tbuckley/cabot-search huggingface dataset:
Molecular cloning and characterization of an isolate of hepatitis delta virus from Taiwan
Authors: You-Chen Chao, Chuan-Mo Lee, Hung-Shang Tang, Sugantha Govindarajan, Michael M. C. Lai
Journal: Hepatology (1991)

The genomic RNA of an Asian isolate of hepatitis delta virus was cloned from a Chinese patient from Taiwan, using the polymerase chain reaction to amplify cDNA for cloning and sequencing. The sequence of this hepatitis delta virus isolate shares an 86% to 88% similarity with the three published hepatitis delta virus RNA sequences, suggesting heterogeneity of hepatitis delta viruses from different geographical areas. Four highly conserved, long stretches of sequence were found. These four regions corresponded to the sequences required for the autocatalytic cleavage activities of the genomic and antigenomic RNAs and the middle and the carboxyl terminal parts of the open reading frame for the delta antigen on the antigenomic strand. The conservation of nucleotide sequence in these four regions was further confirmed by sequencing additional hepatitis delta virus RNAs obtained from three patients with chronic delta hepatitis who lived in Los Angeles. These findings suggest that the conserved sequences are critical for viral replication. These conserved regions offer ideal sites for primer selection to carry out polymerase chain reactions to detect hepatitis delta virus RNA in patients with hepatitis delta virus infection.
Predicting Toxicities of Reactive Metabolite–Positive Drug Candidates
Authors: Amit S. Kalgutkar, Deepak Dalvie
Journal: The Annual Review of Pharmacology and Toxicology (2014)

Because of the inability to predict and quantify the risk of idiosyncratic adverse drug reactions (IADRs) and because reactive metabolites (RMs) are thought to be responsible for the pathogenesis of some IADRs, the potential for RM formation within new chemical entities is routinely examined with the ultimate goal of eliminating or reducing the liability through iterative design. Likewise, avoidance of structural alerts is almost a standard practice in drug design. However, the perceived safety concerns associated with the use of structural alerts and/or RM screening tools as standalone predictors of toxicity risks may be overexaggerated. Numerous marketed drugs form RMs but do not cause idiosyncratic toxicity. In this review article, we present a critique of the structural alert/RM concept as applied in drug discovery and evaluate the evidence linking structural alerts and RMs to observed toxic effects. Pragmatic risk mitigation strategies to aid the advancement of drug candidates that carry a RM liability are also discussed.
Phase II trial of pazopanib (GW786034), an oral multi-targeted angiogenesis inhibitor, for adults with recurrent glioblastoma (North American Brain Tumor Consortium Study 06-02)
Authors: F. M. Iwamoto, K. R. Lamborn, H. I. Robins, M. P. Mehta, S. M. Chang, N. A. Butowski, L. M. DeAngelis, L. E. Abrey, W.-T. Zhang, M. D. Prados, H. A. Fine
Journal: Neuro-Oncology (2010)

