tbuckley/cabot-search huggingface dataset:
Adherence to Medications: Insights Arising from Studies on the Unreliable Link Between Prescribed and Actual Drug Dosing Histories
Authors: Terrence F. Blaschke, Lars Osterberg, Bernard Vrijens, John Urquhart
Journal: The Annual Review of Pharmacology and Toxicology (2011)

Satisfactory adherence to aptly prescribed medications is essential for good outcomes of patient care and reliable evaluation of competing modes of drug treatment. The measure of satisfactory adherence is a dosing history that includes timely initiation of dosing plus punctual and persistent execution of the dosing regimen throughout the specified duration of treatment. Standardized terminology for initiation, execution, and persistence of drug dosing is essential for clarity of communication and scientific progress. Electronic methods for compiling drug dosing histories are now the recognized standard for quantifying adherence, the parameters of which support model-based, continuous projections of drug actions and concentrations in plasma that are confirmable by intermittent, direct measurements at single time points. The frequency of inadequate adherence is usually underestimated by pre-electronic methods and thus is clinically unrecognized as a frequent cause of failed treatment or underestimated effectiveness. Intermittent lapses in dosing are potential sources of toxicity through hazardous rebound effects or recurrent first-dose effects.
The efficacy of pulmonary thromboendarterectomy on long-term gas exchange
Authors: N Tanabe, O Okada, Y Nakagawa, M Masuda, K Kato, N Nakajima, T Kuriyama
Journal: European Respiratory Journal (1997)

It has not been delineated in detail how pulmonary thromboendarterectomy (PTE) affects gas exchange through long-term follow-up. In Japan, this surgery has been undertaken in a limited number of institutions, and the results of PTE have not been well publicized. A total of 25 patients were operated on during the period from 1985 to 1996 at our institution, and the overall mortality rate was 16%. Our criteria for PTE were based on the following: 1) thrombi surgically accessible as judged by angiographic study; 2) mean pulmonary arterial pressure &gt; or = 30 mmHg. The efficacies of PTE were analysed on haemodynamics as well as gas exchange at one month postsurgery and during follow-up (6-24 months). Significant haemodynamic improvement was obtained as early as 1 month after surgery. Improvement of gas exchange lagged, but was then observed during follow-up, and the improvement level of pulmonary haemodynamics was sustained. The early postoperative restrictive impairment and ventilation-perfusion abnormality on lung perfusion scan resolved during the follow-up period. It was concluded that the early postoperative efficacy of pulmonary throm-boendarterectomy was mainly achieved due to the reduction of pulmonary hypertension, whereas improvement in gas exchange was obtained over the longer term.
Characteristics and Predictors of Missed Opportunities in Lung Cancer Diagnosis: An Electronic Health Record–Based Study
Authors: Hardeep Singh, Kamal Hirani, Himabindu Kadiyala, Olga Rudomiotov, Traber Davis, Myrna M. Khan, Terry L. Wahls
Journal: Journal of Clinical Oncology (2010)

Purpose Understanding delays in cancer diagnosis requires detailed information about timely recognition and follow-up of signs and symptoms. This information has been difficult to ascertain from paper-based records. We used an integrated electronic health record (EHR) to identify characteristics and predictors of missed opportunities for earlier diagnosis of lung cancer. Methods Using a retrospective cohort design, we evaluated 587 patients of primary lung cancer at two tertiary care facilities. Two physicians independently reviewed each case, and disagreements were resolved by consensus. Type I missed opportunities were defined as failure to recognize predefined clinical clues (ie, no documented follow-up) within 7 days. Type II missed opportunities were defined as failure to complete a requested follow-up action within 30 days. Results Reviewers identified missed opportunities in 222 (37.8%) of 587 patients. Median time to diagnosis in cases with and without missed opportunities was 132 days and 19 days, respectively (P &lt; .001). Abnormal chest x-ray was the clue most frequently associated with type I missed opportunities (62%). Follow-up on abnormal chest x-ray (odds ratio [OR], 2.07; 95% CI, 1.04 to 4.13) and completion of first needle biopsy (OR, 3.02; 95% CI, 1.76 to 5.18) were associated with type II missed opportunities. Patient adherence contributed to 44% of patients with missed opportunities. Conclusion Preventable delays in lung cancer diagnosis arose mostly from failure to recognize documented abnormal imaging results and failure to complete key diagnostic procedures in a timely manner. Potential solutions include EHR-based strategies to improve recognition of abnormal imaging and track patients with suspected cancers.
The Third Cytoplasmic Loop of the Angiotensin II Type 1 Receptor Exerts Differential Effects on Extracellular Signal–Regulated Kinase (ERK1/ERK2) and Apoptosis via Ras- and Rap1-Dependent Pathways
Authors: Judith Haendeler, Mari Ishida, Laszlo Hunyady, Bradford C. Berk
Journal: Circulation Research (2000)

