tbuckley/cabot-search huggingface dataset:
New Insights into the Mechanism of Action of Amphetamines
Authors: Annette E. Fleckenstein, Trent J. Volz, Evan L. Riddle, James W. Gibb, Glen R. Hanson
Journal: The Annual Review of Pharmacology and Toxicology (2007)

Amphetamine is a psychostimulant commonly used to treat several disorders, including attention deficit, narcolepsy, and obesity. Plasmalemmal and vesicular monoamine transporters, such as the neuronal dopamine transporter and the vesicular monoamine transporter-2, are two of its principal targets. This review focuses on new insights, obtained from both in vivo and in vitro studies, into the molecular mechanisms whereby amphetamine, and the closely related compounds methamphetamine and methylenedioxymethamphetamine, cause monoamine, and particularly dopamine, release. These mechanisms include amphetamine-induced exchange diffusion, reverse transport, and channel-like transport phenomena as well as the weak base properties of amphetamine. Additionally, amphetamine analogs may affect monoamine transporters through phosphorylation, transporter trafficking, and the production of reactive oxygen and nitrogen species. All of these mechanisms have potential implications for both amphetamine- and methamphetamine-induced neurotoxicity, as well as dopaminergic neurodegenerative diseases.
Predictors of readmission after hospitalization for acute exacerbations of chronic obstructive pulmonary disease (AECOPD)
Authors: R.T.M. Sprooten, R.H.J. Slenter, D. Kotz, G. Wesseling, E.F.M. Wouters, G.G.U. Rohde
Journal: European Respiratory Journal (2013)

BACKGROUND:   Patients who survive hospitalized AECOPD are at high risk of readmission and death. Determinants of frequent hospitalizations are still not sufficiently defined.   OBJECTIVES:   To assess the readmission rate and identify potential determinants associated with frequent readmissions for AECOPD.   METHODS:   In a retrospective, observational cohort study 245 consecutive patients admitted between January 1, 2009, and April 1, 2010, for AECOPD were analysed and followed up to one year. Univariate and multivariate analysis were used in order to identify potential predictors of readmissions.   RESULTS:   91 Patients (37%) had one or more readmissions. Patients with readmissions suffered from significantly higher mortality (32% vs. 18%, p 1 , TLCO and RV/TLC, use of LTOT, comorbidity (diabetes mellitus, cardiac, pneumonia), elevated urea during index admission, base excess > 2.5 mmol/l, usage for NPPV more than five days and prior treatment limitation were significantly associated with readmissions. Independent risk factors for readmissions were TLCO [hazard ratio (HR) = 0.98; 95% confidence interval (CI) = 0.968-0.994] and pre-existingcardiac comorbidity [HR = 1.71; 95% CI = 1.011-2.878]. Antibiotic treatment during index admission was associated with reduced risk for readmission [HR = 0.462; 95% CI = 0.287-0.744].   CONCLUSIONS:   Cardiac comorbidity and low TLCO (%pred) are independent predictors of readmissions after hospitalized AECOPD within the first year after the index admission. Antibiotic treatment during hospitalization seems to be an independent protective factor.
The <i>SEM6A6</i> Locus Is Not Associated With Granulomatosis With Polyangiitis or Other Forms of Antineutrophil Cytoplasmic Antibody–Associated Vasculitides in Europeans: Comment on the Article by Xie et al
Authors: Stefan Wieczorek, Julia U. Holle, Jan Willem Cohen Tervaert, Lorraine Harper, Frank Moosig, Wolfgang L. Gross, Joerg T. Epplen
Journal: Arthritis & Rheumatology (2014)
Introduction to the Theme “Cancer Pharmacology”
Authors: Paul A. Insel, Susan G. Amara, Terrence F. Blaschke, Urs A. Meyer
Journal: The Annual Review of Pharmacology and Toxicology (2015)

