tbuckley/cabot-search huggingface dataset:
Novel genome-editing-based approaches to treat motor neuron diseases: Promises and challenges
Authors: Annarita Miccio, Panagiotis Antoniou, Sorana Ciura, Edor Kabashi
Journal: Molecular Therapy (2021)

Motor neuron diseases are untreatable with common pharmacological approaches. Spinal muscular atrophy (SMA) is caused by SMN1 gene mutations leading to lowered SMN expression. Symptoms are alleviated in infants with a higher copy number of the SMN2 gene, which, however, displays a splicing defect resulting in low SMN levels. Amyotrophic lateral sclerosis (ALS) is caused by a number of mutations, with C9orf72 repeat expansions the most common genetic cause and SOD1 gain-of-function mutations the first genetic cause identified for this disease. Genetic therapies based on oligonucleotides that enhance SMN2 splicing and SMN production or lower SOD1 expression have shown promise in initial clinical trials for individuals with SMA and ALS harboring SOD1 mutations, respectively. Gene addition/silencing approaches using adeno-associated viruses (AAVs) are also currently under clinical investigation in trials for SMA and ALS. Here we provide a brief overview of these efforts and their advantages and challenges. We also review genome editing approaches aimed at correcting the disease-causing mutations or modulating the expression of genetic modifiers, e.g., by repairing SOD1 mutations or the SMN2 splicing defect or deleting C9orf72 expanded repeats. These studies have shown promising results to approach therapeutic trials that should significantly lower the progression of these deadly disorders. Motor neuron diseases are untreatable with common pharmacological approaches. Spinal muscular atrophy (SMA) is caused by SMN1 gene mutations leading to lowered SMN expression. Symptoms are alleviated in infants with a higher copy number of the SMN2 gene, which, however, displays a splicing defect resulting in low SMN levels. Amyotrophic lateral sclerosis (ALS) is caused by a number of mutations, with C9orf72 repeat expansions the most common genetic cause and SOD1 gain-of-function mutations the first genetic cause identified for this disease. Genetic therapies based on oligonucleotides that enhance SMN2 splicing and SMN production or lower SOD1 expression have shown promise in initial clinical trials for individuals with SMA and ALS harboring SOD1 mutations, respectively. Gene addition/silencing approaches using adeno-associated viruses (AAVs) are also currently under clinical investigation in trials for SMA and ALS. Here we provide a brief overview of these efforts and their advantages and challenges. We also review genome editing approaches aimed at correcting the disease-causing mutations or modulating the expression of genetic modifiers, e.g., by repairing SOD1 mutations or the SMN2 splicing defect or deleting C9orf72 expanded repeats. These studies have shown promising results to approach therapeutic trials that should significantly lower the progression of these deadly disorders.
Extracellular Vesicles From Epicardial Fat Facilitate Atrial Fibrillation
Authors: Olga Shaihov-Teper, Eilon Ram, Nimer Ballan, Rafael Y. Brzezinski, Nili Naftali-Shani, Rula Masoud, Tamar Ziv, Nir Lewis, Yeshai Schary, La-Paz Levin-Kotler, David Volvovitch, Elchanan M. Zuroff, Sergei Amunts, Neta Regev-Rudzki, Leonid Sternik, Ehud Raanani, Lior Gepstein, Jonathan Leor
Journal: Circulation (2021)