The objective of this phase II single-arm study was to evaluate the efficacy and safety of pazopanib, a multi-targeted tyrosine kinase inhibitor, against vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3, platelet-derived growth factor receptor-α and -β, and c-Kit, in recurrent glioblastoma. Patients with ≤2 relapses and no prior anti-VEGF/VEGFR therapy were treated with pazopanib 800 mg daily on 4-week cycles without planned interruptions. Brain magnetic resonance imaging and clinical reassessment were made every 8 weeks. The primary endpoint was efficacy as measured by 6-month progression-free survival (PFS6). Thirty-five GBM patients with a median age of 53 years and median Karnofsky performance scale of 90 were accrued. Grade 3/4 toxicities included leukopenia (n = 1), lymphopenia (n = 2), thrombocytopenia (n = 1), ALT elevation (n = 3), AST elevation (n = 1), CNS hemorrhage (n = 1), fatigue (n = 1), and thrombotic/embolic events (n = 3); 8 patients required dose reduction. Two patients had a partial radiographic response by standard bidimensional measurements, whereas 9 patients (6 at the 8-week point and 3 only within the first month of treatment) had decreased contrast enhancement, vasogenic edema, and mass effect but <50% reduction in tumor. The median PFS was 12 weeks (95% confidence interval [CI]: 8–14 weeks) and only 1 patient had a PFS time ≥6 months (PFS6 = 3%). Thirty patients (86%) had died and median survival was 35 weeks (95% CI: 24–47 weeks). Pazopanib was reasonably well tolerated with a spectrum of toxicities similar to other anti-VEGF/VEGFR agents. Single-agent pazopanib did not prolong PFS in this patient population but showed in situ biological activity as demonstrated by radiographic responses. ClinicalTrials.gov identifier: NCT00459381.
Neonatal retention of type VII collagen, transient bullous dermolysis of the newborn and recessive epidermolysis bullosa dystrophica inversa
Authors: T. Gedde-Dahl, J.-O. Winberg
Journal: British Journal of Dermatology (1994)

Journal Article Neonatal retention of type VII collagen, transient bullous dermolysis of the newborn and recessive epidermolysis bullosa dystrophica inversa Get access T. Gedde‐Dahl, Jr, T. Gedde‐Dahl, Jr Institute of Forensic Medicine and Department of Dermatology, National Hospital and University of Oslo, Search for other works by this author on: Oxford Academic Google Scholar J.‐O. Winberg J.‐O. Winberg Polar Institute of Medical Genetics, Regional Hospital and University of Tromsö, Norway Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 130, Issue 5, 1 May 1994, Pages 685–686, https://doi.org/10.1111/j.1365-2133.1994.tb13127.x Published: 01 May 1994
Adenoviral Gene Transfer of Activated Phosphatidylinositol 3′-Kinase and Akt Inhibits Apoptosis of Hypoxic Cardiomyocytes In Vitro
Authors: Takashi Matsui, Ling Li, None Federica del Monte, Yasuhisa Fukui, Thomas F. Franke, Roger J. Hajjar, Anthony Rosenzweig
Journal: Circulation (1999)

Background —The intracellular signaling pathways that control cardiomyocyte apoptosis have not been fully defined. Because insulin-like growth factor-1 (IGF-1) prevents cardiomyocyte apoptosis, we examined the role of its downstream signaling molecules in an in vitro model of hypoxia-induced cardiomyocyte apoptosis. Methods and Results —Treatment of rat neonatal cardiomyocytes with IGF-1 increased activity of both phosphatidylinositol 3′ (PI 3)-kinase and its downstream target, Akt (also known as protein kinase B or PKB). Cardiomyocytes were subjected to hypoxia for 24 hours, and apoptosis was assessed by DNA laddering, TUNEL staining, and ELISA for histone-associated DNA fragments. IGF-1 treatment (100 nmol/L) reduced cardiomyocyte apoptosis, and this effect was inhibited by simultaneous treatment with a PI 3-kinase inhibitor. Cardiomyocytes were infected with either a control adenovirus (Ad.EGFP) or adenoviruses carrying constitutively active forms of PI 3-kinase (Ad.BD110) or Akt (Ad.myr-Akt-HA). Ad.BD110 significantly inhibited apoptosis of hypoxic cardiomyocytes compared with Ad.EGFP (61.0±4.6% less DNA fragmentation than in Ad.EGFP-infected cells, P &lt;0.0001). Ad.myr-Akt-HA even more dramatically inhibited apoptosis of hypoxic cardiomyocytes (90.9±1.4% less DNA fragmentation than in controls, P &lt;0.0001). Conclusions —IGF-1 activates PI 3-kinase and Akt in cardiomyocytes. Activated PI 3-kinase and Akt are each sufficient to protect hypoxic cardiomyocytes against apoptosis in vitro. Adenoviral gene transfer provides a useful tool for investigating the role of these signaling pathways in cardiomyocyte apoptosis.
Lumiracoxib is effective in the treatment of osteoarthritis of the knee: a 13 week, randomised, double blind study versus placebo and celecoxib
Authors: H Tannenbaum
Journal: Annals of the Rheumatic Diseases (2004)

