tbuckley/cabot-search huggingface dataset:
The Permeability Transition Pore Complex: A Target for Apoptosis Regulation by Caspases and Bcl-2–related Proteins
Authors: Isabel Marzo, Catherine Brenner, Naoufal Zamzami, Santos A. Susin, Gisela Beutner, Dieter Brdiczka, René Rémy, Zhi-Hua Xie, John C. Reed, Guido Kroemer
Journal: The Journal of Experimental Medicine (1998)

Early in programmed cell death (apoptosis), mitochondrial membrane permeability increases. This is at least in part due to opening of the permeability transition (PT) pore, a multiprotein complex built up at the contact site between the inner and the outer mitochondrial membranes. The PT pore has been previously implicated in clinically relevant massive cell death induced by toxins, anoxia, reactive oxygen species, and calcium overload. Here we show that PT pore complexes reconstituted in liposomes exhibit a functional behavior comparable with that of the natural PT pore present in intact mitochondria. The PT pore complex is regulated by thiol-reactive agents, calcium, cyclophilin D ligands (cyclosporin A and a nonimmunosuppressive cyclosporin A derivative), ligands of the adenine nucleotide translocator, apoptosis-related endoproteases (caspases), and Bcl-2–like proteins. Although calcium, prooxidants, and several recombinant caspases (caspases 1, 2, 3, 4, and 6) enhance the permeability of PT pore-containing liposomes, recombinant Bcl-2 or Bcl-XL augment the resistance of the reconstituted PT pore complex to pore opening. Mutated Bcl-2 proteins that have lost their cytoprotective potential also lose their PT modulatory capacity. In conclusion, the PT pore complex may constitute a crossroad of apoptosis regulation by caspases and members of the Bcl-2 family.
Screening athletes for cardiovascular disease in Africa: a challenging experience
Authors: Christian Schmied, Fernando M Di Paolo, A Yacine Zerguini, Jiri Dvorak, Antonio Pelliccia
Journal: British Journal of Sports Medicine (2013)

Aims Preparticipation cardiovascular (CV) screening has been advocated as an efficient strategy to reduce sudden cardiac death in Caucasian athletes. At present, uncertainty remains if such strategy is feasible and efficient in native African athletes. To this scope, we performed a CV screening in an African setting. Methods 210 male Gabonian football players were examined with history, physical examination, ECG and echocardiography. Results On history, 19 players (9%) referred atypical chest discomfort/oppression. Familial sudden death was referred by 36 (17%). No anomalies were detected at physical examination. ECG showed large proportions of ‘training-related’ abnormalities, that is, ST-segment elevation in precordial leads in 150 (71.4%), and isolated increase in R/S-wave voltage in 116 (55.2%). A substantial subset (12.4%) showed ‘training-unrelated’ abnormalities, that is, inverted T-waves in 10 (4.8%), left atrial enlargement in 8 (4%), deep Q-waves in 3 (1.4%). On echocardiography, one athlete meet criteria for hypertrophic cardiomyopathy (HCM); none showed evidence for arrhythmogenic right ventricular cardiomyopathy (ARVC) or dilated cardiomyopathy (DCM). Other abnormalities included mitral valve prolapse in three, atrial septal defect in two and pulmonary hypertension in one. Conclusions About 12% of native African athletes showed ECG abnormalities unrelated to training and requiring additional testing and periodical follow-up. Structural abnormalities were found, however, in a minority (5%), including HCM in one, but no ARVC or DCM. In conclusion, this study demonstrates that preparticipation CV screening is efficient to identify (or raise suspicion) for CV abnormalities in native African athletes, but challenging for conclusive identification of cardiac diseases in the difficult scenario of a developing African country.
Non-alcoholic fatty liver disease: what's new under the microscope?
Authors: E. M. Brunt
Journal: Gut (2011)