Background: The role of epicardial fat (eFat)-derived extracellular vesicles (EVs) in the pathogenesis of atrial fibrillation (AF) has never been studied. We tested the hypothesis that eFat-EVs transmit proinflammatory, profibrotic, and proarrhythmic molecules that induce atrial myopathy and fibrillation. Methods: We collected eFat specimens from patients with (n=32) and without AF (n=30) during elective heart surgery. eFat samples were grown as organ cultures, and the culture medium was collected every 2 days. We then isolated and purified eFat-EVs from the culture medium, and analyzed the EV number, size, morphology, specific markers, encapsulated cytokines, proteome, and microRNAs. Next, we evaluated the biological effects of unpurified and purified EVs on atrial mesenchymal stromal cells and endothelial cells in vitro. To establish a causal association between eFat-EVs and vulnerability to AF, we modeled AF in vitro using induced pluripotent stem cell–derived cardiomyocytes. Results: Microscopic examination revealed excessive inflammation, fibrosis, and apoptosis in fresh and cultured eFat tissues. Cultured explants from patients with AF secreted more EVs and harbored greater amounts of proinflammatory and profibrotic cytokines, and profibrotic microRNA, as well, than those without AF. The proteomic analysis confirmed the distinctive profile of purified eFat-EVs from patients with AF. In vitro, purified and unpurified eFat-EVs from patients with AF had a greater effect on proliferation and migration of human mesenchymal stromal cells and endothelial cells, compared with eFat-EVs from patients without AF. Last, whereas eFat-EVs from patients with and without AF shortened the action potential duration of induced pluripotent stem cell–derived cardiomyocytes, only eFat-EVs from patients with AF induced sustained reentry (rotor) in induced pluripotent stem cell–derived cardiomyocytes. Conclusions: We show, for the first time, a distinctive proinflammatory, profibrotic, and proarrhythmic signature of eFat-EVs from patients with AF. Our findings uncover another pathway by which eFat promotes the development of atrial myopathy and fibrillation.
Mechanism of cardiac defibrillation in open-chest dogs with unipolar DC-coupled simultaneous activation and shock potential recordings.
Authors: F XWitkowski, P APenkoske, RPlonsey
Journal: Circulation (1990)

The automatic implantable cardioverter-defibrillator has been shown to dramatically improve survival. The future refinement of these devices requires a clear understanding of their mechanism of action. We performed the following study to test two hypotheses: 1) When defibrillation is successful, fibrillating activity must be annihilated in a critical mass of both ventricles; and 2) when defibrillation is unsuccessful, at least one area of the ventricular mass has been left fibrillating. Unipolar Ag/AgCl sintered electrodes were directly coupled from triangular arrays at 40 epicardial locations (total, 120 recording sites) that covered both right and left ventricular surfaces and were designed to measure the voltage gradient generated by the shock at each triangular array as well as the underlying myocardial electrical activity before and immediately after the shock. An algorithm was developed and tested that reliably scored whether a postshock activation was a continuation of the immediately previous fibr...
Mood Disorders and Outcomes of COVID-19 Hospitalizations
Authors: Victor M. Castro, Faith M. Gunning, Thomas H. McCoy, Roy H. Perlis
Journal: American Journal of Psychiatry (2021)

The authors sought to characterize the association between prior mood disorder diagnosis and hospital outcomes among individuals admitted with COVID-19 to six Eastern Massachusetts hospitals. A retrospective cohort was drawn from the electronic health records of two academic medical centers and four community hospitals between February 15 and May 24, 2020. Associations between history of mood disorder and in-hospital mortality and hospital discharge home were examined using regression models among any hospitalized patients with positive tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Among 2,988 admitted individuals, 717 (24.0%) had a prior mood disorder diagnosis. In Cox regression models adjusted for age, sex, and hospital site, presence of a mood disorder prior to admission was associated with greater in-hospital mortality risk beyond hospital day 12 (crude hazard ratio=2.156, 95% CI=1.540, 3.020; fully adjusted hazard ratio=1.540, 95% CI=1.054, 2.250). A mood disorder diagnosis was also associated with greater likelihood of discharge to a skilled nursing facility or other rehabilitation facility rather than home (crude odds ratio=2.035, 95% CI=1.661, 2.493; fully adjusted odds ratio=1.504, 95% CI=1.132, 1.999). Hospitalized individuals with a history of mood disorder may be at risk for greater COVID-19 morbidity and mortality and are at increased risk of need for postacute care. Further studies should investigate the mechanism by which these disorders may confer elevated risk.
145P UpSwinG: Real-world, non-interventional cohort study on TKI activity in patients (pts) with EGFR mutation-positive (EGFRm+) NSCLC with uncommon mutations
Authors: S. Miura, T-C. Hsia, J-Y. Hung, H.A. Jung, J-Y. Shih, T-Y. Yang, C-K. Park, S.H. Lee, T. Okamoto, H.K. Ahn, Y.C. Lee, Y. Sato, S.S. Lee, C. Mascaux, H. Daoud, A. Märten, S. Popat
Journal: Journal of Thoracic Oncology (2021)
Locum GP who lied about advice to mother whose baby later died is suspended for 12 months
Authors: Clare Dyer
Journal: BMJ (2021)

A GP has been suspended from the UK medical register for 12 months after a tribunal found that he failed to recognise the seriousness of symptoms described to him by an 11 month old baby’s mother in a telephone consultation, then lied under oath at a coroner’s inquest into the baby’s subsequent death.