<b>Objectives:</b> To compare the efficacy and safety of lumiracoxib with placebo and celecoxib for osteoarthritis OA in a 13 week, multicentre, randomised, double blind study. <b>Methods:</b> After a 37 day washout period for nonsteroidal antiinflammatory drugs, 1702 patients with knee OA were randomised to lumiracoxib 200 or 400mg once daily od, celecoxib 200mg od, or placebo 2221. A visual analogue scale VAS pain intensity 40mm was required. Primary efficacy variables were OA pain intensity VAS mm in the target knee, patients global assessment of disease activity VAS mm, and WOMAC pain subscale and total scores at 13weeks. OA pain intensity, patients and physicians global assessment of disease activity, and WOMAC total and all subscale scores were analysed by visit as secondary variables. <b>Results:</b> Lumiracoxib showed significant improvements in all primary and secondary variables compared with placebo. Lumiracoxib 200mg od and celecoxib 200mg od achieved similar improvements in OA pain intensity and functional status. Lumiracoxib 400mg od demonstrated better efficacy for OA pain intensity and patients global assessment of disease activity at weeks 2, 4, and 8 and similar efficacy at week 13 compared with celecoxib 200mg od. The incidence of adverse events AEs, serious AEs, and discontinuations due to AEs was similar in each group. <b>Conclusion:</b> Lumiracoxib demonstrated significant improvement in OA pain intensity, patients global assessment of disease activity, and the WOMAC pain subscale and total scores compared with placebo. Lumiracoxib was well tolerated in this study, with overall tolerability similar to that of placebo and celecoxib.
Pediatric Phase I and Pharmacokinetic Study of Erlotinib Followed by the Combination of Erlotinib and Temozolomide: A Children's Oncology Group Phase I Consortium Study
Authors: Regina I. Jakacki, Marta Hamilton, Richard J. Gilbertson, Susan M. Blaney, Jean Tersak, Mark D. Krailo, Ashish M. Ingle, Stephan D. Voss, Janet E. Dancey, Peter C. Adamson
Journal: Journal of Clinical Oncology (2008)

We conducted a phase I and pharmacokinetic study of the epidermal growth factor receptor (EGFR) inhibitor erlotinib as a single agent and in combination with temozolomide in children with refractory solid tumors.Erlotinib was administered orally once daily to cohorts of three to six children for a single 28-day course. Patients then received the combination of daily erlotinib and temozolomide daily for 5 days for all subsequent 28-day courses. An oral erlotinib solution was administered during the dose-finding phase and a tablet formulation was subsequently studied at the maximum-tolerated dose (MTD). Pharmacokinetic studies and ERBB-receptor expression and signaling studies were performed.Forty-six patients, median age 11.5 years, received erlotinib at doses of 35, 50, 65, 85, or 110 mg/m(2)/d. At 110 mg/m(2)/d, two of four patients had dose-limiting toxicity (DLT) consisting of rash and hyperbilirubinemia, whereas one of six patients developed dose-limiting rash at 85 mg/m(2)/d. The most frequent non-DLTs included diarrhea, rash, and hyperbilirubinemia. The combination of erlotinib and temozolomide was well tolerated. The median apparent erlotinib clearance was 3.1 L/h/m(2) and the median terminal half-life was 8.7 hours. One patient with a neurocytoma had stable disease for 19 months, two patients with neuroblastoma remained on study for 23 and 24 months, and one patient with myoepithelioma had a mixed response.The recommended phase II dose of erlotinib in recurrent pediatric solid tumors is 85 mg/m(2)/d, either alone or in combination with temozolomide.
Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus
Authors: Henry N Ginsberg, Marshall B Elam, Laura C Lovato, John R Crouse, Lawrence A Leiter, Peter Linz, William T Friedewald, John B Buse, Hertzel C Gerstein, Jeffrey Probstfield, Richard H Grimm, Faramarz Ismail-Beigi, J Thomas Bigger, David C Goff, William C Cushman, Denise G Simons-Morton, Robert P Byington
Journal: New England Journal of Medicine (2010)

