tbuckley/cabot-search huggingface dataset:
159. Vector Genome Loss Does Not Account for Decline of Plasma cFVIII Protein in Hemophilic Dogs That Demonstrate Long Term Clinical Correction Following Helper-Dependent Adenoviral Gene Therapy
Authors: W. Michael McCormack, Terry K. Bertin, Kiran Ubhayakar, Margaretha Guenther, Viraj P. Mane, Philip Ng, Timothy C. Nichols, Milton J. Finegold, Donna Palmer, Arthur Beaudet, Brendan H. Lee
Journal: Molecular Therapy (2004)

Helper-dependent adenoviral vectors (HDV) offer the advantage of a large cloning capacity, reduced toxicity and extremely efficient transduction of target tissues. These vectors remain episomal in host target cells limiting the possibility of insertional mutagenesis but potentially reducing the duration of transgene expression due to vector genome loss. In previous studies using these vectors in various animal models of disease, long-term expression of both intracellular and secreted proteins has been achieved. However, in canine models of both hemophilia A and B, this has not been the case. The level of canine factor VIII (cFVIII) transgene product in the plasma of hemophilic dogs treated with HDV gene therapy declines at a greater rate than would be expected based on data from other models of disease including hemophilic mice. In these experiments we treated two hemophilia A dogs from the colony at the University of North Carolina with a HDV encoding cFVIII under the control of a liver tissue-restricted phosphoenolpyruvate carboxykinase (PEPCK) promoter. One animal received 1 × 1012 vp/kg and a second received 3 × 1012 vp/kg. The whole blood clotting time (WBCT) in both of the animals was significantly improved for up to 10 months. However, the plasma level of cFVIII declined from peaks at two weeks post-treatment of 1.3% normal in the low dose animal and 70% normal in the high dose animal to less than 1% at 2 months in both. To determine the reason for this a third animal was injected with 3 × 1012 vp/kg and underwent survival liver biopsy at days 18 and 79 after vector administration correlating with the high (35% normal) and low (<1% normal) levels of cFVIII in the plasma. Genomic DNA was isolated from these biopsy samples. Real-time PCR and semi-quantitative PCR indicate that there was a less than 2-fold decline in vector genome from the early to the late time point. Immunohistochemistry of liver tissue from these two time-points with an antibody directed at cFVIII reveals that the protein is localized to the endothelium of the hepatic veins and sinusoids. There does not appear to be an overall decline in cFVIII staining at the later time-point. These data suggest that vector genome loss alone is not sufficient to account for the decline of plasma cFVIII levels. The Bethesda assay in these animals was negative for inhibitory antibodies to cFVIII. However, it is possible that antibodies that do not inhibit function, but that do increase clearance of the cFVIII protein may account for the decline of plasma cFVIII.
Profound inhibition of platelet aggregation with monoclonal antibody 7E3 Fab thrombolytic therapy
Authors: Neal S. Kleiman, E.Magnus Ohman, Robert M. Califf, Barry S. George, Dean Kereiakes, Frank V. Aguirre, Harlan Weisman, Thomas Schaible, Eric J. Topol
Journal: Journal of the American College of Cardiology (1993)
Platelet functional alterations in a Bernard-Soulier syndrome patient with filamin A mutation
Authors: Jiaming Li, KeSheng Dai, Zhaoyue Wang, Lijuan Cao, Xia Bai, Changgeng Ruan
Journal: Journal of Hematology & Oncology (2015)

Defects in filamin A (FLNA) gene could lead to low platelet counts and decreased surface expression of glycoprotein (GP) Ibα. Here, we report and investigate the FLNA genomic alteration of a case with Bernard-Soulier syndrome (BSS), a rare hereditary bleeding disorder caused by quantitative or qualitative abnormalities in the GP Ib-IX-V receptor. DNA sequencing analysis reveals the presence of a GP Ibα c.987G > A mutation and a FLNA c.1582 G > A mutation in this patient. Transient transfection studies show that GP Ibα c.987G > A mutation abolishes the surface expression of GP Ibα on the transfected CHO cells. On the other hand, abnormal responses to collagen, including the platelet aggregation, secretion, and GP VI signaling pathways, are associated with FLNA c.1582G > A mutation. Our findings confirm a central role for FLNA in platelet-adhesive functions. The interaction between FLNA and GP Ibα in platelets deserves to be investigated.
BMA supports full inquiry into the Shipman case
Authors: Linda Beecham
Journal: BMJ (2000)

The BMA supports a full inquiry into the case of Dr Harold Shipman, who was convicted this week of murdering 15 of his women patients.

