tbuckley/cabot-search huggingface dataset:
SAT0231 Analysis of Monotherapy with BIOLOGICS in Rheumatoid Arthritis in Daily Clinical Practice
Authors: L. Sala, M. Arredondo, I. Llorente, E. Tomero, J.P. Lopez Bote, R. García de Vicuña, I. Gonzalez, J.M. Άlvaro Gracia
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Combination therapy with biologics and synthetic disease-modifying antirheumatic drugs (sDMARD) is the standard treatment in patients with rheumatoid arthritis (RA) in which biologics are indicated. However, this is not always the case in daily clinical practice. The reasons and profile of patients on monotherapy have been poorly explored. <h3>Objectives</h3> To analyze the profile of RA patients treated with biologics in monotherapy and compare it with the standard combination treatment. <h3>Methods</h3> An observational cross-sectional study was conducted. Drug dispensation databases and patient clinical records from a tertiary hospital were reviewed. Patients with a clinical diagnosis of RA on any biologic in 2013 were selected for analysis. Demographic and clinical characteristics (age, gender, disease duration, rheumatoid factor status), reason for monotherapy and combination therapy with sDMARD were studied. Statistical comparison was performed by T-test and Chi-squared test. Disease activity was measured by DAS28 and multivariate analysis was used to evaluate the impact of individual parameters on DAS28. <h3>Results</h3> The analysis included 268 patients with RA treated with biologics. Monotherapy accounted for 11.2% of all patients. Patients on monotherapy showed a tendency without statistical significance to longer disease duration compared with combination therapy [15.8 (12.1) vs 13.6 (8.8); *p&gt;0.05], similar age 62.6 (14.5) vs 62.1 (12.6), gender (female 90.0% vs 82.7%), and positive rheumatoid factor (77.8% vs 73.2%). Monotherapy was more frequent as third or later line of biological therapy (24.1% vs 8%; p&lt;0.05). Among patients on monotherapy, Tocilizumab was the most frequently used agent (30%). Regarding to each individual biologic, monotherapy was more frequent in Tocilizumab (36%), and Abatacept (17.4%) than in anti-TNF (7-10%) patients. Reasons for monotherapy were sDMARD intolerance (60.9%) and contraindications (39.1%), such as lung disease (21.7%), liver disease (8.7%), neutropenia (4.3%), and pregnancy (4.3%). DAS28 was non-significantly greater in monotherapy than in combined therapy (p&gt;0.05). Multivariate analysis showed higher DAS28 for third line or later biologic treatment but not for monotherapy (p=0.004). <h3>Conclusions</h3> Biologic monotherapy in RA is related to third or later line of treatment in clinical practice, being Tocilizumab the most frequently used medication for these patients. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.3315
Dispelling the Myths About Addiction: Strategies to Increase Understanding and Strengthen Research Care of Drug Users in General Practice: a Harm Minimisation Approach
Authors: R. Robertson
Journal: BMJ (1998)

Institute of Medicine

National Academy Press, £32.95, pp 218

ISBN 0 309 06401 5

Ed Berry Beaumont Radcliffe Medical Press, £16.50, pp 187 ISBN 1 85775 236 8

The increasing clinical and academic interest in drug dependency has given rise to a rapidly expanding literature. Topics range from the severely pragmatic clinical approach to the scrutiny of addictive processes at a cellular level. The narrowly clinical perspective of drug problems, with its correspondingly limited range of clinical options, has yielded to a new consensus about the need for treatment and a recognition that drug dependency is a disease, requiring treatments that are based on evidence.

The major themes of Dispelling the Myths about Addiction are that …
Abstract LB-40: Inhibition of anchorage-independent growth of melanoma cell lines using Riluzole in combination with PI3 kinase pathway inhibitors
Authors: James S. Goydos, Negar M. Salehomoum, Steve Rosenberg, Joseph L-K Chan, Yu Wen
Journal: Cancer Research (2010)

