for depression, adherence, emotional strain and unsafe sex......) in 24 (16%) individuals. Patients at risk of moderate to major depression were more likely to be non-adherent to medications, to practice unsafe sex and to suffer from emotional strains compared with patients not at risk of depression, both at baseline (2005) and follow-up (2008). Conclusion: This study...

  18. A new in vivo screening paradigm to accelerate antimalarial drug discovery.

    Directory of Open Access Journals (Sweden)

    María Belén Jiménez-Díaz

    Full Text Available The emergence of resistance to available antimalarials requires the urgent development of new medicines. The recent disclosure of several thousand compounds active in vitro against the erythrocyte stage of Plasmodium falciparum has been a major breakthrough, though converting these hits into new medicines challenges current strategies. A new in vivo screening concept was evaluated as a strategy to increase the speed and efficiency of drug discovery projects in malaria. The new in vivo screening concept was developed based on human disease parameters, i.e. parasitemia in the peripheral blood of patients on hospital admission and parasite reduction ratio (PRR, which were allometrically down-scaled into P. berghei-infected mice. Mice with an initial parasitemia (P0 of 1.5% were treated orally for two consecutive days and parasitemia measured 24 h after the second dose. The assay was optimized for detection of compounds able to stop parasite replication (PRR = 1 or induce parasite clearance (PRR >1 with statistical power >99% using only two mice per experimental group. In the P. berghei in vivo screening assay, the PRR of a set of eleven antimalarials with different mechanisms of action correlated with human-equivalent data. Subsequently, 590 compounds from the Tres Cantos Antimalarial Set with activity in vitro against P. falciparum were tested at 50 mg/kg (orally in an assay format that allowed the evaluation of hundreds of compounds per month. The rate of compounds with detectable efficacy was 11.2% and about one third of active compounds showed in vivo efficacy comparable with the most potent antimalarials used clinically. High-throughput, high-content in vivo screening could rapidly select new compounds, dramatically speeding up the discovery of new antimalarial medicines. A global multilateral collaborative project aimed at screening the significant chemical diversity within the antimalarial in vitro hits described in the literature is a

  19. A New In Vivo Screening Paradigm to Accelerate Antimalarial Drug Discovery

    Science.gov (United States)

    Jiménez-Díaz, María Belén; Viera, Sara; Ibáñez, Javier; Mulet, Teresa; Magán-Marchal, Noemí; Garuti, Helen; Gómez, Vanessa; Cortés-Gil, Lorena; Martínez, Antonio; Ferrer, Santiago; Fraile, María Teresa; Calderón, Félix; Fernández, Esther; Shultz, Leonard D.; Leroy, Didier; Wilson, David M.; García-Bustos, José Francisco; Gamo, Francisco Javier; Angulo-Barturen, Iñigo

    2013-01-01

    The emergence of resistance to available antimalarials requires the urgent development of new medicines. The recent disclosure of several thousand compounds active in vitro against the erythrocyte stage of Plasmodium falciparum has been a major breakthrough, though converting these hits into new medicines challenges current strategies. A new in vivo screening concept was evaluated as a strategy to increase the speed and efficiency of drug discovery projects in malaria. The new in vivo screening concept was developed based on human disease parameters, i.e. parasitemia in the peripheral blood of patients on hospital admission and parasite reduction ratio (PRR), which were allometrically down-scaled into P. berghei-infected mice. Mice with an initial parasitemia (P0) of 1.5% were treated orally for two consecutive days and parasitemia measured 24 h after the second dose. The assay was optimized for detection of compounds able to stop parasite replication (PRR = 1) or induce parasite clearance (PRR >1) with statistical power >99% using only two mice per experimental group. In the P. berghei in vivo screening assay, the PRR of a set of eleven antimalarials with different mechanisms of action correlated with human-equivalent data. Subsequently, 590 compounds from the Tres Cantos Antimalarial Set with activity in vitro against P. falciparum were tested at 50 mg/kg (orally) in an assay format that allowed the evaluation of hundreds of compounds per month. The rate of compounds with detectable efficacy was 11.2% and about one third of active compounds showed in vivo efficacy comparable with the most potent antimalarials used clinically. High-throughput, high-content in vivo screening could rapidly select new compounds, dramatically speeding up the discovery of new antimalarial medicines. A global multilateral collaborative project aimed at screening the significant chemical diversity within the antimalarial in vitro hits described in the literature is a feasible task

  20. An in vivo C. elegans model system for screening EGFR-inhibiting anti-cancer drugs.

    Directory of Open Access Journals (Sweden)

    Young-Ki Bae

    Full Text Available The epidermal growth factor receptor (EGFR is a well-established target for cancer treatment. EGFR tyrosine kinase (TK inhibitors, such as gefinitib and erlotinib, have been developed as anti-cancer drugs. Although non-small cell lung carcinoma with an activating EGFR mutation, L858R, responds well to gefinitib and erlotinib, tumors with a doubly mutated EGFR, T790M-L858R, acquire resistance to these drugs. The C. elegans EGFR homolog LET-23 and its downstream signaling pathway have been studied extensively to provide insight into regulatory mechanisms conserved from C. elegans to humans. To develop an in vivo screening system for potential cancer drugs targeting specific EGFR mutants, we expressed three LET-23 chimeras in which the TK domain was replaced with either the human wild-type TK domain (LET-23::hEGFR-TK, a TK domain with the L858R mutation (LET-23::hEGFR-TK[L858R], or a TK domain with the T790M-L858R mutations (LET-23::hEGFR-TK[T790M-L858R] in C. elegans vulval cells using the let-23 promoter. The wild-type hEGFR-TK chimeric protein rescued the let-23 mutant phenotype, and the activating mutant hEGFR-TK chimeras induced a multivulva (Muv phenotype in a wild-type C. elegans background. The anti-cancer drugs gefitinib and erlotinib suppressed the Muv phenotype in LET-23::hEGFR-TK[L858R]-expressing transgenic animals, but not in LET-23::hEGFR-TK[T790M-L858R] transgenic animals. As a pilot screen, 8,960 small chemicals were tested for Muv suppression, and AG1478 (an EGFR-TK inhibitor and U0126 (a MEK inhibitor were identified as potential inhibitors of EGFR-mediated biological function. In conclusion, transgenic C. elegans expressing chimeric LET-23::hEGFR-TK proteins are a model system that can be used in mutation-specific screens for new anti-cancer drugs.

  1. Interactive "Video Doctor" counseling reduces drug and sexual risk behaviors among HIV-positive patients in diverse outpatient settings.

    Directory of Open Access Journals (Sweden)

    Paul Gilbert

    2008-04-01

    Full Text Available Reducing substance use and unprotected sex by HIV-positive persons improves individual health status while decreasing the risk of HIV transmission. Despite recommendations that health care providers screen and counsel their HIV-positive patients for ongoing behavioral risks, it is unknown how to best provide "prevention with positives" in clinical settings. Positive Choice, an interactive, patient-tailored computer program, was developed in the United States to improve clinic-based assessment and counseling for risky behaviors.We conducted a parallel groups randomized controlled trial (December 2003-September 2006 at 5 San Francisco area outpatient HIV clinics. Eligible patients (HIV-positive English-speaking adults completed an in-depth computerized risk assessment. Participants reporting substance use or sexual risks (n = 476 were randomized in stratified blocks. The intervention group received tailored risk-reduction counseling from a "Video Doctor" via laptop computer and a printed Educational Worksheet; providers received a Cueing Sheet on reported risks. Compared with control, fewer intervention participants reported continuing illicit drug use (RR 0.81, 95% CI: 0.689, 0.957, p = 0.014 at 3 months; and RR 0.65, 95% CI: 0.540, 0.785, p<0.001 at 6 months and unprotected sex (RR 0.88, 95% CI: 0.773, 0.993, p = 0.039 at 3 months; and RR 0.80, 95% CI: 0.686, 0.941, p = 0.007 at 6 months. Intervention participants reported fewer mean days of ongoing illicit drug use (-4.0 days vs. -1.3 days, p = 0.346, at 3 months; and -4.7 days vs. -0.7 days, p = 0.130, at 6 months than did controls, and had fewer casual sex partners at (-2.3 vs. -1.4, p = 0.461, at 3 months; and -2.7 vs. -0.6, p = 0.042, at 6 months.The Positive Choice intervention achieved significant cessation of illicit drug use and unprotected sex at the group-level, and modest individual-level reductions in days of ongoing drug use and number of casual sex partners compared with the

  2. Positively Charged Nanostructured Lipid Carriers and Their Effect on the Dissolution of Poorly Soluble Drugs

    Directory of Open Access Journals (Sweden)

    Kyeong-Ok Choi

    2016-05-01

    Full Text Available The objective of this study is to develop suitable formulations to improve the dissolution rate of poorly water soluble drugs. We selected lipid-based formulation as a drug carrier and modified the surface using positively charged chitosan derivative (HTCC to increase its water solubility and bioavailability. Chitosan and HTCC-coated lipid particles had higher zeta-potential values than uncoated one over the whole pH ranges and improved encapsulation efficiency. In vitro drug release showed that all NLC formulations showed higher in vitro release efficiency than drug particle at pH 7.4. Furthermore, NLC formulation prepared with chitosan or HTCC represented good sustained release property. The results indicate that chitosan and HTCC can be excellent formulating excipients of lipid-based delivery carrier for improving poorly water soluble drug delivery.

  3. Positively Charged Nanostructured Lipid Carriers and Their Effect on the Dissolution of Poorly Soluble Drugs.

    Science.gov (United States)

    Choi, Kyeong-Ok; Choe, Jaehyeog; Suh, Seokjin; Ko, Sanghoon

    2016-05-20

    The objective of this study is to develop suitable formulations to improve the dissolution rate of poorly water soluble drugs. We selected lipid-based formulation as a drug carrier and modified the surface using positively charged chitosan derivative (HTCC) to increase its water solubility and bioavailability. Chitosan and HTCC-coated lipid particles had higher zeta-potential values than uncoated one over the whole pH ranges and improved encapsulation efficiency. In vitro drug release showed that all NLC formulations showed higher in vitro release efficiency than drug particle at pH 7.4. Furthermore, NLC formulation prepared with chitosan or HTCC represented good sustained release property. The results indicate that chitosan and HTCC can be excellent formulating excipients of lipid-based delivery carrier for improving poorly water soluble drug delivery.

  4. Induced pluripotent stem cell-derived cardiomyocytes for cardiovascular disease modeling and drug screening.

    Science.gov (United States)

    Sharma, Arun; Wu, Joseph C; Wu, Sean M

    2013-12-24

    Human induced pluripotent stem cells (hiPSCs) have emerged as a novel tool for drug discovery and therapy in cardiovascular medicine. hiPSCs are functionally similar to human embryonic stem cells (hESCs) and can be derived autologously without the ethical challenges associated with hESCs. Given the limited regenerative capacity of the human heart following myocardial injury, cardiomyocytes derived from hiPSCs (hiPSC-CMs) have garnered significant attention from basic and translational scientists as a promising cell source for replacement therapy. However, ongoing issues such as cell immaturity, scale of production, inter-line variability, and cell purity will need to be resolved before human clinical trials can begin. Meanwhile, the use of hiPSCs to explore cellular mechanisms of cardiovascular diseases in vitro has proven to be extremely valuable. For example, hiPSC-CMs have been shown to recapitulate disease phenotypes from patients with monogenic cardiovascular disorders. Furthermore, patient-derived hiPSC-CMs are now providing new insights regarding drug efficacy and toxicity. This review will highlight recent advances in utilizing hiPSC-CMs for cardiac disease modeling in vitro and as a platform for drug validation. The advantages and disadvantages of using hiPSC-CMs for drug screening purposes will be explored as well.

  5. A Systematic Screen of FDA-Approved Drugs for Inhibitors of Biological Threat Agents

    Science.gov (United States)

    Madrid, Peter B.; Chopra, Sidharth; Manger, Ian D.; Gilfillan, Lynne; Keepers, Tiffany R.; Shurtleff, Amy C.; Green, Carol E.; Iyer, Lalitha V.; Dilks, Holli Hutcheson; Davey, Robert A.; Kolokoltsov, Andrey A.; Carrion, Ricardo; Patterson, Jean L.; Bavari, Sina; Panchal, Rekha G.; Warren, Travis K.; Wells, Jay B.; Moos, Walter H.; Burke, RaeLyn L.; Tanga, Mary J.

    2013-01-01

    Background The rapid development of effective medical countermeasures against potential biological threat agents is vital. Repurposing existing drugs that may have unanticipated activities as potential countermeasures is one way to meet this important goal, since currently approved drugs already have well-established safety and pharmacokinetic profiles in patients, as well as manufacturing and distribution networks. Therefore, approved drugs could rapidly be made available for a new indication in an emergency. Methodology/Principal Findings A large systematic effort to determine whether existing drugs can be used against high containment bacterial and viral pathogens is described. We assembled and screened 1012 FDA-approved drugs for off-label broad-spectrum efficacy against Bacillus anthracis; Francisella tularensis; Coxiella burnetii; and Ebola, Marburg, and Lassa fever viruses using in vitro cell culture assays. We found a variety of hits against two or more of these biological threat pathogens, which were validated in secondary assays. As expected, antibiotic compounds were highly active against bacterial agents, but we did not identify any non-antibiotic compounds with broad-spectrum antibacterial activity. Lomefloxacin and erythromycin were found to be the most potent compounds in vivo protecting mice against Bacillus anthracis challenge. While multiple virus-specific inhibitors were identified, the most noteworthy antiviral compound identified was chloroquine, which disrupted entry and replication of two or more viruses in vitro and protected mice against Ebola virus challenge in vivo. Conclusions/Significance The feasibility of repurposing existing drugs to face novel threats is demonstrated and this represents the first effort to apply this approach to high containment bacteria and viruses. PMID:23577127

  6. A systematic screen of FDA-approved drugs for inhibitors of biological threat agents.

    Directory of Open Access Journals (Sweden)

    Peter B Madrid

    Full Text Available BACKGROUND: The rapid development of effective medical countermeasures against potential biological threat agents is vital. Repurposing existing drugs that may have unanticipated activities as potential countermeasures is one way to meet this important goal, since currently approved drugs already have well-established safety and pharmacokinetic profiles in patients, as well as manufacturing and distribution networks. Therefore, approved drugs could rapidly be made available for a new indication in an emergency. METHODOLOGY/PRINCIPAL FINDINGS: A large systematic effort to determine whether existing drugs can be used against high containment bacterial and viral pathogens is described. We assembled and screened 1012 FDA-approved drugs for off-label broad-spectrum efficacy against Bacillus anthracis; Francisella tularensis; Coxiella burnetii; and Ebola, Marburg, and Lassa fever viruses using in vitro cell culture assays. We found a variety of hits against two or more of these biological threat pathogens, which were validated in secondary assays. As expected, antibiotic compounds were highly active against bacterial agents, but we did not identify any non-antibiotic compounds with broad-spectrum antibacterial activity. Lomefloxacin and erythromycin were found to be the most potent compounds in vivo protecting mice against Bacillus anthracis challenge. While multiple virus-specific inhibitors were identified, the most noteworthy antiviral compound identified was chloroquine, which disrupted entry and replication of two or more viruses in vitro and protected mice against Ebola virus challenge in vivo. CONCLUSIONS/SIGNIFICANCE: The feasibility of repurposing existing drugs to face novel threats is demonstrated and this represents the first effort to apply this approach to high containment bacteria and viruses.

  7. Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay.

    Science.gov (United States)

    Alley, M C; Scudiero, D A; Monks, A; Hursey, M L; Czerwinski, M J; Fine, D L; Abbott, B J; Mayo, J G; Shoemaker, R H; Boyd, M R

    1988-02-01

    For the past 30 years strategies for the preclinical discovery and development of potential anticancer agents have been based largely upon the testing of agents in mice bearing transplantable leukemias and solid tumors derived from a limited number of murine as well as human sources. The feasibility of implementing an alternate approach, namely combined in vitro/in vivo screening for selective cytotoxicity among panels of human tumor cell lines derived from a broad spectrum of human solid tumors is under investigation. A group of 30 cell lines acquired from a variety of sources and representing 8 lung cancer pathologies as well as 76 cell lines representing 10 other categories of human cancer (carcinomas of colon, breast, kidney, prostate, ovary, head and neck; glioma; leukemia; melanoma; and sarcoma) have exhibited acceptable growth characteristics and suitable colorimetric profiles in a single, standard culture medium. Measurements of in vitro growth in microculture wells by cell-mediated reduction of tetrazolium showed excellent correlation (0.89 less than r2 less than 0.98) with measurements of cellular protein in adherent cell line cultures as well as viable cell count in suspension cell line cultures (0.94 less than r2 less than 0.99). Since the microculture tetrazolium assay provides sensitive and reproducible indices of growth as well as drug sensitivity in individual cell lines over the course of multiple passages and several months' cultivation, it appears suitable for initial-stage in vitro drug screening.

  8. Role of Open Source Tools and Resources in Virtual Screening for Drug Discovery.

    Science.gov (United States)

    Karthikeyan, Muthukumarasamy; Vyas, Renu

    2015-01-01

    Advancement in chemoinformatics research in parallel with availability of high performance computing platform has made handling of large scale multi-dimensional scientific data for high throughput drug discovery easier. In this study we have explored publicly available molecular databases with the help of open-source based integrated in-house molecular informatics tools for virtual screening. The virtual screening literature for past decade has been extensively investigated and thoroughly analyzed to reveal interesting patterns with respect to the drug, target, scaffold and disease space. The review also focuses on the integrated chemoinformatics tools that are capable of harvesting chemical data from textual literature information and transform them into truly computable chemical structures, identification of unique fragments and scaffolds from a class of compounds, automatic generation of focused virtual libraries, computation of molecular descriptors for structure-activity relationship studies, application of conventional filters used in lead discovery along with in-house developed exhaustive PTC (Pharmacophore, Toxicophores and Chemophores) filters and machine learning tools for the design of potential disease specific inhibitors. A case study on kinase inhibitors is provided as an example.

  9. Risk factors for false positive and for false negative test results in screening with fecal occult blood testing

    NARCIS (Netherlands)

    Stegeman, Inge; de Wijkerslooth, Thomas R.; Stoop, Esther M.; van Leerdam, Monique; van Ballegooijen, M.; Kraaijenhagen, Roderik A.; Fockens, Paul; Kuipers, Ernst J.; Dekker, Evelien; Bossuyt, Patrick M.

    2013-01-01

    Differences in the risk of a false negative or a false positive fecal immunochemical test (FIT) across subgroups may affect optimal screening strategies. We evaluate whether subgroups are at increased risk of a false positive or a false negative FIT result, whether such variability in risk is

  10. Kinase profiling of liposarcomas using RNAi and drug screening assays identified druggable targets

    Directory of Open Access Journals (Sweden)

    Deepika Kanojia

    2017-11-01

    Full Text Available Abstract Background Liposarcoma, the most common soft tissue tumor, is understudied cancer, and limited progress has been made in the treatment of metastatic disease. The Achilles heel of cancer often is their kinases that are excellent therapeutic targets. However, very limited knowledge exists of therapeutic critical kinase targets in liposarcoma that could be potentially used in disease management. Methods Large RNAi and small-molecule tyrosine kinase inhibitor screens were performed against the proliferative capacity of liposarcoma cell lines of different subtypes. Each small molecule inhibitor was either FDA approved or in a clinical trial. Results Screening assays identified several previously unrecognized targets including PTK2 and KIT in liposarcoma. We also observed that ponatinib, multi-targeted tyrosine kinase inhibitor, was the most effective drug with anti-growth effects against all cell lines. In vitro assays showed that ponatinib inhibited the clonogenic proliferation of liposarcoma, and this anti-growth effect was associated with apoptosis and cell cycle arrest at the G0/G1 phase as well as a decrease in the KIT signaling pathway. In addition, ponatinib inhibited in vivo growth of liposarcoma in a xenograft model. Conclusions Two large-scale kinase screenings identified novel liposarcoma targets and a FDA-approved inhibitor, ponatinib with clear anti-liposarcoma activity highlighting its potential therapy for treatment of this deadly tumor.

  11. Human iPSC-derived cardiomyocytes and tissue engineering strategies for disease modeling and drug screening.

    Science.gov (United States)

    Smith, Alec S T; Macadangdang, Jesse; Leung, Winnie; Laflamme, Michael A; Kim, Deok-Ho

    Improved methodologies for modeling cardiac disease phenotypes and accurately screening the efficacy and toxicity of potential therapeutic compounds are actively being sought to advance drug development and improve disease modeling capabilities. To that end, much recent effort has been devoted to the development of novel engineered biomimetic cardiac tissue platforms that accurately recapitulate the structure and function of the human myocardium. Within the field of cardiac engineering, induced pluripotent stem cells (iPSCs) are an exciting tool that offer the potential to advance the current state of the art, as they are derived from somatic cells, enabling the development of personalized medical strategies and patient specific disease models. Here we review different aspects of iPSC-based cardiac engineering technologies. We highlight methods for producing iPSC-derived cardiomyocytes (iPSC-CMs) and discuss their application to compound efficacy/toxicity screening and in vitro modeling of prevalent cardiac diseases. Special attention is paid to the application of micro- and nano-engineering techniques for the development of novel iPSC-CM based platforms and their potential to advance current preclinical screening modalities. Published by Elsevier Inc.

  12. High Throughput Screening Method for Systematic Surveillance of Drugs of Abuse by Multisegment Injection-Capillary Electrophoresis-Mass Spectrometry.

    Science.gov (United States)

    DiBattista, Alicia; Rampersaud, Dianne; Lee, Howard; Kim, Marcus; Britz-McKibbin, Philip

    2017-11-07

    New technologies are urgently required for reliable drug screening given a worldwide epidemic of prescription drug abuse and its devastating socioeconomic impacts on public health. Primary screening of drugs of abuse (DoA) currently relies on immunoassays that are prone to bias and are not applicable to detect an alarming array of psychoactive stimulants, tranquilizers, and synthetic opioids. These limitations impact patient safety when monitoring for medication compliance, drug substitution, or misuse/abuse and require follow-up confirmatory testing by more specific yet lower throughput instrumental methods. Herein, we introduce a high throughput platform for nontargeted screening of a broad spectrum of DoA and their metabolites based on multisegment injection-capillary electrophoresis-mass spectrometry (MSI-CE-MS). We demonstrate that MSI-CE-MS enables serial injections of 10 samples within a single run (high resolution MS with full-scan data acquisition. Unambiguous drug identification was achieved by four or more independent parameters, including comigration with a deuterated internal standard or in silico prediction of electromigration behavior together with accurate mass, most likely molecular formula, as well as MS/MS as required for confirmation testing. Acceptable precision was demonstrated for over 50 DoA at 3 concentration levels over 4 days (median coefficient of variance = 13%, n = 117) with minimal ion suppression, isobaric interferences, and sample carry-over (screening cutoff levels in human urine while allowing for systematic surveillance, specimen verification, and retrospective testing of designer drugs that elude conventional drug tests.

  13. Nonlinear mixed effects dose response modeling in high throughput drug screens: application to melanoma cell line analysis.

    Science.gov (United States)

    Ding, Kuan-Fu; Petricoin, Emanuel F; Finlay, Darren; Yin, Hongwei; Hendricks, William P D; Sereduk, Chris; Kiefer, Jeffrey; Sekulic, Aleksandar; LoRusso, Patricia M; Vuori, Kristiina; Trent, Jeffrey M; Schork, Nicholas J

    2018-01-12

    Cancer cell lines are often used in high throughput drug screens (HTS) to explore the relationship between cell line characteristics and responsiveness to different therapies. Many current analysis methods infer relationships by focusing on one aspect of cell line drug-specific dose-response curves (DRCs), the concentration causing 50% inhibition of a phenotypic endpoint (IC 50 ). Such methods may overlook DRC features and do not simultaneously leverage information about drug response patterns across cell lines, potentially increasing false positive and negative rates in drug response associations. We consider the application of two methods, each rooted in nonlinear mixed effects (NLME) models, that test the relationship relationships between estimated cell line DRCs and factors that might mitigate response. Both methods leverage estimation and testing techniques that consider the simultaneous analysis of different cell lines to draw inferences about any one cell line. One of the methods is designed to provide an omnibus test of the differences between cell line DRCs that is not focused on any one aspect of the DRC (such as the IC 50 value). We simulated different settings and compared the different methods on the simulated data. We also compared the proposed methods against traditional IC 50 -based methods using 40 melanoma cell lines whose transcriptomes, proteomes, and, importantly, BRAF and related mutation profiles were available. Ultimately, we find that the NLME-based methods are more robust, powerful and, for the omnibus test, more flexible, than traditional methods. Their application to the melanoma cell lines reveals insights into factors that may be clinically useful.

  14. High Throughput Screening in Duchenne Muscular Dystrophy: From Drug Discovery to Functional Genomics

    Directory of Open Access Journals (Sweden)

    Thomas J.J. Gintjee

    2014-11-01

    Full Text Available Centers for the screening of biologically active compounds and genomic libraries are becoming common in the academic setting and have enabled researchers devoted to developing strategies for the treatment of diseases or interested in studying a biological phenomenon to have unprecedented access to libraries that, until few years ago, were accessible only by pharmaceutical companies. As a result, new drugs and genetic targets have now been identified for the treatment of Duchenne muscular dystrophy (DMD, the most prominent of the neuromuscular disorders affecting children. Although the work is still at an early stage, the results obtained to date are encouraging and demonstrate the importance that these centers may have in advancing therapeutic strategies for DMD as well as other diseases. This review will provide a summary of the status and progress made toward the development of a cure for this disorder and implementing high-throughput screening (HTS technologies as the main source of discovery. As more academic institutions are gaining access to HTS as a valuable discovery tool, the identification of new biologically active molecules is likely to grow larger. In addition, the presence in the academic setting of experts in different aspects of the disease will offer the opportunity to develop novel assays capable of identifying new targets to be pursued as potential therapeutic options. These assays will represent an excellent source to be used by pharmaceutical companies for the screening of larger libraries providing the opportunity to establish strong collaborations between the private and academic sectors and maximizing the chances of bringing into the clinic new drugs for the treatment of DMD.

  15. High throughput screening in duchenne muscular dystrophy: from drug discovery to functional genomics.

    Science.gov (United States)

    Gintjee, Thomas J J; Magh, Alvin S H; Bertoni, Carmen

    2014-11-14

    Centers for the screening of biologically active compounds and genomic libraries are becoming common in the academic setting and have enabled researchers devoted to developing strategies for the treatment of diseases or interested in studying a biological phenomenon to have unprecedented access to libraries that, until few years ago, were accessible only by pharmaceutical companies. As a result, new drugs and genetic targets have now been identified for the treatment of Duchenne muscular dystrophy (DMD), the most prominent of the neuromuscular disorders affecting children. Although the work is still at an early stage, the results obtained to date are encouraging and demonstrate the importance that these centers may have in advancing therapeutic strategies for DMD as well as other diseases. This review will provide a summary of the status and progress made toward the development of a cure for this disorder and implementing high-throughput screening (HTS) technologies as the main source of discovery. As more academic institutions are gaining access to HTS as a valuable discovery tool, the identification of new biologically active molecules is likely to grow larger. In addition, the presence in the academic setting of experts in different aspects of the disease will offer the opportunity to develop novel assays capable of identifying new targets to be pursued as potential therapeutic options. These assays will represent an excellent source to be used by pharmaceutical companies for the screening of larger libraries providing the opportunity to establish strong collaborations between the private and academic sectors and maximizing the chances of bringing into the clinic new drugs for the treatment of DMD.

  16. Raman spectroscopy based screening of IgG positive and negative sera for dengue virus infection

    Science.gov (United States)

    Bilal, M.; Saleem, M.; Bial, Maria; Khan, Saranjam; Ullah, Rahat; Ali, Hina; Ahmed, M.; Ikram, Masroor

    2017-11-01

    A quantitative analysis for the screening of immunoglobulin-G (IgG) positive human sera samples is presented for the dengue virus infection. The regression model was developed using 79 samples while 20 samples were used to test the performance of the model. The R-square (r 2) value of 0.91 was found through a leave-one-sample-out cross validation method, which shows the validity of this model. This model incorporates the molecular changes associated with IgG. Molecular analysis based on regression coefficients revealed that myristic acid, coenzyme-A, alanine, arabinose, arginine, vitamin C, carotene, fumarate, galactosamine, glutamate, lactic acid, stearic acid, tryptophan and vaccenic acid are positively correlated with IgG; while amide III, collagen, proteins, fatty acids, phospholipids and fucose are negatively correlated. For blindly tested samples, an excellent agreement has been found between the model predicted, and the clinical values of IgG. The parameters, which include sensitivity, specificity, accuracy and the area under the receiver operator characteristic curve, are found to be 100%, 83.3%, 95% and 0.99, respectively, which confirms the high quality of the model.

  17. Onset timing, thoughts of self-harm, and diagnoses in postpartum women with screen-positive depression findings.

    Science.gov (United States)

    Wisner, Katherine L; Sit, Dorothy K Y; McShea, Mary C; Rizzo, David M; Zoretich, Rebecca A; Hughes, Carolyn L; Eng, Heather F; Luther, James F; Wisniewski, Stephen R; Costantino, Michelle L; Confer, Andrea L; Moses-Kolko, Eydie L; Famy, Christopher S; Hanusa, Barbara H

    2013-05-01

    The period prevalence of depression among women is 21.9% during the first postpartum year; however, questions remain about the value of screening for depression. To screen for depression in postpartum women and evaluate positive screen findings to determine the timing of episode onset, rate and intensity of self-harm ideation, and primary and secondary DSM-IV disorders to inform treatment and policy decisions. Sequential case series of women who recently gave birth. Urban academic women's hospital. During the maternity hospitalization, women were offered screening at 4 to 6 weeks post partum by telephone. Screen-positive women were invited to undergo psychiatric evaluations in their homes. A positive screen finding was an Edinburgh Postnatal Depression Scale (EPDS) score of 10 or higher. Self-harm ideation was assessed on EPDS item 10: "The thought of harming myself has occurred to me" (yes, quite often; sometimes; hardly ever; never). Screen-positive women underwent evaluation with the Structured Clinical Interview for DSM-IV for Axis I primary and secondary diagnoses. Ten thousand mothers underwent screening, with positive findings in 1396 (14.0%); of these, 826 (59.2%) completed the home visits and 147 (10.5%) completed a telephone diagnostic interview. Screen-positive women were more likely to be younger, African American, publicly insured, single, and less well educated. More episodes began post partum (40.1%), followed by during pregnancy (33.4%) and before pregnancy (26.5%). In this population, 19.3% had self-harm ideation. All mothers with the highest intensity of self-harm ideation were identified with the EPDS score of 10 or higher. The most common primary diagnoses were unipolar depressive disorders (68.5%), and almost two-thirds had comorbid anxiety disorders. A striking 22.6% had bipolar disorders. The most common diagnosis in screen-positive women was major depressive disorder with comorbid generalized anxiety disorder. Strategies to differentiate

  18. Onset Timing, Thoughts of Self-harm, and Diagnoses in Postpartum Women With Screen-Positive Depression Findings

    Science.gov (United States)

    Wisner, Katherine L.; Sit, Dorothy K. Y.; McShea, Mary C.; Rizzo, David M.; Zoretich, Rebecca A.; Hughes, Carolyn L.; Eng, Heather F.; Luther, James F.; Wisniewski, Stephen R.; Costantino, Michelle L.; Confer, Andrea L.; Moses-Kolko, Eyclie L.; Famy, Christopher S.; Hanusa, Barbara H.

    2015-01-01

    Importance The period prevalence of depression among women is 21.9% during the first postpartum year; however, questions remain about the value of screening for depression. Objectives To screen for depression in postpartum women and evaluate positive screen findings to determine the timing of episode onset, rate and intensity of self-harm ideation, and primary and secondary DSM-IV disorders to inform treatment and policy decisions. Design Sequential case series of women who recently gave birth. Setting Urban academic women’s hospital. Participants During the maternity hospitalization, women were offered screening at 4 to 6 weeks post parturn by telephone. Screen-positive women were invited to undergo psychiatric evaluations in their homes. Main Outcomes and Measures A positive screen finding was an Edinburgh Postnatal Depression Scale (EPDS) score of 10 or higher. Self-harm ideation was assessed on EPDS item 10: “The thought of harming myself has occurred to me” (yes, quite often; sometimes; hardly ever; never). Screen-positive women underwent evaluation with the Structured Clinical Interview for DSM-IV for Axis I primary and secondary diagnoses. Results Ten thousand mothers underwent screening, with positive findings in 1396 (14.0%); of these, 826 (59.2%) completed the home visits and 147 (10.5%) completed a telephone diagnostic interview. Screen-positive women were more likely to be younger, African American, publicly insured, single, and less well educated. More episodes began post partum (40.1%), followed by during pregnancy (33.4%) and before pregnancy (26.5%). In this population, 19.3% had self-harm ideation. All mothers with the highest intensity of self-harm ideation were identified with the EPDS score of 10 or higher. The most common primary diagnoses were unipolar depressive disorders (68.5%), and almost two-thirds had co-morbid anxiety disorders. A striking 22.6% had bipolar disorders. Conclusions and Relevance The most common diagnosis in screen-positive

  19. Fragment screening for drug leads by weak affinity chromatography (WAC-MS).

    Science.gov (United States)

    Ohlson, Sten; Duong-Thi, Minh-Dao

    2018-02-23

    Fragment-based drug discovery is an important tool for design of small molecule hit-to-lead compounds against various biological targets. Several approved drugs have been derived from an initial fragment screen and many such candidates are in various stages of clinical trials. Finding fragment hits, that are suitable for optimisation by medicinal chemists, is still a challenge as the binding between the small fragment and its target is weak in the range of mM to µM of K d and irrelevant non-specific interactions are abundant in this area of transient interactions. Fortunately, there are methods that can study weak interactions quite efficiently of which NMR, surface plasmon resonance (SPR) and X-ray crystallography are the most prominent. Now, a new technology based on zonal affinity chromatography, weak affinity chromatography (WAC), has been introduced which has remedied many of the problems with other technologies. By combining WAC with mass spectrometry (WAC-MS), it is a powerful tool to identify binders quantitatively in terms of affinity and kinetics either from fragment libraries or from complex mixtures of biological extracts. As WAC-MS can be multiplexed by analysing mixtures of fragments (20-100 fragments) in one sample, this approach yields high throughput, where a whole library of e.g. >2000 fragments can be analysed quantitatively within a day. WAC-MS is easy to perform, where the robustness and quality of HPLC is fully utilized. This review will highlight the rationale behind the application of WAC-MS for fragment screening in drug discovery. Copyright © 2018 Elsevier Inc. All rights reserved.

  20. High-throughput screen of drug repurposing library identifies inhibitors of Sarcocystis neurona growth.

    Science.gov (United States)

    Bowden, Gregory D; Land, Kirkwood M; O'Connor, Roberta M; Fritz, Heather M

    2018-04-01

    The apicomplexan parasite Sarcocystis neurona is the primary etiologic agent of equine protozoal myeloencephalitis (EPM), a serious neurologic disease of horses. Many horses in the U.S. are at risk of developing EPM; approximately 50% of all horses in the U.S. have been exposed to S. neurona and treatments for EPM are 60-70% effective. Advancement of treatment requires new technology to identify new drugs for EPM. To address this critical need, we developed, validated, and implemented a high-throughput screen to test 725 FDA-approved compounds from the NIH clinical collections library for anti-S. neurona activity. Our screen identified 18 compounds with confirmed inhibitory activity against S. neurona growth, including compounds active in the nM concentration range. Many identified inhibitory compounds have well-defined mechanisms of action, making them useful tools to study parasite biology in addition to being potential therapeutic agents. In comparing the activity of inhibitory compounds identified by our screen to that of other screens against other apicomplexan parasites, we found that most compounds (15/18; 83%) have activity against one or more related apicomplexans. Interestingly, nearly half (44%; 8/18) of the inhibitory compounds have reported activity against dopamine receptors. We also found that dantrolene, a compound already formulated for horses with a peak plasma concentration of 37.8 ± 12.8 ng/ml after 500 mg dose, inhibits S. neurona parasites at low concentrations (0.065 μM [0.036-0.12; 95% CI] or 21.9 ng/ml [12.1-40.3; 95% CI]). These studies demonstrate the use of a new tool for discovering new chemotherapeutic agents for EPM and potentially providing new reagents to elucidate biologic pathways required for successful S. neurona infection. Copyright © 2018. Published by Elsevier Ltd.

  1. Avoidable surgical consultations in women with a positive screening mammogram: Experience from a southern region of the Dutch breast screening programme

    International Nuclear Information System (INIS)

    Schreutelkamp, J.L.; Kwee, R.M.; Booij, M. de; Adriaensen, M.E.A.P.M.

    2014-01-01

    Introduction: According to current Dutch guidelines, all women with a positive screening mammogram are referred for a full hospital assessment, which includes surgical consultation and radiological assessment. Surgical consultation may be unnecessary for many patients. Our objective was to determine how often surgical consultations can be avoided by radiological pre-assessment. Materials and methods: All women with a positive screening mammogram, referred to our radiology department between 2002 and 2007, were included (n = 1014). Percentage of women that was downstaged to BI-RADS category 1 or 2 by radiological pre-assessment was calculated. Negative predictive value (NPV) for malignancy was estimated from the in-hospital follow-up, which was available up to September 2012. Results: 423 of 1014 women (42%) were downstaged to BI-RADS category 1 or 2 by radiological pre-assessment. During follow-up, 8 of these 423 women (2%) developed a malignancy in the same breast. At least 6 of these malignancies were located at a different location as the original screening findings which led to the initial referral. The estimated NPV for malignancy was 99.5% (95%CI, 98.3–99.9). Conclusion: By referring women with a positive screening mammogram to the radiology department for pre-assessment, a surgical consultation was avoided in 42%, with an estimated NPV of 99.5% for malignancy

  2. New screening methodology for selection of polymeric materials for transdermal drug delivery devices

    Science.gov (United States)

    Falcone, Roberto P.