The chairman of the BMA's council, Dr Ian Bogle, said that he was shocked and horrified by the sequence of events but did not believe that the case would damage the trust between doctors and patients. “It was Shipman who was found guilty,” he said, “not the medical profession and not GPs.”

He said that it was important to …
CD Rom: Electronic DTB, eBNF/eMeReC
Authors: C. P Bradley
Journal: BMJ (1999)

Available from Consumers' Association, £65 for single user, £110 for two to five users Rating: ![Graphic][1]</img>![Graphic][2]</img>![Graphic][3]</img>as a ![Graphic][4]</img>![Graphic][5]</img> as an electronic information source Electronic publication opens up all sorts of possibilities not previously available. As well as allowing vast amounts of text, pictures, sounds, and video to be stored on relatively small, portable, and durable disks, it also allows the information to be swiftly accessed with electronic linking techniques such as hypertext and sophisticated electronic indexing. All these facilities are seen on the world wide web, which is rapidly becoming the epitome of electronic information provision. Standards now emerging … [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif [3]: /embed/inline-graphic-3.gif [4]: /embed/inline-graphic-4.gif [5]: /embed/inline-graphic-5.gif
Human Trichinosis: Studies of Eleven Cases Affecting Two Families in Nova Scotia
Authors: R L OZERE, C van ROOYEN, D L ROY, T W CAMERON, C TANNER
Journal: JAMA (1963)

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
Autonomic and Hemodynamic Origins of Pre-Hypertension
Authors: Jason T. Davis, Fangwen Rao, Dalal Naqshbandi, Maple M. Fung, Kuixing Zhang, Andrew J. Schork, Caroline M. Nievergelt, Michael G. Ziegler, Daniel T. O'Connor
Journal: Journal of the American College of Cardiology (2012)
Changes in Plaque Lipid Content After Short-Term Intensive Versus Standard Statin Therapy
Authors: Annapoorna S. Kini, Usman Baber, Jason C. Kovacic, Atul Limaye, Ziad A. Ali, Joseph Sweeny, Akiko Maehara, Roxana Mehran, George Dangas, Gary S. Mintz, Valentin Fuster, Jagat Narula, Samin K. Sharma, Pedro R. Moreno
Journal: Journal of the American College of Cardiology (2013)
Abstract 15164: Healthy Lifestyle and Heart Rate Variability in the General Population
Authors: Stefanie Aeschbacher, Matthias Bossard, Tobias Schoen, Martin Risch, Lorenz Risch, David Conen
Journal: Circulation (2014)

Background: The combined influence of lifestyle factors such as smoking, diet or obesity on heart rate variability (HRV), a measure of autonomic function, is not well studied. We therefore assessed the relationship of a healthy lifestyle score with 24-hour HRV in the general population. Methods: A population-based cohort of healthy individuals aged 25-41 years without prevalent cardiovascular disease was investigated. 24-hour electrocardiography (ECG) was performed with a validated device. All ECG studies were systematically post-processed, and the standard deviation of all normal RR Intervals (SDNN) used as a marker of HRV. Body mass index (BMI) was calculated as body weight (kg) divided by height (meters) squared. Unhealthy lifestyle habits were summed to a lifestyle score with a scale from 0=healthy to 6=unhealthy. One point was given for smoking cigarettes in the past, consuming &lt;5 portions of fruits or vegetables per day, vigorous physical activity &lt;180 minutes per week and a BMI of 25-30kg/m2; two points were given to current smokers and individuals with a BMI ≥30kg/m2. Results: 2140 participants (median age: 37 years, 47% men) were included in this analysis. Mean SDNN values among men and women were 76 and 66ms (p&lt;0.0001), respectively. Main results are shown in the table. Because of a strong sex by lifestyle score interaction (p&lt;0.0001), sex-specific results were evaluated. Most participants had a score between 2 and 3 (Table). In sex-specific multivariable linear regression analysis with SDNN as the outcome variable we found a β (95% confidence interval (CI)) of -4.73 (-5.64; -3.82), p&lt;0.0001 among men and -2.15 (-2.90; -1.40), p&lt;0.0001 among women. Conclusion: Healthy lifestyle was strongly associated with greater HRV in this large sample of young adults, particularly among men. Our findings provide one potential explanation how a healthy lifestyle may lead to better cardiovascular outcomes.
Porphyria cutanea tarda, iron, inflammation and diabetes mellitus
Authors: R.J. Hift
Journal: British Journal of Dermatology (2011)

