tbuckley/cabot-search huggingface dataset:
Germline Genetic Variation in an Organic Anion Transporter Polypeptide Associated With Methotrexate Pharmacokinetics and Clinical Effects
Authors: Lisa R. Treviño, Noriko Shimasaki, Wenjian Yang, John C. Panetta, Cheng Cheng, Deqing Pei, Diana Chan, Alex Sparreboom, Kathleen M. Giacomini, Ching-Hon Pui, William E. Evans, Mary V. Relling
Journal: Journal of Clinical Oncology (2009)

Methotrexate plasma concentration is related to its clinical effects. Our aim was to identify the genetic basis of interindividual variability in methotrexate pharmacokinetics in children with newly diagnosed acute lymphoblastic leukemia (ALL).We performed a genome-wide analysis of 500,568 germline single-nucleotide polymorphisms (SNPs) to identify how inheritance affects methotrexate plasma disposition among 434 children with ALL who received 3,014 courses of methotrexate at 2 to 5 g/m(2). SNPs were validated in an independent cohort of 206 patients.Adjusting for age, race, sex, and methotrexate regimen, the most significant associations were with SNPs in the organic anion transporter polypeptide, SLCO1B1. Two SNPs in SLCO1B1, rs11045879 (P = 1.7 x 10(-10)) and rs4149081 (P = 1.7 x 10(-9)), were in linkage disequilibrium (LD) with each other (r(2) = 1) and with a functional polymorphism in SLCO1B1, T521C (rs4149056; r(2) > 0.84). rs11045879 and rs4149081 were validated in an independent cohort of 206 patients (P = .018 and P = .017), as were other SLCO1B1 SNPs residing in different LD blocks. SNPs in SLCO1B1 were also associated with GI toxicity (odds ratio, 15.3 to 16.4; P = .03 to .004).A genome-wide interrogation identified inherited variations in a plausible, yet heretofore low-priority candidate gene, SLCO1B1, as important determinants of methotrexate's pharmacokinetics and clinical effects.
Multiple Lineages of R1 Retrotransposable Elements Can Coexist in the rDNA Loci of Drosophila
Authors: Karen L. Gentile, William D. Burke, Thomas H. Eickbush
Journal: Molecular Biology and Evolution (2001)

R1 non–long terminal repeat retrotransposable elements insert specifically into the 28S rRNA genes of arthropods. One aspect of R1 evolution that has been difficult to explain is the presence of divergent lineages of R1 in the rDNA loci of the same species. Multiple lineages should compete for a limited number of insertion sites, in addition to being subject to the concerted evolution processes homogenizing the rRNA genes. The presence of multiple lineages suggests either the ability of the elements to overcome these factors and diverge within rDNA loci, or the introduction of new lineages by horizontal transmission. To address this issue, we attempted to characterize the complete set of R1 elements in the rDNA locus from five Drosophila species groups (melanogaster, obscura, testacea, quinaria, and repleta). Two major R1 lineages, A and B, that diverged about 100 MYA were found to exist in Drosophila. Elements of the A lineage were found in all 35 Drosophila species tested, while elements of the B lineage were found in only 11 species from three species groups. Phylogenetic analysis of the R1 elements, supported by comparison of their rates of nucleotide sequence substitution, revealed that both the A and the B lineages have been maintained by vertical descent. The B lineage was less stable and has undergone numerous, independent elimination events, while the A lineage has diverged into three sublineages, which were, in turn, differentially stable. We conclude that while the differential retention of multiple lineages greatly complicates its phylogenetic history, the available R1 data continue to be consistent with the strict vertical descent of these elements.
Impact of Clinical Trial Results on National Trends in α-Blocker Prescribing, 1996-2002
Authors: Randall S. Stafford
Journal: JAMA (2004)

