tbuckley/cabot-search huggingface dataset:
The US Food and Drug Administration Cardiorenal Advisory Panel and the Drug Approval Process
Authors: Dan M. Roden, Robert Temple
Journal: Circulation (2005)

N ew chemical entities developed by the pharmaceutical industry as potentially useful drugs undergo extensive preclinical evaluation followed by clinical trials to evaluate efficacy and safety in human subjects.In the United States, the Food and Drug Administration (FDA) is charged with evaluating requests from pharmaceutical sponsors for approval to market new drugs or to expand indications for marketed drugs.Some of these decisions are relatively straightforward.Thus, a new drug that shows clear efficacy and little actual or theoretical risk for serious adverse effects and that represents a significant addition to the therapeutic armamentarium does not present a major problem for FDA regulators.Conversely, approval will not be granted for a new drug the efficacy of which cannot be demonstrated, a drug with serious adverse effects that are not shared by alternative treatments, and a drug that does not add importantly to available treatment in at least some patients.In many cases, however, efficacy may not be so clear-cut, risks may be (or may appear to be) more than minimal, and the pharmaceutical sponsor and the FDA may differ in their evaluation of each of these issues.In such cases, the FDA through its Center for Drug Evaluation and Research (CDER) has since 1972 been able to call on panels of experts to provide advice.For cardiovascular drugs, this advice is offered by the Cardiovascular and Renal Drugs Advisory Committee (CRAC).The goal of this article is to summarize how the deliberations of this committee have affected not only individual new drug submissions but also more generally the way in which new drugs are developed and evaluated.Advisory committees do not actually "decide" whether drugs should be approved; rather, they provide advice to the FDA, where the final decisions with regard to drug approval rest.The FDA is not obliged to accept recommendations made by its advisory panels.The topics addressed by the CRAC during the past 7 years are listed in the Table .In some cases, the FDA presents to the CRAC relatively noncontroversial issues, both for the information of CRAC members and to determine whether the committee agrees with the FDA that the issues are indeed straightforward.Often, advice is sought when issues are not clear, and the FDA has occasionally focused the discussion on aspects of the submission that posed a problem rather than on the whole submission.
18-HEPE, an n-3 fatty acid metabolite released by macrophages, prevents pressure overload–induced maladaptive cardiac remodeling
Authors: Jin Endo, Motoaki Sano, Yosuke Isobe, Keiichi Fukuda, Jing X. Kang, Hiroyuki Arai, Makoto Arita
Journal: The Journal of Experimental Medicine (2014)

N-3 polyunsaturated fatty acids (PUFAs) have potential cardiovascular benefit, although the mechanisms underlying this effect remain poorly understood. Fat-1 transgenic mice expressing Caenorhabditis elegans n-3 fatty acid desaturase, which is capable of producing n-3 PUFAs from n-6 PUFAs, exhibited resistance to pressure overload–induced inflammation and fibrosis, as well as reduced cardiac function. Lipidomic analysis revealed selective enrichment of eicosapentaenoic acid (EPA) in fat-1 transgenic bone marrow (BM) cells and EPA-metabolite 18-hydroxyeicosapentaenoic acid (18-HEPE) in fat-1 transgenic macrophages. BM transplantation experiments revealed that fat-1 transgenic BM cells, but not fat-1 transgenic cardiac cells, contributed to the antiremodeling effect and that the 18-HEPE–rich milieu in the fat-1 transgenic heart was generated by BM-derived cells, most likely macrophages. 18-HEPE inhibited macrophage-mediated proinflammatory activation of cardiac fibroblasts in culture, and in vivo administration of 18-HEPE reproduced the fat-1 mice phenotype, including resistance to pressure overload–induced maladaptive cardiac remodeling.
Treatment of herpesvirus associated primary effusion lymphoma with intracavity cidofovir
Authors: M Luppi, R Trovato, P Barozzi, D Vallisa, G Rossi, A Re, L Ravazzini, L Potenza, G Riva, M Morselli, G Longo, L Cavanna, R Roncaglia, G Torelli
Journal: Leukemia (2005)
A novel mutation of the erythroid-specific ?-aminolevulinate synthase gene in a patient with non-inherited pyridoxine-responsive sideroblastic anemia
Authors: Hideo Harigae, Kazumichi Furuyama, Kazuko Kudo, Norio Hayashi, Masayuki Yamamoto, Shigeru Sassa, Takeshi Sasaki
Journal: American Journal of Hematology (1999)