    As medical advances extend the human lifespan, the level of chronic illnesses will increase and thus straining the needs of the health care system that, as a result, governments will need to balance expenses without upsetting national budgets. Therefore, the selection of a precise and affordable drug delivery technology is seen as the most practical solution for governments, health care professionals, and consumers. Transdermal drug delivery patches (TDDP) are one of the best economical technologies that are favored by pharmaceutical companies and physicians alike because it offers fewer complications when compared to other delivery technologies. TDDP provides increased efficiency, safety and convenience for the patient. The TDDP segment within the US and Global drug delivery markets were valued at 5.6 and 12.7 billion respectively in 2009. TDDP is forecasted to reach $31.5 billion in 2015. The present TDDP technology involves the fabrication of a patch that consists of a drug embedded in a polymeric matrix. The diffusion coefficient is determined from the slope of the cumulative drug release versus time. It is a trial and error method that is time and labor consuming. With all the advantages that TDDPs can offer, the methodology used to achieve the so-called optimum design has resulted in several incidents where the safety and design have been put to question in recent times (e.g. Fentanyl). A more logical screening methodology is needed. This work shows the use of a modified Duda Zielinsky equation (DZE). Experimental release curves from commercial are evaluated. The experimental and theoretical Diffusion Coefficient values are found to be within the limits specified in the patent literature. One interesting finding is that the accuracy of the DZE is closer to experimental values when the type of Molecular Shape and Radius are used. This work shows that the modified DZE could be used as an excellent screening tool to determine the optimal polymeric matrices that

  3. High performance in silico virtual drug screening on many-core processors

    Science.gov (United States)

    Price, James; Sessions, Richard B; Ibarra, Amaurys A

    2015-01-01

    Drug screening is an important part of the drug development pipeline for the pharmaceutical industry. Traditional, lab-based methods are increasingly being augmented with computational methods, ranging from simple molecular similarity searches through more complex pharmacophore matching to more computationally intensive approaches, such as molecular docking. The latter simulates the binding of drug molecules to their targets, typically protein molecules. In this work, we describe BUDE, the Bristol University Docking Engine, which has been ported to the OpenCL industry standard parallel programming language in order to exploit the performance of modern many-core processors. Our highly optimized OpenCL implementation of BUDE sustains 1.43 TFLOP/s on a single Nvidia GTX 680 GPU, or 46% of peak performance. BUDE also exploits OpenCL to deliver effective performance portability across a broad spectrum of different computer architectures from different vendors, including GPUs from Nvidia and AMD, Intel’s Xeon Phi and multi-core CPUs with SIMD instruction sets. PMID:25972727

  4. High performance in silico virtual drug screening on many-core processors.

    Science.gov (United States)

    McIntosh-Smith, Simon; Price, James; Sessions, Richard B; Ibarra, Amaurys A

    2015-05-01

    Drug screening is an important part of the drug development pipeline for the pharmaceutical industry. Traditional, lab-based methods are increasingly being augmented with computational methods, ranging from simple molecular similarity searches through more complex pharmacophore matching to more computationally intensive approaches, such as molecular docking. The latter simulates the binding of drug molecules to their targets, typically protein molecules. In this work, we describe BUDE, the Bristol University Docking Engine, which has been ported to the OpenCL industry standard parallel programming language in order to exploit the performance of modern many-core processors. Our highly optimized OpenCL implementation of BUDE sustains 1.43 TFLOP/s on a single Nvidia GTX 680 GPU, or 46% of peak performance. BUDE also exploits OpenCL to deliver effective performance portability across a broad spectrum of different computer architectures from different vendors, including GPUs from Nvidia and AMD, Intel's Xeon Phi and multi-core CPUs with SIMD instruction sets.

  5. Multi-drug-resistant tuberculosis in HIV positive patients in Eastern Europe

    DEFF Research Database (Denmark)

    Post, Frank A; Grint, Daniel; Efsen, Anne Marie Werlinrud

    2014-01-01

    Observational data from Eastern Europe on the management and outcome of multi-drug-resistant tuberculosis (MDR TB) in HIV positive populations remain sparse in the English-language literature.We compared clinical characteristics and outcomes of 55 patients who were diagnosed with HIV and MDR TB...... in Eastern Europe between 2004 and 2006 to 89 patients whose Mycobacterium tuberculosis isolates were susceptible to isoniazid and rifampicin.Patients with HIV and MDR TB were young and predominantly male with high rates of intravenous drug use, imprisonment and hepatitis C co-infection. Eighty-four per cent...... of patients with MDR TB had no history of previous TB drug exposure suggesting that the majority of MDR TB resulted from transmission of drug-resistant M. tuberculosis. The use of non-standardized tuberculosis treatment was common, and the use of antiretroviral therapy infrequent. Compared to those...

  6. 10 CFR 707.7 - Random drug testing requirements and identification of testing designated positions.

    Science.gov (United States)

    2010-01-01

    ... contractor, to have the potential to significantly affect the environment, public health and safety, or... evidence of the use of illegal drugs of employees in testing designated positions identified in this... section shall provide for random tests at a rate equal to 30 percent of the total number of employees in...

  7. Psychometric properties of the Turkish versions of the Drug Use Disorders Identification Test (DUDIT) and the Drug Abuse Screening Test (DAST-10) in the prison setting.

    Science.gov (United States)

    Evren, Cuneyt; Ogel, Kultegin; Evren, Bilge; Bozkurt, Muge

    2014-01-01

    The aim of this study was to evaluate psychometric properties of the Drug Use Disorders Identification Test (DUDIT) and the Drug Abuse Screening Test (DAST-10) in prisoners with (n = 124) or without (n = 78) drug use disorder. Participants were evaluated with the DUDIT, the DAST-10, and the Addiction Profile Index-Short (API-S). The DUDIT and the DAST-10 were found to be psychometrically sound drug abuse screening measures with high convergent validity when compared with each other (r = 0.86), and API-S (r = 0.88 and r = 0.84, respectively), and to have a Cronbach's α of 0.93 and 0.87, respectively. In addition, a single component accounted for 58.28% of total variance for DUDIT, whereas this was 47.10% for DAST-10. The DUDIT had sensitivity and specificity scores of 0.95 and 0.79, respectively, when using the optimal cut-off score of 10, whereas these scores were 0.88 and 0.74 for the DAST-10 when using the optimal cut-off score of 4. Additionally, both the DUDIT and the DAST-10 showed good discriminant validity as they differentiated prisoners with drug use disorder from those without. Findings support the Turkish versions of both the DUDIT and the DAST-10 as reliable and valid drug abuse screening instruments that measure unidimensional constructs.

  8. An FDA-Drug Library Screen for Compounds with Bioactivities against Meticillin-Resistant Staphylococcus aureus (MRSA

    Directory of Open Access Journals (Sweden)

    Qiu Ying Lau

    2015-10-01

    Full Text Available The lack of new antibacterial drugs entering the market and their misuse have resulted in the emergence of drug-resistant bacteria, posing a major health crisis worldwide. In particular, meticillin-resistant Staphylococcus aureus (MRSA, a pathogen responsible for numerous human infections, has become endemic in hospitals worldwide. Drug repurposing, the finding of new therapeutic indications for approved drugs, is deemed a plausible solution to accelerate drug discovery and development in this area. Towards this end, we screened 1163 drugs approved by the Food and Drug Administration (FDA for bioactivities against MRSA in a 10 μM single-point assay. After excluding known antibiotics and antiseptics, six compounds were identified and their MICs were determined against a panel of clinical MRSA strains. A toxicity assay using human keratinocytes was also conducted to gauge their potential for repurposing as topical agents for treating MRSA skin infections.

  9. Photoreactivity of biologically active compounds. VII. Interaction of antimalarial drugs with melanin in vitro as part of phototoxicity screening.

    Science.gov (United States)

    Kristensen, S; Orsteen, A L; Sande, S A; Tønnesen, H H

    1994-10-01

    The drugs commonly used in the treatment of malaria are photochemically unstable. Several of these compounds accumulate in melanin-rich tissues and cause toxic reactions which may be light induced. As part of the screening of the photochemical properties and phototoxic capabilities of antimalarials, the in vitro interaction of eight antimalarials with melanin was studied. The dissociation constant for the drug-melanin complex and the relative number of binding sites on melanin were estimated for six of the drugs using a curve-fitting program. The reaction rate for the formation of the melanin-drug complex was determined, and the complexes were further characterized by zeta potential measurements.

  10. A new in vitro screening system for anticancer drugs for the treatment of non-small cell lung cancer

    International Nuclear Information System (INIS)

    Hanauske, U.; Hanauske, A.R.; Clark, G.M.; Tsen, D.; Buchok, J.; Hoff, D.D. von

    1989-01-01

    We have evaluated a semiautomated radiometric assay (BACTEC 460 system) for screening of activity of anticancer drugs against human non-small cell lung cancer cell lines. Cells from seven cell lines were exposed to standard antineoplastic agents at four different concentrations using a 1-h incubation. Alpha 2-interferon was tested using a continuous incubation. In vitro drug activity was analyzed as a function of the clinically achievable serum concentration. Our results indicate that two cell lines (CALU-3, SK-MES-1) exhibit in vitro drug sensitivity patterns closest to those observed in clinical studies. These two cell lines might therefore be most useful for screening new anticancer compounds for activity against non-small cell lung cancer. The radiometric assay is a semiautomated system which has advantages over other, more time-consuming screening systems

  11. Screening of veterinary drug residues in food by LC-MS/MS. Background and challenges.

    Science.gov (United States)

    Delatour, Thierry; Racault, Lucie; Bessaire, Thomas; Desmarchelier, Aurélien

    2018-04-01

    Regulatory agencies and government authorities have established maximum residue limits (MRL) in various food matrices of animal origin for supporting governments and food operators in the monitoring of veterinary drug residues in the food chain, and ultimately in the consumer's plate. Today, about 200 veterinary drug residues from several families, mainly with antibiotic, antiparasitic or antiinflammatory activities, are regulated in a variety of food matrices such as milk, meat or egg. This article provides a review of the regulatory framework in milk and muscle including data from Codex Alimentarius, Europe, the U.S.A., Canada and China for about 220 veterinary drugs. The article also provides a comprehensive overview of the challenge for food control, and emphasizes the pivotal role of liquid chromatography-mass spectrometry (LC-MS), either in tandem with quadrupoles (LC-MS/MS) or high resolution MS (LC-HRMS), for ensuring an adequate consumer protection combined with an affordable cost. The capability of a streamlined LC-MS/MS platform for screening 152 veterinary drug residues in a broad range of raw materials and finished products is highlighted in a production line perspective. The rationale for a suite of four methods intended to achieve appropriate performance in terms of scope and sensitivity is presented. Overall, the platform encompasses one stream for the determination of 105 compounds in a run (based on acidic QuEChERS-like), plus two streams for 23 β-lactams (alkaline QuEChERS-like) and 10 tetracyclines (low-temperature partitioning), respectively, and a dedicated stream for 14 aminoglycosides (molecularly-imprinted polymer).

  12. Incomplete follow-up of positive HPV tests: overview of randomised controlled trials on primary cervical screening

    DEFF Research Database (Denmark)

    Rebolj, M; Lynge, E

    2010-01-01

    with follow-up in HPV-positive women and relative >/=CIN3 detection was 0.48 (P=0.33).Conclusion:There is at present scant evidence to support the view that the measured sensitivity of HPV screening is a simple reflection of compliance with follow-up. Adjustment of measured cervical intraepithelial neoplasia......Background:It has been suggested that adjustment for incomplete compliance with follow-up in women with positive human papillomavirus (HPV) tests would be appropriate for estimating the true sensitivity of cervical screening with HPV testing. We assessed the compliance and its impact on >/=CIN3...

  13. High-throughput screening and confirmation of 22 banned veterinary drugs in feedstuffs using LC-MS/MS and high-resolution Orbitrap mass spectrometry.

    Science.gov (United States)

    Wang, Xufeng; Liu, Yanghong; Su, Yijuan; Yang, Jianwen; Bian, Kui; Wang, Zongnan; He, Li-Min

    2014-01-15

    A new analytical strategy based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) combined with accurate mass high-resolution Orbitrap mass spectrometry (HR-Orbitrap MS) was performed for high-throughput screening, confirmation, and quantification of 22 banned or unauthorized veterinary drugs in feedstuffs according to Bulletin 235 of the Ministry of Agriculture, China. Feed samples were extracted with acidified acetonitrile, followed by cleanup using solid-phase extraction cartridge. The extracts were first screened by LC-MS/MS in a single selected reaction monitoring mode. The suspected positive samples were subjected to a specific pretreatment for confirmation and quantification of analyte of interest with LC-MS/MS and HR-Orbitrap MS. Mean recoveries for all target analytes (except for carbofuran and chlordimeform, which were about 35 and 45%, respectively) ranged from 52.2 to 90.4%, and the relative standard deviations were screening of real samples obtained from local feed markets and confirmation of the suspected target analytes. It provides a high-throughput, sensitive, and reliable screening, identification, and quantification of banned veterinary drugs in routine monitoring programs of feedstuffs.

  14. Developing and implementing a positive behavioral reinforcement intervention in prison-based drug treatment: Project BRITE.

    Science.gov (United States)

    Burdon, William M; St De Lore, Jef; Prendergast, Michael L

    2011-09-01

    Within prison settings, the reliance on punishment for controlling inappropriate or noncompliant behavior is self-evident. What is not so evident is the similarity between this reliance on punishment and the use of positive reinforcements to increase desired behaviors. However, seldom do inmates receive positive reinforcement for engaging in prosocial behaviors or, for inmates receiving drug treatment, behaviors that are consistent with or support their recovery. This study provides an overview of the development and implementation of a positive behavioral reinforcement intervention in male and female prison-based drug treatment programs. The active involvement of institutional staff, treatment staff, and inmates enrolled in the treatment programs in the development of the intervention along with the successful branding of the intervention were effective at promoting support and participation. However, these factors may also have ultimately impacted the ability of the randomized design to reliably demonstrate the effectiveness of the intervention.

  15. The University of Kansas High-Throughput Screening Laboratory. Part II: enabling collaborative drug-discovery partnerships through cutting-edge screening technology.

    Science.gov (United States)

    McDonald, Peter R; Roy, Anuradha; Chaguturu, Rathnam

    2011-07-01

    The University of Kansas High-Throughput Screening (KU HTS) core is a state-of-the-art drug-discovery facility with an entrepreneurial open-service policy, which provides centralized resources supporting public- and private-sector research initiatives. The KU HTS core was established in 2002 at the University of Kansas with support from an NIH grant and the state of Kansas. It collaborates with investigators from national and international academic, nonprofit and pharmaceutical organizations in executing HTS-ready assay development and screening of chemical libraries for target validation, probe selection, hit identification and lead optimization. This is part two of a contribution from the KU HTS laboratory.

  16. Cost-effectiveness of enhanced syphilis screening among HIV-positive men who have sex with men: a microsimulation model.

    Directory of Open Access Journals (Sweden)

    Ashleigh R Tuite

    Full Text Available Syphilis co-infection risk has increased substantially among HIV-infected men who have sex with men (MSM. Frequent screening for syphilis and treatment of men who test positive might be a practical means of controlling the risk of infection and disease sequelae in this population.We evaluated the cost-effectiveness of strategies that increased the frequency and population coverage of syphilis screening in HIV-infected MSM receiving HIV care, relative to current standard of care.We developed a state-transition microsimulation model of syphilis natural history and medical care in HIV-infected MSM receiving care for HIV. We performed Monte Carlo simulations using input data derived from a large observational cohort in Ontario, Canada, and from published biomedical literature. Simulations compared usual care (57% of the population screened annually to different combinations of more frequent (3- or 6-monthly screening and higher coverage (100% screened. We estimated expected disease-specific outcomes, quality-adjusted survival, costs, and cost-effectiveness associated with each strategy from the perspective of a public health care payer.Usual care was more costly and less effective than strategies with more frequent or higher coverage screening. Higher coverage strategies (with screening frequency of 3 or 6 months were expected to be cost-effective based on usually cited willingness-to-pay thresholds. These findings were robust in the face of probabilistic sensitivity analyses, alternate cost-effectiveness thresholds, and alternate assumptions about duration of risk, program characteristics, and management of underlying HIV.We project that higher coverage and more frequent syphilis screening of HIV-infected MSM would be a highly cost-effective health intervention, with many potentially viable screening strategies projected to both save costs and improve health when compared to usual care. The baseline requirement for regular blood testing in this

  17. Cost-Effectiveness of Enhanced Syphilis Screening among HIV-Positive Men Who Have Sex with Men: A Microsimulation Model

    Science.gov (United States)

    Tuite, Ashleigh R.; Burchell, Ann N.; Fisman, David N.

    2014-01-01

    Background Syphilis co-infection risk has increased substantially among HIV-infected men who have sex with men (MSM). Frequent screening for syphilis and treatment of men who test positive might be a practical means of controlling the risk of infection and disease sequelae in this population. Purpose We evaluated the cost-effectiveness of strategies that increased the frequency and population coverage of syphilis screening in HIV-infected MSM receiving HIV care, relative to current standard of care. Methods We developed a state-transition microsimulation model of syphilis natural history and medical care in HIV-infected MSM receiving care for HIV. We performed Monte Carlo simulations using input data derived from a large observational cohort in Ontario, Canada, and from published biomedical literature. Simulations compared usual care (57% of the population screened annually) to different combinations of more frequent (3- or 6-monthly) screening and higher coverage (100% screened). We estimated expected disease-specific outcomes, quality-adjusted survival, costs, and cost-effectiveness associated with each strategy from the perspective of a public health care payer. Results Usual care was more costly and less effective than strategies with more frequent or higher coverage screening. Higher coverage strategies (with screening frequency of 3 or 6 months) were expected to be cost-effective based on usually cited willingness-to-pay thresholds. These findings were robust in the face of probabilistic sensitivity analyses, alternate cost-effectiveness thresholds, and alternate assumptions about duration of risk, program characteristics, and management of underlying HIV. Conclusions We project that higher coverage and more frequent syphilis screening of HIV-infected MSM would be a highly cost-effective health intervention, with many potentially viable screening strategies projected to both save costs and improve health when compared to usual care. The baseline requirement

  18. Synthesis, Structural Characterization and Biological Screening of Various Sulfa Drugs Derived from 2-Anisidine

    International Nuclear Information System (INIS)

    Abbasi, M.A.; Rehman, A.U.; Muhmood, T.; Khan, K.M.

    2013-01-01

    In the present study, a series of N-alkyl substituted sulfa drugs (sulfonamides) has been synthesized. The reaction of 2-anisidine (1) with 4-methylbenzenesulfonyl chloride (2) yielded N-(2-methoxyphenyl)-4-methylbenzenesulfonamide (3), which on bromination with bromine in the presence of glacial acetic acid gave N-(4,5-dibromo-2-methoxyphenyl) 4-methylbenzenesulfonamide (6). These two products 3 and 6 on further treatment with different alkyl halides in the presence of lithium hydride yielded fourteen new N-substituted sulfonamides. These compounds were characterized by their EI-MS and 1H-NMR spectra and screened against acetylcholinesterase, butyrlcholinesterase and chymotrypsin enzymes. The results revealed that N-propyl-N-(2-methoxyphenyl)-4-methylbenzenesulfonamide (5c), N-(4,5-dibromo-2-methoxy-phenyl)-4-methylbenzenesulfonamide (6) and N-methyl-N-(4,5-dibromo-2-methoxyphenyl) 4-methylbenzenesulfonamide (7e) exhibited good inhibitory potential against acetylcholinesterase, butyrlcholinesterase and chymotrypsin respectively. (author)

  19. Multi-drug-resistant tuberculosis in HIV positive patients in Eastern Europe.

    Science.gov (United States)

    Post, Frank A; Grint, Daniel; Werlinrud, Anne Marie; Panteleev, Alexander; Riekstina, Vieja; Malashenkov, Evgeniy A; Skrahina, Alena; Duiculescu, Dan; Podlekareva, Daria; Karpov, Igor; Bondarenko, Vasiliy; Chentsova, Nelly; Lundgren, Jens; Mocroft, Amanda; Kirk, Ole; Miro, Jose M

    2014-03-01

    Observational data from Eastern Europe on the management and outcome of multi-drug-resistant tuberculosis (MDR TB) in HIV positive populations remain sparse in the English-language literature. We compared clinical characteristics and outcomes of 55 patients who were diagnosed with HIV and MDR TB in Eastern Europe between 2004 and 2006 to 89 patients whose Mycobacterium tuberculosis isolates were susceptible to isoniazid and rifampicin. Patients with HIV and MDR TB were young and predominantly male with high rates of intravenous drug use, imprisonment and hepatitis C co-infection. Eighty-four per cent of patients with MDR TB had no history of previous TB drug exposure suggesting that the majority of MDR TB resulted from transmission of drug-resistant M. tuberculosis. The use of non-standardized tuberculosis treatment was common, and the use of antiretroviral therapy infrequent. Compared to those with susceptible tuberculosis, patients with MDR TB were less likely to achieve cure or complete tuberculosis treatment (21.8% vs. 62.9%, p < 0.0001), and they were more likely to die (65.5% vs. 27.0%, p < 0.0001). Our study documents suboptimal management and poor outcomes in HIV positive patients with MDR TB. Implementation of WHO guidelines, rapid TB diagnostics and TB drug susceptibility testing for all patients remain a priority in this region. Copyright © 2013 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

  20. Assessment of Substances Abuse in Burn Patients by Using Drug Abuse Screening Test

    Directory of Open Access Journals (Sweden)

    Kobra Gaseminegad

    2012-04-01

    Full Text Available There has been an increase in the frequency of substance abuse among hospitalized burn injury patients. However, few studies have investigated substance abuse among burn patients. This study was aimed to identify the incidence of substance abuse in burn injury patients using the "Drug Abuse Screening Test" (DAST-20. We determined the validity of DAST-20 in spring 2010. Subsequently, this descriptive study was performed on 203 burn injury patients who fit the study's inclusion criteria. We chose a score of 6 as the cutoff and thus achieved a sensitivity of 89% and a specificity of 85% for the DAST-20. During the study, we gathered demographic data, burn features and DAST-20 results for all patients. Patients with scores of 6 or more were considered to be substances abusers. A statistical analysis was conducted using SPSS v16 software. According to the DAST-20 results, 33% of the patients were in the user group. The mean score of DAST-20 was significantly higher among users than it was among nonusers (P<0.05. The level of substance abuse was severe in 77% of users. No significant differences were found among the substances, with the exception of alcohol. Substance abuse is an important risk factor for burn patients. In addition, this study showed that DAST-20 is a valid screening measure for studies on burn patients.

  1. Evaluation of a fluorescence-based method for antibabesial drug screening.

    Science.gov (United States)

    Guswanto, Azirwan; Sivakumar, Thillaiampalam; Rizk, Mohamed Abdo; Elsayed, Shimaa Abd Elsalam; Youssef, Mohamed Ahmed; ElSaid, ElSaid El Shirbini; Yokoyama, Naoaki; Igarashi, Ikuo

    2014-08-01

    In vitro evaluation of chemotherapeutic agents against Babesia and Theileria parasites has become routine, and the effectiveness of these chemicals is usually determined by comparing the parasitemia dynamics of untreated and treated parasites. Although microscopy is widely used to calculate parasitemia, several disadvantages are associated with this technique. The present study evaluated a fluorescence-based method using SYBR green I stain (SG I) to screen antibabesial agents in in vitro cultures of Babesia bovis. The linearity between relative fluorescence units (RFU) and parasitemia was found to be well correlated with a 0.9944 goodness-of-fit (r(2)) value. Subsequently, 50% inhibitory concentration (IC50) values were calculated for 3 antiprotozoan agents, diminazene aceturate, nimbolide, and gedunin, by this method. For diminazene aceturate and nimbolide, the IC(50)s determined by the fluorescence-based method (408 nM and 8.13 μM, respectively) and microscopy (400.3 nM and 9.4 μM, respectively) were in agreement. Furthermore, the IC50 of gedunin determined by the fluorescence-based method (19 μM) was similar to the recently described microscopy-based value (21.7 μM) for B. bovis. Additionally, the Z' factor (0.80 to 0.90), signal-to-noise (S/N) ratio (44.15 to 87.64), coefficient of variation at the maximum signal (%CVmax) (0.50 to 2.85), and coefficient of variation at the minimum signal (%CVmin) (1.23 to 2.21) calculated for the fluorescence method using diminazene aceturate were comparable to those previously determined in malaria research for this assay. These findings suggest that the fluorescence-based method might be useful for antibabesial drug screening and may have potential to be developed into a high-throughput screening (HTS) assay. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  2. Stemming the Escalating Cost of Prescription Drugs: A Position Paper of the American College of Physicians.

    Science.gov (United States)

    Daniel, Hilary

    2016-03-29

    This American College of Physicians position paper, initiated and written by its Health and Public Policy Committee and approved by the Board of Regents on 16 February 2016, reports policy recommendations from the American College of Physicians to address the escalating costs of prescription drugs in the United States. Prescription drugs play an important part in treating and preventing disease. However, the United States often pays more for some prescription drugs than other developed countries, and the high price and increasing costs associated with prescription medication is a major concern for patients, physicians, and payers. Pharmaceutical companies have considerable flexibility in how they price drugs, and the costs that payers and patients see are dependent on how payers are able to negotiate discounts or rebates. Beyond setting list prices are issues of regulatory approval, patents and intellectual property, assessment of value and cost-effectiveness, and health plan drug benefits. These issues are linked, and comprehensive efforts will be needed to affect how drugs are priced in the United States.

  3. Recreational drug use and related social factors among HIV-positive men in Japan.

    Science.gov (United States)

    Togari, Taisuke; Inoue, Yoji; Takaku, Yosuke; Abe, Sakurako; Hosokawa, Rikuya; Itagaki, Takashi; Yoshizawa, Shigeyuki; Oki, Sachiko; Katakura, Naoko; Yamauchi, Asae; Wakabayashi, Chihiro; Yajima, Takashi

    2016-07-01

    This study aims to determine the relationship between recreational drug use in HIV-positive males in the past year and socio-economic factors and/or social support networks in Japan. A national online survey in a cross-sectional study was conducted by HIV Futures Japan project from July 2013 to February 2014. Of the 1095 HIV-positive individuals who responded, 913 responses were determined to be valid; responses from the 875 males were analysed. A total of 282 participants used addictive drugs (32.2%) in past year. New psychoactive substances were used by 121 participants (13.8%), methamphetamine or amphetamine by 47 (5.4%), air dusters/sprays/gas by 31 (3.5%), 5-methoxy-N,N-diisopropyltryptamine (5MeO-DIPT) by 16 (1.8%) and cannabis (1.0%) by 9. Multiple logistic regression analysis was performed with the use of alkyl nitrites, addictive drugs, air dusters and thinners, which are low illegality, as dependent variables. We found that the odds ratio (95% confidence interval) for use among participants with full-time and temp/contracted/part-time employees compared to management/administration professions were 2.59 (0.99-6.77) and 2.61 (0.91-7.51). Also, a correlation was observed between alkyl nitrites and new psychoactive substances and usage rates in people engaged in few HIV-positive networks. It is necessary to develop targeted policies for drug use prevention and user support among HIV-positive men and to support and provide care for drug users who are isolated or have a narrow HIV/AIDS support network.

  4. Drug discovery for schistosomiasis: hit and lead compounds identified in a library of known drugs by medium-throughput phenotypic screening.

    Directory of Open Access Journals (Sweden)

    Maha-Hamadien Abdulla

    2009-07-01

    Full Text Available Praziquantel (PZQ is the only widely available drug to treat schistosomiasis. Given the potential for drug resistance, it is prudent to search for novel therapeutics. Identification of anti-schistosomal chemicals has traditionally relied on phenotypic (whole organism screening with adult worms in vitro and/or animal models of disease-tools that limit automation and throughput with modern microtiter plate-formatted compound libraries.A partially automated, three-component phenotypic screen workflow is presented that utilizes at its apex the schistosomular stage of the parasite adapted to a 96-well plate format with a throughput of 640 compounds per month. Hits that arise are subsequently screened in vitro against adult parasites and finally for efficacy in a murine model of disease. Two GO/NO GO criteria filters in the workflow prioritize hit compounds for tests in the animal disease model in accordance with a target drug profile that demands short-course oral therapy. The screen workflow was inaugurated with 2,160 chemically diverse natural and synthetic compounds, of which 821 are drugs already approved for human use. This affords a unique starting point to 'reposition' (re-profile drugs as anti-schistosomals with potential savings in development timelines and costs.Multiple and dynamic phenotypes could be categorized for schistosomula and adults in vitro, and a diverse set of 'hit' drugs and chemistries were identified, including anti-schistosomals, anthelmintics, antibiotics, and neuromodulators. Of those hits prioritized for tests in the animal disease model, a number of leads were identified, one of which compares reasonably well with PZQ in significantly decreasing worm and egg burdens, and disease-associated pathology. Data arising from the three components of the screen are posted online as a community resource.To accelerate the identification of novel anti-schistosomals, we have developed a partially automated screen workflow that

  5. Development and validation of a luminescence-based, medium-throughput assay for drug screening in Schistosoma mansoni.

    Directory of Open Access Journals (Sweden)

    Cristiana Lalli

    2015-01-01

    Full Text Available Schistosomiasis, one of the world's greatest neglected tropical diseases, is responsible for over 280,000 human deaths per annum. Praziquantel, developed in the 1970s, has high efficacy, excellent tolerability, few and transient side effects, simple administration procedures and competitive cost and it is currently the only recommended drug for treatment of human schistosomiasis. The use of a single drug to treat a population of over 200 million infected people appears particularly alarming when considering the threat of drug resistance. Quantitative, objective and validated methods for the screening of compound collections are needed for the discovery of novel anti-schistosomal drugs.The present work describes the development and validation of a luminescence-based, medium-throughput assay for the detection of schistosomula viability through quantitation of ATP, a good indicator of metabolically active cells in culture. This validated method is demonstrated to be fast, highly reliable, sensitive and automation-friendly. The optimized assay was used for the screening of a small compound library on S. mansoni schistosomula, showing that the proposed method is suitable for a medium-throughput semi-automated screening. Interestingly, the pilot screening identified hits previously reported to have some anti-parasitic activity, further supporting the validity of this assay for anthelminthic drug discovery.The developed and validated schistosomula viability luminescence-based assay was shown to be successful and suitable for the identification of novel compounds potentially exploitable in future schistosomiasis therapies.

  6. Does brain slices from pentylenetetrazole-kindled mice provide a more predictive screening model for antiepileptic drugs?

    DEFF Research Database (Denmark)

    Hansen, Suzanne L.; Sterjev, Zoran; Werngreen, Marie

    2012-01-01

    The cortical wedge is a commonly applied model for in vitro screening of new antiepileptic drugs (AEDs) and has been extensively used in characterization of well-known AEDs. However, the predictive validity of this model as a screening model has been questioned as, e.g., carbamazepine has been...... screening model for AEDs. To this end, we compared the in vitro and in vivo pharmacological profile of several selected AEDs (phenobarbital, phenytoin, tiagabine, fosphenytoin, valproate, and carbamazepine) along with citalopram using the PTZ-kindled model and brain slices from naïve, saline...

  7. Effect of radiologist experience on the risk of false-positive results in breast cancer screening programs

    International Nuclear Information System (INIS)

    Zubizarreta Alberdi, Raquel; Llanes, Ana B.F.; Ortega, Raquel Almazan; Exposito, Ruben Roman; Collado, Jose M.V.; Oliveres, Xavier Castells; Queiro Verdes, Teresa; Natal Ramos, Carmen; Sanz, Maria Ederra; Salas Trejo, Dolores

    2011-01-01

    To evaluate the effect of radiologist experience on the risk of false-positive results in population-based breast cancer screening programmes. We evaluated 1,440,384 single-read screening mammograms, corresponding to 471,112 women aged 45-69 years participating in four Spanish programmes between 1990 and 2006. The mammograms were interpreted by 72 radiologists. The overall percentage of false-positive results was 5.85% and that for false-positives resulting in an invasive procedure was 0.38%. Both the risk of false-positives overall and of false-positives leading to an invasive procedure significantly decreased (p 14,999 mammograms with respect to the reference category (<500). The risk of both categories of false-positives was also significantly reduced (p < 0.001) as radiologists' years of experience increased: OR 0.96 and OR 0.84, respectively, for 1 year's experience and OR 0.72 and OR 0.73, respectively, for more than 4 years' experience with regard to the category of <1 year's experience. Radiologist experience is a determining factor in the risk of a false-positive result in breast cancer screening. (orig.)

  8. Positive predictive value estimates for cell-free noninvasive prenatal screening from data of a large referral genetic diagnostic laboratory.

    Science.gov (United States)

    Petersen, Andrea K; Cheung, Sau Wai; Smith, Janice L; Bi, Weimin; Ward, Patricia A; Peacock, Sandra; Braxton, Alicia; Van Den Veyver, Ignatia B; Breman, Amy M

    2017-12-01

    Since its debut in 2011, cell-free fetal DNA screening has undergone rapid expansion with respect to both utilization and coverage. However, conclusive data regarding the clinical validity and utility of this screening tool, both for the originally included common autosomal and sex-chromosomal aneuploidies as well as the more recently added chromosomal microdeletion syndromes, have lagged behind. Thus, there is a continued need to educate clinicians and patients about the current benefits and limitations of this screening tool to inform pre- and posttest counseling, pre/perinatal decision making, and medical risk assessment/management. The objective of this study was to determine the positive predictive value and false-positive rates for different chromosomal abnormalities identified by cell-free fetal DNA screening using a large data set of diagnostic testing results on invasive samples submitted to the laboratory for confirmatory studies. We tested 712 patient samples sent to our laboratory to confirm a cell-free fetal DNA screening result, indicating high risk for a chromosome abnormality. We compiled data from all cases in which the indication for confirmatory testing was a positive cell-free fetal DNA screen, including the common trisomies, sex chromosomal aneuploidies, microdeletion syndromes, and other large genome-wide copy number abnormalities. Testing modalities included fluorescence in situ hybridization, G-banded karyotype, and/or chromosomal microarray analysis performed on chorionic villus samples, amniotic fluid, or postnatally obtained blood samples. Positive predictive values and false-positive rates were calculated from tabulated data. The positive predictive values for trisomy 13, 18, and 21 were consistent with previous reports at 45%, 76%, and 84%, respectively. For the microdeletion syndrome regions, positive predictive values ranged from 0% for detection of Cri-du-Chat syndrome and Prader-Willi/Angelman syndrome to 14% for 1p36 deletion

  9. A household survey on screening practices of household contacts of smear positive tuberculosis patients in Vietnam

    NARCIS (Netherlands)

    Thanh, Thuy Hoang Thi; Ngoc, Sy Dinh; Viet, Nhung Nguyen; van, Hung Nguyen; Horby, Peter; Cobelens, Frank G. J.; Wertheim, Heiman F. L.

    2014-01-01

    Close contacts of tuberculosis (TB) patients are at increased risk of developing tuberculosis. Although passive contact screening guidelines are incorporated in the national TB control program, currently it is unknown how frequent close contacts are screened for TB in Vietnam. This study assesses

  10. Identification of new drug candidates against Borrelia burgdorferi using high-throughput screening

    Directory of Open Access Journals (Sweden)

    Pothineni VR

    2016-04-01

    Full Text Available Venkata Raveendra Pothineni,1 Dhananjay Wagh,1 Mustafeez Mujtaba Babar,1 Mohammed Inayathullah,1 David Solow-Cordero,2 Kwang-Min Kim,1 Aneesh V Samineni,1 Mansi B Parekh,1 Lobat Tayebi,3 Jayakumar Rajadas1 1Biomaterials and Advanced Drug Delivery Laboratory, Stanford Cardiovascular Pharmacology Division, Cardiovascular Institute, Stanford University School of Medicine, Palo Alto, 2Chemical & Systems Biology, Stanford University School of Medicine, Stanford, CA, 3Department of Developmental Sciences, Marquette University School of Dentistry, Milwaukee, WI, USA Abstract: Lyme disease is the most common zoonotic bacterial disease in North America. It is estimated that >300,000 cases per annum are reported in USA alone. A total of 10%–20% of patients who have been treated with antibiotic therapy report the recrudescence of symptoms, such as muscle and joint pain, psychosocial and cognitive difficulties, and generalized fatigue. This condition is referred to as posttreatment Lyme disease syndrome. While there is no evidence for the presence of viable infectious organisms in individuals with posttreatment Lyme disease syndrome, some researchers found surviving Borrelia burgdorferi population in rodents and primates even after antibiotic treatment. Although such observations need more ratification, there is unmet need for developing the therapeutic agents that focus on removing the persisting bacterial form of B. burgdorferi in rodent and nonhuman primates. For this purpose, high-throughput screening was done using BacTiter-Glo assay for four compound libraries to identify candidates that stop the growth of B. burgdorferi in vitro. The four chemical libraries containing 4,366 compounds (80% Food and Drug Administration [FDA] approved that were screened are Library of Pharmacologically Active Compounds (LOPAC1280, the National Institutes of Health Clinical Collection, the Microsource Spectrum, and the Biomol FDA. We subsequently identified 150

  11. Susceptibility of coagulase positive staphylococci isolated from cow's mammary gland to antibacterial drugs

    Directory of Open Access Journals (Sweden)

    Savić-Rajić Nataša

    2009-01-01

    Full Text Available Coagulase positive staphylococci are one of the most common causes of chronic udder infection. Indiscriminate use of antimicrobial drugs and their presence in the environment where animals live has led to coagulase positive staphylococci strains resistant to antimicrobial means. Proper and timely treatment of sub-clinical mastitis, based on the most effective use of antimicrobial drugs, is the key to good health of the milk herd. The aim was to determine the antimicrobial efficacy of selected assets in relation to coagulase positive staphylococci isolated from samples of milk taken from individual udder quarters of cows in cases of udder infection from three farms with different mastitis prevalence. From a total of 9245 samples of milk taken from individual udder quarters of cows from three farms, 852 strains isolated were coagulase positive staphylococci. Coagulase positive staphylococci were isolated on blood agar and identified on the basis of macro-morphological characteristics and the coagulase and catalase test. The sensitivity of the coagulase positive staphylococci was tested by the Kirby Bauer agar diffusion method with the following antimicrobials: penicillin 6µg, amoxicillin / sulbactam (20 +10µg, cloxacillin 25 µg, cefalexin 30 µg, ceftiofur 30µg, linkomycin 15µg, 30 µg gentamycin and tetracycline 30 µg. Sensitivity testing of coagulase positive staphylococci, isolated in cases of intramammary cow infections, established a high degree of sensitivity in vitro towards penicilinasa resistant drugs (amoxicillin-sublactam, cloxacilin, cephalosporins of the first and third generations and linkomycin. The highest levels of resistance to penicillin (70.4% were found on a farm with a moderate prevalence of udder infection, then on the farm with the highest prevalence of intramammary infections (60.2% and the lowest on the farm with controlled levels of resistance of infection (43.7%. .