Pathologist9s observations have remained central to the evolution of the field of non-alcoholic fatty liver disease, even with the advent of increasingly effective non-invasive markers of advanced fibrosis. As the field matures, the role of pathology has also shifted from being largely descriptive to being confirmatory and diagnostic, as well as providing semi-quantitative evaluation of specific findings, particularly in therapeutic interventional trials. Some newly appreciated histopathological findings will be discussed in this review.
Role of prostaglandin E in the biphasic fever response to endotoxin
Authors: RC Skarnes, SK Brown, SS Hull, JA McCracken
Journal: The Journal of Experimental Medicine (1981)

Biphasic fevers were induced in sheep with intravascular infusions or injections of 4-10 μg (80-200 ng/kg) of endotoxin, whereas monophasic fevers were obtained with doses of 1-2/μg (20-40 ng/kg). A marked increase in arterial blood pressure invariably accompanied the onset of fever; the latency of responses to the higher and lower doses of endotoxins averaged 26 min and 42 min, respectively. Prostaglandin (PG) assays of plasma from the carotid artery and jugular vein during fever episodes revealed a surge of PGE and PGF coincident with the pressor response and the first phase of fever, but PG were not detected in plasma samples taken throughout the second phase of fever. PG measurements of arterial and venous plasma collected at a distal site (hind limb) showed a similar surge of PGE and PGF in association with the early fever response, indicating that intravascular PG synthesis and release represents a generalized systemic response to circulating endotoxin. Carotid arterial infusions of PGE(2) produced immediate monophasic fevers and pressor responses, whereas PGD(2) infusions produced an immediate pressor effect but no fever. Infusions of PGF(2α) or prostacyclin, however, evoked neither fever nor pressor effects. Intracarotid infusions of leukocyte pyrogen (LP) caused monophasic fevers with latent periods of 15-20 min but pressor responses were not seen and neither PGE nor PGF were detected in plasma samples from the carotid artery or jugular vein before or during fever. Indomethacin, a potent inhibitor of arachidonic acid metabolism, blocked fever responses to endotoxin and to LP. These findings implicate PGE as the mediator of the early phase of endotoxin fever and imply a role for another pyrogenic metabolite ofarachidonic acid in the mediation of the second phase of fever, i.e., the phase associated with circulating LP. It is possible that both pyrogenic metabolites are generated within the vascular compartment, reaching thermoregulatory centers of the brain by transfer across the blood-brain interface.
Effective cancer therapy with the alpha-particle emitter [211At]astatine in a mouse model of genetically modified sodium/iodide symporter-expressing tumors.
Authors: Thorsten Petrich, Leticia Quintanilla-Martinez, Zekiye Korkmaz, Elenore Samson, Hans J√ºrgen Helmeke, Geerd J√ºrgen Meyer, Wolfram H Knapp, Eyck P√∂tter
Journal: Clinical Cancer Research (2006)

Abstract PURPOSE: The sodium/iodide symporter (NIS) gene is currently explored in several trials to eradicate experimental cancer with radiodine ((131)I) by its beta-emission. We recently characterized NIS-specific cellular uptake of an alternative halide, radioastatine ((211)At), which emits high-energy alpha-particles. The aim of this study was to investigate in vivo effects of the high linear energy transfer (LET) emitter (211)At on tumor growth and outcome in nude mice. EXPERIMENTAL DESIGN: We administered radioastatide in a fractionated therapy scheme to NMRI nude mice harboring rapidly growing solid tumors established from a papillary thyroid carcinoma cell line genetically modified to express NIS (K1-NIS). Animals were observed over 1 year. Tumor growth, body weight, blood counts, survival, and side effects were measured compared with control groups without therapy and/or lack of NIS expression. RESULTS: Within 3 months, radioastatide caused complete primary tumor eradication in all cases of K1-NIS tumor-bearing nude mice (n = 25) with no tumor recurrence during 1 year follow-up. Survival rates of the K1-NIS/(211)At group were 96% after 6 months and 60% after 1 year, in contrast to those of control groups (maximum survival 40 days). CONCLUSION: Our study indicates that (211)At represents a promising substrate for NIS-mediated therapy of various cancers either with endogenous or gene transfer-mediated NIS expression.
Prevention and early detection of prostate cancer
Authors: Jack Cuzick, Mangesh A Thorat, Gerald Andriole, Otis W Brawley, Powel H Brown, Zoran Culig, Rosalind A Eeles, Leslie G Ford, Freddie C Hamdy, Lars Holmberg, Dragan Ilic, Timothy J Key, Carlo La Vecchia, Hans Lilja, Michael Marberger, Frank L Meyskens, Lori M Minasian, Chris Parker, Howard L Parnes, Sven Perner, Harry Rittenhouse, Jack Schalken, Hans-Peter Schmid, Bernd J Schmitz-Dräger, Fritz H Schröder, Arnulf Stenzl, Bertrand Tombal, Timothy J Wilt, Alicja Wolk
Journal: The Lancet Oncology (2014)
Muscle strength, symptom intensity, and exercise capacity in patients with cardiorespiratory disorders.
Authors: A L Hamilton, K J Killian, E Summers, N L Jones
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