A novel missense mutation, G663A, in exon 5 of the erythroid-specific δ-aminolevulinate synthase gene (ALAS2) was identified in a Japanese male with pyridoxine-responsive sideroblastic anemia. Activity of the mutant δ-aminolevulinate synthase protein expressed in vitro was 15.1% compared with the normal control, but was increased up to 34.5% by the addition of pyridoxal 5′-phosphate, consistent with the clinical response of the patient to pyridoxine treatment. The same mutation was also detected in genomic DNA from the oral mucosal membrane of the patient; however, it was not detected in other family members. These findings suggest that this G663A mutation is responsible for sideroblastic anemia in the proband, and may be an index mutation in this pedigree. Am. J. Hematol. 62:112–114, 1999. © 1999 Wiley-Liss, Inc.
Lithium-induced nephrogenic diabetes insipidus: in vivo and in vitro studies
Authors: Irwin Singer, Donald Rotenberg, Jules B. Puschett
Journal: Journal of Clinical Investigation (1972)

The physiological basis for the polyuria and polydipsia occurring in some manic-depressive patients treated with lithium salts was studied in vivo and in vitro. Three lithium-treated polyuric patients, in whom other causes of a concentrating defect were excluded, had abnormal urinary concentrating abilities after a standard water depreviation test. Two of these patients failed to respond to exogenous vasopressin (ADH) and one had a subnormal response. The abilities of these patients to excrete solute-free water (C(H2O)) was comparable to normal subjects during steady-state water diuresis, suggesting no gross abnormalities in sodium transport. However, each of these patients demonstrated abnormally low capacities to reabsorb solute-free water (T(C) (H2O)) under hydropenic conditions after administration of hypertonic saline and vasopressin. These in vivo findings demonstrate at least a nephrogenic basis for the diabetes insipidus syndrome manifested by these three patients. The defect in water transport was further characterized in toad urinary bladders in vitro. Short-circuit current (I) and water flow (W) were studied under basal, ADH-stimulated, and cyclic adenosine 3',5'-monophosphate (c-AMP)-stimulated conditions. Increasing mucosal [Li(+)] progressively inhibited basal I, and both I and W induced by ADH. Significant inhibition of basal and ADH-induced I was observed at mucosal [Li(+)] < 1.1 mEq/liter, and of ADH-induced W at mucosal [Li(+)] = 11 mEq/liter. On the other hand, at these lithium concentrations, neither c-AMP-stimulated W nor I was inhibited. Increasing serosal [Li(+)] produced significant inhibition of basal I only at [Li(+)] at least 50-fold greater than at the mucosal (urinary) surface. These in vitro studies confirm that mucosal lithium inhibits the action of ADH, but not c-AMP. Hence, lithium appears to be a significant inhibitor of ADH-stimulated water flow, probably acts from the urinary surface, and appears to exert its effect at a site biochemically proximal to c-AMP action.
A revised NOTCH1 mutation frequency still impacts survival while the allele burden predicts early progression in chronic lymphocytic leukemia
Authors: P Sportoletti, S Baldoni, B Del Papa, P Aureli, E Dorillo, L Ruggeri, S Plebani, V Amico, A Di Tommaso, E Rosati, P Marconi, M Di Ianni, F Falzetti
Journal: Leukemia (2013)
THE SERUM DIAGNOSIS OF PREGNANCY
Authors: CHARLES C. W. JUDD
Journal: JAMA (1913)

Though normal pregnancy is usually diagnosed with fair exactitude by the patient herself, the early diagnosis of the condition is often open to many fallacies by the trained obstetrician, while even as the months pass by some cases remain obscure. The desirability of an early diagnosis in all cases, and the imperative necessity in some is only too obvious. To these and other ends many signs and symptoms have been described relative to the probability of pregnancy, but until late in gestation no pathognomonic evidence has been adduced by these means. To satisfy this deficiency, of late years serologic methods have been applied. The antitrypsin test has been utilized in this connection by Franz and Jarish,<sup>1</sup>E. Rosenthal<sup>2</sup>Jochmann<sup>3</sup>and others with the fairly uniform result that in pregnancy, beginning practically at the time of implantation, the antitryptic index is materially increased. This test is, however, far
Author's reply to Messe and colleagues
Authors: J. Lenzer
Journal: BMJ (2013)

