tbuckley/cabot-search huggingface dataset:
Cytoskeletal Role in the Transition From Compensated to Decompensated Hypertrophy During Adult Canine Left Ventricular Pressure Overloading
Authors: Hirofumi Tagawa, Masaaki Koide, Hiroshi Sato, Michael R. Zile, Blase A. Carabello, George Cooper
Journal: Circulation Research (1998)

Abstract —Increased microtubule density causes cardiocyte contractile dysfunction in right ventricular (RV) pressure-overload hypertrophy, and these linked phenotypic and contractile abnormalities persist and progress during the transition to failure. Although more severe in cells from failing than hypertrophied RVs, the mechanical defects are normalized in each case by microtubule depolymerization. To define the role of increased microtubule density in left ventricular (LV) pressure-overload hypertrophy and failure, in a given LV we examined ventricular mechanics, sarcomere mechanics, and free tubulin and microtubule levels in control dogs and in dogs with aortic stenosis both with LV hypertrophy alone and with initially compensated hypertrophy that had progressed to LV muscle failure. In comparing initial values with those at study 8 weeks later, dogs with hypertrophy alone had a very substantial increase in LV mass but preservation of a normal ejection fraction and mean systolic wall stress. Dogs with hypertrophy and associated failure had a substantial but lesser increase in LV mass and a reduction in ejection fraction, as well as a marked increase in mean systolic wall stress. Cardiocyte contractile function was equivalent, and unaffected by microtubule depolymerization, in cells from control LVs and those with compensated hypertrophy. In contrast, cardiocyte contractile function in cells from failing LVs was quite depressed but was normalized by microtubule depolymerization. Microtubules were increased only in failing LVs. These contractile and cytoskeletal changes, when assayed longitudinally in a given dog by biopsy, appeared in failing ventricles only when wall stress began to increase and function began to decrease. Thus, the microtubule-based cardiocyte contractile dysfunction characteristic of pressure-hypertrophied myocardium, originally described in the RV, obtains equally in the LV but is shown here to have a specific association with increased wall stress.
Fracture thresholds in osteoporosis: implications for hormone replacement treatment.
Authors: P J Ryan, G M Blake, I Fogelman
Journal: Annals of the Rheumatic Diseases (1992)

The bone mineral densities of the lumbar spine and femoral neck were determined by dual energy chi ray absorptiometry in 110 women aged 40-82 years (average 65 years) with spinal osteoporosis who had had at least one atraumatic vertebral compression fracture and in 1026 normal women aged 40-79 years (average 52 years). The women with osteoporosis showed a significant decrease in bone mineral density (BMD) at the lumbar spine and femoral neck compared with age matched normal women (sixth decade of life -26% spine, -23% femoral neck; seventh decade -26% spine, -16% femoral neck). The fracture threshold, defined as the 90th centile of spinal BMD for women with osteoporosis, was 0.81 g/cm2 at the lumbar spine and 0.656 g/cm2 at the femoral neck. Five per cent of normal women aged 40-49 years, 20% aged 50-59 years, and 45% aged 60-69 years had a BMD below this threshold. To maintain the bones of women above the fracture threshold until the age of 70 years about 50% of postmenopausal women need hormone replacement therapy. However, if the BMD is to be kept above the fracture threshold for a women9s lifetime, e.g. until the age of 80-90 years, then most women will need treatment, though for various lengths of time depending on their initial BMD. Measurements of BMD in postmenopausal women currently help in identifying the risk of osteoporotic fractures but in the lifetime assessment of risk in a single subject they may have a more important role in deciding the duration of hormone replacement therapy.
The ESMO programme of certification and training for medical oncology
Authors: D.J.Th. Wagener, J.B. Vermorken, H.H. Hansen, D.K. Hossfeld
Journal: Annals of Oncology (1998)

ESMO has designed a programme of certification and training in medical oncology. In this paper the background of these programmes is given, and the programme of graduate education is described in greater detail. The standard requirements are a total training period of six years, beginning with a common internship in internal medicine of at least two years, followed by a training programme in oncology for three to four years, which must include at least one year of full-time clinical training in the diagnosis and management of neoplastic diseases, accompanied by one year of experience in an ambulatory care setting.
Aortic Valve Repair for Adult Congenital Heart Disease : A 22-Year Experience
Authors: V. Rao, G. S. Van Arsdell, T. E. David, A. Azakie, W. G. Williams
Journal: Circulation (2000)