Research on factors that influence prescribing patterns and the extent of change produced by clinical trial findings is limited.To examine the changes in prescribing of alpha-blockers for hypertension treatment before and after the April 2000 publication of the unfavorable Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) early termination involving the study's doxazosin mesylate arm. Changes in prescribing were considered in the context of other potential concurrent influences on medication use between 1996 and 2002, including changes in alpha-blocker drug prices, generic conversion, drug promotion, and competition.Using 2 national pharmaceutical market research reports published by IMS HEALTH, alpha-blocker prescription orders reported in the National Prescription Audit-a random computerized sample of about 20 000 of 29 000 retail, independent, and mail order pharmacies and mass merchandise and discount houses--and office-based physician alpha-blocker prescribing patterns reported in the National Disease and Therapeutic Index--a random stratified sample of about 3500 physician offices--were tracked.Trends in physician-reported use of alpha-blockers and alpha-blocker prescribing and dispensing by US pharmacies.There were steady increases in alpha-blocker new prescriptions, dispensed prescriptions, and physician drug use from 1996 through 1999. There was a moderate reversal in these trends following ALLHAT early termination and subsequent publications in early 2000. Between 1999 and 2002, new annual alpha-blocker prescription orders declined by 26% (from 5.15 million to 3.79 million), dispensed prescriptions by 22% (from 17.2 million to 13.4 million), and physician-reported drug use by 54% (from 2.26 million to 1.03 million). Other potential influences did not appear to have contributed significantly to this decline although cessation of alpha-blocker marketing may have hastened the decline.Modest yet statistically significant declines in the use of doxazosin and other alpha-blockers coincided with the early termination of the ALLHAT doxazosin arm. Although physicians responded to this new evidence, strategies to augment the impact of clinical trials on clinical practice are warranted.
Urinary Sodium and Cardiovascular Disease Risk
Authors: Paul K. Whelton
Journal: JAMA (2011)

Evidence supporting sodium guideline recommenda-tions comes from animal studies, knowledge of physi-ologic requirements, scrutiny of isolated populations whoeatanaturaldiet,migrationstudies,observationalanalysisinpopulationswhoconsumeprocessedfoods,andrandom-ized controlled trials. Although there is general agreementthat sodium reduction is appropriate for persons with hy-pertension,therearesomequestionsaboutapplyingthisrec-ommendation to the remainder of the population.
Differential regulation of nitric oxide synthases and their allosteric regulators in heart and vessels of hypertensive rats
Authors: Alina Piech, Chantal Dessy, Xavier Havaux, Olivier Feron, Jean-Luc Balligand
Journal: Cardiovascular Research (2003)

Objective: Nitric oxide synthase (NOS)-derived nitric oxide (NO) production is regulated posttranslationally through enzyme's inhibitory interaction with the caveolar coat protein, caveolin and stimulatory interaction with the chaperone heat shock protein, Hsp90. However, changes in the expression of these regulators with the development of hypertrophic cardiomyopathy are unknown. Methods: Histochemical and immunoblotted signals for the NOS isoforms, caveolin and Hsp90 were compared in left ventricle (LV) and aortic or mesenteric vessels between spontaneously hypertensive rats (SHR; 18 and 63 weeks old) and age-matched normotensive Wistar–Kyoto (WKY) rats. To assess functional impacts on downstream NO signaling, superoxide anions (O2−) and cGMP contents were measured in the same tissues by oxidative fluorescent hydroethidine staining and enzyme immunoassay, respectively. Results: Compared with levels in age-matched WKY rats, endothelial NOS (eNOS) proteins were increased in aorta of SHR at 18 weeks. Conversely, aortic caveolin-1 and -3 were decreased in SHR, whereas Hsp90 remained unchanged. In LV tissue of SHR at 18 weeks, caveolin-1 and -3 were similarly decreased, but Hsp90 upregulated, together with a downregulation of eNOS. However, at 63 weeks, both eNOS and neuronal NOS (nNOS) were markedly upregulated in the LV of SHR, together with an upregulation of Hsp90. No difference in cardiac and aortic cGMP contents was found between the two strains. In LV sections, O2− generation was higher in older compared with younger rats from both strains and highest in 63 weeks SHR. Conclusions: Changes in NOS protein abundance in SHR rats compared with WKY controls are differentially regulated according to the age of hypertension and the tissue examined and are not necessarily correlated with cGMP contents. The coordinate expressional changes in NOS isoforms and their allosteric regulators, such as caveolin and Hsp90, may act as a compensatory mechanism to maintain the production of bioactive NO in the face of increased oxidant stress.
Subtilase cytotoxin cleaves newly synthesized BiP and blocks antibody secretion in B lymphocytes
Authors: Chih-Chi Andrew Hu, Stephanie K. Dougan, Sebastian Virreira Winter, Adrienne W. Paton, James C. Paton, Hidde L. Ploegh
Journal: The Journal of Experimental Medicine (2009)

