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Sample records for normal human heart

  1. General anesthesia suppresses normal heart rate variability in humans

    NASA Astrophysics Data System (ADS)

    Matchett, Gerald; Wood, Philip

    2014-06-01

    The human heart normally exhibits robust beat-to-beat heart rate variability (HRV). The loss of this variability is associated with pathology, including disease states such as congestive heart failure (CHF). The effect of general anesthesia on intrinsic HRV is unknown. In this prospective, observational study we enrolled 100 human subjects having elective major surgical procedures under general anesthesia. We recorded continuous heart rate data via continuous electrocardiogram before, during, and after anesthesia, and we assessed HRV of the R-R intervals. We assessed HRV using several common metrics including Detrended Fluctuation Analysis (DFA), Multifractal Analysis, and Multiscale Entropy Analysis. Each of these analyses was done in each of the four clinical phases for each study subject over the course of 24 h: Before anesthesia, during anesthesia, early recovery, and late recovery. On average, we observed a loss of variability on the aforementioned metrics that appeared to correspond to the state of general anesthesia. Following the conclusion of anesthesia, most study subjects appeared to regain their normal HRV, although this did not occur immediately. The resumption of normal HRV was especially delayed on DFA. Qualitatively, the reduction in HRV under anesthesia appears similar to the reduction in HRV observed in CHF. These observations will need to be validated in future studies, and the broader clinical implications of these observations, if any, are unknown.

  2. ATP flux through creatine kinase in the normal, stressed, and failing human heart.

    PubMed

    Weiss, Robert G; Gerstenblith, Gary; Bottomley, Paul A

    2005-01-18

    The heart consumes more energy per gram than any other organ, and the creatine kinase (CK) reaction serves as its prime energy reserve. Because chemical energy is required to fuel systolic and diastolic function, the question of whether the failing heart is "energy starved" has been debated for decades. Despite the central role of the CK reaction in cardiac energy metabolism, direct measures of CK flux in the beating human heart were not previously possible. Using an image-guided molecular assessment of endogenous ATP turnover, we directly measured ATP flux through CK in normal, stressed, and failing human hearts. We show that cardiac CK flux in healthy humans is faster than that estimated through oxidative phosphorylation and that CK flux does not increase during a doubling of the heart rate-blood pressure product by dobutamine. Furthermore, cardiac ATP flux through CK is reduced by 50% in mild-to-moderate human heart failure (1.6 +/- 0.6 vs. 3.2 +/- 0.9 micromol/g of wet weight per sec, P <0.0005). We conclude that magnetic resonance strategies can now directly assess human myocardial CK energy flux. The deficit in ATP supplied by CK in the failing heart is cardiac-specific and potentially of sufficient magnitude, even in the absence of a significant reduction in ATP stores, to contribute to the pathophysiology of human heart failure. These findings support the pursuit of new therapies that reduce energy demand and/or augment energy transfer in heart failure and indicate that cardiac magnetic resonance can be used to assess their effectiveness. PMID:15647364

  3. ATP flux through creatine kinase in the normal, stressed, and failing human heart

    PubMed Central

    Weiss, Robert G.; Gerstenblith, Gary; Bottomley, Paul A.

    2005-01-01

    The heart consumes more energy per gram than any other organ, and the creatine kinase (CK) reaction serves as its prime energy reserve. Because chemical energy is required to fuel systolic and diastolic function, the question of whether the failing heart is “energy starved” has been debated for decades. Despite the central role of the CK reaction in cardiac energy metabolism, direct measures of CK flux in the beating human heart were not previously possible. Using an image-guided molecular assessment of endogenous ATP turnover, we directly measured ATP flux through CK in normal, stressed, and failing human hearts. We show that cardiac CK flux in healthy humans is faster than that estimated through oxidative phosphorylation and that CK flux does not increase during a doubling of the heart rate-blood pressure product by dobutamine. Furthermore, cardiac ATP flux through CK is reduced by 50% in mild-to-moderate human heart failure (1.6 ± 0.6 vs. 3.2 ± 0.9 μmol/g of wet weight per sec, P < 0.0005). We conclude that magnetic resonance strategies can now directly assess human myocardial CK energy flux. The deficit in ATP supplied by CK in the failing heart is cardiac-specific and potentially of sufficient magnitude, even in the absence of a significant reduction in ATP stores, to contribute to the pathophysiology of human heart failure. These findings support the pursuit of new therapies that reduce energy demand and/or augment energy transfer in heart failure and indicate that cardiac magnetic resonance can be used to assess their effectiveness. PMID:15647364

  4. Increased Heart Rate Variability but Normal Resting Metabolic Rate in Hypocretin/Orexin-Deficient Human Narcolepsy

    PubMed Central

    Fronczek, Rolf; Overeem, Sebastiaan; Reijntjes, Robert; Lammers, Gert Jan; van Dijk, J. Gert; Pijl, Hanno

    2008-01-01

    Study Objectives: We investigated autonomic balance and resting metabolic rate to explore their possible involvement in obesity in hypocretin/orexin-deficient narcoleptic subjects. Methods: Resting metabolic rate (using indirect calorimetry) and variability in heart rate and blood pressure were determined in the fasted resting state. Subjects included 15 untreated, hypocretin-deficient male narcoleptics and 15 male controls matched for age and body mass index. Results: Spectral power analysis revealed greater heart rate and blood pressure variability in hypocretin-deficient male narcoleptic patients (heart rate: p = 0.01; systolic blood pressure: p = 0.02; diastolic: p < 0.01). The low to high frequency ratio of heart rate power did not differ between groups (p = 0.48), nor did resting metabolic rate (controls: 1767 ± 226 kcal/24 h; patients: 1766 ± 227 kcal/24h; p = 0.99). Conclusions: Resting metabolic rate was not reduced in hypocretin-deficient narcoleptic men and therefore does not explain obesity in this group. Whether the increased heart rate and blood pressure variability—suggesting reduced sympathetic tone—is involved in this regard remains to be elucidated. Citation: Fronczek R; Overeem S; Reijntjes R; Lammers GJ; van Dijk JG; Pijl H. Increased heart rate variability but normal resting metabolic rate in hypocretin/orexin-deficient human narcolepsy. J Clin Sleep Med 2008;4(3):248–254. PMID:18595438

  5. Normal and abnormal consequences of apoptosis in the human heart: from postnatal morphogenesis to paroxysmal arrhythmias.

    PubMed Central

    James, T. N.

    1994-01-01

    Apoptosis and necrosis are two distinctly different forms of cell death and both occur in the human heart. In contrast to necrosis, apoptosis is not associated with inflammation and there are two reasons for this. The apoptotic cell does not swell or rupture prior to its being engulfed by either a macrophage or even a neighboring like cell. And the phagocytosis occurs with unusual rapidity. Apoptosis, also thought of as cell suicide, is a tidy way of removing cells no longer useful, in essence a form of selective deletion. These features make apoptosis a valuable component of morphogenesis, mediation of hormonal and immunological responses, and the homeostatic balance between hypertrophy and atrophy or involution. In the human heart apoptosis has been found in the sinus node of patients with the long QT syndrome. It most likely participates in the important postnatal morphogenesis of the sinus node, AV (atrioventricular) node and His bundle. Apoptosis may also participate in the genesis and pathophysiology of cardiomyopathy, paroxysmal arrhythmias or conduction disturbances (some of which may be responsible for sudden death), focal fibromuscular dysplasia of small coronary arteries, hereditary medial degeneration of the tunica media of coronary arteries, and arrhythmogenic right ventricular dysplasia. The possible role of apoptosis in numerous other changes in the human heart merit future investigation, among them being the pathogenesis of atherosclerosis and mechanisms of ageing in the myocardium. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 7 Fig. 8 Fig. 9 Fig. 10 Fig. 11 Fig. 12 Fig. 13 Fig. 14 PMID:7974966

  6. Distribution of normal human left ventricular myofiber stress at end diastole and end systole: a target for in silico design of heart failure treatments

    PubMed Central

    Genet, Martin; Lee, Lik Chuan; Nguyen, Rebecca; Haraldsson, Henrik; Acevedo-Bolton, Gabriel; Zhang, Zhihong; Ge, Liang; Ordovas, Karen; Kozerke, Sebastian

    2014-01-01

    Ventricular wall stress is believed to be responsible for many physical mechanisms taking place in the human heart, including ventricular remodeling, which is frequently associated with heart failure. Therefore, normalization of ventricular wall stress is the cornerstone of many existing and new treatments for heart failure. In this paper, we sought to construct reference maps of normal ventricular wall stress in humans that could be used as a target for in silico optimization studies of existing and potential new treatments for heart failure. To do so, we constructed personalized computational models of the left ventricles of five normal human subjects using magnetic resonance images and the finite-element method. These models were calibrated using left ventricular volume data extracted from magnetic resonance imaging (MRI) and validated through comparison with strain measurements from tagged MRI (950 ± 170 strain comparisons/subject). The calibrated passive material parameter values were C0 = 0.115 ± 0.008 kPa and B0 = 14.4 ± 3.18; the active material parameter value was Tmax = 143 ± 11.1 kPa. These values could serve as a reference for future construction of normal human left ventricular computational models. The differences between the predicted and the measured circumferential and longitudinal strains in each subject were 3.4 ± 6.3 and 0.5 ± 5.9%, respectively. The predicted end-diastolic and end-systolic myofiber stress fields for the five subjects were 2.21 ± 0.58 and 16.54 ± 4.73 kPa, respectively. Thus these stresses could serve as targets for in silico design of heart failure treatments. PMID:24876359

  7. Reconstruction and Visualization of Fiber and Laminar Structure inthe Normal Human Heart from Ex Vivo DTMRI Data

    SciTech Connect

    Rohmer, Damien; Sitek, Arkadiusz; Gullberg, Grant T.

    2006-12-18

    Background - The human heart is composed of a helicalnetwork of muscle fibers. These fibers are organized to form sheets thatare separated by cleavage surfaces. This complex structure of fibers andsheets is responsible for the orthotropic mechanical properties ofcardiac muscle. The understanding of the configuration of the 3D fiberand sheet structure is important for modeling the mechanical andelectrical properties of the heart and changes in this configuration maybe of significant importance to understand the remodeling aftermyocardial infarction.Methods - Anisotropic least square filteringfollowed by fiber and sheet tracking techniques were applied to DiffusionTensor Magnetic Resonance Imaging (DTMRI) data of the excised humanheart. The fiber configuration was visualized by using thin tubes toincrease 3-dimensional visual perception of the complex structure. Thesheet structures were reconstructed from the DTMRI data, obtainingsurfaces that span the wall from the endo- to the epicardium. Allvisualizations were performed using the high-quality ray-tracing softwarePOV-Ray. Results - The fibers are shown to lie in sheets that haveconcave or convex transmural structure which correspond to histologicalstudies published in the literature. The fiber angles varied depending onthe position between the epi- and endocardium. The sheets had a complexstructure that depended on the location within the myocardium. In theapex region the sheets had more curvature. Conclusions - A high-qualityvisualization algorithm applied to demonstrated high quality DTMRI datais able to elicit the comprehension of the complex 3 dimensionalstructure of the fibers and sheets in the heart.

  8. Premature Ventricular Complexes in Apparently Normal Hearts.

    PubMed

    Luebbert, Jeffrey; Auberson, Denise; Marchlinski, Francis

    2016-09-01

    Premature ventricular complexes (PVCs) are consistently associated with worse prognosis and higher morbidity and mortality. This article reviews PVCs and their presentation in patients with an apparently normal heart. Patients with PVCs may be completely asymptomatic, whereas others may note severely disabling symptoms. Cardiomyopathy may occur with frequent PVCs. Diagnostic work-up is directed at obtaining 12-lead ECG to characterize QRS morphology, Holter monitor to assess frequency, and echo and advanced imaging to assess for early cardiomyopathy and exclude structural heart disease. Options for management include watchful waiting, medical therapy, or catheter ablation. Malignant variants of PVCs may induce ventricular fibrillation even in a normal heart. PMID:27521085

  9. Effect of mental challenge induced by movie clips on action potential duration in normal human subjects independent of heart rate

    PubMed Central

    Child, Nicholas; Hanson, Ben; Bishop, Martin; Rinaldi, Christopher A; Bostock, Julian; Western, David; Cooklin, Michael; O’Neil, Mark; Wright, Matthew; Razavi, Reza; Gill, Jaswinder; Taggart, Peter

    2014-01-01

    Background Mental stress and emotion have long been associated with ventricular arrhythmias and sudden death in animal models and humans. The effect of mental challenge on ventricular action potential duration (APD) in conscious healthy humans has not been reported. Methods and Results Activation recovery intervals (ARI) measured from unipolar electrograms as a surrogate for APD (n=19) were recorded from right and left ventricular endocardium during steady state pacing while subjects watched an emotionally charged film clip. To assess the possible modulating role of altered respiration on APD, the subjects then repeated the same breathing pattern they had during the stress, but without the movie clip. Haemodynamic parameters (mean, systolic, and diastolic blood pressure, and rate of pressure increase) and respiration rate increased during the stressful part of the film clip (p=0.001). APD decreased during the stressful parts of the film clip, eg for global RV ARI at end of film clip 193.8ms (SD 14) vs 198.0ms (SD13) during the matched breathing control (end film LV 199.8ms (SD16) vs control 201.6ms (SD15), p=0.004. Respiration rate increased during the stressful part of the film clip (by 2 breaths/minute), and was well matched in the respective control period without any haemodynamic or ARI changes. Conclusions Our results document for the first time direct recordings of the effect of a mental challenge protocol on ventricular action potential duration in conscious humans. The effect of mental challenge on APD was not secondary to emotionally-induced altered respiration or heart rate. PMID:24833641

  10. Cloning, chromosomal localization, and functional expression of the alpha 1 subunit of the L-type voltage-dependent calcium channel from normal human heart.

    PubMed Central

    Schultz, D; Mikala, G; Yatani, A; Engle, D B; Iles, D E; Segers, B; Sinke, R J; Weghuis, D O; Klöckner, U; Wakamori, M

    1993-01-01

    A unique structural variant of the cardiac L-type voltage-dependent calcium channel alpha 1 subunit cDNA was isolated from libraries derived from normal human heart mRNA. The deduced amino acid sequence shows significant homology to other calcium channel alpha 1 subunits. However, differences from the rabbit heart alpha 1 include a shortened N-terminus, a unique C-terminal insertion, and both forms of an alternatively spliced motif IV S3 region. The shortened N-terminus provides optimal access to consensus sequences thought to facilitate translation. Northern blot analysis revealed a single hybridizing mRNA species of 9.4 kb. The gene for the human heart alpha 1 subunit was localized specifically to the distal region of chromosome 12p13. The cloned alpha 1 subunit was expressed in Xenopus oocytes and single-channel analyses revealed native-like pharmacology and channel properties. Images Fig. 3 Fig. 4 Fig. 5 PMID:8392192

  11. The Battle of "The Normal Heart."

    ERIC Educational Resources Information Center

    Rottman, Larry

    1990-01-01

    The history of the controversy over Southwest Missouri State University's production of "The Normal Heart," a play about acquired immune deficiency syndrome, is chronicled and concern is expressed about the resurgence of bitterness and hatred in the debate over academic freedom, even within the academic community. (MSE)

  12. Robert Feulgen Prize Lecture. Distribution and role of gap junctions in normal myocardium and human ischaemic heart disease.

    PubMed

    Green, C R; Severs, N J

    1993-02-01

    In the heart, individual cardiac muscle cells are linked by gap junctions. These junctions form low resistance pathways along which the electrical impulse flows rapidly and repeatedly between all the cells of the myocardium, ensuring their synchronous contraction. To obtain probes for mapping the distribution of gap junctions in cardiac tissue, polyclonal antisera were raised to three synthetic peptides, each matching different cytoplasmically exposed portions of the sequence of connexin43, the major gap-junctional protein reported in the heart. The specificity of each antiserum for the peptide to which it was raised was established by dot blotting. New methods were developed for isolating enriched fractions of gap junctions from whole heart and from dissociated adult myocytes, in which detergent-treatment and raising the temperature (potentially damaging steps in previously described techniques) are avoided. Analysis of these fractions by SDS-polyacrylamide gel electrophoresis revealed major bands at 43 kDa (matching the molecular mass of connexin43) and at 70 kDa. Western blot experiments using our antisera indicated that both the 43-kDa and the 70-kDa bands represent cardiac gap-junctional proteins. Pre-embedding immunogold labelling of isolated gap junctions and post-embedding immunogold labelling of Lowicryl-embedded whole tissue demonstrated the specific binding of the antibodies to ultrastructurally defined gap junctions. One antiserum (raised to residues 131-142) was found to be particularly effective for cytochemical labelling. Using this antiserum for immunofluorescence labelling in combination with confocal scanning laser microscopy enabled highly sensitive detection and three-dimensional mapping of gap junctions through thick slices of cardiac tissue. By means of the serial optical sectioning ability of the confocal microscope, images of the entire gap junction population of complete en face-viewed disks were reconstructed. These reconstructions reveal

  13. Cardiac telocytes in normal and diseased hearts.

    PubMed

    Kostin, Sawa

    2016-07-01

    Our previous studies suggested that an important variable of the progression of contractile dysfunction to terminal heart failure is the imbalance between myocyte cell death and myocyte renewal. For this reason, preventing myocyte cell death and an increasing generation of new myocytes may represent attractive targets in the treatment of human heart failure. Prospective clues to enhance myocardial regeneration are the newly discovered cells termed telocytes, formerly called interstitial Cajal-like cells, which are believed to nurse or guide the endogenous and exogenous stem cells for activation and commitment, but they also act as supporting cells for progenitor cells migration toward injured myocardium. We have recently found that telocytes are reduced in the diseased and failing myocardium. Importantly, the imbalance between telocyte proliferation and telocyte death is responsible for the telocytes depletion in cardiac diseases leading to heart failure. We have also demonstrated that telocytes are influenced by the extracellular matrix protein composition such that the telocytes are almost absent in areas of severe fibrosis. It is plausible that the reduction in telocytes in diseased human hearts could participate in the abnormal three-dimensional spatial organization and disturbed intercellular signalling of the myocardium. Decreased telocytes in diseased hearts would also be predicted to alter the property of telocytes to maintain cardiac stem cell niche by decreasing the pool of cardiac stem cells and thereby impairing cardiac regeneration. PMID:26912117

  14. Non-invasive estimation of myocardial efficiency using positron emission tomography and carbon-11 acetate--comparison between the normal and failing human heart.

    PubMed

    Bengel, F M; Permanetter, B; Ungerer, M; Nekolla, S; Schwaiger, M

    2000-03-01

    The clearance kinetics of carbon-11 acetate, assessed by positron emission tomography (PET), can be combined with measurements of ventricular function for non-invasive estimation of myocardial oxygen consumption and efficiency. In the present study, this approach was applied to gain further insights into alterations in the failing heart by comparison with results obtained in normals. We studied ten patients with idiopathic dilated cardiomyopathy (DCM) and 11 healthy normals by dynamic PET with 11C-acetate and either tomographic radionuclide ventriculography or cine magnetic resonance imaging. A "stroke work index" (SWI) was calculated by: SWI = systolic blood pressure x stroke volume/body surface area. To estimate myocardial efficiency, a "work-metabolic index" (WMI) was then obtained as follows: WMI = SWI x heart rate/k(mono), where k(mono) is the washout constant for 11C-acetate derived from monoexponential fitting. In DCM patients, left ventricular ejection fraction was 19%+/-10% and end-diastolic volume was 92+/-28 ml/m2 (vs 64%+/-7% and 55+/-8 ml/m2 in normals, P<0.001). Myocardial oxidative metabolism, reflected by k(mono), was significantly lower compared with that in normals (0.040+/-0.011/min vs 0.060+/-0.015/min; P<0.003). The SWI (1674+/-761 vs 4736+/-895 mmHg x ml/m2; P<0.001) and the WMI as an estimate of efficiency (2.98+/-1.30 vs 6.20+/-2.25 x 10(6) mmHg x ml/m2; P<0.001) were lower in DCM patients, too. Overall, the WMI correlated positively with ejection parameters (r=0.73, P<0.001 for ejection fraction; r=0.93, P<0.001 for stroke volume), and inversely with systemic vascular resistance (r=-0.77; P<0.001). There was a weak positive correlation between WMI and end-diastolic volume in normals (r=0.45; P=0.17), while in DCM patients, a non-significant negative correlation coefficient (r=-0.21; P=0.57) was obtained. In conclusion non-invasive estimates of oxygen consumption and efficiency in the failing heart were reduced compared with those in normals

  15. Screening for Heart Murmurs. What's Normal and What's Not.

    ERIC Educational Resources Information Center

    Pflieger, Kurt L.; Strong, William B.

    1992-01-01

    A step-by-step guide to auscultating young athletes helps physicians identify normal heart murmurs as well as sounds that might signify underlying cardiac pathology. Rapid, thorough preparticipation screening can help differentiate athletes who may require treatment or activity restriction from those with normal murmurs who can remain active. (SM)

  16. Introduction to Controversial Topics in Nonlinear Science: Is the Normal Heart Rate Chaotic?

    NASA Astrophysics Data System (ADS)

    Glass, Leon

    2009-06-01

    In June 2008, the editors of Chaos decided to institute a new section to appear from time to time that addresses timely and controversial topics related to nonlinear science. The first of these deals with the dynamical characterization of human heart rate variability. We asked authors to respond to the following questions: Is the normal heart rate chaotic? If the normal heart rate is not chaotic, is there some more appropriate term to characterize the fluctuations (e.g., scaling, fractal, multifractal)? How does the analysis of heart rate variability elucidate the underlying mechanisms controlling the heart rate? Do any analyses of heart rate variability provide clinical information that can be useful in medical assessment (e.g., in helping to assess the risk of sudden cardiac death)? If so, please indicate what additional clinical studies would be useful for measures of heart rate variability to be more broadly accepted by the medical community. In addition, as a challenge for analysis methods, PhysioNet [A. L. Goldberger et al., "PhysioBank, PhysioToolkit, and PhysioNet: Components of a new research resource for complex physiologic signals," Circulation 101, e215-e220 (2000)] provided data sets from 15 patients of whom five were normal, five had heart failure, and five had atrial fibrillation (http://www.physionet.org/challenge/chaos/). This introductory essay summarizes the main issues and introduces the essays that respond to these questions.

  17. Biventricular thrombosis in a structurally normal heart at high altitude

    PubMed Central

    Malani, Susheel; Chadha, Davinder; Banerji, Anup

    2014-01-01

    We present a rare case of biventricular thrombus in a young patient with a structurally normal heart at high altitude, complicated with pulmonary embolism. Detailed evaluation revealed him to have protein S deficiency. Altered environmental conditions at high altitude associated with protein S deficiency resulted in thrombus formation at an unusual location; the same is discussed in this case report. PMID:24879736

  18. A novel distributed model of the heart under normal and congestive heart failure conditions.

    PubMed

    Ravanshadi, Samin; Jahed, Mehran

    2013-04-01

    Conventional models of cardiovascular system frequently lack required detail and focus primarily on the overall relationship between pressure, flow and volume. This study proposes a localized and regional model of the cardiovascular system. It utilizes noninvasive blood flow and pressure seed data and temporal cardiac muscle regional activity to predict the operation of the heart under normal and congestive heart failure conditions. The analysis considers specific regions of the heart, namely, base, mid and apex of left ventricle. The proposed method of parameter estimation for hydraulic electric analogy model is recursive least squares algorithm. Based on simulation results and comparison to clinical data, effect of congestive heart failure in the heart is quantified. Accumulated results for simulated ejection fraction percentage of the apex, mid and base regions of the left ventricle in congestive heart failure condition were 39 ± 6, 36 ± 9 and 38 ± 8, respectively. These results are shown to satisfactorily match those found through clinical measurements. The proposed analytical method can in effect be utilized as a preclinical and predictive tool for high-risk heart patients and candidates for heart transplant, assistive device and total artificial heart. PMID:23637212

  19. Universal structures of normal and pathological heart rate variability

    PubMed Central

    Gañán-Calvo, Alfonso M.; Fajardo-López, Juan

    2016-01-01

    The circulatory system of living organisms is an autonomous mechanical system softly tuned with the respiratory system, and both developed by evolution as a response to the complex oxygen demand patterns associated with motion. Circulatory health is rooted in adaptability, which entails an inherent variability. Here, we show that a generalized N-dimensional normalized graph representing heart rate variability reveals two universal arrhythmic patterns as specific signatures of health one reflects cardiac adaptability, and the other the cardiac-respiratory rate tuning. In addition, we identify at least three universal arrhythmic profiles whose presences raise in proportional detriment of the two healthy ones in pathological conditions (myocardial infarction; heart failure; and recovery from sudden death). The presence of the identified universal arrhythmic structures together with the position of the centre of mass of the heart rate variability graph provide a unique quantitative assessment of the health-pathology gradient. PMID:26912108

  20. Universal structures of normal and pathological heart rate variability.

    PubMed

    Gañán-Calvo, Alfonso M; Fajardo-López, Juan

    2016-01-01

    The circulatory system of living organisms is an autonomous mechanical system softly tuned with the respiratory system, and both developed by evolution as a response to the complex oxygen demand patterns associated with motion. Circulatory health is rooted in adaptability, which entails an inherent variability. Here, we show that a generalized N-dimensional normalized graph representing heart rate variability reveals two universal arrhythmic patterns as specific signatures of health one reflects cardiac adaptability, and the other the cardiac-respiratory rate tuning. In addition, we identify at least three universal arrhythmic profiles whose presences raise in proportional detriment of the two healthy ones in pathological conditions (myocardial infarction; heart failure; and recovery from sudden death). The presence of the identified universal arrhythmic structures together with the position of the centre of mass of the heart rate variability graph provide a unique quantitative assessment of the health-pathology gradient. PMID:26912108

  1. Systems Biology Applied to Heart Failure With Normal Ejection Fraction

    PubMed Central

    Mesquita, Evandro Tinoco; Jorge, Antonio Jose Lagoeiro; de Souza, Celso Vale; Cassino, João Paulo Pedroza

    2014-01-01

    Heart failure with normal ejection fraction (HFNEF) is currently the most prevalent clinical phenotype of heart failure. However, the treatments available have shown no reduction in mortality so far. Advances in the omics sciences and techniques of high data processing used in molecular biology have enabled the development of an integrating approach to HFNEF based on systems biology. This study aimed at presenting a systems-biology-based HFNEF model using the bottom-up and top-down approaches. A literature search was conducted for studies published between 1991 and 2013 regarding HFNEF pathophysiology, its biomarkers and systems biology. A conceptual model was developed using bottom-up and top-down approaches of systems biology. The use of systems-biology approaches for HFNEF, a complex clinical syndrome, can be useful to better understand its pathophysiology and to discover new therapeutic targets. PMID:24918915

  2. Data from acellular human heart matrix.

    PubMed

    Sánchez, Pedro L; Fernández-Santos, M Eugenia; Espinosa, M Angeles; González-Nicolas, M Angeles; Acebes, Judith R; Costanza, Salvatore; Moscoso, Isabel; Rodríguez, Hugo; García, Julio; Romero, Jesús; Kren, Stefan M; Bermejo, Javier; Yotti, Raquel; Del Villar, Candelas Pérez; Sanz-Ruiz, Ricardo; Elizaga, Jaime; Taylor, Doris A; Fernández-Avilés, Francisco

    2016-09-01

    Perfusion decellularization of cadaveric hearts removes cells and generates a cell-free extracellular matrix scaffold containing acellular vascular conduits, which are theoretically sufficient to perfuse and support tissue-engineered heart constructs. This article contains additional data of our experience decellularizing and testing structural integrity and composition of a large series of human hearts, "Acellular human heart matrix: a critical step toward whole heat grafts" (Sanchez et al., 2015) [1]. Here we provide the information about the heart decellularization technique, the valve competence evaluation of the decellularized scaffolds, the integrity evaluation of epicardial and myocardial coronary circulation, the pressure volume measurements, the primers used to assess cardiac muscle gene expression and, the characteristics of donors, donor hearts, scaffolds and perfusion decellularization process. PMID:27331090

  3. Predictability of normal heart rhythms and deterministic chaos

    NASA Astrophysics Data System (ADS)

    Lefebvre, J. H.; Goodings, D. A.; Kamath, M. V.; Fallen, E. L.

    1993-04-01

    The evidence for deterministic chaos in normal heart rhythms is examined. Electrocardiograms were recorded of 29 subjects falling into four groups—a young healthy group, an older healthy group, and two groups of patients who had recently suffered an acute myocardial infarction. From the measured R-R intervals, a time series of 1000 first differences was constructed for each subject. The correlation integral of Grassberger and Procaccia was calculated for several subjects using these relatively short time series. No evidence was found for the existence of an attractor having a dimension less than about 4. However, a prediction method recently proposed by Sugihara and May and an autoregressive linear predictor both show that there is a measure of short-term predictability in the differenced R-R intervals. Further analysis revealed that the short-term predictability calculated by the Sugihara-May method is not consistent with the null hypothesis of a Gaussian random process. The evidence for a small amount of nonlinear dynamical behavior together with the short-term predictability suggest that there is an element of deterministic chaos in normal heart rhythms, although it is not strong or persistent. Finally, two useful parameters of the predictability curves are identified, namely, the `first step predictability' and the `predictability decay rate,' neither of which appears to be significantly correlated with the standard deviation of the R-R intervals.

  4. On the nature of heart rate variability in a breathing normal subject: A stochastic process analysis

    NASA Astrophysics Data System (ADS)

    Buchner, Teodor; Petelczyc, Monika; Żebrowski, Jan J.; Prejbisz, Aleksander; Kabat, Marek; Januszewicz, Andrzej; Piotrowska, Anna Justyna; Szelenberger, Waldemar

    2009-06-01

    Human heart rate is moderated by the autonomous nervous system acting predominantly through the sinus node (the main cardiac physiological pacemaker). One of the dominant factors that determine the heart rate in physiological conditions is its coupling with the respiratory rhythm. Using the language of stochastic processes, we analyzed both rhythms simultaneously taking the data from polysomnographic recordings of two healthy individuals. Each rhythm was treated as a sum of a deterministic drift term and a diffusion term (Kramers-Moyal expansion). We found that normal heart rate variability may be considered as the result of a bidirectional coupling of two nonlinear oscillators: the heart itself and the respiratory system. On average, the diffusion (noise) component measured is comparable in magnitude to the oscillatory (deterministic) term for both signals investigated. The application of the Kramers-Moyal expansion may be useful for medical diagnostics providing information on the relation between respiration and heart rate variability. This interaction is mediated by the autonomous nervous system, including the baroreflex, and results in a commonly observed phenomenon—respiratory sinus arrhythmia which is typical for normal subjects and often impaired by pathology.

  5. Cardiac troponin T is necessary for normal development in the embryonic chick heart.

    PubMed

    England, Jennifer; Pang, Kar Lai; Parnall, Matthew; Haig, Maria Isabel; Loughna, Siobhan

    2016-09-01

    The heart is the first functioning organ to develop during embryogenesis. The formation of the heart is a tightly regulated and complex process, and alterations to its development can result in congenital heart defects. Mutations in sarcomeric proteins, such as alpha myosin heavy chain and cardiac alpha actin, have now been associated with congenital heart defects in humans, often with atrial septal defects. However, cardiac troponin T (cTNT encoded by gene TNNT2) has not. Using gene-specific antisense oligonucleotides, we have investigated the role of cTNT in chick cardiogenesis. TNNT2 is expressed throughout heart development and in the postnatal heart. TNNT2-morpholino treatment resulted in abnormal atrial septal growth and a reduction in the number of trabeculae in the developing primitive ventricular chamber. External analysis revealed the development of diverticula from the ventricular myocardial wall which showed no evidence of fibrosis and still retained a myocardial phenotype. Sarcomeric assembly appeared normal in these treated hearts. In humans, congenital ventricular diverticulum is a rare condition, which has not yet been genetically associated. However, abnormal haemodynamics is known to cause structural defects in the heart. Further, structural defects, including atrial septal defects and congenital diverticula, have previously been associated with conduction anomalies. Therefore, to provide mechanistic insights into the effect that cTNT knockdown has on the developing heart, quantitative PCR was performed to determine the expression of the shear stress responsive gene NOS3 and the conduction gene TBX3. Both genes were differentially expressed compared to controls. Therefore, a reduction in cTNT in the developing heart results in abnormal atrial septal formation and aberrant ventricular morphogenesis. We hypothesize that alterations to the haemodynamics, indicated by differential NOS3 expression, causes these abnormalities in growth in cTNT knockdown

  6. Human myocardial Na,K-ATPase concentration in heart failure.

    PubMed

    Bundgaard, H; Kjeldsen, K

    1996-01-01

    The Na,K-ATPase is of major importance for active ion transport across the sarcolemma and thus for electrical as well as contractile function of the myocardium. Furthermore, it is receptor for digitalis glycosides. In human studies of the regulatory aspects of myocardial Na,K-ATPase concentration a major problem has been to obtain tissue samples. Methodological accomplishments in quantification of myocardial Na,K-ATPase using vanadate facilitated 3H-ouabain binding to intact samples have, however, made it possible to obtain reliable measurements on human myocardial necropsies obtained at autopsy as well as on biopsies of a wet weight of only 1-2 mg obtained during heart catheterisation. However, access to the ultimately, normal, vital myocardial tissue has come from the heart transplantation programs, through which myocardial samples from cardiovascular healthy organ donors have become available. In the present paper we evaluate the various values reported for normal human myocardial Na,K-ATPase concentration, its regulation in heart disease and the association with digitalization. Normal myocardial Na,K-ATPase concentration level is found to be 700 pmol/g wet weight. No major variations were found between or within the walls of the heart ventricles. During the first few years of life a marked decrease in myocardial Na,K-ATPase concentration is followed by a stable level obtained in early adulthood and normally maintained throughout life. In patients with enlarged cardiac x-ray silhouette a significant positive, linear correlation between left ventricular ejection fraction (EF) and Na,K-ATPase concentration was established. A maximum reduction in Na,K-ATPase concentration of 89% was obtained when EF was reduced to 20%. Generally, heart failure associated with heart dilatation, myocardial hypertrophy as well as ischaemic heart disease is associated with reductions in myocardial Na,K-ATPase concentration of around 25%. During digoxin treatment of heart failure

  7. Streptococcus agalactiae mural infective endocarditis in a structurally normal heart

    PubMed Central

    Ariyoshi, Nobuhiro; Miyamoto, Keisuke; Bolger, Dennis T.

    2016-01-01

    A 38-year-old Caucasian man with uncontrolled diabetes mellitus type 2 was admitted with a 1-week duration of fevers, chills, and a non-productive cough. He had a left ischiorectal abscess 1 month prior to admission. Physical examination revealed caries on a left upper molar and a well-healed scar on the left buttock, but no heart murmur or evidence of micro-emboli. Blood cultures grew Streptococcus agalactiae. A transesophageal echocardiogram revealed a mobile mass in the right ventricle that attached to chordae tendineae without valvular disease or dysfunction. A computed tomography (CT) with contrast revealed the mass within the right ventricle, a left lung cavitary lesion, and a splenic infarction. He was initially treated with penicillin G for a week. Subsequently, ceftriaxone was continued for a total of 8 weeks. A follow-up CT showed no evidence of right ventricular mass 8 weeks after discharge. This is the first reported case of S. agalactiae mural infective endocarditis in a structurally normal heart. PMID:27124171

  8. Streptococcus agalactiae mural infective endocarditis in a structurally normal heart.

    PubMed

    Ariyoshi, Nobuhiro; Miyamoto, Keisuke; Bolger, Dennis T

    2016-01-01

    A 38-year-old Caucasian man with uncontrolled diabetes mellitus type 2 was admitted with a 1-week duration of fevers, chills, and a non-productive cough. He had a left ischiorectal abscess 1 month prior to admission. Physical examination revealed caries on a left upper molar and a well-healed scar on the left buttock, but no heart murmur or evidence of micro-emboli. Blood cultures grew Streptococcus agalactiae. A transesophageal echocardiogram revealed a mobile mass in the right ventricle that attached to chordae tendineae without valvular disease or dysfunction. A computed tomography (CT) with contrast revealed the mass within the right ventricle, a left lung cavitary lesion, and a splenic infarction. He was initially treated with penicillin G for a week. Subsequently, ceftriaxone was continued for a total of 8 weeks. A follow-up CT showed no evidence of right ventricular mass 8 weeks after discharge. This is the first reported case of S. agalactiae mural infective endocarditis in a structurally normal heart. PMID:27124171

  9. [Sudden cardiac death in individuals with normal hearts: an update].

    PubMed

    González-Melchor, Laila; Villarreal-Molina, Teresa; Iturralde-Torres, Pedro; Medeiros-Domingo, Argelia

    2014-01-01

    Sudden death (SD) is a tragic event and a world-wide health problem. Every year, near 4-5 million people experience SD. SD is defined as the death occurred in 1h after the onset of symptoms in a person without previous signs of fatality. It can be named "recovered SD" when the case received medical attention, cardiac reanimation effective defibrillation or both, surviving the fatal arrhythmia. Cardiac channelopathies are a group of diseases characterized by abnormal ion channel function due to genetic mutations in ion channel genes, providing increased susceptibility to develop cardiac arrhythmias and SD. Usually the death occurs before 40 years of age and in the autopsy the heart is normal. In this review we discuss the main cardiac channelopathies involved in sudden cardiac death along with current management of cases and family members that have experienced such tragic event. PMID:25128006

  10. Mitochondrial Fission and Autophagy in the Normal and Diseased Heart

    PubMed Central

    Iglewski, Myriam; Hill, Joseph A.; Lavandero, Sergio; Rothermel, Beverly A.

    2011-01-01

    Sustained hypertension promotes structural, functional and metabolic remodeling of cardiomyocyte mitochondria. As long-lived, postmitotic cells, cardiomyocytes turn over mitochondria continuously to compensate for changes in energy demands and to remove damaged organelles. This process involves fusion and fission of existing mitochondria to generate new organelles and separate old ones for degradation via autophagy. Autophagy is a lysosome-dependent proteolytic pathway capable of processing cellular components, including organelles and protein aggregates. Autophagy can be either nonselective or selective and contributes to remodeling of the myocardium under stress. Fission of mitochondria, loss of membrane potential, and ubiquitination are emerging as critical steps that direct selective autophagic degradation of mitochondria. This review discusses the molecular mechanisms controlling mitochondrial dynamics, including fission, fusion, transport, and degradation. Furthermore, it examines recent studies revealing the importance of these processes in normal and diseased heart. PMID:20865352

  11. Galnt1 Is Required for Normal Heart Valve Development and Cardiac Function

    PubMed Central

    Tian, E; Stevens, Sharon R.; Guan, Yu; Springer, Danielle A.; Anderson, Stasia A.; Starost, Matthew F.; Patel, Vyomesh; Ten Hagen, Kelly G.; Tabak, Lawrence A.

    2015-01-01

    Congenital heart valve defects in humans occur in approximately 2% of live births and are a major source of compromised cardiac function. In this study we demonstrate that normal heart valve development and cardiac function are dependent upon Galnt1, the gene that encodes a member of the family of glycosyltransferases (GalNAc-Ts) responsible for the initiation of mucin-type O-glycosylation. In the adult mouse, compromised cardiac function that mimics human congenital heart disease, including aortic and pulmonary valve stenosis and regurgitation; altered ejection fraction; and cardiac dilation, was observed in Galnt1 null animals. The underlying phenotype is aberrant valve formation caused by increased cell proliferation within the outflow tract cushion of developing hearts, which is first detected at developmental stage E11.5. Developing valves from Galnt1 deficient animals displayed reduced levels of the proteases ADAMTS1 and ADAMTS5, decreased cleavage of the proteoglycan versican and increased levels of other extracellular matrix proteins. We also observed increased BMP and MAPK signaling. Taken together, the ablation of Galnt1 appears to disrupt the formation/remodeling of the extracellular matrix and alters conserved signaling pathways that regulate cell proliferation. Our study provides insight into the role of this conserved protein modification in cardiac valve development and may represent a new model for idiopathic valve disease. PMID:25615642

  12. Morphology and biomechanics of human heart

    NASA Astrophysics Data System (ADS)

    Chelnokova, Natalia O.; Golyadkina, Anastasiya A.; Kirillova, Irina V.; Polienko, Asel V.; Ivanov, Dmitry V.

    2016-03-01

    Object of study: A study of the biomechanical characteristics of the human heart ventricles was performed. 80 hearts were extracted during autopsy of 80 corpses of adults (40 women and 40 men) aged 31-70 years. The samples were investigated in compliance with the recommendations of the ethics committee. Methods: Tension and compression tests were performed with help of the uniaxial testing machine Instron 5944. Cardiometry was also performed. Results: In this work, techniques for human heart ventricle wall biomechanical properties estimation were developed. Regularities of age and gender variability in deformative and strength properties of the right and left ventricle walls were found. These properties were characterized by a smooth growth of myocardial tissue stiffness and resistivity at a relatively low strain against reduction in their strength and elasticity from 31-40 to 61-70 years. It was found that tissue of the left ventricle at 61-70 years had a lower stretchability and strength compared with tissues of the right ventricle and septum. These data expands understanding of the morphological organization of the heart ventricles, which is very important for the development of personalized medicine. Taking into account individual, age and gender differences of the heart ventricle tissue biomechanical characteristics allows to rationally choosing the type of patching materials during reconstructive operations on heart.

  13. Assessment of QT-prolonging drugs in the isolated normal and failing rabbit hearts.

    PubMed

    Kijtawornrat, Anusak; Sawangkoon, Suwanakiet; Hamlin, Robert L

    2012-01-01

    Lengthening of QTc is the usual signal to indicate torsadogenic potential of a therapeutic agent. The ICH S7B guideline recommends that new chemical entities should be assessed for potential of delayed ventricular repolarization in animal models. The aim of this study was to determine a feasibility of using isolated failing heart rabbit to assess the QT-lengthening drugs in comparison with their effects on isolated normal heart rabbits. Heart failure was induced by ligation of the left anterior descending and descending branch of left circumflex coronary arteries. One month after ligation, all rabbits were anesthetized and the hearts were removed quickly, and they were perfused with the oxygenated Krebs-Henseleit solution to which escalating concentrations of QT-lengthening compounds were added. RR, QT, and QTc(F) were not significantly different, at rest, between failing and normal hearts. During baseline, dP/dtmax was lower and dP/dtmin was higher for failing hearts than for normals. In responses to all three QT-lengthening compounds, RR, QT and QTc(F) lengthened similarly in a dose-response manner in both the failing and normal hearts. Neither the failing nor the normal hearts developed fatal arrhythmias, torsades de pointes. Langendorff preparations of failing hearts are as good as normal isolated hearts and can be use to assess the potential of delayed ventricular repolarization of test articles. PMID:22687985

  14. Nonsustained Ventricular Tachycardia in the Normal Heart: Risk Stratification and Management.

    PubMed

    Marine, Joseph E

    2016-09-01

    Nonsustained ventricular tachycardia (NSVT) may trigger concern, particularly in patients with known congestive heart failure, structural heart disease, or prolonged QT interval. When NSVT occurs in patients with normal hearts, it usually has a benign prognosis. Therefore, establishing the presence or absence of structural or inherited heart disease is a critical step in each patient's evaluation. It is important to approach a wide-complex tachycardia in a systematic manner, to ensure correct diagnosis and treatment. When NSVT occurs in a patient with a normal heart, treatment is targeted toward symptoms and may consist of observation, medical therapy, or catheter ablation. PMID:27521087

  15. Functional engineered human cardiac patches prepared from nature's platform improve heart function after acute myocardial infarction.

    PubMed

    Wang, Qingjie; Yang, Hui; Bai, Aobing; Jiang, Wei; Li, Xiuya; Wang, Xinhong; Mao, Yishen; Lu, Chao; Qian, Ruizhe; Guo, Feng; Ding, Tianling; Chen, Haiyan; Chen, Sifeng; Zhang, Jianyi; Liu, Chen; Sun, Ning

    2016-10-01

    With the advent of induced pluripotent stem cells and directed differentiation techniques, it is now feasible to derive individual-specific cardiac cells for human heart tissue engineering. Here we report the generation of functional engineered human cardiac patches using human induced pluripotent stem cells-derived cardiac cells and decellularized natural heart ECM as scaffolds. The engineered human cardiac patches can be tailored to any desired size and shape and exhibited normal contractile and electrical physiology in vitro. Further, when patching on the infarct area, these patches improved heart function of rats with acute myocardial infarction in vivo. These engineered human cardiac patches can be of great value for normal and disease-specific heart tissue engineering, drug screening, and meet the demands for individual-specific heart tissues for personalized regenerative therapy of myocardial damages in the future. PMID:27509303

  16. Geometry of the capillary net in human hearts.

    PubMed

    Rakusan, K; Cicutti, N; Spatenka, J; Samánek, M

    1997-01-01

    The geometry of the coronary capillary bed in human hearts was studied using samples obtained during cardiac surgery of children operated for tetralogy of Fallot and samples from fresh normal hearts used for valve harvesting. The results revealed a similar coronary capillary density and heterogeneity of capillary spacing in samples from both groups. A double-staining method was used to distinguish between capillary segments close to the feeding arteriole (proximal capillaries) and segments distant from the arteriole (distal capillaries). In both groups of hearts, capillary segment length was consistently shorter on the venular than the arteriolar portion of the capillary. Similarly, capillary domain areas were also smaller and the resulting capillary supply unit was smaller along venular portions compared to arteriolar regions of the capillary bed. This distinctive geometry would provide advantageous geometric conditions for tissue oxygen supply. PMID:9176723

  17. Basic axes of human heart in correlation with heart mass and right ventricular wall thickness.

    PubMed

    Skwarek, M; Grzybiak, M; Kosiński, A; Hreczecha, J

    2006-11-01

    A comparison of the data published in anatomy textbooks and anthropological tables does not reveal any change in basic heart dimensions during the period since the beginning of the 20th century to nowadays. However, normal values of many other parameters have changed up to 30% over the same period. These changes may be caused by the acceleration phenomenon or the extension of average lifespan. The progress of laboratory medicine methodology permitted the introduction of new biochemical tests in myocardial infarct diagnosis, such as myoglobin and troponins T and I measurement, as well as better understanding of cardiac metabolism. Parameters describing the direction and intensity of metabolic changes are substrate extraction and metabolic equilibrium. The expression describing metabolic equilibrium contains heart mass value. Therefore, as studying heart mass in vivo is not possible, it may be important to study it in vitro. The study was performed on a group of 107 formalin-fixed human hearts. The organs came from adults of both sexes: 30 women and 77 men, aged 18 to 90 years. None of the hearts carried signs of macroscopic developmental abnormalities or pathologic changes. PMID:17171620

  18. Heart research advances using database search engines, Human Protein Atlas and the Sydney Heart Bank.

    PubMed

    Li, Amy; Estigoy, Colleen; Raftery, Mark; Cameron, Darryl; Odeberg, Jacob; Pontén, Fredrik; Lal, Sean; Dos Remedios, Cristobal G

    2013-10-01

    This Methodological Review is intended as a guide for research students who may have just discovered a human "novel" cardiac protein, but it may also help hard-pressed reviewers of journal submissions on a "novel" protein reported in an animal model of human heart failure. Whether you are an expert or not, you may know little or nothing about this particular protein of interest. In this review we provide a strategic guide on how to proceed. We ask: How do you discover what has been published (even in an abstract or research report) about this protein? Everyone knows how to undertake literature searches using PubMed and Medline but these are usually encyclopaedic, often producing long lists of papers, most of which are either irrelevant or only vaguely relevant to your query. Relatively few will be aware of more advanced search engines such as Google Scholar and even fewer will know about Quertle. Next, we provide a strategy for discovering if your "novel" protein is expressed in the normal, healthy human heart, and if it is, we show you how to investigate its subcellular location. This can usually be achieved by visiting the website "Human Protein Atlas" without doing a single experiment. Finally, we provide a pathway to discovering if your protein of interest changes its expression level with heart failure/disease or with ageing. PMID:23856366

  19. Virtual histology of the human heart using optical coherence tomography

    PubMed Central

    Ambrosi, Christina M.; Moazami, Nader; Rollins, Andrew M.; Efimov, Igor R.

    2009-01-01

    Optical coherence tomography (OCT) allows for the visualization of micron-scale structures within nontransparent biological tissues. For the first time, we demonstrate the use of OCT in identifying components of the cardiac conduction system and other structures in the explanted human heart. Reconstructions of cardiac structures up to 2 mm below the tissue surface were achieved and validated with Masson Trichrome histology in atrial, ventricular, sinoatrial nodal, and atrioventricular nodal preparations. The high spatial resolution of OCT provides visualization of cardiac fibers within the myocardium, as well as elements of the cardiac conduction system; however, a limiting factor remains its depth penetration, demonstrated to be ∼2 mm in cardiac tissues. Despite its currently limited imaging depth, the use of OCT to identify the structural determinants of both normal and abnormal function in the intact human heart is critical in its development as a potential aid to intracardiac arrhythmia diagnosis and therapy. PMID:19895104

  20. Virtual histology of the human heart using optical coherence tomography

    NASA Astrophysics Data System (ADS)

    Ambrosi, Christina M.; Moazami, Nader; Rollins, Andrew M.; Efimov, Igor R.

    2009-09-01

    Optical coherence tomography (OCT) allows for the visualization of micron-scale structures within nontransparent biological tissues. For the first time, we demonstrate the use of OCT in identifying components of the cardiac conduction system and other structures in the explanted human heart. Reconstructions of cardiac structures up to 2 mm below the tissue surface were achieved and validated with Masson Trichrome histology in atrial, ventricular, sinoatrial nodal, and atrioventricular nodal preparations. The high spatial resolution of OCT provides visualization of cardiac fibers within the myocardium, as well as elements of the cardiac conduction system; however, a limiting factor remains its depth penetration, demonstrated to be ~2 mm in cardiac tissues. Despite its currently limited imaging depth, the use of OCT to identify the structural determinants of both normal and abnormal function in the intact human heart is critical in its development as a potential aid to intracardiac arrhythmia diagnosis and therapy.

  1. Expression of tmp21 in normal adult human tissues

    PubMed Central

    Xie, Jian; Yang, Yuan; Li, Jianbo; Hou, Jing; Xia, Kun; Song, Weihong; Liu, Shengchun

    2014-01-01

    TMP21, known as p23 protein, is one important member of the p24 protein families. The degradation of TMP21 is mediated by the ubiquitin-proteasome pathway, as with the other presenilin-associated γ-secretase complex members. NFAT plays a very important role in regulation of human TMP21 gene expression. Compared with the function of TMP21, the studies about the distribution of this protein in human tissues are limited. We collected 19 normal adult human tissues from a healthy adult man died in a traffic accident and did examination of all the tissues collected for ICH, western blot and RT-PCR. It was shown that the expression of TMP21 is at high levels in heart, liver, lung, kidney and adrenal gland; moderate levels in brain, pancreas, prostate gland, testicle, small intestine, colon, stomach, gall bladder, thyroid gland and trachea; low levels in skeletal muscle, skin and lymphonodus. TMP21 is widely existed in normal adult human tissues. The current study provided for the first time a comprehensive expression of TMP21 in normal adult human tissues. It will benefit on helping in the design and interpretation of future studies focused on expounding the function of TMP21. PMID:25356171

  2. NORMAL HUMAN VARIATION: REFOCUSSING THE ENHANCEMENT DEBATE

    PubMed Central

    Kahane, Guy; Savulescu, Julian

    2015-01-01

    This article draws attention to several common mistakes in thinking about biomedical enhancement, mistakes that are made even by some supporters of enhancement. We illustrate these mistakes by examining objections that John Harris has recently raised against the use of pharmacological interventions to directly modulate moral decision-making. We then apply these lessons to other influential figures in the debate about enhancement. One upshot of our argument is that many considerations presented as powerful objections to enhancement are really strong considerations in favour of biomedical enhancement, just in a different direction. Another upshot is that it is unfortunate that much of the current debate focuses on interventions that will radically transform normal human capacities. Such interventions are unlikely to be available in the near future, and may not even be feasible. But our argument shows that the enhancement project can still have a radical impact on human life even if biomedical enhancement operated entirely within the normal human range. PMID:23906367

  3. Normal human variation: refocussing the enhancement debate.

    PubMed

    Kahane, Guy; Savulescu, Julian

    2015-02-01

    This article draws attention to several common mistakes in thinking about biomedical enhancement, mistakes that are made even by some supporters of enhancement. We illustrate these mistakes by examining objections that John Harris has recently raised against the use of pharmacological interventions to directly modulate moral decision-making. We then apply these lessons to other influential figures in the debate about enhancement. One upshot of our argument is that many considerations presented as powerful objections to enhancement are really strong considerations in favour of biomedical enhancement, just in a different direction. Another upshot is that it is unfortunate that much of the current debate focuses on interventions that will radically transform normal human capacities. Such interventions are unlikely to be available in the near future, and may not even be feasible. But our argument shows that the enhancement project can still have a radical impact on human life even if biomedical enhancement operated entirely within the normal human range. PMID:23906367

  4. Effects of increased heart work on glycolysis and adenine nucleotides in the perfused heart of normal and diabetic rats

    PubMed Central

    Opie, L. H.; Mansford, K. R. L.; Owen, Patricia

    1971-01-01

    1. In the isolated perfused rat heart, the contractile activity and the oxygen uptake were varied by altering the aortic perfusion pressure, or by the atrial perfusion technique (`working heart'). 2. The maximum increase in the contractile activity brought about an eightfold increase in the oxygen uptake. The rate of glycolytic flux rose, while tissue contents of hexose monophosphates, citrate, ATP and creatine phosphate decreased, and contents of ADP and AMP rose. 3. The changes in tissue contents of adenine nucleotides during increased heart work were time-dependent. The ATP content fell temporarily (30s and 2min) after the start of left-atrial perfusion; at 5 and 10min values were normal; and at 30 and 60min values were decreased. ADP and AMP values were increased in the first 15min, but were at control values 30 or 60min after the onset of increased heart work. 4. During increased heart work changes in the tissue contents of adenine nucleotide and of citrate appeared to play a role in altered regulation of glycolysis at the level of phosphofructokinase activity. 5. In recirculation experiments increased heart work for 30min was associated with increased entry of [14C]glucose (11.1mm) and glycogen into glycolysis and a comparable increase in formation of products of glycolysis (lactate, pyruvate and 14CO2). There was no major accumulation of intermediates. Glycogen was not a major fuel for respiration. 6. Increased glycolytic flux in Langendorff perfused and working hearts was obtained by the addition of insulin to the perfusion medium. The concomitant increases in the tissue values of hexose phosphates and of citrate contrasted with the decreased values of hexose monophosphates and of citrate during increased glycolytic flux obtained by increased heart work. 7. Decreased glycolytic flux in Langendorff perfused hearts was obtained by using acute alloxan-diabetic and chronic streptozotocin-diabetic rats; in the latter condition there were decreased tissue

  5. Sustained Ventricular Tachycardia in Apparently Normal Hearts: Ablation Should Be the First Step in Management.

    PubMed

    Moss, Joshua D; Tung, Roderick

    2016-09-01

    Patients without structural heart disease tend to have fewer morphologies of ventricular tachycardia, with automaticity and triggered activity a more common mechanism than re-entry associated with extremely low risk of sudden death. Ablation can be curative in patients with a single morphology of ventricular tachycardia that is focal in origin, particularly in patients without overt structural heart disease. There are limited data in secondary prevention implantable cardioverter defibrillator literature to support the routine implementation of implantable cardioverter defibrillator in normal hearts. Antiarrhythmic drugs have not been shown to reduce all-cause mortality in patients with and without structural heart disease. PMID:27521095

  6. Dynamic mapping of normal human hippocampal development.

    PubMed

    Gogtay, Nitin; Nugent, Tom F; Herman, David H; Ordonez, Anna; Greenstein, Deanna; Hayashi, Kiralee M; Clasen, Liv; Toga, Arthur W; Giedd, Jay N; Rapoport, Judith L; Thompson, Paul M

    2006-01-01

    The hippocampus, which plays an important role in memory functions and emotional responses, has distinct subregions subserving different functions. Because the volume and shape of the hippocampus are altered in many neuropsychiatric disorders, it is important to understand the trajectory of normal hippocampal development. We present the first dynamic maps to reveal the anatomical sequence of normal human hippocampal development. A novel hippocampal mapping technique was applied to a database of prospectively obtained brain magnetic resonance imaging (MRI) scans (100 scans in 31 children and adolescents), scanned every 2 yr for 6-10 yr between ages 4 and 25. Our results establish that the structural development of the human hippocampus is remarkably heterogeneous, with significant differences between posterior (increase over time) and anterior (loss over time) subregions. These distinct developmental trajectories of hippocampal subregions may parallel differences in their functional development. PMID:16826559

  7. Gated magnetic resonance imaging of the normal and diseased heart

    SciTech Connect

    Lieberman, J.M.; Alfidi, R.J.; Nelson, A.D.; Botti, R.E.; Moir, T.W.; Haaga, J.R.; Kopiwoda, S.; Miraldi, F.D.; Cohen, A.M.; Butler, H.E.

    1984-08-01

    Gated cardiac magnetic resonance (MR) images were obtained in two normal volunteers and 21 adults with a variety of cardiovascular abnormalities. The images were correlated with data from clinical examination, electrocardiograms, and cardiac catheterization. Gated cardiac images were superior to nongated images. Combined cardiac and respiratory gated images were superior to images obtained with cardiac gating only, but acquisition time was longer. Portions of the coronary arteries were visualized in seven of 23 examinations (30%), and subacute and old myocardial infarcts were seen in five of nine patients (55%) as areas of thinned myocardium. Normal cardiac anatomy (chambers, valves, and papillary muscles) was well visualized. Examples of aortic stenosis and atherosclerosis of the abdominal aorta are shown.

  8. Cardiac Extracellular Vesicles in Normal and Infarcted Heart

    PubMed Central

    Chistiakov, Dimitry A.; Orekhov, Alexander N.; Bobryshev, Yuri V.

    2016-01-01

    Heart is a complex assembly of many cell types constituting myocardium, endocardium and epicardium that intensively communicate to each other in order to maintain the proper cardiac function. There are many types of intercellular intracardiac signals, with a prominent role of extracellular vesicles (EVs), such as exosomes and microvesicles, for long-distant delivering of complex messages. Cardiomyocytes release EVs, whose content could significantly vary depending on the stimulus. In stress, such as hypoxia, inflammation or injury, cardiomyocytes increase secretion of EVs. In hypoxic conditions, cardiac EVs are enriched with angiogenic and prosurvival factors. In acute myocardial infarction (AMI), damaged cardiac muscle cells produce EVs with increased content of angiogenic, anti-apoptotic, mitogenic and growth factors in order to induce repair and healing of the infarcted myocardium. Exosomal microRNAs play a central role in cardiac regeneration. In AMI, circulating cardiac EVs abundantly contain cardiac-specific miRNAs that serve as indicators of cardiac damage and have a big diagnostic potential as AMI biomarkers. Cardioprotective and regenerative properties of exosomes derived from cardiac and non-cardiac stem/progenitor cells are very helpful to be used in cell-free cardiotherapy and regeneration of post-infarct myocardium. PMID:26742038

  9. Fatty acid uptake in normal human myocardium

    SciTech Connect

    Vyska, K.; Meyer, W.; Stremmel, W.; Notohamiprodjo, G.; Minami, K.; Machulla, H.J.; Gleichmann, U.; Meyer, H.; Koerfer, R. )

    1991-09-01

    Fatty acid binding protein has been found in rat aortic endothelial cell membrane. It has been identified to be a 40-kDa protein that corresponds to a 40-kDa fatty acid binding protein with high affinity for a variety of long chain fatty acids isolated from rat heart myocytes. It is proposed that this endothelial membrane fatty acid binding protein might mediate the myocardial uptake of fatty acids. For evaluation of this hypothesis in vivo, influx kinetics of tracer-labeled fatty acids was examined in 15 normal subjects by scintigraphic techniques. Variation of the plasma fatty acid concentration and plasma perfusion rate has been achieved by modulation of nutrition state and exercise conditions. The clinical results suggest that the myocardial fatty acid influx rate is saturable by increasing fatty acid plasma concentration as well as by increasing plasma flow. For analysis of these data, functional relations describing fatty acid transport from plasma into myocardial tissue in the presence and absence of an unstirred layer were developed. The fitting of these relations to experimental data indicate that the free fatty acid influx into myocardial tissue reveals the criteria of a reaction on a capillary surface in the vicinity of flowing plasma but not of a reaction in extravascular space or in an unstirred layer and that the fatty acid influx into normal myocardium is a saturable process that is characterized by the quantity corresponding to the Michaelis-Menten constant, Km, and the maximal velocity, Vmax, 0.24 {plus minus} 0.024 mumol/g and 0.37 {plus minus} 0.013 mumol/g(g.min), respectively. These data are compatible with a nondiffusional uptake process mediated by the initial interaction of fatty acids with the 40-kDa membrane fatty acid binding protein of cardiac endothelial cells.

  10. Echocardiographic image of an active human heart

    NASA Technical Reports Server (NTRS)

    2003-01-01

    Echocardiographic images provide quick, safe images of the heart as it beats. While a state-of-the art echocardiograph unit is part of the Human Research Facility on International Space Station, quick transmission of images and data to Earth is a challenge. NASA is developing techniques to improve the echocardiography available to diagnose sick astronauts as well as study the long-term effects of space travel on their health. Echocardiography uses ultrasound, generated in a sensor head placed against the patient's chest, to produce images of the structure of the heart walls and valves. However, ultrasonic imaging creates an enormous volume of data, up to 220 million bits per second. This can challenge ISS communications as well as Earth-based providers. Compressing data for rapid transmission back to Earth can degrade the quality of the images. Researchers at the Cleveland Clinic Foundation are working with NASA to develop compression techniques that meet imaging standards now used on the Internet and by the medical community, and that ensure that physicians receive quality diagnostic images.

  11. Human heart conjugate cooling simulation: Unsteady thermo-fluid-stress analysis

    PubMed Central

    Abdoli, Abas; Dulikravich, George S.; Bajaj, Chandrajit; Stowe, David F.; Jahania, M. Salik

    2015-01-01

    The main objective of this work was to demonstrate computationally that realistic human hearts can be cooled much faster by performing conjugate heat transfer consisting of pumping a cold liquid through the cardiac chambers and major veins while keeping the heart submerged in cold gelatin filling a cooling container. The human heart geometry used for simulations was obtained from three-dimensional, high resolution MRI scans. Two fluid flow domains for the right (pulmonic) and left (systemic) heart circulations, and two solid domains for the heart tissue and gelatin solution were defined for multi-domain numerical simulation. Detailed unsteady temperature fields within the heart tissue were calculated during the conjugate cooling process. A linear thermoelasticity analysis was performed to assess the stresses applied on the heart due to the coolant fluid shear and normal forces and to examine the thermal stress caused by temperature variation inside the heart. It was demonstrated that a conjugate cooling effort with coolant temperature at +4°C is capable of reducing the average heart temperature from +37°C to +8°C in 25 minutes for cases in which the coolant was steadily pumped only through major heart inlet veins and cavities. PMID:25045006

  12. Arrhythmogenic and metabolic remodelling of failing human heart.

    PubMed

    Gloschat, C R; Koppel, A C; Aras, K K; Brennan, J A; Holzem, K M; Efimov, I R

    2016-07-15

    Heart failure (HF) is a major cause of morbidity and mortality worldwide. The global burden of HF continues to rise, with prevalence rates estimated at 1-2% and incidence approaching 5-10 per 1000 persons annually. The complex pathophysiology of HF impacts virtually all aspects of normal cardiac function - from structure and mechanics to metabolism and electrophysiology - leading to impaired mechanical contraction and sudden cardiac death. Pharmacotherapy and device therapy are the primary methods of treating HF, but neither is able to stop or reverse disease progression. Thus, there is an acute need to translate basic research into improved HF therapy. Animal model investigations are a critical component of HF research. However, the translation from cellular and animal models to the bedside is hampered by significant differences between species and among physiological scales. Our studies over the last 8 years show that hypotheses generated in animal models need to be validated in human in vitro models. Importantly, however, human heart investigations can establish translational platforms for safety and efficacy studies before embarking on costly and risky clinical trials. This review summarizes recent developments in human HF investigations of electrophysiology remodelling, metabolic remodelling, and β-adrenergic remodelling and discusses promising new technologies for HF research. PMID:27019074

  13. Patient experiences of recovery after heart valve replacement: suffering weakness, struggling to resume normality

    PubMed Central

    2013-01-01

    Background Heart valve disease is becoming a public health problem due to increasing life expectancy and new treatment methods. Patients are at risk of developing depression, anxiety or post-traumatic stress disorder after heart valve surgery. To better plan proper care, describing and understanding patients’ perception of recovery after heart valve replacement is essential. The objective was to describe the experience of recovery at home after heart valve replacement. Methods Qualitative interviews were conducted with 10 patients representing the population and these were later transcribed. The analysis was inspired by Ricoeur’s theory of interpretation, which consists of three levels: naive reading, structured analysis, and critical interpretation and discussion. Results The overall concept that emerged was suffering weakness and struggling to resume normality. Patients all struggled to resume normal living, both in regaining physical strength and in reestablishing balance in overall living. The overall concept can be interpreted in terms of the following themes: Disturbed network: Invaluable relatives, Contact with healthcare staff, Rehabilitation. Disturbed body: Stressful complications, Bodily attention, Physically affected, Physical capability. Recovery: Interrupted living, Suffering weakness, Gradual recovery, Achieving normality. Reflections: Thoughts about the procedure and Feeling sad and fragile. Conclusion The study presents the main themes of network, body, recovery and reflection for ten patients after heart valve replacement. These main themes can overall be summarized as suffering weakness and struggling to resume normality. Patients felt weak with a changed body, but after a long recovery process regained vitality and returned to their daily life. PMID:24070399

  14. Critical Scale Invariance in a Healthy Human Heart Rate

    NASA Astrophysics Data System (ADS)

    Kiyono, Ken; Struzik, Zbigniew R.; Aoyagi, Naoko; Sakata, Seiichiro; Hayano, Junichiro; Yamamoto, Yoshiharu

    2004-10-01

    We demonstrate the robust scale-invariance in the probability density function (PDF) of detrended healthy human heart rate increments, which is preserved not only in a quiescent condition, but also in a dynamic state where the mean level of the heart rate is dramatically changing. This scale-independent and fractal structure is markedly different from the scale-dependent PDF evolution observed in a turbulentlike, cascade heart rate model. These results strongly support the view that a healthy human heart rate is controlled to converge continually to a critical state.

  15. Teaching Recognition of Normal and Abnormal Heart Sounds Using Computer-Assisted Instruction

    ERIC Educational Resources Information Center

    Musselman, Eugene E.; Grimes, George M.

    1976-01-01

    The computer is being used in an innovative manner to teach the recognition of normal and abnormal canine heart sounds at the University of Chicago. Experience thus far indicates that the PLATO program resources allow the maximum development of the student's proficiency in auscultation. (Editor/LBH)

  16. Multivariate Normal Tissue Complication Probability Modeling of Heart Valve Dysfunction in Hodgkin Lymphoma Survivors

    SciTech Connect

    Cella, Laura; Liuzzi, Raffaele; Conson, Manuel; D’Avino, Vittoria; Salvatore, Marco; Pacelli, Roberto

    2013-10-01

    Purpose: To establish a multivariate normal tissue complication probability (NTCP) model for radiation-induced asymptomatic heart valvular defects (RVD). Methods and Materials: Fifty-six patients treated with sequential chemoradiation therapy for Hodgkin lymphoma (HL) were retrospectively reviewed for RVD events. Clinical information along with whole heart, cardiac chambers, and lung dose distribution parameters was collected, and the correlations to RVD were analyzed by means of Spearman's rank correlation coefficient (Rs). For the selection of the model order and parameters for NTCP modeling, a multivariate logistic regression method using resampling techniques (bootstrapping) was applied. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC). Results: When we analyzed the whole heart, a 3-variable NTCP model including the maximum dose, whole heart volume, and lung volume was shown to be the optimal predictive model for RVD (Rs = 0.573, P<.001, AUC = 0.83). When we analyzed the cardiac chambers individually, for the left atrium and for the left ventricle, an NTCP model based on 3 variables including the percentage volume exceeding 30 Gy (V30), cardiac chamber volume, and lung volume was selected as the most predictive model (Rs = 0.539, P<.001, AUC = 0.83; and Rs = 0.557, P<.001, AUC = 0.82, respectively). The NTCP values increase as heart maximum dose or cardiac chambers V30 increase. They also increase with larger volumes of the heart or cardiac chambers and decrease when lung volume is larger. Conclusions: We propose logistic NTCP models for RVD considering not only heart irradiation dose but also the combined effects of lung and heart volumes. Our study establishes the statistical evidence of the indirect effect of lung size on radio-induced heart toxicity.

  17. Evolutionary anticipation of the human heart.

    PubMed Central

    Victor, S.; Nayak, V. M.

    2000-01-01

    We have studied the comparative anatomy of hearts from fish, frog, turtle, snake, crocodile, birds (duck, chicken, quail), mammals (elephant, dolphin, sheep, goat, ox, baboon, wallaby, mouse, rabbit, possum, echidna) and man. The findings were analysed with respect to the mechanism of evolution of the heart. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:11041025

  18. Phase Transition in a Healthy Human Heart Rate

    NASA Astrophysics Data System (ADS)

    Kiyono, Ken; Struzik, Zbigniew R.; Aoyagi, Naoko; Togo, Fumiharu; Yamamoto, Yoshiharu

    2005-07-01

    A healthy human heart rate displays complex fluctuations which share characteristics of physical systems in a critical state. We demonstrate that the human heart rate in healthy individuals undergoes a dramatic breakdown of criticality characteristics, reminiscent of continuous second order phase transitions. By studying the germane determinants, we show that the hallmark of criticality—highly correlated fluctuations—is observed only during usual daily activity, and a breakdown of these characteristics occurs in prolonged, strenuous exercise and sleep. This finding is the first reported discovery of the dynamical phase transition phenomenon in a biological control system and will be a key to understanding the heart rate control system in health and disease.

  19. Treatment of heart failure with normal ejection fraction: an inconvenient truth!

    PubMed

    Paulus, Walter J; van Ballegoij, Joris J M

    2010-02-01

    Despite use of similar drugs, outcomes of recent heart failure (HF) trials were frequently neutral in heart failure with normal left ventricular ejection fraction (HFNEF) and positive in heart failure with reduced left ventricular ejection fraction (HFREF). The neutral outcomes of HFNEF trials were often attributed to deficient HFNEF patient recruitment with inclusion of many HFREF or noncardiac patients. Patient recruitment criteria of 21 HFNEF trials were therefore reviewed in reference to diagnostic guidelines for HFNEF. In the 4 published sets of guidelines, a definite diagnosis of HFNEF required the simultaneous and obligatory presence of signs and/or symptoms of HF and evidence of normal systolic left ventricular (LV) function and of diastolic LV dysfunction. In 3 of 4 sets of guidelines, normal systolic LV function comprised both a left ventricular ejection fraction (LVEF) >50% and an absence of LV dilation. Among the 21 HFNEF trials, LVEF cutoff values ranged from 35% to 50%, with only 8 trials adhering to an LVEF >50%. Furthermore, only 1 trial specified a normal LV end-diastolic dimension as an enrollment criterion and only 7 trials required evidence of diastolic LV dysfunction. Nonadherence to diagnostic guidelines induced excessive enrollment into HFNEF trials of HF patients with eccentric LV remodeling and ischemic heart disease compared with HF patients with concentric LV remodeling and arterial hypertension. Nonadherence to guidelines also led to underpowered HFNEF trials with a low incidence of outcome events such as death or HF hospitalizations. Future HFNEF trials should therefore adhere to diagnostic guidelines for HFNEF. PMID:20152557

  20. Polymorphic Ventricular Tachycardia/Ventricular Fibrillation and Sudden Cardiac Death in the Normal Heart.

    PubMed

    Shah, Ashok J; Hocini, Meleze; Denis, Arnaud; Derval, Nicolas; Sacher, Frederic; Jais, Pierre; Haissaguerre, Michel

    2016-09-01

    Primary electrical diseases manifest with polymorphic ventricular tachycardia (PMVT) and ventricular fibrillation (VF) and along with idiopathic VF contribute to about 10% of sudden cardiac deaths (SCDs) overall. These disorders include long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, short QT syndrome, and early repolarization syndrome. This article reviews the clinical electrophysiological management of PMVT/VF in a structurally normal heart affected with these disorders. PMID:27521091

  1. Changes in oxygen saturation and heart frequency during sleep in young normal subjects.

    PubMed Central

    Gimeno, F; Peset, R

    1984-01-01

    Changes in oxygen saturation and heart frequency were measured during sleep in a group of 21 normal subjects (9 women and 12 men) aged 19-25. At the time of the investigation all were non-smokers, they had no respiratory complaints, and indices of lung function (lung volumes, volume-pressure diagram, and diffusing capacity for carbon monoxide) were within normal limits. In contrast to published data, there were no major changes in oxygen saturation and no differences between men and women. PMID:6474401

  2. The winding road to regenerating the human heart

    PubMed Central

    Gerbin, Kaytlyn A.; Murry, Charles E.

