tbuckley/cabot-search huggingface dataset:
Interactions between Changes in the Intensity and Duration of the Active State in the Characterization of Inotropic Stimuli on Heart Muscle
Authors: ROBERT A. BUCCINO, EDMUND H. SONNENBLICK, JAMES F. SPANN, WILLIAM F. FRIEDMAN, EUGENE BRAUNWALD
Journal: Circulation Research (1967)

The responses of isolated cat papillary muscles and left atrial strips to a variety of procedures were classified systematically according to the induced changes in peak tension (T), mean rate of tension development (δT/δt), and time to peak tension (TTP). Increasing temperature from 25° to 37°C augmented δT/δt but reduced TTP reciprocally so that T remained constant. Increased frequency of contraction, thyroid hormone, and increased temperature markedly augmented δT/δt but shortened TTP, with relatively little alteration in T. Norepinephrine, tyramine, paired electrical stimulation, strophanthidin, and calcium increased T by augmenting ΔT/δt proportionately more than they reduced TTP. Acetylcholine and serotonin augmented T by raising δT/δt with relatively little effect on TTP. Strontium increased T by causing both a prolongation of TTP and an augmentation of δT/Δt. Depression of T in muscles from failing hearts occurred primarily by a reduction of δT/δt, and the negative inotropic effects of hypoxia or pentobarbital resulted from reductions in both δT/δt and TTP. In muscles from hypothyroid cats, depression of δT/δt was partially compensated for by prolongation of TTP. Since δT/δt is related to the intensity of the active state and TTP to its duration, such analysis of these variables should provide a framework for the characterization and quantitative comparison of various types of inotropic stimuli.
Differences in nasal cellular infiltrates between allergic children and age-matched controls
Authors: J.G. Vinke, A. KleinJan, L.W.F.m Severijnen, L.j Hoeve, W.j Fokkens
Journal: European Respiratory Journal (1999)

Little is known about the cellular infiltrates in the nasal mucosa of children. This study was set up to compare the nasal cellular infiltrates in biopsy specimens from allergic children and controls. Atopic children were distinguished from controls on the basis of symptoms of allergic rhinitis and/or asthma, total serum immunoglobulin (Ig)E, family history and specific serum IgE to food and aeroallergens. Fifteen allergic patients (median age 4.3 yrs) and 15 age-matched nonallergic control subjects were evaluated. The number of cells positive for CD1a, CD4, CD8, CD19, CD68, chymase, tryptase, IgE and major basic protein was determined in the mucosa of the inferior turbinate. A significantly higher number of IgE-positive cells and mast cells was found in the epithelia of the allergic group. In the lamina propria, higher numbers of IgE-positive cells and eosinophils were found. Langerhans9 cells positive for IgE were only seen in allergic children with specific serum IgE against aeroallergens. These children also had a higher number of IgE-positive mast cells compared to controls and atopic children without specific serum IgE. These results show that the nasal cellular infiltrates of allergic children differ from nonallergic control subjects. Prior to the detection of specific serum immunoglobulin E, cellular changes can be found in the nasal mucosa of atopic children.
Glucose Control and Cardiovascular Complications: The VA Diabetes Trial
Authors: William C. Duckworth, Madeline McCarren, Carlos Abraira
Journal: Diabetes Care (2001)

The Veterans Affairs Cooperative Studies Program (VACSP) has just initiated a trial of the effect of intensive glucose control on cardiovascular complications in patients with type 2 diabetes. The name of the trial is “VACSP #465, Glycemic Control and Complications in Diabetes Mellitus type 2” (V.A. Diabetes Trial [VADT]). The trial is expected to generate discussion in the diabetes community because the central role of glucose control in preventing or delaying long-term complications is generally accepted.

The data on macrovascular disease are not yet conclusive. The VADT is directed at type 2 diabetic patients with established uncontrolled diabetes. This is the population most frequently encountered by the practicing physician.

Cardiovascular (CV) complications are the major causes of morbidity and mortality in patients with type 2 diabetes (1). Efforts to reduce glucose levels in these patients must be balanced between risks and benefits. Consideration of intensive therapy must include effects of glucose control on microvascular complications, macrovascular complications, complications of therapy, and socioeconomic issues, including patient quality of life, compliance with therapy, and distribution of available funds for care of patients with diabetes.