  12. The Utility of Impulsive Bias and Altered Decision Making as Predictors of Drug Efficacy and Target Selection: Rethinking Behavioral Screening for Antidepressant Drugs.

    Science.gov (United States)

    Marek, Gerard J; Day, Mark; Hudzik, Thomas J

    2016-03-01

    Cognitive dysfunction may be a core feature of major depressive disorder, including affective processing bias, abnormal response to negative feedback, changes in decision making, and increased impulsivity. Accordingly, a translational medicine paradigm predicts clinical action of novel antidepressants by examining drug-induced changes in affective processing bias. With some exceptions, these concepts have not been systematically applied to preclinical models to test new chemical entities. The purpose of this review is to examine whether an empirically derived behavioral screen for antidepressant drugs may screen for compounds, at least in part, by modulating an impulsive biasing of responding and altered decision making. The differential-reinforcement-of-low-rate (DRL) 72-second schedule is an operant schedule with a documented fidelity for discriminating antidepressant drugs from nonantidepressant drugs. However, a theoretical basis for this empirical relationship has been lacking. Therefore, this review will discuss whether response bias toward impulsive behavior may be a critical screening characteristic of DRL behavior requiring long inter-response times to obtain rewards. This review will compare and contrast DRL behavior with the five-choice serial reaction time task, a test specifically designed for assessing motoric impulsivity, with respect to psychopharmacological testing and the neural basis of distributed macrocircuits underlying these tasks. This comparison suggests that the existing empirical basis for the DRL 72-second schedule as a pharmacological screen for antidepressant drugs is complemented by a novel hypothesis that altering impulsive response bias for rodents trained on this operant schedule is a previously unrecognized theoretical cornerstone for this screening paradigm. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  13. Engendering drug problems: Materialising gender in the DUDIT and other screening and diagnostic 'apparatuses'.

    Science.gov (United States)

    Dwyer, Robyn; Fraser, Suzanne

    2017-06-01

    It is widely accepted that alcohol and other drug consumption is profoundly gendered. Just where this gendering is occurring, however, remains the subject of debate. We contend that one important and overlooked site where the gendering of substance consumption and addiction is taking place is through AOD research itself: in particular, through the addiction screening and diagnostic tools designed to measure and track substance consumption and problems within populations. These tools establish key criteria and set numerical threshold scores for the identification of problems. In many of these tools, separate threshold scores for women and men are established or recommended. Drawing on Karen Barad's concept of post-humanist performativity, in this article we examine the ways in which gender itself is being materialised by these apparatuses of measurement. We focus primarily on the Drug Use Disorders Identification Test (DUDIT) tool as an exemplar of gendering processes that operate across addiction tools more broadly. We consider gendering processes operating through tools questions themselves and we also examine the quantification and legitimation processes used in establishing gender difference and the implications these have for women. We find tools rely on and reproduce narrow and marginalising assumptions about women as essentially fragile and vulnerable and simultaneously reinforce normative expectations that women sacrifice pleasure. The seemingly objective and neutral quantification processes operating in tools naturalise gender as they enact it. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Fully automated drug screening of dried blood spots using online LC-MS/MS analysis

    Directory of Open Access Journals (Sweden)

    Stefan Gaugler

    2018-01-01

    Full Text Available A new and fully automated workflow for the cost effective drug screening of large populations based on the dried blood spot (DBS technology was introduced in this study. DBS were prepared by spotting 15 μL of whole blood, previously spiked with alprazolam, amphetamine, cocaine, codeine, diazepam, fentanyl, lysergic acid diethylamide (LSD, 3,4-methylenedioxymethamphet-amine (MDMA, methadone, methamphetamine, morphine and oxycodone onto filter paper cards. The dried spots were scanned, spiked with deuterated standards and directly extracted. The extract was transferred online to an analytical LC column and then to the electrospray ionization tandem mass spectrometry system. All drugs were quantified at their cut-off level and good precision and correlation within the calibration range was obtained. The method was finally applied to DBS samples from two patients with back pain and codeine and oxycodone could be identified and quantified accurately below the level of misuse of 89.6 ng/mL and 39.6 ng/mL respectively.

  15. Establishment of a Fast Chemical Identification System for screening of counterfeit drugs of macrolide antibiotics.

    Science.gov (United States)

    Hu, Chang-Qin; Zou, Wen-Buo; Hu, Wang-Sheng; Ma, Xiao-Kang; Yang, Min-Zhi; Zhou, Shi-Lin; Sheng, Jin-Fang; Li, Yuan; Cheng, Shuang-Hong; Xue, Jing

    2006-01-23

    A Fast Chemical Identification System (FCIS) consisting of two colour reactions based on functional groups in molecules of macrolide antibiotics and two TLC methods was developed for screening of fake macrolide drugs. The active ingredients could be extracted from their oral preparations by absolute alcohol. Sulfuric acid reaction as a common reaction of macrolides was first used to distinguish the macrolides from other types of drugs and then 16-membered macrolides and 14-membered ones were distinguished by potassium permanganate reactions depending on the time of loss of colour in the test solution; after which a TLC method carried out on a GF(254) plate (5 cm x 10 cm) was chosen to further identification of the macrolides. The mobile phase A consisting of ethyl acetate, hexane and ammonia (100:15:15, v/v) was used for the identification of 14-membered macrolides, and the mobile phase B consisting of trichloromethane, methanol and ammonia (100:5:1, v/v) was used for the identification of 16-membered ones. A suspected counterfeit macrolide preparation can be identified within 40 min. The system can be used under different conditions and has the virtues of robustness, simplicity and speed.

  16. Association of positive responses to suicide screening questions with hospital admission and repeated emergency department visits in children and adolescents.

    Science.gov (United States)

    Ballard, Elizabeth D; Horowitz, Lisa M; Jobes, David A; Wagner, Barry M; Pao, Maryland; Teach, Stephen J

    2013-10-01

    Although validated suicide screening tools exist for use among children and adolescents presenting to emergency departments (EDs), the associations between screening positive for suicide risk and immediate psychiatric hospital admission or subsequent ED use, stratified by age, have not been examined. This is a retrospective cohort study of a consecutive case series of patients aged 8 to 18 years presenting with psychiatric chief complaints during a 9-month period to a single urban tertiary care pediatric ED. Eligible patients were administered a subset of questions from the Risk of Suicide Questionnaire. Outcomes included the odds of psychiatric hospitalization at the index visit and repeated ED visits for psychiatric complaints within the following year, stratified by age. Of the 568 patients presenting during the study period, responses to suicide screening questions were available for 442 patients (78%). A total of 159 (36%) of 442 were hospitalized and 130 (29%) of 442 had 1 or more ED visits within the following year. The proportion of patients providing positive responses to 1 or more suicide screening questions did not differ between patients aged 8 to 12 years and those aged 13 to 18 years (77/154 [50%] vs 137/288 [48%], P = 0.63). A positive response to 1 or more of the questions was significantly associated with increased odds of psychiatric hospitalization in the older age group [adjusted odds ratio, 3.82; 95% confidence interval, 2.24-6.54) and with repeated visits to the ED in the younger age group (adjusted odds ratio, 3.55 95% confidence interval, 1.68-7.50). Positive responses to suicide screening questions were associated with acute psychiatric hospitalization and repeated ED visits. Suicide screening in a pediatric ED may identify children and adolescents with increased need of psychiatric resources.

  17. Automated high-content live animal drug screening using C. elegans expressing the aggregation prone serpin α1-antitrypsin Z.

    Directory of Open Access Journals (Sweden)

    Sager J Gosai

    2010-11-01

    Full Text Available The development of preclinical models amenable to live animal bioactive compound screening is an attractive approach to discovering effective pharmacological therapies for disorders caused by misfolded and aggregation-prone proteins. In general, however, live animal drug screening is labor and resource intensive, and has been hampered by the lack of robust assay designs and high throughput work-flows. Based on their small size, tissue transparency and ease of cultivation, the use of C. elegans should obviate many of the technical impediments associated with live animal drug screening. Moreover, their genetic tractability and accomplished record for providing insights into the molecular and cellular basis of human disease, should make C. elegans an ideal model system for in vivo drug discovery campaigns. The goal of this study was to determine whether C. elegans could be adapted to high-throughput and high-content drug screening strategies analogous to those developed for cell-based systems. Using transgenic animals expressing fluorescently-tagged proteins, we first developed a high-quality, high-throughput work-flow utilizing an automated fluorescence microscopy platform with integrated image acquisition and data analysis modules to qualitatively assess different biological processes including, growth, tissue development, cell viability and autophagy. We next adapted this technology to conduct a small molecule screen and identified compounds that altered the intracellular accumulation of the human aggregation prone mutant that causes liver disease in α1-antitrypsin deficiency. This study provides powerful validation for advancement in preclinical drug discovery campaigns by screening live C. elegans modeling α1-antitrypsin deficiency and other complex disease phenotypes on high-content imaging platforms.

  18. Recall of symptoms and treatment of syphilis and yaws by healthy blood donors screening positive for syphilis in Kumasi, Ghana

    Directory of Open Access Journals (Sweden)

    Francis Sarkodie

    2016-09-01

    Conclusions: A small proportion of confirmed seroreactive donors in this sample had any recall of symptoms or treatment for yaws or syphilis. These data suggest that clinical questioning adds little further information to the current screening algorithm. The relative contribution of yaws and syphilis to frequent positive tests in endemic areas remains speculative.

  19. Hypertensive disorders of pregnancy and risk of screening positive for Posttraumatic Stress Disorder : A cross-sectional study

    NARCIS (Netherlands)

    Porcel, Jacqueline; Feigal, Christine; Poye, Laney; Postma, Ineke R.; Zeeman, Gerda G.; Olowoyeye, Abiola; Tsigas, Eleni; Wilson, Melissa

    2013-01-01

    Objectives: Hypertensive Disorders of Pregnancy (HDP) encompass a spectrum of disorders that affect 6-8% of US pregnancies. We aim to determine the impact of self-reported history of HDP as a risk factor for screening positive for Posttraumatic Stress Disorder (PTSD), which results from exposure to

  20. Data Mining Approaches for Genomic Biomarker Development: Applications Using Drug Screening Data from the Cancer Genome Project and the Cancer Cell Line Encyclopedia.

    Directory of Open Access Journals (Sweden)

    David G Covell

    Full Text Available Developing reliable biomarkers of tumor cell drug sensitivity and resistance can guide hypothesis-driven basic science research and influence pre-therapy clinical decisions. A popular strategy for developing biomarkers uses characterizations of human tumor samples against a range of cancer drug responses that correlate with genomic change; developed largely from the efforts of the Cancer Cell Line Encyclopedia (CCLE and Sanger Cancer Genome Project (CGP. The purpose of this study is to provide an independent analysis of this data that aims to vet existing and add novel perspectives to biomarker discoveries and applications. Existing and alternative data mining and statistical methods will be used to a evaluate drug responses of compounds with similar mechanism of action (MOA, b examine measures of gene expression (GE, copy number (CN and mutation status (MUT biomarkers, combined with gene set enrichment analysis (GSEA, for hypothesizing biological processes important for drug response, c conduct global comparisons of GE, CN and MUT as biomarkers across all drugs screened in the CGP dataset, and d assess the positive predictive power of CGP-derived GE biomarkers as predictors of drug response in CCLE tumor cells. The perspectives derived from individual and global examinations of GEs, MUTs and CNs confirm existing and reveal unique and shared roles for these biomarkers in tumor cell drug sensitivity and resistance. Applications of CGP-derived genomic biomarkers to predict the drug response of CCLE tumor cells finds a highly significant ROC, with a positive predictive power of 0.78. The results of this study expand the available data mining and analysis methods for genomic biomarker development and provide additional support for using biomarkers to guide hypothesis-driven basic science research and pre-therapy clinical decisions.

  1. Advantageous use of HepaRG cells for the screening and mechanistic study of drug-induced steatosis

    Energy Technology Data Exchange (ETDEWEB)

    Tolosa, Laia [Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Valencia 46026 (Spain); Gómez-Lechón, M. José [Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Valencia 46026 (Spain); CIBERehd, FIS, Barcelona 08036 (Spain); Jiménez, Nuria [Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Valencia 46026 (Spain); Hervás, David [Biostatistics Unit, Instituto de Investigación Sanitaria La Fe, Valencia 46026 (Spain); Jover, Ramiro [Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Valencia 46026 (Spain); CIBERehd, FIS, Barcelona 08036 (Spain); Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Valencia 46010 (Spain); Donato, M. Teresa, E-mail: donato_mte@gva.es [Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Valencia 46026 (Spain); CIBERehd, FIS, Barcelona 08036 (Spain); Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Valencia 46010 (Spain)

    2016-07-01

    Only a few in vitro assays have been proposed to evaluate the steatotic potential of new drugs. The present study examines the utility of HepaRG cells as a cell-based assay system for screening drug-induced liver steatosis. A high-content screening assay was run to evaluate multiple toxicity-related cell parameters in HepaRG cells exposed to 28 compounds, including drugs reported to cause steatosis through different mechanisms and non-steatotic compounds. Lipid content was the most sensitive parameter for all the steatotic drugs, whereas no effects on lipid levels were produced by non-steatotic compounds. Apart from fat accumulation, increased ROS production and altered mitochondrial membrane potential were also found in the cells exposed to steatotic drugs, which indicates that all these cellular events contributed to drug-induced hepatotoxicity. These findings are of clinical relevance as most effects were observed at drug concentrations under 100-fold of the therapeutic peak plasmatic concentration. HepaRG cells showed increased lipid overaccumulation vs. HepG2 cells, which suggests greater sensitivity to drug-induced steatosis. An altered expression profile of transcription factors and the genes that code key proteins in lipid metabolism was also found in the cells exposed to drugs capable of inducing liver steatosis. Our results generally indicate the value of HepaRG cells for assessing the risk of liver damage associated with steatogenic compounds and for investigating the molecular mechanisms involved in drug-induced steatosis. - Highlights: • HepaRG cells were explored as an in vitro model to detect steatogenic potential. • Multiple toxicity-related endpoints were analysed by HCS. • HepaRG showed a greater sensitivity to drug-induced steatosis than HepG2 cells. • Changes in the expression of genes related to lipid metabolism were revealed. • HepaRG allow mechanistic understanding of liver damage induced by steatogenic drugs.

  2. Advantageous use of HepaRG cells for the screening and mechanistic study of drug-induced steatosis

    International Nuclear Information System (INIS)

    Tolosa, Laia; Gómez-Lechón, M. José; Jiménez, Nuria; Hervás, David; Jover, Ramiro; Donato, M. Teresa

    2016-01-01

    Only a few in vitro assays have been proposed to evaluate the steatotic potential of new drugs. The present study examines the utility of HepaRG cells as a cell-based assay system for screening drug-induced liver steatosis. A high-content screening assay was run to evaluate multiple toxicity-related cell parameters in HepaRG cells exposed to 28 compounds, including drugs reported to cause steatosis through different mechanisms and non-steatotic compounds. Lipid content was the most sensitive parameter for all the steatotic drugs, whereas no effects on lipid levels were produced by non-steatotic compounds. Apart from fat accumulation, increased ROS production and altered mitochondrial membrane potential were also found in the cells exposed to steatotic drugs, which indicates that all these cellular events contributed to drug-induced hepatotoxicity. These findings are of clinical relevance as most effects were observed at drug concentrations under 100-fold of the therapeutic peak plasmatic concentration. HepaRG cells showed increased lipid overaccumulation vs. HepG2 cells, which suggests greater sensitivity to drug-induced steatosis. An altered expression profile of transcription factors and the genes that code key proteins in lipid metabolism was also found in the cells exposed to drugs capable of inducing liver steatosis. Our results generally indicate the value of HepaRG cells for assessing the risk of liver damage associated with steatogenic compounds and for investigating the molecular mechanisms involved in drug-induced steatosis. - Highlights: • HepaRG cells were explored as an in vitro model to detect steatogenic potential. • Multiple toxicity-related endpoints were analysed by HCS. • HepaRG showed a greater sensitivity to drug-induced steatosis than HepG2 cells. • Changes in the expression of genes related to lipid metabolism were revealed. • HepaRG allow mechanistic understanding of liver damage induced by steatogenic drugs.

  3. Linear antenna of an arbitrary orientation and position in cylindric screen

    International Nuclear Information System (INIS)

    Prijmenko, S.D.; Papkovich, V.G.; Khizhnyak, N.A.

    1991-01-01

    An equation of the linear antenna in cylindric screen is formulated. Using the averaging method a solution of this equation for the antenna of arbitrary orientation which does not contact the screen walls or contacts them in one or two ends is received. The obtained asymptotic expression for stream permits to describe in a single manner the case of resonance and non-resonance scattering. These results may be applied in design of UHF and accelerating installations using cylindric screens charged with linear vibrators. 9 refs. (author)

  4. Position paper from the Spanish Society of Rheumatology on biosimilar drugs.

    Science.gov (United States)

    Abad Hernández, Miguel Ángel; Andreu, José Luis; Caracuel Ruiz, Miguel Ángel; Belmonte Serrano, Miguel Ángel; Díaz-González, Federico; Moreno Muelas, José Vicente

    2015-01-01

    A biosimilar (BS) is a biological drug that contains a version of the active substance of an already authorized original biological product. The BSs are marketed after patent period of the original drug has ended and once it has been demonstrated that the differences regarding the innovative medicine have no relevant effect on its safety or clinical efficacy. The Spanish Society of Rheumatology, in line with the European Medicines Agency, considers that because of its nature and complexity of production, a BS cannot be considered to be the same as a generic drug. The Spanish Society of Rheumatology expresses an unequivocal commitment to the sustainability of the health system in our country and our steadfast alignment with all measures designed to ensure continuity, without reducing the quality of care. Therefore, we believe that the advent of BSs will likely facilitate access of patients with rheumatic diseases to the biological drugs. This article reviews the European Medicines Agency requirements for authorization, the Spanish legal framework and controversies on BS and presents the position paper of the Spanish Society of Rheumatology on these drugs. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

  5. On the Estimation of Disease Prevalence by Latent Class Models for Screening Studies Using Two Screening Tests with Categorical Disease Status Verified in Test Positives Only

    Science.gov (United States)

    Chu, Haitao; Zhou, Yijie; Cole, Stephen R.; Ibrahim, Joseph G.

    2010-01-01

    Summary To evaluate the probabilities of a disease state, ideally all subjects in a study should be diagnosed by a definitive diagnostic or gold standard test. However, since definitive diagnostic tests are often invasive and expensive, it is generally unethical to apply them to subjects whose screening tests are negative. In this article, we consider latent class models for screening studies with two imperfect binary diagnostic tests and a definitive categorical disease status measured only for those with at least one positive screening test. Specifically, we discuss a conditional independent and three homogeneous conditional dependent latent class models and assess the impact of misspecification of the dependence structure on the estimation of disease category probabilities using frequentist and Bayesian approaches. Interestingly, the three homogeneous dependent models can provide identical goodness-of-fit but substantively different estimates for a given study. However, the parametric form of the assumed dependence structure itself is not “testable” from the data, and thus the dependence structure modeling considered here can only be viewed as a sensitivity analysis concerning a more complicated non-identifiable model potentially involving heterogeneous dependence structure. Furthermore, we discuss Bayesian model averaging together with its limitations as an alternative way to partially address this particularly challenging problem. The methods are applied to two cancer screening studies, and simulations are conducted to evaluate the performance of these methods. In summary, further research is needed to reduce the impact of model misspecification on the estimation of disease prevalence in such settings. PMID:20191614

  6. Interval Breast Cancer Rates and Histopathologic Tumor Characteristics after False-Positive Findings at Mammography in a Population-based Screening Program.

    Science.gov (United States)

    Hofvind, Solveig; Sagstad, Silje; Sebuødegård, Sofie; Chen, Ying; Roman, Marta; Lee, Christoph I

    2018-04-01

    Purpose To compare rates and tumor characteristics of interval breast cancers (IBCs) detected after a negative versus false-positive screening among women participating in the Norwegian Breast Cancer Screening Program. Materials and Methods The Cancer Registry Regulation approved this retrospective study. Information about 423 445 women aged 49-71 years who underwent 789 481 full-field digital mammographic screening examinations during 2004-2012 was extracted from the Cancer Registry of Norway. Rates and odds ratios of IBC among women with a negative (the reference group) versus a false-positive screening were estimated by using logistic regression models adjusted for age at diagnosis and county of residence. Results A total of 1302 IBCs were diagnosed after 789 481 screening examinations, of which 7.0% (91 of 1302) were detected among women with a false-positive screening as the most recent breast imaging examination before detection. By using negative screening as the reference, adjusted odds ratios of IBCs were 3.3 (95% confidence interval [CI]: 2.6, 4.2) and 2.8 (95% CI: 1.8, 4.4) for women with a false-positive screening without and with needle biopsy, respectively. Women with a previous negative screening had a significantly lower proportion of tumors that were 10 mm or less (14.3% [150 of 1049] vs 50.0% [seven of 14], respectively; P false-positive screening with benign biopsy. A retrospective review of the screening mammographic examinations identified 42.9% (39 of 91) of the false-positive cases to be the same lesion as the IBC. Conclusion By using a negative screening as the reference, a false-positive screening examination increased the risk of an IBC three-fold. The tumor characteristics of IBC after a negative screening were less favorable compared with those detected after a previous false-positive screening. © RSNA, 2017 Online supplemental material is available for this article.

  7. Impact of intermediate mammography assessment on the likelihood of false-positive results in breast cancer screening programmes

    Energy Technology Data Exchange (ETDEWEB)

    Ascunce, Nieves [Public Health Institute, CIBERESP, Navarra Breast Cancer Screening Programme, Pamplona (Spain); Instituto de Salud Publica, Navarra Breast Cancer Screening Programme, Pamplona (Spain); Ederra, Maria; Delfrade, Josu; Erdozain, Nieves [Public Health Institute, CIBERESP, Navarra Breast Cancer Screening Programme, Pamplona (Spain); Baroja, Araceli [Fundacion Rioja Salud, Logrono (Spain); Zubizarreta, Raquel [Public Health and Planning Directorate, Health Office, Galician Breast Cancer Screening Programme, Galicia (Spain); Salas, Dolores [General Directorate Public Health and Centre for Public Health Research (CSISP), Valencia (Spain); Castells, Xavier [Mar Teaching Hospital, CIBERESP, Department of Clinical Epidemiology, Barcelona (Spain)

    2012-02-15

    Breast cancer screening is offered to 100% of the target population in Spain and intermediate mammograms (IMs) are sometimes indicated. This study was aimed at analysing the frequency of IMs, the factors determining their recommendation, and their impact on the risk of false-positive results and the detection rate. Data from 3,471,307 mammograms from Spanish breast cancer screening programmes were included. 3.36% of the mammograms were IMs. The factors associated with the use of IMs were age, initial screening, previous invasive tests, a familial history of breast cancer and use of hormone replacement therapy. In screening episodes with an IM, the probability of a false-positive result was 13.74% (95% CI: 13.43-14.05), almost double that in episodes without IMs (6.02%, 95% CI 5.99-6.05). In young women with previous invasive procedures, a familial history of breast cancer or hormone replacement therapy use who were undergoing their initial screen, this probability was lower when IMs were performed. IMs always increased the detection rate. The factors prompting IMs should be characterised so that radiologists can systematise their recommendations according to the presence of the factors maximising the benefits and minimising the adverse effects of this procedure. (orig.)

  8. Impact of intermediate mammography assessment on the likelihood of false-positive results in breast cancer screening programmes

    International Nuclear Information System (INIS)

    Ascunce, Nieves; Ederra, Maria; Delfrade, Josu; Erdozain, Nieves; Baroja, Araceli; Zubizarreta, Raquel; Salas, Dolores; Castells, Xavier

    2012-01-01

    Breast cancer screening is offered to 100% of the target population in Spain and intermediate mammograms (IMs) are sometimes indicated. This study was aimed at analysing the frequency of IMs, the factors determining their recommendation, and their impact on the risk of false-positive results and the detection rate. Data from 3,471,307 mammograms from Spanish breast cancer screening programmes were included. 3.36% of the mammograms were IMs. The factors associated with the use of IMs were age, initial screening, previous invasive tests, a familial history of breast cancer and use of hormone replacement therapy. In screening episodes with an IM, the probability of a false-positive result was 13.74% (95% CI: 13.43-14.05), almost double that in episodes without IMs (6.02%, 95% CI 5.99-6.05). In young women with previous invasive procedures, a familial history of breast cancer or hormone replacement therapy use who were undergoing their initial screen, this probability was lower when IMs were performed. IMs always increased the detection rate. The factors prompting IMs should be characterised so that radiologists can systematise their recommendations according to the presence of the factors maximising the benefits and minimising the adverse effects of this procedure. (orig.)

  9. High-Throughput Lipolysis in 96-Well Plates for Rapid Screening of Lipid-Based Drug Delivery Systems

    DEFF Research Database (Denmark)

    Mosgaard, Mette D; Sassene, Philip J; Mu, Huiling

    2017-01-01

    The high-throughput in vitro intestinal lipolysis model (HTP) applicable for rapid and low-scale screening of lipid-based drug delivery systems (LbDDSs) was optimized and adjusted as to be conducted in 96-well plates (HTP-96). Three different LbDDSs (I-III) loaded with danazol or cinnarizine were...

  10. AOP: An R Package For Sufficient Causal Analysis in Pathway-based Screening of Drugs and Chemicals for Adversity

    Science.gov (United States)

    Summary: How can I quickly find the key events in a pathway that I need to monitor to predict that a/an beneficial/adverse event/outcome will occur? This is a key question when using signaling pathways for drug/chemical screening in pharma-cology, toxicology and risk assessment. ...

  11. Desorption electrospray ionisation mass spectrometry: A rapid screening tool for veterinary drug preparations and forensic samples from hormone crime investigations

    NARCIS (Netherlands)

    Nielen, M.W.F.; Hooijerink, H.; Claassen, F.C.; Engelen, M.C.; Beek, van T.A.

    2009-01-01

    Hormone and veterinary drug screening and forensics can benefit from the recent developments in desorption electrospray ionisation (DESI) mass spectrometry (MS). In this work the feasibility of DESI application has been studied. Using a linear ion trap or quadrupole time-of-flight (TOF) MS

  12. Brief Screening and Intervention for Alcohol and Drug Use in a College Student Health Clinic: Feasibility, Implementation, and Outcomes

    Science.gov (United States)

    Amaro, Hortensia; Reed, Elizabeth; Rowe, Erin; Picci, Jennifer; Mantella, Philomena; Prado, Guillermo

    2010-01-01

    Objective: Evaluation of the Brief Alcohol Screen and Intervention in College Students (BASICS) in a university primary care setting. Participants/Methods: Undergraduates (N = 449) participated in BASICS and electronic surveys assessing frequency/quantity of alcohol and drug use, psychosocial and mental health outcomes, and demographic…

  13. Simultaneous screening and quantification of 52 common pharmaceuticals and drugs of abuse in hair using UPLC-TOF-MS

    DEFF Research Database (Denmark)

    Nielsen, Marie Katrine Klose; Johansen, Sys Stybe; Dalsgaard, Petur Weihe

    2010-01-01

    An UPLC-TOF-MS method for simultaneous screening and quantification of 52 drugs in hair was developed and validated. The selected drugs represent the most common classes of pharmaceuticals and drugs of abuse such as amphetamines, analgesics, antidepressants, antipsychotics, benzodiazepines, cocaine.......05 ng/mg for 87% of the analytes. A good linear behaviour was achieved for most of the analytes in the range from LOQ to 10 or 25 ng/mg except for the amphetamines. The method showed an acceptable precision and trueness, since the obtained CV and BIAS values were...

  14. Cost effectiveness of screening strategies for early identification of HIV and HCV infection in injection drug users.

    Directory of Open Access Journals (Sweden)

    Lauren E Cipriano

    Full Text Available To estimate the cost, effectiveness, and cost effectiveness of HIV and HCV screening of injection drug users (IDUs in opioid replacement therapy (ORT.Dynamic compartmental model of HIV and HCV in a population of IDUs and non-IDUs for a representative U.S. urban center with 2.5 million adults (age 15-59.We considered strategies of screening individuals in ORT for HIV, HCV, or both infections by antibody or antibody and viral RNA testing. We evaluated one-time and repeat screening at intervals from annually to once every 3 months. We calculated the number of HIV and HCV infections, quality-adjusted life years (QALYs, costs, and incremental cost-effectiveness ratios (ICERs.Adding HIV and HCV viral RNA testing to antibody testing averts 14.8-30.3 HIV and 3.7-7.7 HCV infections in a screened population of 26,100 IDUs entering ORT over 20 years, depending on screening frequency. Screening for HIV antibodies every 6 months costs $30,700/QALY gained. Screening for HIV antibodies and viral RNA every 6 months has an ICER of $65,900/QALY gained. Strategies including HCV testing have ICERs exceeding $100,000/QALY gained unless awareness of HCV-infection status results in a substantial reduction in needle-sharing behavior.Although annual screening for antibodies to HIV and HCV is modestly cost effective compared to no screening, more frequent screening for HIV provides additional benefit at less cost. Screening individuals in ORT every 3-6 months for HIV infection using both antibody and viral RNA technologies and initiating ART for acute HIV infection appears cost effective.

  15. Positive posttraumatic stress disorder screens among first-time medical cannabis patients: prevalence and association with other substance use.

    Science.gov (United States)

    Bohnert, Kipling M; Perron, Brian E; Ashrafioun, Lisham; Kleinberg, Felicia; Jannausch, Mary; Ilgen, Mark A

    2014-10-01

    Twenty-one states and the District of Columbia have passed legislation allowing for the use of medical cannabis for those individuals with qualifying medical conditions, which include posttraumatic stress disorder (PTSD) for a growing number of states. Little information is available regarding PTSD among medical cannabis patients. This study seeks to provide initial data on this topic by examining the prevalence and correlates of positive PTSD screens among a sample of patients seeking medical cannabis certification for the first time (n=186). Twenty-three percent (42/186; 95% confidence interval [CI] =17%-29%) of the patients in the study sample screened positive for PTSD. Moreover, the group that screened positive for PTSD had higher percentages of lifetime prescription opioid, cocaine, prescription sedative, and street opioid use, as well as a higher percentage of recent prescription sedative use, than the group that screened negative for PTSD. These findings highlight the relatively common use of other substances among medical cannabis patients with significant PTSD symptoms, even when compared with other patients seeking medical cannabis for the first time. As a growing number of states include PTSD among the list of qualifying medical conditions for medical cannabis, additional research is needed to better characterize the longitudinal relationship between medical cannabis use and PTSD symptoms. Published by Elsevier Ltd.

  16. Factors associated with false-positive self-reported adherence to antihypertensive drugs.

    Science.gov (United States)

    Tedla, Y G; Bautista, L E

    2017-05-01

    Self-reported medication adherence is known to overestimate true adherence. However, little is known about patient factors that may contribute to the upward bias in self-reported medication adherence. The objective of this study is to examine whether demographic, behavioral, medication and mood factors are associated with being a false-positive self-reported adherer (FPA) to antihypertensive drug treatment. We studied 175 patients (mean age: 50 years; 57% men) from primary-care clinics starting antihypertensive drug treatment. Self-reported adherence (SRA) was measured with the Medication Adherence Report Scale (MARS) and by the number of drug doses missed in the previous week/month, and compared with pill count adherence ratio (PCAR) as gold standard. Data on adherence, demographic, behavioral, medication and mood factors were collected at baseline and every 3 months up to 1 year. FPA was defined as being a non-adherer by PCAR and an adherer by self-report. Mixed effect logistic regression was used for the analysis. Twenty percent of participants were FPA. Anxiety increased (odds ratio (OR): 3.00; P=0.01), whereas smoking (OR: 0.40; P=0.03) and drug side effects (OR: 0.46, P=0.03) decreased the probability for FPA by MARS. Education below high-school completion increased the probability of being an FPA as measured by missing doses in the last month (OR: 1.66; P=0.04) and last week (OR: 1.88; P=0.02). The validity of SRA varies significantly according to drug side effects, behavioral factors and patient's mood. Careful consideration should be given to the use of self-reported measures of adherence among patients likely to be false-positive adherers.

  17. Immunological screening of drugs of abuse and gas chromatographic-mass spectrometric confirmation of opiates and cocaine in hair.

    Science.gov (United States)

    Segura, J; Stramesi, C; Redón, A; Ventura, M; Sanchez, C J; González, G; San, L; Montagna, M

    1999-03-05

    The work presents an analytical strategy to detect drugs of abuse in hair. It involves two sequential steps: a screening by a simple enzyme-linked immunosorbent assay (ELISA) methodology to detect opiates, cocaine and its metabolites, and benzodiacepines, followed by confirmation of opiates and cocaine metabolites in positive samples by gas chromatography coupled to mass spectrometry (GC-MS). In the same GC-MS run other drugs for substitution therapy (e.g. methadone and its main metabolite) can also be detected. After a double washing of hair samples with dichloromethane, hair specimens were cut into small pieces and 10 mg samples were incubated in 2 ml of methanol-trifluoroacetic acid (9:1) mixture, overnight at 37 degrees C. Aliquots of the extract were then evaporated, reconstituted in buffer and analysed according to the ELISA procedure. Confirmation involved solid-phase extraction of another fraction of the extract kept at -20 degrees C, derivatization with heptafluorobutyric anhydride and hexafluoroisopropanol and detection of cocaine, benzoylecgonine, ecgonine methylester, cocaethylene, morphine, codeine, 6-monoacetylmorphine, methadone and 2-ethylidene-1.5-dimethyl-3,3-diphenylpirrolidine (methadone metabolite) by selective ion monitoring after gas chromatographic separation. During the development of the method it was verified that no more than 10% of cocaine, opiates and benzodiacepines were lost when dichloromethane was used to wash real samples. The results also confirmed the increase of extractability power of TFA when it was added to methanol: the recovery for the analytes (cocaine and its metabolites and opiates) added to methanol-TFA alone was of the order of 90% except for benzoylecgonine (75%), and the recovery for the analytes added to methanol-TFA extract of drug-free hair was about 90% for all analytes except for benzoylecgonine and 6-MAM (around 70%). Regarding the stability of labile compounds, only small amounts of ecgonine methylester (2

  18. Raising Awareness of False Positive Newborn Screening Results Arising from Pivalate-Containing Creams and Antibiotics in Europe When Screening for Isovaleric Acidaemia

    Directory of Open Access Journals (Sweden)

    James R. Bonham

    2018-02-01

    Full Text Available While the early and asymptomatic recognition of treatable conditions offered by newborn screening confers clear health benefits for the affected child, the clinical referral of patients with screen positive results can cause significant harm for some families. The use of pivalate-containing antibiotics and more recently the inclusion of neopentanoate as a component within moisturising creams used as nipple balms by nursing mothers can result in a significant number of false positive results when screening for isovaleric acidaemia (IVA by measuring C5 acylcarnitine. A recent survey conducted within centres from nine countries indicated that this form of contamination had been or was a significant confounding factor in the detection of IVA in seven of the nine who responded. In three of these seven the prominent cause was believed to derive from the use of moisturising creams and in another three from antibiotics containing pivalate; one country reported that the cause was mixed. As a result, four of these seven centres routinely perform second tier testing to resolve C5 isobars when an initial C5 result is elevated, and a fifth is considering making this change within their national programme. The use of creams containing neopentanoate by nursing mothers and evolving patterns in the prescription of pivalate-containing antibiotics during pregnancy require those involved in the design and operation of newborn screening programmes used to detect IVA and the doctors who receive clinical referrals from these programmes to maintain an awareness of the potential impact of this form of interference on patient results.

  19. A novel three-dimensional cell culture method enhances antiviral drug screening in primary human cells.

    Science.gov (United States)

    Koban, Robert; Neumann, Markus; Daugs, Aila; Bloch, Oliver; Nitsche, Andreas; Langhammer, Stefan; Ellerbrok, Heinz

    2018-02-01

    Gefitinib is a specific inhibitor of the epidermal growth factor receptor (EGFR) and FDA approved for treatment of non-small cell lung cancer. In a previous study we could show the in vitro efficacy of gefitinib for treatment of poxvirus infections in monolayer (2D) cultivated cell lines. Permanent cell lines and 2D cultures, however, are known to be rather unphysiological; therefore it is difficult to predict whether determined effective concentrations or the drug efficacy per se are transferable to the in vivo situation. 3D cell cultures, which meanwhile are widely distributed across all fields of research, are a promising tool for more predictive in vitro investigations of antiviral compounds. In this study the spreading of cowpox virus and the antiviral efficacy of gefitinib were analyzed in primary human keratinocytes (NHEK) grown in a novel 3D extracellular matrix-based cell culture model and compared to the respective monolayer culture. 3D-cultivated NHEK grew in a polarized and thus a more physiological manner with altered morphology and close cell-cell contact. Infected cultures showed a strongly elevated sensitivity towards gefitinib. EGFR phosphorylation, cell proliferation, and virus replication were significantly reduced in 3D cultures at gefitinib concentrations which were at least 100-fold lower than those in monolayer cultures and well below the level of cytotoxicity. Our newly established 3D cell culture model with primary human cells is an easy-to-handle alternative to conventional monolayer cell cultures and previously described more complex 3D cell culture systems. It can easily be adapted to other cell types and a broad spectrum of viruses for antiviral drug screening and many other aspects of virus research under more in vivo-like conditions. In consequence, it may contribute to a more targeted realization of necessary in vivo experiments. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Commercial herbal medicines used as African traditional medicines: Ngoma Herbal Tonic Immune Booster interferes with a rapid urine drug screening test.