Abstract —The third cytoplasmic loop of the angiotensin (Ang) II type 1 receptor (AT 1 ) is important for receptor coupling to G proteins and activation of downstream events. Therefore, we determined whether specific AT 1 sequences were required for kinase activation and inhibition of apoptosis by transfecting wild-type (AT1Rwt) and mutated AT 1 into 293 cells. Ang II stimulated a 19.4-fold increase in extracellular signal–regulated kinase (ERK1/ERK2) activity in 293 cells transfected with AT1Rwt. However, in 293 cells that expressed a receptor in which amino acids 221 and 222 were deleted (AT1R[Del221/222]), Ang II–mediated ERK1/ERK2 activation was inhibited by &gt;85%. In contrast, c-Jun NH 2 -terminal protein kinase (JNK) activation was similar in AT1Rwt- and AT1R(Del221/222)-transfected cells. Activation of ERK1/ERK2 by AT1Rwt was independent of Ca 2+ , whereas the low level of ERK1/ERK2 activation by AT1R(Del221/222) was completely Ca 2+ dependent. Activation of ERK1/ERK2 in AT1Rwt required Ras, whereas AT1R(Del221/222) required Rap1. These results demonstrate the presence of 2 different pathways for ERK1/ERK2 activation by Ang II, which differ in their requirements for Ca 2+ and small G proteins (Ras versus Rap1). Furthermore, Ang II prevented serum deprivation–induced apoptosis in cells transfected with AT1Rwt but not AT1R(Del221/222). AKT was only phosphorylated by Ang II in AT1Rwt-transfected cells. Overexpression of constitutively active AKT significantly reduced serum deprivation–induced apoptosis in cells transfected with AT1R(Del221/222). This study shows for the first time a direct link between kinase activation and inhibition of apoptosis dependent on amino acids 221 and 222 in the third cytoplasmic loop of the AT 1 .
Arthroscopic Surgery of the Knee
Authors: A. J. Hall
Journal: Annals of the Rheumatic Diseases (1982)

I can thoroughly recommend this book for the more discussion of the scientific basis and interpretation of intelligent sufferer from back pain.Reading it will laboratory tests in the various connective tissue diseasesundoubtedly also help those of us who deal with the rheumatoid arthritis, systemic lupus erythematosus, problem the better to communicate with our patients.mixed connective tissue diseases, rheumatic fever, and the reactive arthritides and amyloid.There is also A. C. BOYLE discussion of antigen-antibody complexes, plasma proteins, lymphocyte identification, and tests of cell- mediated immunity.The remaining third of the text Arthroscopic Surgery of the Knee.By David Dandy.gives detailed descriptions of the performance of the Pp.122.£28-00.Churchill Livingstone: Edinburgh. 1981.most commonly used of the laboratory tests in a clinical immunology laboratory specialising in the connective In the past 10 years diagnostic arthroscopy has become tissue diseases.widely accepted and an essential investigation, par-
Kv1.5 Surface Expression Is Modulated by Retrograde Trafficking of Newly Endocytosed Channels by the Dynein Motor
Authors: Woo Sung Choi, Anu Khurana, Rajesh Mathur, Vijay Viswanathan, David F. Steele, David Fedida
Journal: Circulation Research (2005)

