tbuckley/cabot-search huggingface dataset:
Correlation of rare coding variants in the gene encoding human glucokinase regulatory protein with phenotypic, cellular, and kinetic outcomes
Authors: Matthew G. Rees, David Ng, Sarah Ruppert, Clesson Turner, Nicola L. Beer, Amy J. Swift, Mario A. Morken, Jennifer E. Below, Ilana Blech, James C. Mullikin, Mark I. McCarthy, Leslie G. Biesecker, Anna L. Gloyn, Francis S. Collins
Journal: Journal of Clinical Investigation (2011)

Defining the genetic contribution of rare variants to common diseases is a major basic and clinical science challenge that could offer new insights into disease etiology and provide potential for directed gene- and pathway-based prevention and treatment. Common and rare nonsynonymous variants in the GCKR gene are associated with alterations in metabolic traits, most notably serum triglyceride levels. GCKR encodes glucokinase regulatory protein (GKRP), a predominantly nuclear protein that inhibits hepatic glucokinase (GCK) and plays a critical role in glucose homeostasis. The mode of action of rare GCKR variants remains unexplored. We identified 19 nonsynonymous GCKR variants among 800 individuals from the ClinSeq medical sequencing project. Excluding the previously described common missense variant p.Pro446Leu, all variants were rare in the cohort. Accordingly, we functionally characterized all variants to evaluate their potential phenotypic effects. Defects were observed for the majority of the rare variants after assessment of cellular localization, ability to interact with GCK, and kinetic activity of the encoded proteins. Comparing the individuals with functional rare variants to those without such variants showed associations with lipid phenotypes. Our findings suggest that, while nonsynonymous GCKR variants, excluding p.Pro446Leu, are rare in individuals of mixed European descent, the majority do affect protein function. In sum, this study utilizes computational, cell biological, and biochemical methods to present a model for interpreting the clinical significance of rare genetic variants in common disease.
The Journey Across the Health Care (Dis)Continuum for Vulnerable Patients
Authors: Grace Jenq, Mary E. Tinetti
Journal: JAMA (2012)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Drugs in Cosmetics
Authors: Stephen Rothman
Journal: JAMA (1961)

Cosmetic materials and procedures are aimed at beautifying appearance and promoting attractiveness. This is satisfactorily achieved by nonmedical measures as devised by modern cosmetic chemists. Incorporation of pharmacologically active ingredients into cosmetics which are sold across the counter is objectionable because no absorbable drug should be given without control of dosage. Drugs in very low concentrations may be "safe" but then they are usually biologically ineffective. None of the recommended drugs, vitamins, and hormones in permissible low concentrations have ever been shown to improve appearance. Antibiotics are effective in combating axillary odor, but their indiscriminate use is fraught with danger. Improvement of appearance of diseased skin is a medical task requiring diagnostic procedures and individualized treatment. Therefore, proprietary topical preparations with fixed concentrations of drugs are of little value.
An Open-Label, Multicenter, Phase I/II Study of Single-Agent AT-101 in Men with Castrate-Resistant Prostate Cancer
Authors: Glenn Liu, W. Kevin Kelly, George Wilding, Lance Leopold, Kimberli Brill, Bradley Somer
Journal: Clinical Cancer Research (2009)