Shiga-toxigenic Escherichia coli (STEC) use subtilase cytotoxin (SubAB) to interfere with adaptive immunity. Its inhibition of immunoglobulin secretion is both rapid and profound. SubAB favors cleavage of the newly synthesized immunoglobulin heavy chain–binding protein (BiP) to yield a C-terminal fragment that contains BiP’s substrate-binding domain. In the absence of its regulatory nucleotide-binding domain, the SubAB-cleaved C-terminal BiP fragment remains tightly bound to newly synthesized immunoglobulin light chains, resulting in retention of light chains in the endoplasmic reticulum (ER). Immunoglobulins are thus detained in the ER, making impossible the secretion of antibodies by SubAB-treated B cells. The inhibitory effect of SubAB is highly specific for antibody secretion, because other secretory proteins such as IL-6 are released normally from SubAB-treated B cells. Although SubAB also causes BiP cleavage in HepG2 hepatoma cells, (glyco)protein secretion continues unabated in SubAB-exposed HepG2 cells. This specific block in antibody secretion is a novel means of immune evasion for STEC. The differential cleavage of newly synthesized versus “aged” BiP by SubAB in the ER provides insight into the architecture of the ER compartments involved.
Increased Risk of Childhood Type 1 Diabetes in Children Born After 1985
Authors: Jannet Svensson, Bendix Carstensen, AnneGrete Mølbak, Bjørn Christau, Henrik B. Mortensen, Jørn Nerup, Knut Borch-Johnsen
Journal: Diabetes Care (2002)

OBJECTIVE—The incidence rate of childhood type 1 diabetes is thought to be increasing; however, Danish studies have not confirmed this. Using a national diabetes register initiated in 1996 and two previous regional incidence studies, we studied the age-specific incidence of type 1 diabetes over 30 years. Here, we describe the incidence rates of type 1 diabetes in Danish children from 1996 to 2000 and evaluate trends in age-specific incidence rates from 1970 to 2000. RESEARCH DESIGN AND METHODS—A nationwide registration of all newly diagnosed cases of type 1 diabetes among children under the age of 15 years was established in Denmark in 1996. Incidence rates of type 1 diabetes in Denmark were obtained from this register. Age-specific incidence rates were compared with data collected from 1970 to 1976 and from 1980 to 1984, both population-based studies using existing national routine registration of hospitalizations within the survey areas. Population data were obtained from Statistics Denmark. RESULTS—During the study period, 1,421 Danish children developed type 1 diabetes before the age of 15 years. The incidence rates by age-groups were: 12.7, 19.4, and 26.3 for the 0–4, 5–9, and 10–14 years age-groups, respectively, and 19.5 for the 0–14 years age-group per 100,000 in the period 1996–2000. An age-period-cohort analysis showed a modest drift effect (yearly increase) of 1.2% (0.7–1.8) from 1970 to 2000, and a significant birth cohort effect with an increased risk for children born after 1985 was observed. CONCLUSIONS—The incidence rate of type 1 diabetes is rising in children living in Denmark. The steep increase in the youngest age-group was explained by the increased risk for cohorts born at the beginning of the 1980s.
Activated protein C correlates inversely with thrombin levels in resting healthy individuals
Authors: José A. Fernández, Jari Petäjä, András Gruber, John H. Griffin
Journal: American Journal of Hematology (1997)

To study whether the circulating anticoagulant, activated protein C (APC), could be a regulator of thrombin activity in basal physiological conditions, fibrinopeptide A and activated protein C levels were determined in samples from 40 healthy individuals. There was a significant inverse correlation between the fibrinopeptide A and APC levels (Spearman rank correlation R = −0.487; P = 0.0023). Because of well-known mechanisms by which decreasing APC levels could cause increased thrombin formation, we suggest that APC may downregulate thrombin activity in subjects with normal protein C levels. Regulation of thrombin formation in health is likely significant for maintaining vascular patency but its molecular mechanisms are poorly understood. The current data suggest that a single physiological anticoagulant, namely APC, may be a significant regulator of procoagulant thrombin activity. Am. J. Hematol. 56:29–31, 1997. © 1997 Wiley-Liss, Inc.
Safety at what cost?
Authors: Douglas Kamerow
Journal: BMJ (2007)

Improving patient safety is a complicated business. Sometimes we don't know exactly what to do. Other times we must balance increased safety with decreased patient autonomy or slowed availability of possibly life-saving medications. We have examples of all of these in this week's BMJ . 