In this article we have investigated the mechanisms by which retrograde trafficking regulates the surface expression of the voltage-gated potassium channel, Kv1.5. Overexpression of p50/dynamitin, known to disrupt the dynein-dynactin complex responsible for carrying vesicle cargo, substantially increased outward K+ currents in HEK293 cells stably expressing Kv1.5 (0.57+/-0.07 nA/pF, n=12; to 1.18+/-0.2 nA/pF, n=12, P<0.01), as did treatment of the cells with a dynamin inhibitory peptide, which blocks endocytosis. Nocodazole pretreatment, which depolymerizes the microtubule cytoskeleton along which dynein tracks, also doubled Kv1.5 currents in HEK cells and sustained K+ currents in isolated rat atrial myocytes. These increased currents were blocked by 1 mmol/L 4-aminopyridine, and the specific Kv1.5 antagonist, DMM (100 nM). Confocal imaging of both HEK cells and myocytes, as well as experiments testing the sensitivity of the channel in living cells to external Proteinase K, showed that this increase of K+ current density was caused by a redistribution of channels toward the plasma membrane. Coimmunoprecipitation experiments demonstrated a direct interaction between Kv1.5 and the dynein motor complex in both heterologous cells and rat cardiac myocytes, supporting the role of this complex in Kv1.5 trafficking, which required an intact SH3-binding domain in the Kv1.5 N terminus to occur. These experiments highlight a pathway for Kv1.5 internalization from the cell surface involving early endosomes, followed by later trafficking by the dynein motor along microtubules. This work has significant implications for understanding the way Kv channel surface expression is regulated.
Low-dose terlipressin plus banding ligation versus low-dose terlipressin alone in the prevention of very early rebleeding of oesophageal varices
Authors: G-H Lo, W-C Chen, H-M Wang, C-K Lin, H-H Chan, W-L Tsai, L-C Cheng, H-C Yu, F-W Tsay
Journal: Gut (2009)

<h3>Background:</h3> Very early rebleeding is frequently encountered in patients with acute oesophageal variceal bleeding. A trial was designed to assess the efficacy and safety in patients with no active bleeding at endoscopy, receiving banding ligation association with terlipressin to prevent very early rebleeding. <h3>Methods:</h3> Patients with no active variceal bleeding at endoscopy were evaluated. Eligible patients were randomised to receive terlipressin infusion alone for 5 days (Terlipressin group) or banding ligation plus terlipressin infusion for 2 days (Combined group). Primary endpoints were treatment failure and very early rebleeding. <h3>Results:</h3> The terlipressin group was composed of 46 patients and the Combined group was composed of 47 patients. Both groups were comparable in terms of baseline data. Forty-eight-hour haemostasis was achieved in 91% in the Terlipressin group and 98% in the Combined group (p = 0.20). Very early rebleeding within 48–120 h occurred in 7 patients (15%) in the Terlipressin group but not in any patients (0%) in the Combined group (p = 0.006). Treatment failure was 24% in the Terlipressin group and 2% in the Combined group (p = 0.002). Multivariate analysis revealed that treatment (OR 0.081; 95% CI 0.010 to 0.627) was the only predictive factor of very early rebleeding. Blood requirement was significantly lower in the Combined group than in the Terlipressin group. Complications and 6-week survival were similar in both groups. <h3>Conclusions:</h3> Combination of banding ligation and terlipressin infusion for 2 days was superior to only infusion of terlipressin for 5 days in the reduction of very early rebleeding and treatment failure in patients with inactive variceal bleeding at endoscopy. <h3>Trial registration number:</h3> ISRCTN28353453
Linkage Disequilibrium Mapping of CHEK2: Common Variation and Breast Cancer Risk
Authors: Kristjana Einarsdóttir, Keith Humphreys, Carine Bonnard, Juni Palmgren, Mark M Iles, Arvid Sjölander, Yuqing Li, Kee Seng Chia, Edison T Liu, Per Hall, Jianjun Liu, Sara Wedrén
Journal: PLoS Medicine (2006)

Background Checkpoint kinase 2 (CHEK2) averts cancer development by promoting cell cycle arrest and activating DNA repair in genetically damaged cells. Previous investigation has established a role for the CHEK2 gene in breast cancer aetiology, but studies have largely been limited to the rare 1100delC mutation. Whether common polymorphisms in this gene influence breast cancer risk remains unknown. In this study, we aimed to assess the importance of common CHEK2 variants on population risk for breast cancer by capturing the majority of diversity in the gene using haplotype tagging single nucleotide polymorphisms (tagSNPs). Methods and Findings We analyzed 14 common SNPs spanning 52 kilobases (kb) of the CHEK2 gene in 92 Swedish women. Coverage evaluation indicated that these typed SNPs would efficiently convey association signal also from untyped SNPs in the same region. Six of the 14 SNPs predicted well both the haplotypic and single SNP variations within CHEK2. We genotyped these six tagSNPs in 1,577 postmenopausal breast cancer cases and 1,513 population controls, but found no convincing association between any common CHEK2 haplotype and breast cancer risk. The 1100delC mutation was rare in our Swedish population—0.7% in cases and 0.4% in controls—with a corresponding odds ratio for carriers versus noncarriers of 2.26 (95% confidence interval, 0.99–5.15). Estimates of the population frequency and the odds ratio of 1100delC indicate that our sample is representative of a Northern European population. Conclusions Notwithstanding the involvement of the CHEK2 gene in breast cancer aetiology, we show that common polymorphisms do not influence postmenopausal breast cancer risk.
A New Molecular Predictor of Distant Recurrence in ER-Positive, HER2-Negative Breast Cancer Adds Independent Information to Conventional Clinical Risk Factors
Authors: Martin Filipits, Margaretha Rudas, Raimund Jakesz, Peter Dubsky, Florian Fitzal, Christian F. Singer, Otto Dietze, Richard Greil, Andrea Jelen, Paul Sevelda, Christa Freibauer, Volkmar Müller, Fritz Jänicke, Marcus Schmidt, Heinz Kölbl, Achim Rody, Manfred Kaufmann, Werner Schroth, Hiltrud Brauch, Matthias Schwab, Peter Fritz, Karsten E. Weber, Inke S. Feder, Guido Hennig, Ralf Kronenwett, Mathias Gehrmann, Michael Gnant
Journal: Clinical Cancer Research (2011)