Abstract Purpose: AT-101 binds and inhibits the antiapoptotic function of Bcl-2, Bcl-xL, Mcl-1, and Bcl-w and is a potent stimulator of proapoptotic proteins. In this multi-institution phase I/II trial, we evaluated the safety and efficacy of single-agent AT-101, in men with chemotherapy naïve, castrate-resistant prostate cancer (CRPC). Experimental Design: Patients with progressive CRPC were to be treated with escalating doses of AT-101 on a continuous daily basis until the maximally tolerated dose was achieved. At the recommended phase 2 dose, an additional 21 patients were planned to assess for preliminary evidence of efficacy. Results: Twenty-three patients were enrolled. The phase I starting dose was 30 mg/day on a continuous basis; however, ongoing trials with AT-101 showed increased gastrointestinal toxicity with this daily schedule when given for repetitive cycles. As a result, the phase II starting dose was chosen to be 30 mg/day for 21 of 28 days. The most frequent observed adverse events (any grade) were diarrhea (43.5%), fatigue (34.8%), nausea (21.7%), anorexia (21.7%), and small intestinal obstruction (21.7%). Due to the high incidence of grade 3 small intestinal obstruction (n = 5; 21.7%), a reduction in dose to 20 mg/day for 21 of 28 days was mandated for all patients. Two patients had a confirmed ≥50% posttherapy prostate-specific antigen decline. No objective responses (Response Evaluation Criteria in Solid Tumors) were observed. Conclusion: AT-101 administered at 20 mg/day for 21 of 28 days was well-tolerated. Evidence of single-agent clinical activity was observed with prostate-specific antigen declines in some patients. Further investigation of AT-101 in prostate cancer is warranted and trials combining AT-101 with androgen deprivation, as well as with docetaxel chemotherapy are ongoing.
Gonococcal Perihepatitis in a Male
Authors: Michael W. Kimball, Steven Knee
Journal: New England Journal of Medicine (1970)

THE clinical manifestations of gonococcal infection may take many forms, the most commonly recognized being the urogenital. Extragenital spread or localization can result in gonococcemia with cutaneous manifestations, meningitis, endocarditis, pericarditis, arthritis, tenosynovitis, perihepatitis, parotitis and proctitis.1 2 3 Perihepatitis was first described by Stajano4 in 1919. Curtis,5 in 1930, and Fitz-Hugh, in 19346 and 1936,7 reported on this syndrome, which now bears their names. Reports by Stanley8 (1946) and Vickers and Maloney (1964)9 further defined and described the syndrome as it pertains to females. The purpose of this paper is to report what is considered to be the first recognized case . . .
Experience with a Hemagglutination-lnhibition Test for Carcinoembryonic Antigen.
Authors: I. R. Collmann
Journal: Annals of Internal Medicine (1972)

Meeting Abstracts1 May 1972Experience with a Hemagglutination-lnhibition Test for Carcinoembryonic Antigen.I. R. Collmann, M.D., R. D. Lange, M.D., F.A.C.P., A. I. Chernoff, M.D., F.A.C.P., T. A. Jordan, M. T.I. R. Collmann, M.D.Search for more papers by this author, R. D. Lange, M.D., F.A.C.P.Search for more papers by this author, A. I. Chernoff, M.D., F.A.C.P.Search for more papers by this author, T. A. Jordan, M. T.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-76-5-876_3 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptThis study was undertaken to determine the utilization of the hemagglutination inhibition test for the presence of carcinoembryonic antigen in the sera of patients with entodermally derived malignancies and other nonneoplastic conditions. Antisera to malignant colonic tissue and normal colon was prepared by immunization of rabbits over a 4-week period. The results so far are from approximately 400 patients, and all 46 patients who had entodermally derived neoplasia had positive titers for carcinoembryonic antigen. Nonneoplastic conditions such as cirrhosis of the liver, chronic ulcerative colitis, and regional enteritis in this series had about a 45% incidence of positive titers. Out... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Knoxville, Tenn. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 May 1972Volume 76, Issue 5Page: 876-876KeywordsCarcinoembryonic antigenCirrhosisColonEnteritisHemagglutinationLiverRabbitsUlcerative colitis Issue Published: 1 May 1972 PDF DownloadLoading ...
Pitfalls of Converting Practice Guidelines Into Quality Measures
Authors: Louise C. Walter, Natalie P. Davidowitz, Paul A. Heineken, Kenneth E. Covinsky
Journal: JAMA (2004)