Anthony Ojo was a locum working for an out-of-hours service when the mother called just before midnight on 20 May 2017, reporting symptoms that included vomiting, diarrhoea, fever in the past 12 hours, and cold, clammy skin.

Ojo did not follow relevant guidance on assessing the risks posed to the child in light of his age, history, and symptoms, said chairwoman of the medical practitioners tribunal Louise Sweet. “These …
Does desmopressin acetate reduce blood loss after surgery in patients on cardiopulmonary bypass
Authors: ERocha, RLlorens, J APáramo, RArcas, BCuesta, A MTrenor
Journal: Circulation (1988)

It has been suggested that desmopressin acetate (DDAVP) administration reduces blood loss after cardiac surgery. We have investigated the effect of DDAVP administration in a double-blind, randomized, prospective trial including 100 patients placed on cardiopulmonary bypass during surgery. Fifty patients received 0.3 micrograms/kg DDAVP and 50 patients received a placebo administered in a 50 ml saline solution over 15 min when cardiopulmonary bypass had been concluded. Results showed no significant differences either in total blood loss per square meter (458 +/- 206 ml in the DDAVP group vs 536 +/- 304 ml in the placebo group) or in necessity for red cell transfusions (1642 +/- 705 ml in the DDAVP group vs 1574 +/- 645 ml in the placebo group) in the first 72 hr after surgery. Only intraoperative blood loss per square meter was significantly lower (p less than .02) in the DDAVP group (131 +/- 106 ml) as compared with the placebo group (193 +/- 137 ml). The prolongation of bleeding time and the decrease of ...
Long-term versus intrabeat history of ejection as determinants of canine ventricular end-systolic pressure.
Authors: SSugiura, W CHunter, KSagawa
Journal: Circulation Research (1989)

We studied the effect of ejection on end-systolic pressure in isolated heart preparations. Ejecting beats were compared with isovolumic beats having the same volume as at end systole. While holding end-systolic volume constant, various stroke volumes, including negative stroke volumes (volume injected during systole), were imposed using a predetermined volume command. After switching contraction mode between ejecting and isovolumic, we measured the immediate and steady changes in end-systolic pressure. In the first isovolumic beat after switching from steady-state ejecting beats, the change in end-systolic pressure was variable, depending on the stroke volume. The end-systolic pressure of the ejecting beat exceeded that of the isovolumic beat on average by up to 18 mm Hg with small stroke volume, but the ejecting end-systolic pressure became lower than isovolumic with either large stroke volume (stroke volume/end-systolic volume less than 0.96) or with negative stroke volume. During the transient phase fo...
Prognostic Value of the Insertion/Deletion Polymorphism of the <i>ACE</i> Gene in Type 2 Diabetic Subjects: Results From the Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR), Diabete de type 2, Nephropathie et Genetique (DIAB2NEPHROGENE), and Survie, Diabete de type 2 et Genetique (SURDIAGENE) Studies
Authors: Daniel P.K. Ng
Journal: Diabetes Care (2008)

Hadjadj et al. (1) have recently reported on the potential prognostic value of the ACE insertion/deletion (ACE I/D) polymorphism in their study of Caucasians with type 2 diabetes. The ACE II genotype contributed to the development of end-stage renal failure (ESRF) in their main cohort analyses of patients from the Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR) study ( P = 0.034) (1). This finding was somewhat surprising because the II genotype, which has been linked to lower serum ACE levels, has previously been associated with protection against diabetic nephropathy (2,3). Particularly, a meta-analysis …
Effects of acetylsalicylic acid on the ductus arteriosus and circulation in fetal lambs in utero.
Authors: M AHeymann, A MRudolph
Journal: Circulation Research (1976)