We investigated whether combination therapy with a statin plus a fibrate, as compared with statin monotherapy, would reduce the risk of cardiovascular disease in patients with type 2 diabetes mellitus who were at high risk for cardiovascular disease.
Emergence of MRSA of unknown origin in the Netherlands
Authors: W.S.N. Lekkerkerk, N. van de Sande-Bruinsma, M.A.B. van der Sande, A. Tjon-A-Tsien, A. Groenheide, A. Haenen, A. Timen, P.J. van den Broek, W.J.B. van Wamel, A.J. de Neeling, J.H. Richardus, H.A. Verbrugh, M.C. Vos
Journal: Clinical Microbiology and Infection (2011)

The Netherlands is known for its low methicillin-resistant Staphylococcus aureus (MRSA) prevalence. Yet MRSA with no link to established Dutch risk factors for acquisition, MRSA of unknown origin (MUO), has now emerged and hampers early detection and control by active screening upon hospital admittance. We assessed the magnitude of the problem and determined the differences between MUO and MRSA of known origin (MKO) for CC398 and non-CC398. National MRSA Surveillance data (2008-2009) were analysed for epidemiological determinants and genotypic characteristics (Panton-Valentine leukocidin, spa). A quarter (24%) of the 5545 MRSA isolates registered were MUO, i.e. not from defined risk groups. There are two genotypic MUO groups: CC398 MUO (352; 26%) and non-CC398 MUO (998; 74%). CC398 MUO needs further investigation because it could suggest spread, not by direct contact with livestock (pigs, veal calves), but through the community. Non-CC398 MUO is less likely to be from a nursing home than non-CC398 MKO (relative risk 0.55; 95% CI 0.42-0.72) and Panton-Valentine leukocidin positivity was more frequent in non-CC398 MUO than MKO (relative risk 1.19; 95% CI 1.11-1.29). Exact transmission routes and risk factors for non-CC398 as CC398 MUO remain undefined.
Psychiatric Treatment for Nursing Home Patients: Drug, Alcohol, and Milieu
Authors: CHING-PIAO CHIEN, BERNARD A. STOTSKY, JONATHAN O. COLE
Journal: American Journal of Psychiatry (1973)

Following a four-week control period, 64 nursing home patients receiving doxepin, other psychoactive drugs, or no medication were placed on an alcohol regimen of beer or wine in the ward or in a simulated pub setup. The alcohol produced significant improvement in all groups, especially the doxepin group. However, the pub milieu did not demonstrate a significant superiority over ward milieu. The authors suggest that the pub milieu should be used as a catalyzer, rather than as an independent treatment modality, to facilitate the alcohol therapy.
HbA1c Levels Among American Indian/Alaska Native Adults
Authors: Susan S. Gilliland, Janette S. Carter, Betty Skipper, Kelly J. Acton
Journal: Diabetes Care (2002)