Aortic valve-preserving procedures have resulted in excellent outcomes in selected patients, particularly those with normal aortic valve leaflets and dilated aortic roots. However, several congenital heart lesions are associated with abnormal aortic valve leaflets. The long-term results of aortic valve repair for these lesions are not well defined.We reviewed the clinical records of 54 adult (age >18 years) patients who underwent repair of congenital abnormalities of the aortic valve between 1976 and September 1999. Follow-up data were available on 52 (96%) patients (mean 50+/-67 months, range 1 to 266). Patients underwent repair at a mean age of 34+/-14 years with associated diagnoses of subaortic stenosis (n=10), ventricular septal defect with prolapsing aortic valve (n=17), bicuspid aortic valve (n=23), sinus of Valsalva aneurysm (n=10), and bacterial endocarditis (n=2). There was 1 operative death (1.9%) and 3 late deaths. Survival at 5 and 10 years was 98+/-2% and 74+/-12%, respectively. Freedom from reoperation was 74+/-9% and 51+/-15% at 5 and 10 years, respectively. The presence of a ventricular septal defect predicted failure of valve repair (59% versus 22%, P:=0.01). A bicuspid aortic valve, subaortic stenosis, or the requirement for mitral valve surgery did not affect outcomes.Aortic valve repair in adult patients with congenital heart disease can be performed with minimal morbidity and mortality rates. The medium-term results of repair are acceptable, regardless of valvular or associated pathology. However, only 31 patients (57%) demonstrated long-term competence of the aortic valve, suggesting that most adult patients with congenital aortic valve disease will eventually require aortic valve replacement.
Molecular Profiling and Classification of Sporadic Renal Cell Carcinoma by Quantitative Methylation Analysis
Authors: Mark L. Gonzalgo, Srinivasan Yegnasubramanian, Gai Yan, Craig G. Rogers, Theresa L. Nicol, William G. Nelson, Christian P. Pavlovich
Journal: Clinical Cancer Research (2004)

Preoperative histologic classification of solid renal masses remains limited with current technology. We determine the utility of molecular profiling based on quantitative methylation analysis for characterization of sporadic renal cell carcinoma.Primary renal cell carcinomas representing three different histologic subtypes were obtained from a total of 38 patients who underwent radical nephrectomy for suspected malignant disease. Genomic DNA was isolated from tumors and was subjected to sodium bisulfite modification. The normalized index of methylation (NIM) for each sample was determined by quantitative real-time methylation-specific PCR at 17 different gene promoters. Hierarchical cluster analysis was performed by using an unsupervised neural network with binary tree topology.The majority of gene promoters that were analyzed in this study demonstrated very low levels of methylation (NIM <1.0). The RASSF1A gene promoter, however, was methylated in 30 of 38 (79%) cases. The frequency of RASSF1A methylation in papillary, clear-cell, and oncocytoma subtypes was 100, 90, and 25%, respectively. The highest levels of RASSF1A methylation were observed in the papillary (mean NIM = 78.9) and clear-cell (mean NIM = 13.4) subtypes. The vast majority of oncocytomas were completely unmethylated, and none demonstrated >1% methylation (mean NIM = 0.11). Hierarchical cluster analysis based on quantitative methylation levels resulted in stratification of sporadic renal cell carcinomas into their discrete histologic subtypes.Classification of sporadic renal cell carcinomas into histologic subtypes can be accomplished via multigene quantitative methylation profiling. Validation of this approach and selection of appropriate methylation markers may ultimately lead to use of this technology in the preoperative assessment of suspicious renal masses.
RECORD-2: phase II randomized study of everolimus and bevacizumab versus interferon α-2a and bevacizumab as first-line therapy in patients with metastatic renal cell carcinoma
Authors: A. Ravaud, C.H. Barrios, B. Alekseev, M.-H. Tay, S.S. Agarwala, S. Yalcin, C.-C. Lin, L. Roman, M. Shkolnik, O. Anak, S. Gogov, D. Pelov, A.-L. Louveau, B. Melichar
Journal: Annals of Oncology (2015)
West Nile Virus: Review of the Literature
Authors: Lyle R. Petersen, Aaron C. Brault, Roger S. Nasci
Journal: JAMA (2013)