    2015-01-01

    Regenerating the human heart is a challenge that has engaged researchers and clinicians around the globe for nearly a century. From the repair of the first septal defect in 1953, followed by the first successful heart transplant in 1967, and later to the first infusion of bone-marrow derived cells to the human myocardium in 2002, significant progress has been made in heart repair. Yet, chronic heart failure remains a leading pathological burden worldwide. Why has regenerating the human heart been such a challenge, and how close are we to achieving clinically relevant regeneration? Exciting progress has been made to establish cell transplantation techniques in recent years, and new pre-clinical studies in large animal models have shed light on the promises and challenges that lie ahead. In this review, we will discuss the history of cell therapy approaches and provide an overview of clinical trials using cell transplantation for heart regeneration. Focusing on the delivery of human stem cell-derived cardiomyocytes, current experimental strategies in the field will be discussed as well as their clinical translation potential. Although the human heart has not been regenerated yet, decades of experimental progress have guided us onto a promising pathway. Summary Exciting progress has been made in recent years to establish clinical cell transplantation techniques, and new pre-clinical studies in large animal models have shed light on the promises and challenges that lie ahead. Although the human heart has not been regenerated yet, decades of experimental progress in pre-clinical and clinical trials have guided us onto a promising pathway. PMID:25795463

  3. Insulin sensitivity regulates autonomic control of heart rate variation independent of body weight in normal subjects.

    PubMed

    Bergholm, R; Westerbacka, J; Vehkavaara, S; Seppälä-Lindroos, A; Goto, T; Yki-Järvinen, H

    2001-03-01

    It is unclear whether insulin sensitivity independent of body weight regulates control of heart rate variation (HRV) by the autonomic nervous system. Insulin action on whole-body glucose uptake (M-value) and heart rate variability were measured in 21 normal men. The subjects were divided into 2 groups [normally insulin sensitive (IS, 8.0 +/- 0.4 mg/kg.min) and less insulin sensitive (IR, 5.1 +/- 0.3 mg/kg.min)] based on their median M-value (6.2 mg/kg x min). Spectral power analysis of heart rate variability was performed in the basal state and every 30 min during the insulin infusion. The IS and IR groups were comparable, with respect to age (27 +/- 2 vs. 26 +/- 2 yr), body mass index (22 +/- 1 vs. 23 +/- 1 kg/m(2)), body fat (13 +/- 1 vs. 13 +/- 1%), systolic (121 +/- 16 vs. 117 +/- 14 mm Hg) and diastolic (74 +/- 11 vs. 73 +/- 11 mm Hg) blood pressures, and fasting plasma glucose (5.4 +/- 0.1 vs. 5.5 +/- 0.1 mmol/L) concentrations. Fasting plasma insulin was significantly higher in the IR (30 +/- 4 pmol/L) than in the IS (17 +/- 3 pmol/L, P < 0.05) group. In the IS group, insulin significantly increased the normalized low-frequency (LFn) component, a measure of predominantly sympathetic nervous system activity, from 36 +/- 5 to 48 +/- 4 normalized units (nu; 0 vs. 30-120 min, P < 0.001); whereas the normalized high-frequency (HFn) component, a measure of vagal control of HRV, decreased from 66 +/- 9 to 48 +/- 5 nu (P < 0.001). No changes were observed in either the normalized LF component [35 +/- 5 vs. 36 +/- 2 nu, not significant (NS)] or the normalized HF component (52 +/- 6 vs. 51 +/- 4 nu, NS) in the IR group. The ratio LF/HF, a measure of sympathovagal balance, increased significantly in the IS group (0.92 +/- 0.04 vs. 1.01 +/- 0.04, P < 0.01) but remained unchanged in the IR group (0.91 +/- 0.04 vs. 0.92 +/- 0.03, NS). Heart rate and systolic and diastolic blood pressures remained unchanged during the insulin infusion in both groups. We conclude that

  4. Interpretation of Normalized Spectral Heart Rate Variability Indices In Sleep Research: A Critical Review

    PubMed Central

    Burr, Robert L.

    2007-01-01

    The normalized spectral heart rate variability (HRV) measures low-frequency (LF)nu and high-frequency (HF)nu are frequently used in contemporary sleep research studies to quantify modulation of the sympathetic and parasympathetic branches of the autonomic nervous system. The purpose of this tutorial and methodologic critique is to concisely demonstrate the structural algebraic redundancy inherent in the normalized spectral HRV measures with respect to each other, and also with respect to the well-known HRV index of sympathovagal balance, LF:HF ratio. The statistical problems and interpretational paradoxes related to the mathematical definitions of LFnu and HFnu are briefly outlined. Examples of use of normalized spectral HRV measures in recent articles from the sleep-relevant research literature are critically reviewed. LFnu, HFnu, and LF:HF ratio should be considered equivalent carriers of information about sympathovagal balance. Citation: Burr RL. Interpretation of normalized spectral heart rate variability indices in sleep research: a critical review. SLEEP 2007;30(7):913-919. PMID:17682663

  5. Normal and abnormal human vestibular ocular function

    NASA Technical Reports Server (NTRS)

    Peterka, R. J.; Black, F. O.

    1986-01-01

    The major motivation of this research is to understand the role the vestibular system plays in sensorimotor interactions which result in spatial disorientation and motion sickness. A second goal was to explore the range of abnormality as it is reflected in quantitative measures of vestibular reflex responses. The results of a study of vestibular reflex measurements in normal subjects and preliminary results in abnormal subjects are presented in this report. Statistical methods were used to define the range of normal responses, and determine age related changes in function.

  6. Right Heart 4DMRI Flow Visualization in Normal and Hypertensive subjects

    NASA Astrophysics Data System (ADS)

    Hertzberg, Jean; Browning, James; Fenster, Brett; Schroeder, Joyce

    2015-11-01

    Recent advances in time-resolved 3D cardiac magnetic resonance imaging (4DMRI) have allowed for the 3-dimensional characterization of blood flow in the right ventricle (RV) and right atrium (RA). In this talk, an overview of a large, ongoing, multi-disciplinary investigation of 4D right heart hemodynamics in normal and pathologic patients is given, as well as lessons learned from 4DMRI cardiac research. Time-resolved visualization techniques for understanding and communicating complex right heart flow structures throughout the cardiac cycle are presented. Finally, a qualitative visual comparison of 3D flow structures in the vena cava, RA, and RV between healthy subjects and pulmonary hypertensive patients is presented.

  7. Mapping Molecular Agents Distributions in Whole Mice Hearts Using Born-Normalized Optical Projection Tomography

    PubMed Central

    Razansky, Daniel; Gorbatov, Rostic; Ntziachristos, Vasilis; Sbarbati, Andrea; Nahrendorf, Matthias; Weissleder, Ralph

    2012-01-01

    To date there is a lack of tools to map the spatio-temporal dynamics of diverse cells in experimental heart models. Conventional histology is labor intensive with limited coverage, whereas many imaging techniques do not have sufficiently high enough spatial resolution to map cell distributions. We have designed and built a high resolution, dual channel Born-normalized near-infrared fluorescence optical projection tomography system to quantitatively and spatially resolve molecular agents distribution within whole murine heart. We validated the use of the system in a mouse model of monocytes/macrophages recruitment during myocardial infarction. While acquired, data were processed and reconstructed in real time. Tomographic analysis and visualization of the key inflammatory components were obtained via a mathematical formalism based on left ventricular modeling. We observed extensive monocyte recruitment within and around the infarcted areas and discovered that monocytes were also extensively recruited into non-ischemic myocardium, beyond that of injured tissue, such as the septum. PMID:22509302

  8. How Live Performance Moves the Human Heart

    PubMed Central

    Shoda, Haruka; Adachi, Mayumi; Umeda, Tomohiro

    2016-01-01

    We investigated how the audience member’s physiological reactions differ as a function of listening context (i.e., live versus recorded music contexts). Thirty-seven audience members were assigned to one of seven pianists’ performances and listened to his/her live performances of six pieces (fast and slow pieces by Bach, Schumann, and Debussy). Approximately 10 weeks after the live performance, each of the audience members returned to the same room and listened to the recorded performances of the same pianists’ via speakers. We recorded the audience members’ electrocardiograms in listening to the performances in both conditions, and analyzed their heart rates and the spectral features of the heart-rate variability (i.e., HF/TF, LF/HF). Results showed that the audience’s heart rate was higher for the faster than the slower piece only in the live condition. As compared with the recorded condition, the audience’s sympathovagal balance (LF/HF) was less while their vagal nervous system (HF/TF) was activated more in the live condition, which appears to suggest that sharing the ongoing musical moments with the pianist reduces the audience’s physiological stress. The results are discussed in terms of the audience’s superior attention and temporal entrainment to live performance. PMID:27104377

  9. How Live Performance Moves the Human Heart.

    PubMed

    Shoda, Haruka; Adachi, Mayumi; Umeda, Tomohiro

    2016-01-01

    We investigated how the audience member's physiological reactions differ as a function of listening context (i.e., live versus recorded music contexts). Thirty-seven audience members were assigned to one of seven pianists' performances and listened to his/her live performances of six pieces (fast and slow pieces by Bach, Schumann, and Debussy). Approximately 10 weeks after the live performance, each of the audience members returned to the same room and listened to the recorded performances of the same pianists' via speakers. We recorded the audience members' electrocardiograms in listening to the performances in both conditions, and analyzed their heart rates and the spectral features of the heart-rate variability (i.e., HF/TF, LF/HF). Results showed that the audience's heart rate was higher for the faster than the slower piece only in the live condition. As compared with the recorded condition, the audience's sympathovagal balance (LF/HF) was less while their vagal nervous system (HF/TF) was activated more in the live condition, which appears to suggest that sharing the ongoing musical moments with the pianist reduces the audience's physiological stress. The results are discussed in terms of the audience's superior attention and temporal entrainment to live performance. PMID:27104377

  10. Influence of peak exercise heart rate on normal thallium-201 myocardial clearance

    SciTech Connect

    Kaul, S.; Chesler, D.A.; Pohost, G.M.; Strauss, H.W.; Okada, R.D.; Boucher, C.A.

    1986-01-01

    Measurement of myocardial clearance rates between initial and delayed images is a major justification for adding computer quantification to the interpretation of exercise /sup 201/TI images. To clarify the range of normal thallium clearance and its relationship to the level of exercise achieved, exercise thallium images in 89 normal subjects were analyzed: 45 asymptomatic subjects with less than 1% probability of coronary artery disease (CAD) (Group I), and 44 patients with chest pain found to have no significant CAD on angiography (Group II). Mean initial regional thallium uptake was similar in the two groups, but myocardial thallium clearance (mean +/- 1 s.d.) was slower in Group II, expressed as a longer half-life in the myocardium (8.2 +/- 7.6 hr compared with 3.4 +/- 0.7 hr p less than 0.001). Analysis of variance using ten clinical and exercise variables as covariates showed that the slower clearance in Group II was related to a lower peak exercise heart rate (HR) (154 +/- 27 compared with 183 +/- 11, respectively, p less than 0.001). By linear regression analysis, a decrease in peak HR of 1 beat/min was associated with a slower thallium clearance (longer half-life) of 0.05 hr. Using this formula, the clearance value in each patient was then corrected for peak exercise heart rate by decreasing measured clearance by 0.05 hr multiplied by the amount peak exercise heart rate which was below 183 (the mean value in Group I). There were no differences in the corrected clearance between the two groups. We conclude that thallium myocardial clearance after exercise is related in part to factors other than the presence of CAD, being slower when peak exercise HR is lower. Therefore, thallium clearance rates alone uncorrected for peak exercise heart rate should be used with caution when diagnosing CAD.

  11. The Living Heart Project: A robust and integrative simulator for human heart function.

    PubMed

    Baillargeon, Brian; Rebelo, Nuno; Fox, David D; Taylor, Robert L; Kuhl, Ellen

    2014-11-01

    The heart is not only our most vital, but also our most complex organ: Precisely controlled by the interplay of electrical and mechanical fields, it consists of four chambers and four valves, which act in concert to regulate its filling, ejection, and overall pump function. While numerous computational models exist to study either the electrical or the mechanical response of its individual chambers, the integrative electro-mechanical response of the whole heart remains poorly understood. Here we present a proof-of-concept simulator for a four-chamber human heart model created from computer topography and magnetic resonance images. We illustrate the governing equations of excitation-contraction coupling and discretize them using a single, unified finite element environment. To illustrate the basic features of our model, we visualize the electrical potential and the mechanical deformation across the human heart throughout its cardiac cycle. To compare our simulation against common metrics of cardiac function, we extract the pressure-volume relationship and show that it agrees well with clinical observations. Our prototype model allows us to explore and understand the key features, physics, and technologies to create an integrative, predictive model of the living human heart. Ultimately, our simulator will open opportunities to probe landscapes of clinical parameters, and guide device design and treatment planning in cardiac diseases such as stenosis, regurgitation, or prolapse of the aortic, pulmonary, tricuspid, or mitral valve. PMID:25267880

  12. Spectral characteristics of heart period variability during cold face stress and shock avoidance in normal subjects.

    PubMed

    Friedman, B H; Thayer, J F; Tyrrell, R A

    1996-06-01

    Spectral analysis of heart period variability was used to examine autonomic cardiac control in several tasks used in experimental and clinical assessments of autonomic nervous system function. Cardiovascular measures were recorded in healthy humans during quiet rest, reaction time shock-avoidance, cold face stress, and combined shock-avoidance/cold face stress. Shock-avoidance was characterized by sympathetic beta-adrenergic dominance, as evidenced by (1) shorter heart periods, (2) less high-frequency spectral power, (3) elevated low-frequency power, (4) increased ratios of low- to high-frequency power, and (5) a steep regression line fitted to the log-log plot of the power spectra. Cold face stress yielded (1) longer heart periods, (2) more high-frequency power, (3) decreased low-frequency spectral power, and (4) a flat regression slope, indicating vagal dominance. Quiet rest appeared as mildly vagal, with less total spectral power, and the combination task elicited a mixed vagal-sympathetic pattern. These results are discussed in the context of (1) the autonomic underpinnings of low-frequency power, (2) the autonomic effects of facial cooling, and (3) the utility of spectral analysis of heart period variability during autonomic challenge tasks for basic research and clinical application. PMID:8832123

  13. Construction of a normalized directionally cloned cDNA library from adult heart and analysis of 3040 clones by partial sequencing.

    PubMed

    Tanaka, T; Ogiwara, A; Uchiyama, I; Takagi, T; Yazaki, Y; Nakamura, Y

    1996-07-01

    Large-scale sequencing of clones from cDNA libraries derived from specific tissues is a rapid and efficient way of discovering novel genes expressed in those tissues. However, because the heart is continually contracting and relaxing, it strongly expresses muscle-contractile genes and/or mitochondrial genes, a bias that reduces the efficiency of this method. To improve the efficiency of identifying novel genes expressed in the heart, we constructed a normalized directionally cloned cDNA library from adult heart and partially sequenced 3040 clones. Comparisons of these sequence data with known DNA sequences in the database revealed that 57.1% of the clones matched human genes already known, 23.4% were identical or almost identical to human expressed sequence tags (ESTs), 14.2% bore no significant homology to any sequences in the database, and 1.2% represented repetitive sequences. The remaining 4.1% showed some homology with known genes, and Northern blot analysis of several clones in this category revealed that most of them were expressed mainly in the heart and skeletal muscle. After redundancy was excluded, the 3040 clones accounted for 1395 distinctive ESTs, 446 of which exhibited no match to any known sequence. Our results suggest that our normalized library is less redundant than standard libraries and is a useful resource for cataloging genes expressed in the heart. PMID:8661126

  14. Spectrum of Ventricular Arrhythmias Arising from Papillary Muscle in the Structurally Normal Heart.

    PubMed

    Naksuk, Niyada; Kapa, Suraj; Asirvatham, Samuel J

    2016-09-01

    Papillary muscle is an endocavitary structure that can give rise to ventricular arrhythmias in a structurally normal heart. Its manifestation is generally benign. The papillary muscle's complex anatomy and the presence of intermixed Purkinje fibers can create a substrate for idiopathic ventricular fibrillation. Although differentiating ventricular arrhythmias originating from the papillary muscle and the fascicles is challenging and not always possible, the distinction may be helpful for planning ablation. The propensity for difficulty with ablation of papillary arrhythmias results in a variable success rate. Improvement in techniques to stabilize the catheter, use of imaging, and methods of energy delivery are required to improve ablation outcomes. PMID:27521089

  15. Dynamics and Molecular Mechanisms of Ventricular Fibrillation in Structurally Normal Hearts.

    PubMed

    Jalife, José

    2016-09-01

    Ventricular fibrillation (VF) is the most severe cardiac rhythm disturbance and one of the most important immediate causes of sudden cardiac death. In the structurally normal heart, a small number of stable reentrant sources, perhaps 1 or 2, underlie the mechanism of VF, and the stabilization of the sources, their frequency, and the complexity of the turbulent waves they generate depend on the expression, spatial distribution, and intermolecular interactions of the 2 most important ion channels that control cardiac excitability: the inward rectifier potassium channel, Kir2.1, and the alpha subunit of the main cardiac sodium channel, NaV1.5. PMID:27521093

  16. Right ventricular long noncoding RNA expression in human heart failure

    PubMed Central

    Guo, Yan; Su, Yan Ru; Clark, Travis; Brittain, Evan; Absi, Tarek; Maltais, Simon; Hemnes, Anna

    2015-01-01

    Abstract The expression of long noncoding RNAs (lncRNAs) in human heart failure (HF) has not been widely studied. Using RNA sequencing (RNA-Seq), we compared lncRNA expression in 22 explanted human HF hearts with lncRNA expression in 5 unused donor human hearts. We used Cufflinks to identify isoforms and DESeq to identify differentially expressed genes. We identified the noncoding RNAs by cross-reference to Ensembl release 73 (Genome Reference Consortium human genome build 37) and explored possible functional roles using a variety of online tools. In HF hearts, RNA-Seq identified 84,793 total messenger RNA coding and noncoding different transcripts, including 13,019 protein-coding genes, 2,085 total lncRNA genes, and 1,064 pseudogenes. By Ensembl noncoding RNA categories, there were 48 lncRNAs, 27 pseudogenes, and 30 antisense RNAs for a total of 105 differentially expressed lncRNAs in HF hearts. Compared with donor hearts, HF hearts exhibited differential expression of 7.7% of protein-coding genes, 3.7% of lncRNAs (including pseudogenes), and 2.5% of pseudogenes. There were not consistent correlations between antisense lncRNAs and parent genes and between pseudogenes and parent genes, implying differential regulation of expression. Exploratory in silico functional analyses using online tools suggested a variety of possible lncRNA regulatory roles. By providing a comprehensive profile of right ventricular polyadenylated messenger RNA transcriptome in HF, RNA-Seq provides an inventory of differentially expressed lncRNAs, including antisense transcripts and pseudogenes, for future mechanistic study. PMID:25992278

  17. Isoproterenol effects evaluated in heart slices of human and rat in comparison to rat heart in vivo

    SciTech Connect

    Herrmann, Julia E.; Heale, Jason; Bieraugel, Mike; Ramos, Meg; Fisher, Robyn L.; Vickers, Alison E.M.

    2014-01-15

    Human response to isoproterenol induced cardiac injury was evaluated by gene and protein pathway changes in human heart slices, and compared to rat heart slices and rat heart in vivo. Isoproterenol (10 and 100 μM) altered human and rat heart slice markers of oxidative stress (ATP and GSH) at 24 h. In this in vivo rat study (0.5 mg/kg), serum troponin concentrations increased with lesion severity, minimal to mild necrosis at 24 and 48 h. In the rat and the human heart, isoproterenol altered pathways for apoptosis/necrosis, stress/energy, inflammation, and remodeling/fibrosis. The rat and human heart slices were in an apoptotic phase, while the in vivo rat heart exhibited necrosis histologically and further progression of tissue remodeling. In human heart slices genes for several heat shock 70 kD members were altered, indicative of stress to mitigate apoptosis. The stress response included alterations in energy utilization, fatty acid processing, and the up-regulation of inducible nitric oxide synthase, a marker of increased oxidative stress in both species. Inflammation markers linked with remodeling included IL-1α, Il-1β, IL-6 and TNFα in both species. Tissue remodeling changes in both species included increases in the TIMP proteins, inhibitors of matrix degradation, the gene/protein of IL-4 linked with cardiac fibrosis, and the gene Ccl7 a chemokine that induces collagen synthesis, and Reg3b a growth factor for cardiac repair. This study demonstrates that the initial human heart slice response to isoproterenol cardiac injury results in apoptosis, stress/energy status, inflammation and tissue remodeling at concentrations similar to that in rat heart slices. - Highlights: • Human response to isoproterenol induced cardiac injury evaluated in heart slices. • Isoproterenol altered apoptosis, energy, inflammation and remodeling pathways. • Human model verified by comparison to rat heart slices and rat heart in vivo. • Human and rat respond to isoproterenol

  18. Electrocardiographic evaluation in athletes: 'Normal' changes in the athlete's heart and benefits and disadvantages of screening.

    PubMed

    Machado Leite, Sérgio; Freitas, João; Campelo, Manuel; Maciel, M Júlia

    2016-03-01

    Young athletes are considered the healthiest group in society. Although rare, there are still reports of sudden death or cardiac arrest on the playing fields. Clinical evaluation is of paramount importance for the identification of possible pathological states that confer increased risk of these events. Interpretation of the electrocardiogram of young athletes can help identify changes associated with heart disease that might preclude the participation in sports. In this context, it is essential to recognize the electrocardiographic patterns that represent the structural and electrical remodeling resulting from continued adaptation to exercise, and which thus do not increase the risk of adverse events during exercise. The European Society of Cardiology (ESC) and the American Heart Association (AHA) have issued consensus documents summarizing which electrocardiographic abnormalities should be considered 'physiological', resulting from adaptation to exercise ('athlete's heart'), and which should be considered pathological and thus require further study. However, the two societies have different approaches with respect to the electrocardiographic screening of athletes. This paper provides a brief review of current evidence regarding the electrocardiographic findings considered normal and abnormal in athletes, and presents the arguments of the ESC and AHA for electrocardiographic screening in this population. PMID:26923366

  19. Characteristic parameters of electromagnetic signals from a human heart system

    NASA Astrophysics Data System (ADS)

    Liu, Xin-Yuan; Pei, Liu-Qing; Wang, Yin; Zhang, Su-Ming; Gao, Hong-Lei; Dai, Yuan-Dong

    2011-04-01

    The electromagnetic field of a human heart system is a bioelectromagnetic field. Electrocardiography (ECG) and magnetocardiography (MCG) are both carriers of electromagnetic information about the cardiac system, and they are nonstationary signals. In this study, ECG and MCG data from healthy subjects are acquired; the MCG data are captured using a high-Tc radio frequency superconducting quantum interference device (HTc rf SQUIDs) and the QRS complexes in these data are analysed by the evolutionary spectrum analysis method. The results show that the quality factor Q and the central frequency fz of the QRS complex evolutionary spectrum are the characteristic parameters (CHPs) of ECG and MCG in the time—frequency domain. The confidence intervals of the mean values of the CHPs are estimated by the Student t distribution method in mathematical statistics. We believe that there are threshold ranges of the mean values of Q and fz for healthy subjects. We have postulated the following criterion: if the mean values of CHPs are in the proper ranges, the cardiac system is in a normal condition and it possesses the capability of homeostasis. In contrast, if the mean values of the CHPs do not lie in the proper ranges, the homeostasis of the cardiac system is lacking and some cardiac disease may follow. The results and procedure of MCG CHPs in the study afford a technological route for the application of HTc rf SQUIDs in cardiology.

  20. Transmural progression of morphologic changes during ischemic contracture and reperfusion in the normal and hypertrophied rat heart.

    PubMed Central

    Anderson, P. G.; Bishop, S. P.; Digerness, S. B.

    1987-01-01

    The purpose of this study was to compare the functional and morphologic changes that occur during ischemic contracture and reperfusion in the normal and hypertrophied heart. Hearts from Sprague-Dawley, spontaneously hypertensive (SHR), and normotensive Wistar-Kyoto rats were evaluated using a modified Langendorff perfusion apparatus. After obtaining control data, hearts were potassium-arrested, made ischemic, and studied at various time points. Regional coronary flow was assessed with the use of radiolabeled microspheres or Microfil dye infusion, and morphologic changes were evaluated by means of light and electron microscopy. Sarcomere length changes and qualitative morphologic changes during global ischemia demonstrate a transmural progression of ischemic damage starting at the endocardium and extending, with time, epicardially. The progression of ischemic changes in hypertrophied hearts of SHRs was similar to that of normal hearts; however, hypertrophied hearts developed ischemic contracture sooner than normal hearts. In addition, the development of contraction band change after ischemic contracture occurred only when hearts were reperfused and was related to the development of no-reflow. Images Figure 4 Figure 5 Figure 2 Figure 3 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 PMID:2959155

  1. Understanding Patients’ Experiences of Treatment Burden in Chronic Heart Failure Using Normalization Process Theory

    PubMed Central

    Gallacher, Katie; May, Carl R.; Montori, Victor M.; Mair, Frances S.

    2011-01-01

    PURPOSE Our goal was to assess the burden associated with treatment among patients living with chronic heart failure and to determine whether Normalization Process Theory (NPT) is a useful framework to help describe the components of treatment burden in these patients. METHODS We performed a secondary analysis of qualitative interview data, using framework analysis, informed by NPT, to determine the components of patient “work.” Participants were 47 patients with chronic heart failure managed in primary care in the United Kingdom who had participated in an earlier qualitative study about living with this condition. We identified and examined data that fell outside of the coding frame to determine if important concepts or ideas were being missed by using the chosen theoretical framework. RESULTS We were able to identify and describe components of treatment burden as distinct from illness burden using the framework. Treatment burden in chronic heart failure includes the work of developing an understanding of treatments, interacting with others to organize care, attending appointments, taking medications, enacting lifestyle measures, and appraising treatments. Factors that patients reported as increasing treatment burden included too many medications and appointments, barriers to accessing services, fragmented and poorly organized care, lack of continuity, and inadequate communication between health professionals. Patient “work” that fell outside of the coding frame was exclusively emotional or spiritual in nature. CONCLUSIONS We identified core components of treatment burden as reported by patients with chronic heart failure. The findings suggest that NPT is a theoretical framework that facilitates understanding of experiences of health care work at the individual, as well as the organizational, level. Although further exploration and patient endorsement are necessary, our findings lay the foundation for a new target for treatment and quality improvement

  2. FISH CONSUMPTION, METHYLMERCURY, AND HUMAN HEART DISEASE.

    SciTech Connect

    LIPFERT, F.W.; SULLIVAN, T.M.

    2005-09-21

    Environmental mercury continues to be of concern to public health advocates, both in the U.S. and abroad, and new research continues to be published. A recent analysis of potential health benefits of reduced mercury emissions has opened a new area of public health concern: adverse effects on the cardiovascular system, which could account for the bulk of the potential economic benefits. The authors were careful to include caveats about the uncertainties of such impacts, but they cited only a fraction of the applicable health effects literature. That literature includes studies of the potentially harmful ingredient (methylmercury, MeHg) in fish, as well as of a beneficial ingredient, omega-3 fatty acids or ''fish oils''. The U.S. Food and Drug Administration (FDA) recently certified that some of these fat compounds that are primarily found in fish ''may be beneficial in reducing coronary heart disease''. This paper briefly summarizes and categorizes the extensive literature on both adverse and beneficial links between fish consumption and cardiovascular health, which are typically based on studies of selected groups of individuals (cohorts). Such studies tend to comprise the ''gold standard'' of epidemiology, but cohorts tend to exhibit a great deal of variability, in part because of the limited numbers of individuals involved and in part because of interactions with other dietary and lifestyle considerations. Note that eating fish will involve exposure to both the beneficial effects of fatty acids and the potentially harmful effects of contaminants like Hg or PCBs, all of which depend on the type of fish but tend to be correlated within a population. As a group, the cohort studies show that eating fish tends to reduce mortality, especially due to heart disease, for consumption rates up to about twice weekly, above which the benefits tend to level off. A Finnish cohort study showed increased mortality risks in the highest fish-consuming group ({approx}3 times

  3. From zebrafish heart jogging genes to mouse and human orthologs: using Gene Ontology to investigate mammalian heart development.

    PubMed Central

    Lovering, Ruth C

    2014-01-01

    For the majority of organs in developing vertebrate embryos, left-right asymmetry is controlled by a ciliated region; the left-right organizer node in the mouse and human, and the Kuppfer’s vesicle in the zebrafish. In the zebrafish, laterality cues from the Kuppfer’s vesicle determine asymmetry in the developing heart, the direction of ‘heart jogging’ and the direction of ‘heart looping’.  ‘Heart jogging’ is the term given to the process by which the symmetrical zebrafish heart tube is displaced relative to the dorsal midline, with a leftward ‘jog’. Heart jogging is not considered to occur in mammals, although a leftward shift of the developing mouse caudal heart does occur prior to looping, which may be analogous to zebrafish heart jogging. Previous studies have characterized 30 genes involved in zebrafish heart jogging, the majority of which have well defined orthologs in mouse and human and many of these orthologs have been associated with early mammalian heart development.    We undertook manual curation of a specific set of genes associated with heart development and we describe the use of Gene Ontology term enrichment analyses to examine the cellular processes associated with heart jogging.  We found that the human, mouse and zebrafish ‘heart jogging orthologs’ are involved in similar organ developmental processes across the three species, such as heart, kidney and nervous system development, as well as more specific cellular processes such as cilium development and function. The results of these analyses are consistent with a role for cilia in the determination of left-right asymmetry of many internal organs, in addition to their known role in zebrafish heart jogging.    This study highlights the importance of model organisms in the study of human heart development, and emphasises both the conservation and divergence of developmental processes across vertebrates, as well as the limitations of this approach. PMID:24627794

  4. From zebrafish heart jogging genes to mouse and human orthologs: using Gene Ontology to investigate mammalian heart development.

    PubMed

    Khodiyar, Varsha K; Howe, Doug; Talmud, Philippa J; Breckenridge, Ross; Lovering, Ruth C

    2013-01-01

    For the majority of organs in developing vertebrate embryos, left-right asymmetry is controlled by a ciliated region; the left-right organizer node in the mouse and human, and the Kuppfer's vesicle in the zebrafish. In the zebrafish, laterality cues from the Kuppfer's vesicle determine asymmetry in the developing heart, the direction of 'heart jogging' and the direction of 'heart looping'.  'Heart jogging' is the term given to the process by which the symmetrical zebrafish heart tube is displaced relative to the dorsal midline, with a leftward 'jog'. Heart jogging is not considered to occur in mammals, although a leftward shift of the developing mouse caudal heart does occur prior to looping, which may be analogous to zebrafish heart jogging. Previous studies have characterized 30 genes involved in zebrafish heart jogging, the majority of which have well defined orthologs in mouse and human and many of these orthologs have been associated with early mammalian heart development.    We undertook manual curation of a specific set of genes associated with heart development and we describe the use of Gene Ontology term enrichment analyses to examine the cellular processes associated with heart jogging.  We found that the human, mouse and zebrafish 'heart jogging orthologs' are involved in similar organ developmental processes across the three species, such as heart, kidney and nervous system development, as well as more specific cellular processes such as cilium development and function. The results of these analyses are consistent with a role for cilia in the determination of left-right asymmetry of many internal organs, in addition to their known role in zebrafish heart jogging.    This study highlights the importance of model organisms in the study of human heart development, and emphasises both the conservation and divergence of developmental processes across vertebrates, as well as the limitations of this approach. PMID:24627794

  5. Programming and reprogramming a human heart cell

    PubMed Central

    Sahara, Makoto; Santoro, Federica; Chien, Kenneth R

    2015-01-01

    The latest discoveries and advanced knowledge in the fields of stem cell biology and developmental cardiology hold great promise for cardiac regenerative medicine, enabling researchers to design novel therapeutic tools and approaches to regenerate cardiac muscle for diseased hearts. However, progress in this arena has been hampered by a lack of reproducible and convincing evidence, which at best has yielded modest outcomes and is still far from clinical practice. To address current controversies and move cardiac regenerative therapeutics forward, it is crucial to gain a deeper understanding of the key cellular and molecular programs involved in human cardiogenesis and cardiac regeneration. In this review, we consider the fundamental principles that govern the “programming” and “reprogramming” of a human heart cell and discuss updated therapeutic strategies to regenerate a damaged heart. PMID:25712211

  6. Direct observation of homoclinic orbits in human heart rate variability

    NASA Astrophysics Data System (ADS)

    Żebrowski, J. J.; Baranowski, R.

    2003-05-01

    Homoclinic trajectories of the interbeat intervals between contractions of ventricles of the human heart are identified. The interbeat intervals are extracted from 24-h Holter ECG recordings. Three such recordings are discussed in detail. Mappings of the measured consecutive interbeat intervals are constructed. In the second and in some cases in the fourth iterate of the map of interbeat intervals homoclinic trajectories associated with a hyperbolic saddle are found. The homoclinic trajectories are often persistent for many interbeat intervals, sometimes spanning many thousands of heartbeats. Several features typical for homoclinic trajectories found in other systems were identified, including a signature of the gluing bifurcation. The homoclinic trajectories are present both in recordings of heart rate variability obtained from patients with an increased number of arrhythmias and in cases in which the sinus rhythm is dominant. The results presented are a strong indication of the importance of deterministic nonlinear instabilities in human heart rate variability.

  7. Quantitative comparison of myocardial blood flow in normal and infarcted hearts by high resolution scintigraphy

    SciTech Connect

    Hung, C.Y.; Burow, R.D.; Scherlag, B.J.; Basmadjian, G.P.; Lazzara, R.

    1984-01-01

    The standard method for measuring myocardial blood flow (MBF) with radioactive microspheres requires processing of selected tissue samples and consequent loss of exact relation to myocardial morphology. Also, in myocardial infarction (MI) there are inaccuracies due to overlap of tissues from borders of normal and MI. A new method uses Tc-99m labeled microspheres (20..mu..) which were injected into the left atrium in 18 normal dogs and 12 dogs with MI (5 had 1 day and 7 had 4 day old MI). The excised hearts were rinsed and frozen before ''bread-loaf'' sections, 3 mm thick, were cut. Images were acquired on a gamma camera with a volume resolution of 12 mm/sup 3/. A computer program for determining MBF was checked against the conventional microsphere method. The volume resolution of the latter method was 100 mm/sup 3/. The correlation coefficient between the two methods was r=0.96. Average MBF for a given section of normal RV and LV was 95 +- 13 and 119 +- 15 ml/min/100 g of tissue, respectively. Average MBF was compared in normal LV and from ischemic epicardium (IsZ) of the central MI and endocardial infarcted zone (IZ). The authors' new method, accurately and with high resolution, delineates zones of differing MBF and confirms the increase of MBF in surviving myocardium with healing.

  8. Total lymphatic irradiation and bone marrow in human heart transplantation

    SciTech Connect

    Kahn, D.R.; Hong, R.; Greenberg, A.J.; Gilbert, E.F.; Dacumos, G.C.; Dufek, J.H.

    1984-08-01

    Six patients, aged 36 to 59 years, had heart transplants for terminal myocardial disease using total lymphatic irradiation (TLI) and donor bone marrow in addition to conventional therapy. All patients were poor candidates for transplantation because of marked pulmonary hypertension, unacceptable tissue matching, or age. Two patients are living and well more than four years after the transplants. Two patients died of infection at six and seven weeks with normal hearts. One patient, whose preoperative pulmonary hypertension was too great for an orthotopic heart transplant, died at 10 days after such a procedure. The other patient died of chronic rejection seven months postoperatively. Donor-specific tolerance developed in 2 patients. TLI and donor bone marrow can produce specific tolerance to donor antigens and allow easy control of rejection, but infection is still a major problem. We describe a new technique of administering TLI with early reduction of prednisone that may help this problem.

  9. Application of Laser Doppler Vibrometery for human heart auscultation.

    PubMed

    Koegelenberg, S; Scheffer, C; Blanckenberg, M M; Doubell, A F

    2014-01-01

    In this study the potential of a Laser Doppler Vibrometer (LDV) was tested as a non-contact sensor for the classification of heart sounds. Of the twenty participants recorded using the LDV, five presented with Aortic Stenosis (AS), three were healthy and twelve presented with other pathologies. The recorded heart sounds were denoised and segmented using a combination of the Electrocardiogram (ECG) data and the complexity of the signal. Frequency domain features were extracted from the segmented heart sound cycles and used to train a K-nearest neighbor classifier. Due to the small number of participants, the classifier could not be trained to differentiate between normal and abnormal participants, but could successfully distinguish between participants who presented with AS and those who did not. A sensitivity of 80 % and a specificity of 100 % were achieved a test dataset. PMID:25570986

  10. Physiological roles of the transient outward current Ito in normal and diseased hearts.

    PubMed

    Cordeiro, Jonathan M; Calloe, Kirstine; Aschar-Sobbi, Roozbeh; Kim, Kyoung-Han; Korogyi, Adam; Occhipinti, Dona; Backx, Peter H; Panama, Brian K

    2016-01-01

    The Ca(2+)-independent transient outward K(+) current (I(to)) plays a critical role in underlying phase 1 of repolarization of the cardiac action potential and, as a result, is central to modulating excitation-contraction coupling and propensity for arrhythmia. Additionally, I(to) and its molecular constituents are consistently reduced in cardiac hypertrophy and heart failure. In this review, we discuss the physiological role of I(to) as well as the molecular basis of this current in human and canine hearts, in which I(to) has been thoroughly studied. In particular, we discuss the role of Ito; in the action potential and the mechanisms by which I(to) modulates excitation-contraction coupling. We also describe the effects of mutations in the subunits constituting the Ito channel as well as the role of I(to) in the failing myocardium. Finally, we review pharmacological modulation of I(to) and discuss the evidence supporting the hypothesis that restoration of I(to) in the setting of heart failure may be therapeutically beneficial by enhancing excitation-contraction coupling and cardiac function. PMID:26709904

  11. Influence of heart failure on nucleolar organization and protein expression in human hearts

    SciTech Connect

    Rosello-Lleti, Esther; Rivera, Miguel; Cortes, Raquel; Azorin, Inmaculada; Sirera, Rafael; Martinez-Dolz, Luis; Hove, Leif; Cinca, Juan; Lago, Francisca; Gonzalez-Juanatey, Jose R.; Salvador, Antonio; Portoles, Manuel

    2012-02-10

    Highlights: Black-Right-Pointing-Pointer Heart failure alters nucleolar morphology and organization. Black-Right-Pointing-Pointer Nucleolin expression is significant increased in ischemic and dilated cardiomyopathy. Black-Right-Pointing-Pointer Ventricular function of heart failure patients was related with nucleolin levels. -- Abstract: We investigate for the first time the influence of heart failure (HF) on nucleolar organization and proteins in patients with ischemic (ICM) or dilated cardiomyopathy (DCM). A total of 71 human hearts from ICM (n = 38) and DCM (n = 27) patients, undergoing heart transplantation and control donors (n = 6), were analysed by western-blotting, RT-PCR and cell biology methods. When we compared protein levels according to HF etiology, nucleolin was increased in both ICM (117%, p < 0.05) and DCM (141%, p < 0.01). Moreover, mRNA expression were also upregulated in ICM (1.46-fold, p < 0.05) and DCM (1.70-fold, p < 0.05. Immunofluorescence studies showed that the highest intensity of nucleolin was into nucleolus (p < 0.0001), and it was increased in pathological hearts (p < 0.0001). Ultrastructure analysis by electron microscopy showed an increase in the nucleus and nucleolus size in ICM (17%, p < 0.05 and 131%, p < 0.001) and DCM (56%, p < 0.01 and 69%, p < 0.01). Nucleolar organization was influenced by HF irrespective of etiology, increasing fibrillar centers (p < 0.001), perinucleolar chromatin (p < 0.01) and dense fibrillar components (p < 0.01). Finally, left ventricular function parameters were related with nucleolin levels in ischemic hearts (p < 0.0001). The present study demonstrates that HF influences on morphology and organization of nucleolar components, revealing changes in the expression and in the levels of nucleolin protein.

  12. Mechanical Unloading Promotes Myocardial Energy Recovery in Human Heart Failure

    PubMed Central

    Gupte, Anisha A.; Hamilton, Dale J.; Cordero-Reyes, Andrea M.; Youker, Keith A.; Yin, Zheng; Estep, Jerry D.; Stevens, Robert D.; Wenner, Brett; Ilkayeva, Olga; Loebe, Matthias; Peterson, Leif E.; Lyon, Christopher J.; Wong, Stephen T.C.; Newgard, Christopher B.; Torre-Amione, Guillermo; Taegtmeyer, Heinrich; Hsueh, Willa A.

    2015-01-01

    Background Impaired bioenergetics is a prominent feature of the failing heart, but the underlying metabolic perturbations are poorly understood. Methods and Results We compared metabolomic, gene transcript, and protein data from six paired failing human left ventricular (LV) tissue samples obtained during left ventricular assist device (LVAD) insertion (heart failure (HF) samples) and at heart transplant (post-LVAD samples). Non-failing left ventricular (NFLV) wall samples procured from explanted hearts of patients with right HF served as novel comparison samples. Metabolomic analyses uncovered a distinct pattern in HF tissue: 2.6 fold increased pyruvate concentrations coupled with reduced Krebs cycle intermediates and short-chain acylcarnitines, suggesting a global reduction in substrate oxidation. These findings were associated with decreased transcript levels for enzymes that catalyze fatty acid oxidation and pyruvate metabolism and for key transcriptional regulators of mitochondrial metabolism and biogenesis, peroxisome proliferator-activated receptor gamma co-activator1α (PGC1A, 1.3 fold) and estrogen-related receptor α (ERRA, 1.2 fold) and γ (ERRG, 2.2 fold). Thus, parallel decreases in key transcription factors and their target metabolic enzyme genes can explain the decreases in associated metabolic intermediates. Mechanical support with LVAD improved all of these metabolic and transcriptional defects. Conclusions These observations underscore an important pathophysiologic role for severely defective metabolism in HF, while the reversibility of these defects by LVAD suggests metabolic resilience of the human heart. PMID:24825877

  13. Fluorescence Lifetimes of Normal and Carcinomatous Human Nasopharyngeal Tissues

    NASA Astrophysics Data System (ADS)

    Chen, M.; Li, H.; Li, B.; Chen, R.; Zheng, G.; Song, C.

    2016-03-01

    Time-resolved fluorescence spectra of normal and carcinomatous in vitro human nasopharyngeal tissues are compared. By fitting the time-resolved emission with exponential decays, mean lifetimes were obtained. There were marked differences between the lifetimes of the carcinomatous and the normal tissues. Thus, early diagnosis of nasopharyngeal carcinoma is possible. In general, comprehensive information from human tissue autofluorescence can be acquired via both time-resolved and steady-state fluorescence spectra.

  14. A “PET” area of interest: myocardial metabolism in human systolic heart failure

    PubMed Central

    Kadkhodayan, Ana; Coggan, Andrew R.; Peterson, Linda R.

    2013-01-01

    Myocardial substrate metabolism provides the energy needed for cardiac contraction and relaxation. The normal adult heart uses predominantly fatty acids (FAs) as its primary fuel source. However, the heart can switch and use glucose (and to a lesser extent, ketones, lactate, as well as endogenous triglycerides and glycogen), depending on the metabolic milieu and superimposed conditions. FAs are not a wholly better fuel than glucose, but they do provide more energy per mole than glucose. Conversely, glucose is the more oxygen-efficient fuel. Studies in animal models of heart failure (HF) fairly consistently demonstrate a shift away from myocardial fatty acid metabolism and towards glucose metabolism. Studies in humans are less consistent. Some show the same metabolic switch away from FA metabolism but not all. This may be due to differences in the etiology of HF, sex-related differences, or other mitigating factors. For example, obesity, insulin resistance, and diabetes are all related to an increased risk of HF and may complicate or contribute to its development. However, these conditions are associated with increased FA metabolism. This review will discuss aspects of human heart metabolism in systolic dysfunction as measured by the noninvasive, quantitative method – positron emission tomography. Continued research in this area is vital if we are to ameliorate HF by manipulating heart metabolism with the aim of increasing energy production and/or efficiency. PMID:23180281

  15. Quantification of pulmonary thallium-201 activity after upright exercise in normal persons: importance of peak heart rate and propranolol usage in defining normal values

    SciTech Connect

    Brown, K.A.; Boucher, C.A.; Okada, R.D.; Strauss, H.W.; Pohost, G.M.

    1984-06-01

    Fifty-nine normal patients (34 angiographically normal and 25 clinically normal by Bayesian analysis) underwent thallium-201 imaging after maximal upright exercise. Lung activity was quantitated relative to myocardial activity and a lung/myocardial activity ratio was determined for each patient. Stepwise regression analysis was then used to examine the influence of patient clinical characteristics and exercise variables on the lung/myocardium ratio. Peak heart rate during exercise and propranolol usage both showed significant negative regression coefficients (p less than 0.001). No other patient data showed a significant relation. Using the regression equation and the estimated variance, a 95% confidence level upper limit of normal could be determined for a give peak heart rate and propranolol status. Sixty-one other patients were studied to validate the predicted upper limits of normal based on this model. None of the 27 patients without coronary artery disease had an elevated lung/myocardial ratio, compared with 1 of 8 with 1-vessel disease (difference not significant), 6 of 14 with 2-vessel disease (p less than 0.005), and 6 of 12 with 3-vessel disease (p less than 0.0001). Thus, lung activity on upright exercise thallium-201 studies can be quantitated relative to myocardial activity, and is inversely related to peak heart rate and propranolol use. Use of a regression analysis allows determination of a 95% confidence upper limit of normal to be anticipated in an individual patient.

  16. Clinical iron deficiency disturbs normal human responses to hypoxia

    PubMed Central

    Frise, Matthew C.; Cheng, Hung-Yuan; Nickol, Annabel H.; Curtis, M. Kate; Pollard, Karen A.; Roberts, David J.; Ratcliffe, Peter J.; Dorrington, Keith L.; Robbins, Peter A.

    2016-01-01

    BACKGROUND. Iron bioavailability has been identified as a factor that influences cellular hypoxia sensing, putatively via an action on the hypoxia-inducible factor (HIF) pathway. We therefore hypothesized that clinical iron deficiency would disturb integrated human responses to hypoxia. METHODS. We performed a prospective, controlled, observational study of the effects of iron status on hypoxic pulmonary hypertension. Individuals with absolute iron deficiency (ID) and an iron-replete (IR) control group were exposed to two 6-hour periods of isocapnic hypoxia. The second hypoxic exposure was preceded by i.v. infusion of iron. Pulmonary artery systolic pressure (PASP) was serially assessed with Doppler echocardiography. RESULTS. Thirteen ID individuals completed the study and were age- and sex-matched with controls. PASP did not differ by group or study day before each hypoxic exposure. During the first 6-hour hypoxic exposure, the rise in PASP was 6.2 mmHg greater in the ID group (absolute rises 16.1 and 10.7 mmHg, respectively; 95% CI for difference, 2.7–9.7 mmHg, P = 0.001). Intravenous iron attenuated the PASP rise in both groups; however, the effect was greater in ID participants than in controls (absolute reductions 11.1 and 6.8 mmHg, respectively; 95% CI for difference in change, –8.3 to –0.3 mmHg, P = 0.035). Serum erythropoietin responses to hypoxia also differed between groups. CONCLUSION. Clinical iron deficiency disturbs normal responses to hypoxia, as evidenced by exaggerated hypoxic pulmonary hypertension that is reversed by subsequent iron administration. Disturbed hypoxia sensing and signaling provides a mechanism through which iron deficiency may be detrimental to human health. TRIAL REGISTRATION. ClinicalTrials.gov (NCT01847352). FUNDING. M.C. Frise is the recipient of a British Heart Foundation Clinical Research Training Fellowship (FS/14/48/30828). K.L. Dorrington is supported by the Dunhill Medical Trust (R178/1110). D.J. Roberts was

  17. Multiscale entropy and detrended fluctuation analysis of QT interval and heart rate variability during normal pregnancy.

    PubMed

    Baumert, Mathias; Javorka, Michal; Seeck, Andrea; Faber, Renaldo; Sanders, Prashanthan; Voss, Andreas

    2012-03-01

    Pregnancy leads to physiological changes in various parameters of the cardiovascular system. The aim of this study was to investigate longitudinal changes in the structure and complexity of heart rate variability (HRV) and QT interval variability during the second half of normal gestation. We analysed 30-min high-resolution ECGs recorded monthly in 32 pregnant women, starting from the 20th week of gestation. Heart rate and QT variability were quantified using multiscale entropy (MSE) and detrended fluctuation analyses (DFA). DFA of HRV showed significantly higher scaling exponents towards the end of gestation (p<0.0001). MSE analysis showed a significant decrease in sample entropy of HRV with progressing gestation on scales 1-4 (p<0.05). MSE analysis and DFA of QT interval time series revealed structures significantly different from those of HRV with no significant alteration during the second half of gestation. In conclusion, pregnancy is associated with increases in long-term correlations and regularity of HRV, but it does not affect QT variability. The structure of QT time series is significantly different from that of RR time series, despite its close physiological dependence. PMID:21530956

  18. Re-evaluation of normal splitting of the second heart sound in patients with classical left bundle branch block.

    PubMed

    Xiao, H B; Faiek, A H; Gibson, D G

    1994-07-01

    To study the mechanism of normal splitting of the second heart sound in patients with classical left bundle branch block, we investigated 43 such patients and 15 normal controls, using electro-, phono- and echo-cardiography and comparing the relative timing of mechanical activity in the two ventricles. The splitting of the second heart sound is reversed in only two-thirds of the patients and normal in remaining one-third. Comparing patients with and without reversed splitting, there are no significant differences in left ventricular cavity size, heart rate, pre-ejection period and the distribution of age, gender, or aetiology. QRS duration is longer (P < 0.01) in patients with reversed splitting. Diastolic events of the left ventricle do not differ between groups. The onset of the left ventricular free wall motion is delayed compared with normal by a similar extent in the two groups. In patients with normal splitting, the onset of the right ventricular wall motion is also delayed, both with respect to normal and to those with reversed splitting to an extent similar to that seen in classical right bundle branch block. Normal splitting of the second heart sound associated with an electrocardiographic pattern of left bundle branch block therefore suggests bilateral block. This combination can be documented from the precise timing of the movement of the two ventricles by M-mode echocardiography and identified by simple auscultation. PMID:7960260

  19. Dynamics of Cell Generation and Turnover in the Human Heart.

    PubMed

    Bergmann, Olaf; Zdunek, Sofia; Felker, Anastasia; Salehpour, Mehran; Alkass, Kanar; Bernard, Samuel; Sjostrom, Staffan L; Szewczykowska, Mirosława; Jackowska, Teresa; Dos Remedios, Cris; Malm, Torsten; Andrä, Michaela; Jashari, Ramadan; Nyengaard, Jens R; Possnert, Göran; Jovinge, Stefan; Druid, Henrik; Frisén, Jonas

    2015-06-18

    The contribution of cell generation to physiological heart growth and maintenance in humans has been difficult to establish and has remained controversial. We report that the full complement of cardiomyocytes is established perinataly and remains stable over the human lifespan, whereas the numbers of both endothelial and mesenchymal cells increase substantially from birth to early adulthood. Analysis of the integration of nuclear bomb test-derived (14)C revealed a high turnover rate of endothelial cells throughout life (>15% per year) and more limited renewal of mesenchymal cells (<4% per year in adulthood). Cardiomyocyte exchange is highest in early childhood and decreases gradually throughout life to <1% per year in adulthood, with similar turnover rates in the major subdivisions of the myocardium. We provide an integrated model of cell generation and turnover in the human heart. PMID:26073943

  20. Epithelial cell cultures from normal and cancerous human tissues.

    PubMed

    Owens, R B; Smith, H S; Nelson-Rees, W A; Springer, E L

    1976-04-01

    Thirty epithelial cell strains were isolated from human carcinomas and normal epithelial tissues by collagenase digestion and selective removal of fibroblasts with trypsin-Versene. Most strains were obtained from metastatic carcinomas or epithelia of the urinary and intestinal tracts. The success rate for growth of both neoplastic and normal tissues (excluding skin) was 38%. Six of these strains showed gross morphologic and chromosome changes typical of malignant cells. Nine resembled normal epithelium. The other 15 exhibited some degree of morphologic change from normal. PMID:176412

  1. DNA amplification is rare in normal human cells

    SciTech Connect

    Wright, J.A.; Watt, F.M.; Hudson, D.L.; Stark, G.R. ); Smith, H.S.; Hancock, M.C. )

    1990-03-01

    Three types of normal human cells were selected in tissue culture with three drugs without observing a single amplification event from a total of 5 x 10{sup 8} cells. No drug-resistant colonies were observed when normal foreskin keratinocytes were selected with N-(phosphonacetyl)-L-aspartate or with hydroxyurea or when normal mammary epithelial cells were selected with methotrexate. Some slightly resistant colonies with limited potential for growth were obtained when normal diploid fibroblast cells derived from fetal lung were selected with methotrexate or hydroxyurea but careful copy-number analysis of the dihydrofolate reductase and ribonucleotide reductase genes revealed no evidence of amplification. The rarity of DNA amplification in normal human cells contrasts strongly with the situation in tumors and in established cell lines, where amplification of onogenes and of genes mediating drug resistance is frequent. The results suggest that tumors and cell lines have acquired the abnormal ability to amplify DNA with high frequency.

  2. Adult cardiac fibroblast proliferation is modulated by calcium/calmodulin-dependent protein kinase II in normal and hypertrophied hearts.

    PubMed

    Martin, Tamara P; Lawan, Ahmed; Robinson, Emma; Grieve, David J; Plevin, Robin; Paul, Andrew; Currie, Susan

    2014-02-01

    Increased adult cardiac fibroblast proliferation results in an increased collagen deposition responsible for the fibrosis accompanying pathological remodelling of the heart. The mechanisms regulating cardiac fibroblast proliferation remain poorly understood. Using a minimally invasive transverse aortic banding (MTAB) mouse model of cardiac hypertrophy, we have assessed fibrosis and cardiac fibroblast proliferation. We have investigated whether calcium/calmodulin-dependent protein kinase IIδ (CaMKIIδ) regulates proliferation in fibroblasts isolated from normal and hypertrophied hearts. It is known that CaMKIIδ plays a central role in cardiac myocyte contractility, but nothing is known of its role in adult cardiac fibroblast function. The MTAB model used here produces extensive hypertrophy and fibrosis. CaMKIIδ protein expression and activity is upregulated in MTAB hearts and, specifically, in cardiac fibroblasts isolated from hypertrophied hearts. In response to angiotensin II, cardiac fibroblasts isolated from MTAB hearts show increased proliferation rates. Inhibition of CaMKII with autocamtide inhibitory peptide inhibits proliferation in cells isolated from both sham and MTAB hearts, with a significantly greater effect evident in MTAB cells. These results are the first to show selective upregulation of CaMKIIδ in adult cardiac fibroblasts following cardiac hypertrophy and to assign a previously unrecognised role to CaMKII in regulating adult cardiac fibroblast function in normal and diseased hearts. PMID:23881186

  3. Noninvasive recovery of epicardial potentials in a realistic heart-torso geometry. Normal sinus rhythm.

    PubMed

    Messinger-Rapport, B J; Rudy, Y

    1990-04-01

    The inverse problem in electrocardiography implies the reconstruction of electrical events within the heart from information measured noninvasively on the body surface. Deduction of these electrical events is possible from measured epicardial potentials, and, thus, a noninvasive method of recovering epicardial potentials from body surface data is useful in experimental and clinical studies. In the present study, an inverse method that uses Tikhonov regularization was shown to reconstruct, with good accuracy, important events in cardiac excitation. The inverse procedure was employed on data obtained from a human-torso tank in which a beating canine heart was placed in the correct anatomical position. Comparison with the actual, measured epicardial potentials indicates that positions and shapes of potential features (maxima, minima, zero potential line, saddles, etc.) are recovered with good accuracy throughout the QRS. An error in position of up to 1 cm is typical, while amplitudes are slightly diminished. In addition, application was extended from the above setting, in which the geometry was precisely known and potentials at a large number of leads were measured accurately, to a situation that is more representative of clinical and experimental settings. Effects of inaccuracy in location of the position of the heart were examined. A stylized torso that approximates the actual geometry was designed, and its performance in the inverse computations was evaluated. A systematic method of reduction of the number of leads on the body surface was proposed, and the resulting lead configurations were evaluated in terms of the accuracy of inverse solutions. The results indicate that the inverse problem can be stabilized with respect to different types of uncertainties in measured data and offer promise in the use of the inverse procedure in clinical and experimental situations. PMID:2317885

  4. Influence of heart failure on nucleolar organization and protein expression in human hearts.

    PubMed

    Roselló-Lletí, Esther; Rivera, Miguel; Cortés, Raquel; Azorín, Inmaculada; Sirera, Rafael; Martínez-Dolz, Luis; Hove, Leif; Cinca, Juan; Lago, Francisca; González-Juanatey, José R; Salvador, Antonio; Portolés, Manuel

    2012-02-10

    We investigate for the first time the influence of heart failure (HF) on nucleolar organization and proteins in patients with ischemic (ICM) or dilated cardiomyopathy (DCM). A total of 71 human hearts from ICM (n=38) and DCM (n=27) patients, undergoing heart transplantation and control donors (n=6), were analysed by western-blotting, RT-PCR and cell biology methods. When we compared protein levels according to HF etiology, nucleolin was increased in both ICM (117%, p<0.05) and DCM (141%, p<0.01). Moreover, mRNA expression were also upregulated in ICM (1.46-fold, p<0.05) and DCM (1.70-fold, p<0.05. Immunofluorescence studies showed that the highest intensity of nucleolin was into nucleolus (p<0.0001), and it was increased in pathological hearts (p<0.0001). Ultrastructure analysis by electron microscopy showed an increase in the nucleus and nucleolus size in ICM (17%, p<0.05 and 131%, p<0.001) and DCM (56%, p<0.01 and 69%, p<0.01). Nucleolar organization was influenced by HF irrespective of etiology, increasing fibrillar centers (p<0.001), perinucleolar chromatin (p<0.01) and dense fibrillar components (p<0.01). Finally, left ventricular function parameters were related with nucleolin levels in ischemic hearts (p<0.0001). The present study demonstrates that HF influences on morphology and organization of nucleolar components, revealing changes in the expression and in the levels of nucleolin protein. PMID:22244875

  5. Posture and Gender Differentially Affect Heart Rate Variability of Symptomatic Mitral Valve Prolapse and Normal Adults

    PubMed Central

    Chang, Chien-Jung; Chen, Ya-Chu; Lee, Chih-Hsien; Yang, Ing-Fang; Yang, Ten-Fang

    2016-01-01

    Background Heart rate variability (HRV) has been shown to be a useful measure of autonomic activity in healthy and mitral valve prolapsed (MVP) subjects. However, the effects of posture and gender on HRV in symptomatic MVP and normal adults had not been elucidated in Taiwan. Methods A total of 118 MVP patients (7 males, 39 ± 7 years old; and 111 females, 42 ± 13 years old) and 148 healthy control (54 males, 28 ± 4 years old; and 94 females, 26 ± 6 years old) were investigated. The diagnosis of MVP was confirmed by cross-sectional echocardiography. A locally developed Taiwanese machine was used to record the HRV parameters for MVP and control groups in three stationary positions. Thereafter, the HRV time-domain parameters, and the frequency-domain parameters derived from fast Fourier transform or autoregressive methods were analyzed. Results The MVP group showed a decrease in time domain parameters and obtunded postural effects on frequency domain parameters moreso than the control group. Though the parasympathetic tone was dominant in female (higher RMSSD, nHF and lower nLF vs. male), the sympathetic outflow was higher in MVP female (lower SDNN, NN50 and higher nLF vs. normal female). While the parasympathetic activity was lower in male, sympathetic outflow was dominant in MVP male (lower nHF and higher nLF vs. normal male). Conclusions Both MVP female and male subjects had elevated levels of sympathetic outflow. The obtunded postural effects on frequency domain measures testified to the autonomic dysregulation of MVP subjects. PMID:27471360

  6. Phosphate metabolite concentrations and ATP hydrolysis potential in normal and ischaemic hearts

    PubMed Central

    Wu, Fan; Zhang, Eric Y; Zhang, Jianyi; Bache, Robert J; Beard, Daniel A

    2008-01-01

    To understand how cardiac ATP and CrP remain stable with changes in work rate – a phenomenon that has eluded mechanistic explanation for decades – data from 31phosphate-magnetic resonance spectroscopy (31P-MRS) are analysed to estimate cytoplasmic and mitochondrial phosphate metabolite concentrations in the normal state, during high cardiac workstates, during acute ischaemia and reactive hyperaemic recovery. Analysis is based on simulating distributed heterogeneous oxygen transport in the myocardium integrated with a detailed model of cardiac energy metabolism. The model predicts that baseline myocardial free inorganic phosphate (Pi) concentration in the canine myocyte cytoplasm – a variable not accessible to direct non-invasive measurement – is approximately 0.29 mm and increases to 2.3 mm near maximal cardiac oxygen consumption. During acute ischaemia (from ligation of the left anterior descending artery) Pi increases to approximately 3.1 mm and ATP consumption in the ischaemic tissue is reduced quickly to less than half its baseline value before the creatine phosphate (CrP) pool is 18% depleted. It is determined from these experiments that the maximal rate of oxygen consumption of the heart is an emergent property and is limited not simply by the maximal rate of ATP synthesis, but by the maximal rate at which ATP can be synthesized at a potential at which it can be utilized. The critical free energy of ATP hydrolysis for cardiac contraction that is consistent with these findings is approximately −63.5 kJ mol−1. Based on theoretical findings, we hypothesize that inorganic phosphate is both the primary feedback signal for stimulating oxidative phosphorylation in vivo and also the most significant product of ATP hydrolysis in limiting the capacity of the heart to hydrolyse ATP in vivo. Due to the lack of precise quantification of Piin vivo, these hypotheses and associated model predictions remain to be carefully tested experimentally. PMID:18617566

  7. Effect of Right Ventricular versus Biventricular Pacing on Electrical Remodeling in the Normal Heart

    PubMed Central

    Saba, Samir; Mehdi, Haider; Mathier, Michael A.; Islam, M. Zahadul; Salama, Guy; London, Barry

    2010-01-01

    Background Biventricular (BIV) pacing can improve cardiac function in heart failure by altering the mechanical and electrical substrates. We investigated the effect of BIV versus right ventricular (RV) pacing on the normal heart. Methods and Results Male New Zealand White rabbits (n=33) were divided into 3 groups: sham-operated (control), RV pacing, and BIV pacing groups. Four weeks after surgery, the native QT (p=0.004) interval was significantly shorter in the BIV group compared to the RV or sham-operated groups. Also, compared to rabbits in the RV group, rabbits in the BIV group had shorter RV ventricular effective refractory period (VERP) at all cycle lengths, and shorter LV paced QT interval during the drive train of stimuli and close to refractoriness (p<0.001 for all comparisons). Protein expression of the KVLQT1 was significantly increased in the BIV group compared to the RV and control groups, while protein expression of SCN5A and connexin43 was significantly decreased in the RV compared to the other study groups. Erg protein expression was significantly increased in both pacing groups compared to the controls. Conclusions In this rabbit model, we demonstrate a direct effect of BIV but not RV pacing on shortening the native QT interval as well as the paced QT interval during burst pacing and close to the VERP. These findings underscore the fact that the effect of BIV pacing is partially mediated through direct electrical remodeling and may have implications as to the effect of BIV pacing on arrhythmia incidence and burden. PMID:20042767

  8. Effect of Nebivolol on MIBG Parameters and Exercise in Heart Failure with Normal Ejection Fraction

    PubMed Central

    Messias, Leandro Rocha; Ferreira, Aryanne Guimarães; de Miranda, Sandra Marina Ribeiro; Teixeira, José Antônio Caldas; de Azevedo, Jader Cunha; Messias, Ana Carolina Nader Vasconcelos; Maróstica, Elisabeth; Mesquita, Claudio Tinoco

    2016-01-01

    Background More than 50% of the patients with heart failure have normal ejection fraction (HFNEF). Iodine-123 metaiodobenzylguanidine (123I-MIBG) scintigraphy and cardiopulmonary exercise test (CPET) are prognostic markers in HFNEF. Nebivolol is a beta-blocker with vasodilating properties. Objectives To evaluate the impact of nebivolol therapy on CPET and123I-MIBG scintigraphic parameters in patients with HFNEF. Methods Twenty-five patients underwent 123I-MIBG scintigraphy to determine the washout rate and early and late heart-to-mediastinum ratios. During the CPET, we analyzed the systolic blood pressure (SBP) response, heart rate (HR) during effort and recovery (HRR), and oxygen uptake (VO2). After the initial evaluation, we divided our cohort into control and intervention groups. We then started nebivolol and repeated the tests after 3 months. Results After treatment, the intervention group showed improvement in rest SBP (149 mmHg [143.5-171 mmHg] versus 135 mmHg [125-151 mmHg, p = 0.016]), rest HR (78 bpm [65.5-84 bpm] versus 64.5 bpm [57.5-75.5 bpm, p = 0.028]), peak SBP (235 mmHg [216.5-249 mmHg] versus 198 mmHg [191-220.5 mmHg], p = 0.001), peak HR (124.5 bpm [115-142 bpm] versus 115 bpm [103.7-124 bpm], p= 0.043), HRR on the 1st minute (6.5 bpm [4.75-12.75 bpm] versus 14.5 bpm [6.7-22 bpm], p = 0.025) and HRR on the 2nd minute (15.5 bpm [13-21.75 bpm] versus 23.5 bpm [16-31.7 bpm], p = 0.005), but no change in peak VO2 and 123I-MIBG scintigraphic parameters. Conclusion Despite a better control in SBP, HR during rest and exercise, and improvement in HRR, nebivolol failed to show a positive effect on peak VO2 and 123I-MIBG scintigraphic parameters. The lack of effect on adrenergic activity may be the cause of the lack of effect on functional capacity. PMID:27096522

  9. Decorin and biglycan of normal and pathologic human corneas

    NASA Technical Reports Server (NTRS)

    Funderburgh, J. L.; Hevelone, N. D.; Roth, M. R.; Funderburgh, M. L.; Rodrigues, M. R.; Nirankari, V. S.; Conrad, G. W.

    1998-01-01

    PURPOSE: Corneas with scars and certain chronic pathologic conditions contain highly sulfated dermatan sulfate, but little is known of the core proteins that carry these atypical glycosaminoglycans. In this study the proteoglycan proteins attached to dermatan sulfate in normal and pathologic human corneas were examined to identify primary genes involved in the pathobiology of corneal scarring. METHODS: Proteoglycans from human corneas with chronic edema, bullous keratopathy, and keratoconus and from normal corneas were analyzed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), quantitative immunoblotting, and immunohistology with peptide antibodies to decorin and biglycan. RESULTS: Proteoglycans from pathologic corneas exhibit increased size heterogeneity and binding of the cationic dye alcian blue compared with those in normal corneas. Decorin and biglycan extracted from normal and diseased corneas exhibited similar molecular size distribution patterns. In approximately half of the pathologic corneas, the level of biglycan was elevated an average of seven times above normal, and decorin was elevated approximately three times above normal. The increases were associated with highly charged molecular forms of decorin and biglycan, indicating modification of the proteins with dermatan sulfate chains of increased sulfation. Immunostaining of corneal sections showed an abnormal stromal localization of biglycan in pathologic corneas. CONCLUSIONS: The increased dermatan sulfate associated with chronic corneal pathologic conditions results from stromal accumulation of decorin and particularly of biglycan in the affected corneas. These proteins bear dermatan sulfate chains with increased sulfation compared with normal stromal proteoglycans.

  10. [Ca2+]i in human heart failure: a review and discussion of current areas of controversy.

    PubMed Central

    Liao, R.; Helm, P. A.; Hajjar, R. J.; Saha, C.; Gwathmey, J. K.

    1994-01-01

    Multiple abnormalities have been reported in the setting of human heart failure. It is unclear whether detected changes reflect adaptive alterations in myocardium subjected to increased and sustained hemodynamic overload or are pathogenic to the disease process. As a result of the observation that the primary defect in heart failure is decreased pump function, investigators have concentrated their efforts on determining systolic [Ca2+]i as a logical corollary and a causative mechanism for contractile dysfunction. A simple cause and effect relationship has therefore been proposed with regard to contractile dysfunction and [Ca2+]i. Yet some investigators have found no difference in peak systolic [Ca2+]i between failing and non-failing human myocardium, whereas others have found peak [Ca2+]i to be significantly reduced in failing hearts. Resting calcium concentrations have been reported either to be elevated in failing human myocardium or not different from non-failing human myocardium. Investigators should now appreciate that the force-calcium relationship is not a simple relationship. One must take into account the prolonged time course and slowed mobilization of [Ca2+]i as opposed to simply peak [Ca2+]i. When put in perspective of mechanisms and determinants of the Ca(2+)-force relationship, we begin to realize that failing human myocardium has the "potential" to generate normal levels of force. Only when stressed by [Ca2+]i overload and/or frequency perturbation does myocardium from patients with end-stage heart disease demonstrate contractile failure. Although [Ca2+]i availability and mobilization are likely to play a role in the systolic as well as diastolic dysfunction reported in human heart failure, it is likely that other mechanisms are involved as well (e.g., myocardial energetics). Myocardial energetics is directly related to [Ca2+]i and mobilization in failing human myocardium, because metabolites, e.g., ADP, inhibit pumps, such as sarcoplasmic reticulum

  11. Successful Orthotopic Heart Transplantation and Immunosuppressive Management in 2 Human Immunodeficiency Virus–Seropositive Patients

    PubMed Central

    Kittleson, Michelle M.; Dilibero, Deanna; Hardy, W. David; Kobashigawa, Jon A.; Esmailian, Fardad

    2016-01-01

    Few orthotopic heart transplantations have been performed in patients infected with the human immunodeficiency virus since the first such case was reported in 2001. Since that time, advances in highly active antiretroviral therapy have resulted in potent and durable suppression of the causative human immunodeficiency virus—accompanied by robust immune reconstitution, reversal of previous immunodeficiency, a marked decrease in opportunistic and other infections, and near-normal long-term survival. Although human immunodeficiency virus infection is not an absolute contraindication, few centers in the United States and Canada have performed heart transplantations in this patient population; these patients have been de facto excluded from this procedure in North America. Re-evaluation of the reasons for excluding these patients from cardiac transplantation is warranted in light of such significant advances in antiretroviral therapy. This case report documents successful orthotopic heart transplantation in 2 patients infected with human immunodeficiency virus, and we describe their antiretroviral therapy and immunosuppressive management challenges. Both patients were doing well without sequelae 43 and 38 months after transplantation. PMID:27047290

  12. Noninvasive evaluation of sympathetic nervous system in human heart by positron emission tomography

    SciTech Connect

    Schwaiger, M.; Kalff, V.; Rosenspire, K.; Haka, M.S.; Molina, E.; Hutchins, G.D.; Deeb, M.; Wolfe, E. Jr.; Wieland, D.M. )

    1990-08-01

    The noninvasive functional characterization of the cardiac sympathetic nervous system by imaging techniques may provide important pathophysiological information in various cardiac disease states. Hydroxyephedrine labeled with carbon 11 has been developed as a new catecholamine analogue to be used in the in vivo evaluation of presynaptic adrenergic nerve terminals by positron emission tomography (PET). To determine the feasibility of this imaging approach in the human heart, six normal volunteers and five patients with recent cardiac transplants underwent dynamic PET imaging after intravenous injection of 20 mCi (11C)hydroxyephedrine. Blood and myocardial tracer kinetics were assessed using a regions-of-interest approach. In normal volunteers, blood 11C activity cleared rapidly, whereas myocardium retained 11C activity with a long tissue half-life. Relative tracer retention in the myocardium averaged 79 +/- 31% of peak activity at 60 minutes after tracer injection. The heart-to-blood 11C activity ratio exceeded 6:1 as soon as 30 minutes after tracer injection, yielding excellent image quality. Little regional variation of tracer retention was observed, indicating homogeneous sympathetic innervation throughout the left ventricle. In the transplant recipients, myocardial (11C)hydroxyephedrine retention at 60 minutes was significantly less (-82%) than that of normal volunteers, indicating only little non-neuronal binding of the tracer in the denervated human heart. Thus, (11C)hydroxyephedrine, in combination with dynamic PET imaging, allows the noninvasive delineation of myocardial adrenergic nerve terminals. Tracer kinetic modeling may permit quantitative assessment of myocardial catecholamine uptake, which will in turn provide insights into the effects of various disease processes on the neuronal integrity of the heart.

  13. High Contrast Ultrafast Imaging of the Human Heart

    PubMed Central

    Papadacci, Clement; Pernot, Mathieu; Couade, Mathieu; Fink, Mathias; Tanter, Mickael

    2014-01-01

    Non-invasive ultrafast imaging for human cardiac applications is a big challenge to image intrinsic waves such as electromechanical waves or remotely induced shear waves in elastography imaging techniques. In this paper we propose to perform ultrafast imaging of the heart with adapted sector size by using diverging waves emitted from a classical transthoracic cardiac phased array probe. As in ultrafast imaging with plane wave coherent compounding, diverging waves can be summed coherently to obtain high-quality images of the entire heart at high frame rate in a full field-of-view. To image shear waves propagation at high SNR, the field-of-view can be adapted by changing the angular aperture of the transmitted wave. Backscattered echoes from successive circular wave acquisitions are coherently summed at every location in the image to improve the image quality while maintaining very high frame rates. The transmitted diverging waves, angular apertures and subapertures size are tested in simulation and ultrafast coherent compounding is implemented on a commercial scanner. The improvement of the imaging quality is quantified in phantom and in vivo on human heart. Imaging shear wave propagation at 2500 frame/s using 5 diverging waves provides a strong increase of the Signal to noise ratio of the tissue velocity estimates while maintaining a high frame rate. Finally, ultrafast imaging with a 1 to 5 diverging waves is used to image the human heart at a frame rate of 900 frames/s over an entire cardiac cycle. Thanks to spatial coherent compounding, a strong improvement of imaging quality is obtained with a small number of transmitted diverging waves and a high frame rate, which allows imaging the propagation of electromechanical and shear waves with good image quality. PMID:24474135

  14. A Public University's Defense of Free Expression: The Issues and Events in the Staging of "The Normal Heart."

    ERIC Educational Resources Information Center

    Smith, Ralph R.; Moore, Dale

    In 1989, some Springfield, Missouri residents demanded cancellation of the Southwest Missouri State University (SMSU) theater department's production of Larry Kramer's play, "The Normal Heart," which they alleged to be obscene. Opponents purchased newspaper advertisements which charged that the publicly funded production promoted a "homosexual,…

  15. The relationship between resting heart rate variability and erectile tumescence among men with normal erectile function

    PubMed Central

    Harte, Christopher B.