Abstract We previously reported that the majority of human melanomas express metabotrophic glutamate receptor 1 (GRM1), a cell surface glutamate receptor. We recently completed a Phase 0 trial of Riluzole, a glutamate release inhibitor, in patients with advanced melanoma and showed a clinical response of 34%. We have also shown that Riluzole, can effectively block invasion and migration of melanoma cells in vitro. In our in vitro studies it was observed that the efficacy of Riluzole treatment on anchorage independent growth was attenuated in melanoma lines harboring activated BRAF/NRAS mutations or a PTEN deletion. We have continued our pre-clinical studies by further examining the effects of Riluzole in combination with inhibitors of specific signaling molecules of the PI3 kinase pathway. Specifically, we tested the AKT inhibitor API-2 and the mTOR inhibitor Rapamycin. These inhibitors were used alone or with Riluzole on C8161 (grm1+, braf/nraswt, ptenwt), HT144(GRM1+, BRAFV600E, PTENdel) SKMEL-2(grm1+, nrasq61r) and UACC930(grm1-,brafv600e, ptendel) melanoma cell lines. When treating the GRM1+ cell lines with the individual agents, there was a moderate reduction in the number of colonies relative to the control. However, the combination of Riluzole with API-2 or Rapamycin had a more robust reduction in colony formation. This inhibition was not observed in the GRM1- UACC930 melanoma line where Riluzole in combination with either API-2 or Rapamycin did not induce a significant decrease in colony formation over single treatment with either agent. In addition to the effect on the number of colonies, the combinational treatments had a significant inhibitory effect on the size of the colonies relative to single agent treatments. The monolayer growth assays also demonstrated increased inhibition of growth with the combinational treatments versus single agent treatments. We conclude that the combination of glutamate signaling blockade combined with inhibition of PI3K signaling with either Rapamycin or API-2 is more effective at inhibiting GRM1 expressing melanoma cell proliferation than treatment with any of the agents alone. Combination therapy with Riluzole and either Rapamycin or API-2 may prove a more effective therapy than Riluzole alone in patients with melanoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-40.
Case 74-1962
Authors: Arnold S. Relman, Benjamin Castleman
Journal: New England Journal of Medicine (1962)

Presentation of Case Third admission. A seventy-three-year-old woman was readmitted to the hospital because of joint pain.Five years previously the patient began to have episodes of generalized arthralgia involving most of the joints of the body. The symptoms began in the back and knees and later involved the hands, shoulders, knees and ankles. The pain became marked, with swelling and limitation of motion. Prednisone was started, the dosage varying according to the severity of the attacks, and gave partial relief. She was never free of joint pain, and the symptoms increased in severity; during the six months before . . .
Partnering with parteras: assessment of learning in a multi-collaborator international training programme for traditional birth attendants in Oaxaca, Mexico
Authors: M Alexandra Friedman, Dana R Gossett, Isabello Saucedo, Shayna Weiner, Mimi W Young, Nicholas Penco, Jessica Evert
Journal: The Lancet Global Health (2016)

Background Since 2013 medical students from Northwestern University (Chicago, IL, USA) have delivered a training programme for traditional birth attendants (parteras) in Oaxaca, Mexico. These training sessions are a collaboration between a US-based non-governmental organisation, Child and Family Health International (CFHI), local health-care workers, and the Mexican Ministry of Health. Barriers such as illiteracy, innumeracy, and non-traditional learning styles complicate the training of traditional birth attendants. Here, we evaluate the effectiveness of a verbally administered assessment to determine the effect of the Northwestern University programme on parteras' self-reported knowledge and skills
Identification of BRCA1 and BRCA2 genetic modifiers.
Authors: JD Weyandt, C Snyder, HT Lynch, E Gillanders, TN Holmes, J Bailey-Wilson, RE Ellsworth
Journal: Cancer Research (2009)