<h3>Importance</h3> Since its introduction in North America in 1999, West Nile virus has produced the 3 largest arboviral neuroinvasive disease outbreaks ever recorded in the United States. <h3>Objective</h3> To review the ecology, virology, epidemiology, clinical characteristics, diagnosis, prevention, and control of West Nile virus, with an emphasis on North America. <h3>Evidence Review</h3> PubMed electronic database was searched through February 5, 2013. United States national surveillance data were gathered from the Centers for Disease Control and Prevention. <h3>Findings</h3> West Nile virus is now endemic throughout the contiguous United States, with 16 196 human neuroinvasive disease cases and 1549 deaths reported since 1999. More than 780 000 illnesses have likely occurred. To date, incidence is highest in the Midwest from mid-July to early September. West Nile fever develops in approximately 25% of those infected, varies greatly in clinical severity, and symptoms may be prolonged. Neuroinvasive disease (meningitis, encephalitis, acute flaccid paralysis) develops in less than 1% but carries a fatality rate of approximately 10%. Encephalitis has a highly variable clinical course but often is associated with considerable long-term morbidity. Approximately two-thirds of those with paralysis remain with significant weakness in affected limbs. Diagnosis usually rests on detection of IgM antibody in serum or cerebrospinal fluid. Treatment is supportive; no licensed human vaccine exists. Prevention uses an integrated pest management approach, which focuses on surveillance, elimination of mosquito breeding sites, and larval and adult mosquito management using pesticides to keep mosquito populations low. During outbreaks or impending outbreaks, emphasis shifts to aggressive adult mosquito control to reduce the abundance of infected, biting mosquitoes. Pesticide exposure and adverse human health events following adult mosquito control operations for West Nile virus appear negligible. <h3>Conclusions and Relevance</h3> In North America, West Nile virus has and will remain a formidable clinical and public health problem for years to come.
Imaging Time After Gd-DTPA Injection Is Critical in Using Delayed Enhancement to Determine Infarct Size Accurately With Magnetic Resonance Imaging
Authors: John N. Oshinski, Zequan Yang, Jeffrey R. Jones, Jaime F. Mata, Brent A. French
Journal: Circulation (2001)

In patients with acute myocardial infarction (MI), delayed enhancement is seen in MRI 5 to 7 minutes after gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) injection, and the enhancement occurs in regions that later show recovery of function. However, in a canine model of acute MI, delayed enhancement 20 to 30 minutes after injection only occurs in necrotic regions and not in surrounding, reversibly injured myocardium. The objective of the present study was to determine (1) if the size of the enhanced region varies with time after Gd-DTPA injection and (2) if and when the size of the enhanced region corresponds to the true infarct size.The left coronary artery was occluded in 15 Lewis rats for 30 minutes (n=9) or 2 hours (n=6); this was followed by reperfusion. MRI scans were performed 48+/-2 hours after-MI. Midventricular short-axis images were obtained continuously for 40 minutes after Gd-DTPA injection (0.3 mmol/kg). The sizes of enhanced regions at each time were determined by threshold analysis and compared with triphenyltetrazolium chloride-stained sections of the excised rat heart. In all animals, the enhanced region overestimated infarct size (28+/-5%) immediately after the injection of Gd-DTPA, although it then gradually receded to match the size of the infarct. The time required for enhancement to accurately determine infarct size was significantly different between 2-hour infarcts (16+/-2 minutes) and 30-minute (26+/-4 minutes) infarcts (P<0.05).In reperfused acute MI, accurate determination of infarct size by delayed enhancement MRI requires imaging at specific times after Gd-DTPA injection, and this time varies with the duration of occlusion.
Response to Comment on Edelman et al. AUTONOMY: The First Randomized Trial Comparing Two Patient-Driven Approaches to Initiate and Titrate Prandial Insulin Lispro in Type 2 Diabetes. Diabetes Care 2014;37:2132–2140
Authors: Steve V. Edelman, Rong Liu, Jennal Johnson, Leonard C. Glass
Journal: Diabetes Care (2014)