    Science.gov (United States)

    Mothibe, M E; Osuch, E; Kahler-Venter, C P

    2017-08-25

    The prevalent use of African traditional medicine by the general public has been reported. With commercialisation and marketing, some of the herbal medicines (HMs) used are readily available over the counter, most of them promoted as immune boosters. These commercial HMs have not been taken through clinical trials and other tests that would validate their composition and safety, and other properties such as their effect on laboratory diagnostic tests. To investigate the cross-reactivity of selected HMs with commonly tested drugs of abuse (DoA) using a qualitative rapid urinalysis assay. The six HMs selected were bought from local pharmacies. A rapid urinalysis screening test was performed with the Instant View Multi-Drug of Abuse Test kit from Labstix Diagnostics. Drug-free urine (DFU) was pooled from samples donated by healthy volunteers. Urine samples that had tested positive for DoA were obtained from a pharmacology laboratory. Aliquots of the urine samples were spiked with the HMs in neat and diluted form, and tested at various time intervals. The results for the DFU samples spiked with the HMs remained negative. There were no significant changes in pH or specific gravity of the samples. The results of samples that had tested positive for tetrahydrocannabinol (THC) were not altered by five of the HMs when spiked at 40% v/v. The HM Ngoma Herbal Tonic Immune Booster caused false-negative results for the THC test. An important finding is that the herbal mixture Ngoma Herbal Tonic Immune Booster caused false-negative results for the cannabinoid screening test. It adds to the list of substances that may be potential adulterants of urine for screening tests.

  1. Systematic hybrid LOH: a new method to reduce false positives and negatives during screening of yeast gene deletion libraries

    DEFF Research Database (Denmark)

    Alvaro, D.; Sunjevaric, I.; Reid, R. J.

    2006-01-01

    We have developed a new method, systematic hybrid loss of heterozygosity, to facilitate genomic screens utilizing the yeast gene deletion library. Screening is performed using hybrid diploid strains produced through mating the library haploids with strains from a different genetic background......, to minimize the contribution of unpredicted recessive genetic factors present in the individual library strains. We utilize a set of strains where each contains a conditional centromere construct on one of the 16 yeast chromosomes that allows the destabilization and selectable loss of that chromosome. After...... complementation of any spurious recessive mutations in the library strain, facilitating attribution of the observed phenotype to the documented gene deletion and dramatically reducing false positive results commonly obtained in library screens. The systematic hybrid LOH method can be applied to virtually any...

  2. Monitoring of drug intake during pregnancy by questionnaires and LC-MS/MS drug urine screening: evaluation of both monitoring methods.

    Science.gov (United States)

    Hoeke, Henrike; Roeder, Stefan; Bertsche, Thilo; Lehmann, Irina; Borte, Michael; von Bergen, Martin; Wissenbach, Dirk K

    2015-08-01

    Various studies pointed towards a relationship between chronic diseases such as asthma and allergy and environmental risk factors, which are one aspect of the so-called Exposome. These environmental risk factors include also the intake of drugs. One critical step in human development is the prenatal period, in which exposures might have critical impact on the child's health outcome. Thereby, the health effects of drugs taken during gestation are discussed controversially with regard to newborns' disease risk. Due to this, the drug intake of pregnant women in the third trimester was monitored by questionnaire, in addition to biomonitoring using a local birth cohort study, allowing correlations of drug exposure with disease risk. Therefore, 622 urine samples were analyzed by an untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) urine screening and the results were compared to self-administered questionnaires. In total, 48% (n = 296) reported an intake of pharmaceuticals, with analgesics as the most frequent reported drug class in addition to dietary supplements. 182 times compounds were detected by urine screening, with analgesics (42%; n = 66) as the predominantly drug class. A comparison of reported and detected drug intake was performed for three different time spans between completion of the questionnaires and urine sampling. Even if the level of accordance was low in general, similar percentages (~25%, ~19%, and ~ 20%) were found for all groups. This study illustrates that a comprehensive evaluation of drug intake is neither achieved by questionnaires nor by biomonitoring alone. Instead, a combination of both monitoring methods, providing complementary information, should be considered. Copyright © 2014 John Wiley & Sons, Ltd.

  3. Prevalence and predictors of depressive symptoms among HIV-positive men who inject drugs in Vietnam.

    Science.gov (United States)

    Levintow, Sara N; Pence, Brian W; Ha, Tran Viet; Minh, Nguyen Le; Sripaipan, Teerada; Latkin, Carl A; Vu, Pham The; Quan, Vu Minh; Frangakis, Constantine; Go, Vivian F

    2018-01-01

    HIV infection is common among people who inject drugs (PWID), and HIV-positive PWID may be particularly vulnerable to depression. This study measured the prevalence of depressive symptoms and the factors associated with severe symptoms among 455 HIV-positive PWID in Thai Nguyen, Vietnam. We used cross-sectional data from PWID in a randomized controlled trial of an intervention to reduce high-risk injecting and sexual behaviors in Thai Nguyen from 2009-2013. Depressive symptoms were measured with the Center for Epidemiologic Studies Depression Scale (CES-D). We used logistic regression to assess demographic, clinical, and psychosocial predictors of severe depressive symptoms (CES-D≥23) with prevalence odds ratios (POR) and 95% confidence intervals (CI). The prevalence of severe depressive symptoms (CES-D≥23) was 44%. 25% of participants had mild to moderate depressive symptoms (16≤CES-D<23), and 31% experienced no depressive symptoms (CES-D<16). Not being married, self-rated poor health, greater frequency of injection drug use, history of overdose, no alcohol use, and daily cigarette smoking were positively associated with severe depressive symptoms in unadjusted models and remained predictive in a multivariable model. The strongest predictors of depressive symptoms were self-reported poor health (POR = 2.94, 95% CI: 1.82, 4.76), no current alcohol use (POR = 2.35, 95% CI: 1.47, 3.77), and not currently married or cohabitating (POR = 2.21, 95% CI = 1.40, 3.47). Severe depressive symptoms were common among HIV-positive PWID in Thai Nguyen and were strongly associated with demographic, clinical, and psychosocial factors. Interventions that promote social support from family and reduce drug dependence may particularly benefit PWID experiencing severe depressive symptoms. Greater recognition and treatment of depressive symptoms has the potential to enhance quality of life and improve HIV clinical outcomes for PWID.

  4. Methamphetamine functions as a positive and negative drug feature in a Pavlovian appetitive discrimination task.

    Science.gov (United States)

    Reichel, Carmela M; Wilkinson, Jamie L; Bevins, Rick A

    2007-12-01

    This research determined the ability of methamphetamine to serve as a positive or negative feature, and assessed the ability of bupropion, cocaine, and naloxone to substitute for the methamphetamine features. Rats received methamphetamine (0.5 mg/kg, intraperitoneally) or saline 15 min before a conditioning session. For the feature positive (FP) group, offset of 15-s cue lights was followed by access to sucrose on methamphetamine sessions; sucrose was withheld during saline sessions. For the feature negative (FN) group, the light offset was followed by sucrose on saline sessions; sucrose was withheld during methamphetamine sessions. During acquisition, the FP group had higher responding on methamphetamine sessions than on saline sessions. For the FN group, responding was higher on saline sessions than on methamphetamine sessions. Conditioned responding was sensitive to methamphetamine dose. For the FP group, bupropion and cocaine fully and partially substituted for methamphetamine, respectively. In contrast, both drugs fully substituted for methamphetamine in the FN group. Naloxone did not substitute in either set of rats. FP-trained rats were more sensitive to the locomotor stimulating effects of the test drugs than FN-trained rats. This research demonstrates that the pharmacological effects of methamphetamine function as a FP or FN in this Pavlovian discrimination task and that training history can affect conditioned responding and locomotor effects evoked by a drug.

  5. Differential Risk for Homelessness Among US Male and Female Veterans With a Positive Screen for Military Sexual Trauma.

    Science.gov (United States)

    Brignone, Emily; Gundlapalli, Adi V; Blais, Rebecca K; Carter, Marjorie E; Suo, Ying; Samore, Matthew H; Kimerling, Rachel; Fargo, Jamison D

    2016-06-01

    Military sexual trauma (MST) is associated with adverse physical and mental health outcomes following military separation. Recent research suggests that MST may be a determinant in several factors associated with postdeployment homelessness. To evaluate MST as an independent risk factor for homelessness and to determine whether risk varies by sex. A retrospective cohort study of US veterans who used Veterans Health Administration (VHA) services between fiscal years 2004 and 2013 was conducted using administrative data from the Department of Defense and VHA. Included in the study were 601 892 US veterans deployed in Iraq or Afghanistan who separated from the military between fiscal years 2001 and 2011 and subsequently used VHA services. Positive response to screen for MST administered in VHA facilities. Administrative evidence of homelessness within 30 days, 1 year, and 5 years following the first VHA encounter after last deployment. The mean (SD) age of the 601 892 participants was 38.9 (9.4) years, 527 874 (87.7%) were male, 310 854 (51.6%) were white, and 382 361 (63.5%) were enlisted in the Army. Among veterans with a positive screen for MST, rates of homelessness were 1.6% within 30 days, 4.4% within 1 year, and 9.6% within 5 years, more than double the rates of veterans with a negative MST screen (0.7%, 1.8%, and 4.3%, respectively). A positive screen for MST was significantly and independently associated with postdeployment homelessness. In regression models adjusted for demographic and military service characteristics, odds of experiencing homelessness were higher among those who screened positive for MST compared with those who screened negative (30-day: adjusted odds ratio [AOR], 1.89; 95% CI, 1.58-2.24; 1-year: AOR, 2.27; 95% CI, 2.04-2.53; and 5-year: AOR, 2.63; 95% CI, 2.36-2.93). Military sexual trauma screen status remained independently associated with homelessness after adjusting for co-occurring mental health and substance abuse diagnoses

  6. Disease modeling and phenotypic drug screening for diabetic cardiomyopathy using human induced pluripotent stem cells.

    Science.gov (United States)

    Drawnel, Faye M; Boccardo, Stefano; Prummer, Michael; Delobel, Frédéric; Graff, Alexandra; Weber, Michael; Gérard, Régine; Badi, Laura; Kam-Thong, Tony; Bu, Lei; Jiang, Xin; Hoflack, Jean-Christophe; Kiialainen, Anna; Jeworutzki, Elena; Aoyama, Natsuyo; Carlson, Coby; Burcin, Mark; Gromo, Gianni; Boehringer, Markus; Stahlberg, Henning; Hall, Benjamin J; Magnone, Maria Chiara; Kolaja, Kyle; Chien, Kenneth R; Bailly, Jacques; Iacone, Roberto

    2014-11-06

    Diabetic cardiomyopathy is a complication of type 2 diabetes, with known contributions of lifestyle and genetics. We develop environmentally and genetically driven in vitro models of the condition using human-induced-pluripotent-stem-cell-derived cardiomyocytes. First, we mimic diabetic clinical chemistry to induce a phenotypic surrogate of diabetic cardiomyopathy, observing structural and functional disarray. Next, we consider genetic effects by deriving cardiomyocytes from two diabetic patients with variable disease progression. The cardiomyopathic phenotype is recapitulated in the patient-specific cells basally, with a severity dependent on their original clinical status. These models are incorporated into successive levels of a screening platform, identifying drugs that preserve cardiomyocyte phenotype in vitro during diabetic stress. In this work, we present a patient-specific induced pluripotent stem cell (iPSC) model of a complex metabolic condition, showing the power of this technique for discovery and testing of therapeutic strategies for a disease with ever-increasing clinical significance. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  7. Using Docker Compose for the Simple Deployment of an Integrated Drug Target Screening Platform

    Directory of Open Access Journals (Sweden)

    List Markus

    2017-06-01

    Full Text Available Docker virtualization allows for software tools to be executed in an isolated and controlled environment referred to as a container. In Docker containers, dependencies are provided exactly as intended by the developer and, consequently, they simplify the distribution of scientific software and foster reproducible research. The Docker paradigm is that each container encapsulates one particular software tool. However, to analyze complex biomedical data sets, it is often necessary to combine several software tools into elaborate workflows. To address this challenge, several Docker containers need to be instantiated and properly integrated, which complicates the software deployment process unnecessarily. Here, we demonstrate how an extension to Docker, Docker compose, can be used to mitigate these problems by providing a unified setup routine that deploys several tools in an integrated fashion. We demonstrate the power of this approach by example of a Docker compose setup for a drug target screening platform consisting of five integrated web applications and shared infrastructure, deployable in just two lines of codes.

  8. Using Docker Compose for the Simple Deployment of an Integrated Drug Target Screening Platform.

    Science.gov (United States)

    List, Markus

    2017-06-10

    Docker virtualization allows for software tools to be executed in an isolated and controlled environment referred to as a container. In Docker containers, dependencies are provided exactly as intended by the developer and, consequently, they simplify the distribution of scientific software and foster reproducible research. The Docker paradigm is that each container encapsulates one particular software tool. However, to analyze complex biomedical data sets, it is often necessary to combine several software tools into elaborate workflows. To address this challenge, several Docker containers need to be instantiated and properly integrated, which complicates the software deployment process unnecessarily. Here, we demonstrate how an extension to Docker, Docker compose, can be used to mitigate these problems by providing a unified setup routine that deploys several tools in an integrated fashion. We demonstrate the power of this approach by example of a Docker compose setup for a drug target screening platform consisting of five integrated web applications and shared infrastructure, deployable in just two lines of codes.

  9. A Multi-Modality CMOS Sensor Array for Cell-Based Assay and Drug Screening.

    Science.gov (United States)

    Chi, Taiyun; Park, Jong Seok; Butts, Jessica C; Hookway, Tracy A; Su, Amy; Zhu, Chengjie; Styczynski, Mark P; McDevitt, Todd C; Wang, Hua

    2015-12-01

    In this paper, we present a fully integrated multi-modality CMOS cellular sensor array with four sensing modalities to characterize different cell physiological responses, including extracellular voltage recording, cellular impedance mapping, optical detection with shadow imaging and bioluminescence sensing, and thermal monitoring. The sensor array consists of nine parallel pixel groups and nine corresponding signal conditioning blocks. Each pixel group comprises one temperature sensor and 16 tri-modality sensor pixels, while each tri-modality sensor pixel can be independently configured for extracellular voltage recording, cellular impedance measurement (voltage excitation/current sensing), and optical detection. This sensor array supports multi-modality cellular sensing at the pixel level, which enables holistic cell characterization and joint-modality physiological monitoring on the same cellular sample with a pixel resolution of 80 μm × 100 μm. Comprehensive biological experiments with different living cell samples demonstrate the functionality and benefit of the proposed multi-modality sensing in cell-based assay and drug screening.

  10. Disease Modeling and Phenotypic Drug Screening for Diabetic Cardiomyopathy using Human Induced Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Faye M. Drawnel

    2014-11-01

    Full Text Available Diabetic cardiomyopathy is a complication of type 2 diabetes, with known contributions of lifestyle and genetics. We develop environmentally and genetically driven in vitro models of the condition using human-induced-pluripotent-stem-cell-derived cardiomyocytes. First, we mimic diabetic clinical chemistry to induce a phenotypic surrogate of diabetic cardiomyopathy, observing structural and functional disarray. Next, we consider genetic effects by deriving cardiomyocytes from two diabetic patients with variable disease progression. The cardiomyopathic phenotype is recapitulated in the patient-specific cells basally, with a severity dependent on their original clinical status. These models are incorporated into successive levels of a screening platform, identifying drugs that preserve cardiomyocyte phenotype in vitro during diabetic stress. In this work, we present a patient-specific induced pluripotent stem cell (iPSC model of a complex metabolic condition, showing the power of this technique for discovery and testing of therapeutic strategies for a disease with ever-increasing clinical significance.

  11. Heuristic lipophilicity potential for computer-aided rational drug design: Optimizations of screening functions and parameters

    Science.gov (United States)

    Du, Qishi; Mezey, Paul G.

    1998-09-01

    In this research we test and compare three possible atom-basedscreening functions used in the heuristic molecular lipophilicity potential(HMLP). Screening function 1 is a power distance-dependent function, b_{{i}} /| {R_{{i}}- r} |^γ, screening function 2is an exponential distance-dependent function, biexp(-| {R_i- r} |/d_0 , and screening function 3 is aweighted distance-dependent function, {{sign}}( {b_i } ){{exp}}ξ ( {| {R_i- r} |/| {b_i } |} )For every screening function, the parameters (γ ,d0, and ξ are optimized using 41 common organic molecules of 4 types of compounds:aliphatic alcohols, aliphatic carboxylic acids, aliphatic amines, andaliphatic alkanes. The results of calculations show that screening function3 cannot give chemically reasonable results, however, both the powerscreening function and the exponential screening function give chemicallysatisfactory results. There are two notable differences between screeningfunctions 1 and 2. First, the exponential screening function has largervalues in the short distance than the power screening function, thereforemore influence from the nearest neighbors is involved using screeningfunction 2 than screening function 1. Second, the power screening functionhas larger values in the long distance than the exponential screeningfunction, therefore screening function 1 is effected by atoms at longdistance more than screening function 2. For screening function 1, thesuitable range of parameter d0 is 1.5 < d0 < 3.0, and d0 = 2.0 is recommended. HMLP developed in this researchprovides a potential tool for computer-aided three-dimensional drugdesign.

  12. Effect of radiologist experience on the risk of false-positive results in breast cancer screening programs

    Energy Technology Data Exchange (ETDEWEB)

    Zubizarreta Alberdi, Raquel [Galician Breast Cancer Screening Programme, Public Health and Planning Directorate, Health Office, Galicia (Spain); Edificio Administrativo da Conselleria de Sanidade, Servicio de Programas Poboacionais de Cribado, Direccion Xeral de Saude Publica e Planificacion, Santiago de Compostela, Galicia (Spain); Llanes, Ana B.F.; Ortega, Raquel Almazan [Galician Breast Cancer Screening Programme, Public Health and Planning Directorate, Health Office, Galicia (Spain); Exposito, Ruben Roman; Collado, Jose M.V.; Oliveres, Xavier Castells [Department of Epidemiology and Evaluation, Institut Municipal d' Investigacio Medica-Parc de Salut Mar. CIBERESP, Barcelona (Spain); Queiro Verdes, Teresa [Galician Agency for Health Technology Assessment, Public Health and Planning Directorate, Health Office, Galicia (Spain); Natal Ramos, Carmen [Principality of Asturias Breast Cancer Screening Programme, Principality of Asturias (Spain); Sanz, Maria Ederra [Public Health Institute, Navarra Breast Cancer Screening Programme, Pamplona (Spain); Salas Trejo, Dolores [General Directorate Public Health and Centre for Public Health Research (CSISP), Valencia Breast Cancer Screening Programme, Valencia (Spain)

    2011-10-15

    To evaluate the effect of radiologist experience on the risk of false-positive results in population-based breast cancer screening programmes. We evaluated 1,440,384 single-read screening mammograms, corresponding to 471,112 women aged 45-69 years participating in four Spanish programmes between 1990 and 2006. The mammograms were interpreted by 72 radiologists. The overall percentage of false-positive results was 5.85% and that for false-positives resulting in an invasive procedure was 0.38%. Both the risk of false-positives overall and of false-positives leading to an invasive procedure significantly decreased (p < 0.001) with greater reading volume in the previous year: OR 0.77 and OR 0.78, respectively, for a reading volume 500-1,999 mammograms and OR 0.59 and OR 0.60 for a reading volume of >14,999 mammograms with respect to the reference category (<500). The risk of both categories of false-positives was also significantly reduced (p < 0.001) as radiologists' years of experience increased: OR 0.96 and OR 0.84, respectively, for 1 year's experience and OR 0.72 and OR 0.73, respectively, for more than 4 years' experience with regard to the category of <1 year's experience. Radiologist experience is a determining factor in the risk of a false-positive result in breast cancer screening. (orig.)

  13. Fragmentation of toxicologically relevant drugs in positive-ion liquid chromatography-tandem mass spectrometry.

    Science.gov (United States)

    Niessen, W M A

    2011-01-01

    The identification of drugs and related compounds by LC-MS-MS is an important analytical challenge in several application areas, including clinical and forensic toxicology, doping control analysis, and environmental analysis. Although target-compound based analytical strategies are most frequently applied, at some point the information content of the MS-MS spectra becomes relevant. In this article, the positive-ion MS-MS spectra of a wide variety of drugs and related substances are discussed. Starting point was an MS-MS mass spectral library of toxicologically relevant compounds, available on the internet. The positive-ion MS-MS spectra of ∼570 compounds were interpreted by chemical and therapeutic class, thus involving a wide variety of drug compound classes, such benzodiazepines, beta-blockers, angiotensin-converting enzyme inhibitors, phenothiazines, dihydropyridine calcium channel blockers, diuretics, local anesthetics, vasodilators, as well as various subclasses of anti-diabetic, antidepressant, analgesic, and antihistaminic drugs. In addition, the scientific literature was searched for available MS-MS data of these compound classes and the interpretation thereof. The results of this elaborate study are presented in this article. For each individual compound class, the emphasis is on class-specific fragmentation, as discussing fragmentation of all individual compounds would take far too much space. The recognition of class-specific fragmentation may be quite informative in determining the compound class of a specific unknown, which may further help in the identification. In addition, knowledge on (class-specific) fragmentation may further help in the optimization of the selectivity in targeted analytical approaches of compounds of one particular class. Copyright © 2011 Wiley Periodicals, Inc.

  14. Kiosk versus In-person Screening for Alcohol and Drug Use in the Emergency Department: Patient Preferences and Disclosure

    Directory of Open Access Journals (Sweden)

    Hankin, Abigail

    2015-03-01

    Full Text Available Introduction: Annually eight million emergency department (ED visits are attributable to alcohol use. Screening ED patients for at-risk alcohol and substance use is an integral component of screening, brief intervention, and referral to treatment programs, shown to be effective at reducing substance use. The objective is to evaluate ED patients’ acceptance of and willingness to disclose alcohol/substance use via a computer kiosk versus an in-person interview. Methods: This was a cross-sectional, survey-based study. Eligible participants included those who presented to walk-in triage, were English-speaking, ≥18 years, were clinically stable and able to consent. Patients had the opportunity to access the kiosk in the ED waiting room, and were approached for an in-person survey by a research assistant (9am-5pm weekdays. Both surveys used validated assessment tools to assess drug and alcohol use. Disclosure statistics and preferences were calculated using chi-square tests and McNemar’s test. Results: A total of 1,207 patients were screened: 229 in person only, 824 by kiosk, and 154 by both in person and kiosk. Single-modality participants were more likely to disclose hazardous drinking (p=0.003 and high-risk drug use (OR=22.3 [12.3-42.2]; p<0.0001 via kiosk. Participants who had participated in screening via both modalities were more likely to reveal high-risk drug use on the kiosk (p=0.003. When asked about screening preferences, 73.6% reported a preference for an in-person survey, which patients rated higher on privacy and comfort. Conclusion: ED patients were significantly more likely to disclose at-risk alcohol and substance use to a computer kiosk than an interviewer. Paradoxically patients stated a preference for in-person screening, despite reduced disclosure to a human screener. [West J Emerg Med. 2015;16(2:220–228.

  15. False-positive breast screening due to fat necrosis following mammography

    International Nuclear Information System (INIS)

    Cawson, Jennifer N.; Malara, Frank A.

    2004-01-01

    Traumatic fat necrosis can result in a spectrum of imaging appearances that range from characteristically benign to those indistinguishable from malignancy. In such cases, biopsy might be required for diagnosis. The present case demonstrates a suspicious mammographic mass lesion appearing following a haematoma caused by a previous screening mammogram Copyright (2004) Blackwell Publishing Asia Pty Ltd

  16. The immature electrophysiological phenotype of iPSC-CMs still hampers in vitro drug screening: Special focus on IK1.

    Science.gov (United States)

    Goversen, Birgit; van der Heyden, Marcel A G; van Veen, Toon A B; de Boer, Teun P

    2018-03-01

    Preclinical drug screens are not based on human physiology, possibly complicating predictions on cardiotoxicity. Drug screening can be humanised with in vitro assays using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). However, in contrast to adult ventricular cardiomyocytes, iPSC-CMs beat spontaneously due to presence of the pacemaking current I f and reduced densities of the hyperpolarising current I K1 . In adult cardiomyocytes, I K1 finalises repolarisation by stabilising the resting membrane potential while also maintaining excitability. The reduced I K1 density contributes to proarrhythmic traits in iPSC-CMs, which leads to an electrophysiological phenotype that might bias drug responses. The proarrhythmic traits can be suppressed by increasing I K1 in a balanced manner. We systematically evaluated all studies that report strategies to mature iPSC-CMs and found that only few studies report I K1 current densities. Furthermore, these studies did not succeed in establishing sufficient I K1 levels as they either added too little or too much I K1 . We conclude that reduced densities of I K1 remain a major flaw in iPSC-CMs, which hampers their use for in vitro drug screening. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  17. Likelihood of early detection of breast cancer in relation to false-positive risk in life-time mammographic screening: population-based cohort study.

    Science.gov (United States)

    Otten, J D M; Fracheboud, J; den Heeten, G J; Otto, S J; Holland, R; de Koning, H J; Broeders, M J M; Verbeek, A L M

    2013-10-01

    Women require balanced, high-quality information when making an informed decision on screening benefits and harms before attending biennial mammographic screening. The cumulative risk of a false-positive recall and/or (small) screen-detected or interval cancer over 13 consecutive screening examinations for women aged 50 from the start of screening were estimated using data from the Nijmegen programme, the Netherlands. Women who underwent 13 successive screens in the period 1975-1976 had a 5.3% cumulative chance of a screen-detected cancer, with a 4.2% risk of at least one false-positive recall. The risk of being diagnosed with interval cancer was 3.7%. Two decades later, these estimates were 6.9%, 7.3% and 2.9%, respectively. The chance of detection of a small, favourable invasive breast cancer, anticipating a normal life-expectancy, rose from 2.3% to 3.7%. Extrapolation to digital screening mammography indicates that the proportion of false-positive results will rise to 16%. Dutch women about to participate in the screening programme can be reassured that the chance of false-positive recall in the Netherlands is relatively low. A new screening policy and improved mammography have increased the detection of an early screening carcinoma and lowering the risk of interval carcinoma.

  18. Screening for illicit drugs on Euro banknotes by LC-MS/MS.

    Science.gov (United States)

    Wimmer, Kurt; Schneider, Serge

    2011-03-20

    A method for the simultaneous quantification of illicit drugs on Euro banknotes, using an ultra-performance liquid chromatography tandem mass spectrometry, was developed and validated. The method included cocaine, benzoylecgonine, MDMA, MDEA, MDA, methamphetamine, diacetylmorphine, 6-MAM, morphine and Δ(9)-THC. Drug residues were monitored and quantified via positive ESI mode using multiple reaction monitoring. Banknotes were extracted with methanol by vigorous shaking. Recovery rates were in the range of 60-80%. Calibration was performed with spiked banknotes in the range of 10-100 ng/note (R(2) 0.98-0.99). Intra-day analysis showed fair precision and accuracy (≤ 15%). Matrix effects were in the range from 27% to 235%. 7-15 samples of each denomination were analyzed. The calculated median values per note were 106 ng cocaine, 43 ng benzoylecgonine, 41 ng heroin, 15.5 ng 6-MAM, 16.5 ng morphine, 9 ng MDMA and 7 ng methamphetamine. Δ(9)-THC was detected on 4 banknotes. MDEA and MDA were not detected on any note. A widespread background contamination for cocaine and opiates was demonstrated. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  19. Rat Ultrasonic Vocalizations and Behavioral Neuropharmacology: From the Screening of Drugs to the Study of Disease.

    Science.gov (United States)

    Simola, Nicola

    2015-01-01

    Several lines of evidence indicate that rats emit ultrasonic vocalizations (USVs) in response to a wide range of stimuli that are capable of producing either euphoric (positive) or dysphoric (negative) emotional states. On these bases, recordings of USVs are extensively used in preclinical studies of affect, motivation, and social behavior. Rat USVs are sensitive to the effects of certain classes of psychoactive drugs, suggesting that emission of rat USVs can have relevance not only to neurobiology, but also to neuropharmacology and psychopharmacology. This review summarizes three types of rat USVs, namely 40-kHz USVs emitted by pups, 22-kHz USVs and 50-kHz USVs emitted by young and adult animals, and relevance of these vocalizations to neuropharmacological studies. Attention will be focused on the issues of how rat USVs can be used to evaluate the pharmacological properties of different classes of drugs, and how rat USVs can be combined with other behavioral models used in neuropharmacology. The strengths and limitations of experimental paradigms based on the evaluation of rat USVs will also be discussed.

  20. The Effect of Maternal Body Composition and Triglyceride Levels on Newborn Weight in Non-Diabetic Women with Positive Diabetic Screens

    OpenAIRE

    Cüneyt Eftal Taner; Seçil Kurtulmuş; Ümit Nayki; Ayşen Kızılyar; Yasemin Baskın

    2008-01-01

    OBJECTIVE: To determine the effect of maternal body composition and triglyceride levels on newborn weight in nondiabetic women with positive diabetic screening. STUDY DESIGN : 40 pregnant women with positive diabetic screenings and negative glucose tolerance tests were enrolled as the study group. 72 pregnant women with negative diabetic screenings were enrolled as the control group. 50-gram glucose challenge tests were performed at 24-32 weeks of gestations and serum lipid levels were mea...

  1. Skin test concentrations for systemically administered drugs -- an ENDA/EAACI Drug Allergy Interest Group position paper

    NARCIS (Netherlands)

    Brockow, K.; Garvey, L. H.; Aberer, W.; Atanaskovic-Markovic, M.; Barbaud, A.; Bilo, M. B.; Bircher, A.; Blanca, M.; Bonadonna, B.; Campi, P.; Castro, E.; Cernadas, J. R.; Chiriac, A. M.; Demoly, P.; Grosber, M.; Gooi, J.; Lombardo, C.; Mertes, P. M.; Mosbech, H.; Nasser, S.; Pagani, M.; Ring, J.; Romano, A.; Scherer, K.; Schnyder, B.; Testi, S.; Torres, M.; Trautmann, A.; Terreehorst, I.

    2013-01-01

    Skin tests are of paramount importance for the evaluation of drug hypersensitivity reactions. Drug skin tests are often not carried out because of lack of concise information on specific test concentrations. The diagnosis of drug allergy is often based on history alone, which is an unreliable

  2. A potential model for drug screening by simulating the effect of shear stress in vivo on endothelium.

    Science.gov (United States)

    Xu, Yingqian; Wang, Bochu; Deng, Jia; Liu, Zerong; Zhu, Liancai

    2013-01-01

    The purpose of this paper was to research the potential of a dynamic cell model in drug screening by studying the influence of microvascular wall shear stress on the drug absorption of endothelial cells compared to that in the static state. The cells were grown and seeded on gelatin-coated glass slides and were pretreated with extracts of Salviae miltiorrhizae (200 μg/ml) for 1 h. Then oxidative stress damage was produced by H2O2 (300 μmol/l) for 0.5 h under the 1.5 dyn/cm2 shear stress incorporated in a parallel plate flow chamber. Morphological analysis was conducted with an inverted microscope and image analysis software, and high performance liquid chromatography-mass spectrometry was used for the detection of active compounds. We compared the drug absorption in the dynamic group with that in the static group. In the dynamic model, five compounds and two new metabolite peaks were detected. However, in the static model, four compounds were absorbed by cells, and one metabolite peak was found. This study indicated that there were some effects on the absorption and metabolism of drugs under the microvascular shear stress compared to that under stasis. We infer that shear stress in the microcirculation situation in vivo played a role in causing the differences between drug screening in vitro and in vivo.

  3. General unknown screening procedure for the characterization of human drug metabolites in forensic toxicology: applications and constraints.

    Science.gov (United States)

    Sauvage, François-Ludovic; Picard, Nicolas; Saint-Marcoux, Franck; Gaulier, Jean-Michel; Lachâtre, Gérard; Marquet, Pierre

    2009-09-01

    LC coupled to single (LC-MS) and tandem (LC-MS/MS) mass spectrometry is recognized as the most powerful analytical tools for metabolic studies in drug discovery. In this article, we describe five cases illustrating the utility of screening xenobiotic metabolites in routine analysis of forensic samples using LC-MS/MS. Analyses were performed using a previously published LC-MS/MS general unknown screening (GUS) procedure developed using a hybrid linear IT-tandem mass spectrometer. In each of the cases presented, the presence of metabolites of xenobiotics was suspected after analyzing urine samples. In two cases, the parent drug was also detected and the metabolites were merely useful to confirm drug intake, but in three other cases, metabolite detection was of actual forensic interest. The presented results indicate that: (i) the GUS procedure developed is useful to detect a large variety of drug metabolites, which would have been hardly detected using targeted methods in the context of clinical or forensic toxicology; (ii) metabolite structure can generally be inferred from their "enhanced" product ion scan spectra; and (iii) structure confirmation can be achieved through in vitro metabolic experiments or through the analysis of urine samples from individuals taking the parent drug.

  4. Are Peripheral Blood Mononuclear Cells Derived from Patients with Certain Myopathies Suitable for Personalized Drug Screening?

    Directory of Open Access Journals (Sweden)

    Andriy V. Shatillo

    2014-12-01

    Full Text Available Background: Limb girdle muscular dystrophies (LGMDs and several other disorders which share their specific phenotype are rare, predominantly hereditary conditions with no curative treatment. Differential diagnosis of these myopathies is quite challenging and expensive in many cases. Therefore, a significant proportion of patients remains undiagnosed and untreated for a long time. At the same time there is a huge amount of drugs and supplements potentially able to modify the course of some of these muscular dystrophies. That is why a simple empirical approach able to define a patient’s reaction to a specific compound seems rational. Because most common basic pathogenetic mechanisms for these quite different disorders increase the vulnerability of muscle cells (or decrease ability for reparation during mechanical stress, we propose a simple, noninvasive and inexpensive approach for individualized drug screening based on the drug’s influence on the mechanical vulnerability of peripheral blood mononuclear cells (PBMC. Methods: PBMC derived from 8 patients with Duchenne muscular dystrophy (DMD, 2 patients with LGMD2A, 1 patient with LGMD2B, 1 with MERRF syndrome, 1 with facioscapulohumeral muscular dystrophy (FSHD and 13 matched control subjects were irradiated by ultrasound in the presence of several compounds (lisinopril, vitamin D3, prednisolon, tocopherol, topiramate, glutargin, α-lipoic acid, essentiale, and physiological solution. Then viability indexes of the samples were detected by citotoxic assays based on vital dye (neutral red and resazurin metabolism. Results: In cytotoxicity tests with active transport of neutral red into PBMC derived from DMD patients, the cells showed signs of destruction at 1.06±0.52 minutes of ultrasounding compared to 1.75±0.6 minutes in control. PBMCs from patients with other myopathies have either normal or decreased resistance to ultrasound. The addition of tocopherol significantly changes the PBMC

  5. Chagas' disease: an algorithm for donor screening and positive donor counseling

    Directory of Open Access Journals (Sweden)

    Nelson Hamerschlak

    1997-06-01

    Full Text Available Classical serological screening assays for Chagas' disease are time consuming and subjective. The objective of the present work is to evaluate the enzyme immuno-assay (ELISA methodology and to propose an algorithm for blood banks to be applied to Chagas' disease. Seven thousand, nine hundred and ninety nine blood donor samples were screened by both reverse passive hemagglutination (RPHA and indirect immunofluorescence assay (IFA. Samples reactive on RPHA and/or IFA were submitted to supplementary RPHA, IFA and complement fixation (CFA tests. This strategy allowed us to create a panel of 60 samples to evaluate the ELISA methodology from 3 different manufacturers. The sensitivity of the screening by IFA and the 3 different ELISA's was 100%. The specificity was better on ELISA methodology. For Chagas disease, ELISA seems to be the best test for blood donor screening, because it showed high sensitivity and specificity, it is not subjective and can be automated. Therefore, it was possible to propose an algorithm to screen samples and confirm donor results at the blood bank.Os testes sorológicos clássicos utilizados na triagem de doadores de sangue são trabalhosos e subjetivos. O objetivo do presente trabalho é o de avaliar a metodologia imuno-enzimática (ELISA e propor um algorítmo para doença de Chagas em bancos de sangue. Foram estudados 7999 doadores de sangue e/ou componentes cujas amostras foram testadas com o objetivo de tria-las sorologicamente para doença de Chagas utilizando hemaglutinação passiva reversa (RPHA e imunofluorescência indireta (IFA. As amostras reativas em pelo menos uma destas metodologias, foram retestadas com reativos diferentes por RPHA, IFA e fixação de complemento (CFA. Esta estratégia nos permitiu criar um painel de 60 amostras com as quais tornou-se possível a avaliação do método imunoenzimático (ELISA. A sensibilidade da triagem dos doadores pelos métodos ELISA e IFA foi de 100%. A especificidade

  6. Rapid screening for drugs of abuse in biological fluids by ultra high performance liquid chromatography/Orbitrap mass spectrometry.

    Science.gov (United States)

    Jagerdeo, Eshwar; Schaff, Jason E

    2016-08-01

    We present a UPLC(®)-High Resolution Mass Spectrometric method to simultaneously screen for nineteen benzodiazepines, twelve opiates, cocaine and three metabolites, and three "Z-drug" hypnotic sedatives in both blood and urine specimens. Sample processing consists of a high-speed, high-temperature enzymatic hydrolysis for urine samples followed by a rapid supported liquid extraction (SLE). The combination of ultra-high resolution chromatography with high resolution mass spectrometry allows all 38 analytes to be uniquely detected with a ten minute analytical run. Limits of detection for all target analytes are 3ng/mL or better, with only 0.3mL of specimen used for analysis. The combination of low sample volume with fast processing and analysis makes this method a suitable replacement for immunoassay screening of the targeted drug classes, while providing far superior specificity and better limits of detection than can routinely be obtained by immunoassay. Published by Elsevier B.V.