Intra-arterial and intravenous catheters were inserted in six fetal lambs at 125-130 days of gestation. On the following day, fetal arterial pressures and blood gases were monitored and fetal cardiac output and its distribution were measured by injection of radionuclide-labeled microspheres 15 mum in diameter. Acetylsalicylic acid, 55-90 mg/kg of estimated fetal weight, then was administered into the fetal stomach. Fetal pulmonary arterial pressure rose significantly after an average of 58 minutes, increasing the pressure difference between the pulmonary artery and the aorta from 2 +/- 0.3 (SEM) mm Hg during control to 11.2 +/- 1.6 mm Hg. Resistance across the ductus arteriosus rose from 4.2 +/- 0.5 (SEM) to 27.4 +/- 4.01 units, and flow fell from 495 +/- 44 (SEM) to 409 +/- 20 ml/minute. The proportion of combined ventricular output distributed to the placenta, adrenals, heart, and lungs increased, whereas the proportion of combined ventricular output distributed to the brain, liver, intestine, kidneys, ...
Treatment of sepsis
Authors: D. Matamis, K. Koletsos, A. Grammenos, I. Kioumis, K. Sobolos, D. Rigos, J. J. Lanoret, J. F. Dhainaut, C. J. Fisher, S. M. Opal, J. Zimmerman, P. Nightingale, S. Stephens, R. L. Schein, E. A. Panacek, J. L. Vincent, G. E. Foulke, E. L. Warren, C. Garrard, G. Park, M. W. Bodmer, J. Cohen, G. van der Linden, J. C. Sadoff, F. Pochard, A. Boulot, G. Capellier, E. Racadot, H. Tissot, P. Balvay, A. Cordier, J. Wijdenes, P. Herve, F. Barale, J. J. Lanore, J. Briegel, H. Forst, W. Kellermann, M. Haller, M. Bittl, F. -P. Lenhart, K. Peler, F. Fourrier, C. Chopin, J. J. Huart, I. Runge, C. Caron, H. Mehdaoui, J. Goudemand, A. Rime, C. Socolovski
Journal: Intensive Care Medicine (1992)
A comparison of the electrophysiologic effects of intravenous and oral amiodarone in the same patient.
Authors: H JWellens, PBrugada, HAbdollah, W RDassen
Journal: Circulation (1984)

In 12 patients (nine with Wolff-Parkinson-White syndrome and three with ventricular tachycardia) the electrophysiologic effects of intravenous (5 mg/kg body weight in 1 min) and oral (total dose 9800 to 11,200 mg) amiodarone were studied with programmed stimulation of the heart. Intravenous and oral amiodarone had a similar (p less than .05) effect of lengthening on the effective refractory period of the atrioventricular node. Only intravenous amiodarone prolonged (p less than .05) the AH interval. Oral amiodarone was more effective than intravenous amiodarone in lengthening the anterograde effective refractory period of the accessory atrioventricular pathway. Only oral amiodarone prolonged the effective refractory period of atrium and ventricle and the HV interval, all significantly (p less than .05). Intravenous amiodarone slowed (p less than .05) the rate of circus-movement tachycardia in patients with Wolff-Parkinson-White syndrome, and further slowing was observed after oral amiodarone. Termination o...
Catheter balloon valvuloplasty of aortic and mitral stenosis in adults: 1987.
Authors: S HRahimtoola
Journal: Circulation (1987)

CBV for adults with aortic and mitral stenosis is investigational at the present time and should usually be performed within the guidelines of clinical investigation. The technology is an evolving one with regard to types of catheters and balloons, methods of catheter insertion and placement, and patients and valves that are suitable for and will respond well to CBV. The initial results range from disappointing to excellent and must be kept in perspective. The procedure is clearly a palliative one; ideal results are not being achieved at present. Some of the complications are very serious. Nevertheless, CBV is a most promising catheter interventional technique for patients with valvular heart disease. Proper selection of patients and complete reporting of results is important.
Effect of heparin bonding on catheter-induced fibrin formation and platelet activation.
Authors: A BNichols, JOwen, B AGrossman, J JMarcella, L NFleisher, M MLee
Journal: Circulation (1984)