Due to the massive data sets available for drug candidates, modern drug discovery has advanced to the big data era. Central to this shift is the development of artificial intelligence approaches to implementing innovative modeling based on the dynamic, ...Read More
The Retinoblastoma Family Member pRb2/p130 Is an Independent Predictor of Survival in Human Soft Tissue Sarcomas
Authors: Valeria Masciullo, Ester Berardengo, Antonella Boglione, Alessandro Sgambato, Amelia Bernardi, Marco Forni, Alessandra Linari, Letizia Cito, Giovanni Scambia, Alessandro Comandone, Antonio Giordano
Journal: Clinical Cancer Research (2008)

pRb2/p130, a member of the Retinoblastoma gene family, has been shown to be a powerful prognostic factor in several malignancies. We sought to evaluate pRb2/p130 protein expression and its clinical effect in patients affected with soft tissue sarcomas (STS).Expression of pRb2/p130 was evaluated by immunohistochemistry on formalin-fixed, paraffin-embedded sections in 41 STSs. Results obtained were correlated with clinicopathologic variables and disease-free and overall survival (OS) in univariate and multivariate analysis.Expression of pRb2/p130 was diminished in 25 (61%) tumors, whereas the remaining ones (39%) were classified as high expressors. No correlation between pRb2/p130 expression and clinicopathologic variables was observed. However, a direct relationship between pRb2/p130 expression and clinical outcome of the patients was found in the subgroup of nonmetastatic tumors (n = 31). In univariate analysis, reduced pRb2/p130 expression was a negative prognostic factor and correlated with shorter disease-free survival (P = 0.021) and OS (P = 0.017) survival. In multivariate analysis, reduced pRb2/p130 expression was confirmed to be an independent predictor of shorter OS when considered together with tumor stage and grading (risk ratio, 7.893; confidence interval, 1.618-38.509; P = 0.011).This study shows for the first time the potential prognostic value of pRb2/130 expression evaluated on formalin-fixed, paraffin-embedded sections in STSs patients. pRb2/p130 immunoreactivity can be used to predict OS in patients with nonmetastatic STSs and, therefore, may represent a new prognostic marker.
Active suppression of 1-fluoro-2,4-dinitrobenzene-immune T cells. Requirement of an auxiliary T cell induced by antigen.
Authors: M S Sy, S D Miller, J W Moorhead, H N Claman
Journal: The Journal of Experimental Medicine (1979)

We investigated T-T cell interactions in the suppression of contact sensitivity. Suppressor cells that block the efferent limb of sensitivity (Ts-eff) can inhibit the passive transfer of contact sensitivity mediated by 1-fluoro-2,4-dinitrobenzene immune cells (T DH). But, Ts-eff cannot block the passive transfer of TDH which comes from cyclophosphamide (Cy) pretreated sensitized mice. We interpret these results to indicate that lymph node cells from sensitized mice contain not only TDH but also another intermediate cell which is required for the suppression of TDH by Ts-eff. This intermediate cell is sensitive to cyclophosphamide and requires antigen activation for its development. It is sensitive to adult thymectomy and anti-brain associated theta serum and is therefore designated as an auxiliary T-suppressor cell (Ts-aux). It is not sensitive to splenectomy and it carries I-J determinants. Ts-aux are required for the activity of suppressors of the efferent limb (Ts-eff) but not of suppressors of the afferent limb (Ts-aff). Thus, in the feedback loops in contact sensitivity, the generation of Tdh is coordinated with the development of auxiliary Ts which are essential for the suppression of those TDH.
Placebo-controlled trial of 400 mg amantadine combined with peginterferon alfa-2a and ribavirin for 48 weeks in chronic hepatitis C virus-1 infection
Authors: Michael von Wagner, Wolf Peter Hofmann, Gerlinde Teuber, Thomas Berg, Tobias Goeser, Ulrich Spengler, Holger Hinrichsen, Hans Weidenbach, Guido Gerken, Michael Manns, Peter Buggisch, Eva Herrmann, Stefan Zeuzem
Journal: Hepatology (2008)