Abstract Abstract #1040 Background: Although mutations in BRCA1 and BRCA2 represent the primary lesions in hereditary breast and ovarian cancer (HBOC) families, these mutations are marked by incomplete penetrance, as 15-20% of carriers never develop either cancer. In addition, the expressivity of these gene mutations varies with manifestation in breast, ovary, or both breast and ovary, suggesting other genes may modify the effects of BRCA1 and BRCA2 mutations.&amp;#x2028; Methods: DNA was isolated from nine large HBOC families with known BRCA1 and BRCA2 mutations. SNP data was generated using the GeneChip Mapping 10K Array (Affymetrix, Santa Clara, CA). The data were checked for deviation from Hardy-Weinberg equilibrium and Mendelian errors. SNPs with low completion rates were not used in the analyses. Two-point parametric linkage analysis was performed under dominant and recessive models using VITESSE and GAS.&amp;#x2028; Results: Genotypes were generated for 301 individuals from nine families and included mutation carriers, and non-carriers with and without cancer. When all families were considered together using a dominant model, LOD scores &amp;gt;3.0 were detected for SNPs on chromosomes 6q25.3 and 18q21.3 and &amp;gt;2.0 for chromosomes 2q24, 5p13 and 5q33. When families were segregated by mutation type, linkage was detected at chromosome 22q12 (LOD =2.65) in BRCA1 families, and at 2q24 (LOD=2.17) in BRCA2 families.&amp;#x2028; Conclusions: Chromosomal regions harboring putative genetic modifiers have been identified that may contribute to pathogenesis in both BRCA1 and BRCA2 families. For example, frequent gain of 2q24 has been detected in BRCA1 carriers with ovarian cancer, loss of 5q in breast tumors from BRCA1 patients, and SNP rs720321 is intragenic to the apoptosis gene BCL2 on chromosome 18q21, expression of which has been associated with BRCA2 tumors. Linkage to chromosome 22q12 was specific to BRCA1 families, of note, the loss of the CHEK2 gene, located on chromosome 22q12, may promote tumor progression in BRCA1 tumors. Further elucidation of the underlying genetic lesion from each of these chromosomal regions may improve the risk assessment and treatment regimens of women with BRCA1 and BRCA2 mutations. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1040.
Delayed Uptake of Tc-99m Ethylene Dicysteine in a Post-Transplant Lymphocele Demonstrated on Dynamic Renal Scintigraphy and SPECT/CT
Authors: Raja Senthil, Anish Bhattacharya, Ashish Sharma, Chidambaram Natarajan Balasubramanian Harisankar, Bhagwant Rai Mittal
Journal: Clinical Nuclear Medicine (2011)

Lymphocele is a well-recognized complication following renal transplant surgery. Dynamic renal scintigraphy is routinely used to evaluate renal transplant dysfunction. Conventionally, early appearance of an extrarenal tracer collection suggests a urinoma and a persistently “cold” collection suggests a lymphocele, hematoma, or abscess. The authors describe a renal transplant recipient in whom dynamic renal scintigraphy followed by SPECT/CT with Tc99m-ethylene dicysteine showed slow tracer accumulation in a perirenal collection, which was subsequently confirmed to be a lymphocele.
BM-25 * PRONEURAL TRANSCRIPTION FACTOR Atoh1 DRIVES LEPTOMENINGEAL METASTASIS OF THE SONIC HEDGEHOG SUBGROUP OF MEDULLOBLASTOMA
Authors: K. Picotte, L. Li, H. Zhao
Journal: Neuro-Oncology (2014)

Medulloblastoma, the most common malignant pediatric brain tumor, arises from the cerebellum and spreads throughout the cerebrospinal fluid to the leptomeninges, covering the brain and spinal cord. Leptomeningeal metastasis, a frequent finding at diagnosis and recurrence, is a significant indicator of poor prognosis. Treatment of affected children includes irradiation of the developing brain and spine, and chemotherapy, which cause debilitating neurological complications. Despite the grave consequences of leptomeningeal metastasis, little is known about the cascade of molecular and cellular events that lead to leptomeningeal metastasis. Atonal Homolog 1 (Atoh1), a proneural transcription factor, is crucial for the initiation and progression of the Sonic Hedgehog (Shh) subgroup of medulloblastoma; Atoh1 expression is also detected in metastatic lesions of this tumor subgroup. To examine the role of Atoh1 in leptomeningeal dissemination, we generated transgenic mouse strains that conditionally express Atoh1 using Cre-loxP technology. These Atoh1 transgenic strains (A1G) were further crossed with the Math1-Cre and Ptch1+/- strains, the latter exhibiting aberrant Shh signaling in the cerebellum. Though ∼25% of Ptch1+/- mice develop non-metastatic medulloblastoma in 6-24 months, all Math1-Cre/A1G/Ptch1+/- mice succumbed to medulloblastoma within 5 months. Histological analysis revealed Pax6+ tumor cells with robust expression of Ki67, while the expression of NeuN was significantly decreased or absent, indicating the Atoh1 transgene promotes MB development in Ptch1+/- mice. More importantly, we observed robust leptomeningeal metastasis in these mice: tumor cells were detected within ventricular regions and leptomeningeal spaces covering the spinal cord in all mice, and more than 50% of animals developed metastasis in brain parenchyma, indicating Atoh1 drives leptomeningeal dissemination of medulloblastoma. Similarly, orthotopically transplanted Shh-driven medullolastoma with Atoh1 overexpression exhibited enhanced migration and invasion. Together, our results demonstrate that Atoh1 plays an important role in medulloblastoma leptomeningeal metastasis and may serve as a therapeutic target in this devastating disease.
Correlations between Antepartum Maternal Metabolism and Intelligence of Offspring
Authors: T Rizzo, B E Metzger, W J Burns, K Burns
Journal: New England Journal of Medicine (1991)