Messe, his co-authors, and I agree on one thing: opinion is not science.1 2 However, Messe and colleagues misled BMJ readers by suggesting that I used polls to prove whether a treatment is good or not. On the contrary, I cited the polls because the guideline sponsors need to explain why they failed to include even one sceptic on the guideline writing panel when it seems that most emergency doctors, including prominent and respected experts, do not believe the science supports …
The Treatment of Acute Myocardial Ischemia: An Integrated Medical/Surgical Approach
Authors: I. Martin Grais
Journal: JAMA (1979)

This book brings together information authored by colleagues at Peter Pent Brigham Hospital and Harvard Medical School. In chapter 1 the editor states, "This monograph should again be considered as a state-of-the-art report regarding diagnosis, treatment and pathophysiology of myocardial ischemia; it represents an effort to collate and correlate the essential material of this field into one book by one medical/surgical unit." The authors do present many important concepts emphasizing the critical integration between medical and surgical disciplines in patient care. However, the reader will find the chapter organization and content less integrated. The book has eight chapters. Chapter 2 provides a good review of the pathology of myocardial ischemia. Chapter 3 on pathophysiology and (the timely) modification of infarct size discusses biochemistry with a scarcity of pathophysiology to prepare the reader for the next chapter on emergency revascularization techniques or the following one on the management of unstable angina.
Central insulin action in energy and glucose homeostasis
Authors: L. Plum
Journal: Journal of Clinical Investigation (2006)

Insulin has pleiotropic biological effects in virtually all tissues. However, the relevance of insulin signaling in peripheral tissues has been studied far more extensively than its role in the brain. An evolving body of evidence indicates that in the brain, insulin is involved in multiple regulatory mechanisms including neuronal survival, learning, and memory, as well as in regulation of energy homeostasis and reproductive endocrinology. Here we review insulin’s role as a central homeostatic signal with regard to energy and glucose homeostasis and discuss the mechanisms by which insulin communicates information about the body’s energy status to the brain. Particular emphasis is placed on the controversial current debate about the similarities and differences between hypothalamic insulin and leptin signaling at the molecular level.
Cardiac Vasculitis in Henoch-Schönlein Purpura
Authors: Abdulfatah Osman, Charles J. McCreery
Journal: Circulation (2000)

A 63-year-old man presented with a 1-week history of bloody diarrhea, abdominal pain, nausea, arthralgias, and fatigue.Physical examination revealed an acutely ill patient with a distended, tender abdomen.A purpuric skin rash was noted on the extremities and trunk (Figure 1).Laboratory tests showed leukocytosis, proteinuria, and elevated creatinine.A skin biopsy revealed small-vessel neutrophilic vasculitis.Immunofluorescence was positive for multifocal IgA deposits along the walls of dermal vessels (Figure 2).High-dose prednisone and azathioprine were started.On hospital day 4, the patient developed slow junctional rhythm with hypotension requiring transvenous ventricular pacing.Serum cardiac troponin T was elevated.Sinus rhythm never recovered, and ectopic low atrial
A genetically detoxified derivative of heat-labile Escherichia coli enterotoxin induces neutralizing antibodies against the A subunit.
Authors: M Pizza, M R Fontana, M M Giuliani, M Domenighini, C Magagnoli, V Giannelli, D Nucci, W Hol, R Manetti, R Rappuoli
Journal: The Journal of Experimental Medicine (1994)

Escherichia coli enterotoxin (LT) and the homologous cholera toxin (CT) are A-B toxins that cause travelers' diarrhea and cholera, respectively. So far, experimental live and killed vaccines against these diseases have been developed using only the nontoxic B portion of these toxins. The enzymatically active A subunit has not been used because it is responsible for the toxicity and it is reported to induce a negligible titer of toxin neutralizing antibodies. We used site-directed mutagenesis to inactivate the ADP-ribosyltransferase activity of the A subunit and obtained nontoxic derivatives of LT that elicited a good titer of neutralizing antibodies recognizing the A subunit. These LT mutants and equivalent mutants of CT may be used to improve live and killed vaccines against cholera and enterotoxinogenic E. coli.
Evidence for the role of ammonia in the intracerebral transfer and metabolism of tryptophan
Authors: Patrick Grippon, Monique le Poncin Lafitte, Michèle Boschat, Shwen Wang, Grazyna Faure, Dominique Dutertre, Pierre Opolon
Journal: Hepatology (1986)