Pathologic and experimental evidence indicates that platelet activation and fibrin formation contribute to the pathogenesis of angina pectoris, coronary vasospasm and myocardial infarction. Detection of localized intravascular platelet activation and fibrin formation in vivo by selective blood sampling requires catheters that do not induce coagulation ex vivo. We studied the effect of heparin bonding of catheter surfaces on activation of the coagulation system by cardiovascular catheters. Woven Dacron, polyvinylchloride, and polyurethane catheters were tested and compared with identical catheters with heparin-bonded surfaces in 47 patients undergoing percutaneous cardiac catheterization. Platelet activation was measured by radioimmunoassay of plasma platelet factor 4 (PF4), beta-thromboglobulin (BTG), and thromboxane B2 (TXB2) in blood samples withdrawn through catheters, and fibrin formation was assessed by determination of fibrinopeptide A (FPA) levels. In blood samples collected through conventional ca...
Modification of the cardiac action potential by intracellular injection of adenosine triphosphate and related substances in guinea pig single ventricular cells.
Authors: JTaniguchi, ANoma, HIrisawa
Journal: Circulation Research (1983)

Effects of varying the intracellular adenosine triphosphate level on both the action potential and the membrane current were studied in single ventricular cells isolated from the guinea pig heart, using collagenase. Intracellular injection of adenosine triphosphate elevated the plateau potential level and prolonged the action potential duration. Similar results were obtained by injecting adenosine diphosphate, adenosine monophosphate, or creatine phosphate, i.e., substances considered to increase the intracellular concentration of adenosine triphosphate. In contrast, the action potential was depressed by procedures which could reduce the intracellular adenosine triphosphate level, such as an injection of creatine, superfusion of glucose-free Tyrode's solution containing 5.4 mM cyanide ion, or an injection of adenosine monophosphate into the cyanide-superfused cell. When the membrane current was recorded under the voltage clamp, it was found that the injection of adenosine triphosphate increased the amplit...
Usefulness of Medical Conferences
Authors: Mark Braun
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
Marked decline of coronary heart disease mortality in 35-44-year-old white men in Allegheny County, Pennsylvania.
Authors: L HKuller, N DTraven, G HRutan, J APerper, D GIves
Journal: Circulation (1989)

Trends in coronary heart disease (CHD) mortality were examined among 35-44-year-old white men during 1970-1986. Death certificates were obtained for 1,216 cases. All were coroner-certified natural deaths and noncoroner-certified deaths due to vascular diseases and diabetes mellitus. Autopsy data, coroner's reports, hospital records, physician's reports, and informants were used to validate diagnoses. The reviewers rejected 73 of 805 CHD certifications, but they validated 54 cases not certified as CHD on the death certificate as CHD. The CHD mortality rate fell from 90.6/100,000/year in 1970-1972 to 40.3/100,000/year in 1985-1986. Approximately two thirds of the decline was related to a decline in sudden deaths including 41.6% due to incident sudden CHD death. The proportion of diabetics among validated CHD deaths rose dramatically from 6.5% in 1970-1972 to 23.0% in 1985-1986. The CHD mortality rate among diabetics apparently did not decline during the 17 years of the study. We conclude that primary preven...
Immediate evaluation of endomyocardial biopsies for clinically suspected rejection after heart transplantation.
Authors: G LWinters, P JHauptman, J AJarcho, F JSchoen
Journal: Circulation (1994)

BACKGROUNDAcute rejection may be suspected in heart transplant recipients in the setting of new onset of clinical symptoms or alterations in cardiac function. Immediate diagnosis may be obtained by performing a frozen section on endomyocardial biopsy (EMB) specimens. However, little is known about the indications for, and the diagnostic reliability of, this procedure.METHODS AND RESULTSEMBs with frozen section (n = 98) from 65 of 214 consecutive orthotopic heart transplant recipients were reviewed and divided into early (  45 days; n = 51) posttransplant periods. Frozen section diagnoses (means = 1.5 EMB samples) were compared with corresponding permanent section diagnoses (means = 4.4 EMB samples), and clinical indications were analyzed. Comparison of frozen and permanent section interpretation revealed concordant pathological processes-rejection (n = 31) versus no rejection (n = 37) versus ischemic injury (n = 20)-in 88 of 98 (90%) cases. Discordant pathological process...