OBJECTIVE—Type 2 diabetes is a major public health problem among many American Indian/Alaska Native communities. Elevated levels of HbA1c have been observed in younger American Indian/Alaska Native adults. The objectives of this study were: 1) to determine whether HbA1c levels were elevated among younger American Indian/Alaska Native adults nationally and, if so, 2) to determine the relationship between HbA1c levels and age due to treatment type, BMI, renal disease, duration of diabetes, survival, or a poor diabetes health care index. RESEARCH DESIGN AND METHODS—The national Indian Health Service Diabetes Care and Outcomes Audit was completed for a total of 11,419 American Indian/Alaska Native adults with type 2 diabetes from tribes across the U.S. in 1998. Glucose control was assessed by HbA1c. BMI, diabetes duration, treatment type, and proteinuria were assessed from the Diabetes Care and Outcomes Audit data. To assess diabetes quality of care, an index was developed from six standard of care Diabetes Care and Outcomes Audit variables. RESULTS—We found HbA1c level decreased with increasing age. HbA1c levels were 9.2, 8.9, 8.8, 8.3, and 7.8 for ages 18–39, 40–49, 50–59, 60–69, and ≥70 years, respectively (P &amp;lt; 0.0001). This inverse relationship was not accounted for by differences in BMI, diabetes duration, treatment type, proteinuria, or health care index. CONCLUSIONS—Among American Indian/Alaska Native adults, HbA1c levels were highest in the youngest age-group. With increasing numbers of young American Indian/Alaska Native adults with diabetes, poorer glucose control is expected to bring concomitant increased morbidity and mortality unless more effective and efficient interventions are developed to improve glucose control among young American Indian/Alaska Native adults.
A five year follow-up of lung function among chemical workers using flow-volume and impedance measurements
Authors: S Keman, B Willemse, GJ Wesseling, E Kusters, PJ Borm
Journal: European Respiratory Journal (1996)

Impedance of the respiratory system, measured using the forced oscillation technique (FOT), has repeatedly been proposed as a tool for occupational health screening. The aim of this study was to compare the outcome of impedance measurements and flow-volume curves, and to study relationships between lung function decline and specific exposures and smoking. Both measurements were applied in 136 chemical workers from seven main production/personnel groups during a 5 year follow-up (1990-1995). The prevalence of airway obstruction (forced expiratory volume in one second (FEV1) &lt; 80% of predicted) at both time-points was about 5% but did not necessarily include the same subjects. The average decline in FEV1 over 5 yrs was 200 mL (predicted decline 160 mL). Although most impedance parameters correlated to flow-volume parameters in both years, a rapid 5 year decline of FEV1 (&gt; 330 mL) was only accompanied by a significant decrease in the reactance at 8 Hz (X8) and an increase in the resonance frequency (f0). Interestingly, decline in FEV1 was significantly dependent on age, years of employment, pack-years, FEV1, and all impedance parameters at the start in 1990 (r = 0.35; p = 0.01). Similarly, the increase in f0 was significantly dependent on age, years of employment, pack-years, f0, FEV1, forced vital capacity (FVC), peak expiratory flow (PEF) and maximal mid-expiratory flow (MMEF) at the start (r = 0.56; p &lt; 0.01). Those with a rapid decline in FEV1, were relatively more represented among acid workers (relative risk (RR) = 2.14), maintenance workers (RR = 2.1) and bulk/transport workers (RR = 1.78), but none of these was significant. Lung function, however, was significantly lower in the bulk/transport workers (n = 14) compared to the rest, based both on flow-volume (FEV1, FVC) and impedance (X8, f0) measurements. Smoking had a significant effect on most flow-volume parameters but only for frequency dependence among the impedance outcomes. It is concluded that alterations in impedance parameters do reflect changes in flow-volume curves induced by age. smoking and occupational exposure. Therefore, these data are a valuable extension to current cross-sectional data.
Morale and the planning of psychogeriatric services.
Authors: T Arie
Journal: BMJ (1971)