Journal Article Porphyria cutanea tarda, iron, inflammation and diabetes mellitus Get access R.J. Hift R.J. Hift Division of Medicine, Nelson R. Mandela School of Medicine, University of KwaZulu‐Natal, Durban, South Africa E‐mail: hift@ukzn.ac.za Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 165, Issue 3, 1 September 2011, Pages 453–454, https://doi.org/10.1111/j.1365-2133.2011.10518.x Published: 01 September 2011
MicroRNA‐451 Down‐Regulates Neutrophil Chemotaxis via p38 MAPK
Authors: Koichi Murata, Hiroyuki Yoshitomi, Moritoshi Furu, Masahiro Ishikawa, Hideyuki Shibuya, Hiromu Ito, Shuichi Matsuda
Journal: Arthritis & Rheumatology (2013)

MicroRNAs (miRNAs) are endogenous small noncoding RNAs that regulate the activity of target messenger RNAs (mRNAs) and cellular processes. MicroRNA-451 (miR-451) is one of the miRNAs that is conserved perfectly among vertebrates, and it regulates cell proliferation, invasion, and apoptosis in tumors. However, the role of miR-451 in autoimmune arthritis is unknown. This study was undertaken to identify the role of miR-451 in autoimmune arthritis.We compared the expression of miR-451 in neutrophils from patients with rheumatoid arthritis (RA) and healthy controls. We also evaluated the role of miR-451 in neutrophil chemotaxis in vivo and in vitro using murine neutrophils. The regulation of p38 MAPK by miR-451 was assessed. Double-stranded miR-451 was administered to SKG mice, the arthritis score was determined, and histologic examination was performed.MicroRNA-451 expression in neutrophils isolated from patients with RA was lower than that in healthy controls. Systemic administration of miR-451 significantly disrupted the infiltration of neutrophils in an air-pouch model of local inflammation without affecting apoptosis of neutrophils. Overexpression of miR-451 significantly suppressed the migration of neutrophils to fMLP. We identified CPNE3 and Rab5a as direct targets of miR-451. Overexpression of miR-451 suppressed the phosphorylation of p38 MAPK via 14-3-3ζ, a known target of miR-451, and Rab5a. In SKG mice, miR-451 treatment reduced the severity of arthritis and the number of infiltrating cells.These results suggest that miR-451 suppresses neutrophil chemotaxis via p38 MAPK and is a potential target in the treatment of RA.
Abstract PR01: Adaptive resistance of patient-derived ovarian cancer cells to PI3K/mTOR inhibition
Authors: Ioannis Zervantonakis, Hsing-Yu Chen, Taru Muranen, Joyce Liu, Ronny Drapkin, Ursula Matulonis, Joan Brugge
Journal: Clinical Cancer Research (2015)