    2013-01-01

    Introduction Individuals with erectile dysfunction have been shown to display lower heart rate variability (HRV), suggesting dysregulation of cardiac autonomic function. No studies have explored whether HRV is predictive of erectile response among men with clinically normal erectile function. Aim To examine associations between resting HRV and objective measures of genital response (i.e., resting penile circumference; erectile tumescence) and self-reported sexual function. Methods The sample comprised 59 male community volunteers (mean age = 20.15 years; SD = 2.52) selected from the control conditions of two previously published studies. Participants reported erectile function in the normal range (scoring ≥ 26 on the International Index of Erectile Function [IIEF]) and had no history of cardiovascular disease or myocardial infarct. During a laboratory visit, self-report, anthropometric, cardiovascular, and electrocardiographic data were assessed, as well as resting penile circumference and erectile tumescence in response to viewing an erotic film. Main Outcome Measures Resting penile responses, erectile tumescence (circumferential change via penile plethysmography), self-reported sexual function per the IIEF, and both time-domain (standard deviation of beat-to-beat [NN] intervals [SDNN], square root of the mean squared difference of successive NN intervals [RMSSD], and percent of NN intervals for which successive heartbeat intervals differed by at least 50 msec [pNN50]) and frequency-domain (low frequency [LF], high frequency [HF], LF/HF ratio) parameters of HRV were assessed. Results Higher resting HF power and lower resting LF/HF ratio were associated with greater erectile tumescence. There were marginally significant positive associations between mean NN interval and pNN50 and penile tumescence. HRV was not associated with self-reported sexual function or with resting penile circumference. Conclusions Results suggested that, among men without erectile

  16. RENAL SUBSTRATE EXCHANGE AND GLUCONEOGENESIS IN NORMAL POSTABSORPTIVE HUMANS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Release of glucose by the kidney in postabsorptive normal humans is generally regarded as being wholly due to gluconeogenesis. Although lactate is the most important systemic gluconeogenic precursor and there is appreciable net renal lactate uptake, renal lactate gluconeogenesis has not yet been inv...

  17. A six-time Ultraman winner and a normal heart: A case report.

    PubMed

    de Araújo, Claudio Gil Soares; Belém, Luciano; Gottlieb, Ilan

    2014-01-01

    Number of subjects currently participating in high-endurance aerobic exercise training regimens and competitions has substantially increased in recent years. While there is no doubt that regular exercise practice is fundamental for the maintenance of a good health, there have been reports of cardiac structural changes of subjects exposed to strenuous endurance physical exercise. This article reports a case of a 47-year-old male very successful sportsman-including being a six-time Ultraman winner-who has accumulated more than 50,000 h of training and competition in his 35-year career, averaging 25-30 h/week. Despite this huge amount of aerobic exercise, about 25 times larger than typically recommended dose for health purposes (i.e. 75 min of vigorous exercise per week), no major abnormalities were detected in electrocardiograms (rest and maximal exercise), transthoracic echocardiogram, and magnetic resonance imaging. In fact, after this complete evaluation, his heart was found to be quite normal. PMID:27489641

  18. A six-time Ultraman winner and a normal heart: A case report

    PubMed Central

    Belém, Luciano; Gottlieb, Ilan

    2014-01-01

    Number of subjects currently participating in high-endurance aerobic exercise training regimens and competitions has substantially increased in recent years. While there is no doubt that regular exercise practice is fundamental for the maintenance of a good health, there have been reports of cardiac structural changes of subjects exposed to strenuous endurance physical exercise. This article reports a case of a 47-year-old male very successful sportsman—including being a six-time Ultraman winner—who has accumulated more than 50,000 h of training and competition in his 35-year career, averaging 25–30 h/week. Despite this huge amount of aerobic exercise, about 25 times larger than typically recommended dose for health purposes (i.e. 75 min of vigorous exercise per week), no major abnormalities were detected in electrocardiograms (rest and maximal exercise), transthoracic echocardiogram, and magnetic resonance imaging. In fact, after this complete evaluation, his heart was found to be quite normal. PMID:27489641

  19. Regional pulmonary perfusion following human heart-lung transplantation

    SciTech Connect

    Lisbona, R.; Hakim, T.S.; Dean, G.W.; Langleben, D.; Guerraty, A.; Levy, R.D. )

    1989-08-01

    Ventilation and perfusion scans were obtained in six subjects who had undergone heart-lung transplantation with consequent denervation of the cardiopulmonary axis. Two of the subjects had developed obliterative bronchiolitis, which is believed to be a form of chronic rejection. Their pulmonary function tests demonstrated airflow obstruction and their scintigraphic studies were abnormal. In the remaining four subjects without obstructive airways disease, ventilation and planar perfusion scans were normal. Single photon emission computed tomography imaging of pulmonary perfusion in these patients revealed a layered distribution of blood flow indistinguishable from that of normal individuals. It is concluded that neurogenic mechanisms have little influence on the pattern of local pulmonary blood flow at rest.

  20. Collagen polymorphism in normal and cirrhotic human liver.

    PubMed Central

    Seyer, J M; Hutcheson, E T; Kang, A H

    1977-01-01

    Collagens in normal human liver and in alcoholic cirrhotic liver were investigated. Collagens were solubilized by limited proteolysis with pepsin under nondenaturing conditions, and after purification, were fractionated into types I and III by selective precipitation with NaCl. After carboxymethyl cellulose and agarose chromatography, the resulting alpha-chains from each of the collagen types were analyzed with respect to their amino acid and carbohydrate compositions. A comparison of the results obtained from normal liver with those from the diseases organ revealed no significant differences. The isolated human liver alpha1(I) and alpha1(III) chains were digested with CNBr and the generated peptides were separated and purified by a combination of ion-exchange and molecular sieve chromatography. The molecular weight and the amino acid and the carbohydrate compositions of each of the peptides were identical to those of the corresponding human skin peptides except for the slightly higher content of hydroxylysine in some of the peptides. The relative content of type III in relation to type I collagen in both normal anc cirrhotic liver was determined by digesting washed liver homogenates directly with CNBr and quantitating the resultant alpha1(I) and alpha 1(III) peptides after chromatographic separation. The relative quantities of these peptides indicated that normal human liver contained an average of 47% type III, with the remainder being type I. Cirrhotic liver, on the other hand, contained a significantly smaller proportion of type III, ranging from 18 to 34% in different samples, with a corresponding increase in type I. These findings indicate that although the amino acid and carbohydrate compositions of collagens deposited in cirrhotic liver are normal, the fibrotic process of alcoholic liver disease in humans is accompanied by an alteration in tissue collagen polymorphism, and suggest that the observed alterations may have pathogenetic implications. PMID:833273

  1. Comparison of Immune Profiles in Fetal Hearts with Idiopathic Dilated Cardiomyopathy, Maternal Autoimmune-Associated Dilated Cardiomyopathy and the Normal Fetus.

    PubMed

    Nield, Lynne E; von Both, Ingo; Popel, Najla; Strachan, Kate; Manlhiot, Cedric; Shannon, Patrick; McCrindle, Brian W; Atkinson, Adelle; Miner, Steven E S; Jaeggi, Edgar T; Taylor, Glenn P

    2016-02-01

    The etiology of idiopathic dilated cardiomyopathy (iDCM) remains unknown. Immune therapies have improved outcome in fetuses with DCM born to mothers with autoimmune disease (aDCM). The purpose of this retrospective study was to compare the myocardial B and T cell profiles in fetuses and neonates with idiopathic DCM (iDCM) versus autoimmune-mediated DCM (aDCM) and to describe the normal cell maturation within the human fetal myocardium. Of 60 fetal autopsy cases identified from institutional databases, 10 had aDCM (18-38 weeks), 12 iDCM (19-37 weeks) and 38 had normal hearts (11-40 weeks). Paraffin-embedded myocardium sections were stained for all lymphocyte (CD45), B cells (CD20, CD79a), T cells (CD3, CD4, CD7, CD8) and monocyte (CD68) surface markers. Two independent, blinded cell counts were performed. Normal hearts expressed all B and T cell markers in a bimodal fashion, with peaks at 22 and 37 weeks of gestation. The aDCM cohort was most distinct from normal hearts, with less overall T cell markers [EST -9.1 (2.6) cells/mm(2), p = 0.001], CD4 [EST -2.0 (0.6), p = 0.001], CD3 [EST -3.9 (1.0), p < 0.001], CD7 [EST -3.0 (1.1), p = 0.01] overall B cell markers [EST -4.9 (1.8), p = 0.01] and CD79a counts [EST -2.3 (0.9), p = 0.01]. The iDCM group had less overall B cell markers [EST -4.0 (1.8), p = 0.03] and CD79a [EST -1.7 (0.9), p = 0.05], but no difference in T cell markers. Autoimmune-mediated DCM fetuses have less B and T cell markers, whereas iDCM fetuses have less B cell markers compared with normal fetal hearts. The fetal immune system may play a role in the normal development of the heart and evolution of dilated cardiomyopathy. PMID:26481221

  2. Human Engineered Heart Tissue: Analysis of Contractile Force.

    PubMed

    Mannhardt, Ingra; Breckwoldt, Kaja; Letuffe-Brenière, David; Schaaf, Sebastian; Schulz, Herbert; Neuber, Christiane; Benzin, Anika; Werner, Tessa; Eder, Alexandra; Schulze, Thomas; Klampe, Birgit; Christ, Torsten; Hirt, Marc N; Huebner, Norbert; Moretti, Alessandra; Eschenhagen, Thomas; Hansen, Arne

    2016-07-12

    Analyzing contractile force, the most important and best understood function of cardiomyocytes in vivo is not established in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). This study describes the generation of 3D, strip-format, force-generating engineered heart tissues (EHT) from hiPSC-CM and their physiological and pharmacological properties. CM were differentiated from hiPSC by a growth factor-based three-stage protocol. EHTs were generated and analyzed histologically and functionally. HiPSC-CM in EHTs showed well-developed sarcomeric organization and alignment, and frequent mitochondria. Systematic contractility analysis (26 concentration-response curves) reveals that EHTs replicated canonical response to physiological and pharmacological regulators of inotropy, membrane- and calcium-clock mediators of pacemaking, modulators of ion-channel currents, and proarrhythmic compounds with unprecedented precision. The analysis demonstrates a high degree of similarity between hiPSC-CM in EHT format and native human heart tissue, indicating that human EHTs are useful for preclinical drug testing and disease modeling. PMID:27211213

  3. THERP and HEART integrated methodology for human error assessment

    NASA Astrophysics Data System (ADS)

    Castiglia, Francesco; Giardina, Mariarosa; Tomarchio, Elio

    2015-11-01

    THERP and HEART integrated methodology is proposed to investigate accident scenarios that involve operator errors during high-dose-rate (HDR) treatments. The new approach has been modified on the basis of fuzzy set concept with the aim of prioritizing an exhaustive list of erroneous tasks that can lead to patient radiological overexposures. The results allow for the identification of human errors that are necessary to achieve a better understanding of health hazards in the radiotherapy treatment process, so that it can be properly monitored and appropriately managed.

  4. Snake heart: a case of atavism in a human being.

    PubMed

    Walia, Ishmeet; Arora, Harvinder S; Barker, Esmond A; Delgado, Reynolds M; Frazier, O H

    2010-01-01

    Atavism is the rare reappearance, in a modern organism, of a trait from a distant evolutionary ancestor. We describe an apparent case of atavism involving a 59-year-old man with chest pain whose coronary circulation and myocardial architecture resembled those of the reptilian heart. The chest pain was attributed to a coronary steal phenomenon. The patient was discharged from the hospital on a heightened regimen of β-blockers, and his symptoms improved significantly. To our knowledge, this is only the 2nd reported clinical case of a human coronary circulation similar to that of reptiles. PMID:21224948

  5. Sialyltransferase activity in normal and atherosclerotic human aorta intima.

    PubMed

    Gracheva, E V; Samovilova, N N; Golovanova, N K; Il'inskaya, O P; Tararak, E M; Prokazova, N V

    2001-04-01

    Sialyltransferase activity has been determined in Golgi membrane fractions isolated from atherosclerotic and normal intima of human aorta by measuring the transfer of N-acetylneuraminic acid (NeuAc) from CMP-NeuAc to asialofetuin. The asialofetuin-sialyltransferase activity was found to be twofold higher in the atherosclerotic intima than in the normal intima. The mean value of the apparent Michaelis constant (Km) for the sialylating enzyme in both tissues did not differ and was 57 microM. In contrast, the maximal velocity (Vmax) was 2-fold higher for the atherosclerotic intima than for the normal intima. These results suggest that expression of asialofetuin-sialyltransferases of the aortal intima may be increased in atherosclerosis. PMID:11403646

  6. Autophagy in Normal and Abnormal Early Human Pregnancies.

    PubMed

    Avagliano, Laura; Terraneo, Laura; Virgili, Eleonora; Martinelli, Carla; Doi, Patrizia; Samaja, Michele; Bulfamante, Gaetano Pietro; Marconi, Anna Maria

    2015-07-01

    Autophagy is an inducible catabolic process by which cells degrade and recycle materials to survive stress, starvation, and hypoxia. The aim of this study was to evaluate autophagy at the fetal-maternal interface, to assess autophagy involvement during the early phase of human gestation, and to explore autophagic modification in case of early abnormal pregnancy outcome. Specimens were collected from first-trimester normal gestations undergoing legal termination of pregnancy and first-trimester sporadic spontaneous miscarriages. Autophagy was studied in villous and decidual samples by transmission electron microscopy, immunohistochemistry, immunofluorescence, and Western blotting. Autophagy markers were found in cytotrophoblast, syncytiotrophoblast, extravillous trophoblast, and decidual stromal cells. Autophagy is physiologically involved in early normal gestation. Compared with normal pregnancy, spontaneous miscarriage presents an increase in autophagy expression in villous specimens due to an increment in concentration of autophagic vacuole in syncytiotrophoblast, suggesting a cytoprotective mechanism of the cells to respond to microenvironmental challenge. PMID:25544676

  7. Mechanical properties of normal and osteoarthritic human articular cartilage.

    PubMed

    Robinson, Dale L; Kersh, Mariana E; Walsh, Nicole C; Ackland, David C; de Steiger, Richard N; Pandy, Marcus G

    2016-08-01

    Isotropic hyperelastic models have been used to determine the material properties of normal human cartilage, but there remains an incomplete understanding of how these properties may be altered by osteoarthritis. The aims of this study were to (1) measure the material constants of normal and osteoarthritic human knee cartilage using isotropic hyperelastic models; (2) determine whether the material constants correlate with histological measures of structure and/or cartilage tissue damage; and (3) quantify the abilities of two common isotropic hyperelastic material models, the neo-Hookean and Yeoh models, to describe articular cartilage contact force, area, and pressure. Small osteochondral specimens of normal and osteoarthritic condition were retrieved from human cadaveric knees and from the knees of patients undergoing total knee arthroplasty and tested in unconfined compression at loading rates and large strains representative of weight-bearing activity. Articular surface contact area and lateral deformation were measured concurrently and specimen-specific finite element models then were used to determine the hyperelastic material constants. Structural parameters were measured using histological techniques while the severity of cartilage damage was quantified using the OARSI grading scale. The hyperelastic material constants correlated significantly with OARSI grade, indicating that the mechanical properties of cartilage for large strains change with tissue damage. The measurements of contact area described anisotropy of the tissue constituting the superficial zone. The Yeoh model described contact force and pressure more accurately than the neo-Hookean model, whereas both models under-predicted contact area and poorly described the anisotropy of cartilage within the superficial zone. These results identify the limits by which isotropic hyperelastic material models may be used to describe cartilage contact variables. This study provides novel data for the

  8. Mutagenic effects of alpha particles in normal human skin fibroblasts

    SciTech Connect

    Chen, D.J.; Carpenter, S.; Hanks, T.

    1992-12-31

    Alpha-irradiation to the bronchial airways from inhaled radon progeny increases the risk of developing lung cancer. The molecular mechanism of radon-induced lung cancer is not clear, but one of the most important genetic effects of ionizing radiation is the induction of gene mutation. Mutations, especially those associated with visible chromosome abnormalities in humans, have been associated with cancer. Therefore, our objective is to use a well-defined model system to determine the mutagenic potential of alpha particles in normal human skin cells and to define this action at the molecular level. Normal human skin fibroblasts were irradiated with alpha particles (3.59 MeV, LET 115 keV {mu}m{sup {minus}1}) emitted from the decay of {sup 238}Pu. Mutagenicity was determined at the X-linked hypoxanthine guanine phosphoribosyl transferase (HPRT) locus. Results from this study indicate that beta particles were more efficient in mutation induction than gamma rays. Based on the initial slopes of the dose-response curves, the RBE for mutation is about 8 for alpha particles. HPRT-deficient mutants which are resistant to 6-thioguanine have been isolated and analyzed by the Southern blot technique. To date, we have characterized 69 gamma-ray-induced and 195 alpha-particle-induced HPRT-deficient mutants. Our data indicate that more than 50% of all gamma-ray-induced mutants have band patterns identical to that observed for the normal structural HPRT gene, whereas the remaining mutants (45%) contain either a rearrangement, partial deletion, or total deletion of the HPRT gene. In contrast, only 30% of alpha-particle-induced human HPRT mutants contain a normal Southern blot pattern, and about 50% indicate total deletion of the HPRT gene. Our results support the notion that high-LET radiation produces more unrepaired or misrepaired DNA damage than do gamma rays.

  9. Myocardial commitment from human pluripotent stem cells: Rapid production of human heart grafts.

    PubMed

    Garreta, Elena; de Oñate, Lorena; Fernández-Santos, M Eugenia; Oria, Roger; Tarantino, Carolina; Climent, Andreu M; Marco, Andrés; Samitier, Mireia; Martínez, Elena; Valls-Margarit, Maria; Matesanz, Rafael; Taylor, Doris A; Fernández-Avilés, Francisco; Izpisua Belmonte, Juan Carlos; Montserrat, Nuria

    2016-08-01

    Genome editing on human pluripotent stem cells (hPSCs) together with the development of protocols for organ decellularization opens the door to the generation of autologous bioartificial hearts. Here we sought to generate for the first time a fluorescent reporter human embryonic stem cell (hESC) line by means of Transcription activator-like effector nucleases (TALENs) to efficiently produce cardiomyocyte-like cells (CLCs) from hPSCs and repopulate decellularized human heart ventricles for heart engineering. In our hands, targeting myosin heavy chain locus (MYH6) with mCherry fluorescent reporter by TALEN technology in hESCs did not alter major pluripotent-related features, and allowed for the definition of a robust protocol for CLCs production also from human induced pluripotent stem cells (hiPSCs) in 14 days. hPSCs-derived CLCs (hPSCs-CLCs) were next used to recellularize acellular cardiac scaffolds. Electrophysiological responses encountered when hPSCs-CLCs were cultured on ventricular decellularized extracellular matrix (vdECM) correlated with significant increases in the levels of expression of different ion channels determinant for calcium homeostasis and heart contractile function. Overall, the approach described here allows for the rapid generation of human cardiac grafts from hPSCs, in a total of 24 days, providing a suitable platform for cardiac engineering and disease modeling in the human setting. PMID:27179434

  10. Low Density Lipoprotein transport in the normal human aortic arch

    PubMed Central

    Soulis, JV; Dimitrakopoulou, M; Giannoglou, GD

    2014-01-01

    Background: To understand the genesis and progression of atherosclerosis is essential to elucidate the blood flow and the transport of molecules in the cardiovascular system. The purpose of this computational study is to elucidate the relationship between low wall shear stress (WSS) - high site concentration of low density lipoproteins (LDL) and atherosclerotic sites in the normal human aortic arch under physiological flow and mass transport conditions. Methods: The numerical simulation couples the flow equations with the transport equation applying realistic boundary conditions at the wall in terms of blood-side concentration. The blood is considered to be non-Newtonian fluid obeying to the power law. Suitable mass transport conditions are specified at the wall. Results: Aortic arch walls are exposed to cholesterolemic environment although the applied mass and flow conditions refer to normal human geometry and normal mass-flow conditions. The luminal surface LDL concentration varies inversely with the WSS. Regions of high LDL luminal surface concentration do not necessarily co-locate to the sites of lowest WSS. Concave sides of the aortic arch exhibit, relatively to the convex sides, elevated concentration of the LDL. The area averaged normalized LDL concentration over the entire normal aortic arch is 1.267. The daughter aortic arch vessels exhibit, relatively to the main aorta, elevated LDL concentrations. Conclusions: The near wall paths of the velocities might be the most important factor for the elevated LDL concentration at areas located either at the vicinity of bifurcations regions or at high curvature regions. Hippokratia 2014; 18 (3): 221-225. PMID:25694755

  11. Human factors of flight-deck checklists: The normal checklist

    NASA Technical Reports Server (NTRS)

    Degani, Asaf; Wiener, Earl L.

    1991-01-01

    Although the aircraft checklist has long been regarded as the foundation of pilot standardization and cockpit safety, it has escaped the scrutiny of the human factors profession. The improper use, or the non-use, of the normal checklist by flight crews is often cited as the probable cause or at least a contributing factor to aircraft accidents. An attempt is made to analyze the normal checklist, its functions, format, design, length, usage, and the limitations of the humans who must interact with it. The development of the checklist from the certification of a new model to its delivery and use by the customer are discussed. The influence of the government, particularly the FAA Principle Operations Inspector, the manufacturer's philosophy, the airline's culture, and the end user, the pilot, influence the ultimate design and usage of this device. The effects of airline mergers and acquisitions on checklist usage and design are noted. In addition, the interaction between production pressures and checklist usage and checklist management are addressed. Finally, a list of design guidelines for normal checklists is provided.

  12. Uroplakin Gene Expression by Normal and Neoplastic Human Urothelium

    PubMed Central

    Lobban, E. Dawn; Smith, Barbara A.; Hall, Geoffrey D.; Harnden, Patricia; Roberts, Paul; Selby, Peter J.; Trejdosiewicz, Ludwik K.; Southgate, Jennifer

    1998-01-01

    cDNA sequences for human uroplakins UPIa, UPIb, UPII, and UPIII were cloned and used to investigate uroplakin transcription by normal and neoplastic urothelial cells. Normal urothelium expressed mRNA for all four uroplakins, although UPIII could be detected only by ribonuclease protection assay. By in situ hybridization, UPIa and UPII were confined to superficial cells and UPIb was also expressed by intermediate cells. Cultured normal human urothelial cells showed a proliferative basal/intermediate cell phenotype and constitutive expression of UPIb only. Uroplakin expression by transitional cell carcinoma cell lines was related to their differentiated phenotype in vitro. RT4 cells expressed all uroplakins, VM-CUB-3 expressed three uroplakins, RT112 and HT1376 cells expressed only UPIb in high abundance, and COLO232, KK47, and EJ cells had no detectable expression. These results correlated with patterns of uroplakin expression in tumors. UPIa and UPII were detected superficially only in well differentiated transitional cell carcinoma papillae. UPIb was positive in seven of nine and overexpressed in five of nine noninvasive transitional cell carcinomas and was also present in four of eight invasive transitional cell carcinomas. Lymph node metastases retained the same pattern of UPIb expression as the primary tumor. Unlike the three differentiation-regulated uroplakins, UPIb may have an alternative role in urothelial cell/tissue processes. PMID:9846985

  13. Uroplakin gene expression by normal and neoplastic human urothelium.

    PubMed

    Lobban, E D; Smith, B A; Hall, G D; Harnden, P; Roberts, P; Selby, P J; Trejdosiewicz, L K; Southgate, J

    1998-12-01

    cDNA sequences for human uroplakins UPIa, UPIb, UPII, and UPIII were cloned and used to investigate uroplakin transcription by normal and neoplastic urothelial cells. Normal urothelium expressed mRNA for all four uroplakins, although UPIII could be detected only by ribonuclease protection assay. By in situ hybridization, UPIa and UPII were confined to superficial cells and UPIb was also expressed by intermediate cells. Cultured normal human urothelial cells showed a proliferative basal/intermediate cell phenotype and constitutive expression of UPIb only. Uroplakin expression by transitional cell carcinoma cell lines was related to their differentiated phenotype in vitro. RT4 cells expressed all uroplakins, VM-CUB-3 expressed three uroplakins, RT112 and HT1376 cells expressed only UPIb in high abundance, and COLO232, KK47, and EJ cells had no detectable expression. These results correlated with patterns of uroplakin expression in tumors. UPIa and UPII were detected superficially only in well differentiated transitional cell carcinoma papillae. UPIb was positive in seven of nine and overexpressed in five of nine noninvasive transitional cell carcinomas and was also present in four of eight invasive transitional cell carcinomas. Lymph node metastases retained the same pattern of UPIb expression as the primary tumor. Unlike the three differentiation-regulated uroplakins, UPIb may have an alternative role in urothelial cell/tissue processes. PMID:9846985

  14. Hierarchical Structure of Heart Rate Variability in Humans

    NASA Astrophysics Data System (ADS)

    Gao, X. Z.; Ching, E. S. C.; Lin, D. C.

    2004-03-01

    We show a hierarchical structure (HS) of the She-Leveque form in the beat-to-beat RR intervals of heart rate variability (HRV) in humans. This structure, first found as an empirical law in turbulent fluid flows, implies further details in the HRV multifractal scaling. We tested HS using daytime RRi data from healthy subjects and heart diseased patients with congestive heart failure and found a universal law C(b) where b characterizes the multifractality of HRV and C is related to a co-dimension parameter of the most violent events in the fluctuation. The potential of diagnosis is discussed based on the characteristics of this finding. To model the HRV phenomenology, we propose a local-feedback-global-cascade (LFGC) model based on the She-Waymire (SW) cascade solution to the HS in fluid turbulence. This model extends from the previous work in that it integrates additive law multiplicatively into the cascade structure. It is an attempt to relate to the cardiovascular physiology which consists of numerous feedback controls that function primarily on the principle of additive law. In particular, the model is based on the same philosophy as the SW cascade that its multifractal dynamics consists of a singular and a modulating component. In the LFGC model, we introduce local feedback to model the dynamics of the modulating effect. The novelty of our model is to incorporate the cascade structure in the scheduling for the feedback control. This model also represents an alternative solution to the HS. We will present the simulation results by the LFGC model and discuss its implication in physiology terms.

  15. Organophosphate inhibition of human heart muscle cholinesterase isoenzymes.

    PubMed

    Chemnitius, J M; Sadowski, R; Winkel, H; Zech, R

    1999-05-14

    The rate of acetylcholine hydrolysis of mammalian heart muscle influences cardiac responses to vagal innervation. We characterized cholinesterases of human left ventricular heart muscle with respect to both substrate specificity and irreversible inhibition kinetics with the organophosphorus inhibitor N,N'-di-isopropylphosphorodiamidic fluoride (mipafox). Specimens were obtained postmortem from three men and four women (61 +/- 5 years) with no history of cardiovascular disease. Myocardial choline ester hydrolyzing activity was determined with acetylthiocholine (ASCh; 1.25 mM), acetyl-beta-methylthiocholine (AbetaMSCh; 2.0 mM), and butyrylthiocholine (BSCh; 30 mM). After irreversible and covalent inhibition (60 min; 25 degrees C) with a wide range of mipafox concentrations (50 nM-5 mM), residual choline ester hydrolyzing activities were fitted to a sum of up to five exponentials using weighted least-squares non-linear curve fitting. In each ease, quality of curve fitting reached its optimum on the basis of a four component model. Final classification of heart muscle cholinesterases was achieved according to substrate hydrolysis patterns (nmol/min per g wet weight) and to second-order organophosphate inhibition rate constants k2 (1/mol per min); one choline ester hydrolyzing enzyme was identified as acetylcholinesterase (AChE; k2/mipafox = 6.1 (+/- 0.8) x 10(2)), and one as butyrylcholinesterase (BChE; k2/mipafox = 5.3 (+/- 1.1) x 10(3)). An enzyme exhibiting both ChE-like substrate specificity and relative resistance to mipafox inhibition (k2/mipafox = 5.2 (+/- 1.0) x 10(-1)) was classified as atypical cholinesterase. PMID:10421452

  16. Hemodynamic aspects of normal human feto-placental (umbilical) circulation.

    PubMed

    Acharya, Ganesh; Sonesson, Sven-Erik; Flo, Kari; Räsänen, Juha; Odibo, Anthony

    2016-06-01

    Understanding the changes in normal circulatory dynamics that occur during the course of pregnancy is essential for improving our knowledge of pathophysiological mechanisms associated with feto-placental diseases. The umbilical circulation is the lifeline of the fetus, and it is accessible for noninvasive assessment. However, not all hemodynamic parameters can be reliably measured in utero using currently available technology. Experimental animal studies have been crucial in validating major concepts related to feto-placental circulatory physiology, but caution is required in directly translating the findings of such studies into humans due to species differences. Furthermore, it is important to establish normal reference ranges and take into account gestational age associated changes while interpreting the results of clinical investigation. Therefore, it is necessary to critically evaluate, synthesize and summarize the knowledge available from the studies performed on human pregnancies to be able to appropriately apply them in clinical practice. This narrative review is an attempt to present contemporary concepts on hemodynamics of feto-placental circulation based on human studies. PMID:27130575

  17. Thyroxine monodeiodination in normal human kidney tissue in vitro.

    PubMed

    Boye, N

    1986-08-01

    The present study deals with thyroxine monodeiodination in normal human kidney. To allow for comparison with previous reports, the present methods are similar to those used by others in rat tissue studies. The microsomal cell fraction of normal human kidney tissue was obtained by differential ultracentrifugation. The microsomes were incubated under various conditions and the deiodination products assayed with radioimmunoassay. A type I 5'-monodeiodinase was demonstrated, pH optimum around 6.5. Competitive inhibition was observed of T3 generation from T4 by rT3 with a Km of 3.0 microM and a Ki of 4 microM. Vmax was 26.1 pmol/min/mg protein. Likewise rT3 was generated from added T4, but it was rapidly degraded, while T3 was relatively stable as is the case in rat tissue preparations. Propylthiouracil inhibited 5'-deiodination in a dose dependent fashion with complete abolishment of deiodination at propylthiouracil concentration of 10(-4) M. Ipodate inhibited the reaction with complete inhibition at 10(-2) M. The data demonstrate that a human kidney particulate cell-fraction contained considerable amounts of T4 deiodinases, very similar to the type I deiodinase of various rat tissue, although the handling of rT3 and the inhibitory action of this iodothyronine on T4 to T3 conversion seem to be slightly different in the two species. PMID:3751464

  18. Effects of water immersion on plasma catecholamines in normal humans

    NASA Technical Reports Server (NTRS)

    Epstein, M.; Johnson, G.; Denunzio, A. G.

    1983-01-01

    An investigation was conducted in order to determine whether water immersion to the neck (NI) alters plasma catecholamines in normal humans. Eight normal subjects were studied during a seated control study (C) and during 4 hr of NI, and the levels of norepinephrine (NE) and epinephrine (E) as determined by radioenzymatic assay were measured hourly. Results show that despite the induction of a marked natriuresis and diuresis indicating significant central hypervolemia, NI failed to alter plasma NE or E levels compared with those of either C or the corresponding prestudy 1.5 hr. In addition, the diuresis and natriuresis was found to vary independently of NE. These results indicate that the response of the sympathetic nervous system to acute volume alteration may differ from the reported response to chronic volume expansion.

  19. Optical Properties of Human Cancer and Normal Cells

    NASA Astrophysics Data System (ADS)

    Sander, Christopher; Sun, Nan; Johnson, Jeffrey; Stack, Sharon; Tanner, Carol; Ruggiero, Steven

    2014-03-01

    We have investigated the optical properties of human oral and ovarian cancer and normal cells. Specifically, we have measured the absolute optical extinction for both whole cells and intra-cellular material in aqueous suspension. Measurements were conducted over a wavelength range of 250 to 1000nm with 1 nm resolution using Light Transmission Spectroscopy (LTS). This provides both the absolute extinction of materials under study and, with Mie inversion, the absolute number of particles of a given diameter as a function of diameter in the range of 1 to 3000 nm. Our preliminary studies show significant differences in both the extinction and particle size distributions associated with cancer versus normal cells, which appear to be correlated with differences in the particle size distribution in the range of ~ 50 to 250 nm.

  20. Human heart rate variability relation is unchanged during motion sickness

    NASA Technical Reports Server (NTRS)

    Mullen, T. J.; Berger, R. D.; Oman, C. M.; Cohen, R. J.

    1998-01-01

    In a study of 18 human subjects, we applied a new technique, estimation of the transfer function between instantaneous lung volume (ILV) and instantaneous heart rate (HR), to assess autonomic activity during motion sickness. Two control recordings of ILV and electrocardiogram (ECG) were made prior to the development of motion sickness. During the first, subjects were seated motionless, and during the second they were seated rotating sinusoidally about an earth vertical axis. Subjects then wore prism goggles that reverse the left-right visual field and performed manual tasks until they developed moderate motion sickness. Finally, ILV and ECG were recorded while subjects maintained a relatively constant level of sickness by intermittent eye closure during rotation with the goggles. Based on analyses of ILV to HR transfer functions from the three conditions, we were unable to demonstrate a change in autonomic control of heart rate due to rotation alone or due to motion sickness. These findings do not support the notion that moderate motion sickness is manifested as a generalized autonomic response.

  1. Statistical Properties of the Interbeat Interval Cascade in Human Hearts

    NASA Astrophysics Data System (ADS)

    Ghasemi, Fatemeh; Peinke, J.; Reza Rahimi Tabar, M.; Sahimi, Muhammad

    Statistical properties of interbeat intervals cascade in human hearts are evaluated by considering the joint probability distribution P (Δx2, τ2 Δx1, τ1) for two interbeat increments Δx1 and Δx2 of different time scales τ1 and τ2. We present evidence that the conditional probability distribution P (Δx2, τ2 | Δx1, τ1) may be described by a Chapman-Kolmogorov equation. The corresponding Kramers-Moyal (KM) coefficients are evaluated. The analysis indicates that while the first and second KM coefficients take on well-defined and significant values, the higher-order coefficients in the KM expansion are small. As a result, the joint probability distributions of the increments in the interbeat intervals are described by a Fokker-Planck equation, with the first two KM coefficients acting as the drift and diffusion coefficients. The method provides a novel technique for distinguishing two classes of subjects, namely, healthy ones and those with congestive heart failure, in terms of the drift and diffusion coefficients which behave differently for two classes of the subjects.

  2. Regulation of p53 during senescence in normal human keratinocytes

    PubMed Central

    Kim, Reuben H; Kang, Mo K; Kim, Terresa; Yang, Paul; Bae, Susan; Williams, Drake W; Phung, Samantha; Shin, Ki-Hyuk; Hong, Christine; Park, No-Hee

    2015-01-01

    p53, the guardian of the genome, is a tumor suppressor protein and critical for the genomic integrity of the cells. Many studies have shown that intracellular level of p53 is enhanced during replicative senescence in normal fibroblasts, and the enhanced level of p53 is viewed as the cause of senescence. Here, we report that, unlike in normal fibroblasts, the level of intracellular p53 reduces during replicative senescence and oncogene-induced senescence (OIS) in normal human keratinocytes (NHKs). We found that the intracellular p53 level was also decreased in age-dependent manner in normal human epithelial tissues. Senescent NHKs exhibited an enhanced level of p16INK4A, induced G2 cell cycle arrest, and lowered the p53 expression and transactivation activity. We found that low level of p53 in senescent NHKs was due to reduced transcription of p53. The methylation status at the p53 promoter was not altered during senescence, but senescent NHKs exhibited notably lower level of acetylated histone 3 (H3) at the p53 promoter in comparison with rapidly proliferating cells. Moreover, p53 knockdown in rapidly proliferating NHKs resulted in the disruption of fidelity in repaired DNA. Taken together, our study demonstrates that p53 level is diminished during replicative senescence and OIS and that such diminution is associated with H3 deacetylation at the p53 promoter. The reduced intracellular p53 level in keratinocytes of the elderly could be a contributing factor for more frequent development of epithelial cancer in the elderly because of the loss of genomic integrity of cells. PMID:26138448

  3. Chronic Heart Failure Slows Late Sodium Current in Human and Canine Ventricular Myocytes: Implications for Repolarization Variability

    PubMed Central

    Maltsev, Victor A.; Silverman, Norman; Sabbah, Hani N.; Undrovinas., Albertas I.

    2006-01-01

    Background Late Na+ current (INaL) in human and dog hearts has been implicated in abnormal repolarization associated with heart failure (HF). HF slows inactivation gating of late Na+ channels, which could contribute to these abnormalities. Aims To test how altered gating affects INaL time course, Na+ influx, and action potential (AP) repolarization. Methods INaL and AP were measured by patch clamp in left ventricular cardiomyocytes from normal and failing hearts of humans and dogs. Canine HF was induced by coronary microembolization. Results INaL decay was slower and INaL density was greater in failing hearts than in normal hearts at 24°C (human hearts: τ=659±16 vs. 529±21 ms; n=16 and 4 hearts, respectively; mean±SEM; p<0.002; dog hearts: 561±13 vs. 420±17 ms; and 0.307±0.014 vs. 0.235±0.019 pA/pF; n=25 and 14 hearts, respectively; p<0.005) and at 37°C this difference tended to increase. These INaL changes resulted in much greater (53.6%) total Na+ influx in failing cardiomyocytes. INaL was sensitive to cadmium but not to cyanide and exhibited low sensitivity to saxitoxin (IC50=62nM) or tetrodotoxin (IC50=1.2μM) tested in dogs. A 50% INaL inhibition by toxins or passing current opposite to INaL, decreased beat-to-beat AP variability and eliminated early afterdepolarizations in failing cardiomyocytes. Conclusions Chronic HF leads to larger and slower INaL generated mainly by the cardiac-type Na+ channel isoform, contributing to larger Na+ influx and AP duration variability. Interventions designed to reduce/normalize INaL represent a potential cardioprotective mechanism in HF via reduction of related Na+ and Ca2+ overload and improvement of repolarization. PMID:17067855

  4. Mitochondrial depolarization and electrophysiological changes during ischemia in the rabbit and human heart.

    PubMed

    Sulkin, Matthew S; Boukens, Bas J; Tetlow, Megan; Gutbrod, Sarah R; Ng, Fu Siong; Efimov, Igor R

    2014-10-15

    Instability of the inner mitochondrial membrane potential (ΔΨm) has been implicated in electrical dysfunction, including arrhythmogenesis during ischemia-reperfusion. Monitoring ΔΨm has led to conflicting results, where depolarization has been reported as sporadic and as a propagating wave. The present study was designed to resolve the aforementioned difference and determine the unknown relationship between ΔΨm and electrophysiology. We developed a novel imaging modality for simultaneous optical mapping of ΔΨm and transmembrane potential (Vm). Optical mapping was performed using potentiometric dyes on preparations from 4 mouse hearts, 14 rabbit hearts, and 7 human hearts. Our data showed that during ischemia, ΔΨm depolarization is sporadic and changes asynchronously with electrophysiological changes. Spatially, ΔΨm depolarization was associated with action potential duration shortening but not conduction slowing. Analysis of focal activity indicated that ΔΨm is not different within the myocardium where the focus originates compared with normal ventricular tissue. Overall, our data suggest that during ischemia, mitochondria maintain their function at the expense of sarcolemmal electrophysiology, but ΔΨm depolarization does not have a direct association to ischemia-induced arrhythmias. PMID:25128175

  5. Heart rate variability of human in hypoxic oxygen-argon environment

    NASA Astrophysics Data System (ADS)

    Khayrullina, Rezeda; Smoleevskiy, Alexandr; Bubeev, Yuri

    Human adaptive capacity, reliability and stability in extreme environments depend primarily on the individual resistance to stresses, includes both innate and acquired components. We have conducted studies in six healthy subjects - men aged between 24 to 42 years who psychophysiological indicators acterizing the severity of stress reactions studied directly during an emergency situation, before and after it. The subjects were in a hypoxic oxygen-argon atmosphere 10 days. Cardiovascular system is one of the first to respond to stressful reaction. The method of heart rate variability (HRV) allows us to estimate balance of sympathetic and parasympathetic parts of vegetative nervous system. In the course of the baseline study it was found that resting heart rate (HR) in the examined individuals is within normal limits. During the experiment in all subjects there was a trend towards more frequent heartbeat. Each subject at one stage or another stay in a hypoxic oxygen-argon environment heart rate go beyond the group norm, but the extent and duration of these abnormalities were significantly different. Marked increase in middle heart rate during of subjects experiment, fluctuating within a wide range (from 2.3% to 29.1%). Marked increase in middle heart rate during of subjects experiment, fluctuating within a wide range (from 2.3% to 29.1%). This suggests that the ability to adapt to living in the investigated gas environment have marked individual differences. SDNN (mean square deviation of all R-R intervals) is the integral indicator of the total effect of the sinus node to the sympathetic and parasympathetic parts of vegetative nervous system, as well as indicating the higher functional reserves of the cardiovascular systems. Increase in heart rate in the majority of subject was accompanied by an increase in individual SDNN. This suggests that the parasympathetic system is able to balance the increase in activity of the sympathetic system, and functional reserves are

  6. Divergent viral presentation among human tumors and adjacent normal tissues.

    PubMed

    Cao, Song; Wendl, Michael C; Wyczalkowski, Matthew A; Wylie, Kristine; Ye, Kai; Jayasinghe, Reyka; Xie, Mingchao; Wu, Song; Niu, Beifang; Grubb, Robert; Johnson, Kimberly J; Gay, Hiram; Chen, Ken; Rader, Janet S; Dipersio, John F; Chen, Feng; Ding, Li

    2016-01-01

    We applied a newly developed bioinformatics system called VirusScan to investigate the viral basis of 6,813 human tumors and 559 adjacent normal samples across 23 cancer types and identified 505 virus positive samples with distinctive, organ system- and cancer type-specific distributions. We found that herpes viruses (e.g., subtypes HHV4, HHV5, and HHV6) that are highly prevalent across cancers of the digestive tract showed significantly higher abundances in tumor versus adjacent normal samples, supporting their association with these cancers. We also found three HPV16-positive samples in brain lower grade glioma (LGG). Further, recurrent HBV integration at the KMT2B locus is present in three liver tumors, but absent in their matched adjacent normal samples, indicating that viral integration induced host driver genetic alterations are required on top of viral oncogene expression for initiation and progression of liver hepatocellular carcinoma. Notably, viral integrations were found in many genes, including novel recurrent HPV integrations at PTPN13 in cervical cancer. Finally, we observed a set of HHV4 and HBV variants strongly associated with ethnic groups, likely due to viral sequence evolution under environmental influences. These findings provide important new insights into viral roles of tumor initiation and progression and potential new therapeutic targets. PMID:27339696

  7. Divergent viral presentation among human tumors and adjacent normal tissues

    PubMed Central

    Cao, Song; Wendl, Michael C.; Wyczalkowski, Matthew A.; Wylie, Kristine; Ye, Kai; Jayasinghe, Reyka; Xie, Mingchao; Wu, Song; Niu, Beifang; Grubb, Robert; Johnson, Kimberly J.; Gay, Hiram; Chen, Ken; Rader, Janet S.; Dipersio, John F.; Chen, Feng; Ding, Li

    2016-01-01

    We applied a newly developed bioinformatics system called VirusScan to investigate the viral basis of 6,813 human tumors and 559 adjacent normal samples across 23 cancer types and identified 505 virus positive samples with distinctive, organ system- and cancer type-specific distributions. We found that herpes viruses (e.g., subtypes HHV4, HHV5, and HHV6) that are highly prevalent across cancers of the digestive tract showed significantly higher abundances in tumor versus adjacent normal samples, supporting their association with these cancers. We also found three HPV16-positive samples in brain lower grade glioma (LGG). Further, recurrent HBV integration at the KMT2B locus is present in three liver tumors, but absent in their matched adjacent normal samples, indicating that viral integration induced host driver genetic alterations are required on top of viral oncogene expression for initiation and progression of liver hepatocellular carcinoma. Notably, viral integrations were found in many genes, including novel recurrent HPV integrations at PTPN13 in cervical cancer. Finally, we observed a set of HHV4 and HBV variants strongly associated with ethnic groups, likely due to viral sequence evolution under environmental influences. These findings provide important new insights into viral roles of tumor initiation and progression and potential new therapeutic targets. PMID:27339696

  8. Telocytes and putative stem cells in ageing human heart

    PubMed Central

    Popescu, Laurentiu M; Curici, Antoanela; Wang, Enshi; Zhang, Hao; Hu, Shengshou; Gherghiceanu, Mihaela

    2015-01-01

    Tradition considers that mammalian heart consists of about 70% non-myocytes (interstitial cells) and 30% cardiomyocytes (CMs). Anyway, the presence of telocytes (TCs) has been overlooked, since they were described in 2010 (visit http://www.telocytes.com). Also, the number of cardiac stem cells (CSCs) has not accurately estimated in humans during ageing. We used electron microscopy to identify and estimate the number of cells in human atrial myocardium (appendages). Three age-related groups were studied: newborns (17 days–1 year), children (6–17 years) and adults (34–60 years). Morphometry was performed on low-magnification electron microscope images using computer-assisted technology. We found that interstitial area gradually increases with age from 31.3 ± 4.9% in newborns to 41 ± 5.2% in adults. Also, the number of blood capillaries (per mm2) increased with several hundreds in children and adults versus newborns. CMs are the most numerous cells, representing 76% in newborns, 88% in children and 86% in adults. Images of CMs mitoses were seen in the 17-day newborns. Interestingly, no lipofuscin granules were found in CMs of human newborns and children. The percentage of cells that occupy interstitium were (depending on age): endothelial cells 52–62%; vascular smooth muscle cells and pericytes 22–28%, Schwann cells with nerve endings 6–7%, fibroblasts 3–10%, macrophages 1–8%, TCs about 1% and stem cells less than 1%. We cannot confirm the popular belief that cardiac fibroblasts are the most prevalent cell type in the heart and account for about 20% of myocardial volume. Numerically, TCs represent a small fraction of human cardiac interstitial cells, but because of their extensive telopodes, they achieve a 3D network that, for instance, supports CSCs. The myocardial (very) low capability to regenerate may be explained by the number of CSCs, which decreases fivefold by age (from 0.5% to 0.1% in newborns versus adults). PMID:25545142

  9. Long-Term Outcome of Non-Sustained Ventricular Tachycardia in Structurally Normal Hearts

    PubMed Central

    Lin, Chin-Yu; Chang, Shih-Lin; Chung, Fa-Po; Chen, Yun-Yu; Lin, Yenn-Jiang; Lo, Li-Wei; Hu, Yu-Feng; Tuan, Ta-Chuan; Chao, Tze-Fan; Liao, Jo-Nan; Chang, Yao-Ting; Lin, Chung-Hsing; Allamsetty, Suresh; Walia, Rohit; Te, Abigail Louise D.; Yamada, Shinya; Chiang, Shuo-Ju; Tsao, Hsuan-Ming; Chen, Shih-Ann

    2016-01-01

    Background The impact of non-sustained ventricular tachycardia (NSVT) on the risk of thromboembolic event and clinical outcomes in patients without structural heart disease remains undetermined. This study aimed to evaluate the association between NSVT and clinical outcomes. Methods The study population of 5903 patients was culled from the “Registry of 24-hour ECG monitoring at Taipei Veterans General Hospital” (REMOTE database) between January 1, 2002 and December 31, 2004. Of that total, we enrolled 3767 patients without sustained ventricular tachycardia, structural heart disease, and permanent pacemaker. For purposes of this study, NSVT was defined as 3 or more consecutive beats arising below the atrioventricular node with an RR interval of <600 ms (>100 beats/min) and lasting < 30 seconds. Result There were 776 deaths, 2042 hospitalizations for any reason, 638 cardiovascular (CV)-related hospitalizations, 350 ischemic strokes, 409 transient ischemic accident (TIA), 368 new-onset heart failure (HF), and 260 new-onset atrial fibrillation (AF) with a mean follow-up duration of 10 ± 1 years. In multivariate analysis, the presence of NSVT was independently associated with death (hazard ratio [HR]: 1.362, 95% confidence interval [CI]: 1.071–1.731), CV hospitalization (HR: 1.527, 95% CI: 1.171–1.992), ischemic stroke (HR: 1.436, 95% CI: 1.014–2.032), TIA (HR 1.483, 95% CI: 1.069–2.057), and new-onset HF (HR: 1.716, 95% CI: 1.243–2.368). There was no significant association between the presence of NSVT and all-cause hospitalization or new-onset AF. Conclusion In patients without structural heart disease, presence of NSVT on 24-hour monitoring was independently associated with death, CV hospitalization, ischemic stroke, TIA, and new onset heart failure. PMID:27548469

  10. Effects of digoxin on muscle reflexes in normal humans.

    PubMed

    Janssen, Christophe; Lheureux, Olivier; Beloka, Sofia; Adamopoulos, Dionysios; Naeije, Robert; van de Borne, Philippe

    2009-11-01

    Blockade of the skeletal muscle Na(+)-K(+)-ATPase pump by digoxin could result in a more marked hyperkaliema during a forearm exercise, which in turn could stimulate the mechano- and metaboreceptors. In a randomized, double-blinded, placebo-controlled, and cross-over-design study, we measured mean blood pressure (MBP), heart rate (HR), ventilation (V(E)), oxygen saturation (SpO(2)), muscle sympathetic nerve activity (MSNA), venous plasma potassium and lactic acid during dynamic handgrip exercises, and local circulatory arrest in 11 healthy subjects. Digoxin enhanced MBP during exercise but not during the post-handgrip ischemia and had no effect on HR, V(E), SpO(2), and MSNA. Venous plasma potassium and lactic acid were also not affected by digoxin-induced skeletal muscle Na(+)-K(+)-ATPase blockade. We conclude that digoxin increased MBP during dynamic exercise in healthy humans, independently of changes in potassium and lactic acid. A modest direct sensitization of the muscle mechanoreceptors is unlikely and other mechanisms, independent of muscle reflexes and related to the inotropic effects of digoxin, might be implicated. PMID:19701647

  11. A Simple Dissection Method for the Conduction System of the Human Heart

    ERIC Educational Resources Information Center

    Yanagawa, Nariaki; Nakajima, Yuji

    2009-01-01

    A simple dissection guide for the conduction system of the human heart is shown. The atrioventricular (AV) node, AV bundle, and right bundle branch were identified in a formaldehyde-fixed human heart. The sinu-atrial (SA) node could not be found, but the region in which SA node was contained was identified using the SA nodal artery. Gross…

  12. Elastic Modulus Determination of Normal and Glaucomatous Human Trabecular Meshwork

    PubMed Central

    Last, Julie A.; Pan, Tingrui; Ding, Yuzhe; Reilly, Christopher M.; Keller, Kate; Acott, Ted S.; Fautsch, Michael P.; Murphy, Christopher J.; Russell, Paul

    2011-01-01

    Purpose. Elevated intraocular pressure (IOP) is a risk factor for glaucoma. The principal outflow pathway for aqueous humor in the human eye is through the trabecular meshwork (HTM) and Schlemm's canal (SC). The junction between the HTM and SC is thought to have a significant role in the regulation of IOP. A possible mechanism for the increased resistance to flow in glaucomatous eyes is an increase in stiffness (increased elastic modulus) of the HTM. In this study, the stiffness of the HTM in normal and glaucomatous tissue was compared, and a mathematical model was developed to predict the impact of changes in stiffness of the juxtacanalicular layer of HTM on flow dynamics through this region. Methods. Atomic force microscopy (AFM) was used to measure the elastic modulus of normal and glaucomatous HTM. According to these results, a model was developed that simulated the juxtacanalicular layer of the HTM as a flexible membrane with embedded pores. Results. The mean elastic modulus increased substantially in the glaucomatous HTM (mean = 80.8 kPa) compared with that in the normal HTM (mean = 4.0 kPa). Regional variation was identified across the glaucomatous HTM, possibly corresponding to the disease state. Mathematical modeling suggested an increased flow resistance with increasing HTM modulus. Conclusions. The data indicate that the stiffness of glaucomatous HTM is significantly increased compared with that of normal HTM. Modeling exercises support substantial impairment in outflow facility with increased HTM stiffness. Alterations in the biophysical attributes of the HTM may participate directly in the onset and progression of glaucoma. PMID:21220561

  13. Developing a novel comprehensive framework for the investigation of cellular and whole heart electrophysiology in the in situ human heart: historical perspectives, current progress and future prospects.

    PubMed

    Taggart, Peter; Orini, Michele; Hanson, Ben; Hayward, Martin; Clayton, Richard; Dobrzynski, Halina; Yanni, Joseph; Boyett, Mark; Lambiase, Pier D

    2014-08-01

    Understanding the mechanisms of fatal ventricular arrhythmias is of great importance. In view of the many electrophysiological differences that exist between animal species and humans, the acquisition of basic electrophysiological data in the intact human heart is essential to drive and complement experimental work in animal and in-silico models. Over the years techniques have been developed to obtain basic electrophysiological signals directly from the patients by incorporating these measurements into routine clinical procedures which access the heart such as cardiac catheterisation and cardiac surgery. Early recordings with monophasic action potentials provided valuable information including normal values for the in vivo human heart, cycle length dependent properties, the effect of ischaemia, autonomic nervous system activity, and mechano-electric interaction. Transmural recordings addressed the controversial issue of the mid myocardial "M" cell. More recently, the technique of multielectrode mapping (256 electrodes) developed in animal models has been extended to humans, enabling mapping of activation and repolarisation on the entire left and right ventricular epicardium in patients during cardiac surgery. Studies have examined the issue of whether ventricular fibrillation was driven by a "mother" rotor with inhomogeneous and fragmented conduction as in some animal models, or by multiple wavelets as in other animal studies; results showed that both mechanisms are operative in humans. The simpler spatial organisation of human VF has important implications for treatment and prevention. To link in-vivo human electrophysiological mapping with cellular biophysics, multielectrode mapping is now being combined with myocardial biopsies. This technique enables region-specific electrophysiology changes to be related to underlying cellular biology, for example: APD alternans, which is a precursor of VF and sudden death. The mechanism is incompletely understood but related

  14. Exercise training normalizes the blunted central component of the baroreflex in rats with heart failure: role of the PVN.

    PubMed

    Patel, Kaushik P; Salgado, Helio C; Liu, Xuefei; Zheng, Hong

    2013-07-15

    Exercise training (ExT) normalizes the increased sympathetic outflow in chronic heart failure (HF). The underlying mechanisms are not clearly understood. We hypothesized that ExT normalized the blunted central component of the baroreflex control of renal sympathetic nerve activity (RSNA) in HF. Four groups of rats [sham operated (sham)-sedentary (Sed), sham-ExT, HF-Sed, and HF-ExT] were used. HF was induced by left coronary artery ligation, and ExT consisted of 3 wk of treadmill running. In anesthetized rats, the decrease in RSNA in response to aortic depressor nerve stimulation (5-40 Hz) in the HF-Sed group was significantly lower than that in the sham-Sed group (-37 ± 7% vs. -63 ± 8% at 40 Hz, P < 0.05). In the HF-ExT group, responses in RSNA, mean arterial pressure (MAP), and heart rate (HR) were not significantly different from those in the sham-Sed or sham-ExT groups. ExT normalized blunted RSNA, MAP, and HR responses to bicuculline microinjections into the paraventricular nucleus (PVN) in rats with HF. Activation of the PVN by blockade of GABA receptors with bicuculline in normal control rats blunted the centrally component of the baroreflex arc. GABAA-α1 and -β1 receptor protein expression were significantly lower (by 48% and 30%) in the HF-Sed group, but ExT normalized this difference between the HF and sham groups. These data suggest that one mechanism by which ExT alleviates elevated sympathetic outflow in HF may be through normalization of central integrative mechanisms, perhaps via improving the inhibitory GABAergic mechanism within the PVN, on the baroreflex arc. PMID:23686710

  15. Human cancers overexpress genes that are specific to a variety of normal human tissues

    PubMed Central

    Lotem, Joseph; Netanely, Dvir; Domany, Eytan; Sachs, Leo

    2005-01-01

    We have analyzed gene expression data from three different kinds of samples: normal human tissues, human cancer cell lines, and leukemic cells from lymphoid and myeloid leukemia pediatric patients. We have searched for genes that are overexpressed in human cancer and also show specific patterns of tissue-dependent expression in normal tissues. Using the expression data of the normal tissues, we identified 4,346 genes with a high variability of expression and clustered these genes according to their relative expression level. Of 91 stable clusters obtained, 24 clusters included genes preferentially expressed either only in hematopoietic tissues or in hematopoietic and one to two other tissues; 28 clusters included genes preferentially expressed in various nonhematopoietic tissues such as neuronal, testis, liver, kidney, muscle, lung, pancreas, and placenta. Analysis of the expression levels of these two groups of genes in the human cancer cell lines and leukemias identified genes that were highly expressed in cancer cells but not in their normal counterparts and, thus, were overexpressed in the cancers. The different cancer cell lines and leukemias varied in the number and identity of these overexpressed genes. The results indicate that many genes that are overexpressed in human cancer cells are specific to a variety of normal tissues, including normal tissues other than those from which the cancer originated. It is suggested that this general property of cancer cells plays a major role in determining the behavior of the cancers, including their metastatic potential. PMID:16339305

  16. A fast method to measure the 3D surface of the human heart

    NASA Astrophysics Data System (ADS)

    Cao, Yiping; Su, Xianyu; Xiang, Liqun; Chen, Wenjing; Zhang, Qican

    2003-12-01

    Three-dimensional (3-D) automatic measurement of an object is widely used in many fields. In Biology and Medicine society, it can be applicable for surgery, orthopedics, viscera disease analysis and diagnosis etc. Here a new fast method to measure the 3D surface of human heart is proposed which can provide doctors a lot of information, such as the size of heart profile, the sizes of the left or right heart ventricle, and the curvature center and radius of heart ventricle, to fully analyze and diagnose pathobiology of human heart. The new fast method is optically and noncontacted and based upon the Phase Measurement Profilometry (PMP), which has higher measuring precision. A human heart specimen experiment has verified our method.

  17. Morphological Study of Chordae Tendinae in Human Cadaveric Hearts

    PubMed Central

    Gunnal, S. A.; Wabale, R. N.; Farooqui, M. S.

    2015-01-01

    Objectives: The chordae tendinae (CT) are strong, fibrous connections between the valve leaflets and the papillary muscles. Dysfunction of the papillary muscles and chordae is frequent. Mitral valve replacement with preservation of CT and papillary muscles may preserve postoperative left ventricular function better than conventional mitral valve replacement in patients with chronic mitral regurgitation. Methods: The study was carried out on 116 human cadaveric hearts. The heart was opened through the atrioventricular valve to view the constituents of the complex. Origin, attachments, insertions, distribution, branching pattern and gross structure of CT were observed and studied in detail. Results: In the present study more than 21 terminologies of CT were defined by classifying it into six different types. Classification is done according to the origin, attachments, insertion, distribution, branching pattern and gross structure. Terminologies defined are as follows. Apical pillar chordae, Basal pillar chordae, True chordae, False chordae, Interpillar chordae, Pillar wall chordae, Cusp chordae, Cleft chordae, Commissural chordae, First order chordae, Second order chordae, Free zone chordae, Marginal chordae, Rough zone chordae, Straight chordae, Branched-fan shaped chordae, Spiral chordae, Irregular-web chordae, Tendinous chordae, Muscular chordae, Membranous chordae. Basal pillar chordae are found in 9.48%. Mean number of chordae taking origin from apical half of a single papillary muscle or single head of papillary muscle was 9.09 with the range of 3-18. Mean number of the marginal chordae attached to a single cusp was 22.63 ranging from 11 to 35. Strut chordae showed interesting insertion with broad aponeurosis in 38.79% and large muscular flaps in 13.79%. Chordae muscularis were found in 14% and membranous chordae were found in 6%. Conclusions: This knowledge may prove useful for cardiologists and cardiac surgeons. PMID:25838872

  18. Heart disease is common in humans and chimpanzees, but is caused by different pathological processes.

    PubMed

    Varki, Nissi; Anderson, Dan; Herndon, James G; Pham, Tho; Gregg, Christopher J; Cheriyan, Monica; Murphy, James; Strobert, Elizabeth; Fritz, Jo; Else, James G; Varki, Ajit

    2009-02-01

    Heart disease is common in both humans and chimpanzees, manifesting typically as sudden cardiac arrest or progressive heart failure. Surprisingly, although chimpanzees are our closest evolutionary relatives, the major cause of heart disease is different in the two species. Histopathology data of affected chimpanzee hearts from two primate centers, and analysis of literature indicate that sudden death in chimpanzees (and in gorillas and orangutans) is commonly associated with diffuse interstitial myocardial fibrosis of unknown cause. In contrast, most human heart disease results from coronary artery atherosclerosis, which occludes myocardial blood supply, causing ischemic damage. The typical myocardial infarction of humans due to coronary artery thrombosis is rare in these apes, despite their human-like coronary-risk-prone blood lipid profiles. Instead, chimpanzee 'heart attacks' are likely due to arrythmias triggered by myocardial fibrosis. Why do humans not often suffer from the fibrotic heart disease so common in our closest evolutionary cousins? Conversely, why do chimpanzees not have the kind of heart disease so common in humans? The answers could be of value to medical care, as well as to understanding human evolution. A preliminary attempt is made to explore possibilities at the histological level, with a focus on glycosylation changes. PMID:25567850

  19. Protection against hyperacute xenograft rejection of transgenic rat hearts expressing human decay accelerating factor (DAF) transplanted into primates.

    PubMed Central

    Charreau, B.; Ménoret, S.; Tesson, L.; Azimzadeh, A.; Audet, M.; Wolf, P.; Marquet, R.; Verbakel, C.; Ijzermans, J.; Cowan, P.; Pearse, M.; d'Apice, A.; Soulillou, J. P.; Anegon, I.

    1999-01-01

    BACKGROUND: Production of transgenic pigs for multiple transgenes is part of a potential strategy to prevent immunological events involved in xenograft rejection. Use of a genetically engineerable rodent as a donor in primates could allow testing in vivo of the effects of different transgenes on controlling xenograft rejection. As a first step in the development of a donor containing multiple transgenes, transgenic rats for human decay-accelerating factor (DAF) were used as heart donors to test their resistance against complement (C)-mediated rejection by non-human primates. MATERIALS AND METHODS: Transgenic rats were generated by using a construct containing the human DAF cDNA under the transcriptional control of the endothelial cell (EC)-specific human ICAM-2 promoter. DAF expression was evaluated by immunohistology and by FACS analysis of purified ECs. Resistance of transgenic hearts against C-mediated damage was evaluated by ex vivo perfusion with human serum and by transplantation into cynomolgus monkeys. RESULTS: Immunohistological analysis of DAF expression in several organs from two transgenic lines showed uniform expression on the endothelium of all blood vessels. ECs purified from transgenic hearts showed 50% DAF expression compared to human ECs and >70% reduction of C-dependent cell lysis compared to control rat ECs. Hemizygous transgenic hearts perfused with human serum showed normal function for >60 min vs. 11. 2 +/- 1.7 min in controls. Hemi- or homozygous transgenic hearts transplanted into cynomolgus monkeys showed longer survival (15.2 +/- 7 min and >4.5 hr, respectively) than controls (5.5 +/- 1.4 min). In contrast to hyperacutely rejected control hearts, rejected homozygous DAF hearts showed signs of acute vascular rejection (AVR) characterized by edema, hemorrhage, and an intense PMN infiltration. CONCLUSIONS: We demonstrate that endothelial-specific DAF expression increased heart transplant survival in a rat-to-primate model of

  20. Effect of left vs. right recumbency on the vertebral heart score in normal dogs.

    PubMed

    Greco, Adelaide; Meomartino, Leonardo; Raiano, Vera; Fatone, Gerardo; Brunetti, Arturo

    2008-01-01

    The effect of right vs. left recumbency on computation of the vertebral heart score (VHS) was assessed in 63 healthy dogs. The VHS was significantly higher in right lateral recumbency (9.8 +/- 0.6 vs. 9.5 +/- 0.8; P < 0.0004). Gender and dog size did not significantly influence VHS values while there was m oredifference between left and right side measurements when considering the type of thorax (P = 0.055). PMID:18833953

  1. Characterization of mitochondria isolated from normal and ischemic hearts in rats utilizing atomic force microscopy.

    PubMed

    Lee, Gi-Ja; Chae, Su-Jin; Jeong, Jae Hoon; Lee, So-Ra; Ha, Sang-Jin; Pak, Youngmi Kim; Kim, Weon; Park, Hun-Kuk

    2011-04-01

    Mitochondria play critical roles in both the life and the death of cardiac myocytes. Various factors, such as the loss of ATP synthesis and increase of ATP hydrolysis, impairment in ionic homeostasis, formation of reactive oxygen species (ROS), and release of proapoptotic proteins are related to the generation of irreversible damage. It has been proposed that the release of cytochrome c is caused by a swelling of the mitochondrial matrix triggered by the apoptotic stimuli. However, there is a controversy about whether or not the mitochondria, indeed, swell during apoptosis. The major advantages of atomic force microscopy (AFM) over conventional optical and electron microscopes for bio-imaging include the fact that no special coating and vacuum are required and imaging can be done in all environments--air, vacuum or aqueous conditions. In addition, AFM force-distance curve measurements have become a fundamental tool in the fields of surface chemistry, biochemistry, and material science. In this study, we used AFM to observe the morphological and property changes in heart mitochondria that were isolated from a rat myocardial infarction model. From the shape parameters of the mitochondria in the AFM topographic image, it seemed that myocardial infarction caused the mitochondrial swelling. Also, the results of force-distance measurements showed that the adhesion force of heart mitochondria was significantly decreased by myocardial in infarction. Therefore, we suggested that myocardial infarction might be the cause of mitochondrial swelling and the changes in outer membrane of heart mitochondria. PMID:21050769

  2. Gene Profile Identifies Zinc Transporters Differentially Expressed in Normal Human Organs and Human Pancreatic Cancer

    PubMed Central

    Yang, J.; Zhang, Y.; Cui, X.; Yao, W.; Yu, X.; Cen, P.; Hodges, S.E.; Fisher, W.E.; Brunicardi, F.C.; Chen, C.; Yao, Q.; Li, M.

    2013-01-01

    Deregulated expression of zinc transporters was linked to several cancers. However, the detailed expression profile of all human zinc transporters in normal human organs and in human cancer, especially in pancreatic cancer is not available. The objectives of this study are to investigate the complete expression patterns of 14 ZIP and 10 ZnT transporters in a large number of normal human organs and in human pancreatic cancer tissues and cell lines. We examined the expression patterns of ZIP and ZnT transporters in 22 different human organs and tissues, 11 pairs of clinical human pancreatic cancer specimens and surrounding normal/benign tissues, as well as 10 established human pancreatic cancer cell lines plus normal human pancreatic ductal epithelium (HPDE) cells, using real time RT-PCR and immunohistochemistry. The results indicate that human zinc transporters have tissue specific expression patterns, and may play different roles in different organs or tissues. Almost all the ZIPs except for ZIP4, and most ZnTs were down-regulated in human pancreatic cancer tissues compared to the surrounding benign tissues. The expression patterns of individual ZIPs and ZnTs are similar among different pancreatic cancer lines. Those results and our previous studies suggest that ZIP4 is the only zinc transporter that is significantly up-regulated in human pancreatic cancer and might be the major zinc transporter that plays an important role in pancreatic cancer growth. ZIP4 might serve as a novel molecular target for pancreatic cancer diagnosis and therapy. PMID:23331012

  3. Mitochondrial respiratory control and early defects of oxidative phosphorylation in the failing human heart.

    PubMed

    Lemieux, Hélène; Semsroth, Severin; Antretter, Herwig; Höfer, Daniel; Gnaiger, Erich

    2011-12-01

    Heart failure is a consequence of progressive deterioration of cardiac performance. Little is known about the role of impaired oxidative phosphorylation in the progression of the disease, since previous studies of mitochondrial injuries are restricted to end-stage chronic heart failure. The present study aimed at evaluating the involvement of mitochondrial dysfunction in the development of human heart failure. We measured the control of oxidative phosphorylation with high-resolution respirometry in permeabilized myocardial fibres from donor hearts (controls), and patients with no or mild heart failure but presenting with heart disease, or chronic heart failure due to dilated or ischemic cardiomyopathy. The capacity of the phosphorylation system exerted a strong limitation on oxidative phosphorylation in the human heart, estimated at 121 pmol O(2)s(-1)mg(-1) in the healthy left ventricle. In heart disease, a specific defect of the phosphorylation system, Complex I-linked respiration, and mass-specific fatty acid oxidation were identified. These early defects were also significant in chronic heart failure, where the capacities of the oxidative phosphorylation and electron transfer systems per cardiac tissue mass were decreased with all tested substrate combinations, suggesting a decline of mitochondrial density. Oxidative phosphorylation and electron transfer system capacities were higher in ventricles compared to atria, but the impaired mitochondrial quality was identical in the four cardiac chambers of chronic heart failure patients. Coupling was preserved in heart disease and chronic heart failure, in contrast to the mitochondrial dysfunction observed after prolonged cold storage of cardiac tissue. Mitochondrial defects in the phosphorylation system, Complex I respiration and mass-specific fatty acid oxidation occurred early in the development of heart failure. Targeting these mitochondrial injuries with metabolic therapy may offer a promising approach to delay

  4. Bioartificial Heart: A Human-Sized Porcine Model – The Way Ahead

    PubMed Central

    Weymann, Alexander; Patil, Nikhil Prakash; Sabashnikov, Anton; Jungebluth, Philipp; Korkmaz, Sevil; Li, Shiliang; Veres, Gabor; Soos, Pal; Ishtok, Roland; Chaimow, Nicole; Pätzold, Ines; Czerny, Natalie; Schies, Carsten; Schmack, Bastian; Popov, Aron-Frederik; Simon, André Rüdiger; Karck, Matthias; Szabo, Gabor

    2014-01-01

    Background A bioartificial heart is a theoretical alternative to transplantation or mechanical left ventricular support. Native hearts decellularized with preserved architecture and vasculature may provide an acellular tissue platform for organ regeneration. We sought to develop a tissue-engineered whole-heart neoscaffold in human-sized porcine hearts. Methods We decellularized porcine hearts (n = 10) by coronary perfusion with ionic detergents in a modified Langendorff circuit. We confirmed decellularization by histology, transmission electron microscopy and fluorescence microscopy, quantified residual DNA by spectrophotometry, and evaluated biomechanical stability with ex-vivo left-ventricular pressure/volume studies, all compared to controls. We then mounted the decellularized porcine hearts in a bioreactor and reseeded them with murine neonatal cardiac cells and human umbilical cord derived endothelial cells (HUVEC) under simulated physiological conditions. Results Decellularized hearts lacked intracellular components but retained specific collagen fibers, proteoglycan, elastin and mechanical integrity; quantitative DNA analysis demonstrated a significant reduction of DNA compared to controls (82.6±3.2 ng DNA/mg tissue vs. 473.2±13.4 ng DNA/mg tissue, p<0.05). Recellularized porcine whole-heart neoscaffolds demonstrated re-endothelialization of coronary vasculature and measurable intrinsic myocardial electrical activity at 10 days, with perfused organ culture maintained for up to 3 weeks. Conclusions Human-sized decellularized porcine hearts provide a promising tissue-engineering platform that may lead to future clinical strategies in the treatment of heart failure. PMID:25365554

  5. Sustained Ventricular Tachycardia in Apparently Normal Hearts: Medical Therapy Should be the First Step in Management.

    PubMed

    Saeid, Ali Kazemi; Klein, George J; Leong-Sit, Peter

    2016-09-01

    Sustained monomorphic ventricular tachycardia or repetitive premature ventricular complexes can be seen in patients with structurally normal hearts. Among these types of patients, the prognosis is predominantly benign and the treatment mostly focused on elimination of symptoms rather than improving survival or reduction of mortality. This article focuses on the pharmacologic options for management and compares them with invasive options. Based on the current literature, we demonstrate that medical therapies should be used as first-line management and favored over invasive therapies. Understanding the arrhythmia mechanism is critical in choosing the appropriate medication among the wide variety of antiarrhythmic drugs available. PMID:27521096

  6. Inhibition of phagocytosis and chemiluminescence in human leukocytes by a lipid soluble factor in normal tissues.

    PubMed Central

    Huang, T S; Hurd, R E; Chopra, I J; Stevens, P; Solomon, D H; Young, L S

    1984-01-01

    Homogenates of normal rat tissues inhibited several functional parameters of normal human peripheral blood leukocytes, including luminol-dependent chemiluminescence induced by both soluble (phorbol myristate acetate) and particulate (Escherichia coli) stimuli; in vitro uptake of radiolabeled E. coli; and in vitro phagocytosis and killing of E. coli. The doses of rat tissue protein that caused a 50% inhibition of leukocyte chemiluminescence were ca. 6.2 micrograms for small intestine, 83 micrograms for kidney; 100 micrograms for heart; 132 micrograms for liver, 190 micrograms for skeletal muscle, and 307 micrograms for brain. The putative phagocytosis inhibitor (PI) in rat liver was more plentiful in particulate fractions than in the cytosol. The PI activity in the original or Miranol-solubilized rat liver homogenate was nondialyzable, and it was reduced substantially by heating at 90 degrees C for 30 min but not at 56 degrees C for 30 min. It was unaffected by aprotinin, a potent inhibitor of proteolytic activity. Treatment of tissues with trypsin did not reduce PI activity, whereas treatment with phospholipase A2 clearly increased it. The bulk (up to 88%) of PI in rat liver or small intestine could be extracted by lipid solvents, e.g., diethyl ether. Purified fatty acids were potent inhibitors of leukocyte chemiluminescence; other lipids had little or no inhibiting activity. The various data suggest that (i) normal tissues contain a potent PI and (ii) that the PI is a lipid moiety. PMID:6389349

  7. Exploration of the normal human bronchoalveolar lavage fluid proteome

    PubMed Central

    Chen, Jinzhi; Ryu, Soyoung; Gharib, Sina A.; Goodlett, David R.; Schnapp, Lynn M.