### Microvascular disease

Both the Diabetes Control and Complications Trial (DCCT) (type 1 diabetes) and the UK Prospective Diabetes Study (UKPDS) (new-onset type 2 diabetes) showed a significant beneficial effect of glucose control on microvascular complications (2,3), as did the smaller Kumamoto study (4). Basic biochemical and animal studies provide a solid foundation for these findings, as do epidemiological studies. From a clinical standpoint, this issue is more complicated. Risk-to-benefit ratios must be considered. This has not been adequately addressed in older established patients with type 2 diabetes.

In the UKPDS the main effect of glucose control after 10.5 years was a 3/1,000 reduction in photocoagulation for retinal disease (from 1.1% in the standard arm to 0.8% in the …
Discovery and Validation of Protein Abundance Differences between Follicular Thyroid Neoplasms
Authors: Romana T. Netea-Maier, Stephen W. Hunsucker, Brigiet M. Hoevenaars, Steve M. Helmke, Pieter J. Slootweg, Ad R. Hermus, Bryan R. Haugen, Mark W. Duncan
Journal: Cancer Research (2008)

Abstract Distinguishing between benign follicular thyroid adenoma (FTA) and malignant follicular thyroid carcinoma (FTC) by cytologic features alone is not possible. Molecular markers may aid distinguishing FTA from FTC in patients with indeterminate cytology. The aim of this study is to define protein abundance differences between FTC from FTA through a discovery (proteomics) and validation (immunohistochemistry) approach. Difference gel electrophoresis (DIGE) and peptide mass fingerprinting were performed on protein extracts from five patients with FTC and compared with six patients with FTA. Individual gel comparisons (i.e., each FTC extract versus FTA pool) were also performed for the five FTC patients. Immunohistochemical validation studies were performed on three of the identified proteins. Based on DIGE images, 680 protein spots were matched on individual gels. Of these, 102 spots showed statistically significant differences in abundance between FTC and FTA in the individual gel analyses and were therefore studied further. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was used to identify 54 of these protein spots. Three candidates involved in protein folding (heat shock protein gp96, protein disulfide isomerase A3, and calreticulin) were studied by immunohistochemistry. Moderate calreticulin immunohistochemical staining was the best single marker with a high negative predictive value (88%); combining all three markers (any marker less than moderate staining) had the best positive predictive value (75%) while still retaining a good negative predictive value (68%). With DIGE, we identified 54 proteins differentially abundant between FTC and FTA. Three of these were validated by immunohistochemistry. These findings provide further insights into the diagnosis, prognosis, and pathophysiology of follicular-derived thyroid neoplasms. [Cancer Res 2008;68(5):1572–80]
Mechanisms of vascular injury
Authors: L Raij
Journal: Journal of the American Society of Nephrology (1991)

Evidence is increasing that vascular tone is highly dependent on the health of the endothelium and on the delicate balancing act between endothelium-derived relaxing and endothelium-derived contracting factors. Moreover, there is also evidence supporting the notion that the same factors which affect vascular tone also regulate, either in an autocrine or paracrine fashion, changes in vascular architecture. Synthesis and release of both endothelium-derived relaxing and contracting factors are affected by a number of physiologic and therapeutic agents as well as by other factors, among them vascular injury in disease states such as atherosclerosis, hypertension, diabetes, and acute renal failure. A number of trials indicate that therapeutic intervention may be capable of modulating the synthesis and release of these substances and the balance between the two as well as influencing the processes which control vascular remodeling.
Acute Hyperglycemia Alters Mood State and Impairs Cognitive Performance in People With Type 2 Diabetes
Authors: Andrew J. Sommerfield, Ian J. Deary, Brian M. Frier
Journal: Diabetes Care (2004)