After portacaval shunt in the rat, the transport of tryptophan and other neutral amino acids across the blood-brain barrier is enhanced. To determine the role of NH3 in the intracerebral transfer of tryptophan and serotonin metabolism, solutions containing either saline or NH3 or tryptophan or NH3 + tryptophan together were infused, respectively, into the internal carotid artery of rats in order to achieve blood levels similar to those observed after liver ischemia. After tryptophan infusion, a significant increase in the hypothalamic levels of tryptophan and 5-hydroxyindoleacetic acid was observed. A similar increment was found after NH3 infusion. NH3 + tryptophan infusion induced a significant increment in hypothalamic tryptophan and 5-hydroxyindoleacetic acid levels which were 2-fold greater than after tryptophan infusion. There was no significant change in 5-hydroxytryptamine levels in any of these experiments. Glutamine levels increased significantly after NH3 infusion. When tryptophan and NH3 were infused simultaneously, a significant reduction in glutamine levels occurred. These results cannot be explained by any modification of cerebral blood flow nor of the cerebral intercellular pH. Our data suggest that NH3 enhances the transfer of tryptophan across the blood-brain barrier and thus stimulates serotonin metabolism. The mechanism by which tryptophan transfer across the blood-brain barrier is facilitated is unknown. The reduction in glutamine levels in the hypothalamus when NH3 and tryptophan are infused together may be explained either by an inhibition of synthesis or by an intercellular influx of neutral amino acids and an efflux of glutamine as suggested by James et al.
The Empiricists Strike Back
Authors: Robert M. Golub
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 Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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) 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
Evidence for increased lipid peroxidation in the non-ischaemic portion of the heart with coronary occlusion
Authors: K. HERBACZYNSKA-CEDRO, W. GORDON-MAJSZAK
Journal: Cardiovascular Research (1989)

Lipid peroxidation products, malondialdehyde (MDA), conjugated double bonds (CDB), and fluorescent end products (RF), were measured in porcine left ventricular myocardium. Myocardial samples were taken 15–20 min after left anterior descending coronary artery (LAD) ligation from ischaemic and non-ischaemic regions. Products of lipid peroxidation were also measured in the left ventricular myocardium of sham operated pigs. Non-ischaemic regions of the hearts with LAD occlusion showed a significantly higher content of lipid peroxidation products than intact hearts of sham operated pigs. The results suggest that enhancement of lipid peroxidation reflecting increased free radical generation may contribute to myocardial damage in the non-ischaemic, apparently "healthy" portion of the heart with acute coronary occlusion.
Letter: Sexual disorders in the male.
Authors: H A Mason
Journal: BMJ (1975)

Vomiting with Clonidine Withdrawal SIR,-We would like to report a case of persistent vomiting in a patient after rapid withdrawal of clonidine (Catapres).The dangers of paroxysmal hypertension asso- ciated with raised catecholamine levels following rapid withdrawal of clonidine are well documented.'We have found no previous report of persistent vomiting occur- ring in this situation.
The Sex Ratio
Authors: P. Stocks
Journal: BMJ (1937)

A double blind, placebo controlled trial examined the effects of folinic acid on the efficacy and toxicity of methotrexate in 27 patients with rheumatoid arthritis. Clinical and laboratory indices of disease activity worsened significantly in the 13 patients treated with folinic acid after four weeks of treatment, but not in the 14 patients treated with placebo. Exacerbation of rheumatoid arthritis led to withdrawal of the test drug in seven of the patients treated with folinic acid but in none of those treated with placebo. It is concluded that excerbation of rheumatoid arthritis is likely when folinic acid is given shortly after the weekly dose of methotrexate.
Fractional laser-mediated photodynamic therapy of high-risk basal cell carcinomas - a randomized clinical trial
Authors: C.S. Haak, K. Togsverd-Bo, D. Thaysen-Petersen, H.C. Wulf, U. Paasch, R.R. Anderson, M. Haedersdal
Journal: British Journal of Dermatology (2014)