We thank Drs. Rodbard and Karolicki for their commentary (1) to clarify key points related to the FullSTEP study discussed in our article (2), in particular, the use of self-titration algorithms to adjust prandial insulin dose. The FullSTEP (3) study and AUTONOMY (Study of Insulin Lispro in Participants With Inadequately Controlled Type 2 Diabetes) (2) trial highlight the importance of patient involvement in care and the effectiveness of self-titration of prandial insulin doses. In this regard, the two studies complement each other, supporting patient-centric approaches to insulin therapy intensification. We appreciate that the authors of FullSTEP have taken this opportunity to reinforce how a patient-centric approach to insulin therapy …
The Mechanisms and Therapeutic Potential of SGLT2 Inhibitors in Diabetes Mellitus
Authors: Volker Vallon
Journal: Annual Review of Medicine (2014)

The kidneys in normoglycemic humans filter 160-180 g of glucose per day (∼30% of daily calorie intake), which is reabsorbed and returned to the systemic circulation by the proximal tubule. Hyperglycemia increases the filtered and reabsorbed glucose up to two- to three-fold. The sodium glucose cotransporter SGLT2 in the early proximal tubule is the major pathway for renal glucose reabsorption. Inhibition of SGLT2 increases urinary glucose and calorie excretion, thereby reducing plasma glucose levels and body weight. The first SGLT2 inhibitors have been approved as a new class of antidiabetic drugs in type 2 diabetes mellitus, and studies are under way to investigate their use in type 1 diabetes mellitus. These compounds work independent of insulin, improve glycemic control in all stages of diabetes mellitus in the absence of clinically relevant hypoglycemia, and can be combined with other antidiabetic agents. By lowering blood pressure and diabetic glomerular hyperfiltration, SGLT2 inhibitors may induce protective effects on the kidney and cardiovascular system beyond blood glucose control.
Vascular Healing 4 Years After the Implantation of Sirolimus-Eluting Stent in Humans
Authors: J. Eduardo Sousa, Marco A. Costa, Andrew Farb, Alexandre Abizaid, Amanda Sousa, Ana C. Seixas, Lilian M. da Silva, Fausto Feres, Ibraim Pinto, Luiz A. Mattos, Renu Virmani
Journal: Circulation (2004)
Within-Subject Variability and Boosting of T-Cell Interferon-γ Responses after Tuberculin Skin Testing
Authors: Richard N. van Zyl-Smit, Madhukar Pai, Kwaku Peprah, Richard Meldau, Jackie Kieck, June Juritz, Motasim Badri, Alimuddin Zumla, Leonardo A. Sechi, Eric D. Bateman, Keertan Dheda
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Rationale: The optimal strategy for the diagnosis of latent tuberculosis infection is controversial. Adoption of a two-step strategy (tuberculin skin test [TST] followed by an IFN-γ release assay [IGRA], compared with an IGRA alone), may be limited by TST-mediated boosting of subsequent IGRA responses. Assessment of within-subject IGRA variability will aid in establishing thresholds for conversions and reversions, and interpretation of serial testing results.Objectives: To determine short-term IGRA variability and the impact of TST on subsequent IGRA results.Methods: Within-subject variability and TST-mediated boosting of IGRA responses were evaluated in 26 South African participants with varying exposure risk. IGRAs (T-SPOT.TB, QuantiFERON-TB Gold In-Tube [QuantiFERON-TB-GIT], PPD, and heparin-binding hemagglutinin) were repeated four times over 21 days pre-TST, and on Days 3, 7, 28, and 84 post-TST administration.Measurements and Main Results: All participants showed within-subject IGRA variability. Changes of ±3 spots (T-SPOT.TB) or ±80% from the mean IFN-γ response (QuantiFERON-TB-GIT) over 3 weeks explained 95% of the variability. Spontaneous conversions/reversions occurred in 7 of 26 subjects (27%) (6 for T-SPOT.TB and 1 for QuantiFERON-TB-GIT [P = 0.049]) during the within-patient variability studies (pre-TST). After the TST eight subjects (33%) boosted above the defined baseline variability. By Day 7 post-TST, but not Day 3, 2 (12.5%) initially IGRA-negative test subjects converted. By contrast, boosting of PPD and heparin-binding hemagglutinin occurred by Day 3 post-TST.Conclusions: When using a two-step screening strategy it appears safe to perform a QuantiFERON-TB-GIT or T-SPOT.TB IGRA within 3 days of performing the TST. A 3-spot or 80% IFN-γ response variation, on either side of baseline values, explains 95% of the short-term variability and may be useful for interpreting conversions and reversions, and values close to the cut-point.
Targeting FRβ+ tumor associated macrophages with car T cells in ovarian cancer
Authors: Rachel C Lynn, Takami Matsuyama, Daniel J Powell
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Chimeric antigen receptor (CAR) T cell therapy has shown dramatic clinical success in CD19+ leukemia and lymphoma patients. However, CAR T cell therapy for epithelial cancers has been less successful. Developing effective CAR T cell therapies for other types of cancer may involve
Combining a Recombinant Cancer Vaccine with Standard Definitive Radiotherapy in Patients with Localized Prostate Cancer
Authors: James L. Gulley, Philip M. Arlen, Anne Bastian, Steven Morin, Jennifer Marte, Patricia Beetham, Kwong-Yok Tsang, Junko Yokokawa, James W. Hodge, Cynthia Ménard, Kevin Camphausen, C. Norman Coleman, Francis Sullivan, Seth M. Steinberg, Jeffrey Schlom, William Dahut
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Many patients with clinically localized prostate cancer develop biochemical failure despite excellent local therapy perhaps due to occult metastatic disease. One potential solution is the utilization of a well-tolerated systemic therapy (e.g., vaccine) in concert with local therapy. Experimental Design: We present a randomized phase II clinical trial designed to determine if a poxviral vaccine encoding prostate-specific antigen (PSA) can induce a PSA-specific T-cell response when combined with radiotherapy in patients with clinically localized prostate cancer. Thirty patients were randomized in a 2:1 ratio into vaccine plus radiotherapy or radiotherapy-only arms. Those patients in the combination arm received a “priming” vaccine with recombinant vaccinia (rV) PSA plus r V containing the T-cell costimulatory molecule B7.1 (rV-B7.1) followed by monthly booster vaccines with recombinant fowlpox PSA. The vaccines were given with local granulocyte-macrophage colony-stimulating factor and low-dose systemic interleukin-2. Standard external beam radiation therapy was given between the fourth and the sixth vaccinations. Results: Seventeen of 19 patients in the combination arm completed all eight vaccinations and 13 of these 17 patients had increases in PSA-specific T cells of at least 3-fold versus no detectable increases in the radiotherapy-only arm (P &amp;lt; 0.0005). There was also evidence of de novo generation of T cells to well-described prostate-associated antigens not found in the vaccine, providing indirect evidence of immune-mediated tumor killing. The vaccine was well tolerated. Conclusion: This vaccine regimen can be safely given in patients undergoing radiation therapy for localized prostate cancer, with the majority of patients generating a PSA-specific cellular immune response to vaccine.
The Limits and Intensity of Plasmodium falciparum Transmission: Implications for Malaria Control and Elimination Worldwide
Authors: Carlos A Guerra, Priscilla W Gikandi, Andrew J Tatem, Abdisalan M Noor, Dave L Smith, Simon I Hay, Robert W Snow
Journal: PLoS Medicine (2008)