    2015-01-01

    We obtained insight into normal lung function by proteome analysis of bronchoalveolar lavage fluid (BALF) from six normal human subjects using a “Lyse-N-Go’ shotgun proteomic protocol. Intra-sample variation was calculated using three different label-free methods, (i) protein sequence coverage; (ii) peptide spectral counts and (iii) peptide single-ion current areas (PICA), which generates protein expression data by summation of the area under the curve for a given peptide single-ion current trace and then adding values for all peptides from that same parent protein. PICA gave the least intra-subject variability and was used to calculate differences in protein expression between the six subjects. We observed an average threefold inter-sample variability, which affects analysis of changes in protein expression that occur in different diseases. We detected 167 unique proteins with >100 proteins detected in each of the six individual BAL samples, 42 of which were common to all six subjects. Gene ontology analysis demonstrated enrichment of several biological processes in the lung, reflecting its expected role in gas exchange and host defense as an immune organ. The same biological processes were enriched compared to either plasma or total genome proteome, suggesting an active enrichment of plasma proteins in the lung rather than passive capillary leak. PMID:21136857

  8. Relationship between deoxyribonucleic acid content and nucleoli in human heart muscle cells and estimation of cell number during cardiac growth and hyperfunction.

    PubMed

    Adler, C P

    1975-01-01

    In the myocardium of 30 human hearts of all age groups quantitative deoxyribonucleic acid (DNA) measurements were performed and the results of the measurements were correlated with the pure myocardium weight. By means of the diphenylamine reaction the total amount of DNA (DNA concentration and DNA amount) in the myocardium was estimated. By means of Feulgen cytophotometry the DNA amount exclusively in the heart muscle cell nuclei was measured. With the use of myocardial tissue spread on slides, the nuclear areas of the heart muscle nuclei were planimetrically measured. After preparation with DNase and staining with gallocyanine chromalumn the nucleoli in heart muscle nuclei were specifically presented and their number per nucleus as well as their area values were demonstrated. From the biochemical and cytophotometric results of the myocardial DNA content it was possible to estimate the absolute cell number of the hearts, keeping the pure myocardium weight in consideration. The investigations led to the following results. In growing childrens' hearts the DNA concentration decreases to a constant level of 0.3-0.4 mg/g. The amount of DNA rises with increasing heart weight. During the growth of the heart of a child between the ages of 8 and 12 the DNA amount doubles in the heart muscle nuclei, and most of the muscle nuclei of an adult have a tetraploid DNA content. In pathological heart hypertrophy a further polyploidization of the heart muscle nuclei occurs. The areas of the nuclei increases with growing polyploidization. The nuclear areas form the same grouping as the ploidy classes. With growing nuclear areas, the total areas of the nucleoli and their number per nucleus also increase. Right after birth an increase in the number of connective tissue and heart muscle cells follows. A normal heart contains about 2 x 10(9) muscle cells. In hypertrophic hearts the number of muscle cells can double. PMID:129834

  9. Differential Intracochlear Sound Pressure Measurements in Normal Human Temporal Bones

    NASA Astrophysics Data System (ADS)

    Nakajima, Hideko Heidi; Dong, Wei; Olson, Elizabeth S.; Merchant, Saumil N.; Ravicz, Michael E.; Rosowski, John J.

    2009-02-01

    We present the first simultaneous sound pressure measurements in scala vestibuli and scala tympani of the cochlea in human cadaveric temporal bones. Micro-scale fiberoptic pressure sensors enabled the study of differential sound pressure at the cochlear base. This differential pressure is the input to the cochlear partition, driving cochlear waves and auditory transduction. Results showed that: pressure of scala vestibuli was much greater than scala tympani except at low and high frequencies where scala tympani pressure affects the input to the cochlea; the differential pressure proved to be an excellent measure of normal ossicular transduction of sound (shown to decrease 30-50 dB with ossicular disarticulation, whereas the individual scala pressures were significantly affected by non-ossicular conduction of sound at high frequencies); the middle-ear gain and differential pressure were generally bandpass in frequency dependence; and the middle-ear delay in the human was over twice that of the gerbil. Concurrent stapes velocity measurements allowed determination of the differential impedance across the partition and round-window impedance. The differential impedance was generally resistive, while the round-window impedance was consistent with a compliance in conjunction with distributed inertia and damping. Our techniques can be used to study inner-ear conductive pathologies (e.g., semicircular dehiscence), as well as non-ossicular cochlear stimulation (e.g., round-window stimulation) - situations that cannot be completely quantified by measurements of stapes velocity or scala-vestibuli pressure by themselves.

  10. Ventricular Arrhythmias in Apparently Normal Hearts: Who Needs an Implantable Cardiac Defibrillator?

    PubMed

    Tan, Alex Y; Ellenbogen, Kenneth

    2016-09-01

    Idiopathic ventricular tachycardia is often considered a benign form of ventricular arrhythmia in patients without apparent structural heart disease. However, a subset of patients may develop malignant ventricular arrhythmias and present with syncope and sudden cardiac arrest. Survivors of cardiac arrest are candidates for implantable cardiac defibrillators (ICDs). The indications for ICDs in patients with less than a full-blown cardiac arrest presentation but with electrocardiographically high-risk ectopy features remain uncertain. This article addresses some of the uncertainties and pitfalls in ICD risk stratification in this patient group and explores potential mechanisms for malignant conversion of benign premature ventricular complexes to sustained arrhythmia. PMID:27521094

  11. Role of Genetic Testing in Patients with Ventricular Arrhythmias in Apparently Normal Hearts.

    PubMed

    Hofman, Nynke; Wilde, Arthur A M

    2016-09-01

    Ventricular arrhythmias without structural heart disease are responsible for ∼35% of patients who have sudden cardiac death before the age of 40 years. Molecular autopsy and/or cardiological investigation of nearby family members often reveals the diagnosis and genetic testing can be helpful in family screening and risk stratification in disease carriers. Extended gene panels can be screened in a short period of time at low cost. A multidisciplinary team of (genetically) specialized clinicians is necessary to judge all the available details and to decide on the significance of the variant and further strategies. PMID:27521086

  12. Three-dimensional heart dose reconstruction to estimate normal tissue complication probability after breast irradiation using portal dosimetry

    SciTech Connect

    Louwe, R. J. W.; Wendling, M.; Herk, M. B. van; Mijnheer, B. J.

    2007-04-15

    Irradiation of the heart is one of the major concerns during radiotherapy of breast cancer. Three-dimensional (3D) treatment planning would therefore be useful but cannot always be performed for left-sided breast treatments, because CT data may not be available. However, even if 3D dose calculations are available and an estimate of the normal tissue damage can be made, uncertainties in patient positioning may significantly influence the heart dose during treatment. Therefore, 3D reconstruction of the actual heart dose during breast cancer treatment using electronic imaging portal device (EPID) dosimetry has been investigated. A previously described method to reconstruct the dose in the patient from treatment portal images at the radiological midsurface was used in combination with a simple geometrical model of the irradiated heart volume to enable calculation of dose-volume histograms (DVHs), to independently verify this aspect of the treatment without using 3D data from a planning CT scan. To investigate the accuracy of our method, the DVHs obtained with full 3D treatment planning system (TPS) calculations and those obtained after resampling the TPS dose in the radiological midsurface were compared for fifteen breast cancer patients for whom CT data were available. In addition, EPID dosimetry as well as 3D dose calculations using our TPS, film dosimetry, and ionization chamber measurements were performed in an anthropomorphic phantom. It was found that the dose reconstructed using EPID dosimetry and the dose calculated with the TPS agreed within 1.5% in the lung/heart region. The dose-volume histograms obtained with EPID dosimetry were used to estimate the normal tissue complication probability (NTCP) for late excess cardiac mortality. Although the accuracy of these NTCP calculations might be limited due to the uncertainty in the NTCP model, in combination with our portal dosimetry approach it allows incorporation of the actual heart dose. For the anthropomorphic

  13. 3D reconstruction of a human heart fascicle using SurfDriver

    NASA Astrophysics Data System (ADS)

    Rader, Robert J.; Phillips, Steven J.; LaFollette, Paul S., Jr.

    2000-06-01

    The Temple University Medical School has a sequence of over 400 serial sections of adult normal ventricular human heart tissue, cut at 25 micrometer thickness. We used a Zeiss Ultraphot with a 4x planapo objective and a Pixera digital camera to make a series of 45 sequential montages to use in the 3D reconstruction of a fascicle (muscle bundle). We wrote custom software to merge 4 smaller image fields from each section into one composite image. We used SurfDriver software, developed by Scott Lozanoff of the University of Hawaii and David Moody of the University of Alberta, for registration, object boundary identification, and 3D surface reconstruction. We used an Epson Stylus Color 900 printer to get photo-quality prints. We describe the challenge and our solution to the following problems: image acquisition and digitization, image merge, alignment and registration, boundary identification, 3D surface reconstruction, 3D visualization and orientation, snapshot, and photo-quality prints.

  14. Time-lapse imaging of human heart motion with switched array UWB radar.

    PubMed

    Brovoll, Sverre; Berger, Tor; Paichard, Yoann; Aardal, Øyvind; Lande, Tor Sverre; Hamran, Svein-Erik

    2014-10-01

    Radar systems for detection of human heartbeats have mostly been single-channel systems with limited spatial resolution. In this paper, a radar system for ultra-wideband (UWB) imaging of the human heart is presented. To make the radar waves penetrate the human tissue the antenna is placed very close to the body. The antenna is an array with eight elements, and an antenna switch system connects the radar to the individual elements in sequence to form an image. Successive images are used to build up time-lapse movies of the beating heart. Measurements on a human test subject are presented and the heart motion is estimated at different locations inside the body. The movies show rhythmic motion consistent with the beating heart, and the location and shape of the reflections correspond well with the expected response form the heart wall. The spatial dependent heart motion is compared to ECG recordings, and it is confirmed that heartbeat modulations are seen in the radar data. This work shows that radar imaging of the human heart may provide valuable information on the mechanical movement of the heart. PMID:25350945

  15. Contribution of the Arterial System and the Heart to Blood Pressure during Normal Aging – A Simulation Study

    PubMed Central

    Westerhof, Nico; Westerhof, Berend E.; Broomé, Michael; Stergiopulos, Nikos

    2016-01-01

    During aging, systolic blood pressure continuously increases over time, whereas diastolic pressure first increases and then slightly decreases after middle age. These pressure changes are usually explained by changes of the arterial system alone (increase in arterial stiffness and vascular resistance). However, we hypothesise that the heart contributes to the age-related blood pressure progression as well. In the present study we quantified the blood pressure changes in normal aging by using a Windkessel model for the arterial system and the time-varying elastance model for the heart, and compared the simulation results with data from the Framingham Heart Study. Parameters representing arterial changes (resistance and stiffness) during aging were based on literature values, whereas parameters representing cardiac changes were computed through physiological rules (compensated hypertrophy and preservation of end-diastolic volume). When taking into account arterial changes only, the systolic and diastolic pressure did not agree well with the population data. Between 20 and 80 years, systolic pressure increased from 100 to 122 mmHg, and diastolic pressure decreased from 76 to 55 mmHg. When taking cardiac adaptations into account as well, systolic and diastolic pressure increased from 100 to 151 mmHg and decreased from 76 to 69 mmHg, respectively. Our results show that not only the arterial system, but also the heart, contributes to the changes in blood pressure during aging. The changes in arterial properties initiate a systolic pressure increase, which in turn initiates a cardiac remodelling process that further augments systolic pressure and mitigates the decrease in diastolic pressure. PMID:27341106

  16. A Multiscale Model of Cardiovascular System Including an Immersed Whole Heart in the Cases of Normal and Ventricular Septal Defect (VSD).

    PubMed

    Lee, Wanho; Jung, Eunok

    2015-07-01

    A mathematical and computational model combining the heart and circulatory system has been developed to understand the hemodynamics of circulation under normal conditions and ventricular septal defect (VSD). The immersed boundary method has been introduced to describe the interaction between the moving two-dimensional heart and intracardiac blood flow. The whole-heart model is governed by the Navier-Stokes system; this system is combined with a multi-compartment model of circulation using pressure-flow relations and the linearity of the discretized Navier-Stokes system. We investigate the velocity field, flowmeters, and pressure-volume loop in both normal and VSD cases. Simulation results show qualitatively good agreements with others found in the literature. This model, combining the heart and circulation, is useful for understanding the complex, hemodynamic mechanisms involved in normal circulation and cardiac diseases. PMID:26223734

  17. A broken heart: Right-to-left shunt in the setting of normal cardiac pressures

    PubMed Central

    Gomperts, Natalie; Fowler, Robert; Horlick, Eric; McLaughlin, Peter

    2008-01-01

    A patent foramen ovale (PFO) is a common structural cardiac variant occurring in approximately 30% of the general population. Patients are usually asymptomatic because the defect is flap-like and does not permit significant left-to-right shunting. However, pathological conditions that result in cardiac rotation or higher than normal right atrial pressures can reverse the normal left atrial to right atrial pressure gradient and cause a right-to-left shunt through a PFO. If the right-to-left shunt is persistent, systemic hypoxemia or paradoxical emboli may result. The present report describes a case of refractory hypoxemia in a critically ill patient with a PFO who had a right-to-left shunt with normal right-sided cardiac pressures. PMID:18340396

  18. A broken heart: right-to-left shunt in the setting of normal cardiac pressures.

    PubMed

    Gomperts, Natalie; Fowler, Robert; Horlick, Eric; McLaughlin, Peter

    2008-03-01

    A patent foramen ovale (PFO) is a common structural cardiac variant occurring in approximately 30% of the general population. Patients are usually asymptomatic because the defect is flap-like and does not permit significant left-to-right shunting. However, pathological conditions that result in cardiac rotation or higher than normal right atrial pressures can reverse the normal left atrial to right atrial pressure gradient and cause a right-to-left shunt through a PFO. If the right-to-left shunt is persistent, systemic hypoxemia or paradoxical emboli may result. The present report describes a case of refractory hypoxemia in a critically ill patient with a PFO who had a right-to-left shunt with normal right-sided cardiac pressures. PMID:18340396

  19. ProBNP1-108 Processing and Degradation in Human Heart Failure

    PubMed Central

    Huntley, Brenda K.; Sandberg, Sharon M.; Heublein, Denise M.; Sangaralingham, S. Jeson; Burnett, John C.; Ichiki, Tomoko

    2014-01-01

    Background We have reported that proBNP1-108 circulates and is processed to mature BNP1-32 in human blood. Building on these findings, we sought to determine whether proBNP1-108 processed forms in normal circulation are biologically active and stimulate cGMP, and whether proBNP1-108 processing and activity are altered in human heart failure (HF) compared to normal. Since BNP1-32 is deficient while proBNP1-108 is abundant in HF, we hypothesize that proBNP1-108 processing and degradation are impaired in HF patients ex vivo. Methods and Results We measured circulating molecular forms including BNP1-32, proBNP1-108, and NT-proBNP and all were significantly higher in HF patients compared to normals. Fresh serum samples from normals or HF patients were incubated with or without exogenous non-glycosylated proBNP1-108 tagged with 6 C-terminal Histidines to facilitate peptide isolation. His-tag ProBNP1-108 was efficiently processed into BNP1-32/3-32 at 5 min in normal serum, persisted for 15 min, then disappeared. Delayed processing of proBNP1-108 was observed in HF samples and the degradation pattern differed depending on LV function. The 5 min processed forms from both normal and HF serums were active and generated cGMP via GC-A receptors, however the 180 min samples were not active. The proBNP1-108 processing enzyme corin and BNP degrading enzyme DPPIV were reduced in HF versus normal, perhaps contributing to differential BNP metabolism in HF. Conclusions Exogenous proBNP1-108 is processed into active BNP1-32 and ultimately degraded in normal circulation. The processing and degradation of BNP molecular forms was altered but complete in HF which may contribute the pathophysiology of HF. PMID:25339504

  20. Inhibition of hydrogen sulfide restores normal breathing stability and improves autonomic control during experimental heart failure

    PubMed Central

    Del Rio, Rodrigo; Marcus, Noah J.

    2013-01-01

    Cardiovascular autonomic imbalance and breathing instability are major contributors to the progression of heart failure (CHF). Potentiation of the carotid body (CB) chemoreflex has been shown to contribute to these effects. Hydrogen sulfide (H2S) recently has been proposed to mediate CB hypoxic chemoreception. We hypothesized that H2S synthesis inhibition should decrease CB chemoreflex activation and improve breathing stability and autonomic function in CHF rats. Using the irreversible inhibitor of cystathione γ-lyase dl-propargylglycine (PAG), we tested the effects of H2S inhibition on resting breathing patterns, the hypoxic and hypercapnic ventilatory responses, and the hypoxic sensitivity of CB chemoreceptor afferents in rats with CHF. In addition, heart rate variability (HRV) and systolic blood pressure variability (SBPV) were calculated as an index of autonomic function. CHF rats, compared with sham rats, exhibited increased breath interval variability and number of apneas, enhanced CB afferent discharge and ventilatory responses to hypoxia, decreased HRV, and increased low-frequency SBPV. Remarkably, PAG treatment reduced the apnea index by 90%, reduced breath interval variability by 40–60%, and reversed the enhanced hypoxic CB afferent and chemoreflex responses observed in CHF rats. Furthermore, PAG treatment partially reversed the alterations in HRV and SBPV in CHF rats. Our results show that PAG treatment restores breathing stability and cardiac autonomic function and reduces the enhanced ventilatory and CB chemosensory responses to hypoxia in CHF rats. These results support the idea that PAG treatment could potentially represent a novel pathway to control sympathetic outflow and breathing instability in CHF. PMID:23449938

  1. A quantitative transcriptome reference map of the normal human hippocampus.

    PubMed

    Caracausi, Maria; Rigon, Vania; Piovesan, Allison; Strippoli, Pierluigi; Vitale, Lorenza; Pelleri, Maria Chiara

    2016-01-01

    We performed an innovative systematic meta-analysis of 41 gene expression profiles of normal human hippocampus to provide a quantitative transcriptome reference map of it, i.e. a reference typical value of expression for each of the 30,739 known mapped and the 16,258 uncharacterized (unmapped) transcripts. For this aim, we used the software called TRAM (Transcriptome Mapper), which is able to generate transcriptome maps based on gene expression data from multiple sources. We also analyzed differential expression by comparing the hippocampus with the whole brain transcriptome map to identify a typical expression pattern of this subregion compared with the whole organ. Finally, due to the fact that the hippocampus is one of the main brain region to be severely affected in trisomy 21 (the best known genetic cause of intellectual disability), a particular attention was paid to the expression of chromosome 21 (chr21) genes. Data were downloaded from microarray databases, processed, and analyzed using TRAM software. Among the main findings, the most over-expressed loci in the hippocampus are the expressed sequence tag cluster Hs.732685 and the member of the calmodulin gene family CALM2. The tubulin folding cofactor B (TBCB) gene is the best gene at behaving like a housekeeping gene. The hippocampus vs. the whole brain differential transcriptome map shows the over-expression of LINC00114, a long non-coding RNA mapped on chr21. The hippocampus transcriptome map was validated in vitro by assaying gene expression through several magnitude orders by "Real-Time" reverse transcription polymerase chain reaction (RT-PCR). The highly significant agreement between in silico and experimental data suggested that our transcriptome map may be a useful quantitative reference benchmark for gene expression studies related to human hippocampus. Furthermore, our analysis yielded biological insights about those genes that have an intrinsic over-/under-expression in the hippocampus. PMID

  2. Heart Anatomy

    MedlinePlus

    ... Incredible Machine Bonus poster (PDF) The Human Heart Anatomy Blood The Conduction System The Coronary Arteries The ... of the Leg Vasculature of the Torso Heart anatomy illustrations and animations for grades K-6. Heart ...

  3. Mutations in NTRK3 suggest a novel signaling pathway in human congenital heart disease

    PubMed Central

    Werner, Petra; Paluru, Prasuna; Simpson, Anisha M.; Latney, Brande; Iyer, Radhika; Brodeur, Garrett M.; Goldmuntz, Elizabeth

    2014-01-01

    Congenital heart defects (CHDs) are the most common major birth defects and the leading cause of death from congenital malformations. The etiology remains largely unknown, though genetic variants clearly contribute. In a previous study, we identified a large copy number variant (CNV) that deleted 46 genes in a patient with a malalignment type ventricular septal defect (VSD). The CNV included the gene NTRK3 encoding neurotrophic tyrosine kinase receptor C (TrkC), which is essential for normal cardiogenesis in animal models. To evaluate the role of NTRK3 in human CHDs, we studied 467 patients with related heart defects for NTRK3 mutations. We identified four missense mutations in four patients with VSDs that were not found in ethnically matched controls and were predicted to be functionally deleterious. Functional analysis using neuroblastoma cell lines expressing mutant TrkC demonstrated that one of the mutations (c.278C>T, p.T93M) significantly reduced autophosphorylation of TrkC in response to ligand binding, subsequently decreasing phosphorylation of downstream target proteins. In addition compared to WT, three of the four cell lines expressing mutant TrkC showed altered cell growth in low-serum conditions without supplemental NT-3. These findings suggest a novel pathophysiological mechanism involving NTRK3 in the development of VSDs. PMID:25196463

  4. 7Li NMR study of normal human erythrocytes

    NASA Astrophysics Data System (ADS)

    Pettegrew, J. W.; Post, J. F. M.; Panchalingam, K.; Withers, G.; Woessner, D. E.

    The biological action of lithium is of great interest because of the therapeutic efficacy of the cation in manic-depressive illness. To investigate possible molecular interactions of lithium, 7Li NMR studies were conducted on normal human erythrocytes which had been incubated with lithium chloride. The uptake of lithium ions was followed by 7Li NMR, using a dysprosium, tripolyphosphate shift reagent. Lithium uptake followed single-exponential kinetics with a time constant of 14.7 h. The intracellular lithium relaxation times were T 1 ⋍ 5 s and T 2 ⋍ 0.15 s, which implies a lengthening of the lithium correlation time. It was found that lithium does not interact significantly with hemoglobin, the erythrocyte membrane, or artificial phospholipid membranes. Based on measurements of lithium T1 and T2 in concentrated agar gels, the large difference between T1 and T2 for intracellular lithium ions may be due to diffusion of the hydrated lithium ion through heterogeneous electrostatic field gradients created by the erythrocyte membrane-associated cytoskeletal network. Lithium binding to the membrane-associated cytoskeleton, however, cannot be ruled out. Because of the large differences between T1 and T2 of intracellular lithium ions, 1Li NMR may be a sensitive and promising noninvasive method to probe the intracellular environment.

  5. Expression of interleukin-17RC protein in normal human tissues

    PubMed Central

    Ge, Dongxia; You, Zongbing

    2008-01-01

    Background Interleukin-17 (IL-17) cytokines and receptors play an important role in many autoimmune and inflammatory diseases. IL-17 receptors IL-17RA and IL-17RC have been found to form a heterodimer for mediating the signals of IL-17A and IL-17F cytokines. While the function and signaling pathway of IL-17RA has been revealed, IL-17RC has not been well characterized. The function and signaling pathway of IL-17RC remain largely unknown. The purpose of the present study was to systematically examine IL-17RC protein expression in 53 human tissues. Results IL-17RC expression in 51 normal human tissues and two benign tumors (i.e., lymphangioma and parathyroid adenoma) on the tissue microarrays was determined by immunohistochemical staining, using two polyclonal antibodies against IL-17RC. IL-17RC protein was expressed in many cell types including the myocardial cells, vascular and lymphatic endothelial cells, glandular cells (of the adrenal, parathyroid, pituitary, thyroid, pancreas, parotid salivary, and subepidermal glands), epithelial cells (of the esophagus, stomach, intestine, anus, renal tubule, breast, cervix, Fallopian tube, epididymis, seminal vesicle, prostate, gallbladder, bronchus, lung, and skin), oocytes in the ovary, Sertoli cells in the testis, motor neurons in the spinal cord, autonomic ganglia and nerves in the intestine, skeletal muscle cells, adipocytes, articular chondrocytes, and synovial cells. High levels of IL-17RC protein expression were observed in most vascular and lymphatic endothelium and squamous epithelium. The epithelium of the breast, cervix, Fallopian tube, kidney, bladder and bronchus also expressed high levels of IL-17RC, so did the glandular cells in the adrenal cortex, parotid salivary and subepidermal glands. In contrast, IL-17RC protein was not detectable in the smooth muscle cells, fibroblasts, antral mucosa of the stomach, mucosa of the colon, endometrium of the uterus, neurons of the brain, hepatocytes, or lymphocytes

  6. Human gene copy number spectra analysis in congenital heart malformations.

    PubMed

    Tomita-Mitchell, Aoy; Mahnke, Donna K; Struble, Craig A; Tuffnell, Maureen E; Stamm, Karl D; Hidestrand, Mats; Harris, Susan E; Goetsch, Mary A; Simpson, Pippa M; Bick, David P; Broeckel, Ulrich; Pelech, Andrew N; Tweddell, James S; Mitchell, Michael E

    2012-05-01

    The clinical significance of copy number variants (CNVs) in congenital heart disease (CHD) continues to be a challenge. Although CNVs including genes can confer disease risk, relationships between gene dosage and phenotype are still being defined. Our goal was to perform a quantitative analysis of CNVs involving 100 well-defined CHD risk genes identified through previously published human association studies in subjects with anatomically defined cardiac malformations. A novel analytical approach permitting CNV gene frequency "spectra" to be computed over prespecified regions to determine phenotype-gene dosage relationships was employed. CNVs in subjects with CHD (n = 945), subphenotyped into 40 groups and verified in accordance with the European Paediatric Cardiac Code, were compared with two control groups, a disease-free cohort (n = 2,026) and a population with coronary artery disease (n = 880). Gains (≥200 kb) and losses (≥100 kb) were determined over 100 CHD risk genes and compared using a Barnard exact test. Six subphenotypes showed significant enrichment (P ≤ 0.05), including aortic stenosis (valvar), atrioventricular canal (partial), atrioventricular septal defect with tetralogy of Fallot, subaortic stenosis, tetralogy of Fallot, and truncus arteriosus. Furthermore, CNV gene frequency spectra were enriched (P ≤ 0.05) for losses at: FKBP6, ELN, GTF2IRD1, GATA4, CRKL, TBX1, ATRX, GPC3, BCOR, ZIC3, FLNA and MID1; and gains at: PRKAB2, FMO5, CHD1L, BCL9, ACP6, GJA5, HRAS, GATA6 and RUNX1. Of CHD subjects, 14% had causal chromosomal abnormalities, and 4.3% had likely causal (significantly enriched), large, rare CNVs. CNV frequency spectra combined with precision phenotyping may lead to increased molecular understanding of etiologic pathways. PMID:22318994

  7. Human gene copy number spectra analysis in congenital heart malformations

    PubMed Central

    Mahnke, Donna K.; Struble, Craig A.; Tuffnell, Maureen E.; Stamm, Karl D.; Hidestrand, Mats; Harris, Susan E.; Goetsch, Mary A.; Simpson, Pippa M.; Bick, David P.; Broeckel, Ulrich; Pelech, Andrew N.; Tweddell, James S.; Mitchell, Michael E.

    2012-01-01

    The clinical significance of copy number variants (CNVs) in congenital heart disease (CHD) continues to be a challenge. Although CNVs including genes can confer disease risk, relationships between gene dosage and phenotype are still being defined. Our goal was to perform a quantitative analysis of CNVs involving 100 well-defined CHD risk genes identified through previously published human association studies in subjects with anatomically defined cardiac malformations. A novel analytical approach permitting CNV gene frequency “spectra” to be computed over prespecified regions to determine phenotype-gene dosage relationships was employed. CNVs in subjects with CHD (n = 945), subphenotyped into 40 groups and verified in accordance with the European Paediatric Cardiac Code, were compared with two control groups, a disease-free cohort (n = 2,026) and a population with coronary artery disease (n = 880). Gains (≥200 kb) and losses (≥100 kb) were determined over 100 CHD risk genes and compared using a Barnard exact test. Six subphenotypes showed significant enrichment (P ≤ 0.05), including aortic stenosis (valvar), atrioventricular canal (partial), atrioventricular septal defect with tetralogy of Fallot, subaortic stenosis, tetralogy of Fallot, and truncus arteriosus. Furthermore, CNV gene frequency spectra were enriched (P ≤ 0.05) for losses at: FKBP6, ELN, GTF2IRD1, GATA4, CRKL, TBX1, ATRX, GPC3, BCOR, ZIC3, FLNA and MID1; and gains at: PRKAB2, FMO5, CHD1L, BCL9, ACP6, GJA5, HRAS, GATA6 and RUNX1. Of CHD subjects, 14% had causal chromosomal abnormalities, and 4.3% had likely causal (significantly enriched), large, rare CNVs. CNV frequency spectra combined with precision phenotyping may lead to increased molecular understanding of etiologic pathways. PMID:22318994

  8. The human subject: an integrative animal model for 21st century heart failure research

    PubMed Central

    Chandrasekera, P Charukeshi; Pippin, John J

    2015-01-01

    Heart failure remains a leading cause of death and it is a major cause of morbidity and mortality affecting tens of millions of people worldwide. Despite decades of extensive research conducted at enormous expense, only a handful of interventions have significantly impacted survival in heart failure. Even the most widely prescribed treatments act primarily to slow disease progression, do not provide sustained survival advantage, and have adverse side effects. Since mortality remains about 50% within five years of diagnosis, the need to increase our understanding of heart failure disease mechanisms and development of preventive and reparative therapies remains critical. Currently, the vast majority of basic science heart failure research is conducted using animal models ranging from fruit flies to primates; however, insights gleaned from decades of animal-based research efforts have not been proportional to research success in terms of deciphering human heart failure and developing effective therapeutics for human patients. Here we discuss the reasons for this translational discrepancy which can be equally attributed to the use of erroneous animal models and the lack of widespread use of human-based research methodologies and address why and how we must position our own species at center stage as the quintessential animal model for 21st century heart failure research. If the ultimate goal of the scientific community is to tackle the epidemic status of heart failure, the best way to achieve that goal is through prioritizing human-based, human-relevant research. PMID:26550463

  9. Automated identification of normal and diabetes heart rate signals using nonlinear measures.

    PubMed

    Rajendra Acharya, U; Faust, Oliver; Adib Kadri, Nahrizul; Suri, Jasjit S; Yu, Wenwei

    2013-10-01

    Diabetes mellitus (DM) affects considerable number of people in the world and the number of cases is increasing every year. Due to a strong link to the genetic basis of the disease, it is extremely difficult to cure. However, it can be controlled to prevent severe consequences, such as organ damage. Therefore, diabetes diagnosis and monitoring of its treatment is very important. In this paper, we have proposed a non-invasive diagnosis support system for DM. The system determines whether or not diabetes is present by determining the cardiac health of a patient using heart rate variability (HRV) analysis. This analysis was based on nine nonlinear features namely: Approximate Entropy (ApEn), largest Lyapunov exponet (LLE), detrended fluctuation analysis (DFA) and recurrence quantification analysis (RQA). Clinically significant measures were used as input to classification algorithms, namely AdaBoost, decision tree (DT), fuzzy Sugeno classifier (FSC), k-nearest neighbor algorithm (k-NN), probabilistic neural network (PNN) and support vector machine (SVM). Ten-fold stratified cross-validation was used to select the best classifier. AdaBoost, with least squares (LS) as weak learner, performed better than the other classifiers, yielding an average accuracy of 90%, sensitivity of 92.5% and specificity of 88.7%. PMID:24034744

  10. In situ expression of cytokines in human heart allografts.

    PubMed Central

    Van Hoffen, E.; Van Wichen, D.; Stuij, I.; De Jonge, N.; Klöpping, C.; Lahpor, J.; Van Den Tweel, J.; Gmelig-Meyling, F.; De Weger, R.

    1996-01-01

    Although allograft rejection, the major complication of human organ transplantation, has been extensively studied, little is known about the exact cellular localization of the cytokine expression inside the graft during rejection. Therefore, we used in situ hybridization and immunohistochemistry to study local cytokine mRNA and protein expression in human heart allografts, in relation to the phenotypical characteristics of the cellular infiltrate. Clear expression of mRNA for interleukin (IL)-6, IL-8, IL-9, and IL-10 and weak expression for IL-2, IL-4, IL-5, and tumor necrosis factor (TNF)-alpha was detected in biopsies exhibiting high rejection grades (grade 3A/B). Also at lower grades of rejection, mRNA for IL-6 and IL-9 was present. Some mRNA for IL-1 beta, TNF-beta, and interferon (IFN)-gamma was detected in only a few biopsies. Using immunohistochemistry, IL-2, IL-3, and IL-10 protein was detected in biopsies with high rejection grades, whereas few cells expressed IL-6, IL-8, and IFN-gamma. In biopsies with lower grades of rejection, a weaker expression of these cytokines was observed. IL-4 was hardly detected in any of the biopsies. The level of IL-12 expression was equal in all biopsies. Although mRNA expression of several cytokines was expressed at a low level compared with the protein level of those cytokines, there was a good correlation between localization of cytokine mRNA and protein. Expression of IL-2, IL-4, IL-5, TNF-alpha, and IFN-gamma was mainly detected in lymphocytes. IL-3, IL-6, IL-10, and IL-12 were not detected or not only detected in lymphocytes but also in other stromal elements (eg, macrophages). Macrophage production of IL-3 and IL-12 was confirmed by immunofluorescent double labeling with CD68. We conclude that cardiac allograft rejection is not simply regulated by T helper cell cytokine production, but other intragraft elements contribute considerably to this process. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:8952534

  11. Usefulness of verapamil for congestive heart failure associated with abnormal left ventricular diastolic filling and normal left ventricular systolic performance

    SciTech Connect

    Setaro, J.F.; Zaret, B.L.; Schulman, D.S.; Black, H.R.; Soufer, R. )

    1990-10-15

    Normal left ventricular systolic performance with impaired left ventricular diastolic filling may be present in a substantial number of patients with congestive heart failure (CHF). To evaluate the effect of oral verapamil in this subset, 20 men (mean age 68 +/- 5 years) with CHF, intact left ventricular function (ejection fraction greater than 45%) and abnormal diastolic filling (peak filling rate less than 2.5 end-diastolic volumes per second (edv/s)) were studied in a placebo-controlled, double-blind 5-week crossover trial. All patients underwent echocardiography to rule out significant valvular disease, and thallium-201 stress scintigraphy to exclude major active ischemia. Compared to baseline values, verapamil significantly improved exercise capacity by 33% (13.9 +/- 4.3 vs 10.7 +/- 3.4 minutes at baseline) and peak filling rate by 30% (2.29 +/- 0.54 vs 1.85 +/- 0.45 edv/s at baseline) (all p less than 0.05). Placebo values were 12.3 +/- 4.0 minutes and 2.16 +/- 0.48 edv/s, respectively (difference not significant for both). Improvement from baseline in an objective clinico-radiographic heart failure score (scale 0 to 13) was significantly greater with verapamil compared to placebo (median improvement in score: 3 vs 1, p less than 0.01). Mean ejection fraction and systolic blood pressure were unchanged from baseline; diastolic blood pressure and heart rate decreased to a small degree. Verapamil may have therapeutic efficacy in patients with CHF, preserved systolic function and impaired diastolic filling.

  12. Effects of GUASHA on Heart Rate Variability in Healthy Male Volunteers under Normal Condition and Weightlifters after Weightlifting Training Sessions

    PubMed Central

    Wang, Xingze; Chatchawan, Uraiwan; Nakmareong, Saowanee; Silsirivanit, Atit; Wang, Yingying; Xie, Dongbei; Yang, Jinsheng; Eungpinichpong, Wichai

    2015-01-01

    Objectives. This paper aims at exploring the effects of GUASHA on heart rate variability between healthy volunteers under normal condition and weightlifters after training sessions. Methods. Ten healthy male volunteers under normal condition and 15 male weightlifters after weightlifting training sessions were recruited into two groups. Electrocardiography was recorded before and immediately after 20-minute GUASHA. HRV was calculated in both the time domain and the frequency domain. Results. Stress index was reduced, while standard deviation of N-N intervals (SDNN), proportion derived by dividing the number of interval differences of successive N-N intervals greater than 50 ms, and root mean square of successive differences (RMSSD) were enhanced after GUASHA therapy in the two groups. The changes in SDNN and RMSSD were higher in the healthy men group than in the weightlifters group. In addition, low frequency was decreased whereas high frequency was significantly increased in healthy men after the GUASHA session. Conclusions. GUASHA therapy facilitates the parasympathetic nervous activity and modulates the balance between parasympathetic and sympathetic activities in both healthy men under normal condition and weightlifters after training sessions as indicated. Although the changes of the HRV parameters were similar in both groups, the responsiveness was more pronounced in healthy men than in male weightlifters. PMID:26120346

  13. Echocardiography of the normal camel (Camelus dromedaries) heart: technique and cardiac dimensions

    PubMed Central

    2012-01-01

    Background Echocardiography and intra-cardiac dimensions have not previously been reported in adult camels despite its potential application for medical purpose. The aim of this study was to describe the results of a prospective study, aiming to report normal cardiac appearance and normal chamber dimensions in adult camels (Camelus dromedarius). Results On the right side, when the probe was placed in the 5th or 4th intercostal space (ICS), the caudal long-axis four-chamber view of the ventricles, atria, and the interventricular septum was obtained. Placing the probe slightly more cranially in the 4th ICS, the caudal long-axis four-chamber view and the caudal long-axis view of the left ventricular outflow tract (LVOT) were imaged. In 7 camels, a hybrid view between a “four-chamber” and “LVOT view” was imaged from the same position. The short-axis view of the ventricles was obtained in the 4th ICS where the transducer was rotated between 0° and 25°. Placement of the transducer in the 3rd ICS allowed visualisation of the right ventricular outflow tract (RVOT). On the left side, when the probe was placed in the 5th or 4th ICS, a four-chamber view was obtained. The LVOT is imaged in the 4th ICS and the RVOT was seen from the 3rd ICS. Conclusions This study showed that it is possible to obtain good-quality echocardiograms in adult camels and provide normal cardiac dimensions. This study could be used as a reference for further studies concerning camels with cardiac diseases. PMID:22862855

  14. Tyrosine Administration Decreases Vulnerability to Ventricular Fibrillation in the Normal Canine Heart

    NASA Astrophysics Data System (ADS)

    Scott, Neal A.; Desilva, Regis A.; Lown, Bernard; Wurtman, Richard J.

    1981-02-01

    Intravenous infusion of tyrosine (1, 2, or 4 milligrams per kilogram) for 20 to 30 minutes caused dose-dependent increases in the ventricular fibrillation threshold in normal dogs. Administration of valine, a neutral amino acid that competes with tyrosine for uptake at the blood-brain barrier, in a dose equimolar to the most effective dose of tyrosine, slightly decreased the ventricular fibrillation threshold when given alone and significantly blocked elevation of the ventricular fibrillation threshold after tyrosine infusion. Hence, tyrosine, presumably acting in the central nervous system, can protect against certain ventricular arrhythmias.

  15. Longitudinal Evaluation of Fatty Acid Metabolism in Normal and Spontaneously Hypertensive Rat Hearts with Dynamic MicroSPECT Imaging

    DOE PAGESBeta

    Reutter, Bryan W.; Huesman, Ronald H.; Brennan, Kathleen M.; Boutchko, Rostyslav; Hanrahan, Stephen M.; Gullberg, Grant T.

    2011-01-01

    The goal of this project is to develop radionuclide molecular imaging technologies using a clinical pinhole SPECT/CT scanner to quantify changes in cardiac metabolism using the spontaneously hypertensive rat (SHR) as a model of hypertensive-related pathophysiology. This paper quantitatively compares fatty acid metabolism in hearts of SHR and Wistar-Kyoto normal rats as a function of age and thereby tracks physiological changes associated with the onset and progression of heart failure in the SHR model. The fatty acid analog, 123 I-labeled BMIPP, was used in longitudinal metabolic pinhole SPECT imaging studies performed every seven months for 21 months. The uniquenessmore » of this project is the development of techniques for estimating the blood input function from projection data acquired by a slowly rotating camera that is imaging fast circulation and the quantification of the kinetics of 123 I-BMIPP by fitting compartmental models to the blood and tissue time-activity curves.« less

  16. Signals consistent with microbubbles detected in legs of normal human subjects after exercise.

    PubMed

    Wilbur, J C; Phillips, S D; Donoghue, T G; Alvarenga, D L; Knaus, D A; Magari, P J; Buckey, J C

    2010-02-01

    Exercise may produce micronuclei (presumably gas-filled bubbles) in tissue, which could serve as nucleation sites for bubbles during subsequent decompression stress. These micronuclei have never been directly detected in humans. Dual-frequency ultrasound (DFU) is a resonance-based, ultrasound technique capable of detecting and sizing small stationary bubbles. We surveyed for bubbles in the legs of six normal human subjects (ages 28-52 yr) after exercise using DFU. Eleven marked sites on the left thigh and calf were imaged using standard imaging ultrasound. Subjects then rested in a reclining chair for 2 h before exercise. For the hour before exercise, a series of baseline measurements was taken at each site using DFU. At least six baseline measurements were taken at each site. Subjects exercised at 80% of their age-adjusted maximal heart rate for 30 min on an upright bicycle ergometer. After exercise, the subjects returned to the chair, and multiple postexercise measurements were taken at the marked sites. Measurements continued until no further signals consistent with bubbles were returned or 1 h had elapsed. All subjects showed signals consistent with bubbles after exercise at at least one site. The percentage of sites in a given subject showing signals significantly greater than baseline (P < 0.01) at first measurement ranged from 9.1 to 100%. Overall, 58% of sites showed signals consistent with bubbles at the first postexercise measurement. Signals decreased over time after exercise. These data strongly suggest that exercise produces bubbles detectable using DFU. PMID:19875715

  17. Visualization of Fiber Structurein the Left and Right Ventricleof a Human Heart

    SciTech Connect

    Rohmer, Damien; Sitek, Arkadiusz; Gullberg, Grant T.

    2006-07-12

    The human heart is composed of a helical network of musclefibers. Anisotropic least squares filtering followed by fiber trackingtechniques were applied to Diffusion Tensor Magnetic Resonance Imaging(DTMRI) data of the excised human heart. The fiber configuration wasvisualized by using thin tubes to increase 3-dimensional visualperception of the complex structure. All visualizations were performedusing the high-quality ray-tracing software POV-Ray. The fibers are shownwithin the left and right ventricles. Both ventricles exhibit similarfiber architecture and some bundles of fibers are shown linking right andleft ventricles on the posterior region of the heart.

  18. Minimal changes in heart rate of incubating American Oystercatchers (Haematopus palliatus) in response to human activity

    USGS Publications Warehouse

    Borneman, Tracy E.; Rose, Eli T.; Simons, Theodore R.

    2014-01-01

    An organism's heart rate is commonly used as an indicator of physiological stress due to environmental stimuli. We used heart rate to monitor the physiological response of American Oystercatchers (Haematopus palliatus) to human activity in their nesting environment. We placed artificial eggs with embedded microphones in 42 oystercatcher nests to record the heart rate of incubating oystercatchers continuously for up to 27 days. We used continuous video and audio recordings collected simultaneously at the nests to relate physiological response of birds (heart rate) to various types of human activity. We observed military and civilian aircraft, off-road vehicles, and pedestrians around nests. With the exception of high-speed, low-altitude military overflights, we found little evidence that oystercatcher heart rates were influenced by most types of human activity. The low-altitude flights were the only human activity to significantly increase average heart rates of incubating oystercatchers (12% above baseline). Although statistically significant, we do not consider the increase in heart rate during high-speed, low-altitude military overflights to be of biological significance. This noninvasive technique may be appropriate for other studies of stress in nesting birds.

  19. Thyroid Function Within the Normal Range and Risk of Coronary Heart Disease

    PubMed Central

    Åsvold, Bjørn O.; Vatten, Lars J.; Bjøro, Trine; Bauer, Douglas C.; Bremner, Alexandra; Cappola, Anne R.; Ceresini, Graziano; den Elzen, Wendy P. J.; Ferrucci, Luigi; Franco, Oscar H.; Franklyn, Jayne A.; Gussekloo, Jacobijn; Iervasi, Giorgio; Imaizumi, Misa; Kearney, Patricia M.; Khaw, Kay-Tee; Maciel, Rui M. B.; Newman, Anne. B.; Peeters, Robin P.; Psaty, Bruce M.; Razvi, Salman; Sgarbi, José A.; Stott, David J.; Trompet, Stella; Vanderpump, Mark P. J.; Völzke, Henry; Walsh, John P.; Westendorp, Rudi G. J.; Rodondi, Nicolas

    2016-01-01

    Importance Some experts suggest that serum thyrotropin levels in the upper part of the current reference range should be considered abnormal, an approach that would reclassify many individuals as having mild hypothyroidism. Health hazards associated with such thyrotropin levels are poorly documented, but conflicting evidence suggests that thyrotropin levels in the upper part of the reference range may be associated with an increased risk of coronary heart disease (CHD). Objective To assess the association between differences in thyroid function within the reference range and CHD risk. Design, Setting, and Participants Individual participant data analysis of 14 cohorts with baseline examinations between July 1972 and April 2002 and with median follow-up ranging from 3.3 to 20.0 years. Participants included 55 412 individuals with serum thyrotropin levels of 0.45 to 4.49 mIU/L and no previously known thyroid or cardiovascular disease at baseline. Exposures Thyroid function as expressed by serum thyrotropin levels at baseline. Mainoutcomes and Measures Hazard ratios (HRs) of CHD mortality and CHD events according to thyrotropin levels after adjustment for age, sex, and smoking status. Results Among 55 412 individuals, 1813 people (3.3%) died of CHD during 643 183 person-years of follow-up. In 10 cohorts with information on both nonfatal and fatal CHD events, 4666 of 48 875 individuals (9.5%) experienced a first-time CHD event during 533 408 person-years of follow-up. For each 1-mIU/L higher thyrotropin level, the HR was 0.97 (95% CI, 0.90-1.04) for CHD mortality and 1.00 (95% CI, 0.97-1.03) for a first-time CHD event. Similarly, in analyses by categories of thyrotropin, the HRs of CHD mortality (0.94 [95% CI, 0.74-1.20]) and CHD events (0.97 [95% CI, 0.83-1.13]) were similar among participants with the highest (3.50-4.49 mIU/L) compared with the lowest (0.45-1.49 mIU/L) thyrotropin levels. Subgroup analyses by sex and age group yielded similar results. Conclusions and

  20. Multiplane magnetic resonance imaging of the heart and major vessels: studies in normal volunteers

    SciTech Connect

    Higgins, C.B.; Stark, D.; McNamara, M.; Lanzer, P.; Crooks, L.E.; Kaufman, L.

    1984-04-01

    The feasibility of magnetic resonance imaging for defining anatomy of internal cardiac structures and major blood vessels was assessed in 14 normal subjects. Both electrocardiogram-gated and standard spin-echo images were obtained. Gated images provided better visualization of internal cardiac morphology and of upper mediastinal vessels than did nongated images. Trabecular detail and components of the mitral valve could be resolved. All segments of the left ventricular wall could be evaluated by combining axial, coronal, and sagittal images. Gated acquisition of magnetic resonance images did not increase imaging time; five transverse slices of the left ventricle were obtained in 6.0-8.5 min. The good image quality, ease of gated acquisition, large field of view, capability of direct imaging in multiple planes, and noninvasiveness of the technique suggest that it will be an important imaging method in cardiovascular disease.

  1. Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts.

    PubMed

    Shiba, Yuji; Fernandes, Sarah; Zhu, Wei-Zhong; Filice, Dominic; Muskheli, Veronica; Kim, Jonathan; Palpant, Nathan J; Gantz, Jay; Moyes, Kara White; Reinecke, Hans; Van Biber, Benjamin; Dardas, Todd; Mignone, John L; Izawa, Atsushi; Hanna, Ramy; Viswanathan, Mohan; Gold, Joseph D; Kotlikoff, Michael I; Sarvazyan, Narine; Kay, Matthew W; Murry, Charles E; Laflamme, Michael A

    2012-09-13

    Transplantation studies in mice and rats have shown that human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) can improve the function of infarcted hearts, but two critical issues related to their electrophysiological behaviour in vivo remain unresolved. First, the risk of arrhythmias following hESC-CM transplantation in injured hearts has not been determined. Second, the electromechanical integration of hESC-CMs in injured hearts has not been demonstrated, so it is unclear whether these cells improve contractile function directly through addition of new force-generating units. Here we use a guinea-pig model to show that hESC-CM grafts in injured hearts protect against arrhythmias and can contract synchronously with host muscle. Injured hearts with hESC-CM grafts show improved mechanical function and a significantly reduced incidence of both spontaneous and induced ventricular tachycardia. To assess the activity of hESC-CM grafts in vivo, we transplanted hESC-CMs expressing the genetically encoded calcium sensor, GCaMP3 (refs 4, 5). By correlating the GCaMP3 fluorescent signal with the host ECG, we found that grafts in uninjured hearts have consistent 1:1 host–graft coupling. Grafts in injured hearts are more heterogeneous and typically include both coupled and uncoupled regions. Thus, human myocardial grafts meet physiological criteria for true heart regeneration, providing support for the continued development of hESC-based cardiac therapies for both mechanical and electrical repair. PMID:22864415

  2. Identification of cardiac-related circulating microRNA profile in human chronic heart failure

    PubMed Central

    Li, Huaping; Fan, Jiahui; Yin, Zhongwei; Wang, Feng; Chen, Chen; Wang, Dao Wen

    2016-01-01

    Background During chronic heart failure, levels of circulating miRNAs endued with characteristics of diseased cells could be identified as biomarkers. In this study, we sought to identify cardiac-related circulating miRNAs as biomarkers of failing heart. Methods Total RNA of plasma and heart samples was extracted from 10 normal controls and 14 patients with chronic heart failure. Microarray was applied for miRNA profiles. Validation and organ/tissue distribution analysis was performed by qRT-PCR. In addition, bioinformatics analysis was performed to understand the critical roles of these cardiac-related circulating miRNAs in heart failure. Results Results showed that levels of more than half of the miRNAs dysregulated in heart failed to show any differences in plasma. Meanwhile, more than 90% of the miRNAs dysregulated in plasma remained stable in heart. Four cardiac fibroblast-derived miRNAs (miR-660-3p, miR-665, miR-1285-3p and miR-4491) were found significantly upregulated in heart and plasma during heart failure. These 4 miRNAs strongly discriminated patients from controls, and 3 of them showed significant correlations with LVEF. Conclusions This study provides global profiles of miRNAs changes in plasma and failing heart, and using a circulation-tissue miRNA profiling comparison model, we successfully identify 3 cardiac-related circulating miRNAs as potential biomarkers for diagnosis of heart failure. PMID:26683101

  3. Dietary induced subclinical vitamin K deficiency in normal human subjects.

    PubMed Central

    Ferland, G; Sadowski, J A; O'Brien, M E

    1993-01-01

    A subclinical vitamin K deficiency was induced in 32 healthy subjects (four groups of eight males and females) aged 20-40 and 60-80 yr residing in the Metabolic Research Unit of the Human Nutrition Research Center on Aging at Tufts University. Volunteers were initially fed (4 d) a baseline-period diet containing the recommended daily allowance for vitamin K which is equivalent to 80 micrograms/d of phylloquinone (vitamin K1). During the baseline period various parameters of vitamin K nutritional status were monitored. The baseline period was followed by a 13-d depletion period during which the subjects were fed a very low vitamin K1 diet (approximately 10 micrograms/d). After depletion, the subjects entered a 16-d repletion period (four stages lasting 4 d each) during which time they were repleted with 5, 15, 25, and 45 micrograms of vitamin K1 per day. Vitamin K1 depletion dramatically and significantly decreased plasma vitamin K1 levels (P < 0.0001) in both elderly and young groups to values 13-18% of day 1 (elderly 0.22 nM, young 0.14 nM). Repleting the subjects with up to 45 micrograms of vitamin K1 per day failed, in the case of the young subjects, to bring plasma vitamin K1 levels back into the normal range. Dietary vitamin K1 restriction induced different responses in the urinary excretion of gamma-carboxyglutamic acid between the young and the elderly subjects with values decreasing significantly (P < 0.03) in the young while remaining unchanged in the elderly. The vitamin K1 depletion period had no significant effect on either prothrombin and activated partial thromboplastin times, or Factor VII and protein C (as determined by antigenic and functional assays). By using a monoclonal antibody, decarboxy prothrombin was found to increase slightly but significantly in both groups (P < 0.05) as a consequence of the low vitamin K1 diet. This study clearly shows that a diet low in vitamin K1 can result in a functional subclinical deficiency of vitamin K

  4. Heart Rate and Heart Rate Variability in Dairy Cows with Different Temperament and Behavioural Reactivity to Humans

    PubMed Central

    Tőzsér, János; Szenci, Ottó; Póti, Péter; Pajor, Ferenc

    2015-01-01

    From the 1990s, extensive research was started on the physiological aspects of individual traits in animals. Previous research has established two extreme (proactive and reactive) coping styles in several animal species, but the means of reactivity with the autonomic nervous system (ANS) activity has not yet been investigated in cattle. The aim of this study was the characterization of cardiac autonomic activity under different conditions in cows with different individual characteristics. For this purpose, we investigated heart rate and ANS-related heart rate variability (HRV) parameters of dairy cows (N = 282) on smaller- and larger-scale farms grouped by (1) temperament and (2) behavioural reactivity to humans (BRH). Animals with high BRH scores were defined as impulsive, while animals with low BRH scores were defined as reserved. Cardiac parameters were calculated for undisturbed lying (baseline) and for milking bouts, the latter with the presence of an unfamiliar person (stressful situation). Sympathetic tone was higher, while vagal activity was lower in temperamental cows than in calm animals during rest both on smaller- and larger-scale farms. During milking, HRV parameters were indicative of a higher sympathetic and a lower vagal activity of temperamental cows as compared to calm ones in farms of both sizes. Basal heart rate did not differ between BRH groups either on smaller- or larger-scale farms. Differences between basal ANS activity of impulsive and reserved cows reflected a higher resting vagal and lower sympathetic activity of reserved animals compared to impulsive ones both on smaller- and larger-scale farms. There was no difference either in heart rate or in HRV parameters between groups during milking neither in smaller- nor in larger-scale farms. These two groupings allowed to draw possible parallels between personality and cardiac autonomic activity during both rest and milking in dairy cows. Heart rate and HRV seem to be useful for

  5. Heart rate dynamics distinguish among atrial fibrillation, normal sinus rhythm and sinus rhythm with frequent ectopy.

    PubMed

    Carrara, Marta; Carozzi, Luca; Moss, Travis J; de Pasquale, Marco; Cerutti, Sergio; Ferrario, Manuela; Lake, Douglas E; Moorman, J Randall

    2015-09-01

    Atrial fibrillation (AF) is usually detected by inspection of the electrocardiogram waveform, a task made difficult when the signal is distorted by noise. The RR interval time series is more frequently available and accurate, yet linear and nonlinear time series analyses that detect highly varying and irregular AF are vulnerable to the common finding of frequent ectopy. We hypothesized that different nonlinear measures might capture characteristic features of AF, normal sinus rhythm (NSR), and sinus rhythm (SR) with frequent ectopy in ways that linear measures might not. To test this, we studied 2722 patients with 24 h ECG recordings in the University of Virginia Holter database. We found dynamical phenotypes for the three rhythm classifications. As expected, AF records had the highest variability and entropy, and NSR the lowest. SR with ectopy could be distinguished from AF, which had higher entropy, and from NSR, which had different fractal scaling, measured as higher detrended fluctuation analysis slope. With these dynamical phenotypes, we developed successful classification strategies, and the nonlinear measures improved on the use of mean and variability alone, even after adjusting for age. Final models using all variables had excellent performance, with positive predictive values for AF, NSR and SR with ectopy as high as 97, 98 and 90%, respectively. Since these classifiers can reliably detect rhythm changes utilizing segments as short as 10 min, we envision their application in noisy settings and in personal monitoring devices where only RR interval time series may be available. PMID:26246162

  6. Cardiac expression of a mini-dystrophin that normalizes skeletal muscle force only partially restores heart function in aged Mdx mice.

    PubMed

    Bostick, Brian; Yue, Yongping; Long, Chun; Marschalk, Nate; Fine, Deborah M; Chen, Jing; Duan, Dongsheng

    2009-02-01

    Duchenne muscular dystrophy (DMD) affects both skeletal and cardiac muscle. It is currently unclear whether the strategies developed for skeletal muscle can ameliorate cardiomyopathy. Synthetic mini-/micro-dystrophin genes have yielded impressive skeletal muscle protection in animal models. The 6-kb DeltaH2-R19 minigene is particularly promising because it completely restores skeletal muscle force to wild-type levels. Here, we examined whether expressing this minigene in the heart, but not skeletal muscle, could normalize cardiac function in the mdx model of DMD cardiomyopathy. Transgenic mdx mice were generated to express the DeltaH2-R19 minigene under the control of the alpha-myosin heavy-chain promoter. Heart structure and function were examined in adult and very old mice. The DeltaH2-R19 minigene enhanced cardiomyocyte sarcolemmal strength and prevented myocardial fibrosis. It also restored the dobutamine response and enhanced treadmill performance. Surprisingly, heart-restricted DeltaH2-R19 minigene expression did not completely normalize electrocardiogram and hemodynamic abnormalities. Overall, systolic function and ejection fraction were restored to normal levels but stroke volume and cardiac output remained suboptimal. Our results demonstrate that the skeletal muscle-proven DeltaH2-R19 minigene can correct cardiac histopathology but cannot fully normalize heart function. Novel strategies must be developed to completely restore heart function in DMD. PMID:19066599

  7. Encounters with the Human Heart: An Interview with John Stone.

    ERIC Educational Resources Information Center

    Flynn, Dale Bachman

    1995-01-01

    Interviews Dale Bachman Flynn, professor of cardiology and dean of admissions and student affairs at Emory University School of Medicine, about his "In the Country of Hearts," a collection of stories about his medical practice. Discusses Flynn's personal life; his life-long practice of writing; and his interest in the intersections among medicine,…

  8. Congestive heart failure arising from diastolic dysfunction in the presence of normal left-ventricular systolic function.

    PubMed Central

    Stainback, R F

    1999-01-01

    Congestive heart failure due to diastolic dysfunction is a common clinical entity, particularly in the elderly. As outlined, such patients fall into a larger group of all patients with CHF symptoms and normal systolic function. When finding "normal" systolic function, the clinician should embark upon a carefully outlined diagnostic work-up geared toward eliminating confounding or treatable contributing causes of dyspnea or typical CHF symptoms. The prognosis for CHF patients with primarily diastolic dysfunction is not as poor as for those with LV systolic dysfunction, although the prevalence, associated morbidity, and costs are great. In contrast to the large number of successful clinical trials that have guided treatment of LV systolic failure, an extremely limited number of trials have specifically addressed themselves to diastolic dysfunction. Marked symptomatic relief can often be provided with careful attention to tailored therapy, although little is known with regard to outcome. Refinements in noninvasive imaging methods and hemodynamic indices of diastolic function may lead to improved patient care. PMID:10217469

  9. Infrequency of cytomegalovirus genome in coronary arteriopathy of human heart allografts.

    PubMed Central

    Gulizia, J. M.; Kandolf, R.; Kendall, T. J.; Thieszen, S. L.; Wilson, J. E.; Radio, S. J.; Costanzo, M. R.; Winters, G. L.; Miller, L. L.; McManus, B. M.

    1995-01-01

    In heart transplantation, long-term engraftment success is severely limited by the rapid development of obliterative disease of the coronary arteries. Data from various groups have been suggestive of a pathogenetic role of herpesviruses, particularly human cytomegalovirus, in accelerated allograft coronary artery disease; however, results are not yet conclusive. This study examines the hypothesis that human cytomegalovirus infection of allograft tissues is related pathogenetically and directly to accelerated coronary artery disease. Using in situ DNA hybridization and polymerase chain reaction, we examined particular coronary artery segments from 41 human heart allografts (ranging from 4 days to greater than 4 years after transplantation; mean, 457 days) and 22 donor age- and gender-comparable, coronary site-matched trauma victims for presence of human cytomegalovirus DNA. Human cytomegalovirus genome was detected in 8 of 41 (19.5%) allografts and in 1 of 22 (4.5%) control hearts. This difference in positivity was not statistically significant (P = 0.10). In the human cytomegalovirus-positive hearts, viral genome was localized to perivascular myocardium or coronary artery media or adventitia. Human cytomegalovirus genome was not detected in arterial intima of any allograft or control heart, although human cytomegalovirus genome was readily identified within intima of small pulmonary arteries from lung tissue with human cytomegalovirus pneumonitis. By statistical analyses, the presence of human cytomegalovirus genome was not associated with the nature or digitized extent of transplant arteriopathy, evidence of rejection, allograft recipient or donor serological data suggestive of human cytomegalovirus infection, duration of allograft implantation, or causes of death or retransplantation. Thus, our data indicate a low frequency of detectable human cytomegalovirus genome in accelerated coronary artery disease and do not support a direct role for human cytomegalovirus

  10. Angiotensin II formation in the intact human heart. Predominance of the angiotensin-converting enzyme pathway.

    PubMed Central

    Zisman, L S; Abraham, W T; Meixell, G E; Vamvakias, B N; Quaife, R A; Lowes, B D; Roden, R L; Peacock, S J; Groves, B M; Raynolds, M V

    1995-01-01

    It has been proposed that the contribution of myocardial tissue angiotensin converting enzyme (ACE) to angiotensin II (Ang II) formation in the human heart is low compared with non-ACE pathways. However, little is known about the actual in vivo contribution of these pathways to Ang II formation in the human heart. To examine angiotensin II formation in the intact human heart, we administered intracoronary 123I-labeled angiotensin I (Ang I) with and without intracoronary enalaprilat to orthotopic heart transplant recipients. The fractional conversion of Ang I to Ang II, calculated after separation of angiotensin peptides by HPLC, was 0.415 +/- 0.104 (n = 5, mean +/- SD). Enalaprilat reduced fractional conversion by 89%, to a value of 0.044 +/- 0.053 (n = 4, P = 0.002). In a separate study of explanted hearts, a newly developed in vitro Ang II-forming assay was used to examine cardiac tissue ACE activity independent of circulating components. ACE activity in solubilized left ventricular membrane preparations from failing hearts was 49.6 +/- 5.3 fmol 125I-Ang II formed per minute per milligram of protein (n = 8, +/- SE), and 35.9 +/- 4.8 fmol/min/mg from nonfailing human hearts (n = 7, P = 0.08). In the presence of 1 microM enalaprilat, ACE activity was reduced by 85%, to 7.3 +/- 1.4 fmol/min/mg in the failing group and to 4.6 +/- 1.3 fmol/min/mg in the nonfailing group (P < 0.001). We conclude that the predominant pathway for angiotensin II formation in the human heart is through ACE. Images PMID:7657820

  11. Contractile reserve and intracellular calcium regulation in mouse myocytes from normal and hypertrophied failing hearts

    NASA Technical Reports Server (NTRS)

    Ito, K.; Yan, X.; Tajima, M.; Su, Z.; Barry, W. H.; Lorell, B. H.; Schneider, M. (Principal Investigator)

    2000-01-01

    Mouse myocyte contractility and the changes induced by pressure overload are not fully understood. We studied contractile reserve in isolated left ventricular myocytes from mice with ascending aortic stenosis (AS) during compensatory hypertrophy (4-week AS) and the later stage of early failure (7-week AS) and from control mice. Myocyte contraction and [Ca(2+)](i) transients with fluo-3 were measured simultaneously. At baseline (0.5 Hz, 1.5 mmol/L [Ca(2+)](o), 25 degrees C), the amplitude of myocyte shortening and peak-systolic [Ca(2+)](i) in 7-week AS were not different from those of controls, whereas contraction, relaxation, and the decline of [Ca(2+)](i) transients were slower. In response to the challenge of high [Ca(2+)](o), fractional cell shortening was severely depressed with reduced peak-systolic [Ca(2+)](i) in 7-week AS compared with controls. In response to rapid pacing stimulation, cell shortening and peak-systolic [Ca(2+)](i) increased in controls, but this response was depressed in 7-week AS. In contrast, the responses to both challenge with high [Ca(2+)](o) and rapid pacing in 4-week AS were similar to those of controls. Although protein levels of Na(+)-Ca(2+) exchanger were increased in both 4-week and 7-week AS, the ratio of SR Ca(2+)-ATPase to phospholamban protein levels was depressed in 7-week AS compared with controls but not in 4-week AS. This was associated with an impaired capacity to increase sarcoplasmic reticulum Ca(2+) load during high work states in 7-week AS myocytes. In hypertrophied failing mouse myocytes, depressed contractile reserve is related to an impaired augmentation of systolic [Ca(2+)](i) and SR Ca(2+) load and simulates findings in human failing myocytes.

  12. High expression of arachidonate 15-lipoxygenase and proinflammatory markers in human ischemic heart tissue

    SciTech Connect

    Magnusson, Lisa U.; Lundqvist, Annika; Asp, Julia; Synnergren, Jane; Johansson, Cecilia Thalen; Palmqvist, Lars; Jeppsson, Anders; Hulten, Lillemor Mattsson

    2012-07-27

    Highlights: Black-Right-Pointing-Pointer We found a 17-fold upregulation of ALOX15 in the ischemic heart. Black-Right-Pointing-Pointer Incubation of human muscle cells in hypoxia showed a 22-fold upregulation of ALOX15. Black-Right-Pointing-Pointer We observed increased levels of proinflammatory markers in ischemic heart tissue. Black-Right-Pointing-Pointer Suggesting a link between ischemia and inflammation in ischemic heart biopsies. -- Abstract: A common feature of the ischemic heart and atherosclerotic plaques is the presence of hypoxia (insufficient levels of oxygen in the tissue). Hypoxia has pronounced effects on almost every aspect of cell physiology, and the nuclear transcription factor hypoxia inducible factor-1{alpha} (HIF-1{alpha}) regulates adaptive responses to low concentrations of oxygen in mammalian cells. In our recent work, we observed that hypoxia increases the proinflammatory enzyme arachidonate 15-lipoxygenase (ALOX15B) in human carotid plaques. ALOX15 has recently been shown to be present in the human myocardium, but the effect of ischemia on its expression has not been investigated. Here we test the hypothesis that ischemia of the heart leads to increased expression of ALOX15, and found an almost 2-fold increase in HIF-1{alpha} mRNA expression and a 17-fold upregulation of ALOX15 mRNA expression in the ischemic heart biopsies from patients undergoing coronary bypass surgery compared with non ischemic heart tissue. To investigate the effect of low oxygen concentration on ALOX15 we incubated human vascular muscle cells in hypoxia and showed that expression of ALOX15 increased 22-fold compared with cells incubated in normoxic conditions. We also observed increased mRNA levels of proinflammatory markers in ischemic heart tissue compared with non-ischemic controls. In summary, we demonstrate increased ALOX15 in human ischemic heart biopsies. Furthermore we demonstrate that hypoxia increases ALOX15 in human muscle cells. Our results yield

  13. Damage initiation sites in osteoporotic and normal human cancellous bone.

    PubMed

    Soicher, Matthew A; Wang, Xiang; Zauel, Roger R; Fyhrie, David P

    2011-03-01

    Using a finite element (FE) method called biomechanical stereology, Wang et al. previously reported increased microcrack formation and propagation in bone samples from patients with a history of osteoporotic fracture as compared to normal subjects. In this study, we re-analyzed the data from Wang's report to determine the microscopic differences between bone tissue from osteoporotic patients and normal subjects that caused these different patterns of bone tissue damage between the groups. The morphological features examined were the number of "voids" (or osteocyte lacunae) visible and the distance of the lacunae from the initiation of the microcracks. We found that bone samples from patients with a history of osteoporotic fracture contained significantly more lacunae than normal control specimens. We also found a significant correlation (r² = 0.483, p = 0.001) between the number of lacunae visible in the image and the number of microcracks formed. These results help to explain the differences in total microcrack number between the osteoporotic and normal subjects reported in our previous work. PMID:21081188

  14. Quantitative analysis of p53 expression in human normal and cancer tissue microarray with global normalization method

    PubMed Central

    Idikio, Halliday A

    2011-01-01

    Tissue microarray based immunohistochemical staining and proteomics are important tools to create and validate clinically relevant cancer biomarkers. Immunohistochemical stains using formalin-fixed tissue microarray sections for protein expression are scored manually and semi-quantitatively. Digital image analysis methods remove some of the drawbacks of manual scoring but may need other methods such as normalization to provide across the board utility. In the present study, quantitative proteomics-based global normalization method was used to evaluate its utility in the analysis of p53 protein expression in mixed human normal and cancer tissue microarray. Global normalization used the mean or median of β-actin to calculate ratios of individual core stain intensities, then log transformed the ratios, calculate a mean or median and subtracted the value from the log of ratios. In the absence of global normalization of p53 protein expression, 44% (42 of 95) of tissue cores were positive using the median of intensity values and 40% (38 of 95) using the mean of intensities as cut-off points. With global normalization, p53 positive cores changed to 20% (19 of 95) when using median of intensities and 15.8%(15 of 95) when the mean of intensities were used. In conclusion, the global normalization method helped to define positive p53 staining in the tissue microarray set used. The method used helped to define clear cut-off points and confirmed all negatively stained tissue cores. Such normalization methods should help to better define clinically useful biomarkers. PMID:21738821

  15. Modulation of cardiac L-type Ca2+ current by angiotensin-(1-7): Normal versus heart failure

    PubMed Central

    Zhou, Peng; Cheng, Che Ping; Li, Tiankai; Ferrario, Carlos M.; Cheng, Heng-Jie

    2016-01-01

    Objective Recent evidence has shown that, in heart failure (HF), clinically relevant concentrations of angiotensin-(1-7) [Ang-(1-7)] counteracts angiotensin II induced cardiac depression and produces positive inotropic effects in both left ventricle (LV) and myocytes. However, the underlying electrophysiological mechanism is unclear. We investigated the role and mechanism of Ang-(1-7) on LV myocyte L-type calcium current (ICa,L) responses in normal state and in HF. Method We compared the effect of Ang-(1-7) (10−5 M) on ICa,L responses in isolated LV myocytes obtained from 11 rats with isoproterenol (ISO) induced HF (3 months after 170 mg/kg subcutaneous for 2 days) and from 8 age-matched normal control rats by patch clamp technique. Results In normal myocytes, compared with baseline, superfusion of Ang-(1-7) caused no significant changes in ICa,L (8.2 ± 0.2 versus 8.0 ± 0.3 pA/pF, p= not significant). In HF myocytes, the baseline ICa,L was significantly reduced (5.3 ± 0.1 versus 8.0 ± 0.3 pA/pF, p < 0.01). Ang-(1-7) produced a 21% increase in ICa,L (6.4±0.1 versus 5.3±0.1 pA/pF, p < 0.01). Pretreatment of HF myocytes with a nitric oxide (NO) synthase inhibitor (L-NAME, 10−5 M) resulted in a significantly greater increase in ICa,L (28%, 8.4 ± 0.1 versus 6.5 ± 0.1 pA/pF, p < 0.01) during Ang-(1-7) superfusion. In contrast, during incubation with the bradykinin (BK) inhibitor HOE 140 (10−6 M), Ang-(1-7) induced increase in ICa,L was significantly decreased. The Ang-(1-7) induced increase in ICa,L was abolished by [D-Ala7]-Ang-(1-7) (A-779, 10−5 M). Conclusions HF alters the response of ICa,L to Ang-(1-7). In normal myocytes, Ang-(1-7) has no significant effect on ICa,L. However, in HF myocytes, Ang-(1-7) increases ICa,L. These effects are mediated by the Ang-(1-7) Mas receptors and involve activation of NO/BK pathways. PMID:26082338

  16. Comparison of human eosinophils from normals and patients with eosinophilia.

    PubMed

    Bass, D A; Grover, W H; Lewis, J C; Szejda, P; DeChatelet, L R; McCall, C E

    1980-12-01

    Previous studies of the biochemistry and physiology of eosinophils have relied upon cells obtained from patients with eosinophilia (EE). It is unknown whether such cells might have been activated or partially exhausted by the pathological state causing eosinophilia. We examined cell surface charge, membrane transport of deoxyglucose, activation of lyso-somal acid phosphatase, and oxidative metabolism to provide a profile to compare EE with purified normal eosinophils (NE) and normal neutrophils. Eosinophils or neutrophils were obtained in >95% purity from normal individuals and patients with eosinophilia of diverse etiologies. Cell surface charge was determined by electrophoretic mobility in micromoles per second per volt per centimeter. Normal eosinophils demonstrated a surface charge of 2.46+/-0.03. Stimulation of the cells by zymosan-activated serum (ZAS) reduced the surface charge to 1.82+/-0.02. In contrast, the charge of "resting" EE was already reduced (1.89+/-0.05) and was not altered by ZAS. Resting and stimulated neutrophils had a charge of 1.98+/-0.01 and 1.69+/-0.02, respectively. Uptake of [(3)H]2-deoxyglucose has been shown to reflect carrier-facilitated hexose transport in granulocytes. Deoxyglucose uptake by resting NE and NE stimulated by ZAS was 2.40+/-0.40 and 5.44+/-0.39 (cpm x 10(-3)/2 x 10(5) eosinophils), respectively. Resting and stimulated EE demonstrated deoxyglucose uptake of 7.55+/-0.58 and 15.3+/-0.6, respectively.Lysosomal acid phosphatase was determined by an electron microscopic cytochemical technique. In normal eosinophils and neutrophils, lysosomal acid phosphatase in mature cells is held in a latent form. Normal eosinophils demonstrated weakly positive acid phosphatase activity in 7.8+/-1.2% of the specific granules. Normal eosinophils, stimulated by opsonized staphylococci or the calcium ionophore A23187, develop rapid activation of acid phosphatase in approximately 80% of the granules throughout the cells. Resting EE were

  17. Effects of cobalt chloride on phenotypes of normal human saphenous vein smooth muscle cells

    PubMed Central

    Li, Jing; Wang, Huai-Ming

    2014-01-01

    To explore the cellular adaptations and responses to hypoxia in normal human saphenous vein smooth muscle cells (SMCs) and presume what roles phenotypic modulation of normal human saphenous vein SMCs would play in varicose vein of lower extremity, we used cobalt chloride (CoCl2), a hypoxia mimetic, to treat normal human saphenous vein SMCs in vitro. The proliferating ability of cells exposed to serial dilutions of CoCl2 (0, 200, 300, 400 and 500 μM) at 24 h, 48 h and 72 h respectively was detected by MTT assay. Wound healing assay was used to observe the migrating ability of cells under CoCl2 (200 μM) treatment for 8 days continuously. Hoechst 33258 stain was used to determine whether hypoxia induced by CoCl2 could cause apoptosis of normal human saphenous vein SMCs. We found that CoCl2 enhanced the proliferation and inhibited the migration of normal human saphenous vein SMCs. The apparent morphous of normal human saphenous vein SMCs under chronic CoCl2 treatment was significantly changed compared to no CoCl2 treated control, but this process did not relate to cell apoptosis. To conclude, our results support the concept that the phenotypes of normal human saphenous vein SMCs could be influenced by hypoxia stimulus. Cellular structural and functional changes under chronic hypoxia in normal human saphenous vein SMCs might play important roles in the development of varicose veins of lower extremity. PMID:25663990

  18. Effects of cobalt chloride on phenotypes of normal human saphenous vein smooth muscle cells.

    PubMed

    Li, Jing; Wang, Huai-Ming

    2014-01-01

    To explore the cellular adaptations and responses to hypoxia in normal human saphenous vein smooth muscle cells (SMCs) and presume what roles phenotypic modulation of normal human saphenous vein SMCs would play in varicose vein of lower extremity, we used cobalt chloride (CoCl2), a hypoxia mimetic, to treat normal human saphenous vein SMCs in vitro. The proliferating ability of cells exposed to serial dilutions of CoCl2 (0, 200, 300, 400 and 500 μM) at 24 h, 48 h and 72 h respectively was detected by MTT assay. Wound healing assay was used to observe the migrating ability of cells under CoCl2 (200 μM) treatment for 8 days continuously. Hoechst 33258 stain was used to determine whether hypoxia induced by CoCl2 could cause apoptosis of normal human saphenous vein SMCs. We found that CoCl2 enhanced the proliferation and inhibited the migration of normal human saphenous vein SMCs. The apparent morphous of normal human saphenous vein SMCs under chronic CoCl2 treatment was significantly changed compared to no CoCl2 treated control, but this process did not relate to cell apoptosis. To conclude, our results support the concept that the phenotypes of normal human saphenous vein SMCs could be influenced by hypoxia stimulus. Cellular structural and functional changes under chronic hypoxia in normal human saphenous vein SMCs might play important roles in the development of varicose veins of lower extremity. PMID:25663990

  19. Evidence for regional catecholamine uptake and storage sites in the transplanted human heart by positron emission tomography

    SciTech Connect

    Schwaiger, M.; Hutchins, G.D.; Kalff, V.; Rosenspire, K.; Haka, M.S.; Mallette, S.; Deeb, G.M.; Abrams, G.D.; Wieland, D. )

    1991-05-01

    Positron emission tomography in combination with the newly introduced catecholamine analogue ({sup 11}C)hydroxyephedrine (({sup 11}C)HED) enables the noninvasive delineation of sympathetic nerve terminals of the heart. To address the ongoing controversy over possible reinnervation of the human transplant, 5 healthy control subjects and 11 patients were studied after cardiac transplant by this imaging approach. Regional ({sup 11}C)HED retention was compared to regional blood flow as assessed by rubidium-82. Transplant patients were divided into two groups. Group I had recent (less than 1 yr, 4.4 +/- 2.3 mo) surgery, while group II patients underwent cardiac transplantation more than 2 yr before imaging (3.5 +/- 1.3 yr). ({sup 11}C)HED retention paralleled blood flow in normals, but was homogeneously reduced in group I. In contrast, group II patients revealed heterogeneous ({sup 11}C)HED retention, with increased uptake in the proximal anterior and septal wall. Quantitative evaluation of ({sup 11}C)HED retention revealed a 70% reduction in group I and 59% reduction in group II patients (P less than 0.001). In group II patients, ({sup 11}C)HED retention reached 60% of normal in the proximal anterior wall. These data suggest the presence of neuronal tissue in the transplanted human heart, which may reflect regional sympathetic reinnervation.