The Department of Veterans Affairs (VA) manages the largest health care system in the United States, and the Institute of Medicine has recommended that many practices of VA quality measurement be applied to the US health care system as a whole. The VA measures quality of care at all of its sites by assessing adherence rates to performance measures, which generally are derived from evidence-based practice guidelines. Higher adherence rates are used as evidence of better quality of care. However, there are problems with converting practice guidelines, intended to offer guidance to clinicians, into performance measures that are meant to identify poor-quality care. We suggest a more balanced perspective on the use of performance measures to define quality by delineating conceptual problems with the conversion of practice guidelines into quality measures. Focusing on colorectal cancer screening, we use a case study at 1 VA facility to illustrate pitfalls that can cause adherence rates to guideline-based performance measures to be poor indicators of the quality of cancer screening. Pitfalls identified included (1) not properly considering illness severity of the sample population audited for adherence to screening, (2) not distinguishing screening from diagnostic procedures when setting achievable target screening rates, and (3) not accounting for patient preferences or clinician judgment when scoring performance measures. For many patients with severe comorbid illnesses or strong preferences against screening, the risks of colorectal cancer screening outweigh the benefits, and the decision to not screen may reflect good quality of care. Performance measures require more thoughtful specification and interpretation to avoid defining high testing rates as good quality of care regardless of who received the test, why it was performed, or whether the patient wanted it.
TREATMENT OF ENCEPHALITIS
Authors: ROSS MOORE
Journal: JAMA (1923)

For more than two years I have been treating certain patients showing symptom groups referable to the basal ganglions by injecting intraspinally their own blood serum, either untreated or inactivated. To summarize a paper I<sup>1</sup>read a year ago: Expectant treatment of epidemic encephalitis is frequently unsatisfactory. At the same time, no other treatment has been found to be more available and useful. The blood serum of patients suffering from encephalitis has been used intraspinally in this series. The cases in which it has been used have been for the most part of very long standing and, therefore, there is likely to have been definite destruction of tissue. In five out of seven cases, temporary but definite improvement has followed these injections. These results may be due either to the irritating effect of the injections, or to therapeutic substances in the blood serum not present in the cerebrospinal fluid.
American Society of Clinical Oncology 2013 Top Five List in Oncology
Authors: Lowell E. Schnipper, Gary H. Lyman, Douglas W. Blayney, J. Russell Hoverman, Derek Raghavan, Dana S. Wollins, Richard L. Schilsky
Journal: Journal of Clinical Oncology (2013)

2013 Top Five List in Oncology are provided solely for informational purposes and are not intended as medical or legal advice or as a substitute for consultation with a medical professional.These items are voluntary and are not meant to replace a
Development of Geriatrics-Oriented Faculty in General Internal Medicine
Authors: Craig D. Rubin, Heather Stieglitz, Belinda Vicioso, Lynne Kirk
Journal: Annals of Internal Medicine (2003)

The need for adequate geriatrics training for the physician workforce has been recognized for decades. However, there are not enough academic geriatricians to provide for the educational needs of trainees, and this situation is not expected to change in the future. General internists are often responsible for teaching medical students and internal medicine residents to care for elderly patients in inpatient and ambulatory settings. These academic general internists could play a pivotal role in providing geriatrics instruction. To characterize what is being done to develop geriatrics-oriented general internal medicine faculty, we identified current practices, best practices, goals and targets, and barriers to achieving those goals and targets. We reviewed the literature on faculty-development programs for general internal medicine faculty, and we held focus groups and structured interviews with general internal medicine unit chiefs and directors of Geriatric Centers of Excellence at 46 medical schools throughout the United States. We found a need for programs to develop geriatrics-oriented academic general internists. Although general internal medicine faculties seem receptive to further geriatrics training, important obstacles exist. These include inadequate time and resources as well as motivational and attitudinal challenges. We discuss potential solutions for overcoming these barriers and the implications of these solutions for stakeholders.
Hypertension and Ischemic Heart Disease in Hiroshima, Japan
Authors: SAM SWITZER
Journal: Circulation (1963)