The contribution of muscle strength to symptom intensity and work capacity was examined in normal individuals and patients with cardiorespiratory disorders. Respiratory muscle strengths (maximal inspiratory and expiratory pressures) and peripheral muscle strengths (leg extension, leg flexion, seated bench press, and seated row) were measured in 4,617 subjects referred for clinical exercise testing. Subjects then rated the intensity of leg effort, discomfort with breathing (dyspnea), and chest pain (Borg scale) during an incremental exercise task (100 kpm/min each minute) to capacity on a cycle ergometer. Subjects were classified into groups on the basis of pulmonary function, drug therapy for cardiac disorders, and the presence of chest pain during exercise with electrocardiographic changes indicative of myocardial ischemia. Respiratory and peripheral muscle strengths, normalized for differences in age, sex, and height, were significantly reduced in patients with cardiorespiratory disorders compared with normal individuals. Muscle strength was a significant contributor to symptom intensity and work capacity in both health and disease; a two-fold increase in muscle strength was associated with a 25 to 30% decrease in the intensity of both leg effort and dyspnea and a 1.4- to 1.6-fold increase in work capacity. These results emphasize the need for an integrative approach in the assessment and therapeutic management of exercise intolerance, which considers the contribution of muscle weakness to excessive symptoms and reduced work capacity, in addition to the contribution of ventilatory, gas exchange, and circulatory impairments.
Improving Relations Between Attorneys and Physicians
Authors: Peter D. Jacobson
Journal: JAMA (2005)

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
Independent Regulation of Cardiac Kv4.3 Potassium Channel Expression by Angiotensin II and Phenylephrine
Authors: Ting-Ting Zhang, Koichi Takimoto, Alexandre F. R. Stewart, Chongxue Zhu, Edwin S. Levitan
Journal: Circulation Research (2001)

Abstract —Hypertrophied cardiac myocytes exhibit prolonged action potentials and decreased transient outward potassium current ( I to ). Because Kv4.3 is a major contributor to I to , we studied regulation of its expression in neonatal rat cardiac myocytes in response to the known stimulators of cardiac myocyte hypertrophy, angiotensin II (Ang II) and phenylephrine (PE). RNase protection assays and immunoblots revealed that Ang II and PE each downregulate Kv4.3 mRNA and protein. However, although PE induces a faster and more extensive hypertrophic response than Ang II, the PE effect on Kv4.3 mRNA develops slowly and is sustained, whereas Ang II rapidly and transiently decreases Kv4.3 mRNA expression. Turnover measurements revealed that Kv4.3 mRNA is very stable, with a half-life &gt;20 hours. This suggests that Ang II must destabilize the channel mRNA. In contrast, PE does not affect the rate of Kv4.3 mRNA degradation. To test for transcriptional regulation, the 5′ flanking region of the rat Kv4.3 gene was cloned, and Kv4.3 promoter-reporter constructs were expressed in cardiac myocytes. Whereas Ang II was found to have no effect on transcription, PE inhibits Kv4.3 promoter activity. Pharmacological experiments also indicate that PE and Ang II act independently to downregulate Kv4.3 gene expression. Thus, regulation of Kv4.3 gene expression is not a simple secondary response to hypertrophy. Rather, Ang II and PE use different mechanisms to decrease Kv4.3 channel expression in neonatal rat cardiac myocytes.
How does evidence based guidance influence determinations of medical negligence?
Authors: Brian Hurwitz
Journal: BMJ (2004)