  20. A new unique form of microRNA from human heart, microRNA-499c, promotes myofibril formation and rescues cardiac development in mutant axolotl embryos

    PubMed Central

    2013-01-01

    Background A recessive mutation “c” in the Mexican axolotl, Ambystoma mexicanum, results in the failure of normal heart development. In homozygous recessive embryos, the hearts do not have organized myofibrils and fail to beat. In our previous studies, we identified a noncoding Myofibril-Inducing RNA (MIR) from axolotls which promotes myofibril formation and rescues heart development. Results We randomly cloned RNAs from fetal human heart. RNA from clone #291 promoted myofibril formation and induced heart development of mutant axolotls in organ culture. This RNA induced expression of cardiac markers in mutant hearts: tropomyosin, troponin and α-syntrophin. This cloned RNA matches in partial sequence alignment to human microRNA-499a and b, although it differs in length. We have concluded that this cloned RNA is unique in its length, but is still related to the microRNA-499 family. We have named this unique RNA, microRNA-499c. Thus, we will refer to this RNA derived from clone #291 as microRNA-499c throughout the rest of the paper. Conclusions This new form, microRNA-499c, plays an important role in cardiac development. PMID:23522091

  1. Human Cardiosphere-Derived Cells From Advanced Heart Failure Patients Exhibit Augmented Functional Potency in Myocardial Repair

    PubMed Central

    Shen, Deliang; Sun, Baiming; Blusztajn, Agnieszka; Xie, Yucai; Ibrahim, Ahmed; Aminzadeh, Mohammad Amin; Liu, Weixin; Li, Tao-Sheng; De Robertis, Michele A.; Marbán, Linda; Czer, Lawrence S. C.; Trento, Alfredo; Marbán, Eduardo

    2014-01-01

    Objectives This study sought to compare the regenerative potency of cells derived from healthy and diseased human hearts. Background Results from pre-clinical studies and the CADUCEUS (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction) trial support the notion that cardiosphere-derived cells (CDCs) from normal and recently infarcted hearts are capable of regenerating healthy heart tissue after myocardial infarction (MI). It is unknown whether CDCs derived from advanced heart failure (HF) patients retain the same regenerative potency. Methods In a mouse model of acute MI, we compared the regenerative potential and functional benefits of CDCs derived from 3 groups: 1) non-failing (NF) donor: healthy donor hearts post-transplantation; 2) MI: patients who had an MI 9 to 35 days before biopsy; and 3) HF: advanced cardiomyopathy tissue explanted at cardiac transplantation. Results Cell growth and phenotype were identical in all 3 groups. Injection of HF CDCs led to the greatest therapeutic benefit in mice, with the highest left ventricular ejection fraction, thickest infarct wall, most viable tissue, and least scar 3 weeks after treatment. In vitro assays revealed that HF CDCs secreted higher levels of stromal cell-derived factor 1 (SDF-1), which may contribute to the cells’ augmented resistance to oxidative stress, enhanced angiogenesis, and improved myocyte survival. Histological analysis indicated that HF CDCs engrafted better, recruited more endogenous stem cells, and induced greater angiogenesis and cardiomyocyte cell-cycle re-entry. CDC-secreted SDF-1 levels correlated with decreases in scar mass over time in CADUCEUS patients treated with autologous CDCs. Conclusions CDCs from advanced HF patients exhibit augmented potency in ameliorating ventricular dysfunction post-MI, possibly through SDF-1–mediated mechanisms. PMID:24511463

  2. Distribution of chloride permeabilities in normal human red cells.

    PubMed Central

    Raftos, J E; Bookchin, R M; Lew, V L

    1996-01-01

    1. The rate of dehydration of K+ permeabilized red cells is influenced by their Cl- permeability (PCl). In instances of pathological K+ permeabilization, cell-to-cell differences in PCl may determine which red cells dehydrate most. The present study was designed to investigate whether PCl differed significantly among red cells from a single blood sample. 2. Previously available methods measure only the mean PCl of red cell populations. We describe a 'profile migration' method in which dilute red cell suspensions in low-K+ media were permeabilized to K+ with a high concentration of valinomycin, rendering PCl the main rate-limiting factor for cell dehydration. As the cells dehydrated, samples were processed to obtain full haemolysis curves at precise times. Variations in PCl among cells would have appeared as progressive changes in the profile of their haemolysis curves, as the curves migrated towards lower tonicities. 3. Red cells from five normal volunteers showed no change in profile of the migrating haemolysis curves, suggesting that their PCl distributions were fairly uniform. Quantitative analysis demonstrated that intercell variation in PCl was less than 7.5%. 4. Results obtained with this technique were analysed using the Lew-Bookchin red cell model. The calculated PCl was within the normal range described in earlier studies. PMID:8815210

  3. Human papilloma virus DNAs immortalize normal human mammary epithelial cells and reduce their growth factor requirements

    SciTech Connect

    Band, V.; Zajchowski, D.; Kulesa, V.; Sager, R. )

    1990-01-01

    Human papilloma virus (HPV) types 16 and 18 are most commonly associated with cervical carcinoma in patients and induce immortalization of human keratinocytes in culture. HPV has not been associated with breast cancer. This report describes the immortalization of normal human mammary epithelial cells (76N) by plasmid pHPV18 or pHPV16, each containing the linearized viral genome. Transfectants were grown continuously for more than 60 passages, whereas 76N cells senesce after 18-20 passages. The transfectants also differ from 76N cells in cloning in a completely defined medium called D2 and growing a minimally supplemented defined medium (D3) containing epidermal growth factor. All transfectant tested contain integrated HPV DNA, express HPV RNA, and produce HPV E7 protein. HPV transfectants do not form tumors in a nude mouse assay. It is concluded that products of the HPV genome induce immortalization of human breast epithelial cells and reduce their growth factor requirements. This result raises the possibility that HPV might be involved in breast cancer. Furthermore, other tissue-specific primary epithelial cells that are presently difficult to grown and investigate may also be immortalized by HPV.

  4. CARDIOTHORACIC RATIO AND VERTEBRAL HEART SCALE IN CLINICALLY NORMAL BLACK-RUMPED AGOUTIS (DASYPROCTA PRYMNOLOPHA, WAGLER 1831).

    PubMed

    de Moura, Charlys Rhands Coelho; das Neves Diniz, Anaemilia; da Silva Moura, Laecio; das Chagas Araújo Sousa, Francisco; Baltazar, Pollyana Irene; Freire, Larisse Danielle; Guerra, Porfírio Candanedo; de Sousa, João Macedo; Giglio, Robson Fortes; Pessoa, Gerson Tavares; de Sá, Renan Paraguassu; Alves, Flávio Ribeiro

    2015-06-01

    Wild rodents, such as the lowland paca (Cuniculus paca), capybara (Hydrochoerus hydrochaeris), rock cavy (Kerodon rupestris), guinea pig (Cavia aperea), and black-rumped agouti (Dasyprocta prymnolopha) are intensely hunted throughout Amazonia and at the semiarid regions of northeastern Brazil. To contribute to the preservation of these species, more information about their anatomy, physiology and pathophysiology is needed. The aim of this study was to standardize the vertebral heart scale (VHS) and cardiothoracic ratio (CTR) in clinically normal black-rumped agouti, as well as to compare the results of these two methods, which are commonly used to evaluate the cardiac silhouette in domestic animals. Twelve healthy black-rumped agoutis, divided into two groups (six males and six females), obtained from the Nucleus for Wild Animal Studies and Conservation at the Federal University of Piauí, were radiographed in right and left lateral and dorsoventral projections. The values of the VHS were 8.00±0.31v (the number of thoracic vertebral length spanned by each dimension, starting at T4) for males and 8.11±0.41v for females, and there was no statistical difference between the decubitus (right and left) or between males and females (P>0.05). The CTR mean values obtained were 0.51±0.03 for males, and 0.52±0.02 for females, and there was no statistical difference between the genders (P>0.05). However, there was positive correlation between VHS and CTR (r=0.77 right decubitus and r=0.82 left decubitus). The thoracic and heart diameter had mean values of 6.72±0.61 and 3.48±0.30 cm (males), and for the females, it was 6.61±0.51 and 3.5±0.30 cm, respectively, and there was statistical difference between the genders. The results demonstrated high correlation between the VHS and CTR producing similar results, indicating similar clinical precision for assessing the size of the cardiac silhouette in the black-rumped agoutis. PMID:26056885

  5. A normal cumulative conception rate after human pituitary gonadotropin.

    PubMed

    Healy, D L; Kovacs, G T; Pepperell, R J; Burger, H G

    1980-10-01

    Forty consecutive women were treated with human pituitary gonadotropin to induce ovulation. Thirty-seven patients (93%) ovulated and thirty (75%) conceived on at least one occasion. The cumulative conception rate for the series equaled that of the general population. Women with a past history of anorexia nervosa had the shortest average time to pregnancy. Of patients who did not conceive, four represented failures of patient selection in that they withdrew from treatment for a variety of psychiatric and social reasons, and six represented failures of treatment, not becoming pregnant despite the induction of ovulation. It is concluded that realistic goals for a contemporary human gonadotropin program include induction of ovulation in all patients and a cumulative conception rate equal to that of the general community. PMID:6252067

  6. Specific binding of beta-endorphin to normal human erythrocytes

    SciTech Connect

    Chenet, B.; Hollis, V. Jr.; Kang, Y.; Simpkins, C.

    1986-03-05

    Beta-endorphin (BE) exhibits peripheral functions which may not be mediated by interactions with receptors in the brain. Recent studies have demonstrated binding of BE to both opioid and non-opioid receptors on lymphocytes and monocytes. Abood has reported specific binding of /sup 3/H-dihydromorphine in erythrocytes. Using 5 x 10/sup -11/M /sup 125/I-beta-endorphin and 10/sup -5/M unlabeled BE, they have detected 50% specific binding to human erythrocytes. This finding is supported by results from immunoelectron microscopy using rabbit anti-BE antibody and biotinylated secondary antibody with avidin-biotin complexes horseradish peroxidase. Binding is clearly observed and is confined to only one side of the cells. Conclusions: (1) BE binding to human erythrocytes was demonstrated by radioreceptor assay and immunoelectron microscopy, and (2) BE binding sites exist on only one side of the cells.

  7. Neurophysiological model of the normal and abnormal human pupil

    NASA Technical Reports Server (NTRS)

    Krenz, W.; Robin, M.; Barez, S.; Stark, L.

    1985-01-01

    Anatomical, experimental, and computer simulation studies were used to determine the structure of the neurophysiological model of the pupil size control system. The computer simulation of this model demonstrates the role played by each of the elements in the neurological pathways influencing the size of the pupil. Simulations of the effect of drugs and common abnormalities in the system help to illustrate the workings of the pathways and processes involved. The simulation program allows the user to select pupil condition (normal or an abnormality), specific site along the neurological pathway (retina, hypothalamus, etc.) drug class input (barbiturate, narcotic, etc.), stimulus/response mode, display mode, stimulus type and input waveform, stimulus or background intensity and frequency, the input and output conditions, and the response at the neuroanatomical site. The model can be used as a teaching aid or as a tool for testing hypotheses regarding the system.

  8. Lactotransferrin immunocytochemistry in Alzheimer and normal human brain.

    PubMed Central

    Kawamata, T.; Tooyama, I.; Yamada, T.; Walker, D. G.; McGeer, P. L.

    1993-01-01

    Lactotransferrin (LF) expression was investigated immunocytochemically in postmortem brain tissues of normal controls and patients with Alzheimer's disease (AD). The antibody to LF stained some neurons weakly in young adult brains, but it stained many neurons as well as the glia of all types in elderly brains. LF expression was greatly up-regulated in both neurons and glia in affected AD tissue. It was very strongly associated with such extracellular pathological entities as diffuse and consolidated amyloid deposits and extracellular neurofibrillary tangles. In addition, it was identified in a minority of intracellular neurofibrillary tangles, neuropil threads, and degenerative neurites. LF is an iron scavenger and a complement inhibitor. Up-regulation may be a defense mechanism in AD-affected brain tissue. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:8494052

  9. Mineral density volume gradients in normal and diseased human tissues

    SciTech Connect

    Djomehri, Sabra I.; Candell, Susan; Case, Thomas; Browning, Alyssa; Marshall, Grayson W.; Yun, Wenbing; Lau, S. H.; Webb, Samuel; Ho, Sunita P.; Aikawa, Elena

    2015-04-09

    Clinical computed tomography provides a single mineral density (MD) value for heterogeneous calcified tissues containing early and late stage pathologic formations. The novel aspect of this study is that, it extends current quantitative methods of mapping mineral density gradients to three dimensions, discretizes early and late mineralized stages, identifies elemental distribution in discretized volumes, and correlates measured MD with respective calcium (Ca) to phosphorus (P) and Ca to zinc (Zn) elemental ratios. To accomplish this, MD variations identified using polychromatic radiation from a high resolution micro-computed tomography (micro-CT) benchtop unit were correlated with elemental mapping obtained from a microprobe X-ray fluorescence (XRF) using synchrotron monochromatic radiation. Digital segmentation of tomograms from normal and diseased tissues (N=5 per group; 40-60 year old males) contained significant mineral density variations (enamel: 2820-3095mg/cc, bone: 570-1415mg/cc, cementum: 1240-1340mg/cc, dentin: 1480-1590mg/cc, cementum affected by periodontitis: 1100-1220mg/cc, hypomineralized carious dentin: 345-1450mg/cc, hypermineralized carious dentin: 1815-2740mg/cc, and dental calculus: 1290-1770mg/cc). A plausible linear correlation between segmented MD volumes and elemental ratios within these volumes was established, and Ca/P ratios for dentin (1.49), hypomineralized dentin (0.32-0.46), cementum (1.51), and bone (1.68) were observed. Furthermore, varying Ca/Zn ratios were distinguished in adapted compared to normal tissues, such as in bone (855-2765) and in cementum (595-990), highlighting Zn as an influential element in prompting observed adaptive properties. Hence, results provide insights on mineral density gradients with elemental concentrations and elemental footprints that in turn could aid in elucidating mechanistic processes for pathologic formations.

  10. Mineral density volume gradients in normal and diseased human tissues

    DOE PAGESBeta

    Djomehri, Sabra I.; Candell, Susan; Case, Thomas; Browning, Alyssa; Marshall, Grayson W.; Yun, Wenbing; Lau, S. H.; Webb, Samuel; Ho, Sunita P.; Aikawa, Elena

    2015-04-09

    Clinical computed tomography provides a single mineral density (MD) value for heterogeneous calcified tissues containing early and late stage pathologic formations. The novel aspect of this study is that, it extends current quantitative methods of mapping mineral density gradients to three dimensions, discretizes early and late mineralized stages, identifies elemental distribution in discretized volumes, and correlates measured MD with respective calcium (Ca) to phosphorus (P) and Ca to zinc (Zn) elemental ratios. To accomplish this, MD variations identified using polychromatic radiation from a high resolution micro-computed tomography (micro-CT) benchtop unit were correlated with elemental mapping obtained from a microprobe X-raymore » fluorescence (XRF) using synchrotron monochromatic radiation. Digital segmentation of tomograms from normal and diseased tissues (N=5 per group; 40-60 year old males) contained significant mineral density variations (enamel: 2820-3095mg/cc, bone: 570-1415mg/cc, cementum: 1240-1340mg/cc, dentin: 1480-1590mg/cc, cementum affected by periodontitis: 1100-1220mg/cc, hypomineralized carious dentin: 345-1450mg/cc, hypermineralized carious dentin: 1815-2740mg/cc, and dental calculus: 1290-1770mg/cc). A plausible linear correlation between segmented MD volumes and elemental ratios within these volumes was established, and Ca/P ratios for dentin (1.49), hypomineralized dentin (0.32-0.46), cementum (1.51), and bone (1.68) were observed. Furthermore, varying Ca/Zn ratios were distinguished in adapted compared to normal tissues, such as in bone (855-2765) and in cementum (595-990), highlighting Zn as an influential element in prompting observed adaptive properties. Hence, results provide insights on mineral density gradients with elemental concentrations and elemental footprints that in turn could aid in elucidating mechanistic processes for pathologic formations.« less

  11. Mineral Density Volume Gradients in Normal and Diseased Human Tissues

    PubMed Central

    Djomehri, Sabra I.; Candell, Susan; Case, Thomas; Browning, Alyssa; Marshall, Grayson W.; Yun, Wenbing; Lau, S. H.; Webb, Samuel; Ho, Sunita P.

    2015-01-01

    Clinical computed tomography provides a single mineral density (MD) value for heterogeneous calcified tissues containing early and late stage pathologic formations. The novel aspect of this study is that, it extends current quantitative methods of mapping mineral density gradients to three dimensions, discretizes early and late mineralized stages, identifies elemental distribution in discretized volumes, and correlates measured MD with respective calcium (Ca) to phosphorus (P) and Ca to zinc (Zn) elemental ratios. To accomplish this, MD variations identified using polychromatic radiation from a high resolution micro-computed tomography (micro-CT) benchtop unit were correlated with elemental mapping obtained from a microprobe X-ray fluorescence (XRF) using synchrotron monochromatic radiation. Digital segmentation of tomograms from normal and diseased tissues (N=5 per group; 40-60 year old males) contained significant mineral density variations (enamel: 2820-3095mg/cc, bone: 570-1415mg/cc, cementum: 1240-1340mg/cc, dentin: 1480-1590mg/cc, cementum affected by periodontitis: 1100-1220mg/cc, hypomineralized carious dentin: 345-1450mg/cc, hypermineralized carious dentin: 1815-2740mg/cc, and dental calculus: 1290-1770mg/cc). A plausible linear correlation between segmented MD volumes and elemental ratios within these volumes was established, and Ca/P ratios for dentin (1.49), hypomineralized dentin (0.32-0.46), cementum (1.51), and bone (1.68) were observed. Furthermore, varying Ca/Zn ratios were distinguished in adapted compared to normal tissues, such as in bone (855-2765) and in cementum (595-990), highlighting Zn as an influential element in prompting observed adaptive properties. Hence, results provide insights on mineral density gradients with elemental concentrations and elemental footprints that in turn could aid in elucidating mechanistic processes for pathologic formations. PMID:25856386

  12. Mineral density volume gradients in normal and diseased human tissues.

    PubMed

    Djomehri, Sabra I; Candell, Susan; Case, Thomas; Browning, Alyssa; Marshall, Grayson W; Yun, Wenbing; Lau, S H; Webb, Samuel; Ho, Sunita P

    2015-01-01

    Clinical computed tomography provides a single mineral density (MD) value for heterogeneous calcified tissues containing early and late stage pathologic formations. The novel aspect of this study is that, it extends current quantitative methods of mapping mineral density gradients to three dimensions, discretizes early and late mineralized stages, identifies elemental distribution in discretized volumes, and correlates measured MD with respective calcium (Ca) to phosphorus (P) and Ca to zinc (Zn) elemental ratios. To accomplish this, MD variations identified using polychromatic radiation from a high resolution micro-computed tomography (micro-CT) benchtop unit were correlated with elemental mapping obtained from a microprobe X-ray fluorescence (XRF) using synchrotron monochromatic radiation. Digital segmentation of tomograms from normal and diseased tissues (N=5 per group; 40-60 year old males) contained significant mineral density variations (enamel: 2820-3095 mg/cc, bone: 570-1415 mg/cc, cementum: 1240-1340 mg/cc, dentin: 1480-1590 mg/cc, cementum affected by periodontitis: 1100-1220 mg/cc, hypomineralized carious dentin: 345-1450 mg/cc, hypermineralized carious dentin: 1815-2740 mg/cc, and dental calculus: 1290-1770 mg/cc). A plausible linear correlation between segmented MD volumes and elemental ratios within these volumes was established, and Ca/P ratios for dentin (1.49), hypomineralized dentin (0.32-0.46), cementum (1.51), and bone (1.68) were observed. Furthermore, varying Ca/Zn ratios were distinguished in adapted compared to normal tissues, such as in bone (855-2765) and in cementum (595-990), highlighting Zn as an influential element in prompting observed adaptive properties. Hence, results provide insights on mineral density gradients with elemental concentrations and elemental footprints that in turn could aid in elucidating mechanistic processes for pathologic formations. PMID:25856386

  13. Inter-ocular contrast normalization in human visual cortex

    PubMed Central

    Moradi, Farshad; Heeger, David J.

    2009-01-01

    The brain combines visual information from the two eyes and forms a coherent percept, even when inputs to the eyes are different. However, it is not clear how inputs from the two eyes are combined in visual cortex. We measured fMRI responses to single gratings presented monocularly, or pairs of gratings presented monocularly or dichoptically with several combinations of contrasts. Gratings had either the same orientation or orthogonal orientations (i.e., plaids). Observers performed a demanding task at fixation to minimize top-down modulation of the stimulus-evoked responses. Dichoptic presentation of compatible gratings (same orientation) evoked greater activity than monocular presentation of a single grating only when contrast was low (<10%). A model that assumes linear summation of activity from each eye failed to explain binocular responses at 10% contrast or higher. However, a model with binocular contrast normalization, such that activity from each eye reduced the gain for the other eye, fitted the results very well. Dichoptic presentation of orthogonal gratings evoked greater activity than monocular presentation of a single grating for all contrasts. However, activity evoked by dichoptic plaids was equal to that evoked by monocular plaids. Introducing an onset asynchrony (stimulating one eye 500 ms before the other, which under attentive vision results in flash suppression) had no impact on the results; the responses to dichoptic and monocular plaids were again equal. We conclude that when attention is diverted, inter-ocular suppression in V1 can be explained by a normalization model in which the mutual suppression between orthogonal orientations does not depend on the eye of origin, nor on the onset times, and cross-orientation suppression is weaker than inter-ocular (same orientation) suppression. PMID:19757952

  14. A new dynamic 3D virtual methodology for teaching the mechanics of atrial septation as seen in the human heart.

    PubMed

    Schleich, Jean-Marc; Dillenseger, Jean-Louis; Houyel, Lucile; Almange, Claude; Anderson, Robert H

    2009-01-01

    Learning embryology remains difficult, since it requires understanding of many complex phenomena. The temporal evolution of developmental events has classically been illustrated using cartoons, which create difficulty in linking spatial and temporal aspects, such correlation being the keystone of descriptive embryology. We synthesized the bibliographic data from recent studies of atrial septal development. On the basis of this synthesis, consensus on the stages of atrial septation as seen in the human heart has been reached by a group of experts in cardiac embryology and pediatric cardiology. This has permitted the preparation of three-dimensional (3D) computer graphic objects for the anatomical components involved in the different stages of normal human atrial septation. We have provided a virtual guide to the process of normal atrial septation, the animation providing an appreciation of the temporal and morphologic events necessary to separate the systemic and pulmonary venous returns. We have shown that our animations of normal human atrial septation increase significantly the teaching of the complex developmental processes involved, and provide a new dynamic for the process of learning. PMID:19363807

  15. Quantitation of small intestinal permeability during normal human drug absorption

    PubMed Central

    2013-01-01

    Background Understanding the quantitative relationship between a drug’s physical chemical properties and its rate of intestinal absorption (QSAR) is critical for selecting candidate drugs. Because of limited experimental human small intestinal permeability data, approximate surrogates such as the fraction absorbed or Caco-2 permeability are used, both of which have limitations. Methods Given the blood concentration following an oral and intravenous dose, the time course of intestinal absorption in humans was determined by deconvolution and related to the intestinal permeability by the use of a new 3 parameter model function (“Averaged Model” (AM)). The theoretical validity of this AM model was evaluated by comparing it to the standard diffusion-convection model (DC). This analysis was applied to 90 drugs using previously published data. Only drugs that were administered in oral solution form to fasting subjects were considered so that the rate of gastric emptying was approximately known. All the calculations are carried out using the freely available routine PKQuest Java (http://www.pkquest.com) which has an easy to use, simple interface. Results Theoretically, the AM permeability provides an accurate estimate of the intestinal DC permeability for solutes whose absorption ranges from 1% to 99%. The experimental human AM permeabilities determined by deconvolution are similar to those determined by direct human jejunal perfusion. The small intestinal pH varies with position and the results are interpreted in terms of the pH dependent octanol partition. The permeability versus partition relations are presented separately for the uncharged, basic, acidic and charged solutes. The small uncharged solutes caffeine, acetaminophen and antipyrine have very high permeabilities (about 20 x 10-4 cm/sec) corresponding to an unstirred layer of only 45 μm. The weak acid aspirin also has a large AM permeability despite its low octanol partition at pH 7.4, suggesting

  16. A Bayesian classification of heart rate variability data

    NASA Astrophysics Data System (ADS)

    Muirhead, R. J.; Puff, R. D.

    2004-05-01

    We propose a simple Bayesian method for the classification of time series signals originating from mutually exclusive sources. In particular, the method is used to address the question of whether a 24-h recording of human heart rate data is produced by a normally functioning heart or by one exhibiting symptoms of congestive heart failure. Our method correctly classifies 18 of 18 normal heart data sets, and 38 of 44 congestive failure data sets.

  17. Mapping the Pairwise Choices Leading from Pluripotency to Human Bone, Heart, and Other Mesoderm Cell Types.

    PubMed

    Loh, Kyle M; Chen, Angela; Koh, Pang Wei; Deng, Tianda Z; Sinha, Rahul; Tsai, Jonathan M; Barkal, Amira A; Shen, Kimberle Y; Jain, Rajan; Morganti, Rachel M; Shyh-Chang, Ng; Fernhoff, Nathaniel B; George, Benson M; Wernig, Gerlinde; Salomon, Rachel E A; Chen, Zhenghao; Vogel, Hannes; Epstein, Jonathan A; Kundaje, Anshul; Talbot, William S; Beachy, Philip A; Ang, Lay Teng; Weissman, Irving L

    2016-07-14

    Stem-cell differentiation to desired lineages requires navigating alternating developmental paths that often lead to unwanted cell types. Hence, comprehensive developmental roadmaps are crucial to channel stem-cell differentiation toward desired fates. To this end, here, we map bifurcating lineage choices leading from pluripotency to 12 human mesodermal lineages, including bone, muscle, and heart. We defined the extrinsic signals controlling each binary lineage decision, enabling us to logically block differentiation toward unwanted fates and rapidly steer pluripotent stem cells toward 80%-99% pure human mesodermal lineages at most branchpoints. This strategy enabled the generation of human bone and heart progenitors that could engraft in respective in vivo models. Mapping stepwise chromatin and single-cell gene expression changes in mesoderm development uncovered somite segmentation, a previously unobservable human embryonic event transiently marked by HOPX expression. Collectively, this roadmap enables navigation of mesodermal development to produce transplantable human tissue progenitors and uncover developmental processes. VIDEO ABSTRACT. PMID:27419872

  18. Heart rate variability in exercising humans: effect of water immersion.

    PubMed

    Perini, R; Milesi, S; Biancardi, L; Pendergast, D R; Veicsteinas, A

    1998-03-01

    Power spectrum analysis of heart-rate variability was made in seven men [mean age 22 (SEM 1) years] in head-out water immersion (W) and in air (A, control) at rest and during steady-state cycling to maximal intensity (maximum oxygen uptake, VO2max). At rest W resulted in a trebled increase in the total power (P < 0.05), coupled with minimal changes in the power (as a percentage of the total) of the high frequency peak (HF, centred at 0.26 Hz; 18% vs 28%) and of the low frequency peak (LF, 0.1 Hz; 24% vs 32%). A third peak at about 0.03 Hz (very low frequency, VLF) represented the remaining power both in W and A. These changes as a whole indicated that immersion caused a vagal dominance in cardiac autonomic interaction, due to the central pooling of blood and/or the pressure of water on the trunk. Exercise caused a decrease in the total power in W and A. The LF% did not change up to about 50% V02max, thereafter decreasing towards nil in both conditions. The HF% decreased in similar ways in W and A to about half at 55%-60% VO2max and then increased to reach 1.5 times the resting values at VO2max. The central frequency of HF increased linearly with oxygen uptake, showing a tendency to be higher in W than in A at medium to high intensities. The VLF% remained unchanged. The lack of differences in the LF peak between W and A during exercise would suggest that blood distribution had no effect on the readjustments in control mechanisms of arterial pressure. On the other hand, the findings of similar HF powers and the very similar values for ventilation in W and A confirmed the direct effect of the respiratory activity in heart rate modulation during exercise. PMID:9562361

  19. Active proliferation of Rous sarcoma virus-infected, but not normal, chicken heart mesenchymal cells in culture medium of physiological composition.

    PubMed Central

    Balk, S D

    1980-01-01

    Normal as well as Rous sarcoma virus-infected chicken pectoral and chicken embryo fibroblasts proliferate actively in a plasma containing medium of physiological ion concentrations (Ca2+, 1.2 mM; Mg2+, 0.7 mM). Reduction of medium calcium and magnesium concentrations is necessary to achieve selective quiescence of normal fibroblasts in these cell systems. By contrast, normal chicken heart mesenchymal cells proliferate only sluggishly (one doubling or less during a 6-day period) in a plasma containing medium of physiologic ion concentrations, whereas Rous sarcoma virus-infected heart mesenchymal cells proliferate actively (more than four doublings during an initial 2-day phase of exponential growth). The chicken heart mesenchymal cell system therefore has great potential for studies of the mechanism that initiates cell replication and of the failure in cellular regulatory processes that is responsible for the autonomous initiation of replication of neoplastic cells. From comparison of the chicken heart mesenchymal cell system to dialyzed plasma-based systems in which 3T3 cells tend to proliferative quiescence, it is argued that this proliferative quiescence of 3T3 cells is a result of cell starvation and is not physiologically meaningful. Images PMID:6256750

  20. Cardiac myosin-Th17 responses promote heart failure in human myocarditis

    PubMed Central

    Myers, Jennifer M.; Cooper, Leslie T.; Kem, David C.; Stavrakis, Stavros; Kosanke, Stanley D.; Shevach, Ethan M.; Fairweather, DeLisa; Stoner, Julie A.; Cox, Carol J.; Cunningham, Madeleine W.

    2016-01-01

    In human myocarditis and its sequela dilated cardiomyopathy (DCM), the mechanisms and immune phenotype governing disease and subsequent heart failure are not known. Here, we identified a Th17 cell immunophenotype of human myocarditis/DCM with elevated CD4+IL17+ T cells and Th17-promoting cytokines IL-6, TGF-β, and IL-23 as well as GM-CSF–secreting CD4+ T cells. The Th17 phenotype was linked with the effects of cardiac myosin on CD14+ monocytes, TLR2, and heart failure. Persistent heart failure was associated with high percentages of IL-17–producing T cells and IL-17–promoting cytokines, and the myocarditis/DCM phenotype included significantly low percentages of FOXP3+ Tregs, which may contribute to disease severity. We demonstrate a potentially novel mechanism in human myocarditis/DCM in which TLR2 peptide ligands from human cardiac myosin stimulated exaggerated Th17-related cytokines including TGF-β, IL-6, and IL-23 from myocarditic CD14+ monocytes in vitro, and an anti-TLR2 antibody abrogated the cytokine response. Our translational study explains how an immune phenotype may be initiated by cardiac myosin TLR ligand stimulation of monocytes to generate Th17-promoting cytokines and development of pathogenic Th17 cells in human myocarditis and heart failure, and provides a rationale for targeting IL-17A as a therapeutic option. PMID:27366791

  1. Sleep Stage Dependence of Invariance Characteristics in Fluctuations of Healthy Human Heart Rate

    NASA Astrophysics Data System (ADS)

    Togo, Fumiharu; Kiyono, Ken; Struzik, Zbigniew R.; Yamamoto, Yoshiharu

    2005-08-01

    The outstanding feature of healthy human heart rate is the robust scale invariance in the non-Gaussian probability density function (PDF), which is preserved not only in a quiescent condition, but also in a dynamic state during waking hours [K. Kiyono et al. Phys. Rev. Lett. 93 (2004)]. Together with 1/f like scaling, this characteristic is a strong indication of far-from-equilibrium, critical-like dynamics of heart rate regulation. Our results suggest that healthy human heart rate departs from a critical state-like operation during sleeping hours, at a rate which is heterogeneous with respect to sleep stages annotated according to traditional techniques. We study specific contributions of sleep stages to the relative departure from criticality through the analysis of sleep stage dependence of the root mean square of multiscale local energy and the multiscale PDF. There is a possibility that the involvement of cortical activity may be important for a critical state-like operation.

  2. Functional mapping of sequence learning in normal humans.

    PubMed

    Grafton, S T; Hazeltine, E; Ivry, R

    1995-01-01

    The brain localization of motor sequence learning was studied in normal subjects with positron emission tomography. Subjects performed a serial reaction time (SRT) task by responding to a series of stimuli that occurred at four different spatial positions. The stimulus locations were either determined randomly or according to a 6-element sequence that cycled continuously. The SRT task was performed under two conditions. With attentional interference from a secondary counting task there was no development of awareness of the sequence. Learning-related increases of cerebral blood flow were located in contralateral motor effector areas including motor cortex, supplementary motor area, and putamen, consistent with the hypothesis that nondeclarative motor learning occurs in cerebral areas that control limb movements. Additional cortical sites included the rostral prefrontal cortex and parietal cortex. The SRT learning task was then repeated with a new sequence and no attentional interference. In this condition, 7 of 12 subjects developed awareness of the sequence. Learning-related blood flow increases were present in right dorsolateral prefrontal cortex, right premotor cortex, right ventral putamen, and biparieto-occipital cortex. The right dorsolateral prefrontal and parietal areas have been previously implicated in spatial working memory and right prefrontal cortex is also implicated in retrieval tasks of verbal episodic memory. Awareness of the sequence at the end of learning was associated with greater activity in bilateral parietal, superior temporal, and right premotor cortex. Motor learning can take place in different cerebral areas, contingent on the attentional demands of the task. PMID:23961907

  3. Expression of K+ channels in normal and cancerous human breast.

    PubMed

    Brevet, Marie; Ahidouch, Ahmed; Sevestre, Henri; Merviel, Philippe; El Hiani, Yassine; Robbe, Micheline; Ouadid-Ahidouch, Halima

    2008-08-01

    Potassium (K+) channels contribute to the regulation of cell proliferation and apoptosis and are also involved in tumor generation and malignant growth. Using immunohistochemical analysis, we investigated the expression of four K+ channels GIRK1 (G-Protein Inwardly Rectifying Potassium Channel 1), Ca2+-activated K channel (K Ca 1.1), voltage activated K+ channels (KV 1.1 and KV 1.3) and of the anti-apoptotic protein Bcl2 in normal and cancerous breast tissues and compared their expression with clinicopathological data. GIRK1 was overexpressed in carcinomatous tissues. In contrast, K V 1.1 and K V 1.3 were less expressed in cancerous tissue. The expression of Bcl-2 was similar in both tissues. As to the clinicopathological data, a correlation between K Ca 1.1 channel and estrogen receptor (ER) expression was observed. GIRK1 was overexpressed in breast carcinoma suggesting its involvement in proliferation and oncogenesis and its possible use as a putative pharmaceutical target. The correlation between K Ca 1.1 channel and ER suggests the involvement of this channel in proliferation. The loss of expression of the two channels K V 1.1 and K V 1.3 may correspond to their role in apoptosis. PMID:18498071

  4. Modulation of Coronary Heart Disease Risk by Insulin Resistance in Subjects With Normal Glucose Tolerance or Prediabetes

    PubMed Central

    Ariel, Danit; Reaven, Gerald

    2014-01-01

    Aims/hypothesis This study is based on the hypothesis that: 1)coronary heart disease (CHD) risk is accentuated in the insulin resistant subset of persons with normal glucose tolerance (NGT) or prediabetes (PreDM); 2)the prevalence of insulin resistance, and associated abnormalities, is greater in subjects with PreDM; and 3)insulin resistance is the major contributor to increased CHD risk in these individuals. Methods A 75 g oral glucose challenge was used to classify volunteers as having NGT or PreDM. Steady-state plasma glucose (SSPG) concentrations during the insulin suppression test subdivided both groups into insulin sensitive (IS=SSPG <8.4 mmol/L) or resistant (IR=SSPG ≥8.4 mmol/L). Measurements were made of demographic characteristics, blood pressure, and lipid and lipoprotein concentrations, and comparisons made between the subgroups. Results Subjects with PreDM (n=127) were somewhat older, more likely to be non-Hispanic men, with increased adiposity than those with NGT (n=315). In addition, they had higher FPG concentrations, were insulin resistant (SSPG concentration; 11.4 vs. 7.2 mmol/L), with higher blood pressures, and a significantly more adverse CHD risk lipid profile (p<0.001). Twice as many subjects with PreDM were IR (72% vs. 35 %), and the CHD risk profile was significantly worse in the IR subgroups in those with either NGT or PreDM. Conclusions/interpretation CHD risk profile is significantly more adverse in subjects with PreDM as compared to individuals with NGT. However, glucose tolerance status is not the only determinant of CHD risk in nondiabetic individuals, and differences in degree of insulin resistance significantly modulate CHD risk in subjects with NGT or PreDM. PMID:25358836

  5. C-Type Natriuretic Peptide Improves Left Ventricular Functional Performance at Rest and Restores Normal Exercise Responses after Heart Failure.

    PubMed

    Li, Tiankai; Cheng, Heng-Jie; Ohte, Nobuyuki; Hasegawa, Hiroshi; Morimoto, Atsushi; Herrington, David M; Little, William C; Li, Weimin; Cheng, Che Ping

    2016-06-01

    In heart failure (HF), the impaired left ventricular (LV) arterial coupling and diastolic dysfunction present at rest are exacerbated during exercise. C-type natriuretic peptide (CNP) is elevated in HF; however, its functional effects are unclear. We tested the hypotheses that CNP with vasodilating, natriuretic, and positive inotropic and lusitropic actions may prevent this abnormal exercise response after HF. We determined the effects of CNP (2 μg/kg plus 0.4 μg/kg per minute, i.v., 20 minutes) on plasma levels of cGMP before and after HF and assessed LV dynamics during exercise in 10 chronically instrumented dogs with pacing-induced HF. Compared with the levels before HF, CNP infusion caused significantly greater increases in cGMP levels after HF. After HF, at rest, CNP administration significantly reduced LV end-systolic pressure (PES), arterial elastance (EA), and end-diastolic pressure. The peak mitral flow (dV/dtmax) was also increased owing to decreased minimum LVP (LVPmin) and the time constant of LV relaxation (τ) (P < 0.05). In addition, LV contractility (EES) was increased. The LV-arterial coupling (EES/EA) was improved. The beneficial effects persisted during exercise. Compared with exercise in HF preparation, treatment with CNP caused significantly less important increases in PES but significantly decreased τ (34.2 vs. 42.6 ms) and minimum left ventricular pressure with further augmented dV/dtmax Both EES, EES/EA (0.87 vs. 0.32) were increased. LV mechanical efficiency improved from 0.38 to 0.57 (P < 0.05). After HF, exogenous CNP produces arterial vasodilatation and augments LV contraction, relaxation, diastolic filling, and LV arterial coupling, thus improving LV performance at rest and restoring normal exercise responses after HF. PMID:27026682

  6. Levodopa: faster and better word learning in normal humans.

    PubMed

    Knecht, Stefan; Breitenstein, Caterina; Bushuven, Stefan; Wailke, Stefanie; Kamping, Sandra; Flöel, Agnes; Zwitserlood, Pienie; Ringelstein, E Bernd

    2004-07-01

    Dopamine is a potent modulator of learning and has been implicated in the encoding of stimulus salience. Repetition, however, as required for the acquisition and reacquisition of sensorimotor or cognitive skills (e.g., in aphasia therapy), decreases salience. We here tested whether increasing brain levels of dopamine during repetitive training improves learning success. Forty healthy humans took 100mg of the dopamine precursor levodopa or placebo daily for 5 days in a randomized double-blind and parallel-group design. Ninety minutes later on each day, subjects were trained on an artificial vocabulary using a high-frequency repetitive approach. Levodopa significantly enhanced the speed, overall success, and long-term retention of novel word learning in a dose-dependent manner. These findings indicate new ways to potentiate learning in a variety of domains if conventional training alone fails. PMID:15236398

  7. Nonlinear time series analysis of normal and pathological human walking

    NASA Astrophysics Data System (ADS)

    Dingwell, Jonathan B.; Cusumano, Joseph P.

    2000-12-01

    Characterizing locomotor dynamics is essential for understanding the neuromuscular control of locomotion. In particular, quantifying dynamic stability during walking is important for assessing people who have a greater risk of falling. However, traditional biomechanical methods of defining stability have not quantified the resistance of the neuromuscular system to perturbations, suggesting that more precise definitions are required. For the present study, average maximum finite-time Lyapunov exponents were estimated to quantify the local dynamic stability of human walking kinematics. Local scaling exponents, defined as the local slopes of the correlation sum curves, were also calculated to quantify the local scaling structure of each embedded time series. Comparisons were made between overground and motorized treadmill walking in young healthy subjects and between diabetic neuropathic (NP) patients and healthy controls (CO) during overground walking. A modification of the method of surrogate data was developed to examine the stochastic nature of the fluctuations overlying the nominally periodic patterns in these data sets. Results demonstrated that having subjects walk on a motorized treadmill artificially stabilized their natural locomotor kinematics by small but statistically significant amounts. Furthermore, a paradox previously present in the biomechanical literature that resulted from mistakenly equating variability with dynamic stability was resolved. By slowing their self-selected walking speeds, NP patients adopted more locally stable gait patterns, even though they simultaneously exhibited greater kinematic variability than CO subjects. Additionally, the loss of peripheral sensation in NP patients was associated with statistically significant differences in the local scaling structure of their walking kinematics at those length scales where it was anticipated that sensory feedback would play the greatest role. Lastly, stride-to-stride fluctuations in the

  8. Heart rate responses provide an objective evaluation of human disturbance stimuli in breeding birds

    PubMed Central

    Ellenberg, Ursula; Mattern, Thomas; Seddon, Philip J.

    2013-01-01

    Intuition is a poor guide for evaluating the effects of human disturbance on wildlife. Using the endangered Yellow-eyed penguin, Megadyptes antipodes, as an example, we show that heart rate responses provide an objective tool to evaluate human disturbance stimuli and encourage the wider use of this simple and low-impact approach. Yellow-eyed penguins are a flagship species for New Zealand's wildlife tourism; however, unregulated visitor access has recently been associated with reduced breeding success and lower first year survival. We measured heart rate responses of Yellow-eyed penguins via artificial eggs to evaluate a range of human stimuli regularly occurring at their breeding sites. We found the duration of a stimulus to be the most important factor, with elevated heart rate being sustained while a person remained within sight. Human activity was the next important component; a simulated wildlife photographer, crawling slowly around during his stay, elicited a significantly higher heart rate response than an entirely motionless human spending the same time at the same distance. Stimuli we subjectively might perceive as low impact, such as the careful approach of a ‘wildlife photographer’, resulted in a stronger response than a routine nest-check that involved lifting a bird up to view nest contents. A single, slow-moving human spending 20 min within 2 m from the nest may provoke a response comparable to that of 10 min handling a bird for logger deployment. To reduce cumulative impact of disturbance, any human presence in the proximity of Yellow-eyed penguins needs to be kept at a minimum. Our results highlight the need for objective quantification of the effects of human disturbance in order to provide a sound basis for guidelines to manage human activity around breeding birds. PMID:27293597

  9. Heart rate responses provide an objective evaluation of human disturbance stimuli in breeding birds.

    PubMed

    Ellenberg, Ursula; Mattern, Thomas; Seddon, Philip J

    2013-01-01

    Intuition is a poor guide for evaluating the effects of human disturbance on wildlife. Using the endangered Yellow-eyed penguin, Megadyptes antipodes, as an example, we show that heart rate responses provide an objective tool to evaluate human disturbance stimuli and encourage the wider use of this simple and low-impact approach. Yellow-eyed penguins are a flagship species for New Zealand's wildlife tourism; however, unregulated visitor access has recently been associated with reduced breeding success and lower first year survival. We measured heart rate responses of Yellow-eyed penguins via artificial eggs to evaluate a range of human stimuli regularly occurring at their breeding sites. We found the duration of a stimulus to be the most important factor, with elevated heart rate being sustained while a person remained within sight. Human activity was the next important component; a simulated wildlife photographer, crawling slowly around during his stay, elicited a significantly higher heart rate response than an entirely motionless human spending the same time at the same distance. Stimuli we subjectively might perceive as low impact, such as the careful approach of a 'wildlife photographer', resulted in a stronger response than a routine nest-check that involved lifting a bird up to view nest contents. A single, slow-moving human spending 20 min within 2 m from the nest may provoke a response comparable to that of 10 min handling a bird for logger deployment. To reduce cumulative impact of disturbance, any human presence in the proximity of Yellow-eyed penguins needs to be kept at a minimum. Our results highlight the need for objective quantification of the effects of human disturbance in order to provide a sound basis for guidelines to manage human activity around breeding birds. PMID:27293597

  10. Proteomic analysis of a podocyte vesicle-enriched fraction from human normal and pathological urine samples.

    PubMed

    Lescuyer, Pierre; Pernin, Agnès; Hainard, Alexandre; Bigeire, Caty; Burgess, Jennifer A; Zimmermann-Ivol, Catherine; Sanchez, Jean-Charles; Schifferli, Jürg A; Hochstrasser, Denis F; Moll, Solange

    2008-07-01

    Podocytes (glomerular visceral epithelial cells) release vesicles into urine. Podocyte vesicle-enriched fractions from normal and pathological human urine samples were prepared for proteomic analysis. An immunoadsorption method was applied and enrichment of podocyte vesicles was assessed. We identified 76 unique proteins. One protein, serum paraoxonase/arylesterase 1 (PON-1), was newly identified in normal human urine sample. We confirmed this result and showed PON-1 expression in normal human kidney. These results demonstrated the potential for using the urine samples enriched in podocyte vesicles as a starting material in studies aimed at discovery of biomarkers for diseases. PMID:21136901

  11. Immunohistochemical studies of neurochemical markers in normal human buccal mucosa.

    PubMed

    Hilliges, M; Hellman, M; Ahlström, U; Johansson, O

    1994-04-01

    The content of various substances, such as regulatory peptides, hormones and structural proteins, was investigated in normal buccal mucosa using indirect immunofluorescence. Thin nerve fibres, which from a morphological point of view were most probably sensory, showed immunoreactivity for substance P (SP), calcitonin gene-related peptide (CGRP), neuropeptide K (NPK) and neurokinin A (NKA). Also galanin (GAL), gamma-melanocyte stimulating hormone (gamma-MSH) and somatostatin (SOM) stained thin fibres were found in the propria, which were, however, few in number and the gamma-MSH staining was weak. CGRP, vasoactive intestinal polypeptide (VIP), peptide histidine isoleucine amide (PHI) and neuropeptide Y (NPY) immunoreactive nerve fibres were observed in close connection to blood vessels. SOM positive cells with processes were found, mostly scattered, in the connective tissue. A population of cells within the epithelium also showed somatostatin immunoreactivity. Protein S-100 (S-100) stained distinct populations of cells at two separate locations. In the propria, cells with one or two slender processes were seen, being mostly single but sometimes forming groups. In the epithelium, dendritic cells with many processes with or without 'spines' were observed, mainly located to the basal layer of the lamina epithelialis. Single nerve fibres and nerve bundles were also stained. Neurofilament (NF) positive fibres, singly and in bundles, as well as endorgan-like structures were seen. Neuron-specific enolase (NSE) and protein gene product 9.5 (PGP 9.5) both stained the same structures, namely single fibres, nerve bundles, nerves surrounding vessels and innervating muscles and glands (if present in the section), as well as Merkel cells. Also with these two markers endorgan-like structures were seen. No clear innervation of the epithelium could be observed with the markers used. No methionine-enkephalin (ENK) or synaptophysin (SYN) immunoreactive material was found. PMID:7523335

  12. mga genosensor for early detection of human rheumatic heart disease.

    PubMed

    Singh, Swati; Kaushal, Ankur; Khare, Shashi; Kumar, Ashok

    2014-05-01

    The 5' amino-labeled DNA probe complementary to mga gene of Streptococcus pyogenes was immobilized on carboxylated multiwall carbon nanotubes electrode and hybridized with 0.1-100 ng/6 μl single-stranded genomic DNA (ssG-DNA) of S. pyogenes from throat swab of suspected rheumatic heart disease (RHD) patients. Electrochemical response was measured by cyclic voltammetry (CV), differential pulse voltammetry (DPV), and electrochemical impedance (EI). The sensitivity of the sensor was 106.03 (μA/cm(2))/ng and limit of detection (LOD) was found 0.014 ng/6 μl with regression coefficient (R(2)) of 0.921 using DPV. The genosensor was characterized by FTIR and SEM, and electrode was found stable for 6 months on storage at 4 °C with 5-6 % loss in initial DPV current. mga genosensor is the first report on RHD sensor which can save life of several suspected patients by early diagnosis in 30 min. PMID:24639090

  13. Visualization of human heart conduction system by means of fluorescence spectroscopy

    NASA Astrophysics Data System (ADS)

    Venius, Jonas; Bagdonas, Saulius; Žurauskas, Edvardas; Rotomskis, Ricardas

    2011-10-01

    The conduction system of the heart is a specific muscular tissue, where a heartbeat signal originates and initiates the depolarization of the ventricles. The muscular origin makes it complicated to distinguish the conduction system from the surrounding tissues. A surgical intervention can lead to the accidental harm of the conduction system, which may eventually result in a dangerous obstruction of the heart functionality. Therefore, there is an immense necessity for developing a helpful method to visualize the conduction system during the operation time. The specimens for the spectroscopic studies were taken from nine diverse human hearts. The localization of distinct types of the tissue was preliminary marked by the pathologist and approved histologically after the spectral measurements. Variations in intensity, as well as in shape, were detected in autofluorescence spectra of different heart tissues. The most distinct differences were observed between the heart conduction system and the surrounding tissues under 330 and 380 nm excitation. The spectral region around 460 nm appeared to be the most suitable for an unambiguous differentiation of the human conduction system avoiding the absorption peak of blood. The visualization method, based on the intensity ratios calculated for two excitation wavelengths, was also demonstrated.

  14. Dysfunction of the β2-spectrin-based pathway in human heart failure.

    PubMed

    Smith, Sakima A; Hughes, Langston D; Kline, Crystal F; Kempton, Amber N; Dorn, Lisa E; Curran, Jerry; Makara, Michael; Webb, Tyler R; Wright, Patrick; Voigt, Niels; Binkley, Philip F; Janssen, Paul M L; Kilic, Ahmet; Carnes, Cynthia A; Dobrev, Dobromir; Rasband, Matthew N; Hund, Thomas J; Mohler, Peter J

    2016-06-01

    β2-Spectrin is critical for integrating membrane and cytoskeletal domains in excitable and nonexcitable cells. The role of β2-spectrin for vertebrate function is illustrated by dysfunction of β2-spectrin-based pathways in disease. Recently, defects in β2-spectrin association with protein partner ankyrin-B were identified in congenital forms of human arrhythmia. However, the role of β2-spectrin in common forms of acquired heart failure and arrhythmia is unknown. We report that β2-spectrin protein levels are significantly altered in human cardiovascular disease as well as in large and small animal cardiovascular disease models. Specifically, β2-spectrin levels were decreased in atrial samples of patients with atrial fibrillation compared with tissue from patients in sinus rhythm. Furthermore, compared with left ventricular samples from nonfailing hearts, β2-spectrin levels were significantly decreased in left ventricle of ischemic- and nonischemic heart failure patients. Left ventricle samples of canine and murine heart failure models confirm reduced β2-spectrin protein levels. Mechanistically, we identify that β2-spectrin levels are tightly regulated by posttranslational mechanisms, namely Ca(2+)- and calpain-dependent proteases. Furthermore, consistent with this data, we observed Ca(2+)- and calpain-dependent loss of β2-spectrin downstream effector proteins, including ankyrin-B in heart. In summary, our findings illustrate that β2-spectrin and downstream molecules are regulated in multiple forms of cardiovascular disease via Ca(2+)- and calpain-dependent proteolysis. PMID:27106045

  15. Heterogeneity of serum low density lipoproteins in normal human subjects

    SciTech Connect

    Shen, M.M.S.; Krauss, R.M.; Lindgren, F.T.; Forte, T.M.

    1981-01-01

    Equilibrium density gradient ultracentrifugation of serum low density lipoprotein (LDL) from twelve healthy human subjects was used to separate six subfractions with mean dinsity ranging from 1.0268 to 1.0597 g/ml. Mean corrected peak flotation rate (S/sup o//sub f/) measured by analytic ultracentrifugation, and mean particle diameter determined by negative staining electron microscopy, both declined significantly with increasing density of the subfractions. Major differences in chemical composition of the subfractions were noted, including a singnificantly lower triglyceride content and higher ratio of cholesteryl ester to triglyceride in the middle fractions compared with those of highest and lowest density. Concentration of fraction 2 correlated positively with HDL (P < 0.01) and negatively with VLDL (P < 0.001); concentration of fraction 4 correlated negatively with HDL (P < 0.05) and positively with VLDL (P < 0.001) and IDL (P < 0.01). LDL may thus include subspecies of differing structure and composition which might also have different metabolic and atherogenic roles.

  16. Reduced response to IKr blockade and altered hERG1a/1b stoichiometry in human heart failure.

    PubMed

    Holzem, Katherine M; Gomez, Juan F; Glukhov, Alexey V; Madden, Eli J; Koppel, Aaron C; Ewald, Gregory A; Trenor, Beatriz; Efimov, Igor R

    2016-07-01

    Heart failure (HF) claims 250,000 lives per year in the US, and nearly half of these deaths are sudden and presumably due to ventricular tachyarrhythmias. QT interval and action potential (AP) prolongation are hallmark proarrhythmic changes in the failing myocardium, which potentially result from alterations in repolarizing potassium currents. Thus, we aimed to examine whether decreased expression of the rapid delayed rectifier potassium current, IKr, contributes to repolarization abnormalities in human HF. To map functional IKr expression across the left ventricle (LV), we optically imaged coronary-perfused LV free wall from donor and end-stage failing human hearts. The LV wedge preparation was used to examine transmural AP durations at 80% repolarization (APD80), and treatment with the IKr-blocking drug, E-4031, was utilized to interrogate functional expression. We assessed the percent change in APD80 post-IKr blockade relative to baseline APD80 (∆APD80) and found that ∆APD80s are reduced in failing versus donor hearts in each transmural region, with 0.35-, 0.43-, and 0.41-fold reductions in endo-, mid-, and epicardium, respectively (p=0.008, 0.037, and 0.022). We then assessed hERG1 isoform gene and protein expression levels using qPCR and Western blot. While we did not observe differences in hERG1a or hERG1b gene expression between donor and failing hearts, we found a shift in the hERG1a:hERG1b isoform stoichiometry at the protein level. Computer simulations were then conducted to assess IKr block under E-4031 influence in failing and nonfailing conditions. Our results confirmed the experimental observations and E-4031-induced relative APD80 prolongation was greater in normal conditions than in failing conditions, provided that the cellular model of HF included a significant downregulation of IKr. In human HF, the response to IKr blockade is reduced, suggesting decreased functional IKr expression. This attenuated functional response is associated with

  17. Mapping of corticotropic cells in the normal human pituitary.

    PubMed

    Trouillas, J; Guigard, M P; Fonlupt, P; Souchier, C; Girod, C

    1996-05-01

    We accomplished the first mapping of corticotropic cells in the whole human adult pituitary. Corticotropic cells were identified by immunocytochemistry (ICC) and quantified by image analysis on 12 pituitaries obtained from people who had died suddenly. An overall view of each pituitary was given by 15-21 sections (mean 18 sections) at 300-micron intervals on six slides. Each section was systematically treated by indirect immunoperoxidase using an anti-ACTH[17-39] polyclonal antiserum. All the measures were done with a x 6.3 objective lens, each field (0. 5 mm2) being considered as the unit area. The mean pituitary density (surface of labeled cells/total surface) of corticotropic cells (9.5 +/- 3.0% per 0. 5 mm2) is significantly higher in men (11.5 +/- 5.1%) than in women (7.0 +/- 1.3%). This difference is due to an inverse relationship between the corticotropic cell density and the weight of the pituitary, which is higher in women than in men. The mean diameter of corticotropic cells is 14.9 micron and their total number per pituitary is approximately 10(7) cells. We confirmed that the spatial distribution of corticotropic cells is nonuniform: they are mainly distributed in the anteromedian part of the anterior lobe. In addition, our results demonstrated that the inferior part of the pituitary contained three times more corticotropic cells than the superior part (mean density 18.0% vs 6.0%) and the anterior part twice as many as the posterior part (mean density 12.3% vs 6.8%). On the horizontal plane, the pituitary was divided into eight zones, in which the mean of area was 2.5-21.0%. The maximal cell density may reach 40-60%. The use of this map should help the pathologist to recognize if there is corticotropic hyperplasia in a small pituitary fragment surgically removed from a patient with Cushing's disease. On the basis of this study, we put forward some criteria for diagnosing corticotropic hyperplasia. PMID:8627004

  18. INTERACTION BETWEEN NORMAL HUMAN DIPLOID CELLS AND CHEMICAL CARCINOGENS/MUTAGENS 'IN VITRO'

    EPA Science Inventory

    The objectives of the present studies were to develop sensitive, reproducible methods for detecting mutations in normal human fibroblast cells and to demonstrate dose-related mutagenesis by known and potential carcinogens. The authors have modified conventional test procedures fo...

  19. Wnt inhibitory factor (WIF)-1 promotes melanogenesis in normal human melanocytes.

    PubMed

    Park, Tae Jun; Kim, Misun; Kim, Hyeran; Park, Sun Yi; Park, Kyoung-Chan; Ortonne, Jean-Paul; Kang, Hee Young

    2014-01-01

    Wnt signaling plays a role in the differentiation as well as the development of melanocytes. Using a microarray analysis, hyperpigmentary skin of melasma expressed high levels of Wnt inhibitory factor-1 (WIF-1) compared with perilesional normal skin. In this study, the expression and functional roles of WIF-1 on melanocytes were investigated. WIF-1 was expressed both in the melanocytes of normal human skin and in cultured melanocytes. The upregulation of WIF-1 on cultured normal human melanocytes significantly induced expressions of MITF and tyrosinase, which were associated with increased melanin content and tyrosinase activity. Consistent with the stimulatory effect of WIF-1, WIF-1 siRNA reduced melanogenesis in the cells. Moreover, WIF-1 increases pigmentation in melanocytes co-cultured with WIF-1-overexpressed fibroblasts and of organ-cultured human skin. These findings suggest that melanocytes express WIF-1 constitutively in vivo and in vitro and that WIF-1 promotes melanogenesis in normal human melanocytes. PMID:24131586

  20. A New MRI-Based Model of Heart Function with Coupled Hemodynamics and Application to Normal and Diseased Canine Left Ventricles

    PubMed Central

    Choi, Young Joon; Constantino, Jason; Vedula, Vijay; Trayanova, Natalia; Mittal, Rajat

    2015-01-01

    A methodology for the simulation of heart function that combines an MRI-based model of cardiac electromechanics (CE) with a Navier–Stokes-based hemodynamics model is presented. The CE model consists of two coupled components that simulate the electrical and the mechanical functions of the heart. Accurate representations of ventricular geometry and fiber orientations are constructed from the structural magnetic resonance and the diffusion tensor MR images, respectively. The deformation of the ventricle obtained from the electromechanical model serves as input to the hemodynamics model in this one-way coupled approach via imposed kinematic wall velocity boundary conditions and at the same time, governs the blood flow into and out of the ventricular volume. The time-dependent endocardial surfaces are registered using a diffeomorphic mapping algorithm, while the intraventricular blood flow patterns are simulated using a sharp-interface immersed boundary method-based flow solver. The utility of the combined heart-function model is demonstrated by comparing the hemodynamic characteristics of a normal canine heart beating in sinus rhythm against that of the dyssynchronously beating failing heart. We also discuss the potential of coupled CE and hemodynamics models for various clinical applications. PMID:26442254

  1. Common multifractality in the heart rate variability and brain activity of healthy humans

    NASA Astrophysics Data System (ADS)

    Lin, D. C.; Sharif, A.

    2010-06-01

    The influence from the central nervous system on the human multifractal heart rate variability (HRV) is examined under the autonomic nervous system perturbation induced by the head-up-tilt body maneuver. We conducted the multifractal factorization analysis to factor out the common multifractal factor in the joint fluctuation of the beat-to-beat heart rate and electroencephalography data. Evidence of a central link in the multifractal HRV was found, where the transition towards increased (decreased) HRV multifractal complexity is associated with a stronger (weaker) multifractal correlation between the central and autonomic nervous systems.

  2. Off-the-shelf human decellularized tissue-engineered heart valves in a non-human primate model.

    PubMed

    Weber, Benedikt; Dijkman, Petra E; Scherman, Jacques; Sanders, Bart; Emmert, Maximilian Y; Grünenfelder, Jürg; Verbeek, Renier; Bracher, Mona; Black, Melanie; Franz, Thomas; Kortsmit, Jeroen; Modregger, Peter; Peter, Silvia; Stampanoni, Marco; Robert, Jérôme; Kehl, Debora; van Doeselaar, Marina; Schweiger, Martin; Brokopp, Chad E; Wälchli, Thomas; Falk, Volkmar; Zilla, Peter; Driessen-Mol, Anita; Baaijens, Frank P T; Hoerstrup, Simon P

    2013-10-01

    Heart valve tissue engineering based on decellularized xenogenic or allogenic starter matrices has shown promising first clinical results. However, the availability of healthy homologous donor valves is limited and xenogenic materials are associated with infectious and immunologic risks. To address such limitations, biodegradable synthetic materials have been successfully used for the creation of living autologous tissue-engineered heart valves (TEHVs) in vitro. Since these classical tissue engineering technologies necessitate substantial infrastructure and logistics, we recently introduced decellularized TEHVs (dTEHVs), based on biodegradable synthetic materials and vascular-derived cells, and successfully created a potential off-the-shelf starter matrix for guided tissue regeneration. Here, we investigate the host repopulation capacity of such dTEHVs in a non-human primate model with up to 8 weeks follow-up. After minimally invasive delivery into the orthotopic pulmonary position, dTEHVs revealed mobile and thin leaflets after 8 weeks of follow-up. Furthermore, mild-moderate valvular insufficiency and relative leaflet shortening were detected. However, in comparison to the decellularized human native heart valve control - representing currently used homografts - dTEHVs showed remarkable rapid cellular repopulation. Given this substantial in situ remodeling capacity, these results suggest that human cell-derived bioengineered decellularized materials represent a promising and clinically relevant starter matrix for heart valve tissue engineering. These biomaterials may ultimately overcome the limitations of currently used valve replacements by providing homologous, non-immunogenic, off-the-shelf replacement constructs. PMID:23810254

  3. Personal Exposure to Submicrometer Particles and Heart Rate Variability in Human Subjects

    PubMed Central

    Chan, Chang-Chuan; Chuang, Kai-Jen; Shiao, Guang-Ming; Lin, Lian-Yu

    2004-01-01

    We conducted a study on two panels of human subjects—9 young adults and 10 elderly patients with lung function impairments—to evaluate whether submicrometer particulate air pollution was associated with heart rate variability (HRV). We measured these subjects’ electrocardiography and personal exposure to number concentrations of submicrometer particles with a size range of 0.02–1 μm (NC0.02–1) continuously during daytime periods. We used linear mixed-effects models to estimate the relationship between NC0.02–1 and log10-transformed HRV, including standard deviation of all normal-to-normal intervals (SDNN), square root of the mean of the sum of the squares of differences between adjacent NN intervals (r-MSSD), low frequency (LF, 0.04–0.15 Hz), and high frequency (HF, 0.15–0.40 Hz), adjusted for age, sex, body mass index, tobacco exposure, and temperature. For the young panel, a 10,000-particle/cm3 increase in NC0.02–1 with 1–4 hr moving average exposure was associated with 0.68–1.35% decreases in SDNN, 1.85–2.58% decreases in r-MSSD, 1.32–1.61% decreases in LF, and 1.57–2.60% decreases in HF. For the elderly panel, a 10,000-particle/cm3 increase in NC0.02–1 with 1–3 hr moving average exposure was associated with 1.72–3.00% decreases in SDNN, 2.72–4.65% decreases in r-MSSD, 3.34–5.04% decreases in LF, and 3.61–5.61% decreases in HF. In conclusion, exposure to NC0.02–1 was associated with decreases in both time-domain and frequency-domain HRV indices in human subjects. PMID:15238278

  4. X Chromosome Abnormalities and Cognitive Development: Implications for Understanding Normal Human Development.

    ERIC Educational Resources Information Center

    Walzer, Stanley

    1985-01-01

    Argues that knowledge from studies of individuals with sex chromosome abnormalities can further understanding of aspects of normal human development. Studies of XO girls, XXY boys, XXX girls, and males with a fragile X chromosome are summarized to demonstrate how results contribute to knowledge about normal cognitive development and about…

  5. The Physiological Effect of Human Grooming on the Heart Rate and the Heart Rate Variability of Laboratory Non-Human Primates: A Pilot Study in Male Rhesus Monkeys

    PubMed Central

    Grandi, Laura Clara; Ishida, Hiroaki

    2015-01-01

    Grooming is a widespread, essential, and complex behavior with social and affiliative valence in the non-human primate world. Its impact at the autonomous nervous system level has been studied during allogrooming among monkeys living in a semi-naturalistic environment. For the first time, we investigated the effect of human grooming to monkey in a typical experimental situation inside laboratory. We analyzed the autonomic response of male monkeys groomed by a familiar human (experimenter), in terms of the heart rate (HR) and heart rate variability (HRV) at different body parts. We considered the HRV in both the time (SDNN, RMSSD, and RMSSD/SDNN) and the frequency domain (HF, LF, and LF/HF). For this purpose, we recorded the electrocardiogram of two male rhesus monkeys seated in a primate chair while the experimenter groomed their mouth, chest, or arm. We demonstrated that (1) the grooming carried out by a familiar human determined a decrement of the HR and an increment of the HRV; (2) there was a difference in relation to the groomed body part. In particular, during grooming the mouth the HRV was higher than during grooming the arm and the chest. Taken together, the results represent the first evidence that grooming carried out by a familiar human on experimental monkeys has the comparable positive physiological effect of allogrooming between conspecifics. Moreover, since the results underlined the positive modulation of both HR and HRV, the present study could be a starting point to improve the well-being of non-human primates in experimental condition by means of grooming by a familiar person. PMID:26664977

  6. Decellularized GGTA1-KO pig heart valves do not bind preformed human xenoantibodies.

    PubMed

    Ramm, Robert; Niemann, Heiner; Petersen, Björn; Haverich, Axel; Hilfiker, Andres

    2016-07-01

    Pre-clinical and clinical data have unequivocally demonstrated the usefulness of decellularized heart valve (HV) matrices implanted for HV replacement therapy. However, human donor valves applicable for decellularization are in short supply, which prompts the search for suitable alternatives, such as porcine grafts. Since decellularization might be insufficient to remove all xenoantigens, we analysed the interaction of human preformed antibodies with decellularized porcine HV in vitro to assess potential immune reactions upon implantation. Detergent-decellularized pulmonary HV from German Landrace wild-type (wt) or α1,3-galactosyltransferase knockout (GGTA1-KO) pigs were investigated by inhibition ELISA and GSL I-B4 staining to localize and quantify matrix-bound αGal epitopes, which represent the most prominent xenoantigen. Additionally, preformed human xenoantibodies were affinity purified by perfusing porcine kidneys. Binding of purified human antibodies to decellularized HV was investigated by inhibition ELISA. Furthermore, binding of human plasma proteins to decellularized matrices was determined by western blot. Decellularized human pulmonary artery served as controls. Decellularization of wt HV led to a reduction of αGal epitopes by 70 %. Residual epitopes were associated with the subendothelial extracellular matrix. As expected, no αGal epitopes were found on decellularized GGTA1-KO matrix. The strongest binding of preformed human anti-pig antibodies was found on wt matrices, whereas GGTA1-KO matrices bound similar or even fewer xenoantibodies than human controls. These results demonstrate the suitability of GGTA1-KO pigs as donors for decellularized heart valves for human patients. Besides the presence of αGal antibodies on decellularized heart valves, no further preformed xenoantibodies against porcine matrix were detected in tested human sera. PMID:27154491

  7. "The state of the heart": Recent advances in engineering human cardiac tissue from pluripotent stem cells.