  7. Screening for illicit and medicinal drugs in whole blood using fully automated SPE and UHPLC-TOF-MS with data-independent acquisition

    DEFF Research Database (Denmark)

    Pedersen, Anders Just; Dalsgaard, Petur Weihe; Rode, Andrej Jaroslav

    2013-01-01

    , butylone, cathine, fentanyl, LSD, mCPP, MDPV, mephedrone, 4-methylamphetamine, p-fluoroamphetamine, and PMMA. In conclusion, using UHPLC-TOF-MS screening with data-independent acquisition resulted in detection of common drugs of abuse as well as new designer-drugs and more rarely occurring drugs. Thus, TOF...

  8. Positioning graphical objects on computer screens: a three-phase model.

    Science.gov (United States)

    Pastel, Robert

    2011-02-01

    This experiment identifies and models phases during the positioning of graphical objects (called cursors in this article) on computer displays. The human computer-interaction community has traditionally used Fitts' law to model selection in graphical user interfaces, whereas human factors experiments have found the single-component Fitts' law inadequate to model positioning of real objects. Participants (N=145) repeatedly positioned variably sized square cursors within variably sized rectangular targets using computer mice. The times for the cursor to just touch the target, for the cursor to enter the target, and for participants to indicate positioning completion were observed. The positioning tolerances were varied from very precise and difficult to imprecise and easy. The time for the cursor to touch the target was proportional to the initial cursor-target distance. The time for the cursor to completely enter the target after touching was proportional to the logarithms of cursor size divided by target tolerances. The time for participants to indicate positioning after entering was inversely proportional to the tolerance. A three-phase model defined by regions--distant, proximate, and inside the target--was proposed and could model the positioning tasks. The three-phase model provides a framework for ergonomists to evaluate new positioning techniques and can explain their deficiencies. The model provides a means to analyze tasks and enhance interaction during positioning.

  9. Cell-based DNA demethylation detection system for screening of epigenetic drugs in 2D, 3D, and xenograft models

    Czech Academy of Sciences Publication Activity Database

    Agrawal, K.; Das, V.; Otmar, Miroslav; Krečmerová, Marcela; Džubák, P.; Hajdúch, M.

    91A, č. 2 (2017), s. 133-143 ISSN 1552-4922 R&D Projects: GA MZd(CZ) NV15-31984A; GA MŠk(CZ) LO1304; GA MŠk(CZ) LM2015064; GA TA ČR(CZ) TE01020028 Institutional support: RVO:61388963 Keywords : DNA methylation * DNA methylation inhibitors * demethylation detection system * epigenetic drugs * high content screening Subject RIV: CC - Organic Chemistry OBOR OECD: Organic chemistry Impact factor: 3.222, year: 2016

  10. Risks, prices, and positions: A social network analysis of illegal drug trafficking in the world-economy.

    Science.gov (United States)

    Boivin, Rémi

    2014-03-01

    Illegal drug prices are extremely high, compared to similar goods. There is, however, considerable variation in value depending on place, market level and type of drugs. A prominent framework for the study of illegal drugs is the "risks and prices" model (Reuter & Kleiman, 1986). Enforcement is seen as a "tax" added to the regular price. In this paper, it is argued that such economic models are not sufficient to explain price variations at country-level. Drug markets are analysed as global trade networks in which a country's position has an impact on various features, including illegal drug prices. This paper uses social network analysis (SNA) to explain price markups between pairs of countries involved in the trafficking of illegal drugs between 1998 and 2007. It aims to explore a simple question: why do prices increase between two countries? Using relational data from various international organizations, separate trade networks were built for cocaine, heroin and cannabis. Wholesale price markups are predicted with measures of supply, demand, risks of seizures, geographic distance and global positioning within the networks. Reported prices (in $US) and purchasing power parity-adjusted values are analysed. Drug prices increase more sharply when drugs are headed to countries where law enforcement imposes higher costs on traffickers. The position and role of a country in global drug markets are also closely associated with the value of drugs. Price markups are lower if the destination country is a transit to large potential markets. Furthermore, price markups for cocaine and heroin are more pronounced when drugs are exported to countries that are better positioned in the legitimate world-economy, suggesting that relations in legal and illegal markets are directed in opposite directions. Consistent with the world-system perspective, evidence is found of coherent world drug markets driven by both local realities and international relations. Copyright © 2013 Elsevier B

  11. Skin test concentrations for systemically administered drugs -- an ENDA/EAACI Drug Allergy Interest Group position paper

    DEFF Research Database (Denmark)

    Brockow, K; Garvey, L H; Aberer, W

    2013-01-01

    Skin tests are of paramount importance for the evaluation of drug hypersensitivity reactions. Drug skin tests are often not carried out because of lack of concise information on specific test concentrations. The diagnosis of drug allergy is often based on history alone, which is an unreliable...... indicator of true hypersensitivity.To promote and standardize reproducible skin testing with safe and nonirritant drug concentrations in the clinical practice, the European Network and European Academy of Allergy and Clinical Immunology (EAACI) Interest Group on Drug Allergy has performed a literature...... search on skin test drug concentration in MEDLINE and EMBASE, reviewed and evaluated the literature in five languages using the GRADE system for quality of evidence and strength of recommendation. Where the literature is poor, we have taken into consideration the collective experience of the group...

  12. A novel high throughput assay for anthelmintic drug screening and resistance diagnosis by real-time monitoring of parasite motility.

    Directory of Open Access Journals (Sweden)

    Michael J Smout

    Full Text Available BACKGROUND: Helminth parasites cause untold morbidity and mortality to billions of people and livestock. Anthelmintic drugs are available but resistance is a problem in livestock parasites, and is a looming threat for human helminths. Testing the efficacy of available anthelmintic drugs and development of new drugs is hindered by the lack of objective high-throughput screening methods. Currently, drug effect is assessed by observing motility or development of parasites using laborious, subjective, low-throughput methods. METHODOLOGY/PRINCIPAL FINDINGS: Here we describe a novel application for a real-time cell monitoring device (xCELLigence that can simply and objectively assess anthelmintic effects by measuring parasite motility in real time in a fully automated high-throughput fashion. We quantitatively assessed motility and determined real time IC(50 values of different anthelmintic drugs against several developmental stages of major helminth pathogens of humans and livestock, including larval Haemonchus contortus and Strongyloides ratti, and adult hookworms and blood flukes. The assay enabled quantification of the onset of egg hatching in real time, and the impact of drugs on hatch rate, as well as discriminating between the effects of drugs on motility of drug-susceptible and -resistant isolates of H. contortus. CONCLUSIONS/SIGNIFICANCE: Our findings indicate that this technique will be suitable for discovery and development of new anthelmintic drugs as well as for detection of phenotypic resistance to existing drugs for the majority of helminths and other pathogens where motility is a measure of pathogen viability. The method is also amenable to use for other purposes where motility is assessed, such as gene silencing or antibody-mediated killing.

  13. Interactive "Video doctor" counseling reduces drug and sexual risk behaviors among HIV-positive patients in diverse outpatient settings

    OpenAIRE

    Gilbert, P; Ciccarone, D; Gansky, SA; Bangsberg, DR; Clanon, K; McPhee, SJ; Calderón, SH; Bogetz, A; Gerbert, B

    2008-01-01

    Background Reducing substance use and unprotected sex by HIV-positive persons improves individual health status while decreasing the risk of HIV transmission. Despite recommendations that health care providers screen and counsel their HIV-positive patients for ongoing behavioral risks, it is unknown how to best provide “prevention with positives” in clinical settings. Positive Choice, an interactive, patient-tailored computer program, was developed in the United States to improve clinic-based...

  14. HERCA WG Medical Applications / Sub WG 'Exposure of Asymptomatic Individuals in Health Care' - 'Position Paper on Screening'

    International Nuclear Information System (INIS)

    Griebel, Juergen; Ebdon-Jackson, Steve

    2012-05-01

    Over the course of several meetings the HERCA-Working Group (WG) 'Medical Applications' has discussed the exposure of asymptomatic individuals in health care. In particular, the discussions focused on the issue of the early detection of severe diseases, by use of X-rays, for those who do not present with symptoms. An important and established example is the use of X-ray mammography to detect early breast cancer and this has traditionally been referred to as screening. An emerging application is the use of computed tomography in a range of circumstances, some of which may be better described as a separate category of medical exposure as they are neither diagnostic nor screening in the accepted sense. The discussions have indicated that it is pivotal to clearly define the relevant terms generally applied and to clearly differentiate these terms from diagnostic examinations used in health care. In this context, it is important to note, that the revision of the Euratom Basic Safety Standards (Euratom BSS) Directive is under way and addresses in particular medical radiological procedures on asymptomatic individuals, intended to be performed for early detection of disease (Draft Proposal 29 September 2011 Article 54). Hereby, two types of examinations of asymptomatic individuals, (that in some cases have both been referred to as screening) are addressed: (1) exposures as part of screening programmes and (2) exposures associated with individual health assessment. On adoption, this directive will have significant implications for and a substantial impact on the work of the radiation protection authorities in Europe. In this position paper the WG 'Medical Applications' proposes a clear distinction between screening and radiological procedures as part of an individual health assessment and highlights special requirements for the latter. Finally, the impact on the work of radiation protection authorities in Europe is addressed

  15. Target screening and confirmation of 35 licit and illicit drugs and metabolites in hair by LC-MSMS.

    Science.gov (United States)

    Lendoiro, Elena; Quintela, Oscar; de Castro, Ana; Cruz, Angelines; López-Rivadulla, Manuel; Concheiro, Marta

    2012-04-10

    A liquid chromatography-tandem mass spectrometry (LC-MSMS) target screening in 50mg hair was developed and fully validated for 35 analytes (Δ9-tetrahidrocannabinol (THC), morphine, 6-acetylmorphine, codeine, methadone, fentanyl, amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine, 3,4-methylenedioxymethamphetamine, benzoylecgonine, cocaine, lysergic acid diethylamide, ketamine, scopolamine, alprazolam, bromazepam, clonazepam, diazepam, flunitrazepam, 7-aminoflunitrazepam, lorazepam, lormetazepam, nordiazepam, oxazepam, tetrazepam, triazolam, zolpidem, zopiclone, amitriptyline, citalopram, clomipramine, fluoxetine, paroxetine and venlafaxine). Hair decontamination was performed with dichloromethane, and incubation in 2 mL of acetonitrile at 50°C overnight. Extraction procedure was performed in 2 steps, first liquid-liquid extraction, hexane:ethyl acetate (55:45, v:v) at pH 9, followed by solid-phase extraction (Strata-X cartridges). Chromatographic separation was performed in AtlantisT3 (2.1 mm × 100 mm, 3 μm) column, acetonitrile and ammonium formate pH 3 as mobile phase, and 32 min total run time. One transition per analyte was monitored in MRM mode. To confirm a positive result, a second injection monitoring 2 transitions was performed. The method was specific (no endogenous interferences, n=9); LOD was 0.2-50 pg/mg and LOQ 0.5-100 pg/mg; linearity ranged from 0.5-100 to 2000-20,000 pg/mg; imprecision drugs of abuse (THC, cocaine, opiates, amphetamines) and medicines (benzodiazepines, antidepressants) was developed and validated, achieving lower cut-offs than Society of Hair Testing recommendations. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  16. Systematic drug screening reveals specific vulnerabilities and co-resistance patterns in endocrine-resistant breast cancer

    International Nuclear Information System (INIS)

    Kangaspeska, Sara; Hultsch, Susanne; Jaiswal, Alok; Edgren, Henrik; Mpindi, John-Patrick; Eldfors, Samuli; Brück, Oscar; Aittokallio, Tero; Kallioniemi, Olli

    2016-01-01

    The estrogen receptor (ER) inhibitor tamoxifen reduces breast cancer mortality by 31 % and has served as the standard treatment for ER-positive breast cancers for decades. However, 50 % of advanced ER-positive cancers display de novo resistance to tamoxifen, and acquired resistance evolves in 40 % of patients who initially respond. Mechanisms underlying resistance development remain poorly understood and new therapeutic opportunities are urgently needed. Here, we report the generation and characterization of seven tamoxifen-resistant breast cancer cell lines from four parental strains. Using high throughput drug sensitivity and resistance testing (DSRT) with 279 approved and investigational oncology drugs, exome-sequencing and network analysis, we for the first time, systematically determine the drug response profiles specific to tamoxifen resistance. We discovered emerging vulnerabilities towards specific drugs, such as ERK1/2-, proteasome- and BCL-family inhibitors as the cells became tamoxifen-resistant. Co-resistance to other drugs such as the survivin inhibitor YM155 and the chemotherapeutic agent paclitaxel also occurred. This study indicates that multiple molecular mechanisms dictate endocrine resistance, resulting in unexpected vulnerabilities to initially ineffective drugs, as well as in emerging co-resistances. Thus, combatting drug-resistant tumors will require patient-tailored strategies in order to identify new drug vulnerabilities, and to understand the associated co-resistance patterns. The online version of this article (doi:10.1186/s12885-016-2452-5) contains supplementary material, which is available to authorized users

  17. Systematic drug screening reveals specific vulnerabilities and co-resistance patterns in endocrine-resistant breast cancer.

    Science.gov (United States)

    Kangaspeska, Sara; Hultsch, Susanne; Jaiswal, Alok; Edgren, Henrik; Mpindi, John-Patrick; Eldfors, Samuli; Brück, Oscar; Aittokallio, Tero; Kallioniemi, Olli

    2016-07-04

    The estrogen receptor (ER) inhibitor tamoxifen reduces breast cancer mortality by 31 % and has served as the standard treatment for ER-positive breast cancers for decades. However, 50 % of advanced ER-positive cancers display de novo resistance to tamoxifen, and acquired resistance evolves in 40 % of patients who initially respond. Mechanisms underlying resistance development remain poorly understood and new therapeutic opportunities are urgently needed. Here, we report the generation and characterization of seven tamoxifen-resistant breast cancer cell lines from four parental strains. Using high throughput drug sensitivity and resistance testing (DSRT) with 279 approved and investigational oncology drugs, exome-sequencing and network analysis, we for the first time, systematically determine the drug response profiles specific to tamoxifen resistance. We discovered emerging vulnerabilities towards specific drugs, such as ERK1/2-, proteasome- and BCL-family inhibitors as the cells became tamoxifen-resistant. Co-resistance to other drugs such as the survivin inhibitor YM155 and the chemotherapeutic agent paclitaxel also occurred. This study indicates that multiple molecular mechanisms dictate endocrine resistance, resulting in unexpected vulnerabilities to initially ineffective drugs, as well as in emerging co-resistances. Thus, combatting drug-resistant tumors will require patient-tailored strategies in order to identify new drug vulnerabilities, and to understand the associated co-resistance patterns.

  18. Hydrophilic interaction chromatography with a focus on the drug-phosphate interaction in drug screening to determine the phospholipidosis induction risk.

    Science.gov (United States)

    Okamoto, Haruka; Hamaguchi, Ryohei; Kuroda, Yukihiro

    2017-04-15

    Cationic amphiphilic drugs (CADs) can induce the hyperaccumulation of phospholipids in cells and tissues. This side effect, which is known as drug-induced phospholipidosis, is sometimes problematic in the development and clinical use of CADs. It is known that CADs generally interact with phospholipids via both hydrophobic and acid-base interactions, and CADs with the larger affinity to phospholipid exhibit the larger induction risk. To develop a chromatographic assay system to predict the phospholipidosis-inducing potential with considering the acid-base interaction between CAD and phosphate group of phospholipid, hydrophilic interaction chromatographic (HILIC) methods were tested in this study. First, a PC HILIC column with phosphocholine groups on a packed material was used. The acid-base or other hydrophilic interactions to the stationary phase differed among basic drugs, and retention to the PC HILIC column did not accurately reflect the induction potential of phospholipidosis. As an alternative HILIC approach, the elution of CADs with the phosphate buffer from an amide column was tested. The elution effect, which is expressed as ratio of retention factors between different phosphate content in the mobile phase, closely correlated with the induction potential. Using the elution effect and retention factor to a reversed-phase HPLC column, the phospholipidosis-inducing drugs were clearly discriminated from the non-inducers. These results suggest that the proposed chromatographic approach can screen phospholipidosis-inducing drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Influenza vaccination of HIV-1-positive and HIV-1-negative former intravenous drug users.

    Science.gov (United States)

    Amendola, A; Boschini, A; Colzani, D; Anselmi, G; Oltolina, A; Zucconi, R; Begnini, M; Besana, S; Tanzi, E; Zanetti, A R

    2001-12-01

    The immunogenicity of an anti-influenza vaccine was assessed in 409 former intravenous drug user volunteers and its effect on the levels of HIV-1 RNA, proviral DNA and on CD4+ lymphocyte counts in a subset HIV-1-positive subjects was measured. HIV-1-positive individuals (n = 72) were divided into three groups on the basis of their CD4+ lymphocyte counts, while the 337 HIV-1-negative participants were allocated into group four. Haemagglutination inhibiting (HI) responses varied from 45.8 to 70% in the HIV-1-positive subjects and were significantly higher in group four (80.7% responses to the H1N1 strain, 81.6% to the H3N2 strain, and 83% to the B strain). The percentage of subjects with HI protective antibody titres (> or = 1:40) increased significantly after vaccination, especially in HIV-1 uninfected subjects. Immunization caused no significant changes in CD4+ counts and in neither plasma HIV-1 RNA nor proviral DNA levels. Therefore, vaccination against influenza may benefit persons infected by HIV-1. Copyright 2001 Wiley-Liss, Inc.

  20. Development of a novel cell-based assay system EPISSAY for screening epigenetic drugs and liposome formulated decitabine

    International Nuclear Information System (INIS)

    Lim, Sue Ping; Callen, David F; Kumar, Raman; Akkamsetty, Yamini; Wang, Wen; Ho, Kristen; Neilsen, Paul M; Walther, Diego J; Suetani, Rachel J; Prestidge, Clive

    2013-01-01

    Despite the potential of improving the delivery of epigenetic drugs, the subsequent assessment of changes in their epigenetic activity is largely dependent on the availability of a suitable and rapid screening bioassay. Here, we describe a cell-based assay system for screening gene reactivation. A cell-based assay system (EPISSAY) was designed based on a silenced triple-mutated bacterial nitroreductase TMnfsB fused with Red-Fluorescent Protein (RFP) expressed in the non-malignant human breast cell line MCF10A. EPISSAY was validated using the target gene TXNIP, which has previously been shown to respond to epigenetic drugs. The potency of a epigenetic drug model, decitabine, formulated with PEGylated liposomes was also validated using this assay system. Following treatment with DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors such as decitabine and vorinostat, increases in RFP expression were observed, indicating expression of RFP-TMnfsB. The EPISSAY system was then used to test the potency of decitabine, before and after PEGylated liposomal encapsulation. We observed a 50% higher potency of decitabine when encapsulated in PEGylated liposomes, which is likely to be due to its protection from rapid degradation. The EPISSAY bioassay system provides a novel and rapid system to compare the efficiencies of existing and newly formulated drugs that reactivate gene expression

  1. Screening for illicit and medicinal drugs in whole blood using fully automated SPE and ultra-high-performance liquid chromatography with TOF-MS with data-independent acquisition.

    Science.gov (United States)

    Pedersen, Anders Just; Dalsgaard, Petur Weihe; Rode, Andrej Jaroslav; Rasmussen, Brian Schou; Müller, Irene Breum; Johansen, Sys Stybe; Linnet, Kristian

    2013-07-01

    A broad forensic screening method for 256 analytes in whole blood based on a fully automated SPE robotic extraction and ultra-high-performance liquid chromatography (UHPLC) with TOF-MS with data-independent acquisition has been developed. The limit of identification was evaluated for all 256 compounds and 95 of these compounds were validated with regard to matrix effects, extraction recovery, and process efficiency. The limit of identification ranged from 0.001 to 0.1 mg/kg, and the process efficiency exceeded 50% for 73 of the 95 analytes. As an example of application, 1335 forensic traffic cases were analyzed with the presented screening method. Of these, 992 cases (74%) were positive for one or more traffic-relevant drugs above the Danish legal limits. Commonly abused drugs such as amphetamine, cocaine, and frequent types of benzodiazepines were the major findings. Nineteen less frequently encountered drugs were detected e.g. buprenorphine, butylone, cathine, fentanyl, lysergic acid diethylamide, m-chlorophenylpiperazine, 3,4-methylenedioxypyrovalerone, mephedrone, 4-methylamphetamine, p-fluoroamphetamine, and p-methoxy-N-methylamphetamine. In conclusion, using UHPLC-TOF-MS screening with data-independent acquisition resulted in the detection of common drugs of abuse as well as new designer drugs and more rarely occurring drugs. Thus, TOF-MS screening of blood samples constitutes a practical way for screening traffic cases, with the exception of δ-9-tetrahydrocannabinol, which should be handled in a separate method. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Parameter optimization of parenchymal texture analysis for prediction of false-positive recalls from screening mammography

    Science.gov (United States)

    Ray, Shonket; Keller, Brad M.; Chen, Jinbo; Conant, Emily F.; Kontos, Despina

    2016-03-01

    This work details a methodology to obtain optimal parameter values for a locally-adaptive texture analysis algorithm that extracts mammographic texture features representative of breast parenchymal complexity for predicting falsepositive (FP) recalls from breast cancer screening with digital mammography. The algorithm has two components: (1) adaptive selection of localized regions of interest (ROIs) and (2) Haralick texture feature extraction via Gray- Level Co-Occurrence Matrices (GLCM). The following parameters were systematically varied: mammographic views used, upper limit of the ROI window size used for adaptive ROI selection, GLCM distance offsets, and gray levels (binning) used for feature extraction. Each iteration per parameter set had logistic regression with stepwise feature selection performed on a clinical screening cohort of 474 non-recalled women and 68 FP recalled women; FP recall prediction was evaluated using area under the curve (AUC) of the receiver operating characteristic (ROC) and associations between the extracted features and FP recall were assessed via odds ratios (OR). A default instance of mediolateral (MLO) view, upper ROI size limit of 143.36 mm (2048 pixels2), GLCM distance offset combination range of 0.07 to 0.84 mm (1 to 12 pixels) and 16 GLCM gray levels was set. The highest ROC performance value of AUC=0.77 [95% confidence intervals: 0.71-0.83] was obtained at three specific instances: the default instance, upper ROI window equal to 17.92 mm (256 pixels2), and gray levels set to 128. The texture feature of sum average was chosen as a statistically significant (p<0.05) predictor and associated with higher odds of FP recall for 12 out of 14 total instances.

  3. Toward the virtual screening of potential drugs in the homology modeled NAD+ dependent DNA ligase from Mycobacterium tuberculosis.

    Science.gov (United States)

    Singh, Vijai; Somvanshi, Pallavi

    2010-02-01

    DNA ligase is an important enzyme and it plays vital role in the replication and repair; also catalyzes nick joining between adjacent bases of DNA. The NAD(+) dependent DNA ligase is selectively present in eubacteria and few viruses; but missing in humans. Homology modeling was used to generate 3-D structure of NAD(+) dependent DNA ligase (LigA) of Mycobacterium tuberculosis using the known template (PDB: 2OWO). Furthermore, the stereochemical quality and torsion angle of 3-D structure was validated. Numerous effective drugs were selected and the active amino acid residue in LigA was targeted and virtual screening through molecular docking was done. In this analysis, four drugs Chloroquine, Hydroxychloroquine, Putrienscine and Adriamycin were found more potent in inhibition of M. tuberculosis through the robust binding affinity between protein-drug interactions in comparison with the other studied drugs. A phylogenetic tree was constructed and it was observed that homology of LigA in M. tuberculosis resembled with other Mycobacterium species. The conserved active amino acids of LigA may be useful to target these drugs. These findings could be used as the starting point of a rational design of novel antibacterial drugs and its analogs.

  4. HPV16/18 genotyping for the triage of HPV positive women in primary cervical cancer screening in Chile.

    Science.gov (United States)

    Lagos, Marcela; Van De Wyngard, Vanessa; Poggi, Helena; Cook, Paz; Viviani, Paola; Barriga, María Isabel; Pruyas, Martha; Ferreccio, Catterina

    2015-01-01

    We previously conducted a population-based screening trial of high-risk human papillomavirus (hrHPV) testing and conventional cytology, demonstrating higher sensitivity (92.7 % vs 22.1 % for CIN2+) but lower positive predictive value (10.5 % vs 23.9 %) of hrHPV testing. Here we report the performance of HPV16/18 genotyping to triage the hrHPV positive participants. Women aged 25 years and older received hrHPV (Hybrid Capture 2) and Papanicolaou testing; positives by either test underwent colposcopy and directed biopsy, as did a sample of double-negatives. hrHPV positive women were reflex-tested with HPV16/18 genotyping (Digene HPV Genotyping PS Test). Among the 8,265 participants, 10.7 % were hrHPV positive, 1.7 % had ASCUS+ cytology, 1.2 % had CIN2+; 776 (88 %) hrHPV positive women had complete results, of whom 38.8 % were positive for HPV16 (24.0 %), HPV18 (9.7 %) or both (5.1 %). CIN2+ prevalence in HPV16/18 positive women (16.3 %, 95 % CI 12.3-20.9) was twice that of HPV16/18 negative women (8.0 %, 95 % CI 5.7-10.8). HPV16/18 genotyping identified 40.5 % of CIN2, 66.7 % of CIN3 and 75.0 % of cancers. Compared to hrHPV screening alone, HPV16/18 triage significantly reduced the referral rate (10.7 % vs 3.7 %) and the number of colposcopies required to detect one CIN2+ (9 vs 6). When HPV16/18 negative women with baseline ASCUS+ cytology were also colposcopied, an additional 14 % of CIN2+ was identified; referral increased slightly to 4.2 %. HPV16/18 triage effectively stratified hrHPV positive women by their risk of high-grade lesions. HPV16/18 positive women must be referred immediately; referral could be deferred in HPV16/18 negative women given the slower progression of non-HPV16/18 lesions, however, they will require active follow-up.

  5. Parallel screening of FDA-approved antineoplastic drugs for identifying sensitizers of TRAIL-induced apoptosis in cancer cells

    International Nuclear Information System (INIS)

    Taylor, David J; Parsons, Christine E; Han, Haiyong; Jayaraman, Arul; Rege, Kaushal

    2011-01-01

    Tumor Necrosis Factor-α Related Apoptosis Inducing Ligand (TRAIL) and agonistic antibodies to death receptor 4 and 5 are promising candidates for cancer therapy due to their ability to induce apoptosis selectively in a variety of human cancer cells, while demonstrating little cytotoxicity in normal cells. Although TRAIL and agonistic antibodies to DR4 and DR5 are considered safe and promising candidates in cancer therapy, many malignant cells are resistant to DR-mediated, TRAIL-induced apoptosis. In the current work, we screened a small library of fifty-five FDA and foreign-approved anti-neoplastic drugs in order to identify candidates that sensitized resistant prostate and pancreatic cancer cells to TRAIL-induced apoptosis. FDA-approved drugs were screened for their ability to sensitize TRAIL resistant prostate cancer cells to TRAIL using an MTT assay for cell viability. Analysis of variance was used to identify drugs that exhibited synergy with TRAIL. Drugs demonstrating the highest synergy were selected as leads and tested in different prostate and pancreatic cancer cell lines, and one immortalized human pancreatic epithelial cell line. Sequential and simultaneous dosing modalities were investigated and the annexin V/propidium iodide assay, in concert with fluorescence microscopy, was employed to visualize cells undergoing apoptosis. Fourteen drugs were identified as having synergy with TRAIL, including those whose TRAIL sensitization activities were previously unknown in either prostate or pancreatic cancer cells or both. Five leads were tested in additional cancer cell lines of which, doxorubicin, mitoxantrone, and mithramycin demonstrated synergy in all lines. In particular, mitoxantrone and mithramycin demonstrated significant synergy with TRAIL and led to reduction of cancer cell viability at concentrations lower than 1 μM. At these low concentrations, mitoxantrone demonstrated selectivity toward malignant cells over normal pancreatic epithelial cells

  6. Parallel screening of FDA-approved antineoplastic drugs for identifying sensitizers of TRAIL-induced apoptosis in cancer cells

    Directory of Open Access Journals (Sweden)

    Taylor David J

    2011-11-01

    Full Text Available Abstract Background Tumor Necrosis Factor-α Related Apoptosis Inducing Ligand (TRAIL and agonistic antibodies to death receptor 4 and 5 are promising candidates for cancer therapy due to their ability to induce apoptosis selectively in a variety of human cancer cells, while demonstrating little cytotoxicity in normal cells. Although TRAIL and agonistic antibodies to DR4 and DR5 are considered safe and promising candidates in cancer therapy, many malignant cells are resistant to DR-mediated, TRAIL-induced apoptosis. In the current work, we screened a small library of fifty-five FDA and foreign-approved anti-neoplastic drugs in order to identify candidates that sensitized resistant prostate and pancreatic cancer cells to TRAIL-induced apoptosis. Methods FDA-approved drugs were screened for their ability to sensitize TRAIL resistant prostate cancer cells to TRAIL using an MTT assay for cell viability. Analysis of variance was used to identify drugs that exhibited synergy with TRAIL. Drugs demonstrating the highest synergy were selected as leads and tested in different prostate and pancreatic cancer cell lines, and one immortalized human pancreatic epithelial cell line. Sequential and simultaneous dosing modalities were investigated and the annexin V/propidium iodide assay, in concert with fluorescence microscopy, was employed to visualize cells undergoing apoptosis. Results Fourteen drugs were identified as having synergy with TRAIL, including those whose TRAIL sensitization activities were previously unknown in either prostate or pancreatic cancer cells or both. Five leads were tested in additional cancer cell lines of which, doxorubicin, mitoxantrone, and mithramycin demonstrated synergy in all lines. In particular, mitoxantrone and mithramycin demonstrated significant synergy with TRAIL and led to reduction of cancer cell viability at concentrations lower than 1 μM. At these low concentrations, mitoxantrone demonstrated selectivity toward

  7. A prediction model-based algorithm for computer-assisted database screening of adverse drug reactions in the Netherlands.

    Science.gov (United States)

    Scholl, Joep H G; van Hunsel, Florence P A M; Hak, Eelko; van Puijenbroek, Eugène P

    2018-02-01

    The statistical screening of pharmacovigilance databases containing spontaneously reported adverse drug reactions (ADRs) is mainly based on disproportionality analysis. The aim of this study was to improve the efficiency of full database screening using a prediction model-based approach. A logistic regression-based prediction model containing 5 candidate predictors was developed and internally validated using the Summary of Product Characteristics as the gold standard for the outcome. All drug-ADR associations, with the exception of those related to vaccines, with a minimum of 3 reports formed the training data for the model. Performance was based on the area under the receiver operating characteristic curve (AUC). Results were compared with the current method of database screening based on the number of previously analyzed associations. A total of 25 026 unique drug-ADR associations formed the training data for the model. The final model contained all 5 candidate predictors (number of reports, disproportionality, reports from healthcare professionals, reports from marketing authorization holders, Naranjo score). The AUC for the full model was 0.740 (95% CI; 0.734-0.747). The internal validity was good based on the calibration curve and bootstrapping analysis (AUC after bootstrapping = 0.739). Compared with the old method, the AUC increased from 0.649 to 0.740, and the proportion of potential signals increased by approximately 50% (from 12.3% to 19.4%). A prediction model-based approach can be a useful tool to create priority-based listings for signal detection in databases consisting of spontaneous ADRs. © 2017 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd.

  8. Application of Sweat Patch Screening for 16 Drugs and Metabolites Using a Fast and Highly Selective LC-MS/MS Method

    NARCIS (Netherlands)

    Koster, Remco A.; Alffenaar, Jan-Willem C.; Greijdanus, Ben; VanDerNagel, Joanneke E. L.; Uges, Donald R. A.

    Background: To facilitate the monitoring of drug abuse by patients, a method was developed and validated for fast and highly selective screening for amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine, methylenedioxyamphetamine, methylenedioxyethylamphetamine, methylphenidate, cocaine,

  9. Seeing through the public health smoke-screen in drug policy.

    Science.gov (United States)

    Csete, Joanne; Wolfe, Daniel

    2017-05-01

    In deliberations on drug policy in United Nations fora, a consensus has emerged that drug use and drug dependence should be treated primarily as public health concerns rather than as crimes. But what some member states mean by "public health approach" merits scrutiny. Some governments that espouse treating people who use drugs as "patients, not criminals" still subject them to prison-like detention in the name of drug-dependence treatment or otherwise do not take measures to provide scientifically sound treatment and humane social support to those who need them. Even drug treatment courts, which the U.S. and other countries hold up as examples of a public health approach to drug dependence, can serve rather to tighten the hold of the criminal justice sector on concerns that should be addressed in the health sector. The political popularity of demonisation of drugs and visibly repressive approaches is an obvious challenge to leadership for truly health-oriented drug control. This commentary offers some thoughts for judging whether a public health approach is worthy of the name and cautions drug policy reformers not to rely on facile commitments to health approaches that are largely rhetorical or that mask policies and activities not in keeping with good public health practise. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Label-free recognition of drug resistance via impedimetric screening of breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Bilge Eker

    Full Text Available We present a novel study on label-free recognition and distinction of drug resistant breast cancer cells (MCF-7 DOX from their parental cells (MCF-7 WT via impedimetric measurements. Drug resistant cells exhibited significant differences in their dielectric properties compared to wild-type cells, exerting much higher extracellular resistance (Rextra . Immunostaining revealed that MCF-7 DOX cells gained a much denser F-actin network upon acquiring drug resistance indicating that remodeling of actin cytoskeleton is probably the reason behind higher Rextra , providing stronger cell architecture. Moreover, having exposed both cell types to doxorubicin, we were able to distinguish these two phenotypes based on their substantially different drug response. Interestingly, impedimetric measurements identified a concentration-dependent and reversible increase in cell stiffness in the presence of low non-lethal drug doses. Combined with a profound frequency analysis, these findings enabled distinguishing distinct cellular responses during drug exposure within four concentration ranges without using any labeling. Overall, this study highlights the possibility to differentiate drug resistant phenotypes from their parental cells and to assess their drug response by using microelectrodes, offering direct, real-time and noninvasive measurements of cell dependent parameters under drug exposure, hence providing a promising step for personalized medicine applications such as evaluation of the disease progress and optimization of the drug treatment of a patient during chemotherapy.

  11. Recombinant yeast screen for new inhibitors of human acetyl-CoA carboxylase 2 identifies potential drugs to treat obesity

    Science.gov (United States)

    Marjanovic, Jasmina; Chalupska, Dominika; Patenode, Caroline; Coster, Adam; Arnold, Evan; Ye, Alice; Anesi, George; Lu, Ying; Okun, Ilya; Tkachenko, Sergey; Haselkorn, Robert; Gornicki, Piotr

    2010-01-01

    Acetyl-CoA carboxylase (ACC) is a key enzyme of fatty acid metabolism with multiple isozymes often expressed in different eukaryotic cellular compartments. ACC-made malonyl-CoA serves as a precursor for fatty acids; it also regulates fatty acid oxidation and feeding behavior in animals. ACC provides an important target for new drugs to treat human diseases. We have developed an inexpensive nonradioactive high-throughput screening system to identify new ACC inhibitors. The screen uses yeast gene-replacement strains depending for growth on cloned human ACC1 and ACC2. In “proof of concept” experiments, growth of such strains was inhibited by compounds known to target human ACCs. The screen is sensitive and robust. Medium-size chemical libraries yielded new specific inhibitors of human ACC2. The target of the best of these inhibitors was confirmed with in vitro enzymatic assays. This compound is a new drug chemotype inhibiting human ACC2 with 2.8 μM IC50 and having no effect on human ACC1 at 100 μM. PMID:20439761

  12. Use of faecal markers in screening for colorectal neoplasia: a European group on tumor markers position paper.

    LENUS (Irish Health Repository)

    Duffy, Michael J

    2012-02-01

    Several randomized controlled trials have shown that population-based screening using faecal occult blood testing (FOBT) can reduce mortality from colorectal neoplasia. Based on this evidence, a number of countries have introduced screening for colorectal cancer (CRC) and high-risk adenoma and many others are considering its introduction. The aim of this article is to critically review the current status of faecal markers as population-based screening tests for these neoplasia. Most of the available faecal tests involve the measurement of either occult blood or a panel of DNA markers. Occult blood may be measured using either the guaiac faecal occult blood test (gFOBT) or a faecal immunochemical test (iFOBT). Although iFOBT may require a greater initial investment, they have several advantages over gFOBT, including greater analytical sensitivity and specificity. Their use results in improved clinical performance and higher uptake rates. Importantly for population screening, some of the iFOBTs can be automated and provide an adjustable cutoff for faecal haemoglobin concentration. However, samples for iFOBT, may be less stable after collection than for gFOBT. For new centres undertaking FOBT for colorectal neoplasia, the European Group on Tumour Markers recommends use of a quantitative iFOBT with an adjustable cutoff point and high throughput analysis. All participants with positive FOBT results should be offered colonoscopy. The panel recommends further research into increasing the stability of iFOBT and the development of improved and affordable DNA and proteomic-based tests, which reduce current false negative rates, simplify sample transport and enable automated analysis.

  13. need for screening for alcohol and drugs in emergency trauma units

    African Journals Online (AJOL)

    2013-05-05

    May 5, 2013 ... Therefore trauma patients require routine toxicological screening to provide basis ... (ii) to identify sociodemographic characteristics that correlated with injury ..... an error in AIS scoring is transferred to the ISS, different injury ...