In response to patient safety concerns many hospitals have set up routine incident reporting systems. Ali Sari and colleagues reviewed the results of such a system …
Pregnancy in Diabetic Women
Authors: Donald R. Coustan
Journal: New England Journal of Medicine (1988)

The care of women with diabetes who become pregnant represents one of the medical success stories of this century. Maternal mortality among diabetics fell sharply after the discovery of insulin in 1922. For decades, stillbirths and neonatal deaths continued to occur in more than one third of the pregnancies complicated by diabetes, but most major centers now report them in less than 3 percent of such pregnancies. Perinatal mortality was prevented initially by the use of new techniques that made it easier to tell when the fetus was about to die in the uterus, so that it could be delivered . . .
Chromosome 4q25 Variants Are Genetic Modifiers of Rare Ion Channel Mutations Associated With Familial Atrial Fibrillation
Authors: Marylyn D. Ritchie, Shane Rowan, Gayle Kucera, Tanya Stubblefield, Marcia Blair, Shannon Carter, Dan M. Roden, Dawood Darbar
Journal: Journal of the American College of Cardiology (2012)
Role of specialists in common chronic diseases
Authors: Linda Gask
Journal: BMJ (2005)

Most people with chronic conditions such as diabetes, congestive heart failure, asthma, and depression are managed in primary care. NHS consultants have traditionally confined their role to patients who are referred to outpatient clinics by their general practitioners. Such patients usually have the most severe and complex problems. Effective care teams for chronic illness must be able to cross practice or organisational boundaries,1 but the current organisational structure of the NHS does not provide many incentives to develop such linkages. General practitioners refer patients they cannot manage and hospitals are funded on the basis of referrals. Time spent on joint work with primary care is not accounted for. To ensure that all patients get the best treatment, the role of consultants needs to change so that their specialist knowledge is more available to everyone dealing with chronic disease. In recent years nurses in the NHS have taken on a larger role in managing patients with chronic disease. Specialist nurses work alongside both general practitioners and consultants to assist in managing people with complex problems in both hospital and community settings, and practice nurses now act as case managers to patients with conditions such as diabetes in primary care. However, there has been little integration of primary and specialist care through shared information systems and clinical protocols, such as that seen in US health maintenance organisations.2 ![][1]</img> During a research fellowship spent in a health maintenance organisation,3 I had the opportunity to observe and discuss how the role of the specialist might differ from the traditional role. On the basis of my experience I believe that changing the role of consultants requires two key conceptual shifts. The first shift required is … [1]: /embed/graphic-1.gif
Redundancy reduction for improved display and analysis of body surface potential maps. I. Spatial compression.
Authors: R L Lux, A K Evans, M J Burgess, R F Wyatt, J A Abildskov
Journal: Circulation Research (1981)

The Karhunen-Loeve technique of random process representation was investigated as a method of quantitatively characterizing body surface potential maps. One hundred ninety-two lead body surface potential maps from 124 normal subjects and 97 patients with independently documented heart disease were used in the study. Each map frame in QRS and ST-T of 34 maps in a test set was represented as a linear sum of orthonormal distributions derived from the covariance matrix estimated from all QRS frames in the 221 training maps. A 16:1 reduction in spatial data of the test set was achieved with rms errors of 45 and 21 microV in QRS and ST-T, respectively. Results suggest that 12 independent waveforms, derived from the 192 measured ECGs, may be used in place of those 192 ECGs. In addition to providing a convenient and familiar method of display for map data, the technique puts the data in an appropriate form for quantitative statistical analysis.
Azathioprine and warts.
Authors: C Moens, P Moens, G Philippart
Journal: Annals of the Rheumatic Diseases (1990)

Laboratory and clinical evaluation of 11 patients with mild active rheumatoid arthritis (group A) and of seven patients with severe active rheumatoid arthritis (group B).Results are given as means (SD) Start of After After treatment 14 days 28 days Group A Ferritin (Rg/l) 30 40 (25 80) 22-00 (15-60) 26-10 (21-00) ESR' (mm/h) 56-16 (28 20) 57 20 (30-10) 59 08 (34 50) IgG (g/1) 14-30 (5-75) 15 51 (5-81) 16-02 (6-24) t2 Microglobulin (mg/I) 2-24 (0-84) 2-97 (0-88) 2-82 (0 78) Ritchie index 22-66 (14-01) 15-58 (10-63) 13 08 (9-23) Grip strength 67-91 (23 32) 90 83 (29-49) 91-66 (28 30) Morning stiffness (min) 49-16 (15-15) 10-83 (6-76) 8-33 (6 05)
Amyloid Precursor Protein Is a Primary Androgen Target Gene That Promotes Prostate Cancer Growth
Authors: Ken-ichi Takayama, Shuichi Tsutsumi, Takashi Suzuki, Kuniko Horie-Inoue, Kazuhiro Ikeda, Kiyofumi Kaneshiro, Tetsuya Fujimura, Jinpei Kumagai, Tomohiko Urano, Yoshiyuki Sakaki, Katsuhiko Shirahige, Hironobu Sasano, Satoru Takahashi, Tadaichi Kitamura, Yasuyoshi Ouchi, Hiroyuki Aburatani, Satoshi Inoue
Journal: Cancer Research (2008)