    PubMed

    Sirabella, Dario; Cimetta, Elisa; Vunjak-Novakovic, Gordana

    2015-08-01

    The pressing need for effective cell therapy for the heart has led to the investigation of suitable cell sources for tissue replacement. In recent years, human pluripotent stem cell research expanded tremendously, in particular since the derivation of human-induced pluripotent stem cells. In parallel, bioengineering technologies have led to novel approaches for in vitro cell culture. The combination of these two fields holds potential for in vitro generation of high-fidelity heart tissue, both for basic research and for therapeutic applications. However, this new multidisciplinary science is still at an early stage. Many questions need to be answered and improvements need to be made before clinical applications become a reality. Here we discuss the current status of human stem cell differentiation into cardiomyocytes and the combined use of bioengineering approaches for cardiac tissue formation and maturation in developmental studies, disease modeling, drug testing, and regenerative medicine. PMID:26069271

  8. Guided Tissue Regeneration in Heart Valve Replacement: From Preclinical Research to First-in-Human Trials

    PubMed Central

    Iop, L.; Gerosa, G.

    2015-01-01

    Heart valve tissue-guided regeneration aims to offer a functional and viable alternative to current prosthetic replacements. Not requiring previous cell seeding and conditioning in bioreactors, such exceptional tissue engineering approach is a very fascinating translational regenerative strategy. After in vivo implantation, decellularized heart valve scaffolds drive their same repopulation by recipient's cells for a prospective autologous-like tissue reconstruction, remodeling, and adaptation to the somatic growth of the patient. With such a viability, tissue-guided regenerated conduits can be delivered as off-the-shelf biodevices and possess all the potentialities for a long-lasting resolution of the dramatic inconvenience of heart valve diseases, both in children and in the elderly. A review on preclinical and clinical investigations of this therapeutic concept is provided with evaluation of the issues still to be well deliberated for an effective and safe in-human application. PMID:26495295

  9. Computerised 3-D anatomical modelling using plastinates: an example utilising the human heart.

    PubMed

    Tunali, S; Kawamoto, K; Farrell, M L; Labrash, S; Tamura, K; Lozanoff, S

    2011-08-01

    Computerised modelling methods have become highly useful for generating electronic representations of anatomical structures. These methods rely on crosssectional tissue slices in databases such as the Visible Human Male and Female, the Visible Korean Human, and the Visible Chinese Human. However, these databases are time consuming to generate and require labour-intensive manual digitisation while the number of specimens is very limited. Plastinated anatomical material could provide a possible alternative to data collection, requiring less time to prepare and enabling the use of virtually any anatomical or pathological structure routinely obtained in a gross anatomy laboratory. The purpose of this study was to establish an approach utilising plastinated anatomical material, specifically human hearts, for the purpose computerised 3-D modelling. Human hearts were collected following gross anatomical dissection and subjected to routine plastination procedures including dehydration (-25(o)C), defatting, forced impregnation, and curing at room temperature. A graphics pipeline was established comprising data collection with a hand-held scanner, 3-D modelling, model polishing, file conversion, and final rendering. Representative models were viewed and qualitatively assessed for accuracy and detail. The results showed that the heart model provided detailed surface information necessary for gross anatomical instructional purposes. Rendering tools facilitated optional model manipulation for further structural clarification if selected by the user. The use of plastinated material for generating 3-D computerised models has distinct advantages compared to cross-sectional tissue images. PMID:21866531

  10. Molecular Portrait of the Normal Human Breast Tissue and Its Influence on Breast Carcinogenesis.

    PubMed

    Margan, Madalin Marius; Jitariu, Andreea Adriana; Cimpean, Anca Maria; Nica, Cristian; Raica, Marius

    2016-06-01

    Normal human breast tissue consists of epithelial and nonepithelial cells with different molecular profiles and differentiation grades. This molecular heterogeneity is known to yield abnormal clones that may contribute to the development of breast carcinomas. Stem cells that are found in developing and mature breast tissue are either positive or negative for cytokeratin 19 depending on their subtype. These cells are able to generate carcinogenesis along with mature cells. However, scientific data remains controversial regarding the monoclonal or polyclonal origin of breast carcinomas. The majority of breast carcinomas originate from epithelial cells that normally express BRCA1. The consecutive loss of the BRCA1 gene leads to various abnormalities in epithelial cells. Normal breast epithelial cells also express hypoxia inducible factor (HIF) 1α and HIF-2α that are associated with a high metastatic rate and a poor prognosis for malignant lesions. The nuclear expression of estrogen receptor (ER) and progesterone receptor (PR) in normal human breast tissue is maintained in malignant tissue as well. Several controversies regarding the ability of ER and PR status to predict breast cancer outcome remain. Both ER and PR act as modulators of cell activity in normal human breast tissue. Ki-67 positivity is strongly correlated with tumor grade although its specific role in applied therapy requires further studies. Human epidermal growth factor receptor 2 (HER2) oncoprotein is less expressed in normal human breast specimens but is highly expressed in certain malignant lesions of the breast. Unlike HER2, epidermal growth factor receptor expression is similar in both normal and malignant tissues. Molecular heterogeneity is not only found in breast carcinomas but also in normal breast tissue. Therefore, the molecular mapping of normal human breast tissue might represent a key research area to fully elucidate the mechanisms of breast carcinogenesis. PMID:27382385

  11. Molecular Portrait of the Normal Human Breast Tissue and Its Influence on Breast Carcinogenesis

    PubMed Central

    Margan, Madalin Marius; Jitariu, Andreea Adriana; Nica, Cristian; Raica, Marius

    2016-01-01

    Normal human breast tissue consists of epithelial and nonepithelial cells with different molecular profiles and differentiation grades. This molecular heterogeneity is known to yield abnormal clones that may contribute to the development of breast carcinomas. Stem cells that are found in developing and mature breast tissue are either positive or negative for cytokeratin 19 depending on their subtype. These cells are able to generate carcinogenesis along with mature cells. However, scientific data remains controversial regarding the monoclonal or polyclonal origin of breast carcinomas. The majority of breast carcinomas originate from epithelial cells that normally express BRCA1. The consecutive loss of the BRCA1 gene leads to various abnormalities in epithelial cells. Normal breast epithelial cells also express hypoxia inducible factor (HIF) 1α and HIF-2α that are associated with a high metastatic rate and a poor prognosis for malignant lesions. The nuclear expression of estrogen receptor (ER) and progesterone receptor (PR) in normal human breast tissue is maintained in malignant tissue as well. Several controversies regarding the ability of ER and PR status to predict breast cancer outcome remain. Both ER and PR act as modulators of cell activity in normal human breast tissue. Ki-67 positivity is strongly correlated with tumor grade although its specific role in applied therapy requires further studies. Human epidermal growth factor receptor 2 (HER2) oncoprotein is less expressed in normal human breast specimens but is highly expressed in certain malignant lesions of the breast. Unlike HER2, epidermal growth factor receptor expression is similar in both normal and malignant tissues. Molecular heterogeneity is not only found in breast carcinomas but also in normal breast tissue. Therefore, the molecular mapping of normal human breast tissue might represent a key research area to fully elucidate the mechanisms of breast carcinogenesis. PMID:27382385

  12. From The Cover: Reconstruction of functionally normal and malignant human breast tissues in mice

    NASA Astrophysics Data System (ADS)

    Kuperwasser, Charlotte; Chavarria, Tony; Wu, Min; Magrane, Greg; Gray, Joe W.; Carey, Loucinda; Richardson, Andrea; Weinberg, Robert A.

    2004-04-01

    The study of normal breast epithelial morphogenesis and carcinogenesis in vivo has largely used rodent models. Efforts at studying mammary morphogenesis and cancer with xenotransplanted human epithelial cells have failed to recapitulate the full extent of development seen in the human breast. We have developed an orthotopic xenograft model in which both the stromal and epithelial components of the reconstructed mammary gland are of human origin. Genetic modification of human stromal cells before the implantation of ostensibly normal human mammary epithelial cells resulted in the outgrowth of benign and malignant lesions. This experimental model allows for studies of human epithelial morphogenesis and differentiation in vivo and underscores the critical role of heterotypic interactions in human breast development and carcinogenesis.

  13. Can stem cells really regenerate the human heart? Use your noggin, dickkopf! Lessons from developmental biology.

    PubMed

    Sommer, Paula

    2013-06-01

    The human heart is the first organ to develop and its development is fairly well characterised. In theory, the heart has the capacity to regenerate, as its cardiomyocytes may be capable of cell division and the adult heart contains a cardiac stem cell niche, presumably capable of differentiating into cardiomyocytes and other cardiac-associated cell types. However, as with most other organs, these mechanisms are not activated upon serious injury. Several experimental options to induce regeneration of the damaged heart tissue are available: activate the endogenous cardiomyocytes to divide, coax the endogenous population of stem cells to divide and differentiate, or add exogenous cell-based therapy to replace the lost cardiac tissue. This review is a summary of the recent research into all these avenues, discussing the reasons for the limited successes of clinical trials using stem cells after cardiac injury and explaining new advances in basic science. It concludes with a reiteration that chances of successful regeneration would be improved by understanding and implementing the basics of heart development and stem cell biology. PMID:24217168

  14. Stretchable, multiplexed pH sensors with demonstrations on rabbit and human hearts undergoing ischemia.

    PubMed

    Chung, Hyun-Joong; Sulkin, Matthew S; Kim, Jong-Seon; Goudeseune, Camille; Chao, Hsin-Yun; Song, Joseph W; Yang, Sang Yoon; Hsu, Yung-Yu; Ghaffari, Roozbeh; Efimov, Igor R; Rogers, John A

    2014-01-01

    Stable pH is an established biomarker of health, relevant to all tissues of the body, including the heart. Clinical monitoring of pH in a practical manner, with high spatiotemporal resolution, is particularly difficult in organs such as the heart due to its soft mechanics, curvilinear geometry, heterogeneous surfaces, and continuous, complex rhythmic motion. The results presented here illustrate that advanced strategies in materials assembly and electrochemical growth can yield interconnected arrays of miniaturized IrOx pH sensors encapsulated in thin, low-modulus elastomers to yield conformal monitoring systems capable of noninvasive measurements on the surface of the beating heart. A thirty channel custom data acquisition system enables spatiotemporal pH mapping with a single potentiostat. In vitro testing reveals super-Nernstian sensitivity with excellent uniformity (69.9 ± 2.2 mV/pH), linear response to temperature (-1.6 mV °C(-1) ), and minimal influence of extracellular ions (<3.5 mV). Device examples include sensor arrays on balloon catheters and on skin-like stretchable membranes. Real-time measurement of pH on the surfaces of explanted rabbit hearts and a donated human heart during protocols of ischemia-reperfusion illustrate some of the capabilities. Envisioned applications range from devices for biological research, to surgical tools and long-term implants. PMID:23868871

  15. Muscle protein analysis. II. Two-dimensional electrophoresis of normal and diseased human skeletal muscle

    SciTech Connect

    Giometti, C.S.; Barany, M.; Danon, M.J.; Anderson, N.G.

    1980-07-01

    High-resolution two-dimensional electrophoresis was used to analyze the major proteins of normal and pathological human-muscle samples. The normal human-muscle pattern contains four myosin light chains: three that co-migrate with the myosin light chains from rabbit fast muscle (extensor digitorum longus), and one that co-migrates with the light chain 2 from rabbit slow muscle (soleus). Of seven Duchenne muscular dystrophy samples, four yielded patterns with decreased amounts of actin and myosin relative to normal muscle, while three samples gave patterns comparable to that for normal muscle. Six samples from patients with myotonic dystrophy also gave normal patterns. In nemaline rod myopathy, in contrast, the pattern was deficient in two of the fast-type myosin light chains.

  16. A Novel Generalized Normal Distribution for Human Longevity and other Negatively Skewed Data

    PubMed Central

    Robertson, Henry T.; Allison, David B.

    2012-01-01

    Negatively skewed data arise occasionally in statistical practice; perhaps the most familiar example is the distribution of human longevity. Although other generalizations of the normal distribution exist, we demonstrate a new alternative that apparently fits human longevity data better. We propose an alternative approach of a normal distribution whose scale parameter is conditioned on attained age. This approach is consistent with previous findings that longevity conditioned on survival to the modal age behaves like a normal distribution. We derive such a distribution and demonstrate its accuracy in modeling human longevity data from life tables. The new distribution is characterized by 1. An intuitively straightforward genesis; 2. Closed forms for the pdf, cdf, mode, quantile, and hazard functions; and 3. Accessibility to non-statisticians, based on its close relationship to the normal distribution. PMID:22623974

  17. [Induction of myocardial neoangiogenesis by human growth factors. A new therapeutic approach in coronary heart disease].

    PubMed

    Stegmann, T J; Hoppert, T; Schneider, A; Gemeinhardt, S; Köcher, M; Ibing, R; Strupp, G

    2000-09-01

    Currently available approaches for treating human coronary heart disease aim to relieve symptoms and the risk of myocardial infarction either by reducing myocardial oxygen demand, preventing further disease progression, restoring coronary blood flow pharmacologically or mechanically, or bypassing the stenotic lesions and obstructed coronary artery segments. Gene therapy, especially using angiogenic growth factors, has emerged recently as a potential new treatment for cardiovascular disease. Following extensive experimental research on angiogenic growth factors, the first clinical studies on patients with coronary heart disease and peripheral vascular lesions have been performed. The polypeptides fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) appear to be particularly effective in initiating neovascularization (neoangiogenesis) in hypoxic or ischemic tissues. The first clinical study on patients with coronary heart disease treated by local intramyocardial injection of FGF-1 showed a 3-fold increase of capillary density mediated by the growth factor. Also, angiogenic growth factor injection intramyocardially as sole therapy for end-stage coronary disease showed an improvement of myocardial perfusion in the target areas as well as a reduction of symptoms and an increase in working capacity. Angiogenic therapy of the human myocardium introduces a new modality of treatment for coronary heart disease in terms of regulation of blood vessel growth. Beyond drug therapy, angioplasty and bypass surgery, this new approach may evolve into a fourth principle of treatment of atherosclerotic cardiovascular disease. PMID:11076317

  18. Vortex ring behavior provides the epigenetic blueprint for the human heart.

    PubMed

    Arvidsson, Per M; Kovács, Sándor J; Töger, Johannes; Borgquist, Rasmus; Heiberg, Einar; Carlsson, Marcus; Arheden, Håkan

    2016-01-01

    The laws of fluid dynamics govern vortex ring formation and precede cardiac development by billions of years, suggesting that diastolic vortex ring formation is instrumental in defining the shape of the heart. Using novel and validated magnetic resonance imaging measurements, we show that the healthy left ventricle moves in tandem with the expanding vortex ring, indicating that cardiac form and function is epigenetically optimized to accommodate vortex ring formation for volume pumping. Healthy hearts demonstrate a strong coupling between vortex and cardiac volumes (R(2) = 0.83), but this optimized phenotype is lost in heart failure, suggesting restoration of normal vortex ring dynamics as a new, and possibly important consideration for individualized heart failure treatment. Vortex ring volume was unrelated to early rapid filling (E-wave) velocity in patients and controls. Characteristics of vortex-wall interaction provide unique physiologic and mechanistic information about cardiac diastolic function that may be applied to guide the design and implantation of prosthetic valves, and have potential clinical utility as therapeutic targets for tailored medicine or measures of cardiac health. PMID:26915473

  19. Vortex ring behavior provides the epigenetic blueprint for the human heart

    PubMed Central

    Arvidsson, Per M.; Kovács, Sándor J.; Töger, Johannes; Borgquist, Rasmus; Heiberg, Einar; Carlsson, Marcus; Arheden, Håkan

    2016-01-01

    The laws of fluid dynamics govern vortex ring formation and precede cardiac development by billions of years, suggesting that diastolic vortex ring formation is instrumental in defining the shape of the heart. Using novel and validated magnetic resonance imaging measurements, we show that the healthy left ventricle moves in tandem with the expanding vortex ring, indicating that cardiac form and function is epigenetically optimized to accommodate vortex ring formation for volume pumping. Healthy hearts demonstrate a strong coupling between vortex and cardiac volumes (R2 = 0.83), but this optimized phenotype is lost in heart failure, suggesting restoration of normal vortex ring dynamics as a new, and possibly important consideration for individualized heart failure treatment. Vortex ring volume was unrelated to early rapid filling (E-wave) velocity in patients and controls. Characteristics of vortex-wall interaction provide unique physiologic and mechanistic information about cardiac diastolic function that may be applied to guide the design and implantation of prosthetic valves, and have potential clinical utility as therapeutic targets for tailored medicine or measures of cardiac health. PMID:26915473

  20. Tracking Fusion of Human Mesenchymal Stem Cells After Transplantation to the Heart

    PubMed Central

    Freeman, Brian T.; Kouris, Nicholas A.

    2015-01-01

    Evidence suggests that transplanted mesenchymal stem cells (MSCs) can aid recovery of damaged myocardium caused by myocardial infarction. One possible mechanism for MSC-mediated recovery is reprogramming after cell fusion between transplanted MSCs and recipient cardiac cells. We used a Cre/LoxP-based luciferase reporter system coupled to biophotonic imaging to detect fusion of transplanted human pluripotent stem cell-derived MSCs to cells of organs of living mice. Human MSCs, with transient expression of a viral fusogen, were delivered to the murine heart via a collagen patch. At 2 days and 1 week later, living mice were probed for bioluminescence indicative of cell fusion. Cell fusion was detected at the site of delivery (heart) and in distal tissues (i.e., stomach, small intestine, liver). Fusion was confirmed at the cellular scale via fluorescence in situ hybridization for human-specific and mouse-specific centromeres. Human cells in organs distal to the heart were typically located near the vasculature, suggesting MSCs and perhaps MSC fusion products have the ability to migrate via the circulatory system to distal organs and engraft with local cells. The present study reveals previously unknown migratory patterns of delivered human MSCs and associated fusion products in the healthy murine heart. The study also sets the stage for follow-on studies to determine the functional effects of cell fusion in a model of myocardial damage or disease. Significance Mesenchymal stem cells (MSCs) are transplanted to the heart, cartilage, and other tissues to recover lost function or at least limit overactive immune responses. Analysis of tissues after MSC transplantation shows evidence of fusion between MSCs and the cells of the recipient. To date, the biologic implications of cell fusion remain unclear. A newly developed in vivo tracking system was used to identify MSC fusion products in living mice. The migratory patterns of fusion products were determined both in the

  1. Proteomics in human disease: cancer, heart and infectious diseases.

    PubMed

    Jungblut, P R; Zimny-Arndt, U; Zeindl-Eberhart, E; Stulik, J; Koupilova, K; Pleissner, K P; Otto, A; Müller, E C; Sokolowska-Köhler, W; Grabher, G; Stöffler, G

    1999-07-01

    In recent years, genomics has increased the understanding of many diseases. Proteomics is a rapidly growing research area that encompasses both genetic and environmental factors. The protein composition represents the functional status of a biological compartment. The five approaches presented here resulted in the detection of disease-associated proteins. Calgranulin B was upregulated in colorectal cancer, and hepatoma-derived aldose reductase-like protein was reexpressed in a rat model during hepatocarcinogenesis. In these two investigations, attention was focused on one protein, obviously differing in amount, directly after two-dimensional electrophoresis (2-DE). Additional methods, such as enzyme activity measurements and immunohistochemistry, confirmed the disease association of the two candidates resulting from 2-DE subtractive analysis. The following three investigations take advantage of the holistic potential of the 2-DE approach. The comparison of 2-DE patterns from dilated cardiomyopathy patients with those of controls revealed 25 statistically significant intensity differences, from which 12 were identified by amino acid analysis, Edman degradation or matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS). A human myocardial 2-DE database was constructed, containing 3300 protein spots and 150 identified protein species. The number of identified proteins was limited by the capacity of our group, rather than by the principle of feasibility. Another field where proteomics proves to be a valuable tool in identifying proteins of importance for diagnosis is proteome analysis of pathogenic microorganisms such as Borrelia burgdorferi (Lyme disease) and Toxoplasma gondii (toxoplasmosis). Sera from patients with early or late symptoms of Lyme borreliosis contained antibodies of various classes against about 80 antigens each, containing the already described antigens OspA, B and C, flagellin, p83/100, and p39. Similarly, antibody reactivity to

  2. The effect of a week's beta-adrenoceptor antagonism on daytime heart-rates, subjective responses to exercise, and physical activity in normal subjects.

    PubMed Central

    Patrick, J M; Wharrad, H J; Wilson, C G; Birmingham, A T

    1985-01-01

    The effects on heart rate (HR) and physical activity of 1 week's treatment with three different beta-adrenoceptor antagonists (20 mg betaxolol (Lorex); 160 mg propranolol LA; or 100 mg atenolol daily) have been compared with placebo in a double-blind study of 12 normal men. On the fifth day of each treatment a body-borne tape-recorder was worn during waking hours for recording of ECG and footfall signals. Each record was calibrated in terms of the subject's response to laboratory ergometer exercise, and a computer analysis provided objective indices of physical activity. While on beta-adrenoceptor antagonists the subjects perceived standard exercise as significantly harder than on placebo and reported more side-effects (albeit mild and transient). Ambulatory monitoring of HR showed that subjects spent 13% of their waking day at heart rates below 50 beats min-1 while on propranolol, compared with 1% on placebo and 20% on atenolol and betaxolol. On these latter drugs, the group spent as much as 10% of their waking time with HR below 45 beats min-1. The lowest individual heart-rates recorded were below 35 beats min-1. Objective indices of physical activity, such as the duration of periods spent with heart rates above the HR found at 100 W in the ergometer test, showed no differences between the treatments. This negative finding was confirmed by pedometer step counts over the whole week. PMID:2859043

  3. Detection of aryl hydrocarbon hydroxylase activity in normal and neoplastic human breast epithelium

    SciTech Connect

    Greiner, J.W.; Malan-Shibley, L.B.; Janss, D.H.

    1980-01-28

    Studies were conducted to determine whether normal and/or neoplastic (MCF-7) human breast epithelial cells contain the microsomal aryl hydrocarbon hydroxylase (AHH) which catalyses the conversion of polycyclic aromatic hydrocarbons (PAH) to carcinogenic intermediates. Low constitutive levels of AHH activity were found in homogenates of both normal human breast epithelial and MCF-7 cells. The addition of 7,12-dimethylbenz(a)anthracene (DMBA) to the culture medium of either cell type significantly increased AHH activity. Peak induction of hydroxylase activity occurred following the in vitro addition of 10 ..mu..M DMBA. A time course of DMBA-induced AHH activity in both normal human breast epithelium and MCF-7 cells revealed maximal induction 16 hr after 10 ..mu..M DMBA was added to the culture medium. Benzo(a)pyrene (BP), 3-methylcholanthrene (MCA) and benz(a)anthracene (BA) also induced AHH activity in normal and MCF-7 cells. For example, the addition of 10 ..mu..M BP to the culture medium of either normal human breast epithelial or MCF-7 cells for 16 hr increased AHH activity 13.8 and 65.3-fold, respectively. For all PAH, the magnitude of AHH induction was substantially greater in MCF-7 than normal breast epithelial cells. Finally, ..cap alpha..-naphthoflavone inhibited BA-induced AHH activity in MCF-7 cells. The study demonstrates the presence of a PAH-inducible AHH enzyme(s) in normal human breast epithelial cells grown in primary culture and in the human breast tumor cell line, MCF-7.

  4. Heart Murmurs (For Kids)

    MedlinePlus

    ... than normal. You also might get an electrocardiogram (EKG), which measures electrical activity of the heart. None ... MORE ON THIS TOPIC The Heart Getting an EKG (Video) Your Heart & Circulatory System Mitral Valve Prolapse ...

  5. A study of the first heart sound spectra in normal anesthetized cats: possible origins and chest wall influences.

    PubMed

    Fazzalari, N L; Mazumdar, J; Ghista, D N; Allen, D G; de Bruin, H

    1984-01-01

    Heart sound recordings were taken from cats. The heart sounds were recorded directly from the chest wall and through an esophageal tube. The phono transducer and the esophageal tube were both placed over the base of the heart. Ultrasound M-mode, or motion-mode, recordings were taken to study the mitral valve dynamics. After analogue to digital conversion, electrocardiogram gated first heart sounds of each phono record were analyzed by the fast Fourier transform to obtain a frequency spectrum. Relative energies in 15 Hz bandwidths up to 150 Hz were correlated with the mitral valve closing velocity of the anterior mitral leaflet, obtained from the M-mode echocardiograms. The closing velocity correlated best with the energy in the 30-45 Hz bandwidth and 60-75 Hz bandwidth for the externally and internally monitored phonocardiogram respectively. The chest wall acted as a low pass filter, that is, the wall favoured the transmission of low frequencies and the energy transmitted decreased as wall thickness increased. PMID:6713253

  6. 2-Deoxy adenosine triphosphate improves contraction in human end-stage heart failure

    PubMed Central

    Moussavi-Harami, Farid; Razumova, Maria V.; Racca, Alice W.; Cheng, Yuanhua; Stempien-Otero, April; Regnier, Michael

    2014-01-01

    We are developing a novel treatment for heart failure by increasing myocardial 2 deoxy-ATP (dATP). Our studies in rodent models have shown that substitution of dATP for adenosine triphosphate (ATP) as the energy substrate in vitro or elevation of dATP in vivo increases myocardial contraction and that small increases in the native dATP pool of heart muscle are sufficient to improve cardiac function. Here we report, for the first time, the effect of dATP on human adult cardiac muscle contraction. We measured the contractile properties of chemically-demembranated multicellular ventricular wall preparations and isolated myofibrils from human subjects with end-stage heart failure. Isometric force was increased at both saturating and physiologic Ca2+ concentrations with dATP compared to ATP. This resulted in an increase in the Ca2+ sensitivity of force (pCa50) by 0.06 pCa units. The rate of force redevelopment (kTR) in demembranated wall muscle was also increased, as was the rate of contractile activation (kACT) in isolated myofibrils, indicating increased cross-bridge binding and cycling compared with ATP in failing human myocardium. These data suggest dATP could increase dP/dT and end systolic pressure in failing human myocardium. Importantly, even though the magnitude and rate of force development was increased, there was no increase in the time to 50% and 90% myofibril relaxation. These data, along with our previous studies in rodent models shows the promise of elevating myocardial dATP to enhance contraction and restore cardiac pump function. These data also support further pre-clinical evaluation of this new approach for treating heart failure. PMID:25498214

  7. Methods from the theory of random heterogeneous media for quantifying myocardial morphology in normal and dilated hearts.

    PubMed

    Karch, Rudolf; Neumann, Friederike; Ullrich, Robert; Heinze, Georg; Neumüller, Josef; Podesser, Bruno K; Neumann, Martin

    2010-02-01

    In the present study, descriptors from the theory of random heterogeneous media were used to characterize the morphology of the myocardial interstitial space in histological sections from hearts of healthy subjects and of patients with idiopathic dilated cardiomyopathy (DCM). Histological sections from resected DCM hearts (n = 9) were compared with donor hearts showing no signs of cardiac disease (n = 6). From control to DCM, the area fraction phi(1) of the interstitial space increased from 0.13 +/- 0.05 to 0.27 +/- 0.08, the chord-length z from 1.67 +/- 0.61 to 5.56 +/- 1.78 microm, the pore-size delta from 0.72 +/- 0.13 to 1.73 +/- 0.40 microm, the distance r (min) of the first local minimum in the two-point correlation function from 10.99 +/- 1.09 to 18.57 +/- 4.36 mum, whereas specific interface length s and decay-rate gamma of the lineal-path function decreased from 0.20 +/- 0.07 to 0.16 +/- 0.04 microm(-1) and from 0.39 +/- 0.09 to 0.16 +/- 0.05 microm(-1), respectively. All descriptors (except for s) were significantly different (p < 0.05) between control and DCM, reflecting an increasingly heterogeneous morphology in DCM hearts. Our results suggest that (1) descriptors originally developed to characterize the morphology of random heterogeneous media are well suited for histomorphometry of DCM, and (2) among the descriptors studied, either pore-size delta or chord-length z qualify best to discriminate between control and DCM hearts. PMID:19937468

  8. PDE4 in the human heart – major player or little helper?

    PubMed Central

    Eschenhagen, Thomas

    2013-01-01

    PDEs restrict the positive inotropic effects of β-adrenoceptor stimulation by degrading cAMP. Hence, PDE inhibitors sensitize the heart to catecholamines and are therefore used as positive inotropes. On the downside, this is accompanied by exaggerated energy expenditure, cell death and arrhythmias. For many years, PDE3 was considered to be the major isoform responsible for the control of cardiac force and rhythm. However, recent work in gene-targeted mice and rodent cells has indicated that PDE4 is also involved. Furthermore, selective PDE4 inhibitors augment catecholamine-stimulated cAMP levels and induce arrhythmias in human atrial preparations, which suggests that PDE4 has a more prominent role in the human heart than anticipated, and that PDE4 inhibitors such as roflumilast may carry an arrhythmogenic risk. In this issue of the journal, a team of researchers from three laboratories report on the effect of PDE3 and PDE4 inhibitors on ventricular trabeculae from explanted human hearts. The key result is that the PDE4 inhibitor rolipram does not affect the positive inotropic effects of β1- or β2-adrenoceptor stimulation. Given that the ventricle rather than the atria is the critical region in terms of arrhythmogenic consequences, this is an important and reassuring finding. Linked Article This article is a commentary on the research paper by Molenaar et al., pp. 528–538 of this issue. To view this paper visit http://dx.doi.org/10.1111/bph.12167 PMID:23489196

  9. Immunoreactivity of anti-streptococcal monoclonal antibodies to human heart valves. Evidence for multiple cross-reactive epitopes.

    PubMed Central

    Gulizia, J. M.; Cunningham, M. W.; McManus, B. M.

    1991-01-01

    Association of group A streptococci with acute rheumatic fever and valvular heart disease is well established; however the basis of valve injury remains unclear. In this study, anti-streptococcal monoclonal antibodies (MAbs) cross-reactive with myocardium were reacted with sections from 22 rheumatic valves, nine normal, five endocarditic, one 'floppy,' and one Marfan valve. In immunohistochemical studies, MAb reactivity was observed with cardiac myocytes, smooth muscle cells, cell surface and cytoplasm of endothelial cells lining valves, and valvular interstitial cells. Endothelial basement membrane and elastin fibrils reacted with the MAbs, whereas collagen was unreactive. Similar reactivity was seen with sera from acute rheumatic fever patients. The anti-streptococcal MAbs reacted with intravalvular myosin and vimentin in Western blots, and purified elastin competitively inhibited the binding of the anti-streptococcal MAbs to whole group A streptococci. The data show that human heart valves have numerous sites of immunoreactivity with anti-streptococcal MAbs and acute rheumatic fever sera of potential importance in the pathogenesis of rheumatic valvular injury. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 PMID:1704188

  10. Human Normal Bronchial Epithelial Cells: A Novel In Vitro Cell Model for Toxicity Evaluation

    PubMed Central

    Huang, Haiyan; Xia, Bo; Liu, Hongya; Li, Jie; Lin, Shaolin; Li, Tiyuan; Liu, Jianjun; Li, Hui

    2015-01-01

    Human normal cell-based systems are needed for drug discovery and toxicity evaluation. hTERT or viral genes transduced human cells are currently widely used for these studies, while these cells exhibited abnormal differentiation potential or response to biological and chemical signals. In this study, we established human normal bronchial epithelial cells (HNBEC) using a defined primary epithelial cell culture medium without transduction of exogenous genes. This system may involve decreased IL-1 signaling and enhanced Wnt signaling in cells. Our data demonstrated that HNBEC exhibited a normal diploid karyotype. They formed well-defined spheres in matrigel 3D culture while cancer cells (HeLa) formed disorganized aggregates. HNBEC cells possessed a normal cellular response to DNA damage and did not induce tumor formation in vivo by xenograft assays. Importantly, we assessed the potential of these cells in toxicity evaluation of the common occupational toxicants that may affect human respiratory system. Our results demonstrated that HNBEC cells are more sensitive to exposure of 10~20 nm-sized SiO2, Cr(VI) and B(a)P compared to 16HBE cells (a SV40-immortalized human bronchial epithelial cells). This study provides a novel in vitro human cells-based model for toxicity evaluation, may also be facilitating studies in basic cell biology, cancer biology and drug discovery. PMID:25861018

  11. Human normal bronchial epithelial cells: a novel in vitro cell model for toxicity evaluation.

    PubMed

    Feng, Wenqiang; Guo, Juanjuan; Huang, Haiyan; Xia, Bo; Liu, Hongya; Li, Jie; Lin, Shaolin; Li, Tiyuan; Liu, Jianjun; Li, Hui

    2015-01-01

    Human normal cell-based systems are needed for drug discovery and toxicity evaluation. hTERT or viral genes transduced human cells are currently widely used for these studies, while these cells exhibited abnormal differentiation potential or response to biological and chemical signals. In this study, we established human normal bronchial epithelial cells (HNBEC) using a defined primary epithelial cell culture medium without transduction of exogenous genes. This system may involve decreased IL-1 signaling and enhanced Wnt signaling in cells. Our data demonstrated that HNBEC exhibited a normal diploid karyotype. They formed well-defined spheres in matrigel 3D culture while cancer cells (HeLa) formed disorganized aggregates. HNBEC cells possessed a normal cellular response to DNA damage and did not induce tumor formation in vivo by xenograft assays. Importantly, we assessed the potential of these cells in toxicity evaluation of the common occupational toxicants that may affect human respiratory system. Our results demonstrated that HNBEC cells are more sensitive to exposure of 10~20 nm-sized SiO2, Cr(VI) and B(a)P compared to 16HBE cells (a SV40-immortalized human bronchial epithelial cells). This study provides a novel in vitro human cells-based model for toxicity evaluation, may also be facilitating studies in basic cell biology, cancer biology and drug discovery. PMID:25861018

  12. Organization of ventricular fibrillation in the human heart: experiments and models.

    PubMed

    ten Tusscher, K H W J; Mourad, A; Nash, M P; Clayton, R H; Bradley, C P; Paterson, D J; Hren, R; Hayward, M; Panfilov, A V; Taggart, P

    2009-05-01

    Sudden cardiac death is a major health problem in the industrialized world. The lethal event is typically ventricular fibrillation (VF), during which the co-ordinated regular contraction of the heart is overthrown by a state of mechanical and electrical anarchy. Understanding the excitation patterns that sustain VF is important in order to identify potential therapeutic targets. In this paper, we studied the organization of human VF by combining clinical recordings of electrical excitation patterns on the epicardial surface during in vivo human VF with simulations of VF in an anatomically and electrophysiologically detailed computational model of the human ventricles. We find both in the computational studies and in the clinical recordings that epicardial surface excitation patterns during VF contain around six rotors. Based on results from the simulated three-dimensional excitation patterns during VF, which show that the total number of electrical sources is 1.4 +/- 0.12 times greater than the number of epicardial rotors, we estimate that the total number of sources present during clinically recorded VF is 9.0 +/- 2.6. This number is approximately fivefold fewer compared with that observed during VF in dog and pig hearts, which are of comparable size to human hearts. We explain this difference by considering differences in action potential duration dynamics across these species. The simpler spatial organization of human VF has important implications for treatment and prevention of this dangerous arrhythmia. Moreover, our findings underline the need for integrated research, in which human-based clinical and computational studies complement animal research. PMID:19168541

  13. Duchenne Muscular Dystrophy Gene Expression in Normal and Diseased Human Muscle

    NASA Astrophysics Data System (ADS)

    Oronzi Scott, M.; Sylvester, J. E.; Heiman-Patterson, T.; Shi, Y.-J.; Fieles, W.; Stedman, H.; Burghes, A.; Ray, P.; Worton, R.; Fischbeck, K. H.

    1988-03-01

    A probe for the 5' end of the Duchenne muscular dystrophy (DMD) gene was used to study expression of the gene in normal human muscle, myogenic cell cultures, and muscle from patients with DMD. Expression was found in RNA from normal fetal muscle, adult cardiac and skeletal muscle, and cultured muscle after myoblast fusion. In DMD muscle, expression of this portion of the gene was also revealed by in situ RNA hybridization, particularly in regenerating muscle fibers.

  14. Effect of resveratrol and zinc on intracellular zinc status in normal human prostate epithelial cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    To evaluate the influence of resveratrol on cellular zinc status, normal human prostate epithelial (NHPrE) cells were treated with 6 levels of resveratrol (0, 0.5, 1, 2.5, 5 and 10 microM) and 4 levels of zinc [0, 4, 16, and 32 microM for zinc-deficient (ZD), zinc-normal (ZN), zinc-adequate (ZA), an...

  15. Muscarinic cholinergic receptor in the human heart evidenced under physiological conditions by positron emission tomography.

    PubMed Central

    Syrota, A; Comar, D; Paillotin, G; Davy, J M; Aumont, M C; Stulzaft, O; Maziere, B

    1985-01-01

    The muscarinic receptor was studied in vivo in the human heart by a noninvasive method, positron emission tomography (PET). The study showed that the binding sites of 11C-labeled methiodide quinuclidinyl benzilate [( 11C]-MQNB), a muscarinic antagonist, were mainly distributed in the ventricular septum (98 pmol/cm3 of heart) and in the left ventricular wall (89 pmol/cm3), while the atria were not visualized. A few minutes after a bolus intravenous injection, the concentration of [11C]MQNB in blood fell to a negligible level (less than 100th of the concentration measured in the ventricular septum). When injected at high specific radioactivity, the concentration of [11C]MQNB in the septum rapidly increased and then remained constant with time. This result was explained by rebinding of the ligand to receptors. It was the major difference observed between the kinetics of binding of [11C]MQNB to receptor sites after intravenous injection in vivo and that of [3H]MQNB to heart homogenates in vitro. The MQNB concentrations in the ventricular septum of different individuals were found to be highest when the heart rate at the time of injection was slow. This result suggests that the antagonist binding site is related to a low-affinity conformational state of the receptor under predominant vagal stimulation. Thus, positron emission tomography might be the ideal method to study the physiologically active form of the muscarinic acetylcholine receptor in man. Images PMID:3871527

  16. Magnetic measurements on human erythrocytes: Normal, beta thalassemia major, and sickle

    NASA Astrophysics Data System (ADS)

    Sakhnini, Lama

    2003-05-01

    In this article magnetic measurements were made on human erythrocytes at different hemoglobin states (normal and reduced hemoglobin). Different blood samples: normal, beta thalassemia major, and sickle were studied. Beta thalassemia major and sickle samples were taken from patients receiving lifelong blood transfusion treatment. All samples examined exhibited diamagnetic behavior. Beta thalassemia major and sickle samples showed higher diamagnetic susceptibilities than that for the normal, which was attributed to the increase of membrane to hemoglobin volume ratio of the abnormal cells. Magnetic measurements showed that the erythrocytes in the reduced state showed less diamagnetic response in comparison with erythrocytes in the normal state. Analysis of the paramagnetic component of magnetization curves gave an effective magnetic moment of μeff=7.6 μB per reduced hemoglobin molecule. The same procedure was applied to sickle and beta thalassemia major samples and values for μeff were found to be comparable to that of the normal erythrocytes.

  17. Normalization of human RNA-seq experiments using chimpanzee RNA as a spike-in standard.

    PubMed

    Yu, Hannah; Hahn, Yoonsoo; Park, Sang-Ryoul; Chung, Sun-Ku; Jeong, Sangkyun; Yang, Inchul

    2016-01-01

    Normalization of human RNA-seq experiments employing chimpanzee RNA as a spike-in standard is reported. Human and chimpanzee RNAs exhibit single nucleotide variations (SNVs) in average 210-bp intervals. Spike-in chimpanzee RNA would behave the same as the human counterparts during the whole NGS procedures owing to the high sequence similarity. After discrimination of species origins of the NGS reads based on SNVs, the chimpanzee reads were used to read-by-read normalize biases and variations of human reads. By this approach, as many as 10,119 transcripts were simultaneously normalized for the entire NGS procedures leading to accurate and reproducible quantification of differential gene expression. In addition, incomparable data sets from different in-process degradations or from different library preparation methods were made well comparable by the normalization. Based on these results, we expect that the normalization approaches using near neighbor genomes as internal standards could be employed as a standard protocol, which will improve both accuracy and comparability of NGS results across different sample batches, laboratories and NGS platforms. PMID:27554056

  18. Normalization of human RNA-seq experiments using chimpanzee RNA as a spike-in standard

    PubMed Central

    Yu, Hannah; Hahn, Yoonsoo; Park, Sang-Ryoul; Chung, Sun-Ku; Jeong, Sangkyun; Yang, Inchul

    2016-01-01

    Normalization of human RNA-seq experiments employing chimpanzee RNA as a spike-in standard is reported. Human and chimpanzee RNAs exhibit single nucleotide variations (SNVs) in average 210-bp intervals. Spike-in chimpanzee RNA would behave the same as the human counterparts during the whole NGS procedures owing to the high sequence similarity. After discrimination of species origins of the NGS reads based on SNVs, the chimpanzee reads were used to read-by-read normalize biases and variations of human reads. By this approach, as many as 10,119 transcripts were simultaneously normalized for the entire NGS procedures leading to accurate and reproducible quantification of differential gene expression. In addition, incomparable data sets from different in-process degradations or from different library preparation methods were made well comparable by the normalization. Based on these results, we expect that the normalization approaches using near neighbor genomes as internal standards could be employed as a standard protocol, which will improve both accuracy and comparability of NGS results across different sample batches, laboratories and NGS platforms. PMID:27554056

  19. Enhanced Electrical Integration of Engineered Human Myocardium via Intramyocardial versus Epicardial Delivery in Infarcted Rat Hearts

    PubMed Central

    Gerbin, Kaytlyn A.; Yang, Xiulan; Murry, Charles E.; Coulombe, Kareen L. K.

    2015-01-01

    Cardiac tissue engineering is a promising approach to provide large-scale tissues for transplantation to regenerate the heart after ischemic injury, however, integration with the host myocardium will be required to achieve electromechanical benefits. To test the ability of engineered heart tissues to electrically integrate with the host, 10 million human embryonic stem cell (hESC)-derived cardiomyocytes were used to form either scaffold-free tissue patches implanted on the epicardium or micro-tissue particles (~1000 cells/particle) delivered by intramyocardial injection into the left ventricular wall of the ischemia/reperfusion injured athymic rat heart. Results were compared to intramyocardial injection of 10 million dispersed hESC-cardiomyocytes. Graft size was not significantly different between treatment groups and correlated inversely with infarct size. After implantation on the epicardial surface, hESC-cardiac tissue patches were electromechanically active, but they beat slowly and were not electrically coupled to the host at 4 weeks based on ex vivo fluorescent imaging of their graft-autonomous GCaMP3 calcium reporter. Histologically, scar tissue physically separated the patch graft and host myocardium. In contrast, following intramyocardial injection of micro-tissue particles and suspended cardiomyocytes, 100% of the grafts detected by fluorescent GCaMP3 imaging were electrically coupled to the host heart at spontaneous rate and could follow host pacing up to a maximum of 300–390 beats per minute (5–6.5 Hz). Gap junctions between intramyocardial graft and host tissue were identified histologically. The extensive coupling and rapid response rate of the human myocardial grafts after intramyocardial delivery suggest electrophysiological adaptation of hESC-derived cardiomyocytes to the rat heart’s pacemaking activity. These data support the use of the rat model for studying electromechanical integration of human cardiomyocytes, and they identify lack of

  20. Deep sequencing as a probe of normal stem cell fate and preneoplasia in human epidermis

    PubMed Central

    Simons, Benjamin D.

    2016-01-01

    Using deep sequencing technology, methods based on the sporadic acquisition of somatic DNA mutations in human tissues have been used to trace the clonal evolution of progenitor cells in diseased states. However, the potential of these approaches to explore cell fate behavior of normal tissues and the initiation of preneoplasia remain underexploited. Focusing on the results of a recent deep sequencing study of eyelid epidermis, we show that the quantitative analysis of mutant clone size provides a general method to resolve the pattern of normal stem cell fate and to detect and characterize the mutational signature of rare field transformations in human tissues, with implications for the early detection of preneoplasia. PMID:26699486

  1. Gia/Mthl5 is an aorta specific GPCR required for Drosophila heart tube morphology and normal pericardial cell positioning.

    PubMed

    Patel, Meghna V; Zhu, Jun-Yi; Jiang, Zhiping; Richman, Adam; VanBerkum, Mark F A; Han, Zhe

    2016-06-01

    G-protein signaling is known to be required for cell-cell contacts during the development of the Drosophila dorsal vessel. However, the identity of the G protein-coupled receptor (GPCR) that regulates this signaling pathway activity is unknown. Here we describe the identification of a novel cardiac specific GPCR, called Gia, for "GPCR in aorta". Gia is the only heart-specific GPCR identified in Drosophila to date and it is specifically expressed in cardioblasts that fuse at the dorsal midline to become the aorta. Gia is the only Drosophila gene so far identified for which expression is entirely restricted to cells of the aorta. Deletion of Gia led to a broken-hearted phenotype, characterized by pericardial cells dissociated from cardioblasts and abnormal distribution of cell junction proteins. Both phenotypes were similar to those observed in mutants of the heterotrimeric cardiac G proteins. Lack of Gia also led to defects in the alignment and fusion of cardioblasts in the aorta. Gia forms a protein complex with G-αo47A, the alpha subunit of the heterotrimeric cardiac G proteins and interacts genetically with G-αo47A during cardiac morphogenesis. Our study identified Gia as an essential aorta-specific GPCR that functions upstream of cardiac heterotrimeric G proteins and is required for morphological integrity of the aorta during heart tube formation. These studies lead to a redefinition of the bro phenotype, to encompass morphological integrity of the heart tube as well as cardioblast-pericardial cell spatial interactions. PMID:26994946

  2. Human engineered heart tissue as a versatile tool in basic research and preclinical toxicology.

    PubMed

    Schaaf, Sebastian; Shibamiya, Aya; Mewe, Marco; Eder, Alexandra; Stöhr, Andrea; Hirt, Marc N; Rau, Thomas; Zimmermann, Wolfram-Hubertus; Conradi, Lenard; Eschenhagen, Thomas; Hansen, Arne

    2011-01-01

    Human embryonic stem cell (hESC) progenies hold great promise as surrogates for human primary cells, particularly if the latter are not available as in the case of cardiomyocytes. However, high content experimental platforms are lacking that allow the function of hESC-derived cardiomyocytes to be studied under relatively physiological and standardized conditions. Here we describe a simple and robust protocol for the generation of fibrin-based human engineered heart tissue (hEHT) in a 24-well format using an unselected population of differentiated human embryonic stem cells containing 30-40% α-actinin-positive cardiac myocytes. Human EHTs started to show coherent contractions 5-10 days after casting, reached regular (mean 0.5 Hz) and strong (mean 100 µN) contractions for up to 8 weeks. They displayed a dense network of longitudinally oriented, interconnected and cross-striated cardiomyocytes. Spontaneous hEHT contractions were analyzed by automated video-optical recording and showed chronotropic responses to calcium and the β-adrenergic agonist isoprenaline. The proarrhythmic compounds E-4031, quinidine, procainamide, cisapride, and sertindole exerted robust, concentration-dependent and reversible decreases in relaxation velocity and irregular beating at concentrations that recapitulate findings in hERG channel assays. In conclusion this study establishes hEHT as a simple in vitro model for heart research. PMID:22028871

  3. Human Engineered Heart Tissue as a Versatile Tool in Basic Research and Preclinical Toxicology

    PubMed Central

    Schaaf, Sebastian; Shibamiya, Aya; Mewe, Marco; Eder, Alexandra; Stöhr, Andrea; Hirt, Marc N.; Rau, Thomas; Zimmermann, Wolfram-Hubertus; Conradi, Lenard

    2011-01-01

    Human embryonic stem cell (hESC) progenies hold great promise as surrogates for human primary cells, particularly if the latter are not available as in the case of cardiomyocytes. However, high content experimental platforms are lacking that allow the function of hESC-derived cardiomyocytes to be studied under relatively physiological and standardized conditions. Here we describe a simple and robust protocol for the generation of fibrin-based human engineered heart tissue (hEHT) in a 24-well format using an unselected population of differentiated human embryonic stem cells containing 30–40% α-actinin-positive cardiac myocytes. Human EHTs started to show coherent contractions 5–10 days after casting, reached regular (mean 0.5 Hz) and strong (mean 100 µN) contractions for up to 8 weeks. They displayed a dense network of longitudinally oriented, interconnected and cross-striated cardiomyocytes. Spontaneous hEHT contractions were analyzed by automated video-optical recording and showed chronotropic responses to calcium and the β-adrenergic agonist isoprenaline. The proarrhythmic compounds E-4031, quinidine, procainamide, cisapride, and sertindole exerted robust, concentration-dependent and reversible decreases in relaxation velocity and irregular beating at concentrations that recapitulate findings in hERG channel assays. In conclusion this study establishes hEHT as a simple in vitro model for heart research. PMID:22028871

  4. Immunochemistry of the Streptococcus mutans BHT cell membrane: detection of determinants cross-reactive with human heart tissue.

    PubMed Central

    Ayakawa, G Y; Siegel, J L; Crowley, P J; Bleiweis, A S

    1985-01-01

    Cell membranes of Streptococcus mutans BHT serotype b were prepared after glass bead disruption or mutanolysin digestion of whole cells. Immunoblot analyses of BHT membrane extracts revealed major polypeptides of 42,000, 46,000, 62,000, and 82,000 daltons, as well as several minor bands, to be reactive with rabbit anti-human heart immunoglobulins. Heart cross-reactive antigens have been reported in the cell walls and culture fluids of several S. mutans serotypes. This represents the first report of cell membrane-localized heart cross-reactive antigens in this oral pathogen. Positive enzyme-linked immunosorbent assay and immunoblot reactions were also obtained with heart tissue antigen and anti-BHT sera, indicating mutual cross-reactivity. The major cross-reactive component detected by immunoblotting of human heart extracts was a 69,000-dalton polypeptide. Images PMID:3886543

  5. Differential gene expression in normal and transformed human mammary epithelial cells in response to oxidative stress

    PubMed Central

    Cortes, Diego F; Sha, Wei; Hower, Valerie; Blekherman, Greg; Laubenbacher, Reinhard; Akman, Steven; Torti, Suzy V; Shulaev, Vladimir

    2011-01-01

    Oxidative stress plays a key role in breast carcinogenesis. To investigate whether normal and malignant breast epithelial cells differ in their responses to oxidative stress, we examined the global gene expression profiles of three cell types, representing cancer progression from a normal to a malignant stage, under oxidative stress. Normal human mammary epithelial cells (HMEC), an immortalized cell line (HMLER-1), and a tumorigenic cell line (HMLER-5), were exposed to increased levels of reactive oxygen species (ROS) by treatment with glucose oxidase. Functional analysis of the metabolic pathways enriched with differentially expressed genes demonstrates that normal and malignant breast epithelial cells diverge substantially in their response to oxidative stress. While normal cells exhibit the up-regulation of antioxidant mechanisms, cancer cells are unresponsive to the ROS insult. However, the gene expression response of normal HMEC cells under oxidative stress is comparable to that of the malignant cells under normal conditions, indicating that altered redox status is persistent in breast cancer cells, which makes them resistant to increased generation of ROS. This study discusses some of the possible adaptation mechanisms of breast cancer cells under persistent oxidative stress that differentiate them from the response to acute oxidative stress in normal mammary epithelial cells. PMID:21397008

  6. Secretion of Unconjugated Androgens and Estrogens by the Normal and Abnormal Human Testis before and after Human Chorionic Gonadotropin

    PubMed Central

    Weinstein, R. L.; Kelch, R. P.; Jenner, M. R.; Kaplan, S. L.; Grumbach, M. M.

    1974-01-01

    The secretion of androgens and estrogens by normal and abnormal testes was compared by determining the concentrations of dehydroepiandrosterone (DHEA), androstenedione (Δ4A), testosterone (T), estrone (E1), and 17β-estradiol (E2) in peripheral and spermatic venous plasma samples from 14 normal men and 5 men with unilateral testicular atrophy. Four normal men and one patient with unilateral atrophy of the testis were given human chorionic gonadotropin (HCG) before surgery. Plasma estrogens were determined by radioimmunoassay; plasma androgens were measured by the double-isotope dilution derivative technique. Peripheral concentrations of these steroids before and after HCG were similar in both the normal men and the patients with unilateral testicular atrophy. In normal men, the mean ±SE spermatic venous concentrations were DHEA, 73.1±11.7 ng/ml; Δ4A, 30.7±7.9 ng/ml; T, 751±114 ng/ml; E1, 306±55 pg/ml; and E2, 1298±216 pg/ml. Three of four subjects with unilateral testicular atrophy had greatly diminished spermatic venous levels of androgens and estrogens. HCG treatment increased the testicular secretion of DHEA and T fivefold, Δ4A threefold, E1 sixfold, and E2 eightfold in normal men. In the single subject with an atrophic testis who received HCG, the spermatic venous concentrations of androgens and estrogens were much less than in normal men similarly treated. We conclude that: (a) E1 is secreted by the human testis, but testicular secretion of E1 accounts for less than 5% of E1 production in normal men; (b) HCG stimulation produces increases in spermatic venous estrogens equal to or greater than the changes in androgens, including testosterone; and (c) strikingly decreased secretion of androgen and estrogen by unilateral atrophic human tests cannot be appreciated by analyses of peripheral steroid concentrations. PMID:4271572

  7. Chromatin defects in normal and malformed human ejaculated and epididymal spermatozoa: a cytochemical ultrastructural study.

    PubMed

    Francavilla, S; Cordeschi, G; Gabriele, A; Gianaroli, L; Properzi, G

    1996-03-01

    Cytochemical defects in chromatin were examined by transmission electron microscopy (TEM) after the staining by alcoholic phosphotungstic acid (PTA) of normal and malformed ejaculated spermatozoa from 35 male partners of infertile couples, and in six sperm samples retrieved from the caput epididymidis of men affected by obstructive azoospermia. PTA staining was also analysed in normal ejaculates of fertile men after incubation of the washed spermatozoa with dithiothreitol (DTT) to reduce disulfides to thiols, or with DTT followed by iodoacetamide, a blocking agent for thiol groups. PTA stained 63 (27-100)% of malformed heads and 25 (10-100)% of normal sperm heads (median (range) n = 35; P = 0.0001, Wilcoxon matched pairs test). The percentage of normal heads stained by PTA was negatively correlated with the percentage of heads of normal form, with condensed chromatin and a normal acrosome (Spearman r = 0.75; P = 0.0001), and positively correlated with the percentage of malformed heads after conventional TEM analysis (Spearman r 0.60; P = 0.0001). Staining with PTA in normal heads was not correlated with the presence of non-condensed chromatin in otherwise normal sperm heads evaluated by conventional TEM analysis. In spermatozoa recovered from the caput epididymidis, 15% of normal heads were stained with PTA, significantly fewer than in ejaculated sperm samples (P = 0.014). The reduction of disulfides to thiols was associated with PTA staining of all normal heads, and this was prevented by incubation with iodoacetamide. We conclude that PTA staining of the nuclei of human ejaculated spermatozoa may indicate a defect of chromatin condensation, owing to an excess of free thiol groups. The lower percentage of normal epididymal sperm heads that stained with PTA in cases of obstructive azoospermia compared with ejaculated sperm may be related to an overoxidation of thils owing to the ageing of spermatozoa. PMID:8699409

  8. Sizing up models of heart failure: Proteomics from flies to humans

    PubMed Central

    Kooij, Viola; Venkatraman, Vidya; Tra, John; Kirk, Jonathan A; Rowell, Janelle; Blice-Baum, Anna; Cammarato, Anthony; Van Eyk, Jennifer E

    2014-01-01

    Cardiovascular disease is the leading cause of death in the western world. Heart failure is a heterogeneous and complex syndrome, arising from various etiologies, which result in cellular phenotypes that vary from patient to patient. The ability to utilize genetic manipulation and biochemical experimentation in animal models has made them indispensable in the study of this chronic condition. Similarly, proteomics has been helpful for elucidating complicated cellular and molecular phenotypes and has the potential to identify circulating biomarkers and drug targets for therapeutic intervention. In this review, the use of human samples and animal model systems (pig, dog, rat, mouse, zebrafish, and fruit fly) in cardiac research is discussed. Additionally, the protein sequence homology between these species and the extent of conservation at the level of the phospho-proteome in major kinase signaling cascades involved in heart failure are investigated. PMID:24723306

  9. Combined use of autogenic therapy and biofeedback in training effective control of heart rate by humans

    NASA Technical Reports Server (NTRS)

    Cowings, P. S.

    1977-01-01

    Experiments were performed on 24 men and women (aged 20-27 yr) in three equal groups who were taught to control their own heart rates by autogenic training and biofeedback under dark and sound-isolated conditions. Group I was parasympathetic dominant, group II was sympathetic dominant, and group III consisted of parasympathetic-dominant subjects and controls who received only biofeedback of their own heart rates. The results corroborate three hypotheses: (1) subjects with para-sympathetic-dominant autonomic profiles perform in a way that is both qualitatively and quantitatively different from subjects with sympathetic-dominant autonomic profiles; (2) tests of interindividual variability yield data relevant to individual performance in visceral learning tasks; and (3) the combined use of autogenic training, biofeedback, and verbal feedback is suitable for conditioning large stable autonomic responses in humans.

  10. Sodium MRI of the human heart at 7.0 T: preliminary results.

    PubMed

    Graessl, Andreas; Ruehle, Anjuli; Waiczies, Helmar; Resetar, Ana; Hoffmann, Stefan H; Rieger, Jan; Wetterling, Friedrich; Winter, Lukas; Nagel, Armin M; Niendorf, Thoralf

    2015-08-01

    The objective of this work was to examine the feasibility of three-dimensional (3D) and whole heart coverage (23)Na cardiac MRI at 7.0 T including single-cardiac-phase and cinematic (cine) regimes. A four-channel transceiver RF coil array tailored for (23)Na MRI of the heart at 7.0 T (f = 78.5 MHz) is proposed. An integrated bow-tie antenna building block is used for (1)H MR to support shimming, localization and planning in a clinical workflow. Signal absorption rate simulations and assessment of RF power deposition were performed to meet the RF safety requirements. (23) Na cardiac MR was conducted in an in vivo feasibility study. 3D gradient echo (GRE) imaging in conjunction with Cartesian phase encoding (total acquisition time T(AQ)  = 6 min 16 s) and whole heart coverage imaging employing a density-adapted 3D radial acquisition technique (T(AQ)  = 18 min 20 s) were used. For 3D GRE-based (23)Na MRI, acquisition of standard views of the heart using a nominal in-plane resolution of (5.0 × 5.0) mm(2) and a slice thickness of 15 mm were feasible. For whole heart coverage 3D density-adapted radial (23)Na acquisitions a nominal isotropic spatial resolution of 6 mm was accomplished. This improvement versus 3D conventional GRE acquisitions reduced partial volume effects along the slice direction and enabled retrospective image reconstruction of standard or arbitrary views of the heart. Sodium cine imaging capabilities were achieved with the proposed RF coil configuration in conjunction with 3D radial acquisitions and cardiac gating. Cardiac-gated reconstruction provided an enhancement in blood-myocardium contrast of 20% versus the same data reconstructed without cardiac gating. The proposed transceiver array enables (23)Na MR of the human heart at 7.0 T within clinical acceptable scan times. This capability is in positive alignment with the needs of explorations that are designed to examine the potential of (23)Na MRI for the assessment of cardiovascular and

  11. Rapid manufacturing techniques for the tissue engineering of human heart valves.

    PubMed

    Lueders, Cora; Jastram, Ben; Hetzer, Roland; Schwandt, Hartmut

    2014-10-01

    Three-dimensional (3D) printing technologies have reached a level of quality that justifies considering rapid manufacturing for medical applications. Herein, we introduce a new approach using 3D printing to simplify and improve the fabrication of human heart valve scaffolds by tissue engineering (TE). Custom-made human heart valve scaffolds are to be fabricated on a selective laser-sintering 3D printer for subsequent seeding with vascular cells from human umbilical cords. The scaffolds will be produced from resorbable polymers that must feature a number of specific properties: the structure, i.e. particle granularity and shape, and thermic properties must be feasible for the printing process. They must be suitable for the cell-seeding process and at the same time should be resorbable. They must be applicable for implementation in the human body and flexible enough to support the full functionality of the valve. The research focuses mainly on the search for a suitable scaffold material that allows the implementation of both the printing process to produce the scaffolds and the cell-seeding process, while meeting all of the above requirements. Computer tomographic data from patients were transformed into a 3D data model suitable for the 3D printer. Our current activities involve various aspects of the printing process, material research and the implementation of the cell-seeding process. Different resorbable polymeric materials have been examined and used to fabricate heart valve scaffolds by rapid manufacturing. Human vascular cells attached to the scaffold surface should migrate additionally into the inner structure of the polymeric samples. The ultimate intention of our approach is to establish a heart valve fabrication process based on 3D rapid manufacturing and TE. Based on the computer tomographic data of a patient, a custom-made scaffold for a valve will be produced on a 3D printer and populated preferably by autologous cells. The long-term goal is to support

  12. Distinct p53 genomic binding patterns in normal and cancer-derived human cells

    SciTech Connect

    Botcheva K.; McCorkle S. R.; McCombie W. R.; Dunn J. J.; Anderson C. W.

    2011-12-15

    We report here genome-wide analysis of the tumor suppressor p53 binding sites in normal human cells. 743 high-confidence ChIP-seq peaks representing putative genomic binding sites were identified in normal IMR90 fibroblasts using a reference chromatin sample. More than 40% were located within 2 kb of a transcription start site (TSS), a distribution similar to that documented for individually studied, functional p53 binding sites and, to date, not observed by previous p53 genome-wide studies. Nearly half of the high-confidence binding sites in the IMR90 cells reside in CpG islands, in marked contrast to sites reported in cancer-derived cells. The distinct genomic features of the IMR90 binding sites do not reflect a distinct preference for specific sequences, since the de novo developed p53 motif based on our study is similar to those reported by genome-wide studies of cancer cells. More likely, the different chromatin landscape in normal, compared with cancer-derived cells, influences p53 binding via modulating availability of the sites. We compared the IMR90 ChIPseq peaks to the recently published IMR90 methylome1 and demonstrated that they are enriched at hypomethylated DNA. Our study represents the first genome-wide, de novo mapping of p53 binding sites in normal human cells and reveals that p53 binding sites reside in distinct genomic landscapes in normal and cancer-derived human cells.

  13. Reference gene alternatives to Gapdh in rodent and human heart failure gene expression studies

    PubMed Central

    2010-01-01

    Background Quantitative real-time RT-PCR (RT-qPCR) is a highly sensitive method for mRNA quantification, but requires invariant expression of the chosen reference gene(s). In pathological myocardium, there is limited information on suitable reference genes other than the commonly used Gapdh mRNA and 18S ribosomal RNA. Our aim was to evaluate and identify suitable reference genes in human failing myocardium, in rat and mouse post-myocardial infarction (post-MI) heart failure and across developmental stages in fetal and neonatal rat myocardium. Results The abundance of Arbp, Rpl32, Rpl4, Tbp, Polr2a, Hprt1, Pgk1, Ppia and Gapdh mRNA and 18S ribosomal RNA in myocardial samples was quantified by RT-qPCR. The expression variability of these transcripts was evaluated by the geNorm and Normfinder algorithms and by a variance component analysis method. Biological variability was a greater contributor to sample variability than either repeated reverse transcription or PCR reactions. Conclusions The most stable reference genes were Rpl32, Gapdh and Polr2a in mouse post-infarction heart failure, Polr2a, Rpl32 and Tbp in rat post-infarction heart failure and Rpl32 and Pgk1 in human heart failure (ischemic disease and cardiomyopathy). The overall most stable reference genes across all three species was Rpl32 and Polr2a. In rat myocardium, all reference genes tested showed substantial variation with developmental stage, with Rpl4 as was most stable among the tested genes. PMID:20331858

  14. Characterisation of the human embryonic and foetal epicardium during heart development

    PubMed Central

    Risebro, Catherine A.; Vieira, Joaquim Miguel; Klotz, Linda; Riley, Paul R.

    2015-01-01

    The epicardium is essential for mammalian heart development. At present, our understanding of the timing and morphogenetic events leading to the formation of the human epicardium has essentially been extrapolated from model organisms. Here, we studied primary tissue samples to characterise human epicardium development. We reveal that the epicardium begins to envelop the myocardial surface at Carnegie stage (CS) 11 and this process is completed by CS15, earlier than previously inferred from avian studies. Contrary to prevailing dogma, the formed human epicardium is not a simple squamous epithelium and we reveal evidence of more complex structure, including novel spatial differences aligned to the developing chambers. Specifically, the ventricular, but not atrial, epicardium exhibited areas of expanded epithelium, preferential cell alignment and spindle-like morphology. Likewise, we reveal distinct properties ex vivo, such that ventricular cells spontaneously differentiate and lose epicardial identity, whereas atrial-derived cells remained ‘epithelial-like’. These data provide insight into the developing human epicardium that may contribute to our understanding of congenital heart disease and have implications for the development of strategies for endogenous cell-based cardiac repair. PMID:26395486

  15. Interleukin 4 inhibits in vitro proliferation of leukemic and normal human B cell precursors.

    PubMed Central

    Pandrau, D; Saeland, S; Duvert, V; Durand, I; Manel, A M; Zabot, M T; Philippe, N; Banchereau, J

    1992-01-01

    In the present study, we have investigated the effects of IL-4 on the proliferation and differentiation of leukemic and normal human B cell precursors (BCP). We have demonstrated that IL-4 significantly inhibited spontaneous [3H]thymidine ([3H]-TdR) incorporation by leukemic blasts from some B lineage acute lymphoblastic leukemia (BCP-ALL) patients (8 of 14). Furthermore, IL-4 was found to suppress the spontaneous and factor-dependent (IL-7 and IL-3) proliferation of normal BCP (CD10+ surface [s] IgM- cells) isolated from fetal bone marrow. Maximum growth inhibition of either leukemic or normal BCP was reached at low IL-4 concentrations (10 U/ml), and the effect was specifically neutralized by anti-IL-4 antibody. IL-4 was further found to induce the expression of CD20 antigen on BCP-ALL cells from a number of the cases examined (5 of 8), but in contrast to leukemic cells, IL-4 failed to induce CD20 antigen on normal BCP. Finally, IL-4 was found to induce neither the expression of cytoplasmic mu chain, nor the appearance of sIgM+ cells in cultures of normal or leukemic BCP. Our data indicate that IL-4 has the potential to inhibit cell proliferation in leukemic and normal human B lymphopoiesis but is unable to drive the transition from BCP to mature B cells. Images PMID:1385474

  16. PULMONARY FUNCTION IN NORMAL HUMANS WITH EXERCISE AND TEMPERATURE-HUMIDITY STRESS

    EPA Science Inventory

    Fifty-eight normal young male human subjects were exposed for 4 h to comfortable conditions or to heat stress conditions with or without exercise. Heat stress produced significant changes in forced vital capacity, and possibly significant interactions were observed in peak expira...

  17. Imaging of matrix-disorder in normal and pathological human dermis using nonlinear optical microscopy

    NASA Astrophysics Data System (ADS)

    Zhuo, Shuangmu; Chen, Jianxin; Xie, Shusen; Zheng, Liqin; Jiang, Xingshan

    2009-11-01

    In dermis, collagen and elastin are important structural proteins of extracellular maxtrix. The matrix-disorder is associated with various physiologic processes, such as localized scleroderma, anetoderma, photoaging. In this work, we demonstrate the capability of nonlinear optical microscopy in imaging structural proteins in normal and pathological human dermis.

  18. Assessing the Toxicities of Regulated and Unregulated Disinfection By-products in Normal Human Colon Cells.

    EPA Science Inventory

    The presence of over six hundred disinfection by-products (DBPs) and less than half of the total organic halides present in finished water has created a need for short-term in vitro assays to address toxicities that might be associated with human exposure. . We are using a normal...

  19. SOX2+ Cell Population from Normal Human Brain White Matter Is Able to Generate Mature Oligodendrocytes

    PubMed Central

    Oliver-De La Cruz, Jorge; Carrión-Navarro, Josefa; García-Romero, Noemí; Gutiérrez-Martín, Antonio; Lázaro-Ibáñez, Elisa; Escobedo-Lucea, Carmen; Perona, Rosario; Belda-Iniesta, Cristobal; Ayuso-Sacido, Angel

    2014-01-01

    Objectives A number of neurodegenerative diseases progress with a loss of myelin, which makes them candidate diseases for the development of cell-replacement therapies based on mobilisation or isolation of the endogenous neural/glial progenitor cells, in vitro expansion, and further implantation. Cells expressing A2B5 or PDGFRA/CNP have been isolated within the pool of glial progenitor cells in the subcortical white matter of the normal adult human brain, all of which demonstrate glial progenitor features. However, the heterogeneity and differentiation potential of this pool of cells is not yet well established. Methods We used diffusion tensor images, histopathology, and immunostaining analysis to demonstrate normal cytoarchitecture and the absence of abnormalities in human temporal lobe samples from patients with mesial temporal sclerosis. These samples were used to isolate and enrich glial progenitor cells in vitro, and later to detect such cells in vivo. Results We have identified a subpopulation of SOX2+ cells, most of them co-localising with OLIG2, in the white matter of the normal adult human brain in vivo. These cells can be isolated and enriched in vitro, where they proliferate and generate immature (O4+) and mature (MBP+) oligodendrocytes and, to a lesser extent, astrocytes (GFAP+). Conclusion Our results demonstrate the existence of a new glial progenitor cell subpopulation that expresses SOX2 in the white matter of the normal adult human brain. These cells might be of use for tissue regeneration procedures. PMID:24901457

  20. Synergistic action of photosensitizers and normal human serum in a bactericidal process. I. Effect of chlorophylls.

    PubMed

    Jankowski, Andrzej; Jankowski, Stanisław; Mirończyk, Agnieszka

    2003-01-01

    Susceptibility of some Gram-negative strains against the bactericidal action of normal human serum (NHS) and of chlorophyll, which induces production of reactive oxygen species by light, was studied. A synergistic bactericidal activity of NHS and chlorophyll against E. coli K1 and Shigella flexneri strains was observed. PMID:15095924

  1. Characterization of human retinal vessel arborisation in normal and amblyopic eyes using multifractal analysis

    PubMed Central

    Tălu, Stefan; Vlăduţiu, Cristina; Lupaşcu, Carmen A.

    2015-01-01

    AIM To characterize the human retinal vessel arborisation in normal and amblyopic eyes using multifractal geometry and lacunarity parameters. METHODS Multifractal analysis using a box counting algorithm was carried out for a set of 12 segmented and skeletonized human retinal images, corresponding to both normal (6 images) and amblyopia states of the retina (6 images). RESULTS It was found that the microvascular geometry of the human retina network represents geometrical multifractals, characterized through subsets of regions having different scaling properties that are not evident in the fractal analysis. Multifractal analysis of the amblyopia images (segmented and skeletonized versions) show a higher average of the generalized dimensions (Dq) for q=0, 1, 2 indicating a higher degree of the tree-dimensional complexity associated with the human retinal microvasculature network whereas images of healthy subjects show a lower value of generalized dimensions indicating normal complexity of biostructure. On the other hand, the lacunarity analysis of the amblyopia images (segmented and skeletonized versions) show a lower average of the lacunarity parameter Λ than the corresponding values for normal images (segmented and skeletonized versions). CONCLUSION The multifractal and lacunarity analysis may be used as a non-invasive predictive complementary tool to distinguish amblyopic subjects from healthy subjects and hence this technique could be used for an early diagnosis of patients with amblyopia. PMID:26558216

  2. Looking at Images with Human Figures: Comparison between Autistic and Normal Children.

    ERIC Educational Resources Information Center

    van der Geest, J. N.; Kemner, C.; Camfferman, G.; Verbaten, M. N.; van Engeland, H.

    2002-01-01

    In this study, the looking behavior of 16 autistic and 14 non-autistic children toward cartoon-like scenes that included a human figure was measured quantitatively using an infrared eye-tracking device. Fixation behavior of autistic children was similar to that of their age-and IQ-matched normal peers. Results do not support the idea that autistic…

  3. Cdx2 modulates proliferation in normal human intestinal epithelial crypt cells

    SciTech Connect

    Escaffit, Fabrice; Pare, Frederic; Gauthier, Remy; Rivard, Nathalie; Boudreau, Francois; Beaulieu, Jean-Francois . E-mail: Jean-Francois.Beaulieu@USherbrooke.ca

    2006-03-31

    The homeobox gene Cdx2 is involved in the regulation of the expression of intestine specific markers such as sucrase-isomaltase and lactase-phlorizin hydrolase. Previous studies performed with immortalized or transformed intestinal cell lines have provided evidence that Cdx2 can promote morphological and functional differentiation in these experimental models. However, no data exist concerning the implication of this factor in normal human intestinal cell physiology. In the present work, we have investigated the role of Cdx2 in normal human intestinal epithelial crypt (HIEC) cells that lack this transcription factor. The establishment of HIEC cells expressing Cdx2 in an inducible manner shows that forced expression of Cdx2 significantly alters the proliferation of intestinal crypt cells and stimulates dipeptidylpeptidase IV expression but is not sufficient to trigger intestinal terminal differentiation. These observations suggest that Cdx2 requires additional factors to activate the enterocyte differentiation program in normal undifferentiated cells.

  4. Identification of normal and cancerous human colorectal muscularis propria by multiphoton microscopy in different sections

    NASA Astrophysics Data System (ADS)

    Zhou, Yi; Chen, Zhifen; Kang, Deyong; li, Lianhuang; Zhuo, Shuangmu; Zhu, Xiaoqin; Guan, Guoxian; Chen, Jianxin

    2016-01-01

    Multiphoton microscopy (MPM) based on two-photon excited fluorescence (TPEF) and second harmonic generation (SHG) as a potential diagnostic tool is attractive. MPM can effectively provide information about morphological and biochemical changes in biological tissues at the molecular level. In this paper, we attempt to identify normal and cancerous human colorectal muscularis propria by multiphoton microscopy in different sections (both in transverse and longitudinal sections). The results show that MPM can display different microstructure changes in the transverse and longitudinal sections of colorectal muscularis propria. MPM also can quantitatively describe the alteration of collagen content between normal and cancerous muscle layers. These are important pathological findings that MPM images can bring more detailed complementary information about tissue architecture and cell morphology through observing the transverse and longitudinal sections of colorectal muscularis propria. This work demonstrates that MPM can be better for identifying the microstructural characteristics of normal and cancerous human colorectal muscularis propria in different sections.