Abstract Relapse due to drug resistance remains a major challenge for successful cancer treatment despite advances in chemotherapy efficacy and the development of targeted therapies. We have previously reported a therapy-induced adaptive response that is associated with treatment resistance and are investigating whether this adaptive response program could be targeted to increase treatment efficacy (Muranen et al, Cancer Cell 2012). The PI3K pathway is amplified in high-grade serous ovarian tumor and represents an attractive target in this cancer subtype. We found that both in vitro and in vivo exposure of patient-derived ovarian cancer cells to the PI3K/mTOR dual inhibitor GNE-493 increases the levels of the anti-apoptotic Bcl-2 protein, and multiple tyrosine kinase receptors, such as EGFR and HER2. Concurrent treatment of these cancer cells with GNE-493 and ABT737 (a Bcl-2 and Bcl-xl dual inhibitor) causes a reduction in cell number and increased cell death. Ongoing studies are underway to comprehensively characterize the adaptive response signature of a panel of patient-derived ovarian cancer cells and study whether targeting multiple different upregulated proteins (e.g. EGFR) may increase PI3K/mTOR treatment efficacy. Therapy resistance has also been associated with exposure of tumor cells to pro-survival factors secreted by supporting cells in the tumor microenvironment (Straussman et al, Nature 2012 and Wilson et al, Nature 2012). We found that the growth-factors EGF, inflammatory cytokine IL-6 and ascites fluid from ovarian cancer patients induces up-regulation of Bcl-2 as well as IGFR, which masked the adaptive response to PI3K/mTOR inhibitors. We are performing ongoing studies using orthotopic patient-derived ovarian cancer xenografts to investigate the patterns of residual disease in vivo with the ultimate goal to identify whether Bcl-2 targeted drugs will enhance the efficacy of PI3K/mTOR inhibition and whether there is differential sensitivity at distinct anatomical sites (pancreas, diaphragm, peritoneal wall). Our studies provide a framework to identify adaptive response programs and tumor microenvironment factors in patient-derived ovarian cancer cells that limit treatment efficacy of PI3K/mTOR pathway inhibition and to develop therapies to abrogate this resistance. Citation Format: Ioannis Zervantonakis, Hsing-Yu Chen, Taru Muranen, Joyce Liu, Ronny Drapkin, Ursula Matulonis, Joan Brugge. Adaptive resistance of patient-derived ovarian cancer cells to PI3K/mTOR inhibition. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr PR01.
Abstract 13939: Incidence Rate of Hyperkalemia-related Hospitalization After Initiation of a Mineralocorticoid Receptor Antagonist in Patients with Heart Failure
Authors: Vishal R Chauhan, Sandesh Dev, Michael Pham, Shoutz Lin, Paul Heidenreich
Journal: Circulation (2014)

Background: Several clinical trials have demonstrated that mineralocorticoid receptor antagonists (MRA) markedly reduce morbidity and mortality in patients with heart failure (HF) with reduced ejection fraction. Despite their benefits, MRAs are associated with hyperkalemia potentially leading to hospitalization. The ACC/AHA guidelines recommend monitoring of serum potassium at 3, 7, 30, 60 and 90 days after initiation of MRA. Methods: We identified patients in the Veterans Health Care System from 2003 to 2013, with a diagnosis of HF who were started on an MRA. The incidence of hospitalization for hyperkalemia was measured at 3 days, 7 days, 14 days, 30 days, 60 days, 90 days and 1 year after the initiation of an MRA. Results: There were 179,541 patients identified with a diagnosis of HF and started on an MRA. Baseline characteristics for the patients included a mean age of 69.5 ±11.4, 98% male, 17% black, 48% with diabetes and 83% with hypertension. HF-related medications included a beta-blocker in 47%, an ACE inhibitor in 54%, ARB in 13%, and a loop diuretic in 58%. The baseline mean creatinine was 1.35±0.9 mg/dl. The incidence rate of hospitalization for hyperkalemia per 10,000 persons per month was 1.7 at 3 days, 3.3 at 7 days, 6.5 at 14 days, 8.3 at 30 days, 7.9 at 60 days, 6.6 at 90 days and 3.7 at 1 year. For those taking an ACEi or ARB (high risk group, n=113,678, 63.3%), the incidence rate was 0.9 at 3 days, 3.4 at 7 days, 7.4 at 14 days, 10.1 at 30 days, 10.1 at 60 days, 8.3 at 90 days and 4.7 days at 1 year. The prevalence of moderate hyperkalemia (k ≥ 5.5) among 65,641 monitored within 14 days after MRA initiation was 7.1% and that of severe hyperkalemia (k ≥ 6.0) among 85,220 monitored within 30 days after MRA initiation was 3.2%. Conclusions: The incidence rate of hospitalization for hyperkalemia in this study peaked at 30 days after MRA initiation but was very low overall. Future studies to optimize the frequency of monitoring, while maintaining low rates of serious hyperkalemia may be warranted.
Warfarin: Less May Be Better
Authors: Wes Carnahan
Journal: Annals of Internal Medicine (1997)