Abstract The impact of amantadine on virologic response rates of interferon-based treatment of chronic hepatitis C is controversial. The aim of this study was to compare virological response rates in patients with chronic hepatitis C virus (HCV)-1 infection treated with 400 mg amantadine or placebo in combination with peginterferon alfa-2a (40 kD) and ribavirin for 48 weeks. Seven hundred four previously untreated chronically HCV-1–infected patients (mean age, 46 ± 12 years) were randomized to (A) amantadine-sulphate (400 mg/day) (n = 352) or (B) placebo (n = 352), both in combination with 180 μg peginterferon alfa-2a once weekly and ribavirin (1000-1200 mg/day) for 48 weeks. End of treatment and sustained virological response after a 24-week follow-up period were assessed by qualitative reverse transcription polymerase chain reaction (RT-PCR) (sensitivity, 50 IU/mL). Demographic and baseline virological parameters were similar in both treatment groups. In groups A and B, 231 of 352 patients (66%) and 256 of 352 patients (72%) achieved an end of treatment response, and 171 of 352 patients (49 %) and 186 of 352 patients (53 %) a sustained virological response, respectively. On-treatment dropout rate in the amantadine group was significantly higher than in the placebo group (32% versus 23%; P = 0.01). However, adverse events and laboratory abnormalities were similar between both groups. Per-protocol analysis revealed similar sustained virological response rates in both treatment groups (53% versus 55%). Conclusion: In this large placebo-controlled multicenter study, amantadine even at a dose of 400 mg/day did not improve virological response rates of peginterferon alfa-2a and ribavirin in patients with chronic genotype HCV-1 infection. (Hepatology 2008.)
Cost of a Community-Based Diabetic Retinopathy Screening Program
Authors: Margaret M. Byrne, Dorothy F. Parker, Stacey L. Tannenbaum, Manuel A. Ocasio, Byron L. Lam, Ingrid Zimmer-Galler, David J. Lee
Journal: Diabetes Care (2014)

The prevalence of diabetes in the U.S. has steadily increased over the last few decades (1). Although adults with diabetes are at increased risk for ocular disease and blindness, primarily related to diabetic retinopathy (2), many are not evaluated for retinopathy. Barriers to vision-screening adherence among adults with diabetes include the perception—and often the reality—that examinations are expensive and a poor understanding of the increased risk of vision loss (3). The goal of this study was to determine the costs of a community-based program to screen adults for diabetic retinopathy.

In this study, free ocular health screening was offered over a 17-month period at a community health center in a low socio-economic area. Fundus photographs were taken, uploaded to a HIPPA-compliant secure Web site, and reviewed for any clinical pathology and specifically for diabetic retinopathy. We collected information on all costs of the screening program. Costs were assessed …
Water and electrolyte absorption by the colon in tropical sprue.
Authors: B S Ramakrishna, V I Mathan
Journal: Gut (1982)