OBJECTIVE—To examine the effects of acute hyperglycemia on cognitive function and mood in people with type 2 diabetes. RESEARCH DESIGN AND METHODS—Twenty subjects with type 2 diabetes, median age 61.5 years (range 53.1–72.0), known duration of diabetes 5.9 years (range 2.8–11.2), BMI 29.8 kg/m2 (range 22.0–34.6), and HbA1c 7.5% (range 6.7–8.4) were studied. Treatment modalities varied from antidiabetic medications to insulin. A hyperinsulinemic glucose clamp was used to maintain arterialized blood glucose at either 4.5 (euglycemia) or 16.5 mmol/l (hyperglycemia) on two occasions in a randomized and counterbalanced fashion. Tests of information processing, immediate and delayed memory, working memory, and attention were administered, along with a mood questionnaire, during each experimental condition. RESULTS—Speed of information processing, working memory, and some aspects of attention were impaired during acute hyperglycemia. Subjects were significantly more dysphoric during hyperglycemia, with reduced energetic arousal and increased sadness and anxiety. CONCLUSIONS—During acute hyperglycemia, cognitive function was impaired and mood state deteriorated in a group of people with type 2 diabetes. These findings are of practical importance because intermittent or chronic hyperglycemia is common in people with type 2 diabetes and may interfere with many daily activities through adverse effects on cognitive function and mood.
Pathogenesis of Paget's Disease: Epidermal Heregulin- , Motility Factor, and the HER Receptor Family
Authors: V. R. J. Schelfhout, E. D. Coene, B. Delaey, S. Thys, D. L. Page, C. R. De Potter
Journal: JNCI Journal of the National Cancer Institute (2000)

In Paget's disease of the breast, the epidermis of the nipple is infiltrated by large neoplastic cells of glandular origin. It has been hypothesized that the spread of Paget cells through the nipple epidermis is induced by a motility factor that acts via the HER2/NEU receptor. To test this hypothesis, we characterized and purified a motility factor released by keratinocytes and identified its target receptors in specimens from patients with Paget's disease and in SK-BR-3 breast adenocarcinoma cells, which overexpress HER2/NEU.We isolated the motility factor from keratinocyte-conditioned medium and sequenced tryptic peptides. These sequences were used to identify the motility factor as heregulin-alpha, which is released by skin keratinocytes. Heregulin-alpha induces spreading, motility, and chemotaxis of SK-BR-3 cells, as does motility factor. Motility factor activities of heregulin-alpha are inhibited by monoclonal antibody AB2, directed against the extracellular domain of HER2/NEU, which blocks the binding of heregulin-alpha. We used in situ hybridization to show that normal epidermal cells produce heregulin-alpha messenger RNA and that heregulin receptors, HER3 and/or HER4, as well as their coreceptor HER2/NEU, are expressed by Paget cells.Heregulin-alpha is a motility factor that is produced and released by normal epidermal keratinocytes and thus plays a key role in the pathogenesis of Paget's disease. Paget cells express heregulin receptors HER2/NEU, as well as HER3 and/or HER4, both of which function as a co-receptor of HER2/NEU. Binding of heregulin-alpha to the receptor complex on Paget cells results in the chemotaxis of these breast cancer cells, which eventually migrate into the overlying nipple epidermis.
Distortions in Genealogies Due to Purifying Selection
Authors: L. E. Nicolaisen, M. M. Desai
Journal: Molecular Biology and Evolution (2012)

Purifying selection can substantially alter patterns of molecular evolution. Its main effect is to reduce overall levels of genetic variation, leading to a reduced effective population size. However, it also distorts genealogies relative to neutral expectations. A structured coalescent method has been used to describe this effect, and forms the basis for numerical methods and simulations. In this study, we extend this approach by making the additional approximation that lineages may be treated independently, which is valid only in the strong selection regime. We show that in this regime, the distortions due to purifying selection can be described by a time-dependent effective population size and mutation rate, confirming earlier intuition. We calculate simple analytical expressions for these functions, Ne(t) and Ue(t). These results allow us to describe the structure of genealogies in a population under strong purifying selection as equivalent to a purely neutral population with varying population size and mutation rate, thereby enabling the use of neutral methods of inference and estimation for populations in the strong selection regime.
A Study of General Practice In Massachusetts
Authors: J. Whitney Brown
Journal: JAMA (1971)