According to current guidelines, molecular tests predicting the outcome of breast cancer patients can be used to assist in making treatment decisions after consideration of conventional markers. We developed and validated a gene expression signature predicting the likelihood of distant recurrence in patients with estrogen receptor (ER)-positive, HER2-negative breast cancer treated with adjuvant endocrine therapy.RNA levels assessed by quantitative reverse transcriptase PCR in formalin-fixed, paraffin-embedded tumor tissue were used to calculate a risk score (Endopredict, EP) consisting of eight cancer-related and three reference genes. EP was combined with nodal status and tumor size into a comprehensive risk score, EPclin. Both prespecified risk scores including cutoff values to determine a risk group for each patient (low and high) were validated independently in patients from two large randomized phase III trials [Austrian Breast and Colorectal Cancer Study Group (ABCSG)-6: n = 378, ABCSG-8: n = 1,324].In both validation cohorts, continuous EP was an independent predictor of distant recurrence in multivariate analysis (ABCSG-6: P = 0.010, ABCSG-8: P < 0.001). Combining Adjuvant!Online, quantitative ER, Ki67, and treatment with EP yielded a prognostic power significantly superior to the clinicopathologic factors alone [c-indices: 0.764 vs. 0.750, P = 0.024 (ABCSG-6) and 0.726 vs. 0.701, P = 0.003 (ABCSG-8)]. EPclin had c-indices of 0.788 and 0.732 and resulted in 10-year distant recurrence rates of 4% and 4% in EPclin low-risk and 28% and 22% in EPclin high-risk patients in ABCSG-6 (P < 0.001) and ABCSG-8 (P < 0.001), respectively.The multigene EP risk score provided additional prognostic information to the risk of distant recurrence of breast cancer patients, independent from clinicopathologic parameters. The EPclin score outperformed all conventional clinicopathologic risk factors.
Detection of MAGE-A Transcripts in Bone Marrow Is an Independent Prognostic Factor in Operable Non–Small-Cell Lung Cancer
Authors: Wulf Sienel, Ingo Mecklenburg, Sebastian Dango, Peter Ehrhardt, Andreas Kirschbaum, Bernward Passlick, Klaus Pantel
Journal: Clinical Cancer Research (2007)