  5. Two-Photon Laser Scanning Microscopy of the Transverse-Axial Tubule System in Ventricular Cardiomyocytes from Failing and Non-Failing Human Hearts

    PubMed Central

    Ohler, Andreas; Weisser-Thomas, Jutta; Piacentino, Valentino; Houser, Steven R.; Tomaselli, Gordon F.; O'Rourke, Brian

    2009-01-01

    Objective. The transverse-axial tubule system (TATS) of cardiomyocytes allows a spatially coordinated conversion of electrical excitation into an intracellular Ca2+ signal and consequently contraction. Previous reports have indicated alterations of structure and/or volume of the TATS in cardiac hypertrophy and failure, suggesting a contribution to the impairment of excitation contraction coupling. To test whether structural alterations are present in human heart failure, the TATS was visualized in myocytes from failing and non-failing human hearts. Methods and Results. In freshly isolated myocytes, the plasmalemmal membranes were labeled with Di-8-ANEPPS and imaged using two-photon excitation at 780 nm. Optical sections were taken every 300 nm through the cells. After deconvolution, the TATS was determined within the 3D data sets, revealing no significant difference in normalized surface area or volume. To rule out possible inhomogeneity in the arrangement of the TATS, Euclidian distance maps were plotted for every section, allowing to measure the closest distance between any cytosolic and any membrane point. There was a trend towards greater spacing in cells from failing hearts, without statistical significance. Conclusion. Only small changes, but no significant changes in the geometrical dimensions of the TATS were observed in cardiomyocytes from failing compared to non-failing human myocardium. PMID:20224636

  6. Heart regeneration.

    PubMed

    Breckwoldt, Kaja; Weinberger, Florian; Eschenhagen, Thomas

    2016-07-01

    Regenerating an injured heart holds great promise for millions of patients suffering from heart diseases. Since the human heart has very limited regenerative capacity, this is a challenging task. Numerous strategies aiming to improve heart function have been developed. In this review we focus on approaches intending to replace damaged heart muscle by new cardiomyocytes. Different strategies for the production of cardiomyocytes from human embryonic stem cells or human induced pluripotent stem cells, by direct reprogramming and induction of cardiomyocyte proliferation are discussed regarding their therapeutic potential and respective advantages and disadvantages. Furthermore, different methods for the transplantation of pluripotent stem cell-derived cardiomyocytes are described and their clinical perspectives are discussed. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel. PMID:26597703

  7. Apoptosis in Heart Failure: Release of Cytochrome c from Mitochondria and Activation of Caspase-3 in Human Cardiomyopathy

    NASA Astrophysics Data System (ADS)

    Narula, Jagat; Pandey, Pramod; Arbustini, Eloisa; Haider, Nezam; Narula, Navneet; Kolodgie, Frank D.; dal Bello, Barbara; Semigran, Marc J.; Bielsa-Masdeu, Anna; Dec, G. William; Israels, Sara; Ballester, Manel; Virmani, Renu; Saxena, Satya; Kharbanda, Surender

    1999-07-01

    Apoptosis has been shown to contribute to loss of cardiomyocytes in cardiomyopathy, progressive decline in left ventricular function, and congestive heart failure. Because the molecular mechanisms involved in apoptosis of cardiocytes are not completely understood, we studied the biochemical and ultrastructural characteristics of upstream regulators of apoptosis in hearts explanted from patients undergoing transplantation. Sixteen explanted hearts from patients undergoing heart transplantation were studied by electron microscopy or immunoblotting to detect release of mitochondrial cytochrome c and activation of caspase-3. The hearts explanted from five victims of motor vehicle accidents or myocardial ventricular tissues from three donor hearts were used as controls. Evidence of apoptosis was observed only in endstage cardiomyopathy. There was significant accumulation of cytochrome c in the cytosol, over myofibrils, and near intercalated discs of cardiomyocytes in failing hearts. The release of mitochondrial cytochrome c was associated with activation of caspase-3 and cleavage of its substrate protein kinase C δ but not poly(ADP-ribose) polymerase. By contrast, there was no apparent accumulation of cytosolic cytochrome c or caspase-3 activation in the hearts used as controls. The present study provides in vivo evidence of cytochrome c-dependent activation of cysteine proteases in human cardiomyopathy. Activation of proteases supports the phenomenon of apoptosis in myopathic process. Because loss of myocytes contributes to myocardial dysfunction and is a predictor of adverse outcomes in the patients with congestive heart failure, the present demonstration of an activated apoptotic cascade in cardiomyopathy could provide the basis for novel interventional strategies.

  8. Glucagon-like-peptide-1 receptor expression in normal and diseased human thyroid and pancreas.

    PubMed

    Waser, Beatrice; Blank, Annika; Karamitopoulou, Eva; Perren, Aurel; Reubi, Jean C

    2015-03-01

    Glucagon-like-peptide-1 (GLP1) analogs may induce thyroid or pancreatic diseases in animals, raising questions about their use in diabetic patients. There is, however, controversy regarding expression of GLP1 receptors (GLP1R) in human normal and diseased thyroid and pancreas. Here, 221 human thyroid and pancreas samples were analyzed for GLP1R immunohistochemistry and compared with quantitative in vitro GLP1R autoradiography. Neither normal nor hyperplastic human thyroids containing parafollicular C cells express GLP1R with either method. Papillary thyroid cancer do not, and medullary thyroid carcinomas rarely express GLP1R. Insulin- and somatostatin-producing cells in the normal pancreas express a high density of GLP1R, whereas acinar cells express them in low amounts. Ductal epithelial cells do not express GLP1R. All benign insulinomas express high densities of GLP1R, whereas malignant insulinomas rarely express them. All ductal pancreatic carcinomas are GLP1R negative, whereas 6/20 PanIN 1/2 and 0/12 PanIN 3 express GLP1R. Therefore, normal thyroid, including normal and hyperplastic C cells, or papillary thyroid cancer are not targets for GLP1 analogs in humans. Conversely, all pancreatic insulin- and somatostatin-producing cells are physiological GLP1 targets, as well as most acini. As normal ductal epithelial cells or PanIN 3 or ductal pancreatic carcinomas do not express GLP1R, it seems unlikely that GLP1R is related to neoplastic transformation in pancreas. GLP1R-positive medullary thyroid carcinomas and all benign insulinomas are candidates for in vivo GLP1R targeting. PMID:25216224

  9. Heart Murmurs and Your Child (For Parents)

    MedlinePlus

    ... Story" 5 Things to Know About Zika & Pregnancy Heart Murmurs and Your Child KidsHealth > For Parents > Heart ... to know how the heart works. How the Heart Works The normal heart has four chambers and ...

  10. Normalized Metadata Generation for Human Retrieval Using Multiple Video Surveillance Cameras.

    PubMed

    Jung, Jaehoon; Yoon, Inhye; Lee, Seungwon; Paik, Joonki

    2016-01-01

    Since it is impossible for surveillance personnel to keep monitoring videos from a multiple camera-based surveillance system, an efficient technique is needed to help recognize important situations by retrieving the metadata of an object-of-interest. In a multiple camera-based surveillance system, an object detected in a camera has a different shape in another camera, which is a critical issue of wide-range, real-time surveillance systems. In order to address the problem, this paper presents an object retrieval method by extracting the normalized metadata of an object-of-interest from multiple, heterogeneous cameras. The proposed metadata generation algorithm consists of three steps: (i) generation of a three-dimensional (3D) human model; (ii) human object-based automatic scene calibration; and (iii) metadata generation. More specifically, an appropriately-generated 3D human model provides the foot-to-head direction information that is used as the input of the automatic calibration of each camera. The normalized object information is used to retrieve an object-of-interest in a wide-range, multiple-camera surveillance system in the form of metadata. Experimental results show that the 3D human model matches the ground truth, and automatic calibration-based normalization of metadata enables a successful retrieval and tracking of a human object in the multiple-camera video surveillance system. PMID:27347961

  11. Normalized Metadata Generation for Human Retrieval Using Multiple Video Surveillance Cameras

    PubMed Central

    Jung, Jaehoon; Yoon, Inhye; Lee, Seungwon; Paik, Joonki

    2016-01-01

    Since it is impossible for surveillance personnel to keep monitoring videos from a multiple camera-based surveillance system, an efficient technique is needed to help recognize important situations by retrieving the metadata of an object-of-interest. In a multiple camera-based surveillance system, an object detected in a camera has a different shape in another camera, which is a critical issue of wide-range, real-time surveillance systems. In order to address the problem, this paper presents an object retrieval method by extracting the normalized metadata of an object-of-interest from multiple, heterogeneous cameras. The proposed metadata generation algorithm consists of three steps: (i) generation of a three-dimensional (3D) human model; (ii) human object-based automatic scene calibration; and (iii) metadata generation. More specifically, an appropriately-generated 3D human model provides the foot-to-head direction information that is used as the input of the automatic calibration of each camera. The normalized object information is used to retrieve an object-of-interest in a wide-range, multiple-camera surveillance system in the form of metadata. Experimental results show that the 3D human model matches the ground truth, and automatic calibration-based normalization of metadata enables a successful retrieval and tracking of a human object in the multiple-camera video surveillance system. PMID:27347961

  12. Establishment of proliferative tetraploid cells from telomerase-immortalized normal human fibroblasts.

    PubMed

    Ohshima, Susumu; Seyama, Atsushi

    2016-06-01

    Aneuploidy is observed in the majority of human cancers and is considered to be causally related to carcinogenesis. Although malignant aneuploid cells are suggested to develop from polyploid cells formed in precancerous lesions, the mechanisms of this process remain elusive. This is partly because no experimental model is available where nontransformed polyploid human cells propagate in vitro. We previously showed that proliferative tetraploid cells can be established from normal human fibroblasts by treatment with the spindle poison demecolcine (DC). However, the limited lifespan of these cells hampered detailed analysis of a link between chromosomal instability and the oncogenic transformation of polyploid cells. Here, we report the establishment of proliferative tetraploid cells from the telomerase-immortalized normal human fibroblast cell line TIG-1. Treatment of immortalized diploid cells with DC for 4 days resulted in proliferation of cells with tetraploid DNA content and near-tetraploid/tetraploid chromosome counts. Established tetraploid cells had functional TP53 despite growing at almost the same rate as diploid cells. The frequency of clonal and sporadic chromosome aberrations in tetraploid cells was higher than in diploid cells and in one experiment, gradually increased with repeated subculture. This study suggests that tetraploid cells established from telomerase-immortalized normal human fibroblasts can be a valuable model for studying chromosomal instability and the oncogenic potential of polyploid cells. © 2016 Wiley Periodicals, Inc. PMID:26917432

  13. Differentiation of normal and transformed human fibroblasts in vitro is influenced by electromagnetic fields

    SciTech Connect

    Rodemann, H.P.; Bayreuther, K.; Pfleiderer, G.

    1989-06-01

    We studied the effect of symmetric, biphasic sinusoidal electromagnetic fields (EMF) (20 Hz, 6 mT) on the differentiation of normal human skin fibroblasts (HH-8), normal human lung fibroblasts (WI38), and SV40-transformed human lung fibroblasts (WI38SV40) in in vitro cultures. Cells were exposed up to 21 days for 2 x 6 h per day to EMF. Normal mitotic human skin and lung fibroblasts could be induced to differentiate into postmitotic cells upon exposure to EMF. Concomitantly, the synthesis of total collagen as well as total cellular protein increased significantly by a factor of 5-13 in EMF-induced postmitotic cells. As analyzed by two-dimensional gel electrophoresis of (/sup 35/S)methionine-labeled polypeptides, EMF-induced postmitotic cells express the same differentiation-dependent and cell type-specific marker proteins as their spontaneously arising counterparts. In SV40-transformed human lung fibroblasts (cell line WI38SV40) the exposure to EMF induced the differentiation of mitotic WI38SV40 cells into postmitotic and degenerating cells in subpopulations of WI38SV40 cell cultures. Other subpopulations of WI38SV40 cells did not show any effect of EMF on cell proliferation and differentiation. These results indicate that long-term EMF exposure of fibroblasts in vitro induces the differentiation of mitotic to postmitotic cells that are characterized by differentiation-specific proteins and differentiation-dependent enhanced metabolic activities.

  14. Effects of acute beta-adrenoceptor blockade with metoprolol on the renal response to dopamine in normal humans.

    PubMed Central

    Olsen, N V; Lang-Jensen, T; Hansen, J M; Plum, I; Thomsen, J K; Strandgaard, S; Leyssac, P P

    1994-01-01

    The present study investigated the contribution of adrenergic beta 1-receptor stimulation to the cardiovascular and renal effects of low-dose dopamine in eight normal, water-loaded humans. Metoprolol (100 mg) or placebo was administered orally at 08.00 h in a randomized, double-blind fashion on two different days. Renal clearance studies were performed during a 1 h baseline period, two 1 h periods with dopamine infusion (3 micrograms kg-1 min-1), and a 1 h recovery period. Cardiac output was measured by an ultrasonic Doppler method, and lithium clearance (CLLi) was used to estimate proximal tubular outflow. Baseline values of heart rate, systolic pressure and mean arterial pressure decreased with metoprolol compared with placebo, but cardiac output, effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) were not significantly changed. Metoprolol significantly decreased baseline CLLi and sodium clearance (CLNa) by 19% (P < 0.01) and 34% (P < 0.01), respectively. Metoprolol blunted the dopamine-induced increases in heart rate and systolic pressure, but cardiac output increased to the same extent on both study days by 26% (placebo, P < 0.05) and by 31% (metoprolol, P < 0.01), respectively. With and without metoprolol, dopamine did not significantly change GFR, and the percentage increases in ERPF were similar on the two study days (40% (P < 0.001) and 42% (P < 0.001), respectively). Dopamine increased CLLi and CLNa by 31% (P < 0.01) and 114% (P < 0.01), respectively, with placebo, and by 36% (P < 0.01) and 114% (P < 0.01), respectively, with metoprolol. Values during infusion remained significantly lower with metoprolol compared with placebo.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8018456

  15. Modulation of the Rho/ROCK pathway in heart and lung after thorax irradiation reveals targets to improve normal tissue toxicity.

    PubMed

    Monceau, Virginie; Pasinetti, Nadia; Schupp, Charlotte; Pouzoulet, Fred; Opolon, Paule; Vozenin, Marie-Catherine

    2010-11-01

    The medical options available to prevent or treat radiation-induced injury are scarce and developing effective countermeasures is still an open research field. In addition, more than half of cancer patients are treated with radiation therapy, which displays a high antitumor efficacy but can cause, albeit rarely, disabling long-term toxicities including radiation fibrosis. Progress has been made in the definition of molecular pathways associated with normal tissue toxicity that suggest potentially effective therapeutic targets. Targeting the Rho/ROCK pathway seems a promising anti-fibrotic approach, at least in the gut; the current study was performed to assess whether this target was relevant to the prevention and/or treatment of injury to the main thoracic organs, namely heart and lungs. First, we showed activation of two important fibrogenic pathways (Smad and Rho/ROCK) in response to radiation-exposure to adult cardiomyocytes; we extended these observations in vivo to the heart and lungs of mice, 15 and 30 weeks post-irradiation. We correlated this fibrogenic molecular imprint with alteration of heart physiology and long-term remodelling of pulmonary and cardiac histological structures. Lastly, cardiac and pulmonary radiation injury and bleomycin-induced pulmonary fibrosis were successfully modulated using Rho/ROCK inhibitors (statins and Y-27632) and this was associated with a normalization of fibrogenic markers. In conclusion, the present paper shows for the first time, activation of Rho/ROCK and Smad pathways in pulmonary and cardiac radiation-induced delayed injury. Our findings thereby reveal a safe and efficient therapeutic opportunity for the abrogation of late thoracic radiation injury, potentially usable either before or after radiation exposure; this approach is especially attractive in (1) the radiation oncology setting, as it does not interfere with prior anti-cancer treatment and in (2) radioprotection, as applicable to the treatment of established

  16. Posttranslational modifications and dysfunction of mitochondrial enzymes in human heart failure.

    PubMed

    Sheeran, Freya L; Pepe, Salvatore

    2016-08-01

    Deficiency of energy supply is a major complication contributing to the syndrome of heart failure (HF). Because the concurrent activity profile of mitochondrial bioenergetic enzymes has not been studied collectively in human HF, our aim was to examine the mitochondrial enzyme defects in left ventricular myocardium obtained from explanted end-stage failing hearts. Compared with nonfailing donor hearts, activity rates of complexes I and IV and the Krebs cycle enzymes isocitrate dehydrogenase, malate dehydrogenase, and aconitase were lower in HF, as determined spectrophotometrically. However, activity rates of complexes II and III and citrate synthase did not differ significantly between the two groups. Protein expression, determined by Western blotting, did not differ between the groups, implying posttranslational perturbation. In the face of diminished total glutathione and coenzyme Q10 levels, oxidative modification was explored as an underlying cause of enzyme dysfunction. Of the three oxidative modifications measured, protein carbonylation was increased significantly by 31% in HF (P < 0.01; n = 18), whereas levels of 4-hydroxynonenal and protein nitration, although elevated, did not differ. Isolation of complexes I and IV and F1FoATP synthase by immunocapture revealed that proteins containing iron-sulphur or heme redox centers were targets of oxidative modification. Energy deficiency in end-stage failing human left ventricle involves impaired activity of key electron transport chain and Krebs cycle enzymes without altered expression of protein levels. Augmented oxidative modification of crucial enzyme subunit structures implicates dysfunction due to diminished capacity for management of mitochondrial reactive oxygen species, thus contributing further to reduced bioenergetics in human HF. PMID:27406740

  17. Do Lambs Perceive Regular Human Stroking as Pleasant? Behavior and Heart Rate Variability Analyses

    PubMed Central

    Coulon, Marjorie; Nowak, Raymond; Peyrat, Julie; Chandèze, Hervé; Boissy, Alain; Boivin, Xavier

    2015-01-01

    Stroking by humans is beneficial to the human-animal relationship and improves welfare in many species that express intraspecific allogrooming, but very few studies have looked at species like sheep that do not express such contact except around parturition. This study investigated the way lambs perceive regular human tactile contact using behavioral and physiological responses. Twenty-four lambs were reared and bucket-fed in groups of four. All were stroked daily by their familiar caregiver. At 8 weeks of age, the lambs were individually tested in their home pen but in a 1×1m open-barred pen after a 15h period of habituation to physical separation from peers while remaining in visual and auditory contact. Half of the lambs received stroking by their caregiver for 8min and half were exposed to their caregiver’s immobile presence. Heart rate and heart rate variability were recorded and analyzed by 2-min slots over the same interval based on three measures: mean heart rate value (HR), root mean square of successive differences (RMSSD) and standard deviation of all intervals measured between consecutive sinus beats (SDNN). Behavioral responses (ear postures of the lamb and time spent in contact with the familiar caregiver, on the knees of the familiar caregiver, and moving) were recorded throughout the test. Lamb HR decreased continuously while in the presence of their caregiver. Lambs being stroked showed slower HR and higher RMSSD which reflected positive emotional states compared to lambs left unstroked. All behavioral variables were highly correlated with the main component axis of the PCA analyses: the more the animals stayed in contact with their caregiver, the less they moved and the more their ears were hanging. This first component clearly differentiates lambs being stroked or not. Behavioral and physiological observations support the hypothesis that gentle physical contact with the caregiver is perceived positively by lambs. PMID:25714604

  18. Do lambs perceive regular human stroking as pleasant? Behavior and heart rate variability analyses.

    PubMed

    Coulon, Marjorie; Nowak, Raymond; Peyrat, Julie; Chandèze, Hervé; Boissy, Alain; Boivin, Xavier

    2015-01-01

    Stroking by humans is beneficial to the human-animal relationship and improves welfare in many species that express intraspecific allogrooming, but very few studies have looked at species like sheep that do not express such contact except around parturition. This study investigated the way lambs perceive regular human tactile contact using behavioral and physiological responses. Twenty-four lambs were reared and bucket-fed in groups of four. All were stroked daily by their familiar caregiver. At 8 weeks of age, the lambs were individually tested in their home pen but in a 1×1m open-barred pen after a 15 h period of habituation to physical separation from peers while remaining in visual and auditory contact. Half of the lambs received stroking by their caregiver for 8 min and half were exposed to their caregiver's immobile presence. Heart rate and heart rate variability were recorded and analyzed by 2-min slots over the same interval based on three measures: mean heart rate value (HR), root mean square of successive differences (RMSSD) and standard deviation of all intervals measured between consecutive sinus beats (SDNN). Behavioral responses (ear postures of the lamb and time spent in contact with the familiar caregiver, on the knees of the familiar caregiver, and moving) were recorded throughout the test. Lamb HR decreased continuously while in the presence of their caregiver. Lambs being stroked showed slower HR and higher RMSSD which reflected positive emotional states compared to lambs left unstroked. All behavioral variables were highly correlated with the main component axis of the PCA analyses: the more the animals stayed in contact with their caregiver, the less they moved and the more their ears were hanging. This first component clearly differentiates lambs being stroked or not. Behavioral and physiological observations support the hypothesis that gentle physical contact with the caregiver is perceived positively by lambs. PMID:25714604

  19. Enhanced engraftment, proliferation, and therapeutic potential in heart using optimized human iPSC-derived cardiomyocytes

    PubMed Central

    Funakoshi, Shunsuke; Miki, Kenji; Takaki, Tadashi; Okubo, Chikako; Hatani, Takeshi; Chonabayashi, Kazuhisa; Nishikawa, Misato; Takei, Ikue; Oishi, Akiko; Narita, Megumi; Hoshijima, Masahiko; Kimura, Takeshi; Yamanaka, Shinya; Yoshida, Yoshinori

    2016-01-01

    Human pluripotent stem cell-derived cardiomyocytes (CMs) are a promising tool for cardiac cell therapy. Although transplantation of induced pluripotent stem cell (iPSC)-derived CMs have been reported in several animal models, the treatment effect was limited, probably due to poor optimization of the injected cells. To optimize graft cells for cardiac reconstruction, we compared the engraftment efficiency of intramyocardially-injected undifferentiated-iPSCs, day4 mesodermal cells, and day8, day20, and day30 purified iPSC-CMs after initial differentiation by tracing the engraftment ratio (ER) using in vivo bioluminescence imaging. This analysis revealed the ER of day20 CMs was significantly higher compared to other cells. Transplantation of day20 CMs into the infarcted hearts of immunodeficient mice showed good engraftment, and echocardiography showed significant functional improvement by cell therapy. Moreover, the imaging signal and ratio of Ki67-positive CMs at 3 months post injection indicated engrafted CMs proliferated in the host heart. Although this graft growth reached a plateau at 3 months, histological analysis confirmed progressive maturation from 3 to 6 months. These results suggested that day20 CMs had very high engraftment, proliferation, and therapeutic potential in host mouse hearts. They also demonstrate this model can be used to track the fate of transplanted cells over a long time. PMID:26743035

  20. Sex differences in healthy human heart rate variability: A meta-analysis.

    PubMed

    Koenig, Julian; Thayer, Julian F

    2016-05-01

    The present meta-analysis aimed to quantify current evidence on sex differences in the autonomic control of the heart, indexed by measures of heart rate variability (HRV) in healthy human subjects. An extensive search of the literature yielded 2020 titles and abstracts, of which 172 provided sufficient reporting of sex difference in HRV. Data from 63,612 participants (31,970 females) were available for analysis. Meta-analysis yielded a total of 1154 effect size estimates (k) across 50 different measures of HRV in a cumulated total of 296,247 participants. Females showed a significantly lower mean RR interval and standard deviation of RR intervals (SDNN). The power spectral density of HRV in females is characterized by significantly less total power that contains significantly greater high- (HF) and less low-frequency (LF) power. This is further reflected by a lower LF/HF ratio. Meta-regression revealed significant effects of age, respiration control and the length of recording available for analysis. Although women showed greater mean heart rate, they showed greater vagal activity indexed by HF power of HRV. Underlying mechanisms of these findings are discussed. PMID:26964804

  1. Plasma levels of intermedin (adrenomedullin-2) in healthy human volunteers and patients with heart failure.

    PubMed

    Bell, David; Gordon, Brian J; Lavery, Anita; Megaw, Katie; Kinney, Michael O; Harbinson, Mark T

    2016-02-01

    Intermedin/adrenomedullin-2 (IMD) is a member of the adrenomedullin/CGRP peptide family. Less is known about the distribution of IMD than for other family members within the mammalian cardiovascular system, particularly in humans. The aim was to evaluate plasma IMD levels in healthy subjects and patients with chronic heart failure. IMD and its precursor fragments, preproIMD(25-56) and preproIMD(57-92), were measured by radioimmunoassay in 75 healthy subjects and levels of IMD were also compared to those of adrenomedullin (AM) and mid-region proadrenomedullin(45-92) (MRproAM(45-92)) in 19 patients with systolic heart failure (LVEF<45%). In healthy subjects, plasma levels (mean+SE) of IMD (6.3+0.6 pg ml(-1)) were lower than, but correlated with those of AM (25.8+1.8 pg ml(-1); r=0.49, p<0.001). Plasma preproIMD(25-56) (39.6+3.1 pg ml(-1)), preproIMD(57-92) (25.9+3.8 pg ml(-1)) and MRproAM(45-92) (200.2+6.7 pg ml(-1)) were greater than their respective bioactive peptides. IMD levels correlated positively with BMI but not age, and were elevated in heart failure (9.8+1.3 pg ml(-1), p<0.05), similarly to MRproAM(45-92) (329.5+41.9 pg ml(-1), p<0.001) and AM (56.8+10.9 pg ml(-1), p<0.01). IMD levels were greater in heart failure patients with concomitant renal impairment (11.3+1.8 pg ml(-1)) than those without (6.5+1.0 pg ml(-1); p<0.05). IMD and AM were greater in patients receiving submaximal compared with maximal heart failure drug therapy and were decreased after 6 months of cardiac resynchronization therapy. In conclusion, IMD is present in the plasma of healthy subjects less abundantly than AM, but is similarly correlated weakly with BMI. IMD levels are elevated in heart failure, especially with concomitant renal impairment, and tend to be reduced by high intensity drug or pacing therapy. PMID:26767798

  2. Radioimmunoassay of erythropoietin: circulating levels in normal and polycythemic human beings.

    PubMed

    Garcia, J F; Ebbe, S N; Hollander, L; Cutting, H O; Miller, M E; Cronkite, E P

    1982-05-01

    Techniques are described in detail for the RIA of human Ep in unextracted plasma or serum. With 100 microliters of sample, the essay is sensitive at an Ep concentration of approximately 4 mU/ml, and when required, the sensitivity can be increased to 0.4 mU/ml, a range considerably less than the concentration observed in normal human beings. This is approximately 100 times more sensitive than existing in vivo bioassays for this hormone. Studies concerned with the validation of the Ep RIA show a high degree of correlation with the polycythemic mouse bioassay. Dilutions of a variety of human serum samples show a parallel relationship with the standard reference preparation for Ep. Validation of the RIA is further confirmed by observations of appropriate increases or decreases in circulating Ep levels in physiological and clinical conditions known to be associated with stimulation of suppression of Ep secretion. Significantly different mean serum concentrations of 17.2 mU/ml for normal male subjects and 18.8 mU/ml for normal female subjects were observed. Mean plasma Ep concentrations in patients with polycythemia vera are significantly decreased, and those of patients with secondary polycythemia are significantly increased as compared to plasma levels in normal subjects. These results demonstrate an initial practical value of the Ep RIA inthe hematology clinic, which will most certainly be expanded with its more extensive use. PMID:7069267

  3. Viscoelastic behaviour of human blood and polyacrylamide model fluids for heart valve testing

    NASA Astrophysics Data System (ADS)

    Lerche, Dietmar; Vlastos, Georgios; Koch, Brigitte; Pohl, Manfred; Affeld, Klaus

    1993-06-01

    New heart valves and other cardiovascular assist systems have to be tested for hydrodynamic performance. In place of human blood simple model fluids like glycerol solutions are employed often due to ethical and practical reasons. But blood exhibits complex non-Newtonian and viscoelastic behaviour. Rheological blood properties are reviewed based on literature and own experimental results. Furthermore we studied polymer solutions with respect to blood-like flow behaviour. Rheology was assessed by means of the low shear rotational viscometer (LS 40, Mettler-Toledo, Switzerland) under stationary and dynamic shear conditions (variation of frequency and angular displacement).

  4. Isolation and characterization of human malignant glioma cells from histologically normal brain.

    PubMed

    Silbergeld, D L; Chicoine, M R

    1997-03-01

    Brain invasion prevents complete surgical extirpation of malignant gliomas; however, invasive cells from distant, histologically normal brain previously have not been isolated, cultured, and characterized. To evaluate invasive human malignant glioma cells, the authors established cultures from gross tumor and histologically normal brain. Three men and one woman, with a mean age of 67 years, underwent two frontal and two temporal lobectomies for tumors, which yielded specimens of both gross tumor and histologically normal brain. Each specimen was acquired a minimum of 4 cm from the gross tumor. The specimens were split: a portion was sent for neuropathological evaluation (three glioblastomas multiforme and one oligodendroglioma) and a portion was used to establish cell lines. Morphologically, the specimens of gross tumor and histologically normal brain were identical in three of the four cell culture pairs. Histochemical staining characteristics were consistent both within each pair and when compared with the specimens sent for neuropathological evaluation. Cultures demonstrated anchorage-independent growth in soft agarose and neoplastic karyotypes. Growth rates in culture were greater for histologically normal brain than for gross tumor in three of the four culture pairs. Although the observed increases in growth rates of histologically normal brain cultures do not correlate with in vivo behavior, these findings corroborate the previously reported stem cell potential of invasive glioma cells. Using the radial dish assay, no significant differences in motility between cultures of gross tumor and histologically normal brain were found. In summary, tumor cells were cultured from histologically normal brain acquired from a distance greater than 4 cm from the gross tumor, indicating the relative insensitivity of standard histopathological identification of invasive glioma cells (and hence the inadequacy of frozen-section evaluation of resection margins). Cell lines

  5. Human neural tuning estimated from compound action potentials in normal hearing human volunteers

    NASA Astrophysics Data System (ADS)

    Verschooten, Eric; Desloovere, Christian; Joris, Philip X.

    2015-12-01

    The sharpness of cochlear frequency tuning in humans is debated. Evoked otoacoustic emissions and psychophysical measurements suggest sharper tuning in humans than in laboratory animals [15], but this is disputed based on comparisons of behavioral and electrophysiological measurements across species [14]. Here we used evoked mass potentials to electrophysiologically quantify tuning (Q10) in humans. We combined a notched noise forward masking paradigm [9] with the recording of trans tympanic compound action potentials (CAP) from masked probe tones in awake human and anesthetized monkey (Macaca mulatta). We compare our results to data obtained with the same paradigm in cat and chinchilla [16], and find that CAP-Q10values in human are ˜1.6x higher than in cat and chinchilla and ˜1.3x higher than in monkey. To estimate frequency tuning of single auditory nerve fibers (ANFs) in humans, we derive conversion functions from ANFs in cat, chinchilla, and monkey and apply these to the human CAP measurements. The data suggest that sharp cochlear tuning is a feature of old-world primates.

  6. Complement Regulatory Activity of Normal Human Intraocular Fluid Is Mediated by MCP, DAF, and CD59

    PubMed Central

    Sohn, Jeong-Hyeon; Kaplan, Henry J.; Suk, Hye-Jung; Bora, Puran S.; Bora, Nalini S.

    2007-01-01

    Purpose To identify the molecules in normal human intraocular fluid (aqueous humor and vitreous) that inhibit the functional activity of the complement system. Methods Aqueous humor and vitreous were obtained from patients with noninflammatory ocular disease at the time of surgery. Samples were incubated with normal human serum (NHS), and the mixture assayed for inhibition of the classical and alternative complement pathways using standard CH50 and AH50 hemolytic assays, respectively. Both aqueous humor and vitreous were fractionated by microconcentrators and size exclusion column chromatography. The inhibitory molecules were identified by immunoblotting as well as by studying the effect of depletion of membrane cofactor protein (MCP), decay-accelerating factor (DAF), and CD59 on inhibitory activity. Results Both aqueous humor and vitreous inhibited the activity of the classical pathway (CH50). Microcentrifugation revealed the major inhibitory activity resided in the fraction with an Mr ≥ 3 kDa. Chromatography on an S-100-HR column demonstrated that the most potent inhibition was associated with the high-molecular-weight fractions (≥ 19.5 kDa). In contrast to unfractionated aqueous and vitreous, fractions with an Mr ≥ 3 kDa also had an inhibitory effect on the alternative pathway activity (AH50). The complement regulatory activity in normal human intraocular fluid was partially blocked by monoclonal antibodies against MCP, DAF, and CD59. Immunoblot analysis confirmed the presence of these three molecules in normal intraocular fluid. Conclusions Our results demonstrate that normal human intraocular fluid (aqueous humor and vitreous) contains complement inhibitory factors. Furthermore, the high-molecular-weight factors appear to be the soluble forms of MCP, DAF, and CD59. PMID:11095615

  7. Morphological description of great cardiac vein in pigs compared to human hearts

    PubMed Central

    Alejandro Gómez, Fabian; Ballesteros, Luis Ernesto; Stella Cortés, Luz

    2015-01-01

    Introduction In spite of its importance as an experimental model, the information on the great cardiac vein in pigs is sparse. Objective To determine the morphologic characteristics of the great cardiac vein and its tributaries in pigs. Methods 120 hearts extracted from pigs destined to the slaughterhouse with stunning method were studied. This descriptive cross-over study evaluated continuous variables with T test and discrete variables with Pearson χ square test. A level of significance P<0.05 was used. The great cardiac vein and its tributaries were perfused with polyester resin (85% Palatal and 15% Styrene) and then subjected to potassium hydroxide infusion to release the subepicardial fat. Calibers were measured, and trajectories and relations with adjacent arterial structures were evaluated. Results The origin of the great cardiac vein was observed at the heart apex in 91 (76%) hearts. The arterio-venous trigone was present in 117 (97.5%) specimens, corresponding to the open expression in its lower segment and to the closed expression in the upper segment in the majority of the cases (65%). The caliber of the great cardiac vein at the upper segment of the paraconal interventricular sulcus was 3.73±0.79 mm. An anastomosis between the great cardiac vein and the middle cardiac vein was found in 59 (49%) specimens. Conclusion The morphological and biometric characteristics of the great cardiac vein and its tributaries had not been reported in prior studies, and due to their similitude with those of the human heart, allows us to propose the pig model for procedural and hemodynamic applications. PMID:25859869

  8. Radiographic Comparison of Human Lung Shape During Normal Gravity and Weightlessness

    NASA Technical Reports Server (NTRS)

    Michels, D. B.; Friedman, P. J.; West, J. B.

    1979-01-01

    Chest radiographs in five seated normal volunteers at 1 G and 0 G were made with a view toward comparing human lung shape during normal gravity and weightlessness. Lung shape was assessed by measuring lung heights and widths in upper, middle and lower lung regions. No significant differences were found between any of the 1-G and 0-G measurements, although there was a slight tendency for the lung to become shorter and wider at 0 G. The evidence that gravity causes regional differences in ventilation by direct action on the lung is consistent with the theoretical analysis of West and Matthews (1972).

  9. Low calcium culture condition induces mesenchymal cell-like phenotype in normal human epidermal keratinocytes

    SciTech Connect

    Takagi, Ryo; Yamato, Masayuki; Murakami, Daisuke; Sugiyama, Hiroaki; Okano, Teruo

    2011-08-26

    Highlights: {yields} Normal human epidermal keratinocytes serially cultured under low calcium concentration were cytokeratin and vimentin double positive cells. {yields} The human keratinocytes expressed some epithelial stem/progenitor cell makers, mesenchymal cell markers, and markers of epithelial-mesenchymal transition. {yields} Mesenchymal cell-like phenotype in the keratinocytes was suppressed under high-calcium condition. -- Abstract: Epithelial-mesenchymal transition (EMT) is an important cellular phenomenon in organ developments, cancer invasions, and wound healing, and many types of transformed cell lines are used for investigating for molecular mechanisms of EMT. However, there are few reports for EMT in normal human epithelial cells, which are non-transformed or non-immortalized cells, in vitro. Therefore, normal human epidermal keratinocytes (NHEK) serially cultured in low-calcium concentration medium (LCM) were used for investigating relations between differentiation and proliferation and mesenchymal-like phenotype in the present study, since long-term cultivation of NHEK is achieved in LCM. Interestingly, NHEK serially cultured in LCM consisted essentially of cytokeratin-vimentin double positive cells (98%), although the NHEK exhibited differentiation under high-calcium culture condition with 3T3 feeder layer. The vimentin expression was suppressed under high-calcium condition. These results may indicate the importance of mesenchymal-like phenotype for serially cultivation of NHEK in vitro.

  10. Native cellular fluorescence characteristics of normal and malignant epithelial cells from human larynx

    NASA Astrophysics Data System (ADS)

    Parmeswearan, Diagaradjane; Ganesan, Singaravelu; Nalini, R.; Aruna, Prakasa R.; Veeraganesh, V.; Alfano, Robert R.

    1997-08-01

    Many applications of native fluorescence spectroscopy of intrinsic biomolecules such as Try, Tyr, Phe, NADH and FAD are reported on both the characterization and the discrimination of malignant tissues from the normal. In the field of diagnostic oncology, extensive studies have been made to distinguish the normal from malignant condition in breast, cervix, colon and bronchus. From the studies made by Alfano and co-workers, it was found that the emission at 340 and 440 nm under UV excitation have shown statistically significant difference between normal and malignant tissues. As tissues are highly complex in nature, it is worth to known whether the changes arise from cells or from other extracellular tissue components, so as to enable us to have better understanding on the transformation mechanism of normal into malignant and to go for an improved approach in the effective optical diagnosis. In this context, the present study addresses the question of whether there are differences in the native cellular fluorescence characteristics between normal and malignant epithelial cells from human larynx. With this aim, the UV fluorescence emission spectra in the wavelength region of excitation between 270 - 310 nm and the excitation spectra for 340 nm emission were measured and analyzed. In order to quantify the altered fluorescence signal between the normal and malignant cells, different ratio parameters were introduced.

  11. Prevalence, Clinical Phenotype, and Outcomes Associated with Normal B-Type Natriuretic Peptide Levels in Heart Failure with Preserved Ejection Fraction

    PubMed Central

    Anjan, Venkatesh Y.; Loftus, Timothy M.; Burke, Michael A.; Akhter, Nausheen; Fonarow, Gregg C.; Gheorghiade, Mihai; Shah, Sanjiv J.

    2012-01-01

    B-type natriuretic peptide (BNP) is used widely to exclude heart failure (HF) in patients with dyspnea. However, most studies of BNP have focused on diagnosing HF with reduced ejection fraction (EF). We hypothesized that a normal BNP (≤ 100 pg/ml) is relatively common in HF with preserved EF (HFpEF), a heterogeneous disorder commonly associated with obesity. We prospectively studied 159 consecutive patients enrolled in the Northwestern University HFpEF Program. All subjects had symptomatic HF with EF>50% and elevated pulmonary capillary wedge pressure (PCWP). BNP was tested at baseline in all subjects. We compared clinical characteristics, echocardiographic parameters, invasive hemodynamics, and outcomes among HFpEF patients with normal (≤ 100 pg/ml) vs. elevated (>100 pg/ml) BNP. Of the 159 HFpEF patients, 46 (29%) had BNP ≤ 100 pg/ml. Subjects with normal BNP were younger, more often female, had higher rates of obesity and higher body-mass index, and less commonly had chronic kidney disease and atrial fibrillation. Both EF and PCWP were similar in normal vs. elevated BNP groups (62±7 vs. 61±7% [P=0.67] and 25±8 vs. 27±9 mmHg [P=0.42], respectively). Elevated BNP was associated with enlarged left atrial volume, worse diastolic function, abnormal right ventricular structure/function, and worse outcomes (e.g., adjusted hazard ratio for HF hospitalization = 4.0, 95% confidence interval 1.6-9.7, P=0.003). In conclusion, a normal BNP is present in 29% of symptomatic outpatients with HFpEF who have elevated PCWP, obesity is likely the primary driver of this finding, and although BNP is useful as a prognostic marker in HFpEF, a normal BNP does not exclude the outpatient diagnosis of HFpEF. PMID:22681864

  12. Ethanolic Extracts of California Mugwort (Artemisia douglasiana Besser) Are Cytotoxic against Normal and Cancerous Human Cells

    PubMed Central

    Somaweera, Himali; Lai, Gary C.; Blackeye, Rachel; Littlejohn, Beverly; Kirksey, Justine; Aguirre, Richard M.; LaPena, Vince; Pasqua, Anna; Hintz, Mary McCarthy

    2013-01-01

    California mugwort (Artemisia douglasiana Besser) is used by many tribes throughout California to treat a variety of conditions, including colds, allergies, and pain. California mugwort is also utilized as women’s medicine. Its use is on the rise outside of Native communities, often without the guidance of a traditional healer or experienced herbalist. Because it has been shown to have antiproliferative activity against plant and animal cells, we investigated whether California mugwort extracts have an effect on normal human cells as well as estrogen receptor positive (ER+) and estrogen receptor negative (ER−) human breast cancer cells. Ethanolic and aqueous extracts of A. douglasiana leaves were tested for cytotoxicity against unstimulated normal human peripheral blood mononuclear cells (hPBMC), as well as against an ER+ human breast cancer cell line (BT-474) and an ER− human breast cancer cell line (MDA-MB-231). An ethanolic leaf extract killed hPBMC, BT-474, and MDA-MB-231 cells with IC50 values of 23.6 ± 0.3, 27 ± 5, and 37 ± 4 μg/ml, respectively. An aqueous extract killed hPBMC with an IC50 value of 60 ± 10 μg/ml, but had no effect on the two cancer cell lines at concentrations up to 100 μg/ml. The results of this study indicate that the cytotoxicity of California mugwort extends to normal human cells, as well as cancerous cells. Therefore, until further is known about the safety of this medicine, caution should be taken when consuming extracts of California mugwort, whether as a tincture or as a tea. PMID:24073389

  13. Cyclic GMP phosphodiesterase activity role in normal and inflamed human dental pulp.

    PubMed

    Spoto, G; Ferrante, M; D'Intino, M; Rega, L; Dolci, M; Trentini, P; Ciavarelli, L

    2004-01-01

    Cyclic GMP phosphodiesterase (cGMP PDE) plays an important role in pulp tissues. High levels of cGMP PDE are found in dental pulp cells. In the present study cGMP PDE activity was analyzed in normal healthy human dental pulps, in reversible pulpitis and in irreversible pulpitis. Enzymatic cGMP PDE control values for normal healthy pulps were 4.74+/-0.32 nmol/mg of proteins. In reversible pulpitis the cGMP PDE activity increased almost 3 times. In irreversible pulpitis specimens the values increased 4.5 times compared with the normal healthy pulps activity. The differences between the groups (control vs. reversible pulpitis and vs. irreversible pulpitis) were statistically significant. These results point to a role of cGMP PDE in the initial pulp response after injury. PMID:16857102

  14. Cyclic Amp phosphodiesterase activity in normal and inflamed human dental pulp.

    PubMed

    Spoto, G; Menna, V; Serra, E; Santoleri, F; Perfetti, G; Ciavarelli, L; Trentini, P

    2004-01-01

    Cyclic AMP phosphodiesterase (cAMP PDE) seems to be important in pulp tissues. High levels of cAMP PDE have been demonstrated to be in dental pulp cells. In the present study cAMP PDE activity was analyzed in normal healthy human dental pulps, in reversible pulpitis and in irreversible pulpitis. Enzymatic cAMP PDE control values for normal healthy pulps were 12.14 +/- 3.74 nmols/mg of proteins. In reversible pulpitis the cAMP PDE activity increased almost 2.5 times. In irreversible pulpitis specimens the values increased 4.5 times compared with normal healthy pulps activity. The differences between the groups (control vs. reversible pulpitis and vs. irreversible pulpitis) were statistically significant. These results could point to a role of cAMP PDE in the initial pulp response after injury. PMID:16857100

  15. FTIR microscopic comparative study on normal, premalignant, and malignant tissues of human intenstine

    NASA Astrophysics Data System (ADS)

    Mordechai, Shaul; Argov, Shmuel; Salman, Ahmad O.; Cohen, Beny; Ramesh, Jagannathan; Erukhimovitch, Vitaly; Goldstein, Jed; Sinelnikov, Igor

    2000-07-01

    Fourier-Transform Infrared Spectroscopy (FTIR) employs a unique approach to optical diagnosis of tissue pathology based on the characteristic molecular vibrational spectra of the tissue. The architectural changes in the cellular and sub-cellular levels developing in abnormal tissue, including a majority of cancer forms, manifest themselves in different optical signatures, which can be detected in infrared spectroscopy. The biological systems we have studied include normal, premalignant (polyp) and malignant human colonic tissues from three patients. Our method is based on microscopic infrared study (FTIR-microscopy) of thin tissue specimens and a direct comparison with normal histopathological analysis, which serves as a `gold' reference. The normal intestine tissue has a stronger absorption than polyp and cancerous types over a wide region in all three cases. The detailed analysis showed that there is a significant decrease in total phosphate and creatine contents for polyp and cancerous tissue types in comparison to the controls.

  16. 3D Normal Human Neural Progenitor Tissue-Like Assemblies: A Model of Persistent VZV Infection

    NASA Technical Reports Server (NTRS)

    Goodwin, Thomas J.

    2013-01-01

    Varicella-zoster virus (VZV) is a neurotropic human alphaherpesvirus that causes varicella upon primary infection, establishes latency in multiple ganglionic neurons, and can reactivate to cause zoster. Live attenuated VZV vaccines are available; however, they can also establish latent infections and reactivate. Studies of VZV latency have been limited to the analyses of human ganglia removed at autopsy, as the virus is strictly a human pathogen. Recently, terminally differentiated human neurons have received much attention as a means to study the interaction between VZV and human neurons; however, the short life-span of these cells in culture has limited their application. Herein, we describe the construction of a model of normal human neural progenitor cells (NHNP) in tissue-like assemblies (TLAs), which can be successfully maintained for at least 180 days in three-dimensional (3D) culture, and exhibit an expression profile similar to that of human trigeminal ganglia. Infection of NHNP TLAs with cell-free VZV resulted in a persistent infection that was maintained for three months, during which the virus genome remained stable. Immediate-early, early and late VZV genes were transcribed, and low-levels of infectious VZV were recurrently detected in the culture supernatant. Our data suggest that NHNP TLAs are an effective system to investigate long-term interactions of VZV with complex assemblies of human neuronal cells.

  17. Modelling sarcomeric cardiomyopathies in the dish: from human heart samples to iPSC cardiomyocytes

    PubMed Central

    Eschenhagen, Thomas; Mummery, Christine; Knollmann, Bjorn C.

    2015-01-01

    One of the obstacles to a better understanding of the pathogenesis of human cardiomyopathies has been poor availability of heart-tissue samples at early stages of disease development. This has possibly changed by the advent of patient-derived induced pluripotent stem cell (hiPSC) from which cardiomyocytes can be derived in vitro. The main promise of hiPSC technology is that by capturing the effects of thousands of individual gene variants, the phenotype of differentiated derivatives of these cells will provide more information on a particular disease than simple genotyping. This article summarizes what is known about the ‘human cardiomyopathy or heart failure phenotype in vitro’, which constitutes the reference for modelling sarcomeric cardiomyopathies in hiPSC-derived cardiomyocytes. The current techniques for hiPSC generation and cardiac myocyte differentiation are briefly reviewed and the few published reports of hiPSC models of sarcomeric cardiomyopathies described. A discussion of promises and challenges of hiPSC-modelling of sarcomeric cardiomyopathies and individualized approaches is followed by a number of questions that, in the view of the authors, need to be answered before the true potential of this technology can be evaluated. PMID:25618410

  18. Monophasic and Biphasic Electrical Stimulation Induces a Precardiac Differentiation in Progenitor Cells Isolated from Human Heart

    PubMed Central

    Pietronave, Stefano; Zamperone, Andrea; Oltolina, Francesca; Colangelo, Donato; Follenzi, Antonia; Novelli, Eugenio; Diena, Marco; Pavesi, Andrea; Consolo, Filippo; Fiore, Gianfranco Beniamino; Soncini, Monica

    2014-01-01

    Electrical stimulation (ES) of cells has been shown to induce a variety of responses, such as cytoskeleton rearrangements, migration, proliferation, and differentiation. In this study, we have investigated whether monophasic and biphasic pulsed ES could exert any effect on the proliferation and differentiation of human cardiac progenitor cells (hCPCs) isolated from human heart fragments. Cells were cultured under continuous exposure to monophasic or biphasic ES with fixed cycles for 1 or 3 days. Results indicate that neither stimulation protocol affected cell viability, while the cell shape became more elongated and reoriented more perpendicular to the electric field direction. Moreover, the biphasic ES clearly induced the upregulation of early cardiac transcription factors, MEF2D, GATA-4, and Nkx2.5, as well as the de novo expression of the late cardiac sarcomeric proteins, troponin T, cardiac alpha actinin, and SERCA 2a. Both treatments increased the expression of connexin 43 and its relocation to the cell membrane, but biphasic ES was faster and more effective. Finally, when hCPCs were exposed to both monophasic and biphasic ES, they expressed de novo the mRNA of the voltage-dependent calcium channel Cav 3.1(α1G) subunit, which is peculiar of the developing heart. Taken together, these results show that ES alone is able to set the conditions for early differentiation of adult hCPCs toward a cardiac phenotype. PMID:24328510

  19. Human Heart Mitochondrial DNA Is Organized in Complex Catenated Networks Containing Abundant Four-way Junctions and Replication Forks*

    PubMed Central

    Pohjoismäki, Jaakko L. O.; Goffart, Steffi; Tyynismaa, Henna; Willcox, Smaranda; Ide, Tomomi; Kang, Dongchon; Suomalainen, Anu; Karhunen, Pekka J.; Griffith, Jack D.; Holt, Ian J.; Jacobs, Howard T.

    2009-01-01

    Analysis of human heart mitochondrial DNA (mtDNA) by electron microscopy and agarose gel electrophoresis revealed a complete absence of the θ-type replication intermediates seen abundantly in mtDNA from all other tissues. Instead only Y- and X-junctional forms were detected after restriction digestion. Uncut heart mtDNA was organized in tangled complexes of up to 20 or more genome equivalents, which could be resolved to genomic monomers, dimers, and linear fragments by treatment with the decatenating enzyme topoisomerase IV plus the cruciform-cutting T7 endonuclease I. Human and mouse brain also contained a population of such mtDNA forms, which were absent, however, from mouse, rabbit, or pig heart. Overexpression in transgenic mice of two proteins involved in mtDNA replication, namely human mitochondrial transcription factor A or the mouse Twinkle DNA helicase, generated abundant four-way junctions in mtDNA of heart, brain, and skeletal muscle. The organization of mtDNA of human heart as well as of mouse and human brain in complex junctional networks replicating via a presumed non-θ mechanism is unprecedented in mammals. PMID:19525233

  20. System parameters for erythropoiesis control model: Comparison of normal values in human and mouse model

    NASA Technical Reports Server (NTRS)

    1979-01-01

    The computer model for erythropoietic control was adapted to the mouse system by altering system parameters originally given for the human to those which more realistically represent the mouse. Parameter values were obtained from a variety of literature sources. Using the mouse model, the mouse was studied as a potential experimental model for spaceflight. Simulation studies of dehydration and hypoxia were performed. A comparison of system parameters for the mouse and human models is presented. Aside from the obvious differences expected in fluid volumes, blood flows and metabolic rates, larger differences were observed in the following: erythrocyte life span, erythropoietin half-life, and normal arterial pO2.

  1. Expression and regulation of normal and polymorphic epithelial sodium channel by human lymphocytes.

    PubMed

    Bubien, J K; Watson, B; Khan, M A; Langloh, A L; Fuller, C M; Berdiev, B; Tousson, A; Benos, D J

    2001-03-16

    Gene expression, protein expression, and function of amiloride-sensitive sodium channels were examined in human lymphocytes from normal individuals and individuals with Liddle's disease. Using reverse transcriptase polymerase chain reactions, expression of all three cloned epithelial sodium channel (ENaC) subunits was detected in lymphocytes. Polyclonal antibodies to bovine alpha-ENaC bound to the plasma membrane of normal and Liddle's lymphocytes. A quantitative analysis of fluorescence-tagged ENaC antibodies indicated a 2.5-fold greater surface binding of the antibodies to Liddle's lymphocytes compared with normal lymphocytes. The relative binding intensity increased significantly (25%; p < 0.001) for both normal and Liddle's cells after treatment with 40 microM 8-CPT-cAMP. Amiloride-sensitive whole cell currents were recorded under basal and cAMP-treated conditions for both cell types. Liddle's cells had a 4.5-fold larger inward sodium conductance compared with normal cells. A specific 25% increase in the inward sodium current was observed in normal cells in response to cAMP treatment. Outside-out patches from both cell types under both treatment conditions revealed no obvious differences in the single channel conductance. The P(open) was 4.2 +/- 3.9% for patches from non-Liddle's cells, and 27.7 +/- 5.4% in patches from Liddle's lymphocytes. Biochemical purification of a protein complex, using the same antibodies used for the immunohistochemistry, yielded a functional sodium channel complex that was inhibited by amiloride when reconstituted into lipid vesicles and incorporated into planar lipid bilayers. These four independent methodologies yielded findings consistent with the hypotheses that human lymphocytes express functional, regulatable ENaC and that the mutation responsible for Liddle's disease induces excessive channel expression. PMID:11113130

  2. A phenotypic in vitro model for the main determinants of human whole heart function.

    PubMed

    Stancescu, Maria; Molnar, Peter; McAleer, Christopher W; McLamb, William; Long, Christopher J; Oleaga, Carlota; Prot, Jean-Matthieu; Hickman, James J

    2015-08-01

    This article details the construction and testing of a phenotypic assay system that models in vivo cardiac function in a parallel in vitro environment with human stem cell derived cardiomyocytes. The major determinants of human whole-heart function were experimentally modeled by integrating separate 2D cellular systems with BioMicroelectromechanical Systems (BioMEMS) constructs. The model features a serum-free defined medium to enable both acute and chronic evaluation of drugs and toxins. The integration of data from both systems produced biologically relevant predictions of cardiac function in response to varying concentrations of selected drugs. Sotalol, norepinephrine and verapamil were shown to affect the measured parameters according to their specific mechanism of action, in agreement with clinical data. This system is applicable for cardiac side effect assessment, general toxicology, efficacy studies, and evaluation of in vitro cellular disease models in body-on-a-chip systems. PMID:25978005

  3. A phenotypic in vitro model for the main determinants of human whole heart function

    PubMed Central

    Stancescu, Maria; Molnar, Peter; McAleer, Christopher W.; McLamb, William; Long, Christopher J.; Oleaga, Carlota; Prot, Jean-Matthieu; Hickman, James J.

    2015-01-01

    This article details the construction and testing of a phenotypic assay system that models in vivo cardiac function in a parallel in vitro environment with human stem cell derived cardiomyocytes. The major determinants of human whole-heart function were experimentally modeled by integrating separate 2D cellular systems with BioMicroelectromechanical Systems (BioMEMS) constructs. The model featured a serum-free defined medium to enable both acute and chronic evaluation of drugs and toxins. The integration of data from both systems produced biologically relevant predictions of cardiac function in response to varying concentrations of selected drugs. Sotalol, norepinephrine and verapamil were shown to affect the measured parameters according to their specific mechanism of action, in agreement with clinical data. This system is applicable for cardiac side effect assessment, general toxicology, efficacy studies, and evaluation of in vitro cellular disease models in body-on-a-chip systems. PMID:25978005

  4. Effect of short-term physical exercise on foetal heart rate and uterine activity in normal and abnormal pregnancies.

    PubMed

    Rauramo, I

    1987-01-01

    The response of a short-term submaximal bicycle ergometer test on foetal heart rate (FHR) and on uterine activity was studied in 61 pregnant women between pregnancy weeks 32 and 40. 28 of the women had uncomplicated pregnancies, 13 were hypertensive, 11 were diabetic, and 9 had intrahepatic cholestasis of pregnancy. After exercise, FHR declined in healthy subjects in pregnancy weeks past 35, whereas no significant change was found in such subjects before week 35 of pregnancy. Analysis of variance revealed a difference of FHR between subjects with umcomplicated and pre-eclamptic pregnancies in relation to time (p = 0.021). Exercise induced uterine contractions in hypertensive subjects. Foetal bradycardia was found in 2 healthy, in 2 pre-eclamptic, and in one cholestatic subject. In healthy pregnant women a non-reactive FHR with concomitant reduced FHR variability was found after exercise (P less than 0.01). The FHR variability of patients with pathologic pregnancies was less affected. These results suggest that, after a relatively strenuous short-term exercise, foetuses of mothers with uneventful pregnancies can be at risk of hypoxia in late pregnancy, but the clinical significance remains uncertain. PMID:3435001

  5. Polymorphism of the long-wavelength cone in normal human colour vision

    NASA Astrophysics Data System (ADS)

    Neitz, Jay; Jacobs, Gerald H.

    1986-10-01

    Colour vision is based on the presence of multiple classes of cone each of which contains a different type of photopigment1. Colour matching tests have long revealed that the normal human has three cone types. Results from these tests have also been used to provide estimates of cone spectral sensitivities2. There are significant variations in colour matches made by individuals whose colour vision is classified as normal3-6. Some of this is due to individual differences in preretinal absorption and photopigment density, but some is also believed to arise because there is variation in the spectral positioning of the cone pigments among those who have normal colour vision. We have used a sensitive colour matching test to examine the magnitude and nature of this individual variation and here report evidence for the existence of two different long-wavelength cone mechanisms in normal humans. The different patterns of colour matches made by male and female subjects indicate these two mechanisms are inherited as an X-chromosome linked trait.

  6. Gonococci causing disseminated gonococcal infection are resistant to the bactericidal action of normal human sera.

    PubMed Central

    Schoolnik, G K; Buchanan, T M; Holmes, K K

    1976-01-01

    The susceptibility of strains of Neisseria gonorrhoeae to the bactericidal action of normal human sera was determined for isolates from patients with disseminated gonococcal infection and uncomplicated gonorrhea. Serum susceptibility was correlated with penicillin susceptibility and auxotype. 38 of 39 strains (97%) of N. gonorrhoeae from Seattle patients with disseminated gonococcal infection were resistant to the complement-dependent bactericidal action of normal human sera. 36 of these were inhibited by less than or equal to mug/ml of penicillin G and required arginine, hypoxanthine, and uracil for growth on chemically defined medium (Arg-Hyx-Ura- auxotype). 12 of 43 isolates from patients with uncomplicated gonorrhea were also of the Arg-Hyx-Ura-auxotype, inhibited by less than or equal to 0.030 mug/ml of penicillin G, and serum resistant. Of the 31 remaining strains of other auxotypes isolated from patients with uncomplicated gonorrhea, 18 (58.1%) were sensitive to normal human sera in titers ranging from 2 to 2,048. The bactericidal action of normal human sera may prevent the dissemination of serum-sensitive gonococci. However, since only a small proportion of individuals infected by serum-resistant strains develop disseminated gonococcal infection, serum resistance appears to be a necessary but not a sufficient virulence factor for dissemination. Host factors such as menstruation and pharyngeal gonococcal infection may favor the dissemination of serum-resistant strains. Since serum-resistant Arg-Hyx-Ura strains are far more frequently isolated from patients with disseminated gonococcal infection than serum-resistant strains of other auxotypes, Arg-Hyx-Ura-strains may possess other virulence factors in addition to serum resistance. PMID:825532

  7. Normalizing and scaling of data to derive human response corridors from impact tests.

    PubMed

    Yoganandan, Narayan; Arun, Mike W J; Pintar, Frank A

    2014-06-01

    It is well known that variability is inherent in any biological experiment. Human cadavers (Post-Mortem Human Subjects, PMHS) are routinely used to determine responses to impact loading for crashworthiness applications including civilian (motor vehicle) and military environments. It is important to transform measured variables from PMHS tests (accelerations, forces and deflections) to a standard or reference population, termed normalization. The transformation process should account for inter-specimen variations with some underlying assumptions used during normalization. Scaling is a process by which normalized responses are converted from one standard to another (example, mid-size adult male to large-male and small-size female adults, and to pediatric populations). These responses are used to derive corridors to assess the biofidelity of anthropomorphic test devices (crash dummies) used to predict injury in impact environments and design injury mitigating devices. This survey examines the pros and cons of different approaches for obtaining normalized and scaled responses and corridors used in biomechanical studies for over four decades. Specifically, the equal-stress equal-velocity and impulse-momentum methods along with their variations are discussed in this review. Methods ranging from subjective to quasi-static loading to different approaches are discussed for deriving temporal mean and plus minus one standard deviation human corridors of time-varying fundamental responses and cross variables (e.g., force-deflection). The survey offers some insights into the potential efficacy of these approaches with examples from recent impact tests and concludes with recommendations for future studies. The importance of considering various parameters during the experimental design of human impact tests is stressed. PMID:24726322

  8. Microgravity alters respiratory sinus arrhythmia and short-term heart rate variability in humans

    NASA Technical Reports Server (NTRS)

    Migeotte, P-F; Prisk, G. Kim; Paiva, M.; West, J. B. (Principal Investigator)

    2003-01-01

    We studied heart rate (HR), heart rate variability (HRV), and respiratory sinus arrhythmia (RSA) in four male subjects before, during, and after 16 days of spaceflight. The electrocardiogram and respiration were recorded during two periods of 4 min controlled breathing at 7.5 and 15 breaths/min in standing and supine postures on the ground and in microgravity. Low (LF)- and high (HF)-frequency components of the short-term HRV (< or =3 min) were computed through Fourier spectral analysis of the R-R intervals. Early in microgravity, HR was decreased compared with both standing and supine positions and had returned to the supine value by the end of the flight. In microgravity, overall variability, the LF-to-HF ratio, and RSA amplitude and phase were similar to preflight supine values. Immediately postflight, HR increased by approximately 15% and remained elevated 15 days after landing. LF/HF was increased, suggesting an increased sympathetic control of HR standing. The overall variability and RSA amplitude in supine decreased postflight, suggesting that vagal tone decreased, which coupled with the decrease in RSA phase shift suggests that this was the result of an adaptation of autonomic control of HR to microgravity. In addition, these alterations persisted for at least 15 days after return to normal gravity (1G).

  9. Expression of 300-kilodalton intermediate filament-associated protein distinguishes human glioma cells from normal astrocytes.

    PubMed Central

    Yang, H Y; Lieska, N; Glick, R; Shao, D; Pappas, G D

    1993-01-01

    The availability of biochemical markers to distinguish glioma cells from normal astrocytes would have enormous diagnostic value. Such markers also may be of value in studying the basic biology of human astrocytomas. The vimentin-binding, 300-kDa intermediate filament (IF)-associated protein (IFAP-300kDa) has recently been shown to be developmentally expressed in radial glia of the central nervous system of the rat. It is not detected in the normal or reactive astrocytes of the adult rat nor in neonatal rat brain astrocytes in primary culture. In the present study, double-label immunofluorescence microscopy using antibodies to IFAP-300kDa and glial fibrillary acidic protein (GFAP, an astrocyte-specific IF structural protein) identifies this IFAP in GFAP-containing tumor cells from examples of all three major types of human astrocytomas (i.e., well-differentiated, anaplastic, and glioblastoma multiforme). Astrocytoma cells in primary cultures prepared from all three astrocytomas also express this protein. It is not detectable in normal adult brain tissue. Immunoblot analyses using the IFAP-300kDa antibody confirm the presence of a 300-kDa polypeptide in fresh astrocytoma preparations enriched for IF proteins. These results suggest the utility of IFAP-300kDa as a marker for identification of human glioma cells both in vitro and in situ. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:8378327

  10. Brachyury identifies a class of enteroendocrine cells in normal human intestinal crypts and colorectal cancer

    PubMed Central

    Pinto, Filipe; Sammut, Stephen J.; Williams, Geraint T.; Gollins, Simon; McFarlane, Ramsay J.; Reis, Rui Manuel; Wakeman, Jane A.

    2016-01-01

    Normal homeostasis of adult intestinal epithelium and repair following tissue damage is maintained by a balance of stem and differentiated cells, many of which are still only poorly characterised. Enteroendocrine cells of the gut are a small population of differentiated, secretory cells that are critical for integrating nutrient sensing with metabolic responses, dispersed amongst other epithelial cells. Recent evidence suggests that sub-sets of secretory enteroendocrine cells can act as reserve stem cells. Given the link between cells with stem-like properties and cancer, it is important that we identify factors that might provide a bridge between the two. Here, we identify a sub-set of chromogranin A-positive enteroendocrine cells that are positive for the developmental and cancer-associated transcription factor Brachyury in normal human small intestinal and colonic crypts. Whilst chromogranin A-positive enteroendocrine cells are also Brachyury-positive in colorectal tumours, expression of Brachyury becomes more diffuse in these samples, suggesting a more widespread function in cancer. The finding of the developmental transcription factor Brachyury in normal adult human intestinal crypts may extend the functional complexity of enteroendocrine cells and serves as a platform for assessment of the molecular processes of intestinal homeostasis that underpins our understanding of human health, cancer and aging. PMID:26862851

  11. Overexpression of wild-type or mutants forms of CEBPA alter normal human hematopoiesis.

    PubMed

    Quintana-Bustamante, O; Lan-Lan Smith, S; Griessinger, E; Reyal, Y; Vargaftig, J; Lister, T A; Fitzgibbon, J; Bonnet, D

    2012-07-01

    CCAAT/enhancer-binding protein-α (C/EBPα/CEBPA) is mutated in approximately 8% of acute myeloid leukemia (AML) in both familial and sporadic AML and, with FLT3 and NPM1, has received most attention as a predictive marker of outcome in patients with normal karyotype disease. Mutations clustering to either the N- or C-terminal (N- and C-ter) portions of the protein have different consequences on the protein function. In familial cases, the N-ter form is inherited with patients exhibiting long latency period before the onset of overt disease, typically with the acquisition of a C-ter mutation. Despite the essential insights murine models provide the functional consequences of wild-type C/EBPα in human hematopoiesis and how different mutations are involved in AML development have received less attention. Our data underline the critical role of C/EBPα in human hematopoiesis and demonstrate that C/EBPα mutations (alone or in combination) are insufficient to convert normal human hematopoietic stem/progenitor cells into leukemic-initiating cells, although individually each altered normal hematopoiesis. It provides the first insight into the effects of N- and C-ter mutations acting alone and to the combined effects of N/C double mutants. Our results mimicked closely what happens in CEBPA mutated patients. PMID:22371011

  12. Antioxidant macromolecules in the epithelial lining fluid of the normal human lower respiratory tract.

    PubMed Central

    Cantin, A M; Fells, G A; Hubbard, R C; Crystal, R G

    1990-01-01

    We hypothesized that the alveolar structures may contain extracellular macromolecules with antioxidant properties to defend against oxidants. To evaluate this 51Cr-labeled human lung fibroblasts (HFL-1) and cat lung epithelial cells (AKD) were exposed to a H2O2-generating system and alveolar epithelial lining fluid (ELF) from healthy nonsmokers was tested for its ability to protect the lung cells from H2O2-mediated injury. The ELF provided marked antioxidant protection, with most from a H2O-soluble fraction in the 100-300-kD range. Plasma proteins with anti-H2O2 properties were in insufficient concentrations to provide the antioxidant protection observed. However, catalase, a normal intracellular antioxidant, was present in sufficient concentration to account for most of the observed anti-H2O2 properties of ELF. Depletion of ELF with an anticatalase antibody abolished the anti-H2O2 macromolecular defenses of ELF. Since catalase is not normally released by cells, a likely explanation for its presence in high concentrations in normal ELF is that it is released by lung inflammatory and parenchymal cells onto the epithelial surface of the lower respiratory tract during their normal turnover and collects there due to the slow turnover of ELF. It is likely that catalase in the ELF of normal individuals plays a role in protecting lung parenchymal cells against oxidants present in the extracellular milieu. Images PMID:2394842

  13. Expression of IL-10 in human normal and cancerous ovarian tissues and cells.

    PubMed

    Rabinovich, Alex; Medina, Liat; Piura, Benjamin; Huleihel, Mahmoud

    2010-06-01

    IL-10 is an 18-kd polypeptide that has been shown to be secreted by multiple cell types, including T and B cells, monocytes and some human tumors. However, which cell population is responsible for the elevated IL-10 levels in the serum and ascites of ovarian cancer patients, whether ovarian carcinoma cells produce IL-10, and how IL-10 influences the development and progression of ovarian carcinoma are issues that remain unclear. The aim of our study was to examine IL-10 production and secretion by ovarian carcinoma tissues and cells, and to determine its possible role in the cell and tumor micro-environment. The mean IL-10 protein levels expressed in normal ovarian tissue homogenates were significantly higher compared to cancerous ovarian tissue (p = 0.002). Yet, the IL-10 mRNA expression was significantly higher in cancerous ovarian tissues as compared to normal tissues (p = 0.021). The IL-10 receptor mRNA expression levels of the cancerous ovarian tissue homogenates were slightly, but not significantly, higher than the normal tissues. IL-10 immunostaining revealed that in both normal and cancerous ovarian tissues, IL-10 expression could be detected mainly in epithelial cells. In normal ovarian tissues, similar levels of IL-10R were demonstrated in epithelial and stromal cells. However, in cancerous ovarian tissues, epithelial cells expressed higher levels of IL-10R than the stroma. Primary normal and cancerous ovarian cell cultures and SKOV-3 cells secreted similar amounts of IL-10 after 24 hours of incubation. Our results suggest that epithelial cells are the main source of IL-10 in the ovary. Nevertheless, the target cells for IL-10 are different in normal and cancerous ovarian cells. Thus, IL-10 and its receptor could be involved in the pathogenesis of ovarian carcinoma. PMID:20430716

  14. Congenital Heart Block Maternal Sera Autoantibodies Target an Extracellular Epitope on the α1G T-Type Calcium Channel in Human Fetal Hearts

    PubMed Central

    Rath, Arianna; Liu, Jie; Silverman, Earl D.; Liu, Xiaoru; Siragam, Vinayakumar; Ackerley, Cameron; Su, Brenda Bin; Yan, Jane Yuqing; Capecchi, Marco; Biavati, Luca; Accorroni, Alice; Yuen, William; Quattrone, Filippo; Lung, Kalvin; Jaeggi, Edgar T.; Backx, Peter H.; Deber, Charles M.; Hamilton, Robert M.

    2013-01-01

    Background Congenital heart block (CHB) is a transplacentally acquired autoimmune disease associated with anti-Ro/SSA and anti-La/SSB maternal autoantibodies and is characterized primarily by atrioventricular (AV) block of the fetal heart. This study aims to investigate whether the T-type calcium channel subunit α1G may be a fetal target of maternal sera autoantibodies in CHB. Methodology/Principal Findings We demonstrate differential mRNA expression of the T-type calcium channel CACNA1G (α1G gene) in the AV junction of human fetal hearts compared to the apex (18–22.6 weeks gestation). Using human fetal hearts (20–22 wks gestation), our immunoprecipitation (IP), Western blot analysis and immunofluorescence (IF) staining results, taken together, demonstrate accessibility of the α1G epitope on the surfaces of cardiomyocytes as well as reactivity of maternal serum from CHB affected pregnancies to the α1G protein. By ELISA we demonstrated maternal sera reactivity to α1G was significantly higher in CHB maternal sera compared to controls, and reactivity was epitope mapped to a peptide designated as p305 (corresponding to aa305–319 of the extracellular loop linking transmembrane segments S5–S6 in α1G repeat I). Maternal sera from CHB affected pregnancies also reacted more weakly to the homologous region (7/15 amino acids conserved) of the α1H channel. Electrophysiology experiments with single-cell patch-clamp also demonstrated effects of CHB maternal sera on T-type current in mouse sinoatrial node (SAN) cells. Conclusions/Significance Taken together, these results indicate that CHB maternal sera antibodies readily target an extracellular epitope of α1G T-type calcium channels in human fetal cardiomyocytes. CHB maternal sera also show reactivity for α1H suggesting that autoantibodies can target multiple fetal targets. PMID:24039792

  15. Human care system for heart-rate and human-movement trajectory in home and its application to detect mental disease

    NASA Astrophysics Data System (ADS)

    Hata, Yutaka; Kanazawa, Seigo; Endo, Maki; Tsuchiya, Naoki; Nakajima, Hiroshi

    2012-06-01

    This paper proposes a heart rate monitoring system for detecting autonomic nervous system by the heart rate variability using an air pressure sensor to diagnose mental disease. Moreover, we propose a human behavior monitoring system for detecting the human trajectory in home by an infrared camera. In day and night times, the human behavior monitoring system detects the human movement in home. The heart rate monitoring system detects the heart rate in bed in night time. The air pressure sensor consists of a rubber tube, cushion cover and pressure sensor, and it detects the heart rate by setting it to bed. It unconstraintly detects the RR-intervals; thereby the autonomic nervous system can be assessed. The autonomic nervous system analysis can examine the mental disease. While, the human behavior monitoring system obtains distance distribution image by an infrared camera. It classifies adult, child and the other object from distance distribution obtained by the camera, and records their trajectories. This behavior, i.e., trajectory in home, strongly corresponds to cognitive disorders. Thus, the total system can detect mental disease and cognitive disorders by uncontacted sensors to human body.