A random sampling of Hiroshima residents, comprising 1,051 males and 1,872 females, has been studied with respect to the interrelations of hypertension, ischemic heart disease, blood lipid levels, and ionizing irradiation experienced during the atom bombing of 1945. No significant effect of ionizing irradiation upon the cardiovascular system has been detected. No major difference in age-sex specific mean blood pressures between Hiroshima residents and a suitable white American comparison group was found. Dissimilarities noted with other groups compared are considered due to the sum of sampling bias, varying technics, and coincidental environmental factors rather than a true racial difference. Blood pressure levels, stable from puberty through young adulthood, begin to rise early in middle age and continue to rise into old age. As a result, hypertension as clinically defined (140/90), is common in middle-aged and elderly Japanese. In 94.4 per cent of instances, or more, a demonstrable etiology for hypertension could not be found; these are considered to represent essential hypertension. An accelerated course with fulminating vascular deterioration was suspected in only 1 per cent of the hypertensive subjects. As a result, advanced retinopathy and renal failure were rarely seen. Electrocardiographic evidence of left ventricular hypertrophy occurred in 7.2 per cent of the hypertensive Japanese in this study, and was readily correlated with the ambient systolic blood pressure. Evidence of ischemic heart disease and congestive failure is rare and distinctly less common than in American males unselected as to blood pressure levels. In contrast, mortality statistics indicate cerebrovascular disease to be at least as common in Japan as in the U. S. Japanese exhibit low serum cholesterol concentrations by Western standards and elevated levels are predominantly limited to the obese. Both factors appear of importance in the occasional hypertensive Japanese with ischemic heart disease. The therapeutic implication of this observation is briefly discussed.
A rapid method to study heterogeneous gene expression in liver by direct assay of messenger RNA from periportal and perivenous cell lysates
Authors: Juhani Saarinen, Ritva Saarelainen, Kai O. Lindros
Journal: Hepatology (1993)

To study zonation of liver gene expression, we obtained periportal or perivenous rat liver cell lysates virtually devoid of nuclear material by site-directed digitonin infusion in situ. Total RNA was isolated, messenger RNAs were reverse transcribed and complementary DNAs were assayed after polymerase chain reaction–mediated amplification. The zonal distribution of messenger RNAs of alcohol dehydrogenase (little zonation), glutamine synthetase (perivenous) and cytochrome P-450 2E1 (perivenous) messenger RNAs, as analyzed by this technique, were found to be similar to the distribution of corresponding apoproteins. Using appropriate primers or complementary DNAs, zonation of many different messenger RNAs can be determined from the same sample by this simple and rapid method. (HEPATOLOGY 1993;17:466–469.)
Don't rush into testing and treating children
Authors: J. Logue, N. Sattar
Journal: BMJ (2012)

Background/Aim: Combination cancer therapy is currently under investigation. This study examined the effect of cancer combination therapy using the E3 and C1 (E3C1) domains of developmental endothelial locus-1 (Del1) and cisplatin (CDDP) in murine transplanted tumors. Materials and Methods: Mice with transplanted tumors (A431, SCCKN or SCC-4 cells) were injected intraperitoneally with CDDP and injected locally with nonviral plasmid vectors encoding E3C1. Histochemical analysis of the transplanted tumors was then performed to assess the effects on prognosis. Results: The CDDP+E3C1 injected group had reduced tumor growth and longer survival compared to the CDDP injected group. In addition, cell death was observed in the tumor of the CDDP+E3C1 group.. Furthermore, angiogenesis and increased blood vessels were observed together with stromal development. Conclusion: The CDDP+E3C1 treatment resulted in improved survival and poor tumor stromal development in mice with transplanted tumors.
ANTIBODY-INDUCED MOVEMENT OF MEMBRANE COMPONENTS OF <i>LEISHMANIA ENRIETTII </i>
Authors: John J. Doyle, Reza Behin, Jacques Mauel, David S. Rowe
Journal: The Journal of Experimental Medicine (1974)