  14. Weighing the Consequences: Self-Disclosure of HIV-Positive Status among African American Injection Drug Users

    Science.gov (United States)

    Valle, Maribel; Levy, Judith

    2009-01-01

    Theorists posit that personal decisions to disclose being HIV positive are made based on the perceived consequences of that disclosure. This study examines the perceived costs and benefits of self-disclosure among African American injection drug users (IDUs). A total of 80 African American IDUs were interviewed in-depth subsequent to testing HIV…

  15. Development of a web-based tool for automated processing and cataloging of a unique combinatorial drug screen.

    Science.gov (United States)

    Dalecki, Alex G; Wolschendorf, Frank

    2016-07-01

    Facing totally resistant bacteria, traditional drug discovery efforts have proven to be of limited use in replenishing our depleted arsenal of therapeutic antibiotics. Recently, the natural anti-bacterial properties of metal ions in synergy with metal-coordinating ligands have shown potential for generating new molecule candidates with potential therapeutic downstream applications. We recently developed a novel combinatorial screening approach to identify compounds with copper-dependent anti-bacterial properties. Through a parallel screening technique, the assay distinguishes between copper-dependent and independent activities against Mycobacterium tuberculosis with hits being defined as compounds with copper-dependent activities. These activities must then be linked to a compound master list to process and analyze the data and to identify the hit molecules, a labor intensive and mistake-prone analysis. Here, we describe a software program built to automate this analysis in order to streamline our workflow significantly. We conducted a small, 1440 compound screen against M. tuberculosis and used it as an example framework to build and optimize the software. Though specifically adapted to our own needs, it can be readily expanded for any small- to medium-throughput screening effort, parallel or conventional. Further, by virtue of the underlying Linux server, it can be easily adapted for chemoinformatic analysis of screens through packages such as OpenBabel. Overall, this setup represents an easy-to-use solution for streamlining processing and analysis of biological screening data, as well as offering a scaffold for ready functionality expansion. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Stimulus-Food Pairings Produce Stimulus-Directed Touch Screen Responding in Cynomolgus Monkeys ("Macaca Fascicularis") with or without a Positive Response Contingency

    Science.gov (United States)

    Bullock, Christopher E.; Myers, Todd M.

    2009-01-01

    Acquisition and maintenance of touch-screen responding was examined in naive cynomolgus monkeys ("Macaca fascicularis") under automaintenance and classical conditioning arrangements. In the first condition of Experiment 1, we compared acquisition of screen touching to a randomly positioned stimulus (a gray square) that was either stationary or…

  17. Syphilis sero-positivity in recently admitted and long-term psychiatric inpatients: Screening, prevalence and diagnostic profile

    Directory of Open Access Journals (Sweden)

    Maria P Henning

    2012-12-01

    Full Text Available Background. Syphilis research has neglected the prevalence of the disease among psychiatric patients, and traditional syphilis screening has been reported as inadequate. Objectives. (i To assess the syphilis prevalence among psychiatric patients; (ii to compare psychiatric diagnoses of syphilis-infected and -uninfected patients; (iii to assess self-reported high-risk sexual behaviour; (iv to establish syphilis/HIV co-morbidity; and (v to investigate the performance of the rapid plasma reagin (RPR test in syphilis screening, compared with the Treponema pallidum haemagglutination (TPHA test. Methods. Psychiatric inpatients at Weskoppies Hospital, Pretoria, who consented to participate in the study (N=195 were categorised according to gender and length of admission (long-term or recent. Non-treponemal RPR, confirmatory TPHA, HIV-rapid and HIV enzyme-linked immunosorbent assay (ELISA tests were performed. A reactive TPHA test was used to diagnose syphilis. Results. The estimated prevalence of syphilis was 11.7%. There was no significant association between TPHA sero-positivity and primary psychiatric diagnosis or self-reported high-risk sexual behaviour. Significant co-morbidity existed between syphilis and HIV (p=0.012. Compared with the TPHA test, the RPR test performed poorly, identifying only 2/23 patients who had a sero-positive TPHA test (8.7% sensitivity and 100% specificity. Conclusions. The prevalence of syphilis was higher than anticipated, supporting the need for routine testing. The significant co-morbidity and alarming prevalence of HIV and syphilis warrant testing for both conditions in all psychiatric admissions. Current syphilis screening with a single RPR test is inadequate; both RPR and TPHA tests should be performed.

  18. Costs and Cost Effectiveness of Three Approaches for Cervical Cancer Screening among HIV-Positive Women in Johannesburg, South Africa.

    Science.gov (United States)

    Lince-Deroche, Naomi; Phiri, Jane; Michelow, Pam; Smith, Jennifer S; Firnhaber, Cindy

    2015-01-01

    South Africa has high rates of HIV and HPV and high incidence and mortality from cervical cancer. However, cervical cancer is largely preventable when early screening and treatment are available. We estimate the costs and cost-effectiveness of conventional cytology (Pap), visual inspection with acetic acid (VIA) and HPV DNA testing for detecting cases of CIN2+ among HIV-infected women currently taking antiretroviral treatment at a public HIV clinic in Johannesburg, South Africa. Method effectiveness was derived from a validation study completed at the clinic. Costs were estimated from the provider perspective using micro-costing between June 2013-April 2014. Capital costs were annualized using a discount rate of 3%. Two different service volume scenarios were considered. Threshold analysis was used to explore the potential for reducing the cost of HPV DNA testing. VIA was least costly in both scenarios. In the higher volume scenario, the average cost per procedure was US$ 3.67 for VIA, US$ 8.17 for Pap and US$ 54.34 for HPV DNA. Colposcopic biopsies cost on average US$ 67.71 per procedure. VIA was least sensitive but most cost-effective at US$ 17.05 per true CIN2+ case detected. The cost per case detected for Pap testing was US$ 130.63 using a conventional definition for positive results and US$ 187.52 using a more conservative definition. HPV DNA testing was US$ 320.09 per case detected. Colposcopic biopsy costs largely drove the total and per case costs. A 71% reduction in HPV DNA screening costs would make it competitive with the conservative Pap definition. Women need access to services which meet their needs and address the burden of cervical dysplasia and cancer in this region. Although most cost-effective, VIA may require more frequent screening due to low sensitivity, an important consideration for an HIV-positive population with increased risk for disease progression.

  19. Costs and Cost Effectiveness of Three Approaches for Cervical Cancer Screening among HIV-Positive Women in Johannesburg, South Africa.

    Directory of Open Access Journals (Sweden)

    Naomi Lince-Deroche

    Full Text Available South Africa has high rates of HIV and HPV and high incidence and mortality from cervical cancer. However, cervical cancer is largely preventable when early screening and treatment are available. We estimate the costs and cost-effectiveness of conventional cytology (Pap, visual inspection with acetic acid (VIA and HPV DNA testing for detecting cases of CIN2+ among HIV-infected women currently taking antiretroviral treatment at a public HIV clinic in Johannesburg, South Africa.Method effectiveness was derived from a validation study completed at the clinic. Costs were estimated from the provider perspective using micro-costing between June 2013-April 2014. Capital costs were annualized using a discount rate of 3%. Two different service volume scenarios were considered. Threshold analysis was used to explore the potential for reducing the cost of HPV DNA testing.VIA was least costly in both scenarios. In the higher volume scenario, the average cost per procedure was US$ 3.67 for VIA, US$ 8.17 for Pap and US$ 54.34 for HPV DNA. Colposcopic biopsies cost on average US$ 67.71 per procedure. VIA was least sensitive but most cost-effective at US$ 17.05 per true CIN2+ case detected. The cost per case detected for Pap testing was US$ 130.63 using a conventional definition for positive results and US$ 187.52 using a more conservative definition. HPV DNA testing was US$ 320.09 per case detected. Colposcopic biopsy costs largely drove the total and per case costs. A 71% reduction in HPV DNA screening costs would make it competitive with the conservative Pap definition.Women need access to services which meet their needs and address the burden of cervical dysplasia and cancer in this region. Although most cost-effective, VIA may require more frequent screening due to low sensitivity, an important consideration for an HIV-positive population with increased risk for disease progression.

  20. Identifying kinase dependency in cancer cells by integrating high-throughput drug screening and kinase inhibition data.

    Science.gov (United States)

    Ryall, Karen A; Shin, Jimin; Yoo, Minjae; Hinz, Trista K; Kim, Jihye; Kang, Jaewoo; Heasley, Lynn E; Tan, Aik Choon

    2015-12-01

    Targeted kinase inhibitors have dramatically improved cancer treatment, but kinase dependency for an individual patient or cancer cell can be challenging to predict. Kinase dependency does not always correspond with gene expression and mutation status. High-throughput drug screens are powerful tools for determining kinase dependency, but drug polypharmacology can make results difficult to interpret. We developed Kinase Addiction Ranker (KAR), an algorithm that integrates high-throughput drug screening data, comprehensive kinase inhibition data and gene expression profiles to identify kinase dependency in cancer cells. We applied KAR to predict kinase dependency of 21 lung cancer cell lines and 151 leukemia patient samples using published datasets. We experimentally validated KAR predictions of FGFR and MTOR dependence in lung cancer cell line H1581, showing synergistic reduction in proliferation after combining ponatinib and AZD8055. KAR can be downloaded as a Python function or a MATLAB script along with example inputs and outputs at: http://tanlab.ucdenver.edu/KAR/. aikchoon.tan@ucdenver.edu. Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  1. Towards holistic dual diagnosis care: physical health screening in a Victorian community-based alcohol and drug treatment service.

    Science.gov (United States)

    Jackson, Lara; Felstead, Boyce; Bhowmik, Jahar; Avery, Rachel; Nelson-Hearity, Rhonda

    2016-01-01

    The poorer health outcomes experienced by people with mental illness have led to new directions in policy for routine physical health screening of service users. By contrast, little attention has been paid to the physical health needs of consumers of alcohol and other drug (AOD) services, despite a similar disparity in physical health outcomes compared with the general population. The majority of people with problematic AOD use have comorbid mental illness, known as a dual diagnosis, likely to exacerbate their vulnerability to poor physical health. With the potential for physical health screening to improve health outcomes for AOD clients, a need exists for systematic identification and management of common health conditions. Within the current health service system, those with a dual diagnosis are more likely to have their physical health surveyed and responded to if they present for treatment in the mental health system. In this study, a physical health screening tool was administered to clients attending a community-based AOD service. The tool was administered by a counsellor during the initial phase of treatment, and referrals to health professionals were made as appropriate. Findings are discussed in terms of prevalence, types of problems identified and subsequent rates of referral. The results corroborate the known link between mental and physical ill health, and contribute to developing evidence that AOD clients present with equally concerning physical ill health to that of mental health clients and should equally be screened for such when presenting for AOD treatment.

  2. Dosage and dose schedule screening of drug combinations in agent-based models reveals hidden synergies

    Directory of Open Access Journals (Sweden)

    Lisa Corina Barros de Andrade e Sousa1

    2016-01-01

    Full Text Available The fungus Candida albicans is the most common causative agent of human fungal infections and better drugs or drug combination strategies are urgently needed. Here, we present an agent-based model of the interplay of C. albicans with the host immune system and with the microflora of the host. We took into account the morphological change of C. albicans from the yeast to hyphae form and its dynamics during infection. The model allowed us to follow the dynamics of fungal growth and morphology, of the immune cells and of microflora in different perturbing situations. We specifically focused on the consequences of microflora reduction following antibiotic treatment. Using the agent-based model, different drug types have been tested for their effectiveness, namely drugs that inhibit cell division and drugs that constrain the yeast-to-hyphae transition. Applied individually, the division drug turned out to successfully decrease hyphae while the transition drug leads to a burst in hyphae after the end of the treatment. To evaluate the effect of different drug combinations, doses, and schedules, we introduced a measure for the return to a healthy state, the infection score. Using this measure, we found that the addition of a transition drug to a division drug treatment can improve the treatment reliability while minimizing treatment duration and drug dosage. In this work we present a theoretical study. Although our model has not been calibrated to quantitative experimental data, the technique of computationally identifying synergistic treatment combinations in an agent based model exemplifies the importance of computational techniques in translational research.

  3. HCS-Neurons: identifying phenotypic changes in multi-neuron images upon drug treatments of high-content screening.

    Science.gov (United States)

    Charoenkwan, Phasit; Hwang, Eric; Cutler, Robert W; Lee, Hua-Chin; Ko, Li-Wei; Huang, Hui-Ling; Ho, Shinn-Ying

    2013-01-01

    High-content screening (HCS) has become a powerful tool for drug discovery. However, the discovery of drugs targeting neurons is still hampered by the inability to accurately identify and quantify the phenotypic changes of multiple neurons in a single image (named multi-neuron image) of a high-content screen. Therefore, it is desirable to develop an automated image analysis method for analyzing multi-neuron images. We propose an automated analysis method with novel descriptors of neuromorphology features for analyzing HCS-based multi-neuron images, called HCS-neurons. To observe multiple phenotypic changes of neurons, we propose two kinds of descriptors which are neuron feature descriptor (NFD) of 13 neuromorphology features, e.g., neurite length, and generic feature descriptors (GFDs), e.g., Haralick texture. HCS-neurons can 1) automatically extract all quantitative phenotype features in both NFD and GFDs, 2) identify statistically significant phenotypic changes upon drug treatments using ANOVA and regression analysis, and 3) generate an accurate classifier to group neurons treated by different drug concentrations using support vector machine and an intelligent feature selection method. To evaluate HCS-neurons, we treated P19 neurons with nocodazole (a microtubule depolymerizing drug which has been shown to impair neurite development) at six concentrations ranging from 0 to 1000 ng/mL. The experimental results show that all the 13 features of NFD have statistically significant difference with respect to changes in various levels of nocodazole drug concentrations (NDC) and the phenotypic changes of neurites were consistent to the known effect of nocodazole in promoting neurite retraction. Three identified features, total neurite length, average neurite length, and average neurite area were able to achieve an independent test accuracy of 90.28% for the six-dosage classification problem. This NFD module and neuron image datasets are provided as a freely downloadable

  4. Effects of a health education and telephone counseling program on patients with a positive fecal occult blood test result for colorectal cancer screening: A randomized controlled trial.

    Science.gov (United States)

    Chiu, Hui-Chuan; Hung, Hsin-Yuan; Lin, Hsiu-Chen; Chen, Shu-Ching

    2017-10-01

    Our purpose was to evaluate the effects of a health education and telephone counseling program on knowledge and attitudes about colorectal cancer and screening and the psychological impact of positive screening results. A randomized controlled trial was conducted with 2 groups using a pretest and posttest measures design. Patients with positive colorectal cancer screening results were selected and randomly assigned to an experimental (n = 51) or control (n = 51) group. Subjects in the experimental group received a health education and telephone counseling program, while the control group received routine care only. Patients were assessed pretest before intervention (first visit to the outpatient) and posttest at 4 weeks after intervention (4 weeks after first visit to the outpatient). Patients in the experimental group had a significantly better level of knowledge about colorectal cancer and the psychological impact of a positive screening result than did the control group. Analysis of covariance revealed that the health education and telephone counseling program had a significant main effect on colorectal cancer knowledge. A health education and telephone counseling program can improve knowledge about colorectal cancer and about the psychological impact in patients with positive colorectal cancer screening results. The health education and telephone counseling program is an easy, simple, and convenient method of improving knowledge, improving attitudes, and alleviating psychological distress in patients with positive colorectal cancer screening results, and this program can be expanded to other types of cancer screening. Copyright © 2016 John Wiley & Sons, Ltd.

  5. An effective HIV-1 integrase inhibitor screening platform: Rationality validation of drug screening, conformational mobility and molecular recognition analysis for PFV integrase complex with viral DNA.

    Science.gov (United States)

    Du, Wenyi; Zuo, Ke; Sun, Xin; Liu, Wei; Yan, Xiao; Liang, Li; Wan, Hua; Chen, Fengzheng; Hu, Jianping

    2017-11-01

    As an important target for the development of novel anti-AIDS drugs, HIV-1 integrase (IN) has been widely concerned. However, the lack of a complete accurate crystal structure of HIV-1 IN greatly blocks the discovery of novel inhibitors. In this work, an effective HIV-1 IN inhibitor screening platform, namely PFV IN, was filtered from all species of INs. Next, the 40.8% similarity with HIV-1 IN, as well as the high efficiency of virtual screening and the good agreement between calculated binding free energies and experimental ones all proved PFV IN is a promising screening platform for HIV-1 IN inhibitors. Then, the molecular recognition mechanism of PFV IN by its substrate viral DNA and six naphthyridine derivatives (NRDs) inhibitors was investigated through molecular docking, molecular dynamics simulations and water-mediated interactions analyses. The functional partition of NRDs IN inhibitors could be divided into hydrophobic and hydrophilic ones, and the Mg 2+ ions, water molecules and conserved DDE motif residues all interacted with the hydrophilic partition, while the bases in viral DNA and residues like Tyr212, Pro214 interacted with the hydrophobic one. Finally, the free energy landscape (FEL) and cluster analyses were performed to explore the molecular motion of PFV IN-DNA system. It is found that the association with NRDs inhibitors would obviously decrease the motion amplitude of PFV IN-DNA, which may be one of the most potential mechanisms of IN inhibitors. This work will provide a theoretical basis for the inhibitor design based on the structure of HIV-1 IN. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Drug discovery for hearing loss: Phenotypic screening of chemical compounds on primary cultures of the spiral ganglion.

    Science.gov (United States)

    Whitlon, Donna S

    2017-06-01

    In the United States there are, at present, no drugs that are specifically FDA approved to treat hearing loss. Although several clinical trials are ongoing, including one testing D-methionine that is supported by the US Army, none of these trials directly address the effect of noise exposure on cochlear spiral ganglion neurons. We recently published the first report of a systematic chemical compound screen using primary, mammalian spiral ganglion cultures in which we were able to detect a compound and others in its class that increased neurite elongation, a critical step in restoring cochlear synapses after noise induced hearing loss. Here we discuss the issues, both pro and con, that influenced the development of our approach. These considerations may be useful for future compound screens that target the same or other attributes of cochlear spiral ganglion neurons. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Noise-driven diamagnetic susceptibility of impurity doped quantum dots: Role of anisotropy, position-dependent effective mass and position-dependent dielectric screening function

    International Nuclear Information System (INIS)

    Bera, Aindrila; Saha, Surajit; Ganguly, Jayanta; Ghosh, Manas

    2016-01-01

    Highlights: • Diamagnetic susceptibility (DMS) of doped quantum dot is studied. • The dot is subjected to Gaussian white noise. • Role of anisotropy, PDEM and PDDSF have been analyzed. • Noise amplifies and suppresses DMS depending on particular condition. • Findings bear significant technological importance. - Abstract: We explore Diamagnetic susceptibility (DMS) of impurity doped quantum dot (QD) in presence of Gaussian white noise introduced to the system additively and multiplicatively. In view of this profiles of DMS have been pursued with variations of geometrical anisotropy and dopant location. We have invoked position-dependent effective mass (PDEM) and position-dependent dielectric screening function (PDDSF) of the system. Presence of noise sometimes suppresses and sometimes amplifies DMS from that of noise-free condition and the extent of suppression/amplification depends on mode of application of noise. It is important to mention that the said suppression/amplification exhibits subtle dependence on use of PDEM, PDDSF and geometrical anisotropy. The study reveals that DMS, or more fundamentally, the effective confinement of LDSS, can be tuned by appropriate mingling of geometrical anisotropy/effective mass/dielectric constant of the system with noise and also on the pathway of application of latter.

  8. Aerosol Drug Delivery During Noninvasive Positive Pressure Ventilation: Effects of Intersubject Variability and Excipient Enhanced Growth.

    Science.gov (United States)

    Walenga, Ross L; Longest, P Worth; Kaviratna, Anubhav; Hindle, Michael

    2017-06-01

    Nebulized aerosol drug delivery during the administration of noninvasive positive pressure ventilation (NPPV) is commonly implemented. While studies have shown improved patient outcomes for this therapeutic approach, aerosol delivery efficiency is reported to be low with high variability in lung-deposited dose. Excipient enhanced growth (EEG) aerosol delivery is a newly proposed technique that may improve drug delivery efficiency and reduce intersubject aerosol delivery variability when coupled with NPPV. A combined approach using in vitro experiments and computational fluid dynamics (CFD) was used to characterize aerosol delivery efficiency during NPPV in two new nasal cavity models that include face mask interfaces. Mesh nebulizer and in-line dry powder inhaler (DPI) sources of conventional and EEG aerosols were both considered. Based on validated steady-state CFD predictions, EEG aerosol delivery improved lung penetration fraction (PF) values by factors ranging from 1.3 to 6.4 compared with conventional-sized aerosols. Furthermore, intersubject variability in lung PF was very high for conventional aerosol sizes (relative differences between subjects in the range of 54.5%-134.3%) and was reduced by an order of magnitude with the EEG approach (relative differences between subjects in the range of 5.5%-17.4%). Realistic in vitro experiments of cyclic NPPV demonstrated similar trends in lung delivery to those observed with the steady-state simulations, but with lower lung delivery efficiencies. Reaching the lung delivery efficiencies reported with the steady-state simulations of 80%-90% will require synchronization of aerosol administration during inspiration and reducing the size of the EEG aerosol delivery unit. The EEG approach enabled high-efficiency lung delivery of aerosols administered during NPPV and reduced intersubject aerosol delivery variability by an order of magnitude. Use of an in-line DPI device that connects to the NPPV mask appears to be a

  9. The Positive Thinking Skills Scale: A screening measure for early identification of depressive thoughts.

    Science.gov (United States)

    Bekhet, Abir K; Garnier-Villarreal, Mauricio

    2017-12-01

    Depression is currently considered the second leading cause of disability worldwide. Positive thinking is a cognitive process that helps individuals to deal with problems more effectively, and has been suggested as a useful strategy for coping with adversity, including depression. The Positive Thinking Skills Scale (PTSS) is a reliable and valid measure that captures the frequency of use of positive thinking skills that can help in the early identification of the possibility of developing depressive thoughts. However, no meaningful cutoff score has been established for the PTSS. To establish a cutoff score for the PTSS for early identification of risk for depression. This study used a receiver operating characteristic (ROC) curve to establish a PTSS cutoff score for risk for depression, using the Center for Epidemiological Studies-Depression Scale (CES-D) as the gold standard measure. In a sample of 109 caregivers, the ROC showed that the cutoff score of PTSS that best classify the participants is 13.5. With this PTSS score, 77.8% of the subjects with low CES-D are classify correctly, and 69.6% of the subjects with high CES-D are classify correctly. Since the PTSS score should be integer numbers, functionally the cutoff would be 13. The study showed that a cut off score of 13 is a point at which referral, intervention, or treatment would be recommended. Consequently, this can help in the early identification of depressive symptoms that might develop because of the stress of caregiving. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Novel High-Throughput Drug Screening Platform for Chemotherapy-Induced Axonal Neuropathy

    Science.gov (United States)

    2014-05-01

    from anti-cancer drug therapy [1,2]. Platinum drugs, taxanes, proteasome inhibitors, vinca alkaloids, epothilones, and immunomodulators are the...and immunomodulators are the standard of anti-cancer therapies for the six most cancers. An estimated 2010 incidence of 994, 680 cases for these

  11. Bioanalysis of antibody-drug conjugates: American Association of Pharmaceutical Scientists Antibody-Drug Conjugate Working Group position paper.

    Science.gov (United States)

    Gorovits, Boris; Alley, Stephen C; Bilic, Sanela; Booth, Brian; Kaur, Surinder; Oldfield, Phillip; Purushothama, Shobha; Rao, Chetana; Shord, Stacy; Siguenza, Patricia

    2013-05-01

    Antibody-drug conjugates (ADCs) typically consist of a cytotoxic drug covalently bound to an antibody by a linker. These conjugates have the potential to substantially improve efficacy and reduce toxicity compared with cytotoxic small-molecule drugs. Since ADCs are generally complex heterogeneous mixtures of multiple species, these novel therapeutic products present unique bioanalytical challenges. The growing number of ADCs being developed across the industry suggests the need for alignment of the bioanalytical methods or approaches used to assess the multiple species and facilitate consistent interpretation of the bioanalytical data. With limited clinical data, the current strategies that can be used to provide insight into the relationship between the multiple species and the observed clinical safety and efficacy are still evolving. Considerations of the bioanalytical strategies for ADCs based on the current industry practices that take into account the complexity and heterogeneity of ADCs are discussed.

  12. Screening, prevalence, and risk factors for cervical lesions among HIV positive and HIV negative women in Swaziland

    Directory of Open Access Journals (Sweden)

    Pauline E. Jolly

    2017-02-01

    Full Text Available Abstract Background Cervical Cancer (CC is the number one cancer among women in sub-Saharan Africa. Although CC is preventable, most women in developing countries do not have access to screening. Methods This cross-sectional study was conducted to determine the prevalence and risk factors for cervical lesions using visual inspection with acetic acid (VIA among 112 HIV positive and 161 negative women aged 18–69 years. Results The presence of cervical lesions was greater among HIV positive (22.9% than HIV negative women (5.7%; p < 0.0001. In logistic models, the risk of cervical lesions among HIV positive women was 5.24 times higher when adjusted by age (OR 5.24, CI 2.31–11.88, and 4.06 times higher in a full model (OR 4.06, CI 1.61–10.25, than among HIV negative women. In the age-adjusted model women who had ≥2 lifetime sexual partners were 3 times more likely (OR 3.00, CI 1.02–8.85 to have cervical lesions compared to women with one lifetime partner and the odds of cervical lesions among women with a history of STIs were 2.16 greater (OR 2.16, CI 1.04–4.50 than among women with no previous STI. In the fully adjusted model women who had a previous cervical exam were 2.5 times more likely (OR 2.53, CI 1.06–6.05 to have cervical lesions than women who had not. Conclusions The high prevalence of HIV infection and the strong association between HIV and cervical lesions highlight the need for substantial scale-up of cervical screening to decrease the rate of CC in Swaziland.

  13. Identification of Novel "Inks" for 3D Printing Using High-Throughput Screening: Bioresorbable Photocurable Polymers for Controlled Drug Delivery.

    Science.gov (United States)

    Louzao, Iria; Koch, Britta; Taresco, Vincenzo; Ruiz-Cantu, Laura; Irvine, Derek J; Roberts, Clive J; Tuck, Christopher; Alexander, Cameron; Hague, Richard; Wildman, Ricky; Alexander, Morgan R

    2018-02-28

    A robust methodology is presented to identify novel biomaterials suitable for three-dimensional (3D) printing. Currently, the application of additive manufacturing is limited by the availability of functional inks, especially in the area of biomaterials; this is the first time when this method is used to tackle this problem, allowing hundreds of formulations to be readily assessed. Several functional properties, including the release of an antidepressive drug (paroxetine), cytotoxicity, and printability, are screened for 253 new ink formulations in a high-throughput format as well as mechanical properties. The selected candidates with the desirable properties are successfully scaled up using 3D printing into a range of object architectures. A full drug release study and degradability and tensile modulus experiments are presented on a simple architecture to validating the suitability of this methodology to identify printable inks for 3D printing devices with bespoke properties.

  14. Screening of drugs inhibiting in vitro oligomerization of Cu/Zn-superoxide dismutase with a mutation causing amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Itsuki Anzai

    2016-08-01

    Full Text Available Dominant mutations in Cu/Zn-superoxide dismutase (SOD1 gene have been shown to cause a familial form of amyotrophic lateral sclerosis (SOD1-ALS. A major pathological hallmark of this disease is abnormal accumulation of mutant SOD1 oligomers in the affected spinal motor neurons. While no effective therapeutics for SOD1-ALS is currently available, SOD1 oligomerization will be a good target for developing cures of this disease. Recently, we have reproduced the formation of SOD1 oligomers abnormally cross-linked via disulfide bonds in a test tube. Using our in vitro model of SOD1 oligomerization, therefore, we screened 640 FDA-approved drugs for inhibiting the oligomerization of SOD1 proteins, and three effective classes of chemical compounds were identified. Those hit compounds will provide valuable information on the chemical structures for developing a novel drug candidate suppressing the abnormal oligomerization of mutant SOD1 and possibly curing the disease.

  15. Parallel screening of wild-type and drug-resistant targets for anti-resistance neuraminidase inhibitors.

    Directory of Open Access Journals (Sweden)

    Kai-Cheng Hsu

    Full Text Available Infection with influenza virus is a major public health problem, causing serious illness and death each year. Emergence of drug-resistant influenza virus strains limits the effectiveness of drug treatment. Importantly, a dual H275Y/I223R mutation detected in the pandemic influenza A 2009 virus strain results in multidrug resistance to current neuraminidase (NA drugs. Therefore, discovery of new agents for treating multiple drug-resistant (MDR influenza virus infections is important. Here, we propose a parallel screening strategy that simultaneously screens wild-type (WT and MDR NAs, and identifies inhibitors matching the subsite characteristics of both NA-binding sites. These may maintain their potency when drug-resistant mutations arise. Initially, we analyzed the subsite of the dual H275Y/I223R NA mutant. Analysis of the site-moiety maps of NA protein structures show that the mutant subsite has a relatively small volume and is highly polar compared with the WT subsite. Moreover, the mutant subsite has a high preference for forming hydrogen-bonding interactions with polar moieties. These changes may drive multidrug resistance. Using this strategy, we identified a new inhibitor, Remazol Brilliant Blue R (RB19, an anthraquinone dye, which inhibited WT NA and MDR NA with IC(50 values of 3.4 and 4.5 µM, respectively. RB19 comprises a rigid core scaffold and a flexible chain with a large polar moiety. The former interacts with highly conserved residues, decreasing the probability of resistance. The latter forms van der Waals contacts with the WT subsite and yields hydrogen bonds with the mutant subsite by switching the orientation of its flexible side chain. Both scaffolds of RB19 are good starting points for lead optimization. The results reveal a parallel screening strategy for identifying resistance mechanisms and discovering anti-resistance neuraminidase inhibitors. We believe that this strategy may be applied to other diseases with high

  16. Identification of active Plasmodium falciparum calpain to establish screening system for Pf-calpain-based drug development

    Directory of Open Access Journals (Sweden)

    Soh Byoung

    2013-02-01

    Full Text Available Abstract Background With the increasing resistance of malaria parasites to available drugs, there is an urgent demand to develop new anti-malarial drugs. Calpain inhibitor, ALLN, is proposed to inhibit parasite proliferation by suppressing haemoglobin degradation. This provides Plasmodium calpain as a potential target for drug development. Pf-calpain, a cysteine protease of Plasmodium falciparum, belongs to calpain-7 family, which is an atypical calpain not harboring Ca2+-binding regulatory motifs. In this present study, in order to establish the screening system for Pf-calpain specific inhibitors, the active form of Pf-calpain was first identified. Methods Recombinant Pf-calpain including catalytic subdomain IIa (rPfcal-IIa was heterologously expressed and purified. Enzymatic activity was determined by both fluorogenic substrate assay and gelatin zymography. Molecular homology modeling was carried out to address the activation mode of Pf-calpain in the aspect of structural moiety. Results Based on the measurement of enzymatic activity and protease inhibitor assay, it was found that the active form of Pf-calpain only contains the catalytic subdomain IIa, suggesting that Pf-calpain may function as a monomeric form. The sequence prediction indicates that the catalytic subdomain IIa contains all amino acid residues necessary for catalytic triad (Cys-His-Asn formation. Molecular modeling suggests that the Pf-calpain subdomain IIa makes an active site, holding the catalytic triad residues in their appropriate orientation for catalysis. The mutation analysis further supports that those amino acid residues are functional and have enzymatic activity. Conclusion The identified active form of Pf-calpain could be utilized to establish high-throughput screening system for Pf-calpain inhibitors. Due to its unique monomeric structural property, Pf-calpain could be served as a novel anti-malarial drug target, which has a high specificity for malaria parasite

  17. Successful management of drug-induced hypercapnic acidosis with naloxone and noninvasive positive pressure ventilation.

    Science.gov (United States)

    Agrafiotis, Michalis; Tryfon, Stavros; Siopi, Demetra; Chassapidou, Georgia; Galanou, Artemis; Tsara, Venetia

    2015-02-01

    A 74-year-old man was referred to our hospital due to deteriorating level of consciousness and desaturation. His Glasgow Coma Scale was 6, and his pupils were constricted but responded to light. Chest radiograph was negative for significant findings. Arterial blood gas evaluation on supplemental oxygen revealed severe acute on chronic respiratory acidosis: pH 7.15; PCO2, 133 mm Hg; PO2,64 mm Hg; and HCO3, 31 mmol/L. He regained full consciousness (Glasgow Coma Scale, 15) after receiving a 0.4 mg dose of naloxone, but because of persistent severe respiratory acidosis (pH 7.21; PCO2, 105 mm Hg), he was immediately commenced on noninvasive positive pressure ventilation (NIV) displaying a remarkable improvement in arterial blood gas values within the next few hours. However, in the days that followed, he remained dependent on NIV, and he was finally discharged on a home mechanical ventilation prescription. In cases of drug-induced respiratory depression, NIV should be regarded as an acceptable treatment, as it can provide ventilatory support without the increased risks associated with invasive mechanical ventilation.

  18. Multicentric Castleman's Disease in a Hepatitis C-Positive Intravenous Drug User: A Case Report

    Directory of Open Access Journals (Sweden)

    D. Y. Talukder

    2011-01-01

    Full Text Available Introduction. We report a rare presentation of Castleman's disease in a hepatitis C-positive patient and present a short review of treatments described in other similar case reports and studies. Case Presentation. A 46-year-old male with untreated hepatitis C and a 16-year history of intravenous drug use presented with pleuritic chest pain and bony pain in the knee, hip, and lower back, on a background of unexplained weight loss of 40 kilograms, fevers, night sweats, and repeated infections over the last two years. Examination discovered tender hepatomegaly, a warm right knee effusion, and painless lymphadenopathy. The patient was reactive to Epstein Barr virus and cytomegalovirus; however, HIV and HHV-8 viral testing was negative. Osteomyelitis of vertebrae T8–T11 and septic arthritis of the knee were found on investigation. A lymph node biopsy revealed histology suggestive of plasmacytic Castleman's disease. The patient is to commence rituximab treatment. Conclusion. Castleman's disease continues to present in novel ways, which may lead to difficulties in clinicopathologic diagnosis. A growing body of evidence suggests larger studies are required to determine the best treatment for multicentric Castleman's disease, particularly in patients with a concomitant disease, including hepatitis C.

  19. False positive results using calcitonin as a screening method for medullary thyroid carcinoma

    Directory of Open Access Journals (Sweden)

    Rafael Loch Batista

    2013-01-01

    Full Text Available The role of serum calcitonin as part of the evaluation of thyroid nodules has been widely discussed in literature. However there still is no consensus of measurement of calcitonin in the initial evaluation of a patient with thyroid nodule. Problems concerning cost-benefit, lab methods, false positive and low prevalence of medullary thyroid carcinoma (MTC are factors that limit this approach. We have illustrated two cases where serum calcitonin was used in the evaluation of thyroid nodule and rates proved to be high. A stimulation test was performed, using calcium as secretagogue, and calcitonin hyper-stimulation was confirmed, but anatomopathologic examination did not evidence medullar neoplasia. Anatomopathologic diagnosis detected Hashimoto thyroiditis in one case and adenomatous goiter plus an occult papillary thyroid carcinoma in the other one. Recommendation for routine use of serum calcitonin in the initial diagnostic evaluation of a thyroid nodule, followed by a confirming stimulation test if basal serum calcitonin is showed to be high, is the most currently recommended approach, but questions concerning cost-benefit and possibility of diagnosis error make the validity of this recommendation discussible.

  20. A review of human pluripotent stem cell-derived cardiomyocytes for high-throughput drug discovery, cardiotoxicity screening, and publication standards.

    Science.gov (United States)

    Mordwinkin, Nicholas M; Burridge, Paul W; Wu, Joseph C

    2013-02-01

    Drug attrition rates have increased in past years, resulting in growing costs for the pharmaceutical industry and consumers. The reasons for this include the lack of in vitro models that correlate with clinical results and poor preclinical toxicity screening assays. The in vitro production of human cardiac progenitor cells and cardiomyocytes from human pluripotent stem cells provides an amenable source of cells for applications in drug discovery, disease modeling, regenerative medicine, and cardiotoxicity screening. In addition, the ability to derive human-induced pluripotent stem cells from somatic tissues, combined with current high-throughput screening and pharmacogenomics, may help realize the use of these cells to fulfill the potential of personalized medicine. In this review, we discuss the use of pluripotent stem cell-derived cardiomyocytes for drug discovery and cardiotoxicity screening, as well as current hurdles that must be overcome for wider clinical applications of this promising approach.

  1. Live demonstration: Screen printed, microwave based level sensor for automated drug delivery

    KAUST Repository

    Karimi, Muhammad Akram; Arsalan, Muhammad; Shamim, Atif

    2018-01-01

    Level sensors find numerous applications in many industries to automate the processes involving chemicals. Recently, some commercial ultrasound based level sensors are also being used to automate the drug delivery process [1]. Some of the most

  2. Simultaneous screening and confirmation of multiple classes of drug residues in fish by liquid chromatography-ion trap mass spectrometry.

    Science.gov (United States)

    Smith, Shani; Gieseker, Charles; Reimschuessel, Renate; Decker, Christie-Sue; Carson, Mary C

    2009-11-13

    LC-ion trap mass spectrometry was used to screen and confirm 38 compounds from a variety of drug classes in four species of fish: trout, salmon, catfish, and tilapia. Samples were extracted with acetonitrile and hexane. The acetonitrile phase was evaporated, redissolved in water and acetonitrile, and analyzed by gradient chromatography on a phenyl column. MS(2) or MS(3) spectra were monitored for each compound. Qualitative method performance was evaluated by the analysis over several days of replicate samples of control fish, fish fortified with a drug mixture at 1 ppm, 0.1 ppm and 0.01 ppm, and fish dosed with a representative from each drug class. Half of the 38 drugs were confirmed at 0.01 ppm, the lowest fortification level. This included all of the quinolones and fluoroquinolones, the macrolides, malachite green, and most of the imidazoles. Florfenicol amine, metronidazole, sulfonamides, tetracyclines, and most of the betalactams were confirmed at 0.1 ppm. Ivermectin and penicillin G were only detectable in the 1 ppm fortified samples. With the exception of amoxicillin, emamectin, metronidazole, and tylosin, residue presence was confirmed in all the dosed fish.

  3. Application of EU guidelines for the validation of screening methods for veterinary drugs

    NARCIS (Netherlands)

    Stolker, A.A.M.