Abstract Androgen receptor (AR) is a critical transcription factor that regulates various target genes and contributes to the pathophysiology of prostate cancer hormone dependently. Here, we identify amyloid precursor protein (APP) as a primary androgen target through chromatin immunoprecipitation (ChIP) combined with genome tiling array analysis (ChIP-chip). ChIP-treated DNA were obtained from prostate cancer LNCaP cells with R1881 or vehicle treatment using AR or acetylated histone H3 antibodies. Ligand-dependent AR binding was further enriched by PCR subtraction. Using chromosome 21/22 arrays, we identified APP as one of the androgen-regulated genes with adjacent functional AR binding sites. APP expression is androgen-inducible in LNCaP cells and APP immunoreactivity was correlated with poor prognosis in patients with prostate cancer. Gain-of-function and loss-of-function studies revealed that APP promotes the tumor growth of prostate cancer. The present study reveals a novel APP-mediated pathway responsible for the androgen-dependent growth of prostate cancer. Our findings will indicate that APP could be a potential molecular target for the diagnosis and treatment of prostate cancer. [Cancer Res 2009;69(1):137–42]
Hepatic Dysfunction during Promazine Therapy
Authors: Leo Waitzkin
Journal: New England Journal of Medicine (1957)

PROMAZINE hydrochloride is a relatively new drug whose pharmacologic properties are stated to be similar to those of chlorpromazine.1 2 3 Both are derivatives of phenothiazine. Promazine differs from chlorpromazine in lacking a chlorine radical.It is well known that hepatic dysfunction and jaundice may occur during chlorpromazine therapy.4 Liver involvement during promazine therapy has not yet been reported.In the case reported below, hepatic dysfunction and urticaria appeared while promazine was being administered.Case ReportA 26-year-old robust man with the diagnosis of schizophrenic reaction, catatonic type, was admitted to the Veterans Administration Hospital on March 26, 1956.On April 12 . . .
Abstract P2-12-04: Music Therapy Reduces Radiotherapy-Induced Fatigue in Patients with Breast or Gynecological Cancer: A Randomized Trial
Authors: NMA Freitas, TRMA Silva, R Freitas-Junior, Junior W Paula, DJ Silva, GDP Machado, MKA Ribeiro, JP Carneiro
Journal: Cancer Research (2012)

Abstract BACKGROUND: Fatigue is a frequent side effect of radiotherapy, and may interfere with self-esteem, social activities, and quality of life. The authors investigated the influence of music therapy (MT) on the reduction of fatigue in women with breast or gynecological malignant neoplasia during radiotherapy. METHODS: Randomized controlled trial (control group-CG and music therapy group-MTG) to assess fatigue, quality of life using the Functional Assessment of Cancer Therapy (FACT-F and FACT-G) version 4 and symptoms of depression using Beck Depression Inventory (BDI) in women undergoing radiotherapy in three distinct moments (during the first and the last week of radiotherapy, and on the week of the intermediary phase). Individual 30–40 minute sessions of music therapy were offered to participants of the MTG. RESULTS: In this study, 164 women were randomized and 116 (63 CG and 53 MTG) were included in the analyses, with mean age of 52.9 years (CG) and 51.85 years (MTG). Participants in the MTG had an average of 10 MT sessions, during the study. FACT-F results were significant regarding Trial Outcome Index (TOI), synthesis of the Physical and functional well-being areas of FACT-F (p = 0.011), FACT-G (p = 0.005), FACT-F (p = 0.001) for MTG compared with CG. The depressive symptons were reduced to the minimum levels in the MTG (p = 0,005) with risk reduction of 74% (RR = 0,26; CI 0,10–0,70). CONCLUSIONS: Individual MT sessions are effective to reduce fatigue related to cancer and symptoms of depression, as well as to improve quality of life for women with breast or gynecological cancer undergoing radiotherapy. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-12-04.