<h3>Abstract</h3> <h3>Background</h3> Sexually Transmitted Diseases (STDs) are common and costly, impacting approximately one in five people annually. Reddit, the sixth most used internet site in the world, is a user-generated social media discussion platform that may be useful in monitoring discussion about STD symptoms and exposure. <h3>Objective</h3> This study sought to define and identify patterns and insights into STD related discussions on Reddit over the course of the COVID-19 pandemic. <h3>Methods</h3> We extracted posts from Reddit from March 2019 through July 2021. We used a machine learning text mining method, Latent Dirichlet Allocation (LDA), to conduct a text analysis to identify the most common topics discussed in the Reddit posts. We then used word clouds, qualitative topic labelling, and spline regression to characterize the content and distribution of topics observed. <h3>Results</h3> Our extraction resulted in 24,311 total posts. LDA Coding showed that with 8 topics for each time period we achieved high coherence values (pre-COVID=0.41, pre-vaccine=0.42; post-vaccine=0.44). While most topic categories remained the same over time, the relative proportion of topics changed and new topics emerged. Spline regression revealed some key terms had variability in the percentage of posts that coincided with COVID-19 pre- and post-periods, while others were uniform across the study periods. <h3>Conclusions</h3> Our study’s use of Reddit is a novel way to gain insights into STD symptoms experienced, potential exposures, testing decisions, common questions, and behavior patterns (e.g., during lock down periods). For example, reduction in STD screening may result in observed negative health outcomes due to missed cases, which also impacts onward transmission. As Reddit use is anonymous, users may discuss sensitive topics with greater detail, and more freely than in clinical encounters. Data from anonymous Reddit posts may be leveraged to enhance understanding of the distribution of disease and need for targeted outreach/screening programs. This study demonstrates Reddit has feasibility and utility to enhance understanding of sexual behaviors, STD experiences, and needed health engagement with the public.
Cytosolic carboxypeptidase CCP6 is required for megakaryopoiesis by modulating Mad2 polyglutamylation
Authors: Buqing Ye, Chong Li, Zhao Yang, Yanying Wang, Junfeng Hao, Li Wang, Yi Li, Ying Du, Lu Hao, Benyu Liu, Shuo Wang, Pengyan Xia, Guanling Huang, Lei Sun, Yong Tian, Zusen Fan
Journal: The Journal of Experimental Medicine (2014)

Bone marrow progenitor cells develop into mature megakaryocytes (MKs) to produce platelets for hemostasis and other physiological functions. However, the molecular mechanisms underlying megakaryopoiesis are not completely defined. We show that cytosolic carboxypeptidase (CCP) 6 deficiency in mice causes enlarged spleens and increased platelet counts with underdeveloped MKs and dysfunctional platelets. The prominent phenotypes of CCP6 deficiency are different from those of CCP1-deficient mice. We found that CCP6 and tubulin tyrosine ligase-like family (TTLL) members TTLL4 and TTLL6 are highly expressed in MKs. We identify Mad2 (mitotic arrest deficient 2) as a novel substrate for CCP6 and not CCP1. Mad2 can be polyglutamylated by TTLL4 and TTLL6 to modulate the maturation of MKs. CCP6 deficiency causes hyperglutamylation of Mad2 to promote activation of Aurora B, leading to suppression of MK maturation. We reveal that Mad2 polyglutamylation plays a critical role in the regulation of megakaryopoiesis.
Postoperative Adjuvant Lapatinib and Concurrent Chemoradiotherapy Followed by Maintenance Lapatinib Monotherapy in High-Risk Patients With Resected Squamous Cell Carcinoma of the Head and Neck: A Phase III, Randomized, Double-Blind, Placebo-Controlled Study
Authors: Kevin Harrington, Stephane Temam, Hisham Mehanna, Anil D'Cruz, Minish Jain, Ida D'Onofrio, Georgy Manikhas, Zsuzsanna Horvath, Yan Sun, Stefan Dietzsch, Pavol Dubinsky, Petra Holeckova, Iman El-Hariry, Natalie Franklin, Nigel Biswas-Baldwin, Philippe Legenne, Paul Wissel, Thelma Netherway, John Farrell, Catherine Ellis, Jing Wang-Silvanto, Mayur Amonkar, Nazma Ahmed, Sergio Santillana, Jean Bourhis
Journal: Journal of Clinical Oncology (2015)