    2012-01-01

    Commission Decision (CD) 2002/657/EC describes detailed rules for method validation within the framework of residue monitoring programmes. The approach described in this CD is based on criteria. For (qualitative) screening methods, the most important criteria is that the CCß has to be below any

  4. Yield of facility-based verbal screening amongst household contacts of patients with multi-drug resistant tuberculosis in Pakistan

    Directory of Open Access Journals (Sweden)

    Ejaz Qadeer

    2017-05-01

    Full Text Available Background: Household contacts of multidrug-resistant tuberculosis (MDR-TB patients are at a high risk of getting infected with TB/MDR-TB, therefore symptomatic or vulnerable individuals should be screened and treated early. Methods: A cross-sectional study was conducted among household contacts of MDR-TB patients in three high-burden TB sites in Pakistan from July 2013 to June 2014. MDR-TB index patients were asked to provide a list of all members of their household and were asked whether any of them had TB symptoms such as productive cough, fever, weight loss and night sweat (“facility-based verbal screening”. Symptomatic contacts were defined as presumptive TB cases and were invited for investigations at the facility. Those who did not come were paid a home-visit. Confirmed TB/MDR-TB patients were registered in the nearest treatment facility. Results: Of 209 MDR-TB index patients, 1467 household contacts were identified and screened, 95 of them children < 5 years. Of these 172 (12% were symptomatic. Most common symptoms were cough 157 (91% and fever 107 (62%. 58 (34% presumptive TB contacts were not investigated. Of total contacts, 56 (3.8% were diagnosed with TB, among them 54(96% with MDR-TB and 2(4% with drug-susceptible-TB. The number needed to screen (NNS to identify a new MDR-TB case among adult household contacts was 27 and among presumptive adult and pediatric TB contacts was three. All 56 confirmed patients were registered for treatment. Conclusion: Screening household contacts of MDR-TB index cases may be considered a feasible and high yield option, in high-burden, low-resource settings within Pakistan. The number of presumptive TB contacts required to screen to identify a new MDR-TB case was unusually low, indicating an effective strategy that could easily be scaled-up. The screening and management of vulnerable adults and children living with patients having TB of any form is a major priority in the combined efforts

  5. Formulation of 3D Printed Tablet for Rapid Drug Release by Fused Deposition Modeling: Screening Polymers for Drug Release, Drug-Polymer Miscibility and Printability.

    Science.gov (United States)

    Solanki, Nayan G; Tahsin, Md; Shah, Ankita V; Serajuddin, Abu T M

    2018-01-01

    The primary aim of this study was to identify pharmaceutically acceptable amorphous polymers for producing 3D printed tablets of a model drug, haloperidol, for rapid release by fused deposition modeling. Filaments for 3D printing were prepared by hot melt extrusion at 150°C with 10% and 20% w/w of haloperidol using Kollidon ® VA64, Kollicoat ® IR, Affinsiol ™ 15 cP, and HPMCAS either individually or as binary blends (Kollidon ® VA64 + Affinisol ™ 15 cP, 1:1; Kollidon ® VA64 + HPMCAS, 1:1). Dissolution of crushed extrudates was studied at pH 2 and 6.8, and formulations demonstrating rapid dissolution rates were then analyzed for drug-polymer, polymer-polymer and drug-polymer-polymer miscibility by film casting. Polymer-polymer (1:1) and drug-polymer-polymer (1:5:5 and 2:5:5) mixtures were found to be miscible. Tablets with 100% and 60% infill were printed using MakerBot printer at 210°C, and dissolution tests of tablets were conducted at pH 2 and 6.8. Extruded filaments of Kollidon ® VA64-Affinisol ™ 15 cP mixtures were flexible and had optimum mechanical strength for 3D printing. Tablets containing 10% drug with 60% and 100% infill showed complete drug release at pH 2 in 45 and 120 min, respectively. Relatively high dissolution rates were also observed at pH 6.8. The 1:1-mixture of Kollidon ® VA64 and Affinisol ™ 15 cP was thus identified as a suitable polymer system for 3D printing and rapid drug release. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  6. Plants used in Guatemala for the treatment of respiratory diseases. 1. Screening of 68 plants against gram-positive bacteria.

    Science.gov (United States)

    Caceres, A; Alvarez, A V; Ovando, A E; Samayoa, B E

    1991-02-01

    Respiratory ailments are important causes of morbidity and mortality in developing countries. Ethnobotanical surveys and literature reviews conducted in Guatemala during 1986-88 showed that 234 plants from 75 families, most of them of American origin, have been used for the treatment of respiratory ailments. Three Gram-positive bacteria causing respiratory infections (Staphylococcus aureus, Streptococcus pneumoniae and Streptococcus pyogenes) were used to screen 68 of the most commonly used plants for activity. Twenty-eight of these (41.2%) inhibited the growth of one or more of the bacteria tested. Staphylococcus aureus was inhibited by 18 of the plant extracts, while 7 extracts were effective against Streptococcus pyogenes. Plants of American origin which exhibited antibacterial activity were: Gnaphalium viscosum, Lippia alba, Lippia dulcis, Physalis philadelphica, Satureja brownei, Solanum nigrescens and Tagetes lucida. These preliminary in vitro results provide scientific basis for the use of these plants against bacterial respiratory infections.

  7. Aerosol Drug Delivery During Noninvasive Positive Pressure Ventilation: Effects of Intersubject Variability and Excipient Enhanced Growth

    Science.gov (United States)

    Walenga, Ross L.; Kaviratna, Anubhav; Hindle, Michael

    2017-01-01

    Abstract Background: Nebulized aerosol drug delivery during the administration of noninvasive positive pressure ventilation (NPPV) is commonly implemented. While studies have shown improved patient outcomes for this therapeutic approach, aerosol delivery efficiency is reported to be low with high variability in lung-deposited dose. Excipient enhanced growth (EEG) aerosol delivery is a newly proposed technique that may improve drug delivery efficiency and reduce intersubject aerosol delivery variability when coupled with NPPV. Materials and Methods: A combined approach using in vitro experiments and computational fluid dynamics (CFD) was used to characterize aerosol delivery efficiency during NPPV in two new nasal cavity models that include face mask interfaces. Mesh nebulizer and in-line dry powder inhaler (DPI) sources of conventional and EEG aerosols were both considered. Results: Based on validated steady-state CFD predictions, EEG aerosol delivery improved lung penetration fraction (PF) values by factors ranging from 1.3 to 6.4 compared with conventional-sized aerosols. Furthermore, intersubject variability in lung PF was very high for conventional aerosol sizes (relative differences between subjects in the range of 54.5%–134.3%) and was reduced by an order of magnitude with the EEG approach (relative differences between subjects in the range of 5.5%–17.4%). Realistic in vitro experiments of cyclic NPPV demonstrated similar trends in lung delivery to those observed with the steady-state simulations, but with lower lung delivery efficiencies. Reaching the lung delivery efficiencies reported with the steady-state simulations of 80%–90% will require synchronization of aerosol administration during inspiration and reducing the size of the EEG aerosol delivery unit. Conclusions: The EEG approach enabled high-efficiency lung delivery of aerosols administered during NPPV and reduced intersubject aerosol delivery variability by an order of magnitude. Use of an in

  8. Optimization of a Fluorescence-Based Assay for Large-Scale Drug Screening against Babesia and Theileria Parasites.

    Science.gov (United States)

    Rizk, Mohamed Abdo; El-Sayed, Shimaa Abd El-Salam; Terkawi, Mohamed Alaa; Youssef, Mohamed Ahmed; El Said, El Said El Shirbini; Elsayed, Gehad; El-Khodery, Sabry; El-Ashker, Maged; Elsify, Ahmed; Omar, Mosaab; Salama, Akram; Yokoyama, Naoaki; Igarashi, Ikuo

    2015-01-01

    A rapid and accurate assay for evaluating antibabesial drugs on a large scale is required for the discovery of novel chemotherapeutic agents against Babesia parasites. In the current study, we evaluated the usefulness of a fluorescence-based assay for determining the efficacies of antibabesial compounds against bovine and equine hemoparasites in in vitro cultures. Three different hematocrits (HCTs; 2.5%, 5%, and 10%) were used without daily replacement of the medium. The results of a high-throughput screening assay revealed that the best HCT was 2.5% for bovine Babesia parasites and 5% for equine Babesia and Theileria parasites. The IC50 values of diminazene aceturate obtained by fluorescence and microscopy did not differ significantly. Likewise, the IC50 values of luteolin, pyronaridine tetraphosphate, nimbolide, gedunin, and enoxacin did not differ between the two methods. In conclusion, our fluorescence-based assay uses low HCT and does not require daily replacement of culture medium, making it highly suitable for in vitro large-scale drug screening against Babesia and Theileria parasites that infect cattle and horses.

  9. Optimization of a Fluorescence-Based Assay for Large-Scale Drug Screening against Babesia and Theileria Parasites.

    Directory of Open Access Journals (Sweden)

    Mohamed Abdo Rizk

    Full Text Available A rapid and accurate assay for evaluating antibabesial drugs on a large scale is required for the discovery of novel chemotherapeutic agents against Babesia parasites. In the current study, we evaluated the usefulness of a fluorescence-based assay for determining the efficacies of antibabesial compounds against bovine and equine hemoparasites in in vitro cultures. Three different hematocrits (HCTs; 2.5%, 5%, and 10% were used without daily replacement of the medium. The results of a high-throughput screening assay revealed that the best HCT was 2.5% for bovine Babesia parasites and 5% for equine Babesia and Theileria parasites. The IC50 values of diminazene aceturate obtained by fluorescence and microscopy did not differ significantly. Likewise, the IC50 values of luteolin, pyronaridine tetraphosphate, nimbolide, gedunin, and enoxacin did not differ between the two methods. In conclusion, our fluorescence-based assay uses low HCT and does not require daily replacement of culture medium, making it highly suitable for in vitro large-scale drug screening against Babesia and Theileria parasites that infect cattle and horses.

  10. High-throughput untargeted screening of veterinary drug residues and metabolites in tilapia using high resolution orbitrap mass spectrometry.

    Science.gov (United States)

    Jia, Wei; Chu, Xiaogang; Chang, James; Wang, Perry G; Chen, Ying; Zhang, Feng

    2017-03-08

    An analytical method was developed and validated for simultaneous analysis of one hundred and thirty-seven veterinary drug residues and metabolites from sixteen different classes in tilapia utilizing an improved fully non-targeted way of data acquisition with fragmentation. The automated on-line extraction procedure was achieved in a simple disposable pipet extraction. Ultrahigh-performance liquid chromatography and electrospray ionization quadrupole Orbitrap high-resolution mass spectrometry (UHPLC Q-Orbitrap) was used for the separation and detection of all the analytes. The methodology was validated by taking into consideration the guidelines specified in European SANCO/12571/2013 Guideline 2013 and Commission Decision 2002/657/EC. The extraction recoveries ranged from 81% to 111%. The limits of decision ranged from 0.01 to 2.73 μg kg -1 and the detection capabilities ranged from 0.01 to 4.73 μg kg -1 . The one hundred and thirty-seven compounds behave dynamic 0.1-500 μg kg -1 , with correlation coefficient >0.99. The fully non-targeted data acquisition way improves both sensitivity and selectivity for the fragments, which is beneficial for screening performance and identification capability. This validated method has been successfully applied on screening of veterinary drug residues and metabolites in muscle of tilapia, an important and intensively produced fish in aquaculture. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. A genome-wide RNAi screen identifies novel targets of neratinib sensitivity leading to neratinib and paclitaxel combination drug treatments.

    Science.gov (United States)

    Seyhan, Attila A; Varadarajan, Usha; Choe, Sung; Liu, Yan; McGraw, John; Woods, Matthew; Murray, Stuart; Eckert, Amy; Liu, Wei; Ryan, Terence E

    2011-06-01

    ErbB2 is frequently activated in tumors, and influences a wide array of cellular functions, including proliferation, apoptosis, cell motility and adhesion. HKI-272 (neratinib) is a small molecule pan-kinase inhibitor of the ErbB family of receptor tyrosine kinases, and shows strong antiproliferative activity in ErbB2-overexpressing breast cancer cells. We undertook a genome-wide pooled lentiviral RNAi screen to identify synthetic lethal or enhancer (synthetic modulator screen) genes that interact with neratinib in a human breast cancer cell line (SKBR-3). These genes upon knockdown would modulate cell viability in the presence of subeffective concentrations of neratinib. We discovered a diverse set of genes whose depletion selectively impaired or enhanced the viability of SKBR-3 cells in the presence of neratinib. We observed diverse pathways including EGFR, hypoxia, cAMP, and protein ubiquitination that, when co-treated with RNAi and neratinib, resulted in arrest of cell proliferation. Examining the changes of these genes and their protein products also led to a rationale for clinically relevant drug combination treatments. Treatment of cells with either paclitaxel or cytarabine in combination with neratinib resulted in a strong antiproliferative effect. The identification of novel mediators of cellular response to neratinib and the development of potential drug combination treatments have expanded our understanding of neratinib's mode-of-action for the development of more effective therapeutic regimens. Notably, our findings support a paclitaxel and neratinib phase III clinical trial in breast cancer patients.

  12. Current use of high-resolution mass spectrometry in drug screening relevant to clinical and forensic toxicology and doping control.

    Science.gov (United States)

    Ojanperä, Ilkka; Kolmonen, Marjo; Pelander, Anna

    2012-05-01

    Clinical and forensic toxicology and doping control deal with hundreds or thousands of drugs that may cause poisoning or are abused, are illicit, or are prohibited in sports. Rapid and reliable screening for all these compounds of different chemical and pharmaceutical nature, preferably in a single analytical method, is a substantial effort for analytical toxicologists. Combined chromatography-mass spectrometry techniques with standardised reference libraries have been most commonly used for the purpose. In the last ten years, the focus has shifted from gas chromatography-mass spectrometry to liquid chromatography-mass spectrometry, because of progress in instrument technology and partly because of the polarity and low volatility of many new relevant substances. High-resolution mass spectrometry (HRMS), which enables accurate mass measurement at high resolving power, has recently evolved to the stage that is rapidly causing a shift from unit-resolution, quadrupole-dominated instrumentation. The main HRMS techniques today are time-of-flight mass spectrometry and Orbitrap Fourier-transform mass spectrometry. Both techniques enable a range of different drug-screening strategies that essentially rely on measuring a compound's or a fragment's mass with sufficiently high accuracy that its elemental composition can be determined directly. Accurate mass and isotopic pattern acts as a filter for confirming the identity of a compound or even identification of an unknown. High mass resolution is essential for improving confidence in accurate mass results in the analysis of complex biological samples. This review discusses recent applications of HRMS in analytical toxicology.

  13. Drug allergy passport and other documentation for patients with drug hypersensitivity - An ENDA/EAACI Drug Allergy Interest Group Position Paper

    NARCIS (Netherlands)

    Brockow, K.; Aberer, W.; Atanaskovic-Markovic, M.; Bavbek, S.; Bircher, A.; Bilo, B.; Blanca, M.; Bonadonna, P.; Burbach, G.; Calogiuri, G.; Caruso, C.; Celik, G.; Cernadas, J.; Chiriac, A.; Demoly, P.; Oude Elberink, J. N. G.; Fernandez, J.; Gomes, E.; Garvey, L. H.; Gooi, J.; Gotua, M.; Grosber, M.; Kauppi, P.; Kvedariene, V.; Laguna, J. J.; Makowska, J. S.; Mosbech, H.; Nakonechna, A.; Papadopolous, N. G.; Ring, J.; Romano, A.; Rockmann, H.; Sargur, R.; Sedlackova, L.; Sigurdardottir, S.; Schnyder, B.; Storaas, T.; Torres, M.; Zidarn, M.; Terreehorst, I.

    2016-01-01

    The strongest and best-documented risk factor for drug hypersensitivity (DH) is the history of a previous reaction. Accidental exposures to drugs may lead to severe or even fatal reactions in sensitized patients. Preventable prescription errors are common. They are often due to inadequate medical

  14. Do HIV-positive adult immigrants need to be screened for measles-mumps-rubella and varicella zoster virus immunization?

    Science.gov (United States)

    Llenas-García, Jara; Rubio, Rafael; Hernando, Asunción; Arrazola, Pilar; Pulido, Federico

    2013-08-01

    A systematic screening for measles, mumps, rubella (MMR) and varicella zoster virus (VZV) in HIV-positive adult immigrants in Spain was evaluated, and factors associated with MMR and VZV vaccines' indication were studied. Every HIV-positive immigrant was tested for VZV and MMR-IgG. MMR vaccine was indicated to patients with lymphocytes CD4+ >200 cells/mm³ and a negative measles-IgG, a negative mumps-IgG and/or a negative rubella-IgG. VZV vaccine was indicated to every VZV-IgG negative patient with CD4+ >400 cells/mm³. In total, 289 patients were screened; seroprevalence was 95.2%, 92.2%, 70.3% and 89.3% for VZV, measles, mumps and rubella IgG, respectively. Having a negative VZV-IgG was statistically associated with coming from sub-Saharan Africa (prevalence ratio [PR]: 6.52; 95% CI: 1.71-24.84; p=0.006), while having secondary education was a protective factor (PR: 0.25; 95% CI: 0.07-0.97; p=0.045). Fourteen patients (4.8%) had indication of VZV vaccine; vaccination was feasible in 21.4% of them at first visit. Eighty-one patients (29.7%) had indication of MMR vaccine, most of them due to mumps-IgG negative (53.1%) or rubella-IgG negative (24.7%). Age Especial attention should be given to immigrant women of childbearing age.

  15. Advantages of analyzing postmortem brain samples in routine forensic drug screening—case series of three non-natural deaths tested positive for lysergic acid diethylamide (LSD)

    DEFF Research Database (Denmark)

    Mardal, Marie; Johansen, Sys Stybe; Thomsen, Ragnar

    2017-01-01

    Three case reports are presented, including autopsy findings and toxicological screening results, which were tested positive for the potent hallucinogenic drug lysergic acid diethylamide (LSD). LSD and its main metabolites were quantified in brain tissue and femoral blood, and furthermore hematoma...... and urine when available. LSD, its main metabolite 2-oxo-3-hydroxy-LSD (oxo-HO-LSD), and iso-LSD were quantified in biological samples according to a previously published procedure involving liquid-liquid extraction and ultra-high performance liquid chromatography − tandem mass spectrometry (UHPLC......-MS/MS). LSD was measured in the brain tissue of all presented cases at a concentration level from 0.34 −10.8 μg/kg. The concentration level in the target organ was higher than in peripheral blood. Additional psychoactive compounds were quantified in blood and brain tissue, though all below toxic concentration...

  16. Sensitive screening of abused drugs in dried blood samples using ultra-high-performance liquid chromatography-ion booster-quadrupole time-of-flight mass spectrometry.

    Science.gov (United States)

    Chepyala, Divyabharathi; Tsai, I-Lin; Liao, Hsiao-Wei; Chen, Guan-Yuan; Chao, Hsi-Chun; Kuo, Ching-Hua

    2017-03-31

    An increased rate of drug abuse is a major social problem worldwide. The dried blood spot (DBS) sampling technique offers many advantages over using urine or whole blood sampling techniques. This study developed a simple and efficient ultra-high-performance liquid chromatography-ion booster-quadrupole time-of-flight mass spectrometry (UHPLC-IB-QTOF-MS) method for the analysis of abused drugs and their metabolites using DBS. Fifty-seven compounds covering the most commonly abused drugs, including amphetamines, opioids, cocaine, benzodiazepines, barbiturates, and many other new and emerging abused drugs, were selected as the target analytes of this study. An 80% acetonitrile solvent with a 5-min extraction by Geno grinder was used for sample extraction. A Poroshell column was used to provide efficient separation, and under optimal conditions, the analytical times were 15 and 5min in positive and negative ionization modes, respectively. Ionization parameters of both electrospray ionization source and ion booster (IB) source containing an extra heated zone were optimized to achieve the best ionization efficiency of the investigated abused drugs. In spite of their structural diversity, most of the abused drugs showed an enhanced mass response with the high temperature ionization from an extra heated zone of IB source. Compared to electrospray ionization, the ion booster (IB) greatly improved the detection sensitivity for 86% of the analytes by 1.5-14-fold and allowed the developed method to detect trace amounts of compounds on the DBS cards. The validation results showed that the coefficients of variation of intra-day and inter-day precision in terms of the signal intensity were lower than 19.65%. The extraction recovery of all analytes was between 67.21 and 115.14%. The limits of detection of all analytes were between 0.2 and 35.7ngmL -1 . The stability study indicated that 7% of compounds showed poor stability (below 50%) on the DBS cards after 6 months of storage at

  17. Drug screen in patient cells suggests quinacrine to be repositioned for treatment of acute myeloid leukemia

    International Nuclear Information System (INIS)

    Eriksson, A; Österroos, A; Hassan, S; Gullbo, J; Rickardson, L; Jarvius, M; Nygren, P; Fryknäs, M; Höglund, M; Larsson, R

    2015-01-01

    To find drugs suitable for repositioning for use against leukemia, samples from patients with chronic lymphocytic, acute myeloid and lymphocytic leukemias as well as peripheral blood mononuclear cells (PBMC) were tested in response to 1266 compounds from the LOPAC 1280 library (Sigma). Twenty-five compounds were defined as hits with activity in all leukemia subgroups (<50% cell survival compared with control) at 10 μM drug concentration. Only one of these compounds, quinacrine, showed low activity in normal PBMCs and was therefore selected for further preclinical evaluation. Mining the NCI-60 and the NextBio databases demonstrated leukemia sensitivity and the ability of quinacrine to reverse myeloid leukemia gene expression. Mechanistic exploration was performed using the NextBio bioinformatic software using gene expression analysis of drug exposed acute myeloid leukemia cultures (HL-60) in the database. Analysis of gene enrichment and drug correlations revealed strong connections to ribosomal biogenesis nucleoli and translation initiation. The highest drug–drug correlation was to ellipticine, a known RNA polymerase I inhibitor. These results were validated by additional gene expression analysis performed in-house. Quinacrine induced early inhibition of protein synthesis supporting these predictions. The results suggest that quinacrine have repositioning potential for treatment of acute myeloid leukemia by targeting of ribosomal biogenesis

  18. Incorporation of in silico biodegradability screening in early drug development--a feasible approach?

    Science.gov (United States)

    Steger-Hartmann, Thomas; Länge, Reinhard; Heuck, Klaus

    2011-05-01

    The concentration of a pharmaceutical found in the environment is determined by the amount used by the patient, the excretion and metabolism pattern, and eventually by its persistence. Biological degradation or persistence of a pharmaceutical is experimentally tested rather late in the development of a pharmaceutical, often shortly before submission of the dossier to regulatory authorities. To investigate whether the aspect of persistence of a compound could be assessed early during drug development, we investigated whether biodegradation of pharmaceuticals could be predicted with the help of in silico tools. To assess the value of in silico prediction, we collected results for the OECD 301 degradation test ("ready biodegradability") of 42 drugs or drug synthesis intermediates and compared them to the prediction of the in silico tool BIOWIN. Of these compounds, 38 were predictable with BIOWIN, which is a module of the Estimation Programs Interface (EPI) Suite™ provided by the US EPA. The program failed to predict the two drugs which proved to be readily biodegradable in the degradation tests. On the other hand, BIOWIN predicted two compounds to be readily biodegradable which, however, proved to be persistent in the test setting. The comparison of experimental data with the predicted one resulted in a specificity of 94% and a sensitivity of 0%. The results of this study do not indicate that application of the biodegradation prediction tool BIOWIN is a feasible approach to assess the ready biodegradability during early drug development.

  19. A comparative analysis of the impact of a positive list system on new chemical entity drugs and incrementally modified drugs in South Korea.

    Science.gov (United States)

    Ha, DongMun; Choi, Yong; Kim, Dae Up; Chung, Kyu Hyuck; Lee, Eui-Kyung

    2011-07-01

    Medical costs in South Korea have risen, in part due to increased demand and consumption of pharmaceutical products by an aging population and also because of the introduction of newer, more expensive drugs. In an effort to stabilize the financing of health insurance and alleviate the financial burden on individuals, the government implemented a policy changing the national health insurance drug-listing system from a negative list system to a positive list system (PLS). The goal of this study was to compare differences in drug-listing rates for new chemical entities (NCEs) and incrementally modified drugs (IMDs) after South Korea introduced the PLS in December 2006. Parameters significantly affecting NCE and IMD listings were also identified. New drug-listing data for 2007 and 2008 were obtained from the databases of the Health Insurance Review Agency and the Ministry of Health and Welfare. Descriptive analyses on the reimbursement rate and logistic regression analysis were conducted. Statistical significance was tested for all results, and P system by decreasing the drug-listing rate and lengthening the period for reimbursement determinations. These effects were more pronounced for NCE listings than for IMD listings. Crown Copyright © 2011. Published by EM Inc USA. All rights reserved.

  20. A human genome-wide loss-of-function screen identifies effective chikungunya antiviral drugs.

    Science.gov (United States)

    Karlas, Alexander; Berre, Stefano; Couderc, Thérèse; Varjak, Margus; Braun, Peter; Meyer, Michael; Gangneux, Nicolas; Karo-Astover, Liis; Weege, Friderike; Raftery, Martin; Schönrich, Günther; Klemm, Uwe; Wurzlbauer, Anne; Bracher, Franz; Merits, Andres; Meyer, Thomas F; Lecuit, Marc

    2016-05-12

    Chikungunya virus (CHIKV) is a globally spreading alphavirus against which there is no commercially available vaccine or therapy. Here we use a genome-wide siRNA screen to identify 156 proviral and 41 antiviral host factors affecting CHIKV replication. We analyse the cellular pathways in which human proviral genes are involved and identify druggable targets. Twenty-one small-molecule inhibitors, some of which are FDA approved, targeting six proviral factors or pathways, have high antiviral activity in vitro, with low toxicity. Three identified inhibitors have prophylactic antiviral effects in mouse models of chikungunya infection. Two of them, the calmodulin inhibitor pimozide and the fatty acid synthesis inhibitor TOFA, have a therapeutic effect in vivo when combined. These results demonstrate the value of loss-of-function screening and pathway analysis for the rational identification of small molecules with therapeutic potential and pave the way for the development of new, host-directed, antiviral agents.

  1. Drug discovery for male subfertility using high-throughput screening: a new approach to an unsolved problem.

    Science.gov (United States)

    Martins da Silva, Sarah J; Brown, Sean G; Sutton, Keith; King, Louise V; Ruso, Halil; Gray, David W; Wyatt, Paul G; Kelly, Mark C; Barratt, Christopher L R; Hope, Anthony G

    2017-05-01

    Can pharma drug discovery approaches be utilized to transform investigation into novel therapeutics for male infertility? High-throughput screening (HTS) is a viable approach to much-needed drug discovery for male factor infertility. There is both huge demand and a genuine clinical need for new treatment options for infertile men. However, the time, effort and resources required for drug discovery are currently exorbitant, due to the unique challenges of the cellular, physical and functional properties of human spermatozoa and a lack of appropriate assay platform. Spermatozoa were obtained from healthy volunteer research donors and subfertile patients undergoing IVF/ICSI at a hospital-assisted reproductive techniques clinic between January 2012 and November 2016. A HTS assay was developed and validated using intracellular calcium ([Ca2+]i) as a surrogate for motility in human spermatozoa. Calcium fluorescence was detected using a Flexstation microplate reader (384-well platform) and compared with responses evoked by progesterone, a compound known to modify a number of biologically relevant behaviours in human spermatozoa. Hit compounds identified following single point drug screen (10 μM) of an ion channel-focussed library assembled by the University of Dundee Drug Discovery Unit were rescreened to ensure potency using standard 10 point half-logarithm concentration curves, and tested for purity and integrity using liquid chromatography and mass spectrometry. Hit compounds were grouped by structure activity relationships and five representative compounds then further investigated for direct effects on spermatozoa, using computer-assisted sperm assessment, sperm penetration assay and whole-cell patch clamping. Of the 3242 ion channel library ligands screened, 384 compounds (11.8%) elicited a statistically significant increase in calcium fluorescence, with greater than 3× median absolute deviation above the baseline. Seventy-four compounds eliciting ≥50% increase

  2. Combinatorial Strategies and High Throughput Screening in Drug Discovery Targeted to the Channel of Botulinum Neurotoxin

    National Research Council Canada - National Science Library

    Montal, Mauricio

    2006-01-01

    .... The major focus thus far has been the implementation of a reliable and robust high-throughput screen for blockers specific for BoNT using Neuro 2A cells in which BoNTA forms channels with similar properties to those previously characterized in lipid bilayers. The immediate task during the present reporting period involved the detailed characterization of the channel and chaperone activity of BoNTA on Neuro2A cells.

  3. Upscaling and automation of electrophysiology: toward high throughput screening in ion channel drug discovery

    DEFF Research Database (Denmark)

    Asmild, Margit; Oswald, Nicholas; Krzywkowski, Karen M

    2003-01-01

    by developing two lines of automated patch clamp products, a traditional pipette-based system called Apatchi-1, and a silicon chip-based system QPatch. The degree of automation spans from semi-automation (Apatchi-1) where a trained technician interacts with the system in a limited way, to a complete automation...... (QPatch 96) where the system works continuously and unattended until screening of a full compound library is completed. The performance of the systems range from medium to high throughputs....

  4. Using label-free screening technology to improve efficiency in drug discovery.

    Science.gov (United States)

    Halai, Reena; Cooper, Matthew A

    2012-02-01

    Screening assays have traditionally utilized reporter labels to quantify biological responses relevant to the disease state of interest. However, there are limitations associated with the use of labels that may be overcome with temporal measurements possible with label-free. This review comprises general and system-specific information from literature searches using PubMed, published books and the authors' personal experience. This review highlights the label-free approaches in the context of various applications. The authors also note technical issues relevant to the development of label-free assays and their application to HTS. The limitations associated with the use of transfected cell lines and the use of label-based assays are gradually being realized. As such, greater emphasis is being placed on label-free biophysical techniques using native cell lines. The introduction of 96- and 384-well plate label-free systems is helping to broker a wider acceptance of these approaches in high-throughput screening. However, potential users of the technologies remain skeptical, primarily because the physical basis of the signals generated, and their contextual relevance to cell biology and signal transduction, has not been fully elucidated. Until this is done, these new technology platforms are more likely to complement, rather than replace, traditional screening platforms.

  5. The effect of information about false negative and false positive rates on people's attitudes towards colorectal cancer screening using faecal occult blood testing (FOBt).

    Science.gov (United States)

    Miles, Anne; Rodrigues, Vania; Sevdalis, Nick

    2013-11-01

    To examine the impact of numeric risk information about false negative (FN) and false positive (FP) rates in faecal occult blood testing (FOBt) on attitudes towards screening. 95 people aged 45-59, living in England, read 6 hypothetical vignettes presented online about the use of FOB testing to detect bowel cancer, in which information about FN and FP rates was systematically varied. Both verbal and numeric FN risk information reduced people's interest in screening compared with no FN information. Numeric FN risk information reduced people's perceptions of screening effectiveness and lowered perceived trust in the results of screening compared with both verbal FN information and no FN information. FP information did not affect attitudes towards FOB testing. There was limited evidence that FN information reduced interest and perceptions of screening effectiveness more in educated groups. Numeric FN risk information decreased people's perceptions of screening effectiveness and trust in the results of screening but did not affect people's interest in screening anymore than verbal FN risk information. Numeric FN information could be added to patient information without affecting interest in screening, although this needs to be replicated in a larger, more representative sample. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  6. High throughput screening for small molecule enhancers of the interferon signaling pathway to drive next-generation antiviral drug discovery.

    Directory of Open Access Journals (Sweden)

    Dhara A Patel

    Full Text Available Most of current strategies for antiviral therapeutics target the virus specifically and directly, but an alternative approach to drug discovery might be to enhance the immune response to a broad range of viruses. Based on clinical observation in humans and successful genetic strategies in experimental models, we reasoned that an improved interferon (IFN signaling system might better protect against viral infection. Here we aimed to identify small molecular weight compounds that might mimic this beneficial effect and improve antiviral defense. Accordingly, we developed a cell-based high-throughput screening (HTS assay to identify small molecules that enhance the IFN signaling pathway components. The assay is based on a phenotypic screen for increased IFN-stimulated response element (ISRE activity in a fully automated and robust format (Z'>0.7. Application of this assay system to a library of 2240 compounds (including 2160 already approved or approvable drugs led to the identification of 64 compounds with significant ISRE activity. From these, we chose the anthracycline antibiotic, idarubicin, for further validation and mechanism based on activity in the sub-µM range. We found that idarubicin action to increase ISRE activity was manifest by other members of this drug class and was independent of cytotoxic or topoisomerase inhibitory effects as well as endogenous IFN signaling or production. We also observed that this compound conferred a consequent increase in IFN-stimulated gene (ISG expression and a significant antiviral effect using a similar dose-range in a cell-culture system inoculated with encephalomyocarditis virus (EMCV. The antiviral effect was also found at compound concentrations below the ones observed for cytotoxicity. Taken together, our results provide proof of concept for using activators of components of the IFN signaling pathway to improve IFN efficacy and antiviral immune defense as well as a validated HTS approach to identify

  7. Rapid wide-scope screening of drugs of abuse, prescription drugs with potential for abuse and their metabolites in influent and effluent urban wastewater by ultrahigh pressure liquid chromatography-quadrupole-time-of-flight-mass spectrometry

    International Nuclear Information System (INIS)

    Hernandez, Felix; Bijlsma, Lubertus; Sancho, Juan V.; Diaz, Ramon; Ibanez, Maria

    2011-01-01

    This work illustrates the potential of hybrid quadrupole-time-of-flight mass spectrometry (QTOF MS) coupled to ultrahigh pressure liquid chromatography (UHPLC) to investigate the presence of drugs of abuse in wastewater. After solid-phase extraction with Oasis MCX cartridges, seventy-six illicit drugs, prescription drugs with potential for abuse, and metabolites were investigated in the samples by TOF MS using electrospray interface under positive ionization mode, with MS data acquired over an m/z range of 50-1000 Da. For 11 compounds, reference standards were available, and experimental data (e.g., retention time and fragmentation data) could be obtained, facilitating a more confident identification. The use of a QTOF instrument enabled the simultaneous application of two acquisition functions with different collision energies: a low energy (LE) function, where none or poor fragmentation took place, and a high energy (HE) function, where fragmentation in the collision cell was promoted. This approach, known as MS E , enabled the simultaneous acquisition of full-spectrum accurate mass data of both protonated molecules and fragment ions in a single injection, providing relevant information that facilitates the rapid detection and reliable identification of these emerging contaminants in the sample matrices analyzed. In addition, isomeric compounds, like the opiates, morphine and norcodeine, could be discriminated by their specific fragments observed in HE TOF MS spectra, without the need of reference standards. UHPLC-QTOF MS was proven to be a powerful and efficient technique for rapid wide-scope screening and identification of many relevant drugs in complex matrices, such as influent and effluent urban wastewater.

  8. Rapid wide-scope screening of drugs of abuse, prescription drugs with potential for abuse and their metabolites in influent and effluent urban wastewater by ultrahigh pressure liquid chromatography-quadrupole-time-of-flight-mass spectrometry

    Energy Technology Data Exchange (ETDEWEB)

    Hernandez, Felix, E-mail: felix.hernandez@qfa.uji.es [Research Institute for Pesticides and Water, University Jaume I, Avda. Sos Baynat s/n, E-12071 Castellon (Spain); Bijlsma, Lubertus, E-mail: bijlsma@guest.uji.es [Research Institute for Pesticides and Water, University Jaume I, Avda. Sos Baynat s/n, E-12071 Castellon (Spain); Sancho, Juan V.; Diaz, Ramon; Ibanez, Maria [Research Institute for Pesticides and Water, University Jaume I, Avda. Sos Baynat s/n, E-12071 Castellon (Spain)

    2011-01-17

    This work illustrates the potential of hybrid quadrupole-time-of-flight mass spectrometry (QTOF MS) coupled to ultrahigh pressure liquid chromatography (UHPLC) to investigate the presence of drugs of abuse in wastewater. After solid-phase extraction with Oasis MCX cartridges, seventy-six illicit drugs, prescription drugs with potential for abuse, and metabolites were investigated in the samples by TOF MS using electrospray interface under positive ionization mode, with MS data acquired over an m/z range of 50-1000 Da. For 11 compounds, reference standards were available, and experimental data (e.g., retention time and fragmentation data) could be obtained, facilitating a more confident identification. The use of a QTOF instrument enabled the simultaneous application of two acquisition functions with different collision energies: a low energy (LE) function, where none or poor fragmentation took place, and a high energy (HE) function, where fragmentation in the collision cell was promoted. This approach, known as MS{sup E}, enabled the simultaneous acquisition of full-spectrum accurate mass data of both protonated molecules and fragment ions in a single injection, providing relevant information that facilitates the rapid detection and reliable identification of these emerging contaminants in the sample matrices analyzed. In addition, isomeric compounds, like the opiates, morphine and norcodeine, could be discriminated by their specific fragments observed in HE TOF MS spectra, without the need of reference standards. UHPLC-QTOF MS was proven to be a powerful and efficient technique for rapid wide-scope screening and identification of many relevant drugs in complex matrices, such as influent and effluent urban wastewater.

  9. Detection and identification of 700 drugs by multi-target screening with a 3200 Q TRAP LC-MS/MS system and library searching.

    Science.gov (United States)

    Dresen, S; Ferreirós, N; Gnann, H; Zimmermann, R; Weinmann, W

    2010-04-01

    The multi-target screening method described in this work allows the simultaneous detection and identification of 700 drugs and metabolites in biological fluids using a hybrid triple-quadrupole linear ion trap mass spectrometer in a single analytical run. After standardization of the method, the retention times of 700 compounds were determined and transitions for each compound were selected by a "scheduled" survey MRM scan, followed by an information-dependent acquisition using the sensitive enhanced product ion scan of a Q TRAP hybrid instrument. The identification of the compounds in the samples analyzed was accomplished by searching the tandem mass spectrometry (MS/MS) spectra against the library we developed, which contains electrospray ionization-MS/MS spectra of over 1,250 compounds. The multi-target screening method together with the library was included in a software program for routine screening and quantitation to achieve automated acquisition and library searching. With the help of this software application, the time for evaluation and interpretation of the results could be drastically reduced. This new multi-target screening method has been successfully applied for the analysis of postmortem and traffic offense samples as well as proficiency testing, and complements screening with immunoassays, gas chromatography-mass spectrometry, and liquid chromatography-diode-array detection. Other possible applications are analysis in clinical toxicology (for intoxication cases), in psychiatry (antidepressants and other psychoactive drugs), and in forensic toxicology (drugs and driving, workplace drug testing, oral fluid analysis, drug-facilitated sexual assault).