It is not clear to what extent maternal metabolism during pregnancy affects the cognitive and behavioral function of the offspring by altering brain development in utero. To investigate this question, we correlated measures of metabolism in pregnant diabetic and nondiabetic women with the intellectual development of their offspring.The study included 223 pregnant women and their singleton offspring: 89 women had diabetes before pregnancy (pregestational diabetes mellitus), 99 had the onset of diabetes during pregnancy (gestational diabetes mellitus), and 35 had normal carbohydrate metabolism during their pregnancy. We correlated measures of maternal glucose and lipid metabolism (fasting plasma glucose levels, hemoglobin A1c levels, episodes of hypoglycemia, episodes of acetonuria, and plasma beta-hydroxybutyrate and free fatty acid levels) with two measures of intellectual development in the offspring--the mental development index of the Bayley Scales of Infant Development, given at the age of two years, and the Stanford--Binet Intelligence Scale, given at the ages of three, four, and five years and expressed as an average of the three scores.After correction for socioeconomic status, race or ethnic origin, and patient group, the children's mental-development-index scores at the age of two years correlated inversely with the mothers' third-trimester plasma beta-hydroxybutyrate levels (r = -0.21, P less than 0.01); the average Stanford-Binet scores correlated inversely with third-trimester plasma beta-hydroxybutyrate (r = -0.20, P less than 0.02) and free fatty acid (r = -0.27, P less than 0.002) levels. No other correlations were significant. Including various perinatal events (e.g., prematurity and acidemia) in the analyses did not alter the results.Maternal diabetes during pregnancy may affect behavioral and intellectual development in the offspring. The associations between gestational ketonemia in the mother and a lower IQ in the child warrant continued efforts to avoid ketoacidosis and accelerated starvation in all pregnant women.
T and B leukemic cell lines exhibit different requirements for cell death: correlation between caspase activation, DFF40/DFF45 expression, DNA fragmentation and apoptosis in T cell lines but not in Burkitt's lymphoma
Authors: F Luciano, J-E Ricci, M Herrant, C Bertolotto, B Mari, J-L Cousin, P Auberger
Journal: Leukemia (2002)
Abstract B42: Methotrexate inhibits histone deacetylase activity and exhibits anti-tumor activity <i>via</i> acetylation and stabilization of p53
Authors: Ching-Chow Chen
Journal: Cancer Research (2009)

Abstract Methotrexate (MTX) is a dihydrofolate reductase (DHFR) inhibit or that has been widely used as an anti-cancer drug in different kinds of human cancers. Histone deacetylase (HDAC) overexpression is usually found in tumors, which inhibits the expression of tumor suppressor genes. HDAC inhibitors (HDACi) reactivate these tumor suppressor genes and serve as potential anticancer drugs. In the present study, we found that MTX shared structural similarity with HDACi. Molecular modeling analysis provided an evidence for the interaction of MTX with HDAC. In vitro HDAC activity assay demonstrated its inhibition on HDAC activity in various human cancer cells. The global acetylation of histone-H3 was also induced by MTX. Post-translational modification of p53 plays a critical role in regulating its activity and stability. MTX promoted p53 acetylaion at Lys 373/382 and phosphorylation at Ser15 and Ser392, then increasing its stability and transcriptional activity. Stabilized p53 further induced the expression of its downstream gene, p21. MTX induced apoptosis and inhibited cell viability, which was dependent on p53 expression. This study provides the first time that MTX acts as a HDACi. In addition, MTX induces p53 acetylation and stabilization, and mediates p53-dependent apoptosis and growth inhibition in human cancer cells. Citation Information: Cancer Res 2009;69(23 Suppl):B42.
Development of Contraceptives — Obstacles and Opportunities
Authors: Luigi Mastroianni, Peter J. Donaldson, Thomas T. Kane
Journal: New England Journal of Medicine (1990)