Abstract Purpose: MAGE-A gene expression in humans is mostly restricted to tumor cells, and the role of MAGE-A transcripts and peptides as diagnostic markers and therapeutic targets is currently under investigation. Thus far, the clinical relevance of MAGE-A transcripts as marker for disseminated tumor cells in bone marrow of patients with operable lung cancer without overt metastases is still unclear. Experimental Design: Preoperative bone marrow aspirates from 50 consecutive patients with operable non–small-cell lung cancer free of distant metastases (i.e., pT1-4 pN0-2 M0 R0) were admitted to the study. Each bone marrow sample was divided and examined using multimarker MAGE-A reverse transcription-PCR (RT-PCR) and immunocytochemical staining with the anti-pancytokeratin antibody A45-B/B3. Multimarker MAGE-A RT-PCR consisted of multiple subtype-specific nested RT-PCRs with primers for MAGE-A1, MAGE-A2, MAGE-A3/6, MAGE-A4, and MAGE-A12. The median follow-up duration was 92 months (range, 18-110 months). Results: Twenty-six (52%) lung cancer patients harbored MAGE-A transcripts in their bone marrow, as opposed to none of the 30 healthy controls tested. In all 7 patients with immunocytochemically positive bone marrow, MAGE-A transcripts were also detected. All different MAGE-A subtypes (MAGE-A1, MAGE-A2, MAGE-A3/6, MAGE-A4, and MAGE-A12) were observed. Sixty-five percent of patients with MAGE-A transcripts in bone marrow exhibited only one subtype. Univariate (P = 0.03, log-rank-test) and multivariate survival analysis showed that MAGE-A transcripts in bone marrow were associated with poor outcome in pN0 patients (P = 0.02; relative risk, 7.6). Conclusions: Detection of MAGE-A transcripts in bone marrow predicts an unfavorable outcome in patients with early-stage operable lung cancer. This finding indicates that MAGE-A transcripts are clinically relevant markers of micrometastatic spread in lung cancer and supports further investigation of MAGE-A as potential future therapeutic target.
Outcome of 154 patients with severe aplastic anemia who received transplants from unrelated donors: the Japan Marrow Donor Program
Authors: Seiji Kojima, Takaharu Matsuyama, Shunichi Kato, Hisato Kigasawa, Ryoji Kobayashi, Atsushi Kikuta, Hisashi Sakamaki, Koichiro Ikuta, Masahiro Tsuchida, Yasutaka Hoshi, Yasuo Morishima, Yoshihisa Kodera
Journal: Blood (2002)
Genetic Basis of Atherosclerosis: Insights From Mice and Humans
Authors: Ioannis M. Stylianou, Robert C. Bauer, Muredach P. Reilly, Daniel J. Rader
Journal: Circulation Research (2012)

Atherosclerosis is a complex and heritable disease involving multiple cell types and the interactions of many different molecular pathways. The genetic and molecular mechanisms of atherosclerosis have, in part, been elucidated by mouse models; at least 100 different genes have been shown to influence atherosclerosis in mice. Importantly, unbiased genome-wide association studies have recently identified a number of novel loci robustly associated with atherosclerotic coronary artery disease. Here, we review the genetic data elucidated from mouse models of atherosclerosis, as well as significant associations for human coronary artery disease. Furthermore, we discuss in greater detail some of these novel human coronary artery disease loci. The combination of mouse and human genetics has the potential to identify and validate novel genes that influence atherosclerosis, some of which may be candidates for new therapeutic approaches.
Don’t Ignore the Patients
Authors: Donnell D. Etzwiler
Journal: Diabetes Care (2001)

Over 90% of the daily long-term treatment of most chronic conditions is carried out by patients themselves in their own homes. Consequently, patients must be recognized and accepted as legitimate members of the health care team, with all of the associated rights and responsibilities. Chronic illnesses will, both now and in the foreseeable future, continue to be our nation’s leading causes of death, disability, and medical expenditures, and as such, they will demand a delivery system responsive …
Non-dinitrophenyl-binding immunoglobulin that bears a dominant idiotype (Id460) associated with antidinitrophenyl antibody is specific for an antigen on Pasteurella pneumotropica.
Authors: T N Marion, E A Dzierzak, H S Lee, R L Adams, C A Janeway
Journal: The Journal of Experimental Medicine (1984)

We have previously described an idiotype (Id460) that transiently dominates anti-2,4-dinitrophenyl (DNP) antibody responses of mice that possess the appropriate Igh-V and V kappa genotypes. Normal serum has significant levels of Id460 that does not bind DNP, and hybridomas derived from spleen cell fusions that produce monoclonal antibodies with these characteristics have been generated. Many of these monoclonal, Id460-positive antibodies bind the opportunistic mouse pathogen Pasteurella pneumotropica. P. pneumotropica induces a marked increase in serum Id460 titers without significantly increasing serum anti-DNP titers. Both normal serum and P. pneumotropica-induced Ig460-positive immunoglobulin specifically bind to P. pneumotropica. These results suggest that the normal serum Id460-positive immunoglobulin is induced by environmentally encountered antigens on P. pneumotropica. We propose that this naturally occurring Id460 activates antiidiotypic regulatory cells that in turn promote production of Id460-positive anti-DNP antibody following DNP-ovalbumin immunization. These data are compatible with those obtained in several other idiotypic systems that suggest that dominant idiotypes may be associated with antibodies that have been evolutionarily selected for expression because of their specificity for antigens on environmentally encountered pathogens.