This multicenter phase III study evaluated the efficacy and safety of lapatinib, an epidermal growth factor receptor/ErbB2 inhibitor, administered concomitantly with chemoradiotherapy and as maintenance monotherapy in patients with high-risk surgically treated squamous cell carcinoma of the head and neck (SCCHN).Patients with resected stage II to IVA SCCHN, with a surgical margin ≤ 5 mm and/or extracapsular extension, were randomly assigned to chemoradiotherapy (66 Gy total radiation dose and cisplatin 100 mg/m(2) per day administered on days 1, 22, and 43) plus placebo or lapatinib (1,500 mg per day) before and during chemoradiotherapy, followed by 12 months of maintenance monotherapy.Six hundred eighty-eight patients were enrolled (lapatinib, n = 346; placebo, n = 342). With a median follow-up time of 35.3 months, the study ended early because of the apparent plateauing of disease-free survival (DFS) events. Median DFS assessed by an independent review committee was 53.6 months and not reached for lapatinib and placebo, respectively (hazard ratio, 1.10; 95% CI, 0.85 to 1.43). Investigator-assessed results confirmed the independent review committee assessment. No significant differences in DFS by human papillomavirus status or overall survival were observed between treatment arms. Similar numbers of patients in both treatment arms experienced adverse events (AEs), with more patients in the lapatinib arm than the placebo arm experiencing serious AEs (48% v 40%, respectively). The most commonly observed treatment-related AEs were diarrhea and rash, both predominantly in the lapatinib arm.Addition of lapatinib to chemoradiotherapy and its use as long-term maintenance therapy does not offer any efficacy benefits and had additional toxicity compared with placebo in patients with surgically treated high-risk SCCHN.
Genome-Wide Array-Based Comparative Genomic Hybridization of Diffuse Large B-Cell Lymphoma
Authors: Hiroyuki Tagawa, Shinobu Tsuzuki, Ritsuro Suzuki, Sivasundaram Karnan, Akinobu Ota, Yoshihiro Kameoka, Miyuki Suguro, Keitaro Matsuo, Motoko Yamaguchi, Masataka Okamoto, Yasuo Morishima, Shigeo Nakamura, Masao Seto
Journal: Cancer Research (2004)

Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin’s lymphoma and exhibits aggressive and heterogeneous clinical behavior. To genetically characterize DLBCL, we established our own array-based comparative genomic hybridization and analyzed a total of 70 cases [26 CD-positive (CD5+) DLBCL and 44 CD5-negative (CD5−) DLBCL cases]. Regions of genomic aberrations observed in &amp;gt;20% of cases of both the CD5+ and CD5− groups were gains of 1q21-q31, 1q32, 3p25-q29, 5p13, 6p21-p25, 7p22-q31, 8q24, 11q23-q24, 12q13-q21, 16p13, 18, and X and losses of 1p36, 3p14, 6q14-q25, 6q27, 9p21, and 17p11-p13. Because CD5 expression marks a subgroup with poor prognosis, we subsequently analyzed genomic gains and losses of CD5+ DLBCL compared with those of CD5−. Although both groups showed similar genomic patterns of gains and losses, gains of 10p14-p15 and 19q13 and losses of 1q43-q44 and 8p23 were found to be characteristic of CD5+ DLBCL. By focusing on the gain of 13q21-q34 and loss of 1p34-p36, we were also able to identify prognostically distinct subgroups among CD5+ DLBCL cases. These results suggest that array-based comparative genomic hybridization analysis provides a platform of genomic aberrations of DLBCL both common and specific to clinically distinct subgroups.
Mouse CD94/NKG2A Is a Natural Killer Cell Receptor for the Nonclassical Major Histocompatibility Complex (MHC) Class I Molecule Qa-1b
Authors: Russell E. Vance, Jennifer R. Kraft, John D. Altman, Peter E. Jensen, David H. Raulet
Journal: The Journal of Experimental Medicine (1998)

Natural killer (NK) cells preferentially lyse targets that express reduced levels of major histocompatibility complex (MHC) class I proteins. To date, the only known mouse NK receptors for MHC class I belong to the Ly49 family of C-type lectin homodimers. Here, we report the cloning of mouse NKG2A, and demonstrate it forms an additional and distinct class I receptor, a CD94/NKG2A heterodimer. Using soluble tetramers of the nonclassical class I molecule Qa-1b, we provide direct evidence that CD94/NKG2A recognizes Qa-1b. We further demonstrate that NK recognition of Qa-1b results in the inhibition of target cell lysis. Inhibition appears to depend on the presence of Qdm, a Qa-1b-binding peptide derived from the signal sequences of some classical class I molecules. Mouse NKG2A maps adjacent to CD94 in the heart of the NK complex on mouse chromosome six, one of a small cluster of NKG2-like genes. Our findings suggest that mouse NK cells, like their human counterparts, use multiple mechanisms to survey class I expression on target cells.
Reducing errors made by emergency physicians in interpreting radiographs: longitudinal study
Authors: J. A Espinosa
Journal: BMJ (2000)