A study of 12,835 patient visits to 15 Massachusetts practitioners indicated that while illness was the reason for 75% of the visits, nonsickness was the most common diagnosis recorded by the physician, accounting for almost 25% of the diagnoses. Fifty-two percent of the sick patients had multiple diagnoses and 20% raised additional problems about other family members. Visits were coded using the International Classification of Disease (ICD). The ICD was intended primarily as a classification of hospital patients and proved inadequate for classifying primary care. There was a correlation between the physician's age and that of his patients with the youngest physicians having the higher percentage of younger patients. The study findings suggest that some tasks proposed for the new family physician are being accomplished although none of the participating physicians were specifically trained for family medicine. The future family physician will almost certainly require different training if he is to effectively respond to the needs of his patients.
Local Hydrogel Release of Recombinant TIMP-3 Attenuates Adverse Left Ventricular Remodeling After Experimental Myocardial Infarction
Authors: Shaina R. Eckhouse, Brendan P. Purcell, Jeremy R. McGarvey, David Lobb, Christina B. Logdon, Heather Doviak, Jason W. O’Neill, James A. Shuman, Craig P. Novack, Kia N. Zellars, Sara Pettaway, Roy A. Black, Aarif Khakoo, TaeWeon Lee, Rupak Mukherjee, Joseph H. Gorman, Robert C. Gorman, Jason A. Burdick, Francis G. Spinale
Journal: Science Translational Medicine (2014)

Delivery of a hydrogel providing sustained release of recombinant TIMP-3 attenuated adverse ventricular remodeling after myocardial infarction in pigs.
Nonsense-Mediated mRNA Decay and Ubiquitin–Proteasome System Regulate Cardiac Myosin-Binding Protein C Mutant Levels in Cardiomyopathic Mice
Authors: Nicolas Vignier, Saskia Schlossarek, Bodvael Fraysse, Giulia Mearini, Elisabeth Krämer, Hervé Pointu, Nathalie Mougenot, Josiane Guiard, Rudolph Reimer, Heinrich Hohenberg, Ketty Schwartz, Muriel Vernet, Thomas Eschenhagen, Lucie Carrier
Journal: Circulation Research (2009)

Rationale: Mutations in the MYBPC3 gene encoding cardiac myosin-binding protein (cMyBP)-C are frequent causes of hypertrophic cardiomyopathy, but the mechanisms leading from mutations to disease remain elusive. Objective: The goal of the present study was therefore to gain insights into the mechanisms controlling the expression of MYBPC3 mutations. Methods and Results: We developed a cMyBP-C knock-in mouse carrying a point mutation. The level of total cMyBP-C mRNAs was 50% and 80% lower in heterozygotes and homozygotes, respectively. Surprisingly, the single G&gt;A transition on the last nucleotide of exon 6 resulted in 3 different mutant mRNAs: missense (exchange of G for A), nonsense (exon skipping, frameshift, and premature stop codon) and deletion/insertion (as nonsense but with additional partial retention of downstream intron, restoring of the reading frame, and almost full-length protein). Inhibition of nonsense-mediated mRNA decay in cultured cardiac myocytes or in vivo with emetine or cycloheximide increased the level of nonsense mRNAs severalfold but not of the other mRNAs. By using sequential protein fractionation and a new antibody directed against novel amino acids produced by the frameshift, we showed that inhibition of the proteasome with epoxomicin via osmotic minipumps increased the level of (near) full-length mutants but not of truncated proteins. Homozygotes exhibited myocyte and left ventricular hypertrophy, reduced fractional shortening, and interstitial fibrosis; heterozygotes had no major phenotype. Conclusions: These data reveal (1) an unanticipated complexity of the expression of a single point mutation in the whole animal and (2) the involvement of both nonsense-mediated mRNA decay and the ubiquitin–proteasome system in lowering the level of mutant proteins.
PATTERNING AND SPECIFICATION OF THE CEREBRAL CORTEX
Authors: Pat Levitt, Mary F. Barbe, Kathie L. Eagleson
Journal: Annual Review of Neuroscience (1997)