  10. A new system for parallel drug screening against multiple-resistant HIV mutants based on lentiviral self-inactivating (SIN vectors and multi-colour analyses

    Directory of Open Access Journals (Sweden)

    Prokofjeva Maria M

    2013-01-01

    Full Text Available Abstract Background Despite progress in the development of combined antiretroviral therapies (cART, HIV infection remains a significant challenge for human health. Current problems of cART include multi-drug-resistant virus variants, long-term toxicity and enormous treatment costs. Therefore, the identification of novel effective drugs is urgently needed. Methods We developed a straightforward screening approach for simultaneously evaluating the sensitivity of multiple HIV gag-pol mutants to antiviral drugs in one assay. Our technique is based on multi-colour lentiviral self-inactivating (SIN LeGO vector technology. Results We demonstrated the successful use of this approach for screening compounds against up to four HIV gag-pol variants (wild-type and three mutants simultaneously. Importantly, the technique was adapted to Biosafety Level 1 conditions by utilising ecotropic pseudotypes. This allowed upscaling to a large-scale screening protocol exploited by pharmaceutical companies in a successful proof-of-concept experiment. Conclusions The technology developed here facilitates fast screening for anti-HIV activity of individual agents from large compound libraries. Although drugs targeting gag-pol variants were used here, our approach permits screening compounds that target several different, key cellular and viral functions of the HIV life-cycle. The modular principle of the method also allows the easy exchange of various mutations in HIV sequences. In conclusion, the methodology presented here provides a valuable new approach for the identification of novel anti-HIV drugs.

  11. CRISPR-Cas9-mediated saturated mutagenesis screen predicts clinical drug resistance with improved accuracy.

    Science.gov (United States)

    Ma, Leyuan; Boucher, Jeffrey I; Paulsen, Janet; Matuszewski, Sebastian; Eide, Christopher A; Ou, Jianhong; Eickelberg, Garrett; Press, Richard D; Zhu, Lihua Julie; Druker, Brian J; Branford, Susan; Wolfe, Scot A; Jensen, Jeffrey D; Schiffer, Celia A; Green, Michael R; Bolon, Daniel N

    2017-10-31

    Developing tools to accurately predict the clinical prevalence of drug-resistant mutations is a key step toward generating more effective therapeutics. Here we describe a high-throughput CRISPR-Cas9-based saturated mutagenesis approach to generate comprehensive libraries of point mutations at a defined genomic location and systematically study their effect on cell growth. As proof of concept, we mutagenized a selected region within the leukemic oncogene BCR-ABL1 Using bulk competitions with a deep-sequencing readout, we analyzed hundreds of mutations under multiple drug conditions and found that the effects of mutations on growth in the presence or absence of drug were critical for predicting clinically relevant resistant mutations, many of which were cancer adaptive in the absence of drug pressure. Using this approach, we identified all clinically isolated BCR-ABL1 mutations and achieved a prediction score that correlated highly with their clinical prevalence. The strategy described here can be broadly applied to a variety of oncogenes to predict patient mutations and evaluate resistance susceptibility in the development of new therapeutics. Published under the PNAS license.

  12. Need for screening for alcohol and drugs in Emergency Trauma Units

    African Journals Online (AJOL)

    Objectives: To examine the prevalence of alcohol and drug use and abuse, to identify socio-demographic characteristics that correlated with injury and to identify risk factors for injury in a Nigerian Trauma unit. Design: Descriptive cross sectional study. Setting: The study was carried out a general hospital trauma unit in ...

  13. Development of a screening method for co-amorphous formulations of drugs and amino acids

    DEFF Research Database (Denmark)

    Kasten, Georgia; Grohganz, Holger; Rades, Thomas

    2016-01-01

    Using amino acids (AA) as low molecular weight excipients in the preparation of co-amorphous blends with the aim to stabilize the drug in the amorphous form have been discussed in a range of studies. However, there is currently no theoretical consensus behind which AA would be a suitable co...

  14. Improved Conversion Rates in Drug Screening Applications sing Miniaturized Electrochemical Cells with Frit Channels

    NARCIS (Netherlands)

    Odijk, Mathieu; Olthuis, Wouter; van den Berg, Albert; Qiao, L.; Girault, H.

    2012-01-01

    This paper reports a novel design of a miniaturized three-electrode electrochemical cell, the purpose of which is aimed at generating drug metabolites with a high conversion efficiency. The working electrode and the counter electrode are placed in two separate channels to isolate the reaction

  15. Drug delivery to solid tumors: the predictive value of the multicellular tumor spheroid model for nanomedicine screening

    Directory of Open Access Journals (Sweden)

    Millard M

    2017-10-01

    Full Text Available Marie Millard,1,2 Ilya Yakavets,1–3 Vladimir Zorin,3,4 Aigul Kulmukhamedova,1,2,5 Sophie Marchal,1,2 Lina Bezdetnaya1,2 1Centre de Recherche en Automatique de Nancy, Centre National de la Recherche Scientifique UMR 7039, Université de Lorraine, 2Research Department, Institut de Cancérologie de Lorraine, Vandœuvre-lès-Nancy, France; 3Laboratory of Biophysics and Biotechnology, 4International Sakharov Environmental Institute, Belarusian State University, Minsk, Belarus; 5Department of Radiology, Medical Company Sunkar, Almaty, Kazakhstan Abstract: The increasing number of publications on the subject shows that nanomedicine is an attractive field for investigations aiming to considerably improve anticancer chemotherapy. Based on selective tumor targeting while sparing healthy tissue, carrier-mediated drug delivery has been expected to provide significant benefits to patients. However, despite reduced systemic toxicity, most nanodrugs approved for clinical use have been less effective than previously anticipated. The gap between experimental results and clinical outcomes demonstrates the necessity to perform comprehensive drug screening by using powerful preclinical models. In this context, in vitro three-dimensional models can provide key information on drug behavior inside the tumor tissue. The multicellular tumor spheroid (MCTS model closely mimics a small avascular tumor with the presence of proliferative cells surrounding quiescent cells and a necrotic core. Oxygen, pH and nutrient gradients are similar to those of solid tumor. Furthermore, extracellular matrix (ECM components and stromal cells can be embedded in the most sophisticated spheroid design. All these elements together with the physicochemical properties of nanoparticles (NPs play a key role in drug transport, and therefore, the MCTS model is appropriate to assess the ability of NP to penetrate the tumor tissue. This review presents recent developments in MCTS models for a

  16. Parental expectations, physical punishment, and violence among adolescents who score positive on a psychosocial screening test in primary care.

    Science.gov (United States)

    Ohene, Sally-Ann; Ireland, Marjorie; McNeely, Clea; Borowsky, Iris Wagman

    2006-02-01

    We sought to examine the relationship between perceived and stated parental expectations regarding adolescents' use of violence, parental use of physical punishment as discipline, and young adolescents' violence-related attitudes and involvement. Surveys were completed by 134 youth and their parents attending 8 pediatric practices. All youth were 10 to 15 years of age and had scored positive on a psychosocial screening test. Multivariate analyses revealed that perceived parental disapproval of the use of violence was associated with a more prosocial attitude toward interpersonal peer violence and a decreased likelihood of physical fighting by the youth. Parental report of whether they would advise their child to use violence in a conflict situation (stated parental expectations) was not associated with the adolescents' attitudes toward interpersonal peer violence, intentions to fight, physical fighting, bullying, or violence victimization. Parental use of corporal punishment as a disciplining method was inversely associated with a prosocial attitude toward interpersonal peer violence among the youth and positively correlated with youths' intentions to fight and fighting, bullying, and violence victimization. Perceived parental disapproval of the use of violence may be an important protective factor against youth involvement in violence, and parental use of physical punishment is associated with both violence perpetration and victimization among youth. Parents should be encouraged to clearly communicate to their children how to resolve conflicts without resorting to violence and to model these skills themselves by avoiding the use of physical punishment.

  17. Recall of symptoms and treatment of syphilis and yaws by healthy blood donors screening positive for syphilis in Kumasi, Ghana.

    Science.gov (United States)

    Sarkodie, Francis; Owusu-Dabo, Ellis; Hassall, Oliver; Bates, Imelda; Bygbjerg, Ib C; Ullum, Henrik

    2016-09-01

    To describe the recalled medical history, clinical manifestations, and treatment of yaws and syphilis by syphilis seroreactive blood donors in Kumasi, Ghana. Of the blood donors at Komfo Anokye Teaching Hospital, Kumasi, Ghana tested with the syphilis rapid diagnostic test (RDT) and later by rapid plasma reagin (RPR) test, 526 were seroreactive. Four hundred and seventy-one (89.5%) of these subjects were confirmed with the Ortho-Vitros Syphilis TP test as the gold standard and were interviewed to determine past or present clinical manifestations of yaws and syphilis. Of the 471 respondent donors, 28 (5.9%) gave a history of skin lesions and sores; four (14.3%) of these subjects, who were all male and RPR-positive, recalled a diagnosis of syphilis. All four reported having had skin lesions/bumps with slow-healing sores, but only one of them had had these symptoms before the age of 15 years. A small proportion of confirmed seroreactive donors in this sample had any recall of symptoms or treatment for yaws or syphilis. These data suggest that clinical questioning adds little further information to the current screening algorithm. The relative contribution of yaws and syphilis to frequent positive tests in endemic areas remains speculative. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  18. A Novel Multiparametric Drug-Scoring Method for High-Throughput Screening of 3D Multicellular Tumor Spheroids Using the Celigo Image Cytometer.

    Science.gov (United States)

    Cribbes, Scott; Kessel, Sarah; McMenemy, Scott; Qiu, Jean; Chan, Leo Li-Ying

    2017-06-01

    Three-dimensional (3D) tumor models have been increasingly used to investigate and characterize cancer drug compounds. The ability to perform high-throughput screening of 3D multicellular tumor spheroids (MCTS) can highly improve the efficiency and cost-effectiveness of discovering potential cancer drug candidates. Previously, the Celigo Image Cytometer has demonstrated a novel method for high-throughput screening of 3D multicellular tumor spheroids. In this work, we employed the Celigo Image Cytometer to examine the effects of 14 cancer drug compounds on 3D MCTS of the glioblastoma cell line U87MG in 384-well plates. Using parameters such as MCTS diameter and invasion area, growth and invasion were monitored for 9 and 3 d, respectively. Furthermore, fluorescent staining with calcein AM, propidium iodide, Hoechst 33342, and caspase 3/7 was performed at day 9 posttreatment to measure viability and apoptosis. Using the kinetic and endpoint data generated, we created a novel multiparametric drug-scoring system for 3D MCTS that can be used to identify and classify potential drug candidates earlier in the drug discovery process. Furthermore, the combination of quantitative and qualitative image data can be used to delineate differences between drugs that induce cytotoxic and cytostatic effects. The 3D MCTS-based multiparametric scoring method described here can provide an alternative screening method to better qualify tested drug compounds.

  19. Cervical cancer screening by high risk HPV testing in routine practice: results at one year recall of high risk HPV-positive and cytology-negative women.

    Science.gov (United States)

    Del Mistro, Annarosa; Frayle, Helena; Ferro, Antonio; Callegaro, Susanna; Del Sole, Annamaria; Stomeo, Anna; Cirillo, Emanuela; Fedato, Chiara; Pagni, Silvana; Barzon, Luisa; Zorzi, Manuel

    2014-03-01

    Cervical cancer screening by human papillomavirus (HPV) testing requires the use of additional triage and follow-up analyses. We evaluated women's compliance with and the performance of this strategy in a routine setting. Five cervical service screening programmes in North-East Italy. Eligible women aged 25-64 invited for a new screening episode underwent HPV testing for high risk types (hrHPV by Hybrid Capture 2) and cytology triage. Women with positive HPV and cytology results were referred for colposcopy; women with positive HPV but negative cytology results were referred to 1-year repeat hrHPV testing. Of 46,694 women screened by HPV testing up to December 2011, 3,211 (6.9%) tested hrHPV positive; 45% of these had a positive triage cytology. Those with negative cytology were invited for 1-yr repeat testing. Compliance with invitation was 61.6% at baseline and 85.3% at 1-yr repeat. Rate of persistent hrHPV positivity was 58% (830/1,435). Colposcopy performed in women with a positive hrHPV test at 1-yr repeat accounted for 36% of all colposcopies performed within the screening programmes. Cumulatively, a histological high-grade lesion was detected in 276 women (5.9‰ detection rate), 234 at baseline (85%), and 42 (15%) at 1-yr repeat. Compliance with hrHPV-based screening programmes was high both at baseline and at 1-yr repeat. Compared with the randomized trials, a higher proportion of triage cytology was read as positive, and only a small number of high-grade lesions were detected among the group of hrHPV positive cytology negative women who repeated testing 1-yr after baseline.

  20. Virtual screening and evaluation of Ketol-Acid Reducto-Isomerase (KARI as a putative drug target for Aspergillosis

    Directory of Open Access Journals (Sweden)

    Morya Vivek K

    2012-02-01

    Full Text Available Abstract Aspergillus is a leading causative agent for fungal morbidity and mortality in immuno-compromised patients. To identify a putative target to design or identify new antifungal drug, against Aspergillus is required. In our previous work, we have analyzed the various biochemical pathways, and we found Ketol Acid Reducto-Isomerase (KARI an enzyme involves in the amino acid biosynthesis, could be a better target. This enzyme was found to be unique by comparing to host proteome through BLASTp analysis. A homology based model of KARI was generated by Swiss model server. The generated model had been validated by PROCHECK and WHAT IF programs. The Zinc library was generated within the limitation of the Lipinski rule of five, for docking study. Based on the dock-score six molecules have been studied for ADME/TOX analysis and subjected for pharmacophore model generation. The Zinc ID of the potential inhibitors is ZINC00720614, ZINC01068126, ZINC0923, ZINC02090678, ZINC00663057 and ZINC02284065 and found to be pharmacologically active agonist and antagonist of KARI. This study is an attempt to Insilco evaluation of the KARI as a drug target and the screened inhibitors could help in the development of the better drug against Aspergillus.

  1. High-throughput oxidation screen of antibody-drug conjugates by analytical protein A chromatography following IdeS digest.

    Science.gov (United States)

    Buecheler, Jakob W; Winzer, Matthias; Weber, Christian; Gieseler, Henning

    2018-05-01

    Oxidation of protein therapeutics is a major chemical degradation pathway which may impact bioactivity, serum half-life and stability. Therefore, oxidation is a relevant parameter which has to be monitored throughout formulation development. Methods such as HIC, RPLC and LC/MS achieve a separation of oxidized and non-oxidized species by differences in hydrophobicity. Antibody-drug conjugates (ADC) although are highly more complex due to the heterogeneity in linker, drug, drug-to-antibody ratio (DAR) and conjugation site. The analytical protein A chromatography can provide a simple and fast alternative to these common methods. A miniature analytical protein A chromatography method in combination with an IdeS digest was developed to analyse ADCs. The IdeS digest efficiency of an IgG1 was monitored using SEC-HPLC and non-reducing SDS-PAGE. An antibody-fluorescent dye conjugate was conjugated at different dye-to-antibody ratios as model construct to mimic an ADC. With IdeS, an almost complete digest of a model IgG1 can be achieved (digested protein amount >98%). This enables subsequent analytical protein A chromatography, which consequently eliminates any interference of payload with the stationary phase. A novel high-throughput method for an interchain cysteine-linked ADC oxidation screens during formulation development was developed. © 2018 Royal Pharmaceutical Society.

  2. Description of 15 DNA-positive and antibody-negative "window-period" blood donations identified during prospective screening for Babesia microti.

    Science.gov (United States)

    Moritz, Erin D; Tonnetti, Laura; Hewins, Mary Ellen; Berardi, Victor P; Dodd, Roger Y; Stramer, Susan L

    2017-07-01

    Blood donation screening detecting only antibodies fails to identify donors in the earliest stage of infection, before a detectable immunologic response, that is, the "window period" (WP). We present data on WP donations identified during prospective screening for Babesia microti, a transfusion-transmissible parasite of increasing concern in the United States. Blood donations collected in Connecticut, Massachusetts, Minnesota, and Wisconsin were screened using polymerase chain reaction (PCR) and arrayed fluorescence immunoassay (AFIA) to detect B. microti DNA and antibodies, respectively. Parasite loads were estimated using quantitative PCR. Red blood cell (RBC) samples were inoculated into hamsters to assess infectivity. Donors screening reactive were indefinitely deferred, tested by supplemental methods, and followed to assess DNA and antibody clearance. Demographic data from WP donors (i.e., those screening PCR positive and AFIA negative) were compared to data from other positive donors. Of 220,479 donations screened from June 2012 to August 2016, a total of 700 were positive, of which 15 (2% of positive donations or 1 per 14,699 screened donations) were confirmed WP donations. The median estimated parasite load in WP donations was 350 parasites/mL, no different than AFIA-positive and PCR-positive donors. Parasite loads in RBC samples from WP units ranged from 14 to 11,022 parasites/mL; RBC samples from three of 10 (30%) WP donations infected hamsters. The mean age of WP donors was 48 years (range, 17-75 years); three (20%) were female. WP donor demographics did not differ significantly from demographics of other donors. We report one per 15,000 B. microti WP infections in blood donors in endemic areas, demonstrating the importance of nucleic acid testing to mitigate the risk of transfusion-transmitted babesiosis. © 2017 AABB.

  3. [Two news drugs (ivacaftor & bedaquiline), one biomarker (florbetapir) and a re-positioned drug (propranolol) on the market].

    Science.gov (United States)

    Monneret, C

    2014-07-01

    Among the new molecular entities approved by the EMEA and the FDA in 2012, four have caught our attention for their significant contribution to the health of patient. First of all, among the notable 2012 approvals, is ivacaftor or Kalydeco®. This is the first treatment that targets one of the gene defects that is underlying cause of cystic fibrosis. This is also an example of the promise of personalized medicine. The benefits with bedaquiline or Sirturo® are its ability to likely provide clinically relevant activity as part of multi-drug regimens against tuberculosis (TB) based on clinical data in multi-drug resistant tuberculosis (MDR TB) patients, who were defined as being at least resistant against the two major tuberculostatic medicines (isaoniazide and rifampicine). On December 2012 and then, on December 2013, the FDA and European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has recommended granting a conditional marketing authorization for Sirturo® (bedaquiline), respectively, for use as part of a combination therapy for pulmonary multidrug resistant tuberculosis in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability. Amyvid®, which is a solution for injection that contains the active substance florbetapir (18F), is a radiopharmaceutical that emits low amounts of radiation and works by targeting and attaching to β-amyloid plaques in the brain. This enables doctors to know whether or not significant amount of plaques are present in order to know if the patient is unlikely or not, to have Alzheimer's disease. Finally, the last topics addresses the propranolol, which is a beta-blocker, used alone or together with other medicines to treat high blood pressure. Propranolol is gaining a new lease of life for treating infantile hemangioma. Copyright © 2014. Published by Elsevier Masson SAS.

  4. Drug Testing

    Science.gov (United States)

    ... testing, substance abuse testing, toxicology screen, tox screen, sports doping tests What is it used for? Drug screening is used to find out whether or not a person has taken a certain drug or drugs. It ... Sports organizations. Professional and collegiate athletes usually need to ...

  5. Post processing of protein-compound docking for fragment-based drug discovery (FBDD): in-silico structure-based drug screening and ligand-binding pose prediction.

    Science.gov (United States)

    Fukunishi, Yoshifumi

    2010-01-01

    For fragment-based drug development, both hit (active) compound prediction and docking-pose (protein-ligand complex structure) prediction of the hit compound are important, since chemical modification (fragment linking, fragment evolution) subsequent to the hit discovery must be performed based on the protein-ligand complex structure. However, the naïve protein-compound docking calculation shows poor accuracy in terms of docking-pose prediction. Thus, post-processing of the protein-compound docking is necessary. Recently, several methods for the post-processing of protein-compound docking have been proposed. In FBDD, the compounds are smaller than those for conventional drug screening. This makes it difficult to perform the protein-compound docking calculation. A method to avoid this problem has been reported. Protein-ligand binding free energy estimation is useful to reduce the procedures involved in the chemical modification of the hit fragment. Several prediction methods have been proposed for high-accuracy estimation of protein-ligand binding free energy. This paper summarizes the various computational methods proposed for docking-pose prediction and their usefulness in FBDD.

  6. Evaluating the predictivity of virtual screening for ABL kinase inhibitors to hinder drug resistance

    DEFF Research Database (Denmark)

    Gani, Osman A B S M; Narayanan, Dilip; Engh, Richard A

    2013-01-01

    decoy sets and tested with virtual screening approaches with and without explicit use of target structures (docking). We show how various scoring functions and choice of inactive ligand sets influence overall and early enrichment of the libraries. Although ligand-based methods, for example principal...... component analyses of chemical properties, can distinguish some decoy sets from active compounds, the addition of target structural information via docking improves enrichment, and explicit consideration of multiple target conformations (i.e. types I and II) achieves best enrichment of active versus...

  7. Alcohol use and positive screening results for depression and anxiety are highly prevalent among Chinese children with strabismus.

    Science.gov (United States)

    Lin, Shibin; Congdon, Nathan; Yam, Jason C S; Huang, Yuqiang; Qiu, Kunliang; Ma, Di; Chen, Bin; Li, Liping; Zhang, Mingzhi

    2014-04-01

    To study associations between strabismus and alcohol use, anxiety, and depression among 10- to 17-year-old children in Guangdong, southern China. Cross-sectional, population-based study. Among 7537 children aged 6-17 years from 9 randomly selected primary and middle schools, ocular alignment was assessed with the Hirschberg light reflex, cover-uncover testing, and alternate cover testing at distance (6 m) and near (40 cm). Additionally, 4000 children (53.1%) aged 10+ years received self-administered questionnaires containing screening questions on alcohol use, anxiety, and depression. Examinations were completed on 7464 of 7537 subjects (99.0%), including 3928 boys (52.6%), with a mean age of 11.1 ± 1.8 years. The prevalence of any strabismus, including exotropia (2.7%), esotropia (0.2%), and intermittent exotropia (3.9%), was 6.8%. Strabismus was more prevalent in urban students (7.3%) and female subjects (7.4%) compared to rural students (6.0%) and male subjects (6.2%) (all P children (97.6%) answering questionnaires, history of alcohol use (62.3% vs 36.3%) and positive screening responses for depression (26.0% vs 11.6%) and anxiety (10.3% vs 4.9%) were significantly (P children with strabismus. These Chinese children with strabismus had a significantly higher prevalence of alcohol use and possible markers of emotional problems than children without strabismus. Further research should focus on the appropriateness of classifying surgical treatment for strabismus as "cosmetic" (ineligible for reimbursement) under China's rural health insurance. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. Computation-based virtual screening for designing novel antimalarial drugs by targeting falcipain-III: a structure-based drug designing approach.

    Science.gov (United States)

    Kesharwani, Rajesh Kumar; Singh, Durg Vijay; Misra, Krishna

    2013-01-01

    Cysteine proteases (falcipains), a papain-family of enzymes of Plasmodium falciparum, are responsible for haemoglobin degradation and thus necessary for its survival during asexual life cycle phase inside the human red blood cells while remaining non-functional for the human body. Therefore, these can act as potential targets for designing antimalarial drugs. The P. falciparum cysteine proteases, falcipain-II and falcipain- III are the enzymes which initiate the haemoglobin degradation, therefore, have been selected as targets. In the present study, we have designed new leupeptin analogues and subjected to virtual screening using Glide at the active site cavity of falcipain-II and falcipain-III to select the best docked analogues on the basis of Glide score and also compare with the result of AutoDock. The proposed analogues can be synthesized and tested in vivo as future potent antimalarial drugs. Protein falcipain-II and falcipain-III together with bounds inhibitors epoxysuccinate E64 (E64) and leupeptin respectively were retrieved from protein data bank (PDB) and latter leupeptin was used as lead molecule to design new analogues by using Ligbuilder software and refined the molecules on the basis of Lipinski rule of five and fitness score parameters. All the designed leupeptin analogues were screened via docking simulation at the active site cavity of falcipain-II and falcipain-III by using Glide software and AutoDock. The 104 new leupeptin-based antimalarial ligands were designed using structure-based drug designing approach with the help of Ligbuilder and subjected for virtual screening via docking simulation method against falcipain-II and falcipain-III receptor proteins. The Glide docking results suggest that the ligands namely result_037 shows good binding and other two, result_044 and result_042 show nearly similar binding than naturally occurring PDB bound ligand E64 against falcipain-II and in case of falcipain-III, 15 designed leupeptin analogues having

  9. Grid heterogeneity in in-silico experiments: an exploration of drug screening using DOCK on cloud environments.

    Science.gov (United States)

    Yim, Wen-Wai; Chien, Shu; Kusumoto, Yasuyuki; Date, Susumu; Haga, Jason

    2010-01-01

    Large-scale in-silico screening is a necessary part of drug discovery and Grid computing is one answer to this demand. A disadvantage of using Grid computing is the heterogeneous computational environments characteristic of a Grid. In our study, we have found that for the molecular docking simulation program DOCK, different clusters within a Grid organization can yield inconsistent results. Because DOCK in-silico virtual screening (VS) is currently used to help select chemical compounds to test with in-vitro experiments, such differences have little effect on the validity of using virtual screening before subsequent steps in the drug discovery process. However, it is difficult to predict whether the accumulation of these discrepancies over sequentially repeated VS experiments will significantly alter the results if VS is used as the primary means for identifying potential drugs. Moreover, such discrepancies may be unacceptable for other applications requiring more stringent thresholds. This highlights the need for establishing a more complete solution to provide the best scientific accuracy when executing an application across Grids. One possible solution to platform heterogeneity in DOCK performance explored in our study involved the use of virtual machines as a layer of abstraction. This study investigated the feasibility and practicality of using virtual machine and recent cloud computing technologies in a biological research application. We examined the differences and variations of DOCK VS variables, across a Grid environment composed of different clusters, with and without virtualization. The uniform computer environment provided by virtual machines eliminated inconsistent DOCK VS results caused by heterogeneous clusters, however, the execution time for the DOCK VS increased. In our particular experiments, overhead costs were found to be an average of 41% and 2% in execution time for two different clusters, while the actual magnitudes of the execution time

  10. Induced pluripotent stem cell-derived cardiomyocytes for cardiovascular disease modeling and drug screening

    OpenAIRE

    Sharma, Arun; Wu, Joseph C; Wu, Sean M

    2013-01-01

    Human induced pluripotent stem cells (hiPSCs) have emerged as a novel tool for drug discovery and therapy in cardiovascular medicine. hiPSCs are functionally similar to human embryonic stem cells (hESCs) and can be derived autologously without the ethical challenges associated with hESCs. Given the limited regenerative capacity of the human heart following myocardial injury, cardiomyocytes derived from hiPSCs (hiPSC-CMs) have garnered significant attention from basic and translational scienti...

  11. Lipophilicity screening of novel drug-like compounds and comparison to clog P.

    Science.gov (United States)

    Lu, Dujuan; Chambers, Peter; Wipf, Peter; Xie, Xiang-Qun; Englert, Danielle; Weber, Stephen

    2012-10-05

    We determined the distribution coefficients of solutes between a polymer film phase (polyvinyl chloride (PVC) with 67% (w/w) dioctyl sebacate (DOS)) and an aqueous phase in a 96-well format. The parallel measurement approach is efficient and uses very little material. Polymer-water distribution coefficients (D(pw)) at different pH values yield the pKa and polymer-water partition coefficient values (P(pw)) of the solutes. log P(pw) of a prominent drug-like compound, 2H-1,2,6-thiadiazine, 3-methyl-5-phenyl-,1,1-dioxide, is in good agreement with clog P, while the pK(a) value is substantially different from calculated values. This method has been also successfully applied to a library of novel drug-like compounds. log D(pw) values (at pH 4.0, 7.0, 10.0) of 24 novel drug-like compounds have been determined with good reproducibility with the 96-well plate approach. Differences between experimental values and a variety of available calculated values are significant. This emphasizes the need for laboratory separations-based measurements of log D. Copyright © 2012 Elsevier B.V. All rights reserved.

  12. 3-D Bioprinting of Neural Tissue for Applications in Cell Therapy and Drug Screening

    Directory of Open Access Journals (Sweden)

    Michaela Thomas

    2017-11-01

    Full Text Available Neurodegenerative diseases affect millions of individuals in North America and cost the health-care industry billions of dollars for treatment. Current treatment options for degenerative diseases focus on physical rehabilitation or drug therapies, which temporarily mask the effects of cell damage, but quickly lose their efficacy. Cell therapies for the central nervous system remain an untapped market due to the complexity involved in growing neural tissues, controlling their differentiation, and protecting them from the hostile environment they meet upon implantation. Designing tissue constructs for the discovery of better drug treatments are also limited due to the resolution needed for an accurate cellular representation of the brain, in addition to being expensive and difficult to translate to biocompatible materials. 3-D printing offers a streamlined solution for engineering brain tissue for drug discovery or, in the future, for implantation. New microfluidic and bioplotting devices offer increased resolution, little impact on cell viability and have been tested with several bioink materials including fibrin, collagen, hyaluronic acid, poly(caprolactone, and poly(ethylene glycol. This review details current efforts at bioprinting neural tissue and highlights promising avenues for future work.

  13. Multi-residue screening of prioritised human pharmaceuticals, illicit drugs and bactericides in sediments and sludge.

    Science.gov (United States)

    Langford, Katherine H; Reid, Malcolm; Thomas, Kevin V

    2011-08-01

    A robust multi-residue method was developed for the analysis of a selection of pharmaceutical compounds, illicit drugs and personal care product bactericides in sediments and sludges. Human pharmaceuticals were selected for analysis in Scottish sewage sludge and freshwater sediments based on prescription, physico-chemical and occurrence data. The method was suitable for the analysis of the selected illicit drugs amphetamine, benzoylecgonine, cocaine, and methamphetamine, the pharmaceuticals atenolol, bendroflumethiazide, carbamazepine, citalopram, diclofenac, fluoxetine, ibuprofen, and salbutamol, and the bactericides triclosan and triclocarban in sewage sludge and freshwater sediment. The method provided an overall recovery of between 56 and 128%, RSDs of between 2 and 19% and LODs of between 1 and 50 ng g(-1). Using the methodology the human pharmaceuticals atenolol, carbamazepine and citalopram and the bactericides triclosan and triclocarban were detected in Scottish sewage sludge. The illicit drugs cocaine, its metabolite benzoylecgonine, amphetamine and methamphetamine were not detected in any of the samples analysed. Triclosan and triclocarban were present at the highest concentrations with triclocarban detected in all but one sample and showing a pattern of co-occurrence in both sludge and sediment samples.

  14. Current position of high-resolution MS for drug quantification in clinical & forensic toxicology.

    Science.gov (United States)

    Meyer, Markus R; Helfer, Andreas G; Maurer, Hans H

    2014-08-01

    This paper reviews high-resolution MS approaches published from January 2011 until March 2014 for the quantification of drugs (of abuse) and/or their metabolites in biosamples using LC-MS with time-of-flight or Orbitrap™ mass analyzers. Corresponding approaches are discussed including sample preparation and mass spectral settings. The advantages and limitations of high-resolution MS for drug quantification, as well as the demand for a certain resolution or a specific mass accuracy are also explored.

  15. Position Statement: Drug Holiday in Osteoporosis Treatment with Bisphosphonates in South Korea

    Science.gov (United States)

    Lee, Seung Hun; Gong, Hyun Sik; Kim, Tae-Hee; Park, Si Young; Shin, Jung-Ho; Cho, Sun Wook

    2015-01-01

    Bisphosphonates have been widely used in the treatment of osteoporosis with robust data from many placebo-controlled trials demonstrating its efficacy in fracture risk reduction over 3 to 5 years of treatment. Although bisphosphonates are generally safe and well tolerated, concerns have emerged about the adverse effects related to its long-term use, including osteonecrosis of the jaw and atypical femur fractures. Because bisphosphonates are incorporated into the skeleton and continue to exert an anti-resorptive effect for a period of time after the discontinuation of drugs, the concept of a "drug holiday" has emerged, whereby the risk of adverse effects might be decreased while the patient still benefits from anti-fracture efficacy. As randomized clinical trial evidence is not yet available on who may qualify for a drug holiday, there is considerable controversy regarding the selection of candidates for the drug holiday and monitoring during a drug holiday, both of which should be based on individual assessments of risk and benefit. This statement will provide suggestions for clinicians in South Korea on the identification of possible candidates and monitoring during a bisphosphonate drug holiday. PMID:26713307

  16. Self-collection based HPV testing for cervical cancer screening among women living with HIV in Uganda: a descriptive analysis of knowledge, intentions to screen and factors associated with HPV positivity.

    Science.gov (United States)

    Mitchell, Sheona M; Pedersen, Heather N; Eng Stime, Evelyn; Sekikubo, Musa; Moses, Erin; Mwesigwa, David; Biryabarema, Christine; Christilaw, Jan; Byamugisha, Josaphat K; Money, Deborah M; Ogilvie, Gina S

    2017-01-13

    Women living with HIV (WHIV) are disproportionately impacted by cervical dysplasia and cancer. The burden is greatest in low-income countries where limited or no access to screening exists. The goal of this study was to describe knowledge and intentions of WHIV towards HPV self-collection for cervical cancer screening, and to report on factors related to HPV positivity among women who participated in testing. A validated survey was administered to 87 HIV positive women attending the Kisenyi Health Unit aged 30-69 years old, and data was abstracted from chart review. At a later date, self-collection based HPV testing was offered to all women. Specimens were tested for high risk HPV genotypes, and women were contacted with results and referred for care. Descriptive statistics, Chi Square and Fischer-exact statistical tests were performed. The vast majority of WHIV (98.9%) women did not think it necessary to be screened for cervical cancer and the majority of women had never heard of HPV (96.4%). However, almost all WHIV found self-collection for cervical cancer screening to be acceptable. Of the 87 WHIV offered self-collection, 40 women agreed to provide a sample at the HIV clinic. Among women tested, 45% were oncogenic HPV positive, where HPV 16 or 18 positivity was 15% overall. In this group of WHIV engaged in HIV care, there was a high prevalence of oncogenic HPV, a large proportion of which were HPV genotypes 16 or 18, in addition to low knowledge of HPV and cervical cancer screening. Improved education and cervical cancer screening for WHIV are sorely needed; self-collection based screening has the potential to be integrated with routine HIV care in this setting.

  17. Voltammetric Determination of Anti-Hypertensive Drug Hydrochlorothiazide Using Screen-Printed Electrodes Modified with L-Glutamic Acid

    Directory of Open Access Journals (Sweden)

    Camilo González-Vargas

    2017-09-01

    Full Text Available This work deals with the development of screen-printed carbon electrodes modified with L-glutamic acid via two different approaches: electropolymerization (SPCE/PGA and aryl diazonium electrochemical grafting (SPCE/EGA. SPCE/PGA and SPCE/EGA were analytically compared in the determination of hydrochlorothiazide (HCTZ by differential pulse voltammetry. Both electrochemical characterization and analytical performance indicate that SPCE/EGA is a much better sensor for HCTZ. The detection and quantification limits were at the level of μmol L−1 with a very good linearity in the studied concentration range. In addition, the proposed SPCE/EGA was successfully applied for the determination of HCTZ in an anti-hypertensive drug with high reproducibility and good trueness.

  18. Three dimensional de novo micro bone marrow and its versatile application in drug screening and regenerative medicine.

    Science.gov (United States)

    Li, Guanqun; Liu, Xujun; Du, Qian; Gao, Mei; An, Jing

    2015-08-01

    The finding that bone marrow hosts several types of multipotent stem cell has prompted extensive research aimed at regenerating organs and building models to elucidate the mechanisms of diseases. Conventional research depends on the use of two-dimensional (2D) bone marrow systems, which imposes several obstacles. The development of 3D bone marrow systems with appropriate molecules and materials however, is now showing promising results. In this review, we discuss the advantages of 3D bone marrow systems over 2D systems and then point out various factors that can enhance the 3D systems. The intensive research on 3D bone marrow systems has revealed multiple important clinical applications including disease modeling, drug screening, regenerative medicine, etc. We also discuss some possible future directions in the 3D bone marrow research field. © 2015 by the Society for Experimental Biology and Medicine.

  19. 3D Printing of Tissue Engineered Constructs for in vitro Modeling of Disease Progression and Drug Screening

    Science.gov (United States)

    Vanderburgh, Joseph; Sterling, Julie A.

    2016-01-01

    2D cell culture and preclinical animal models have traditionally been implemented for investigating the underlying cellular mechanisms of human disease progression. However, the increasing significance of 3D versus 2D cell culture has initiated a new era in cell culture research in which 3D in vitro models are emerging as a bridge between traditional 2D cell culture and in vivo animal models. Additive manufacturing (AM, also known as 3D printing), defined as the layer-by-layer fabrication of parts directed by digital information from a 3D computer-aided design (CAD) file, offers the advantages of simultaneous rapid prototyping and biofunctionalization as well as the precise placement of cells and extracellular matrix with high resolution. In this review, we highlight recent advances in 3D printing of tissue engineered constructs (TECs) that recapitulate the physical and cellular properties of the tissue microenvironment for investigating mechanisms of disease progression and for screening drugs. PMID:27169894

  20. A High Throughput, 384-Well, Semi-Automated, Hepatocyte Intrinsic Clearance Assay for Screening New Molecular Entities in Drug Discovery.

    Science.gov (United States)

    Heinle, Lance; Peterkin, Vincent; de Morais, Sonia M; Jenkins, Gary J; Badagnani, Ilaria

    2015-01-01

    A high throughput, semi-automated clearance screening assay in hepatocytes was developed allowing a scientist to generate data for 96 compounds in one week. The 384-well format assay utilizes a Thermo Multidrop Combi and an optimized LC-MS/MS method. The previously reported LCM