On February 14, 1990, the National Research Council's Committee on Contraceptive Development released a report on a two-year study of the process by which contraceptives are developed and approved for use in the United States.* The committee was established on the basis of a request to the Committee on Population of the National Research Council and the Institute of Medicine and received support from the Andrew W. Mellon Foundation. Among the topics considered were the pace at which new products were being brought to the market, the effects of organizational and policy issues on the contraceptive-development process, and ways of . . .
P612 OSTEOPONTIN NEUTRALIZATION ABROGATES THE LIVER PROGENITOR CELL RESPONSE AND FIBROGENIC OUTCOMES IN MICE
Authors: J.D. Coombes, M. Swiderska-Syn, L. Dollé, D.T. Reid, B. Eksteen, L.C. Claridge, M.A. Briones-Orta, S. Shishir, Y.H. Oo, A. Riva, S. Chokshi, S. Papa, Z. Mi, P.C. Kuo, R. Williams, A. Canbay, D.H. Adams, L.A. van Grunsven, A.M. Diehl, S.S. Choi, W.-K. Syn
Journal: Journal of Hepatology (2014)
The ETS1 transcription factor is required for the development and cytokine-induced expansion of ILC2
Authors: Erin C. Zook, Kevin Ramirez, Xiaohuan Guo, Grant van der Voort, Mikael Sigvardsson, Eric C. Svensson, Yang-Xin Fu, Barbara L. Kee
Journal: The Journal of Experimental Medicine (2016)

Group 2 innate lymphoid cells (ILC2s) are a subset of ILCs that play a protective role in the response to helminth infection, but they also contribute to allergic lung inflammation. Here, we report that the deletion of the ETS1 transcription factor in lymphoid cells resulted in a loss of ILC2s in the bone marrow and lymph nodes and that ETS1 promotes the fitness of the common progenitor of all ILCs. ETS1-deficient ILC2 progenitors failed to up-regulate messenger RNA for the E protein transcription factor inhibitor ID2, a critical factor for ILCs, and these cells were unable to expand in cytokine-driven in vitro cultures. In vivo, ETS1 was required for the IL-33–induced accumulation of lung ILC2s and for the production of the T helper type 2 cytokines IL-5 and IL-13. IL-25 also failed to elicit an expansion of inflammatory ILC2s when these cells lacked ETS1. Our data reveal ETS1 as a critical regulator of ILC2 expansion and cytokine production and implicate ETS1 in the regulation of Id2 at the inception of ILC2 development.
Antibiotic-Associated Pseudomembranous Colitis Due to Toxin-Producing Clostridia
Authors: John G. Bartlett, Te Wen Chang, Marc Gurwith, Sherwood L. Gorbach, Andrew B. Onderdonk
Journal: New England Journal of Medicine (1978)

A substance producing cytotoxicity in tissue culture was detected in stool specimens from all of four patients with pseudomembranous colitis due to antibiotics and in one of 54 with antibiotic-associated diarrhea. These stools also caused enterocolitis when injected intracecally into hamsters. On each occasion, cytotoxicity in tissue culture and enterocolitis in hamsters were neutralized by pretreatment with gas-gangrene antitoxin. The toxicity in both tissue cultures and hamsters could be reproduced with broth cultures of clostridia strains isolated from four of the five stools. These results suggest that toxin-producing clostridia are responsible for antibiotic-associated pseudomembranous colitis.
Soundings: Dr A will see you now
Authors: Colin Douglas
Journal: BMJ (2005)

He will see you now. He may not see what you really want him to see, or even what you think he ought to see for himself, but he will see you, and he will almost certainly do his best.

But Dr A will see you through a glass darkly; and just how darkly will depend on the degree of his impairment, which may be anything from a minor blunting of empathy to total emotional colour blindness.

If you are a normal human being, as most patients are, he—and for reasons of biological determinism Dr A is most likely to be a he—may strike you as brusque, lacking in warmth, or just a bit odd. If you happen to be the complaining type you might find yourself asking how people like that ever get into medical school.

Actually it's not difficult. Passing the necessary exams at the required level is easy if you have the focus, appetite for detail, and indifference to the distractions of late teenage life that may all come free along with the problems of the disorder as outlined above. And through medical school and into later medical life the same combination of deficits and possibly compensating strengths may take you far—though perhaps not always with patients.

And maybe not with colleagues either, but Dr Asperger might well be the last to notice little things like that. And there are many areas within medicine where a capacity for the solitary pursuit of ever more specialist knowledge through a relentless accumulation of minutiae that might bore others witless may—together with the sometimes liberating influence of having little or no value for, or even awareness of, the feelings of others—lead to a truly brilliant career.

But that is exceptional. Dr A is more likely to be found as an odd, insensitive clinician stuck in the middle order or—perhaps less unhappily—tucked away in an impenetrable laboratory, hunched over a friendly microscope or an unthreatening computer, content in his fashion and perhaps even doing some good.

Should anything be done about all this? In fact quite a lot's been done already: perhaps a 40% reduction over 40 years in the numbers of Asperger's folk entering the profession. Really. It's just one of the many blessings already flowing from the inexorable rise of women in medicine.