▪ Abstract Regionalization of the cerebral cortex occurs during development by the formation of anatomically and functionally discrete areas of the brain. Descriptive evidence based on expression of molecules and structural features suggests that an early parcelation of the cerebral wall may occur during fetal development. Experimental strategies using tissue transplants and cell culture models have explored the nature of the timing of areal specification. New signaling systems displaying the sensitivity of precursor cells to environmental cues that define the fate of neurons destined for specific areas of the cortex have been discovered. Studies in the field now suggest mechanisms of regulating cell phenotype in the cortex that are common to all parts of the neuraxis.
EPTIFIBATIDE IN POST-MYOCARDIAL INFARCTION PATIENTS WITH ONGOING ISCHEMIC PAIN WHO REFUSED FOR INTERVENTION: AJMER POST-MYOCARDIAL INFARCTION ANGINA EPTIFIBATIDE RESEARCH (AJMER) STUDY
Authors: Rajendra Gokhroo, Kamal Kishor, Deepak Padmanabhan, Devendra Bisht, Sajal Gupta, Bhanwar Ranwa
Journal: Journal of the American College of Cardiology (2014)
Improved survival for HIV infected patients with severe Pneumocystis jirovecii pneumonia is independent of highly active antiretroviral therapy
Authors: R F Miller
Journal: Thorax (2006)

Despite a decline in incidence of Pneumocystis jirovecii pneumonia (PCP), severe PCP continues to be a common cause of admission to the intensive care unit (ICU) where mortality remains high. A study was undertaken to examine the outcome from intensive care for patients with PCP and to identify prognostic factors.A retrospective cohort study was conducted of HIV infected adults admitted to a university affiliated hospital ICU between November 1990 and October 2005. Case note review collected information on demographic variables, use of prophylaxis and highly active antiretroviral therapy (HAART), and hospital course. The main outcome was 1 month mortality, either on the ICU or in hospital.Fifty nine patients were admitted to the ICU on 60 occasions. Thirty four patients (57%) required mechanical ventilation. Overall mortality was 53%. No patient received HAART before or during ICU admission. Multivariate analysis showed that the factors associated with mortality were the year of diagnosis (before mid 1996 (mortality 71%) compared with later (mortality 34%; p = 0.008)), age (p = 0.016), and the need for mechanical ventilation and/or development of pneumothorax (p = 0.031). Mortality was not associated with sex, ethnicity, prior receipt of sulpha prophylaxis, haemoglobin, serum albumin, CD4 count, PaO2, A-aO2 gradient, co-pathology in bronchoscopic lavage fluid, medical co-morbidity, APACHE II score, or duration of mechanical ventilation.Observed improved outcomes from severe PCP for patients admitted to the ICU occurred in the absence of intervention with HAART and probably reflect general improvements in ICU management of respiratory failure and ARDS rather than improvements in the management of PCP.
Association of Bone Activity, Calcium Load, Aortic Stiffness, and Calcifications in ESRD
Authors: Ge[Combining Acute Accent]rard M. London, Sylvain J. Marchais, Alain P. Gue[Combining Acute Accent]rin, Pierre Boutouyrie, Fabien Me[Combining Acute Accent]tivier, Marie-Christine de Vernejoul
Journal: Journal of the American Society of Nephrology (2008)

An inverse relationship between arterial calcifications and bone activity has been documented in patients with ESRD. Calcium overload is associated with arterial calcification, which is associated with arterial stiffening. Whether bone activity interacts with calcium load, aortic stiffness, or arterial calcification is unknown. This study assessed the impact of bone activity on the relationships between the dosage of calcium-containing phosphate binders and aortic stiffness (measured by pulse wave velocity) or abdominal aorta calcification score. Aortic stiffness and calcification were both positively associated with calcium load and negatively associated with bone activity. A significant interaction was found between dosage of calcium-containing phosphate binders and bone activity such that calcium load had a significantly greater influence on aortic calcifications and stiffening in the presence of adynamic bone disease. Independent of any other factor, including dosage of calcium-containing phosphate binders, adynamic bone was associated with greater aortic stiffening, suggesting cross-talk between the bone and arterial walls.