Incubation in vitro of viable Leishmania enriettii with antibodies from infected or immune guinea pigs and a fluorescein-labeled antiguinea pig Ig conjugate induced aggregation of surface antigens to form a "cap" over the anterior pole of the amastigote and over both the anterior and posterior poles of the promastigote form of the parasite. Cap formation occurred only with optimum quantities of guinea pig antibodies and was inhibited by low temperature and the metabolic inhibitors, sodium azide and iodoacetamide. The aggregated antigens were rapidly lost from the surface of the parasite but reappeared after 3 h of incubation at 23°C. This phenomenon of ligand-induced membrane antigen movement is apparently similar to that described in mammalian cells, and may represent the first stage of the interaction between host antibodies and the surface membrane of protozoal parasites.
Life-Threatening Flecainide Toxicity
Authors: BERNHARD R. WINKELMANN
Journal: Annals of Internal Medicine (1987)

Ventricular tachyarrhythmias and severe bradycardia, flecainide acetate's most serious side effects, occur in patients with chronic heart disease or in healthy persons after frank overdose. Toxic effects appear to correlate closely with drug levels in plasma. The surface electrocardiogram can indicate toxicity by demonstrating this drug's electrophysiologic potency to depress all major cardiac conduction pathways with marked prolongation of the PR and QRS intervals. We report the clinical course of a young, healthy person who developed polymorphous ventricular tachycardia after taking a 3800-mg dose of flecainide acetate. Sinus rhythm was restored without pacing or cardioversion after infusion of a beta-sympathomimetic agent, physostigmine, and a sodium load. The initial flecainide serum levels were five times greater than the usual upper therapeutic level. Electrocardiography showed that the lengthened electrocardiographic time intervals decreased in correlation with falling drug levels. Flecainide-associated life-threatening arrhythmias and available therapeutic interventions are discussed.
Pulmonary Biomarkers Based on Alterations in Protein Expression after Exposure to Arsenic
Authors: R. Clark Lantz, Brandon J. Lynch, Scott Boitano, Gerald S. Poplin, Sally Littau, George Tsaprailis, Jefferey L. Burgess
Journal: Environmental Health Perspectives (2007)

ObjectiveEnvironmental exposure to arsenic results in multiple adverse effects in the lung. Our objective was to identify potential pulmonary protein biomarkers in the lung-lining fluid of mice chronically exposed to low-dose As and to validate these protein changes in human populations exposed to As.MethodsMice were administered 10 or 50 ppb As (sodium arsenite) in their drinking water for 4 weeks. Proteins in the lung-lining fluid were identified using two-dimensional gel electrophoresis (n = 3) or multidimensional protein identification technology (MUDPIT) (n = 2) coupled with mass spectrometry. Lung-induced sputum samples were collected from 57 individuals (tap water As ranged from ~ 5 to 20 ppb). Protein levels in sputum were determined by ELISA, and As species were analyzed in first morning void urine.ResultsProteins in mouse lung-lining fluid whose expression was consistently altered by As included glutathione-S-transferase (GST)-omega-1, contraspin, apolipoprotein A-I and A-IV, enolase-1, peroxiredoxin-6, and receptor for advanced glycation end products (RAGE). Validation of the putative biomarkers was carried out by evaluating As-induced alterations in RAGE in humans. Regression analysis demonstrated a significant negative correlation (p = 0.016) between sputum levels of RAGE and total urinary inorganic As, similar to results seen in our animal model.ConclusionCombinations of proteomic analyses of animal models followed by specific analysis of human samples provide an unbiased determination of important, previously unidentified putative biomarkers that may be related to human disease.
Influence of oxygen radicals generated by xanthine oxidase in the isolated perfused rat heart
Authors: K. YTREHUS, R. MYKLEBUST, O. D MJOS
Journal: Cardiovascular Research (1986)

To investigate the cardiac effects of enzymatically generated oxygen radicals isolated Langendorff rat heart preparations were perfused with hypoxanthine (0.96 mmol-litre−1) plus xanthine oxidase (0.025 U-ml−1). Oxygen radicals produced an immediate increase in coronary flow. After 10 min a pronounced reduction in contractile performance, as well as in concentrations of high energy phosphates, was seen. Electron microscopical examination showed damage with cellular oedema as a prominent finding. These effects were all effectively reversed by the specific enzymes, superoxide dismutase and catalase, proving that they were due to oxygen radicals.