> “Any doctor not fulfilling the standards and quality of care in the appropriate treatment that are set out in these Clinical Guidelines, will have this taken into account if, for any reason, consideration of their performance in this clinical area is undertaken.” Department of Health, 1999.1 

Evidence based guidance arguably offers the most trustworthy advice available to clinicians concerning medical management. Their authoritative status may explain why clinical guidelines are sometimes prefaced with vague warnings that link guideline compliance with accountability. But how authoritative can guidelines actually be, and does evidence based guidance entirely supplant clinical discretion?

The legal status of evidence based guidance is examined, including whether guidelines from the National Institute for Clinical Excellence (NICE) should be understood to carry special importance in helping courts to decide whether or not allegations of negligence should be upheld.

Evidence is a generic notion of great importance to many practices and enquiries. Cardinal to spying, journalism, historical and scientific research, and the practice of medicine, semantically the term bundles together two approaches to supporting belief, perception, and understanding. Whether evidence refers to marks or indications conspicuous to an observer, to reasoning and judgment about such indications, or to analysis of data arising from experiments, evidence leads on to and supports hypotheses and conclusions, however provisional and conditional.

Evidence—and the more recently minted compound term “evidence based”—refers to reliable observational, inferential, or experimental information forming part of the grounds for upholding or rejecting claims or beliefs. Evidence based medicine (EBM) has not developed a new concept of evidence2; its major contribution lies in the emphasis it places on a hierarchy of evidential reliability, in which conclusions related to evidence from controlled experiments are accorded greater credibility than conclusions grounded in other sorts of evidence. Since studies underpinning most medical …
Erratum to: The RNA editing enzyme APOBEC1 induces somatic mutations and a compatible mutational signature is present in esophageal adenocarcinomas
Authors: Giulia Saraconi, Francesco Severi, Cesare Sala, Giorgio Mattiuz, Silvestro G Conticello
Journal: Genome biology (2014)

The AID/APOBECs are deaminases that act on cytosines in a diverse set of pathways and some of them have been linked to the onset of genetic alterations in cancer. Among them, APOBEC1 is the only family member to physiologically target RNA, as the catalytic subunit in the Apolipoprotein B mRNA editing complex. APOBEC1 has been linked to cancer development in mice but its oncogenic mechanisms are not yet well understood.We analyze whether expression of APOBEC1 induces a mutator phenotype in vertebrate cells, likely through direct targeting of genomic DNA. We show its ability to increase the inactivation of a stably inserted reporter gene in a chicken cell line that lacks any other AID/APOBEC proteins, and to increase the number of imatinib-resistant clones in a human cellular model for chronic myeloid leukemia through induction of mutations in the BCR-ABL1 fusion gene. Moreover, we find the presence of an AID/APOBEC mutational signature in esophageal adenocarcinomas, a type of tumor where APOBEC1 is expressed, that mimics the one preferred by APOBEC1 in vitro.Our findings suggest that the ability of APOBEC1 to trigger genetic alterations represents a major layer in its oncogenic potential. Such APOBEC1-induced mutator phenotypes could play a role in the onset of esophageal adenocarcinomas. APOBEC1 could be involved in cancer promotion at the very early stages of carcinogenesis, as it is highly expressed in Barrett's esophagus, a condition often associated with esophageal adenocarcinoma.
Serum Proteomics in Cancer Diagnosis and Management
Authors: Kevin P. Rosenblatt, Peter Bryant-Greenwood, J. Keith Killian, Arpita Mehta, David Geho, Virginia Espina, Emanuel F. Petricoin, Lance A. Liotta
Journal: Annual Review of Medicine (2004)