Letters15 August 1997Warfarin: Less May Be BetterWes Carnahan, PharmD and James Bracikowski, MDWes Carnahan, PharmDNashville Veterans Affairs Medical Center; Nashville, TN 37212Search for more papers by this author and James Bracikowski, MDNashville Veterans Affairs Medical Center; Nashville, TN 37212Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-127-4-199708150-00018 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:We read with interest the report by Harrison and colleagues [1]. The authors measured the early changes in clotting factor levels in patients given a 10-mg warfarin loading dose compared with changes in patients receiving a 5-mg dose. Another important clinical end point is the time it takes for a patient to achieve a stable therapeutic warfarin dose. This can be defined as the number of days after initiation of warfarin therapy until the patient attains two consecutive INRs in the desired therapeutic range [2], measured at least 72 hours apart. In a prospective study of a ...References1. Harrison L, Johnston M, Massicotte MP, Crowther M, Moffat K, Hirsch J. Comparison of 5-mg and 10-mg loading doses in initiation of warfarin therapy. Ann Intern Med. 1997; 126:133-6. Google Scholar2. Dalen JE, Hirsch J. Fourth ACCP Consensus Conference on Antithrombotic Therapy. Chest. 1995; 108:225S-522S. Google Scholar Author, Article, and Disclosure InformationAuthors: Wes Carnahan, PharmD; James Bracikowski, MDAffiliations: Nashville Veterans Affairs Medical Center; Nashville, TN 37212 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 15 August 1997Volume 127, Issue 4 Page: 332-333 Keywords International normalized ratio Laboratory tests Necrosis Prospective studies ePublished: 15 August 2000 Issue Published: 15 August 1997 Copyright & PermissionsCopyright © 1997 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Comparison of Hospital Risk-Standardized Mortality Rates using In-hospital and 30-Day Models: Implications for Hospital Profiling
Authors: Elizabeth Drye, Sharon-Lise T. Normand, Yun Wang, Joseph S. Ross, Geoffrey C. Schreiner, Lein Han, Michael Rapp, Harlan M. Krumholz
Journal: Annals of Internal Medicine (2012)

Background
In-hospital mortality measures, which are widely used to assess hospital quality, are not based on a standardized follow-up period and may systematically favor hospitals with shorter lengths of stay (LOS).
Abstract 13788: Ventilatory Inefficiency, Mitral Regurgitation and Pulmonary Hypertension During Exercise: the Culprit Interaction in Heart Failure Reduced Ejection Fraction
Authors: Greta Generati, Francesco Bandera, Marta Pellegrino, Eleonora Alfonzetti, Valentina Labate, Marco Guazzi
Journal: Circulation (2014)

Introduction: Dyspnea and exercise intolerance are landmark manifestations of heart failure (HF). An impaired efficiency in ventilation (VE) as indicated by a steep increase in VE vs CO2 output during exercise provides remarkable prognostic indications.

Hypothesis: We aimed at defining the role of different hemodynamic components that may determine the most unfavorable ventilatory phenotype and worse clinical status.

Methods: 71 HF reduced ejection fraction patients (mean age 67±11; male 72%; ischemic etiology 61%; NYHA class I, II, III and IV 13%, 36%, 39% and 12%, mean ejection fraction 33±9%) underwent cardiopulmonary exercise test evaluation on tiltable cycle-ergometer combined with simultaneous echocardiographic assessment.

Results: Patients were divided in 4 ventilatory classes (VC) according to the VE/VCO2 slope classification focusing on peak exercise variables. We observed a VC related increase in E/e’ ratio, mitral regurgitation and pulmonary artery systolic pressure and a progressive reduction in TAPSE and peak VO2. The best correlation with VC groups was found for E/e’ ratio and peak VO2.

Conclusions: A remarkable culprit interaction emerged between the degree of diastolic dysfunction, mitral regurgitation, pulmonary hypertension and right heart dysfunction with inefficient VE during exercise. A systematic analysis of these hemodynamic determinants by stress echo combined with gas exchange analysis may become a valuable addition for appropriately refining therapeutic interventions.

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