<h3>Abstract</h3> <b>Objectives:</b> To reduce errors made in the interpretation of radiographs in an emergency department. <b>Design:</b> Longitudinal study. <b>Setting:</b> Hospital emergency department. <b>Interventions:</b> All staff reviewed all clinically significant discrepancies at monthly meetings. A file of clinically significant errors was created; the file was used for teaching. Later a team redesigned the process. A system was developed for interpreting radiographs that would be followed regardless of the day of the week or time of day. All standard radiographs were brought directly to the emergency physician for immediate interpretation. Radiologists reviewed the films within 12 hours as a quality control measure, and if a significant misinterpretation was found patients were asked to return. <b>Main outcome measures:</b> Reduction in number of clinically significant errors (such as missed fractures or foreign bodies) on radiographs read in the emergency department. Data on the error rate for radiologists and the effect of the recall procedure were not available so reliability modelling was used to assess the effect of these on overall safety. <b>Results:</b> After the initial improvements the rate of false negative errors fell from 3% (95% confidence interval 2.8% to 3.2%) to 1.2% (1.03% to 1.37%). After the processes were redesigned it fell further to 0.3% (0.26% to 0.34%). Reliability modelling showed that the number of potential adverse effects per 1000 cases fell from 19 before the improvements to 3 afterwards and unmitigated adverse effects fell from 2.2/1000 before to 0.16/1000 afterwards, assuming 95% success in calling patients back. <b>Conclusion:</b> Systems of radiograph interpretation that optimise the skills of all clinicians involved and contain reliable processes for mitigating errors can reduce error rates substantially.
The Increasing Prevalence of Atrial Fibrillation among Hemodialysis Patients
Authors: Wolfgang C. Winkelmayer, Amanda R. Patrick, Jun Liu, M. Alan Brookhart, Soko Setoguchi
Journal: Journal of the American Society of Nephrology (2011)

A half million Americans have ESRD, which puts them at high risk for cardiovascular disease and poor outcomes. Little is known about the epidemiology of atrial fibrillation among patients with ESRD. We analyzed data from annual cohorts (1992 to 2006) of prevalent hemodialysis patients from the United States Renal Data System. In each cohort, we searched 1 year of medical claims for relevant diagnosis codes to determine the prevalence of atrial fibrillation. Among 2.5 million patient observations, 7.7% had atrial fibrillation, with the prevalence increasing 3-fold from 3.5% (1992) to 10.7% (2006). The number of affected patients increased from 3620 to 23,893 (6.6-fold) during this period. Older age, male gender, and several comorbid conditions were associated with increased risk for atrial fibrillation. Compared with otherwise similar Caucasians, the prevalence of atrial fibrillation rates was substantially lower for blacks, Asians, and Native Americans. One-year mortality was twice as high among hemodialysis patients with atrial fibrillation compared with those without (39% versus 19%), and this increased risk was constant during the 15 years of the study. In conclusion, the prevalence of diagnosed atrial fibrillation among patients receiving hemodialysis in the United States is increasing, varies by race, and remains associated with substantially increased mortality. Identifying potentially modifiable risk factors for incident atrial fibrillation requires further investigation.
Challenging competency based training
Authors: J. Boddington
Journal: BMJ (2014)

I applaud Jonathan Glass’s timely critique of competency based training.1 This fashion in medical education constitutes part of the wider “industrialisation” of medicine: a phenomenon that reduces the complex psychosocial roles of doctors to discrete production line components.2 The selective focus on the measurable, which is inherent in this world view, devalues and marginalises the higher order skills that are essential to becoming a wise, humane, empathic practitioner. …