Mass spectrometry-based diagnostics has the potential to revolutionize molecular medicine. Using modern mass-spectrometer technologies, clinical tests can be developed that are practical, robust, accurate, and inexpensive. Serum proteomic pattern profiling couples mass spectrometry with adaptive artificial-intelligence-based bioinformatics, which can now be employed to detect pathological states reflected in the serum proteome. With this approach, rapid and cost-effective tests with exquisite clinical sensitivity and specificity are emerging. These tools may dramatically change how disease is detected, monitored, and managed.
Management of stage 1 endometrial carcinoma
Authors: M. P M Burger
Journal: BMJ (2001)

Endometrial adenocarcinoma mainly affects postmenopausal women. The mainstay of treatment is hysterectomy with bilateral salpingo-oophorectomy. Most women are diagnosed with stage1 disease, where the tumour is limited to the body of the uterus. Within this stage the differentiation grade and depth of myometrial invasion are among the most important predictors for the presence of regional (pelvic and para-aortic) lymph node metastases and recurrence. 1 2

In the absence of mature results from randomised trials, debate continues on the merits of pelvic and para-aortic lymphadenectomy and postoperative radiotherapy.

The practice of lymphadenectomy varies considerably.3 Several opinion leaders, mainly from the United States, state that every women with endometrial carcinoma should undergo complete lymphadenectomy. Some gynaecologists who as a rule do complete lymphadenectomies restrict themselves to selective node sampling in certain subgroups of women. One subgroup comprises patients who are less suited to complete lymphadenectomy because of age, obesity, or frailty from complicating medical problems—and up to 70% of patients with clinically early stage uterine cancer …
HISTORICAL LANDMARKS IN RESEARCH ON SCHIZOPHRENIA IN THE UNITED STATES
Authors: W. K. MCKNIGHT
Journal: American Journal of Psychiatry (1958)

In an effort to highlight the type and extent of research in schizophrenia in the United States during the past 190 years various references have been described according to certain categories of investigation. While no single review of all the studies which comprise the literature to date is intended, it is believed that from a historical standpoint the present contribution may be of interest and use. The research projects reported all contain bibliographies which in themselves are additionally representative of many studies of importance and of the scope of the subject under consideration.
Uptake and Release of Cholesterol by Rabbit Atheromatous Lesions
Authors: H. A. I. Newman, D. B. Zilversmit
Journal: Circulation Research (1966)

Rabbits were fed 1 g of cholesterol per day for 92 days. At the end of this period all animals were transferred to Purina rabbit chow for 63 days at which time half of the animals were fed cholesterol again and half were continued on Purina chow. After either two or three weeks, flux of cholesterol into aorta was measured with C 14 -cholesterol. The flux of cholesterol into the aortas with similar degrees of atheromatosis varied directly with the plasma cholesterol concentrations. Rabbits were injected with serum containing C 14 -cholesterol in the free form only. Esterification of C 14 -cholesterol entering the aorta was minimal. Apparently esterified aortic cholesterol is derived by direct transfer from plasma. Influx and release of cholesterol were investigated in vitro under different conditions of incubation. Boiling of the aorta or the addition of cyanide and fluoride did not stop influx of cholesterol. The release of cholesterol from boiled aortic halves was, for free cholesterol 25% of the amount of the C 14 in control halves and, for esterified cholesterol, 3% of the control.
Results of a Multicenter Randomized Controlled Trial of the Clinical Effectiveness of Schema Therapy for Personality Disorders
Authors: Lotte L.M. Bamelis, Silvia M.A.A. Evers, Philip Spinhoven, Arnoud Arntz
Journal: American Journal of Psychiatry (2013)

Schema therapy, an integrative psychotherapy that emphasizes processing negative experiences and using the therapeutic relationships as a way to fulfill unmet needs, was superior to treatment as usual and clarification-oriented psychotherapy in patients with personality disorders, adding to the growing evidence for this combination therapy.