Background The efficient allocation of financial resources for malaria control using appropriate combinations of interventions requires accurate information on the geographic distribution of malaria risk. An evidence-based description of the global range of Plasmodium falciparum malaria and its endemicity has not been assembled in almost 40 y. This paper aims to define the global geographic distribution of P. falciparum malaria in 2007 and to provide a preliminary description of its transmission intensity within this range. Methods and Findings The global spatial distribution of P. falciparum malaria was generated using nationally reported case-incidence data, medical intelligence, and biological rules of transmission exclusion, using temperature and aridity limits informed by the bionomics of dominant Anopheles vector species. A total of 4,278 spatially unique cross-sectional survey estimates of P. falciparum parasite rates were assembled. Extractions from a population surface showed that 2.37 billion people lived in areas at any risk of P. falciparum transmission in 2007. Globally, almost 1 billion people lived under unstable, or extremely low, malaria risk. Almost all P. falciparum parasite rates above 50% were reported in Africa in a latitude band consistent with the distribution of Anopheles gambiae s.s. Conditions of low parasite prevalence were also common in Africa, however. Outside of Africa, P. falciparum malaria prevalence is largely hypoendemic (less than 10%), with the median below 5% in the areas surveyed. Conclusions This new map is a plausible representation of the current extent of P. falciparum risk and the most contemporary summary of the population at risk of P. falciparum malaria within these limits. For 1 billion people at risk of unstable malaria transmission, elimination is epidemiologically feasible, and large areas of Africa are more amenable to control than appreciated previously. The release of this information in the public domain will help focus future resources for P. falciparum malaria control and elimination.