Photodynamic therapy (PDT) is approved for selected nodular basal cell carcinomas (nBCC) but efficacy is reduced for large and thick tumours. Ablative fractional lasers (AFXL) facilitate uptake of methyl aminolaevulinate (MAL) and may thus improve PDT outcome.To evaluate efficacy and safety of AFXL-mediated PDT (AFXL-PDT) compared with conventional PDT of high-risk nBCC.Patients with histologically verified facial nBCC (n = 32) defined as high-risk tumours were included; diameter > 15 mm, tumours located in high-risk zones, or on severely sun-damaged skin. Tumours were debulked and patients randomized to either AFXL-PDT (n = 16) or PDT (n = 16). Fractional CO2 laser treatment was applied at 5% density and 1000 μm (80 mJ) ablation depth. MAL was applied under occlusion for 3 h and illuminated with a 633-nm light-emitting diode source, 37 J cm(-2) . Clinical assessments were performed at 3, 6, 9 and 12 months and biopsies were taken at 12 months.Clinical cure rates at 3 months were 100% (16 of 16 AFXL-PDT) and 88% (14 of 16 PDT, P = 0·484). Recurrences tended to occur later and in lower numbers after AFXL-PDT at 6, 9 and 12 months (6%, 19%, 19%) than PDT (25%, 38%, 44%) (P = 0·114). Histology at 12 months documented equal tumour clearance after AFXL-PDT (63%, 10 of 16) and PDT (56%, 9 of 16). Cosmetic outcomes were highly satisfactory after both treatments (P > 0·090).Long-term efficacy was similar after PDT and AFXL-PDT with a trend for a favourable short-term cure rate after AFXL-PDT. AFXL-PDT needs further refinement for nBCC and at present is not recommended over PDT.
Asbestos-related bilateral diffuse pleural thickening: natural history of radiographic and lung function abnormalities.
Authors: D H Yates, K Browne, P N Stidolph, E Neville
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

Sixty-four subjects with asbestos-related diffuse pleural thickening attending the London Medical Boarding Centre for Respiratory Diseases (formerly, the Central Pneumoconiosis Panel) were studied to investigate symptomatology, lung function, and radiographic change over an average period of 8 to 9 yr. Chest pain was a common symptom, occurring in over half of the subjects. Approximately one-third of the subjects had a history of pleurisy or pleural effusion. Full long function, available in all cases, showed a highly significant decrement (p < 0.001) compared with predicted values in all variables except gas transfer coefficient (Kco) at initial presentation, consistent with a restrictive ventilatory defect. Longitudinal lung function, available over a mean period of 8.9 yr in 36 subjects, showed a significant decrement above that predicted in FEV1 and FVC only (p < 0.05). Decreases in other parameters were observed, although statistical significance was not achieved. Radiographic score increased with time but there was no correlation between change in lung function and increasing radiographic score, probably reflecting the initial severity of the disease in subjects studied. These observations confirm an initial decrement in lung function in diffuse pleural thickening which is followed by comparatively little change over time.
Raised serum urate concentration as risk factor for premature mortality in middle aged men.
Authors: H Takkunen, A Reunanen, A Aromaa, P Knekt
Journal: BMJ (1984)

and foot was not increased in such patients.3What we should therefore be looking for is a trophic factor that selectively stimulates connective tissue overgrowth and induces a periosteal reaction, not a generalised vaso- dilator such as vasointestinal polypeptide, which increases skin blood flow.As for gynaecomastia, it has long been known that this may occur in patients with hypertro- phic pulmonary osteoarthropathy secondary to infective lung disease.Nearly 100 years ago Bamberger noted swelling of the breast in three men with this disease and likened this to the mammary enlargement that may occur in young men at puberty.4Our observation, however, that oestrogen metabolism may be altered irrespective of the presence of gynae- comastia requires reinvestigation in the light of modern endocrinological techniques.5It would therefore be of interest if Dr Braude and his colleagues included endocrinological assessment, with dynamic testing as required, in their proposed prospective study of cystic fibrosis.This would provide objective infor- mation of chemical changes in hypertrophic pulmonary osteoarthropathy rather than yet another unsubstantiated theory of its pathogenesis.
Rates of functional bowel disorders among Israeli Bedouins in rural areas compared with those who moved to permanent towns
Authors: Ami D. Sperber, Michael Friger, Pesach Shvartzman, Muhammed Abu-Rabia, Rasmieh Abu-Rabia, Muhammed Abu-Rashid, Khalil Albedour, Othaman Alkranawi, Alex Eisenberg, Alex Kazanoviz, Liyobov Mazingar, Alex Fich
Journal: Clinical Gastroenterology and Hepatology (2005)