community immunity (which is minimal anyway), and the policy can be changed with any unlikely upsurge in the global prevalence of smallpox or in a world emergency.Though this policy of deferring vaccination until required was suggested some years ago we are, perhaps, waiting for the Americans to lead us, for Lane and Millar"5 and Foege'9 have recently argued that in the U.S.A. the benefits of childhood *Though not infectious during the incubation period smallpox patients are highly infective at the onset of the illness-before the rash appears.The disease is difficult to diagnose at the onset and health personnel who have not been recently revaccinated are at high risk.tThe immune population, in any event, in the United Kingdom at present, are essentially the under 5-year-olds, who are unlikely to make much contribution to the control of a disease which spreads essentially in adults in this country.vaccination no longer outweigh its risks, and they have suggested that consideration should be given to its discontinuance.In Canada in the past 20 years there has been only one fatal case of smallpox but 21 deaths from vaccination complications.It is little wonder that some epidemiologists in Canada are saying that a case can now be made out to reconsider the benefits of vaccination vis-a-vis the risk of death from it.Many years ago Sir Graham Wilson said, "it is much easier to introduce a given measure into the public health practice of this country than to remove it once it has become firmly established."20The time is overdue3 21 to debate the advantages and disadvantages of retaining smallpox immunization as one of our routine procedures.
DNA Variation in the 5′ Upstream Region of the Adh Locus of the Wild Plants Arabidopsis thaliana and Arabis gemmifera
Authors: Naohiko T. Miyashita
Journal: Molecular Biology and Evolution (2001)

To investigate the level and pattern of DNA polymorphism in the noncoding regulatory region in the plant nuclear genome, 2.4 kb of nucleotide sequence of the 5′ upstream region of Adh was determined for 14 ecotypes of Arabidopsis thaliana and five accessions of Arabis gemmifera. Using this data set and previously determined Adh sequence data, DNA variation was analyzed in a 4.4-kb region of the locus. Two divergent sequence types detected in the transcriptional unit of Adh were not present in the 5′ region of the Adh gene in A. thaliana. Nucleotide diversity of the entire 5′ region was estimated to be 0.0040, which is lower than that in the transcriptional unit. The level of variation was not uniform. There were peaks of variations in a ∼400-bp region where cis-regulatory elements for Adh expression were clustered and in exon 4. In interspecific comparison with A. gemmifera, lower divergence was observed in the 5′ flanking region than in the exons. High peaks of divergence in the 400-bp regulatory region and exon 4 were also detected, although there were many other peaks. These results indicate that regions of functional importance have a high level of polymorphism and divergence in the Adh locus of these genera. The possibility of balancing selection in the Adh gene of these plants is discussed.
Validity of physical activity monitors in adults participating in free-living activities
Authors: S. Berntsen, R. Hageberg, A. Aandstad, P. Mowinckel, S. A. Anderssen, K.-H. Carlsen, L. B. Andersen
Journal: British Journal of Sports Medicine (2008)

<h3>Background</h3> For a given subject, time in moderate to very vigorous intensity physical activity (MVPA) varies substantially among physical activity monitors. <h3>Objective</h3> In the present study, the primary objective, whether time in MVPA recorded with SenseWear Pro<sub>2</sub> Armband (Armband; BodyMedia, Pittsburgh, Pennsylvania, USA), ActiGraph (7164, LLC, Fort Walton Beach, Florida, USA), ikcal (Teltronic AG, Biberist, Switzerland) and ActiReg (PreMed AS, Oslo, Norway) is different compared with indirect calorimetry, was determined. The secondary objective, whether these activity monitors estimate energy expenditure differently compared with indirect calorimetry, was also determined. <h3>Material and methods</h3> The activity monitors and a portable oxygen analyser were worn by 14 men and 6 women for 120 min doing a variety of activities of different intensities. Resting metabolic rate was measured with indirect calorimetry. The cutoff points defining moderate, vigorous and very vigorous intensity were three, six and nine times resting metabolic rate. <h3>Results</h3> Time in MVPA was overestimated by 2.9% and 2.5% by Armband and ActiGraph, respectively, and was underestimated by 11.6% and 98.7% by ikcal and ActiReg, respectively. ActiReg (p = 0.004) and ActiGraph (p = 0.007) underestimated energy expenditure in MVPA, and all monitors underestimated total energy expenditure (by 5% to 21%). <h3>Conclusions</h3> Recorded time in MVPA and energy expenditure varies substantially among physical activity monitors. Thus, when comparing physical activity level among studies, it is essential to know the type of physical activity monitor being used.