  16. Towards causally cohesive genotype–phenotype modelling for characterization of the soft-tissue mechanics of the heart in normal and pathological geometries

    PubMed Central

    Nordbø, Øyvind; Gjuvsland, Arne B.; Nermoen, Anders; Land, Sander; Niederer, Steven; Lamata, Pablo; Lee, Jack; Smith, Nicolas P.; Omholt, Stig W.; Vik, Jon Olav

    2015-01-01

    A scientific understanding of individual variation is key to personalized medicine, integrating genotypic and phenotypic information via computational physiology. Genetic effects are often context-dependent, differing between genetic backgrounds or physiological states such as disease. Here, we analyse in silico genotype–phenotype maps (GP map) for a soft-tissue mechanics model of the passive inflation phase of the heartbeat, contrasting the effects of microstructural and other low-level parameters assumed to be genetically influenced, under normal, concentrically hypertrophic and eccentrically hypertrophic geometries. For a large number of parameter scenarios, representing mock genetic variation in low-level parameters, we computed phenotypes describing the deformation of the heart during inflation. The GP map was characterized by variance decompositions for each phenotype with respect to each parameter. As hypothesized, the concentric geometry allowed more low-level parameters to contribute to variation in shape phenotypes. In addition, the relative importance of overall stiffness and fibre stiffness differed between geometries. Otherwise, the GP map was largely similar for the different heart geometries, with little genetic interaction between the parameters included in this study. We argue that personalized medicine can benefit from a combination of causally cohesive genotype–phenotype modelling, and strategic phenotyping that captures effect modifiers not explicitly included in the mechanistic model. PMID:25833237

  17. Effect of heart rate on left ventricular diastolic transmitral flow velocity patterns assessed by Doppler echocardiography in normal subjects.

    PubMed

    Harrison, M R; Clifton, G D; Pennell, A T; DeMaria, A N

    1991-03-15

    Although a number of factors, including age and ventricular loading, are known to influence the pattern of left ventricular (LV) filling as depicted by Doppler echocardiographic transmitral flow velocities, few and conflicting data are available regarding the influence of heart rate (HR). Therefore, 20 volunteers (mean age 30 years) were evaluated with pulsed-wave Doppler echocardiography, performed with the sample volume placed at the mitral anulus level in the apical 4-chamber projection. Transmitral flow measurements comprised peak and integrated early passive (E) and late atrial (A) filling velocities and the slope of velocity decline from peak E filling. Measurements were recorded during baseline (sinus rhythm, mean 70 beats/min) and during transesophageal atrial pacing (mean 88 beats/min). LV end-diastolic dimension, mean arterial pressure and PR interval (corrected for pacing-induced delay in interatrial conduction time) were unchanged during pacing versus baseline measurements. Peak and integrated E filling velocities averaged 0.59 +/- 0.09 m/s and 6 +/- 1 cm, respectively, at baseline and were not significantly greater at the higher HR. In contrast, baseline peak and integrated A velocities averaged 0.37 +/- 0.06 m/s and 2.3 +/- 0.7 cm, respectively, but were significantly greater at the higher HR (0.5 +/- 0.07 m/s and 3.2 +/- 1.1 cm, respectively [p less than 0.003 vs baseline for each]). Further analysis of a subgroup of 9 subjects for whom Doppler measurements were available at 3 HRs (sinus 70; pacing 80 and 90) yielded strong evidence for a linear relation between HR and peak A velocity (A = 0.008 HR - 0.21, with p less than 0.0001 for significance of the linear trend).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2000796

  18. Imaging of Keratoconic and normal human cornea with a Brillouin imaging system (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Besner, Sebastien; Shao, Peng; Scarcelli, Giuliano; Pineda, Roberto; Yun, Seok-Hyun (Andy)

    2016-03-01

    Keratoconus is a degenerative disorder of the eye characterized by human cornea thinning and morphological change to a more conical shape. Current diagnosis of this disease relies on topographic imaging of the cornea. Early and differential diagnosis is difficult. In keratoconus, mechanical properties are found to be compromised. A clinically available invasive technique capable of measuring the mechanical properties of the cornea is of significant importance for understanding the mechanism of keratoconus development and improve detection and intervention in keratoconus. The capability of Brillouin imaging to detect local longitudinal modulus in human cornea has been demonstrated previously. We report our non-contact, non-invasive, clinically viable Brillouin imaging system engineered to evaluate mechanical properties human cornea in vivo. The system takes advantage of a highly dispersive 2-stage virtually imaged phased array (VIPA) to detect weak Brillouin scattering signal from biological samples. With a 1.5-mW light beam from a 780-nm single-wavelength laser source, the system is able to detect Brillouin frequency shift of a single point in human cornea less than 0.3 second, at a 5μm/30μm lateral/axial resolution. Sensitivity of the system was quantified to be ~ 10 MHz. A-scans at different sample locations on a human cornea with a motorized human interface. We imaged both normal and keratoconic human corneas with this system. Whereas no significantly difference were observed outside keratocnic cones compared with normal cornea, a highly statistically significantly decrease was found in the cone regions.

  19. Simple Dispersion Equation Based on Lamb-Wave Model for Propagating Pulsive Waves in Human Heart Wall

    NASA Astrophysics Data System (ADS)

    Bekki, Naoaki; Shintani, Seine A.

    2015-12-01

    We consider the Rayleigh-Lamb-type equation for propagating pulsive waves excited by aortic-valve closure at end-systole in the human heart wall. We theoretically investigate the transcendental dispersion equation of pulsive waves for the asymmetrical zero-order mode of the Lamb wave. We analytically find a simple dispersion equation with a universal constant for a small Lamb wavenumber. We show that the simple dispersion equation can qualitatively explain the myocardial noninvasive measurements in vivo of pulsive waves in the human heart wall. We can also consistently estimate the viscoelastic constant of the myocardium in the human heart wall using the simple dispersion equation for a small Lamb wavenumber instead of using a complex nonlinear optimization.

  20. Distribution of somatostatin receptors in normal and neoplastic human tissues: recent advances and potential relevance.

    PubMed Central

    Reubi, J. C.; Schaer, J. C.; Markwalder, R.; Waser, B.; Horisberger, U.; Laissue, J.

    1997-01-01

    This short review describes the localization of somatostatin receptors with in vitro receptor autoradiography techniques in several non-classical, normal human somatostatin target tissues as well as in selected human tumors. In addition to brain, gut and neuroendocrine localizations, somatostatin receptors are expressed in most lymphatic tissues, including gut-associated lymphatic tissue, spleen and thymus; in the cortical and medullary area of the kidney; in the stroma of the prostate and in the epithelial cells of the thyroid. Among human tumors, the extremely high density of somatostatin receptors in medulloblastomas should be stressed as well as the favorable prognostic role of the presence of somatostatin receptors in neuroblastomas. Moreover, several types of mesenchymal tumors have somatostatin receptors as well. The receptor subtypes expressed by distinct tumors may vary: Whereas medulloblastomas and neuroblastomas predominantly express sst2, prostate cancers express sst1 rather than sst2. A further emerging somatostatin target is represented by the peritumoral veins, also known to express sst2 receptors. The multiple somatostatin targets in normal and pathological human tissues represents the basis for potential diagnostic and clinical applications of somatostatin analogs. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:9825475

  1. Noninvasive prediction of the exercise-induced elevation in left ventricular filling pressure in post-heart transplant patients with normal left ventricular ejection fraction

    PubMed Central

    Meluzin, Jaroslav; Hude, Petr; Krejci, Jan; Spinarova, Lenka; Podrouzkova, Helena; Leinveber, Pavel; Dusek, Ladislav; Soska, Vladimir; Tomandl, Josef; Nemec, Petr

    2013-01-01

    OBJECTIVES: At present, there are conflicting data on the ability of echocardiographic parameters to predict the exercise-induced elevation of left ventricular (LV) filling pressure. The purpose of the present study was to validate the ratio of early diastolic transmitral (E) to mitral annular velocity (e′) obtained at peak exercise in its capacity to determine the exercise-induced elevation of pulmonary capillary wedge pressure (PCWP) and to reveal new noninvasive parameters with such capacity. METHODS: Sixty-one patients who had undergone heart transplantation with normal LV ejection fraction underwent simultaneous exercise echocardiography and right heart catheterization. RESULTS: In 50 patients with a normal PCWP at rest, exercise E/e′ ≥8.5 predicted exercise PCWP ≥25 mmHg with a sensitivity of 64.3% and a specificity of 84.2% (area under the curve [AUC]=0.74). A comparable or slightly better prediction was achieved by exercise E/peak systolic mitral annular velocity (s′) ≥11.0 (sensitivity 79.3%; specificity 57.9%; AUC=0.75) and exercise E/LV systolic longitudinal strain rate ≤−105 cm (sensitivity 78.9%; specificity 78.6%; AUC=0.87). Combined, exercise E/s′ and exercise E/e′ resulted in a trend toward a slightly more precise prediction (sensitivity 53.6%; specificity 89.5%; AUC=0.78) than did either variable alone. CONCLUSIONS: Exercise E/e′, used as a sole parameter, is not sufficiently precise to predict the exercise-induced elevation of PCWP. Exercise E/s′, E/LV systolic longitudinal strain rate or combinations of these parameters may represent further promising possibilities for predicting exercise PCWP elevation. PMID:23940422

  2. PARP Inhibitors in Clinical Use Induce Genomic Instability in Normal Human Cells

    PubMed Central

    Ito, Shuhei; Murphy, Conleth G.; Doubrovina, Ekaterina; Jasin, Maria; Moynahan, Mary Ellen

    2016-01-01

    Poly(ADP-ribose) polymerases (PARPs) are the first proteins involved in cellular DNA repair pathways to be targeted by specific inhibitors for clinical benefit. Tumors harboring genetic defects in homologous recombination (HR), a DNA double-strand break (DSB) repair pathway, are hypersensitive to PARP inhibitors (PARPi). Early phase clinical trials with PARPi have been promising in patients with advanced BRCA1 or BRCA2-associated breast, ovary and prostate cancer and have led to limited approval for treatment of BRCA-deficient ovary cancer. Unlike HR-defective cells, HR-proficient cells manifest very low cytotoxicity when exposed to PARPi, although they mount a DNA damage response. However, the genotoxic effects on normal human cells when agents including PARPi disturb proficient cellular repair processes have not been substantially investigated. We quantified cytogenetic alterations of human cells, including primary lymphoid cells and non-tumorigenic and tumorigenic epithelial cell lines, exposed to PARPi at clinically relevant doses by both sister chromatid exchange (SCE) assays and chromosome spreading. As expected, both olaparib and veliparib effectively inhibited poly-ADP-ribosylation (PAR), and caused marked hypersensitivity in HR-deficient cells. Significant dose-dependent increases in SCEs were observed in normal and non-tumorigenic cells with minimal residual PAR activity. Clinically relevant doses of the FDA-approved olaparib led to a marked increase of SCEs (5-10-fold) and chromatid aberrations (2-6-fold). Furthermore, olaparib potentiated SCE induction by cisplatin in normal human cells. Our data have important implications for therapies with regard to sustained genotoxicity to normal cells. Genomic instability arising from PARPi warrants consideration, especially if these agents will be used in people with early stage cancers, in prevention strategies or for non-oncologic indications. PMID:27428646

  3. A Myocardial Slice Culture Model Reveals Alpha-1A-Adrenergic Receptor Signaling in the Human Heart

    PubMed Central

    Thomas, R. Croft; Singh, Abhishek; Cowley, Patrick; Myagmar, Bat-Erdene; Montgomery, Megan D.; Swigart, Philip M.; De Marco, Teresa; Baker, Anthony J.; Simpson, Paul C.

    2016-01-01

    Background Translation of preclinical findings could benefit from a simple, reproducible, high throughput human model to study myocardial signaling. Alpha-1A-adrenergic receptors (ARs) are expressed at very low levels in the human heart, and it is unknown if they function. Objectives To develop a high throughput human myocardial slice culture model, and to test the hypothesis that alpha-1A- ARs are functional in the human heart. Methods Cores of LV free wall 8 mm diameter were taken from 52 hearts (18 failing and 34 nonfailing). Slices 250 μm thick were cut with a Krumdieck apparatus and cultured using a rotating incubation unit. Results About 60 slices were cut from each LV core, and a typical study could use 96 slices. Myocyte morphology was maintained, and diffusion into the slice center was rapid. Slice viability was stable for at least 3 days in culture by ATP and MTT assays. The beta-AR agonist isoproterenol stimulated phospholamban phosphorylation, and the alpha-1A-AR agonist A61603 stimulated ERK phosphorylation, with nanomolar EC50 values in slices from both failing and nonfailing hearts. Strips cut from the slices were used to quantify activation of contraction by isoproterenol, A61603, and phenylephrine. The slices supported transduction by adenovirus. Conclusions We have developed a simple, high throughput LV myocardial slice culture model to study signaling in the human heart. This model can be useful for translational studies, and we show for the first time that the alpha-1A-AR is functional in signaling and contraction in the human heart. PMID:27453955

  4. Oxygen uptake, heart rate and blood lactate concentration during a normal training session of an aerobic dance class.

    PubMed

    De Angelis, M; Vinciguerra, G; Gasbarri, A; Pacitti, C

    1998-07-01

    The aim of this research was to investigate the physiological responses and, in particular, the participation of lactic acid anaerobic metabolism in aerobic dance, which is claimed to be pure aerobic exercise. In contrast to previous studies, that have put subjects in very unfamiliar situations, the parameters were monitored in the familiar context of gymnasium, practice routine and habitual instructor. A group of 30 skilled fairly well-trained women performed their usual routine, a combination of the two styles: low (LI) and high impact (HI), and were continuously monitored for heart rate (HR) and every 8 min for blood lactate concentration ([La-]b). Of the group, 15 were tested to determine their maximal aerobic power (VO2max) using a cycle-ergometer. They were also monitored during the routine for oxygen uptake (VO2) by a light telemetric apparatus. The oxygen pulses of the routine and of the corresponding exercise intensity in the incremental test were not statistically different. The mean values in the exercise session were: peak HR 92.8 (SD 7.8)% of the subject's maximal theoretical value, peak VO2 99.5 (SD 12.4)% of VO2max, maximal [La-]b 6.1 (SD 1.7) mmol x l(-1), and mean 4.8 (SD 1.3) mmol x l(-1). Repeated measures ANOVA found statistically significant differences between the increasing [La-]b values (P < 0.001). In particular, the difference between the [La-]b values at the end of the mainly LI phase and those of the LI-HI combination phase, and the difference between the samples during the combination LI-HI phase were both statistically significant (both P = 0.002 and P = 0.002). The similar oxygen pulses confirmed the validity of the present experiment design and the reliability of HR monitoring in this activity. The HR, VO2 and, above all, the increase of [La-]b to quite high values, showing a non steady state, demonstrated the high metabolic demand made by this activity that involved lactic acid metabolism at a much higher level than expected. PMID

  5. Broken Heart Syndrome

    MedlinePlus

    ... heart attacks are caused by blockages and blood clots forming in the coronary arteries, which supply the heart with blood. If these ... who experience broken heart syndrome have fairly normal coronary arteries, without severe blockages or clots. The heart cells are “stunned” by stress hormones ...

  6. Antigens of human trophoblasts: A working hypothesis for their role in normal and abnormal pregnancies

    PubMed Central

    Faulk, W. Page; Temple, Anne; Lovins, R. E.; Smith, Nancy

    1978-01-01

    This report describes the preparation and characterization of antisera to human trophoblast membranes. Rabbit antisera were raised to trophoblast microvilli prepared by differential ultracentrifugation. Antibodies to serum proteins were removed by solid-phase immunoabsorption with normal human serum, and indirect immunofluorescence experiments with cryostat sections of human placentas showed that the absorbed anti-trophoblast sera reacted with trophoblasts as well as with stromal cells and endothelium of chorionic villi. The antisera also produced membrane fluorescence when studied on viable lymphocytes and certain human cell lines. These anti-trophoblast sera were also lymphocytotoxic, and this reaction was abolished by prior absorption of the antisera with leukocytes. The leukocyte-absorbed anti-trophoblast sera retained their ability to react with trophoblasts and certain human cell lines, but no longer reacted with lymphocytes or placental stromal cells and endothelium. Two categories of trophoblast membrane antigens are thus defined: one present on trophoblasts and certain human cells lines (tentatively designated TA1), and the other on trophoblasts and lymphocytes, villous fibroblasts, and endothelium (tentatively designated TA2). A working hypothesis is proposed stating that normal pregnancy involves the generation of anti-TA2 subsequent to blastocyst implantation and entrance of trophoblasts into the maternal circulation. This involves a mechanism similar to allogeneic cell stimulation and results in antibodies that block either the recognition or cytotoxicity of TA1. Failure to mount this response allows TA1 recognition and trophoblast immunopathology. Experimental and clinical studies in support of this working hypothesis, particularly involving abortion and toxemia, are cited from published reports. Images PMID:273921

  7. The SRI24 multichannel atlas of normal adult human brain structure.

    PubMed

    Rohlfing, Torsten; Zahr, Natalie M; Sullivan, Edith V; Pfefferbaum, Adolf

    2010-05-01

    This article describes the SRI24 atlas, a new standard reference system of normal human brain anatomy, that was created using template-free population registration of high-resolution magnetic resonance images acquired at 3T in a group of 24 normal control subjects. The atlas comprises anatomical channels (T1, T2, and proton density weighted), diffusion-related channels (fractional anisotropy, mean diffusivity, longitudinal diffusivity, mean diffusion-weighted image), tissue channels (CSF probability, gray matter probability, white matter probability, tissue labels), and two cortical parcellation maps. The SRI24 atlas enables multichannel atlas-to-subject image registration. It is uniquely versatile in that it is equally suited for the two fundamentally different atlas applications: label propagation and spatial normalization. Label propagation, herein demonstrated using diffusion tensor image fiber tracking, is enabled by the increased sharpness of the SRI24 atlas compared with other available atlases. Spatial normalization, herein demonstrated using data from a young-old group comparison study, is enabled by its unbiased average population shape property. For both propagation and normalization, we also report the results of quantitative comparisons with seven other published atlases: Colin27, MNI152, ICBM452 (warp5 and air12), and LPBA40 (SPM5, FLIRT, AIR). Our results suggest that the SRI24 atlas, although based on 3T MR data, allows equally accurate spatial normalization of data acquired at 1.5T as the comparison atlases, all of which are based on 1.5T data. Furthermore, the SRI24 atlas is as suitable for label propagation as the comparison atlases and detailed enough to allow delineation of anatomical structures for this purpose directly in the atlas. PMID:20017133

  8. The SRI24 Multi-Channel Atlas of Normal Adult Human Brain Structure

    PubMed Central

    Rohlfing, Torsten; Zahr, Natalie M.; Sullivan, Edith V.; Pfefferbaum, Adolf

    2010-01-01

    This paper describes the SRI24 atlas, a new standard reference system of normal human brain anatomy, that was created using template-free population registration of high-resolution magnetic resonance images acquired at 3T in a group of 24 normal control subjects. The atlas comprises anatomical channels (T1, T2, and proton density weighted), diffusion-related channels (fractional anisotropy, mean diffusivity, longitudinal diffusivity, mean diffusion-weighted image), tissue channels (CSF probability, gray matter probability, white matter probability, tissue labels), and two cortical parcellation maps. The SRI24 atlas enables multi-channel atlas-to-subject image registration. It is uniquely versatile in that it is equally suited for the two fundamentally different atlas applications: label propagation and spatial normalization. Label propagation, herein demonstrated using DTI fiber tracking, is enabled by the increased sharpness of the SRI24 atlas compared with other available atlases. Spatial normalization, herein demonstrated using data from a young-old group comparison study, is enabled by its unbiased average population shape property. For both propagation and normalization, we also report the results of quantitative comparisons with seven other published atlases: Colin27, MNI152, ICBM452 (warp5 and air12), and LPBA40 (SPM5, FLIRT, AIR). Our results suggest that the SRI24 atlas, although based on 3T MR data, allows equally accurate spatial normalization of data acquired at 1.5T as the comparison atlases, all of which are based on 1.5T data. Furthermore, the SRI24 atlas is as suitable for label propagation as the comparison atlases and detailed enough to allow delineation of anatomical structures for this purpose directly in the atlas. PMID:20017133

  9. Role of Cardiac Myocytes Heart Fatty Acid Binding Protein Depletion (H-FABP) in Early Myocardial Infarction in Human Heart (Autopsy Study)

    PubMed Central

    Shabaiek, Amany; Ismael, Nour El-Hoda; Elsheikh, Samar; Amin, Hebat Allah

    2016-01-01

    BACKGROUND: Many immunohistochemical markers have been used in the postmortem detection of early myocardial infarction. AIM: In the present study we examined the role of Heart-type fatty acid binding protein (H-FABP), in the detection of early myocardial infarction. MATERIAL AND METHODS: We obtained samples from 40 human autopsy hearts with/without histopathological signs of ischemia. RESULTS: All cases of definite and probable myocardial infarction showed a well-defined area of H-FABP depletion. All of the control cases showed strong H-FABP expression, except two markedly autolysed myocardial samples that showed affected antigenicity. CONCLUSION: Thus, we suggest H-FABP as being one of the valuable tools facing the problem of postmortem detection of early myocardial infarction/ischemia, but not in autolysis.

  10. Human colonic crypts in culture: segregation of immunochemical markers in normal versus adenoma-derived

    PubMed Central

    Dame, Michael K; Jiang, Yan; Appelman, Henry D; Copley, Kelly D; McClintock, Shannon D; Aslam, Muhammad Nadeem; Attili, Durga; Elmunzer, B Joseph; Brenner, Dean E; Varani, James; Turgeon, D Kim

    2014-01-01

    In order to advance a culture model of human colonic neoplasia, we developed methods for the isolation and in vitro maintenance of intact colonic crypts from normal human colon tissue and adenomas. Crypts were maintained in three-dimensional Matrigel culture with a simple, serum-free, low Ca2+ (0.15 mM) medium. Intact colonic crypts from normal human mucosa were viably maintained for 3–5 days with preservation of the in situ crypt-like architecture, presenting a distinct base and apex. Abnormal structures from adenoma tissue could be maintained through multiple passages (up to months), with expanding buds/tubules. Immunohistochemical markers for intestinal stem cells (Lgr5), growth (Ki67), differentiation (E-cadherin, cytokeratin 20 (CK20) and mucin 2 (MUC2)) and epithelial turnover (Bax, cleaved Caspase-3), paralleled the changes in function. The epithelial cells in normal crypts followed the physiological sequence of progression from proliferation to differentiation to dissolution in a spatially and temporally appropriate manner. Lgr5 expression was seen in a few basal cells of freshly isolated crypts, but was not detected after 1–3 days in culture. After 24 h in culture, crypts from normal colonic tissue continued to show strong Ki67 and MUC2 expression at the crypt base, with a gradual decrease over time such that by days 3–4 Ki67 was not expressed. The differentiation marker CK20 increased over the same period, eventually becoming intense throughout the whole crypt. In adenoma-derived structures, expression of markers for all stages of progression persisted for the entire time in culture. Lgr5 showed expression in a few select cells after months in culture. Ki67 and MUC2 were largely associated with the proliferative budding regions while CK20 was localized to the parent structure. This ex vivo culture model of normal and adenomatous crypts provides a readily accessible tool to help understand the growth and differentiation process in human colonic

  11. Regulation of Glucagon Secretion in Normal and Diabetic Human Islets by γ-Hydroxybutyrate and Glycine*

    PubMed Central

    Li, Changhong; Liu, Chengyang; Nissim, Itzhak; Chen, Jie; Chen, Pan; Doliba, Nicolai; Zhang, Tingting; Nissim, Ilana; Daikhin, Yevgeny; Stokes, David; Yudkoff, Marc; Bennett, Michael J.; Stanley, Charles A.; Matschinsky, Franz M.; Naji, Ali

    2013-01-01

    Paracrine signaling between pancreatic islet β-cells and α-cells has been proposed to play a role in regulating glucagon responses to elevated glucose and hypoglycemia. To examine this possibility in human islets, we used a metabolomic approach to trace the responses of amino acids and other potential neurotransmitters to stimulation with [U-13C]glucose in both normal individuals and type 2 diabetics. Islets from type 2 diabetics uniformly showed decreased glucose stimulation of insulin secretion and respiratory rate but demonstrated two different patterns of glucagon responses to glucose: one group responded normally to suppression of glucagon by glucose, but the second group was non-responsive. The non-responsive group showed evidence of suppressed islet GABA levels and of GABA shunt activity. In further studies with normal human islets, we found that γ-hydroxybutyrate (GHB), a potent inhibitory neurotransmitter, is generated in β-cells by an extension of the GABA shunt during glucose stimulation and interacts with α-cell GHB receptors, thus mediating the suppressive effect of glucose on glucagon release. We also identified glycine, acting via α-cell glycine receptors, as the predominant amino acid stimulator of glucagon release. The results suggest that glycine and GHB provide a counterbalancing receptor-based mechanism for controlling α-cell secretory responses to metabolic fuels. PMID:23266825

  12. Regulation of glucagon secretion in normal and diabetic human islets by γ-hydroxybutyrate and glycine.

    PubMed

    Li, Changhong; Liu, Chengyang; Nissim, Itzhak; Chen, Jie; Chen, Pan; Doliba, Nicolai; Zhang, Tingting; Nissim, Ilana; Daikhin, Yevgeny; Stokes, David; Yudkoff, Marc; Bennett, Michael J; Stanley, Charles A; Matschinsky, Franz M; Naji, Ali

    2013-02-01

    Paracrine signaling between pancreatic islet β-cells and α-cells has been proposed to play a role in regulating glucagon responses to elevated glucose and hypoglycemia. To examine this possibility in human islets, we used a metabolomic approach to trace the responses of amino acids and other potential neurotransmitters to stimulation with [U-(13)C]glucose in both normal individuals and type 2 diabetics. Islets from type 2 diabetics uniformly showed decreased glucose stimulation of insulin secretion and respiratory rate but demonstrated two different patterns of glucagon responses to glucose: one group responded normally to suppression of glucagon by glucose, but the second group was non-responsive. The non-responsive group showed evidence of suppressed islet GABA levels and of GABA shunt activity. In further studies with normal human islets, we found that γ-hydroxybutyrate (GHB), a potent inhibitory neurotransmitter, is generated in β-cells by an extension of the GABA shunt during glucose stimulation and interacts with α-cell GHB receptors, thus mediating the suppressive effect of glucose on glucagon release. We also identified glycine, acting via α-cell glycine receptors, as the predominant amino acid stimulator of glucagon release. The results suggest that glycine and GHB provide a counterbalancing receptor-based mechanism for controlling α-cell secretory responses to metabolic fuels. PMID:23266825

  13. Expression of gangliosides on glial and neuronal cells in normal and pathological adult human brain.

    PubMed

    Marconi, Silvia; De Toni, Luca; Lovato, Laura; Tedeschi, Elisa; Gaetti, Luigi; Acler, Michele; Bonetti, Bruno

    2005-12-30

    Few studies have assessed the glycolipid phenotype of glial cells in the human central nervous system (CNS) in situ. We investigated by immunohistochemistry the expression and cellular distribution of a panel of gangliosides (GM1, GM2, acetyl-GM3, GD1a, GD1b, GD2, GD3, GT1b, GQ1b and the A2B5 antibody) in adult, human normal and pathological brain, namely multiple sclerosis (MS) and other neurological diseases (OND). In normal conditions, we found diffuse expression in the white matter of most gangliosides tested, with the exception of acetyl-GM3, GT1b and GQ1b. By double immunofluorescence with phenotypic markers, GM1 and GD1b were preferentially expressed on GFAP+ astrocytes, GD1a on NG2+ oligodendrocyte precursors, A2B5 immunostained both populations, while GD2 was selectively present on mature oligodendrocytes. In the gray matter, only GM1, GD2 and A2B5 were present on neuronal cells. Interestingly, those gangliosides present on astrocytes in normal conditions were preferentially expressed on NG2+ cells in chronic MS lesions and in OND. Selective expression of GT1b upon astrocytes and NG2+ cells was instead observed in MS lesions, but not in OND. The definition of the glycolipid phenotype of CNS glial cells may be useful to identify distinct biological glial subsets and provide insights on the potential autoantigenic role of gangliosides in CNS autoimmune diseases. PMID:16313974

  14. Analysis of differential protein expression in normal and neoplastic human breast epithelial cell lines

    SciTech Connect

    Williams, K.; Chubb, C.; Huberman, E.; Giometti, C.S.

    1997-07-01

    High resolution two dimensional get electrophoresis (2DE) and database analysis was used to establish protein expression patterns for cultured normal human mammary epithelial cells and thirteen breast cancer cell lines. The Human Breast Epithelial Cell database contains the 2DE protein patterns, including relative protein abundances, for each cell line, plus a composite pattern that contains all the common and specifically expressed proteins from all the cell lines. Significant differences in protein expression, both qualitative and quantitative, were observed not only between normal cells and tumor cells, but also among the tumor cell lines. Eight percent of the consistently detected proteins were found in significantly (P < 0.001) variable levels among the cell lines. Using a combination of immunostaining, comigration with purified protein, subcellular fractionation, and amino-terminal protein sequencing, we identified a subset of the differentially expressed proteins. These identified proteins include the cytoskeletal proteins actin, tubulin, vimentin, and cytokeratins. The cell lines can be classified into four distinct groups based on their intermediate filament protein profile. We also identified heat shock proteins; hsp27, hsp60, and hsp70 varied in abundance and in some cases in the relative phosphorylation levels among the cell lines. Finally, we identified IMP dehydrogenase in each of the cell lines, and found the levels of this enzyme in the tumor cell lines elevated 2- to 20-fold relative to the levels in normal cells.

  15. White matter maturation of normal human fetal brain. An in vivo diffusion tensor tractography study

    PubMed Central

    Zanin, Emilie; Ranjeva, Jean-Philippe; Confort-Gouny, Sylviane; Guye, Maxime; Denis, Daniele; Cozzone, Patrick J; Girard, Nadine

    2011-01-01

    We demonstrate for the first time the ability to determine in vivo and in utero the transitions between the main stages of white matter (WM) maturation in normal human fetuses using magnetic resonance diffusion tensor imaging (DTI) tractography. Biophysical characteristics of water motion are used as an indirect probe to evaluate progression of the tissue matrix organization in cortico-spinal tracts (CSTs), optic radiations (OR), and corpus callosum (CC) in 17 normal human fetuses explored between 23 and 38 weeks of gestation (GW) and selected strictly on minimal motion artifacts. Nonlinear polynomial (third order) curve fittings of normalized longitudinal and radial water diffusivities (Z-scores) as a function of age identify three different phases of maturation with specific dynamics for each WM bundle type. These phases may correspond to distinct cellular events such as axonal organization, myelination gliosis, and myelination, previously reported by other groups on post-mortem fetuses using immunostaining methods. According to the DTI parameter dynamics, we suggest that myelination (phase 3) appears early in the CSTs, followed by the OR and by the CC, respectively. DTI tractography provides access to a better understanding of fetal WM maturation. PMID:22399089

  16. Classification of normal and malignant human gastric mucosa tissue with confocal Raman microspectroscopy and wavelet analysis

    NASA Astrophysics Data System (ADS)

    Hu, Yaogai; Shen, Aiguo; Jiang, Tao; Ai, Yong; Hu, Jiming

    2008-02-01

    Thirty-two samples from the human gastric mucosa tissue, including 13 normal and 19 malignant tissue samples were measured by confocal Raman microspectroscopy. The low signal-to-background ratio spectra from human gastric mucosa tissues were obtained by this technique without any sample preparation. Raman spectral interferences include a broad featureless sloping background due to fluorescence and noise. They mask most Raman spectral feature and lead to problems with precision and quantitation of the original spectral information. A preprocessed algorithm based on wavelet analysis was used to reduce noise and eliminate background/baseline of Raman spectra. Comparing preprocessed spectra of malignant gastric mucosa tissues with those of counterpart normal ones, there were obvious spectral changes, including intensity increase at ˜1156 cm -1 and intensity decrease at ˜1587 cm -1. The quantitative criterion based upon the intensity ratio of the ˜1156 and ˜1587 cm -1 was extracted for classification of the normal and malignant gastric mucosa tissue samples. This could result in a new diagnostic method, which would assist the early diagnosis of gastric cancer.

  17. pH-profile of cystine and glutamate transport in normal and cystinotic human fibroblasts.

    PubMed

    Forster, S; Lloyd, J B

    1985-04-11

    In the human recessive condition cystinosis, cystine transport has been reported to be normal in the plasma membrane but defective in the lysosome membrane. A possible explanation is that the transport systems at the two cellular sites are identical and that the defect in cystinosis affects the porter's ability to operate at the low pH of the lysosome. To test this hypothesis the uptake of 3H-labelled cystine and glutamate by normal and cystinotic human skin fibroblasts has been measured in vitro at pH 5.8, 6.5, 7.0, 7.4 and 8.0. Uptake of glutamate was more rapid than that of cystine. Uptake of cystine increased with increasing pH, but uptake of glutamate showed no marked pH-dependence. Transport in cystinotic cells was similar to that in normal cells, and similarly affected by pH. This finding is incompatible with the hypothesis proposed above. It is concluded that the cystine porters of the plasma membrane and the lysosome membrane are probably genetically distinct. PMID:2858219

  18. MRI assessment of pacing induced ventricular dyssynchrony in an isolated human heart.

    PubMed

    Eggen, Michael D; Bateman, Michael G; Rolfes, Christopher D; Howard, Stephen A; Swingen, Cory M; Iaizzo, Paul A

    2010-02-01

    This study demonstrates the capabilities of MRI in the assessment of cardiac pacing induced ventricular dyssynchrony, and the findings support the need for employing more physiological pacing. A human donor heart deemed non-viable for transplantation, was reanimated using an MR compatible, four-chamber working perfusion system. The heart was imaged using a 1.5T MR scanner while being paced from the right ventricular apex (RVA) via an epicardial placed lead. Four-chamber, short-axis, and tagged short-axis cines were acquired in order to track wall motion and intramyocardial strain during pacing. The results of this study revealed that the activation patterns of the left ventricle (LV) during RVA pacing demonstrated intraventricular dyssynchrony; as the left ventricular mechanical activation proceeded from the septum and anterior wall to the lateral wall, with the posterior wall being activated last. As such, the time difference to peak contraction between the septum and lateral wall was approximately 125 msec. Likewise, interventricular dyssynchrony was demonstrated from the four-chamber cine as the time difference between the peak LV and RV free wall motion was 180 msec. With the ongoing development of MR safe and MR compatible pacing systems, we can expect MRI to be added to the list of imaging modalities used to optimize cardiac resynchronization therapy (CRT) and/or alternate site pacing. PMID:20099368

  19. Assessment of Mitochondrial Dysfunction and Monoamine Oxidase Contribution to Oxidative Stress in Human Diabetic Hearts.

    PubMed

    Duicu, O M; Lighezan, R; Sturza, A; Balica, R; Vaduva, A; Feier, H; Gaspar, M; Ionac, A; Noveanu, L; Borza, C; Muntean, D M; Mornos, C

    2016-01-01

    Mitochondria-related oxidative stress is a pathomechanism causally linked to coronary heart disease (CHD) and diabetes mellitus (DM). Recently, mitochondrial monoamine oxidases (MAOs) have emerged as novel sources of oxidative stress in the cardiovascular system and experimental diabetes. The present study was purported to assess the mitochondrial impairment and the contribution of MAOs-related oxidative stress to the cardiovascular dysfunction in coronary patients with/without DM. Right atrial appendages were obtained from 75 patients randomized into 3 groups: (1) Control (CTRL), valvular patients without CHD; (2) CHD, patients with confirmed CHD; and (3) CHD-DM, patients with CHD and DM. Mitochondrial respiration was measured by high-resolution respirometry and MAOs expression was evaluated by RT-PCR and immunohistochemistry. Hydrogen peroxide (H2O2) emission was assessed by confocal microscopy and spectrophotometrically. The impairment of mitochondrial respiration was substrate-independent in CHD-DM group. MAOs expression was comparable among the groups, with the predominance of MAO-B isoform but no significant differences regarding oxidative stress were detected by either method. Incubation of atrial samples with MAOs inhibitors significantly reduced the H2O2 in all groups. In conclusion, abnormal mitochondrial respiration occurs in CHD and is more severe in DM and MAOs contribute to oxidative stress in human diseased hearts with/without DM. PMID:27190576

  20. Perturbations of heart development and function in cardiomyocytes from human embryonic stem cells with trisomy 21.

    PubMed

    Bosman, Alexis; Letourneau, Audrey; Sartiani, Laura; Del Lungo, Martina; Ronzoni, Flavio; Kuziakiv, Rostyslav; Tohonen, Virpi; Zucchelli, Marco; Santoni, Federico; Guipponi, Michel; Dumevska, Biljana; Hovatta, Outi; Antonarakis, Stylianos E; Jaconi, Marisa E

    2015-05-01

    Congenital heart defects (CHD) occur in approximately 50% of patients with Down syndrome (DS); the mechanisms for this occurrence however remain unknown. In order to understand how these defects evolve in early development in DS, we focused on the earliest stages of cardiogenesis to ascertain perturbations in development leading to CHD. Using a trisomy 21 (T21) sibling human embryonic stem cell (hESC) model of DS, we show that T21-hESC display many significant differences in expression of genes and cell populations associated with mesodermal, and more notably, secondary heart field (SHF) development, in particular a reduced number of ISL1(+) progenitor cells. Furthermore, we provide evidence for two candidate genes located on chromosome 21, ETS2 and ERG, whose overexpression during cardiac commitment likely account for the disruption of SHF development, as revealed by downregulation or overexpression experiments. Additionally, we uncover an abnormal electrophysiological phenotype in functional T21 cardiomyocytes, a result further supported by mRNA expression data acquired using RNA-Seq. These data, in combination, revealed a cardiomyocyte-specific phenotype in T21 cardiomyocytes, likely due to the overexpression of genes such as RYR2, NCX, and L-type Ca(2+) channel. These results contribute to the understanding of the mechanisms involved in the development of CHD. Stem Cells 2015;33:1434-1446. PMID:25645121

  1. Assessment of Mitochondrial Dysfunction and Monoamine Oxidase Contribution to Oxidative Stress in Human Diabetic Hearts

    PubMed Central

    Duicu, O. M.; Lighezan, R.; Sturza, A.; Balica, R.; Vaduva, A.; Feier, H.; Gaspar, M.; Ionac, A.; Noveanu, L.; Borza, C.; Muntean, D. M.; Mornos, C.

    2016-01-01

    Mitochondria-related oxidative stress is a pathomechanism causally linked to coronary heart disease (CHD) and diabetes mellitus (DM). Recently, mitochondrial monoamine oxidases (MAOs) have emerged as novel sources of oxidative stress in the cardiovascular system and experimental diabetes. The present study was purported to assess the mitochondrial impairment and the contribution of MAOs-related oxidative stress to the cardiovascular dysfunction in coronary patients with/without DM. Right atrial appendages were obtained from 75 patients randomized into 3 groups: (1) Control (CTRL), valvular patients without CHD; (2) CHD, patients with confirmed CHD; and (3) CHD-DM, patients with CHD and DM. Mitochondrial respiration was measured by high-resolution respirometry and MAOs expression was evaluated by RT-PCR and immunohistochemistry. Hydrogen peroxide (H2O2) emission was assessed by confocal microscopy and spectrophotometrically. The impairment of mitochondrial respiration was substrate-independent in CHD-DM group. MAOs expression was comparable among the groups, with the predominance of MAO-B isoform but no significant differences regarding oxidative stress were detected by either method. Incubation of atrial samples with MAOs inhibitors significantly reduced the H2O2 in all groups. In conclusion, abnormal mitochondrial respiration occurs in CHD and is more severe in DM and MAOs contribute to oxidative stress in human diseased hearts with/without DM. PMID:27190576

  2. [The function of the heart changes in implementation of the diving reactions in humans].

    PubMed

    Baranova, T I; Berlov, D N; Zavarina, L B; Minigalin, A D; Smith, N Y; Xu, S; Yanvareva, I N

    2015-03-01

    The changes of chronotropic function of the heart and of the myocardium in the implementation of the diving response in humans were studied by the electrocardiographic method. The study involved 80 students aged 18-20 years. Diving simulation was performed by immersing the face in cold water during breath-hold exhale. When the water temperature was 12.3 +/- 2.3 degrees C, average duration of apnea was 31 +/- 11 s. The oxygen content in the exhaled air after apnea was 98.8 +/- 8.7 mm Hg, carbon dioxide--49.1 +/- 3.5 mm Hg. It was observed slowing of the heart rate, mainly due to the increasing of diastole in 41 of the 80 surveyed during simulating diving. But it also can be observed symptoms of conduction deterioration: atrioventricular block type I (22% of reactive type and 29% of the highly reactive type subjects), and exceeds standards QTc-interval prolongation (at 7.5% of the subjects). These responses are adaptive in nature and disappear in the recovery process. But the fact abnormalities of conduction in the myocardium must be considered when using the diving reflex in medical practice, as may be due to a predisposition to a certain pathology of the cardiovascular system. PMID:26016327

  3. MRI Assessment of Pacing Induced Ventricular Dyssynchrony in an Isolated Human Heart

    PubMed Central

    Eggen, Michael D.; Bateman, Michael G.; Rolfes, Christopher D.; Howard, Stephen A.; Swingen, Cory M.; Iaizzo, Paul A.

    2010-01-01

    This study demonstrates the capabilities of MR imaging in the assessment of cardiac pacing induced ventricular dyssynchrony, and findings support the need for employing more physiological pacing. A human donor heart deemed non-viable for transplantation, was reanimated using an MR compatible, four-chamber working perfusion system. The heart was imaged using a 1.5T MR scanner while being paced from the right ventricular apex (RVA) via an epicardial placed lead. Four-chamber, short-axis, and tagged short-axis cines were acquired in order track wall motion and intramyocardial strain during pacing. The results of this study revealed that the activation patterns of the left ventricle (LV) during RVA pacing demonstrated intraventricular dyssynchrony; as the left ventricular mechanical activation proceeded from the septum and anterior wall to the lateral wall, with the posterior wall being activated last. As such, the time difference to peak contraction between the septum and lateral wall was ∼125 ms. Likewise, interventricular dyssynchrony was demonstrated from the four-chamber cine as the time difference between the peak LV and RV free wall motion was 180 ms. With the ongoing development of MR safe and MR compatible pacing systems, we can expect MRI to be added to the list of imaging modalities used to optimize cardiac resynchronization therapy and/or alternate site pacing. PMID:20099368

  4. An Update on Heart Transplantation in Human Immunodeficiency Virus-Infected Patients.

    PubMed

    Agüero, F; Castel, M A; Cocchi, S; Moreno, A; Mestres, C A; Cervera, C; Pérez-Villa, F; Tuset, M; Cartañà, R; Manzardo, C; Guaraldi, G; Gatell, J M; Miró, J M

    2016-01-01

    Cardiovascular diseases have become a significant cause of morbidity in patients with human immunodeficiency virus (HIV) infection. Heart transplantation (HT) is a well-established treatment of end-stage heart failure (ESHF) and is performed in selected HIV-infected patients in developed countries. Few data are available on the prognosis of HIV-infected patients undergoing HT in the era of combined antiretroviral therapy (cART) because current evidence is limited to small retrospective cohorts, case series, and case reports. Many HT centers consider HIV infection to be a contraindication for HT; however, in the era of cART, HT recipients with HIV infection seem to achieve satisfactory outcomes without developing HIV-related events. Consequently, selected HIV-infected patients with ESHF who are taking effective cART should be considered candidates for HT. The present review provides epidemiological data on ESHF in HIV-infected patients from all published experience on HT in HIV-infected patients since the beginning of the epidemic. The practical management of these patients is discussed, with emphasis on the challenging issues that must be addressed in the pretransplant (including HIV criteria) and posttransplant periods. Finally, proposals are made for future management and research priorities. PMID:26523614

  5. Fetal heart extract facilitates the differentiation of human umbilical cord blood-derived mesenchymal stem cells into heart muscle precursor cells.

    PubMed

    Pham, Truc Le-Buu; Nguyen, Tam Thanh; Van Bui, Anh; Nguyen, My Thu; Van Pham, Phuc

    2016-08-01

    Human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) are a promising stem cell source with the potential to modulate the immune system as well as the capacity to differentiate into osteoblasts, chondrocytes, and adipocytes. In previous publications, UCB-MSCs have been successfully differentiated into cardiomyocytes. This study aimed to improve the efficacy of differentiation of UCB-MSCs into cardiomyocytes by combining 5-azacytidine (Aza) with mouse fetal heart extract (HE) in the induction medium. UCB-MSCs were isolated from umbilical cord blood according to a published protocol. Murine fetal hearts were used to produce fetal HE using a rapid freeze-thaw procedure. MSCs at the 3rd to 5th passage were differentiated into cardiomyocytes in two kinds of induction medium: complete culture medium plus Aza (Aza group) and complete culture medium plus Aza and fetal HE (Aza + HE group). The results showed that the cells in both kinds of induction medium exhibited the phenotype of cardiomyocytes. At the transcriptional level, the cells expressed a number of cardiac muscle-specific genes such as Nkx2.5, Gata 4, Mef2c, HCN2, hBNP, α-Ca, cTnT, Desmin, and β-MHC on day 27 in the Aza group and on day 18 in the Aza + HE group. At the translational level, sarcomic α-actin was expressed on day 27 in the Aza group and day 18 in the Aza + HE group. Although they expressed specific genes and proteins of cardiac muscle cells, the induced cells in both groups did not contract and beat spontaneously. These properties are similar to properties of heart muscle precursor cells in vivo. These results demonstrated that the fetal HE facilitates the differentiation process of human UCB-MSCs into heart muscle precursor cells. PMID:25377264

  6. Human colon tissue in organ culture: preservation of normal and neoplastic characteristics

    PubMed Central

    Bhagavathula, Narasimharao; Mankey, Cohra; DaSilva, Marissa; Paruchuri, Tejaswi; Aslam, Muhammad Nadeem; Varani, James

    2009-01-01

    Normal and neoplastic human colon tissue obtained at surgery was used to establish conditions for organ culture. Optimal conditions included an atmosphere of 5% CO2 and 95% O2; tissue partially submerged with mucosa at the gas interface; and serum-free medium with 1.5 mM Ca2+ and a number of growth supplements. Histological, histochemical, and immunohistochemical features that distinguish normal and neoplastic tissue were preserved over a 2-d period. With normal tissue, this included the presence of elongated crypts with small, densely packed cells at the crypt base and mucin-containing goblet cells in the upper portion. Ki67 staining, for proliferating cells, was confined to the lower third of the crypt, while expression of extracellular calcium-sensing receptor was seen in the upper third and surface epithelium. E-cadherin and β-catenin were expressed throughout the epithelium and confined to the cell surface. In tumor tissue, the same disorganized, abnormal glandular structures seen at time zero were present after 2 d. The majority of cells in these structures were mucin-poor, but occasional goblet cells were seen and mucin staining was present. Ki67 staining was seen throughout the abnormal epithelium and calcium-sensing receptor expression was weak and variable. E-cadherin was seen at the cell surface (similar to normal tissue), but in some places, there was diffuse cytoplasmic staining. Finally, intense cytoplasmic and nuclear β-catenin staining was observed in cultured neoplastic tissue. PMID:19915935

  7. Functional Effects of Delivering Human Mesenchymal Stem Cell-Seeded Biological Sutures to an Infarcted Heart.

    PubMed

    Hansen, Katrina J; Favreau, John T; Guyette, Jacques P; Tao, Ze-Wei; Coffin, Spencer T; Cunha-Gavidia, Anny; D'Amore, Brian; Perreault, Luke R; Fitzpatrick, John P; DeMartino, Angelica; Gaudette, Glenn R

    2016-01-01

    Stem cell therapy has the potential to improve cardiac function after myocardial infarction (MI); however, existing methods to deliver cells to the myocardium, including intramyocardial injection, suffer from low engraftment rates. In this study, we used a rat model of acute MI to assess the effects of human mesenchymal stem cell (hMSC)-seeded fibrin biological sutures on cardiac function at 1 week after implant. Biological sutures were seeded with quantum dot (Qdot)-loaded hMSCs for 24 h before implantation. At 1 week postinfarct, the heart was imaged to assess mechanical function in the infarct region. Regional parameters assessed were regional stroke work (RSW) and systolic area of contraction (SAC) and global parameters derived from the pressure waveform. MI (n = 6) significantly decreased RSW (0.026 ± 0.011) and SAC (0.022 ± 0.015) when compared with sham operation (RSW: 0.141 ± 0.009; SAC: 0.166 ± 0.005, n = 6) (p < 0.05). The delivery of unseeded biological sutures to the infarcted hearts did not change regional mechanical function compared with the infarcted hearts (RSW: 0.032 ± 0.004, SAC: 0.037 ± 0.008, n = 6). The delivery of hMSC-seeded sutures exerted a trend toward increase of regional mechanical function compared with the infarcted heart (RSW: 0.057 ± 0.011; SAC: 0.051 ± 0.014, n = 6). Global function showed no significant differences between any group (p > 0.05); however, there was a trend toward improved function with the addition of either unseeded or seeded biological suture. Histology demonstrated that Qdot-loaded hMSCs remained present in the infarcted myocardium after 1 week. Analysis of serial sections of Masson's trichrome staining revealed that the greatest infarct size was in the infarct group (7.0% ± 2.2%), where unseeded (3.8% ± 0.6%) and hMSC-seeded (3.7% ± 0.8%) suture groups maintained similar infarct sizes. Furthermore, the remaining suture area was

  8. Functional Effects of Delivering Human Mesenchymal Stem Cell-Seeded Biological Sutures to an Infarcted Heart

    PubMed Central

    Hansen, Katrina J.; Favreau, John T.; Guyette, Jacques P.; Tao, Ze-Wei; Coffin, Spencer T.; Cunha-Gavidia, Anny; D'Amore, Brian; Perreault, Luke R.; Fitzpatrick, John P.; DeMartino, Angelica; Gaudette, Glenn R.

    2016-01-01

    Abstract Stem cell therapy has the potential to improve cardiac function after myocardial infarction (MI); however, existing methods to deliver cells to the myocardium, including intramyocardial injection, suffer from low engraftment rates. In this study, we used a rat model of acute MI to assess the effects of human mesenchymal stem cell (hMSC)-seeded fibrin biological sutures on cardiac function at 1 week after implant. Biological sutures were seeded with quantum dot (Qdot)-loaded hMSCs for 24 h before implantation. At 1 week postinfarct, the heart was imaged to assess mechanical function in the infarct region. Regional parameters assessed were regional stroke work (RSW) and systolic area of contraction (SAC) and global parameters derived from the pressure waveform. MI (n = 6) significantly decreased RSW (0.026 ± 0.011) and SAC (0.022 ± 0.015) when compared with sham operation (RSW: 0.141 ± 0.009; SAC: 0.166 ± 0.005, n = 6) (p < 0.05). The delivery of unseeded biological sutures to the infarcted hearts did not change regional mechanical function compared with the infarcted hearts (RSW: 0.032 ± 0.004, SAC: 0.037 ± 0.008, n = 6). The delivery of hMSC-seeded sutures exerted a trend toward increase of regional mechanical function compared with the infarcted heart (RSW: 0.057 ± 0.011; SAC: 0.051 ± 0.014, n = 6). Global function showed no significant differences between any group (p > 0.05); however, there was a trend toward improved function with the addition of either unseeded or seeded biological suture. Histology demonstrated that Qdot-loaded hMSCs remained present in the infarcted myocardium after 1 week. Analysis of serial sections of Masson's trichrome staining revealed that the greatest infarct size was in the infarct group (7.0% ± 2.2%), where unseeded (3.8% ± 0.6%) and hMSC-seeded (3.7% ± 0.8%) suture groups maintained similar infarct sizes. Furthermore, the remaining suture area

  9. Integrated Central-Autonomic Multifractal Complexity in the Heart Rate Variability of Healthy Humans

    PubMed Central

    Lin, D. C.; Sharif, A.

    2012-01-01

    Purpose of Study: The aim of this study was to characterize the central-autonomic interaction underlying the multifractality in heart rate variability (HRV) of healthy humans. Materials and Methods: Eleven young healthy subjects participated in two separate ~40 min experimental sessions, one in supine (SUP) and one in, head-up-tilt (HUT), upright (UPR) body positions. Surface scalp electroencephalography (EEG) and electrocardiogram (ECG) were collected and fractal correlation of brain and heart rate data was analyzed based on the idea of relative multifractality. The fractal correlation was further examined with the EEG, HRV spectral measures using linear regression of two variables and principal component analysis (PCA) to find clues for the physiological processing underlying the central influence in fractal HRV. Results: We report evidence of a central-autonomic fractal correlation (CAFC) where the HRV multifractal complexity varies significantly with the fractal correlation between the heart rate and brain data (P = 0.003). The linear regression shows significant correlation between CAFC measure and EEG Beta band spectral component (P = 0.01 for SUP and P = 0.002 for UPR positions). There is significant correlation between CAFC measure and HRV LF component in the SUP position (P = 0.04), whereas the correlation with the HRV HF component approaches significance (P = 0.07). The correlation between CAFC measure and HRV spectral measures in the UPR position is weak. The PCA results confirm these findings and further imply multiple physiological processes underlying CAFC, highlighting the importance of the EEG Alpha, Beta band, and the HRV LF, HF spectral measures in the supine position. Discussion and Conclusion: The findings of this work can be summarized into three points: (i) Similar fractal characteristics exist in the brain and heart rate fluctuation and the change toward stronger fractal correlation implies the change toward more complex

  10. Macro-micro imaging of cardiac–neural circuits in co-cultures from normal and diseased hearts

    PubMed Central

    Bub, Gil; Burton, Rebecca-Ann B

    2015-01-01

    The autonomic nervous system plays an important role in the modulation of normal cardiac rhythm, but is also implicated in modulating the heart’s susceptibility to re-entrant ventricular and atrial arrhythmias. The mechanisms by which the autonomic nervous system is pro-arrhythmic or anti-arrhythmic is multifaceted and varies for different types of arrhythmia and their cardiac substrates. Despite decades of research in this area, fundamental questions related to how neuron density and spatial organization modulate cardiac wave dynamics remain unanswered. These questions may be ill-posed in intact tissues where the activity of individual cells is often experimentally inaccessible. Development of simplified biological models that would allow us to better understand the influence of neural activation on cardiac activity can be beneficial. This Symposium Review summarizes the development of in vitro cardiomyocyte cell culture models of re-entrant activity, as well as challenges associated with extending these models to include the effects of neural activation. PMID:25398529

  11. Widespread expression of serum amyloid A in histologically normal human tissues. Predominant localization to the epithelium.

    PubMed

    Urieli-Shoval, S; Cohen, P; Eisenberg, S; Matzner, Y

    1998-12-01

    Serum amyloid A (SAA) is an acute-phase reactant whose level in the blood is elevated to 1000-fold as part of the body's responses to various injuries, including trauma, infection, inflammation, and neoplasia. As an acute-phase reactant, the liver has been considered to be the primary site of expression. However, limited extrahepatic SAA expression was described in mouse tissues and in cells of human atherosclerotic lesions. Here we describe nonradioactive in situ hybridization experiments revealing that the SAA mRNA is widely expressed in many histologically normal human tissues. Expression was localized predominantly to the epithelial components of a variety of tissues, including breast, stomach, small and large intestine, prostate, lung, pancreas, kidney, tonsil, thyroid, pituitary, placenta, skin epidermis, and brain neurons. Expression was also observed in lymphocytes, plasma cells, and endothelial cells. RT-PCR analysis of selected tissues revealed expression of the SAA1, SAA2, and SAA4 genes but not of SAA3, consistent with expression of these genes in the liver. Immunohistochemical staining revealed SAA protein expression that co-localized with SAA mRNA expression. These data indicate local production of the SAA proteins in histologically normal human extrahepatic tissues. PMID:9815279

  12. Anti-DNA autoantibody-producing hybridomas of normal human lymphoid cell origin.

    PubMed Central

    Cairns, E; Block, J; Bell, D A

    1984-01-01

    Fusion of human myeloma cell line GM 4672 and tonsillar lymphoid cells from a normal donor resulted in 13 primary hybridomas, which produced IgM anti-single-stranded DNA (ssDNA) antibodies, as determined in enzyme-linked immunosorbent assay. Nine of these primary hybridomas have been cloned and a total of 34 clones were obtained. Supernatants of these cloned hybridomas were tested for binding to ssDNA, native DNA, RNA, low molecular weight supernatant DNA, polydeoxyguanylate-polydeoxycitidylate, polydeoxyadenylate-thymidylate sodium salt, and cardiolipin. Supernatants from all clones but one showed polyspecificity when reacting with the antigens tested. That the clones were true hybridomas rather than transformed lymphoid cells was evidence by IgM anti-DNA antibody secretion, karyotype analysis, and HLA typing. These studies imply that immunoglobulin genes encoding for anti-DNA autoantibodies with a spectrum of nucleic acid specificities similar to systemic lupus erythematosus, exist among normal B lymphocytes. PMID:6470143

  13. Surface modification of microparticles causes differential uptake responses in normal and tumoral human breast epithelial cells

    NASA Astrophysics Data System (ADS)

    Patiño, Tania; Soriano, Jorge; Barrios, Lleonard; Ibáñez, Elena; Nogués, Carme

    2015-06-01

    The use of micro- and nanodevices as multifunctional systems for biomedical applications has experienced an exponential growth during the past decades. Although a large number of studies have focused on the design and fabrication of new micro- and nanosystems capable of developing multiple functions, a deeper understanding of their interaction with cells is required. In the present study, we evaluated the effect of different microparticle surfaces on their interaction with normal and tumoral human breast epithelial cell lines. For this, AlexaFluor488 IgG functionalized polystyrene microparticles (3 μm) were coated with Polyethyleneimine (PEI) at two different molecular weights, 25 and 750 kDa. The effect of microparticle surface properties on cytotoxicity, cellular uptake and endocytic pathways were assessed for both normal and tumoral cell lines. Results showed a differential response between the two cell lines regarding uptake efficiency and mechanisms of endocytosis, highlighting the potential role of microparticle surface tunning for specific cell targeting.

  14. Dimensional analysis of heart rate variability in heart transplant recipients

    SciTech Connect

    Zbilut, J.P.; Mayer-Kress, G.; Geist, K.

    1987-01-01

    We discuss periodicities in the heart rate in normal and transplanted hearts. We then consider the possibility of dimensional analysis of these periodicities in transplanted hearts and problems associated with the record.

  15. Intracrine angiotensin II functions originate from noncanonical pathways in the human heart.

    PubMed

    Ferrario, Carlos M; Ahmad, Sarfaraz; Varagic, Jasmina; Cheng, Che Ping; Groban, Leanne; Wang, Hao; Collawn, James F; Dell Italia, Louis J

    2016-08-01

    Although it is well-known that excess renin angiotensin system (RAS) activity contributes to the pathophysiology of cardiac and vascular disease, tissue-based expression of RAS genes has given rise to the possibility that intracellularly produced angiotensin II (Ang II) may be a critical contributor to disease processes. An extended form of angiotensin I (Ang I), the dodecapeptide angiotensin-(1-12) [Ang-(1-12)], that generates Ang II directly from chymase, particularly in the human heart, reinforces the possibility that an alternative noncanonical renin independent pathway for Ang II formation may be important in explaining the mechanisms by which the hormone contributes to adverse cardiac and vascular remodeling. This review summarizes the work that has been done in evaluating the functional significance of Ang-(1-12) and how this substrate generated from angiotensinogen by a yet to be identified enzyme enhances knowledge about Ang II pathological actions. PMID:27233763

  16. Wavelet analysis of nonequilibrium ionic currents in human heart sodium channel (hH1a).

    PubMed

    Hosein-Sooklal, A; Kargol, A

    2002-08-01

    Nonequilibrium response spectroscopy (NRS), the technique of using rapidly fluctuating voltage pulses in the study of ion channels, is applied here. NRS is known to drive an ensemble of ion channels far from equilibrium where, it has been argued, new details of ion channel kinetics can be studied under nonequilibrium conditions. In this paper, a single-pulse NRS technique with custom-designed waveforms built from wavelets is used. The pulses are designed to produce different responses from two competing models of a human heart isoform of the sodium channel (hH1a). Experimental data using this new type of pulses are obtained through whole-cell recordings from mammalian cells (HEK 293). Wavelet analysis of the model response and the experimental data is introduced to show how these NRS pulses can aid in distinguishing the better of the two models and thus introduces another important application of this new technique. PMID:12181611

  17. Mesenchymal progenitor cell markers in human articular cartilage: normal distribution and changes in osteoarthritis

    PubMed Central

    Grogan, Shawn P; Miyaki, Shigeru; Asahara, Hiroshi; D'Lima, Darryl D; Lotz, Martin K

    2009-01-01

    Introduction Recent findings suggest that articular cartilage contains mesenchymal progenitor cells. The aim of this study was to examine the distribution of stem cell markers (Notch-1, Stro-1 and VCAM-1) and of molecules that modulate progenitor differentiation (Notch-1 and Sox9) in normal adult human articular cartilage and in osteoarthritis (OA) cartilage. Methods Expression of the markers was analyzed by immunohistochemistry (IHC) and flow cytometry. Hoechst 33342 dye was used to identify and sort the cartilage side population (SP). Multilineage differentiation assays including chondrogenesis, osteogenesis and adipogenesis were performed on SP and non-SP (NSP) cells. Results A surprisingly high number (>45%) of cells were positive for Notch-1, Stro-1 and VCAM-1 throughout normal cartilage. Expression of these markers was higher in the superficial zone (SZ) of normal cartilage as compared to the middle zone (MZ) and deep zone (DZ). Non-fibrillated OA cartilage SZ showed reduced Notch-1 and Sox9 staining frequency, while Notch-1, Stro-1 and VCAM-1 positive cells were increased in the MZ. Most cells in OA clusters were positive for each molecule tested. The frequency of SP cells in cartilage was 0.14 ± 0.05% and no difference was found between normal and OA. SP cells displayed chondrogenic and osteogenic but not adipogenic differentiation potential. Conclusions These results show a surprisingly high number of cells that express putative progenitor cell markers in human cartilage. In contrast, the percentage of SP cells is much lower and within the range of expected stem cell frequency. Thus, markers such as Notch-1, Stro-1 or VCAM-1 may not be useful to identify progenitors in cartilage. Instead, their increased expression in OA cartilage implicates involvement in the abnormal cell activation and differentiation process characteristic of OA. PMID:19500336

  18. Thomsen-Friedenreich-related carbohydrate antigens in normal adult human tissues: a systematic and comparative study.

    PubMed

    Cao, Y; Stosiek, P; Springer, G F; Karsten, U

    1996-08-01

    A broad variety of normal human tissues were examined for the expression of Thomsen-Friedenreich (TF)-related histo-blood group antigens, TF (Gal beta 1-3GalNAc alpha 1-R), Tn (TF precursor, GalNAc alpha 1-R), sialosyl-Tn (NeuAc alpha 2-6GalNAc alpha 1-R), considered to be useful in cancer diagnosis and immunotherapy, and sialosyl-TF, the cryptic form of TF. These antigens or, more correctly, glycotopes, were determined by immunohistochemistry with at least two monoclonal antibodies (mAbs) each (except sialosyl-TF) as well as by lectin histochemistry. For a better dissection of sialosyl-TF and TF glycotopes, tissue sections were pretreated with galactose oxidase or the galactose oxidase-Schiff sequence. Staining with mAbs appeared to be more restricted than with the lectins used. Distribution patterns among normal epithelia were different for all four antigens. These antigens were also detected in some non-epithelial tissues. They can be classified in the following sequence according to the frequency of their occurrence in normal tissues: sialosyl-TF > > sialosyl-Tn > Tn > TF. Most of the positively staining sites for TF, Tn, and sialosyl-Tn are located in immunologically privileged areas. The complex results obtained with anti-TF mAbs (after treatment of the tissue sections with sialidase from Vibrio cholerae) and the lectins amaranthin and jacalin revealed a differential distribution of the subtypes of sialosyl-TF [NeuAc alpha 2-3Gal beta 1-3GalNAc alpha 1-R and Gal beta 1-3 (NeuAc alpha 2-6)GalNAc alpha 1-R] in normal human tissues. From our data it can be inferred that TF, Tn, and sialosyl-Tn are promising targets for a cancer vaccine. PMID:8877380

  19. Prefrontal GABA(A) receptor alpha-subunit expression in normal postnatal human development and schizophrenia.

    PubMed

    Duncan, Carlotta E; Webster, Maree J; Rothmond, Debora A; Bahn, Sabine; Elashoff, Michael; Shannon Weickert, Cynthia

    2010-07-01

    Cortical GABA deficits that are consistently reported in schizophrenia may reflect an etiology of failed normal postnatal neurotransmitter maturation. Previous studies have found prefrontal cortical GABA(A) receptor alpha subunit alterations in schizophrenia, yet their relationship to normal developmental expression profiles in the human cortex has not been determined. The aim of this study was to quantify GABA(A) receptor alpha-subunit mRNA expression patterns in human dorsolateral prefrontal cortex (DLPFC) during normal postnatal development and in schizophrenia cases compared to controls. Transcript levels of GABA(A) receptor alpha subunits were measured using microarray and qPCR analysis of 60 normal individuals aged 6weeks to 49years and in 37 patients with schizophrenia/schizoaffective disorder and 37 matched controls. We detected robust opposing changes in cortical GABA(A) receptor alpha1 and alpha5 subunits during the first few years of postnatal development, with a 60% decrease in alpha5 mRNA expression and a doubling of alpha1 mRNA expression with increasing age. In our Australian schizophrenia cohort we detected decreased GAD67 mRNA expression (p=0.0012) and decreased alpha5 mRNA expression (p=0.038) in the DLPFC with no significant change of other alpha subunits. Our findings confirm that GABA deficits (reduced GAD67) are a consistent feature of schizophrenia postmortem brain studies. Our study does not confirm alterations in cortical alpha1 or alpha2 mRNA levels in the schizophrenic DLPFC, as seen in previous studies, but instead we report a novel down-regulation of alpha5 subunit mRNA suggesting that post-synaptic alterations of inhibitory receptors are an important feature of schizophrenia but may vary between cohorts. PMID:20100621

  20. Characterization and amino acid sequence of a fatty acid-binding protein from human heart.

    PubMed

    Offner, G D; Brecher, P; Sawlivich, W B; Costello, C E; Troxler, R F

    1988-05-15

    The complete amino acid sequence of a fatty acid-binding protein from human heart was determined by automated Edman degradation of CNBr, BNPS-skatole [3'-bromo-3-methyl-2-(2-nitrobenzenesulphenyl)indolenine], hydroxylamine, Staphylococcus aureus V8 proteinase, tryptic and chymotryptic peptides, and by digestion of the protein with carboxypeptidase A. The sequence of the blocked N-terminal tryptic peptide from citraconylated protein was determined by collisionally induced decomposition mass spectrometry. The protein contains 132 amino acid residues, is enriched with respect to threonine and lysine, lacks cysteine, has an acetylated valine residue at the N-terminus, and has an Mr of 14768 and an isoelectric point of 5.25. This protein contains two short internal repeated sequences from residues 48-54 and from residues 114-119 located within regions of predicted beta-structure and decreasing hydrophobicity. These short repeats are contained within two longer repeated regions from residues 48-60 and residues 114-125, which display 62% sequence similarity. These regions could accommodate the charged and uncharged moieties of long-chain fatty acids and may represent fatty acid-binding domains consistent with the finding that human heart fatty acid-binding protein binds 2 mol of oleate or palmitate/mol of protein. Detailed evidence for the amino acid sequences of the peptides has been deposited as Supplementary Publication SUP 50143 (23 pages) at the British Library Lending Division, Boston Spa, Yorkshire LS23 7BQ, U.K., from whom copies may be obtained as indicated in Biochem. J. (1988) 249, 5. PMID:3421901

  1. Differential extraction of keratin subunits and filaments from normal human epidermis.

    PubMed

    Eichner, R; Kahn, M

    1990-04-01

    We have investigated keratin interactions in vivo by sequentially extracting water-insoluble proteins from normal human epidermis with increasing concentrations of urea (2, 4, 6, and 9.5 M) and examining each extract by one- and two-dimensional gel electrophoresis, immunoblot analysis using monoclonal anti-keratin antibodies, and EM. The viable layers of normal human epidermis contain keratins K1, K2, K5, K10/11, K14, and K15, which are sequentially expressed during the course of epidermal differentiation. Only keratins K5, K14, and K15, which are synthesized by epidermal basal cells, were solubilized in 2 M urea. Extraction of keratins K1, K2, and K10/11, which are expressed only in differentiating suprabasal cells, required 4-6 M urea. Negative staining of the 2-M urea extract revealed predominantly keratin filament subunits, whereas abundant intermediate-sized filaments were observed in the 4-urea and 6-M urea extracts. These results indicate that in normal human epidermis, keratins K5, K14, and K15 are more soluble than the differentiation-specific keratins K1, K2, and K10/11. This finding suggests that native keratin filaments of different polypeptide composition have differing properties, despite their similar morphology. Furthermore, the observation of stable filaments in 4 and 6 M urea suggests that epidermal keratins K1, K2, and K10/11, which ultimately form the bulk of the protective, nonviable stratum corneum, may comprise filaments that are unusually resistant to denaturation. PMID:1691188

  2. The significance of paired astrocyte nuclei in normal human nervous tissue.

    PubMed Central

    Pittella, J E; Brasileiro-Filho, G

    1987-01-01

    A quantitative study of astrocytes was carried out in 80 microscopic fields and the number of paired nuclei in 100 consecutive astrocytes of the temporo-occipital gyrus cortex was determined in 13 patients with no cerebral or liver disease. No significant correlation was found between astrocyte number and the percentage of paired nuclei. When studies on astrocytes in hepatic encephalopathy, liver cirrhosis and hepatosplenic schistosomiasis are taken into consideration it is suggested that these cells are in continuous variable renewal in normal adult human nervous tissue, as occurs in other animal species. Images Fig. 1 PMID:3654344

  3. Autofluorescence of normal and tumor mucosa of human colon: a comprehensive analysis

    NASA Astrophysics Data System (ADS)

    Bottiroli, Giovanni F.; Marchesini, Renato; Croce, Anna C.; Dal Fante, Marco; Cuzzoni, Carolina; Di Palma, Silvana; Spinelli, Pasquale

    1993-08-01

    Both 'in vivo' and 'ex vivo' spectrofluorometric studies of neoplastic and non-neoplastic mucosa of human colon have been carried out, in order to verify the potentials of tissue natural fluorescence as a possible parameter to distinguish normal from diseased tissues, Spectrofluorometric analysis performed at colonoscopy on patients affected by neoplasia, showed that adenocarcinoma, adenoma and non-neoplastic mucosa differ in the fluorescence emissions. The results have been interpreted according to the data obtained on cryostatic sections from biopsies by means of a microspectrofluorometric analysis carried out on each histological component.

  4. Nystagmus responses in a group of normal humans during earth-horizontal axis rotation

    NASA Technical Reports Server (NTRS)

    Wall, Conrad, III; Furman, Joseph M. R.

    1989-01-01

    Horizontal eye movement responses to earth-horizontal yaw axis rotation were evaluated in 50 normal human subjects who were uniformly distributed in age (20-69 years) and each age group was then divided by gender. Subjects were rotated with eyes open in the dark, using clockwise and counter-clockwise 60 deg velocity trapezoids. The nystagmus slow component velocity is analyzed. It is shown that, despite large intersubject variability, parameters which describe earth-horizontal yaw axis responses are loosely interrelated, and some of them vary significantly with gender and age.

  5. [Gestational trophoblastic neoplasia after spontaneous normalization of human chorionic gonadotropin in patient with partial hydatidiform mole].

    PubMed

    Matos, Michelle; Ferraz, Leda; Lopes, Patrícia de Fátima; Lozoya, Consuelo; Amim Junior, Joffre; Rezende-Filho, Jorge; Braga, Antonio

    2015-07-01

    We report here a case of gestational trophoblastic neoplasia after spontaneous normalization of human chorionic gonadotropin in a patient with a partial hydatidiform mole. This is the second occurrence of this event to be reported and the first one with proven immunohistochemical evidence. Besides showing the treatment for this pregnancy complication, this case report discusses the possibility of reducing the duration of post-molar follow-up, as well as strategies for early recognition of gestational trophoblastic neoplasia after spontaneous remission of molar pregnancy. PMID:26247255

  6. Ecological Effect of Ceftaroline-Avibactam on the Normal Human Intestinal Microbiota

    PubMed Central

    Rashid, Mamun-Ur; Rosenborg, Staffan; Panagiotidis, Georgios; Söderberg-Löfdal, Karin; Weintraub, Andrej

    2015-01-01

    Ceftaroline-avibactam is a new combination of the antibiotic ceftaroline with a novel non-β-lactam β-lactamase inhibitor, avibactam. The purpose of the present study was to investigate the effect of ceftaroline-avibactam on the human intestinal microbiota. Fourteen healthy volunteers received ceftaroline-avibactam (600 mg ceftaroline fosamil and 600 mg avibactam) intravenously over 2 h every 8 h on days 1 to 6 and as a single dose on day 7. Fecal samples were collected on day −1 (within 24 h of the first infusion on day 1) and on days 2, 5, 7, 9, 14, and 21. Escherichia coli numbers decreased during the study and normalized on day 21. An increased number of Klebsiella bacteria appeared on day 14 and normalized on day 21. The number of other enterobacteria decreased during the study, and the number of enterococci decreased from days 2 to 7 and normalized on day 9. Candida numbers increased from days 5 to 9 and normalized after day 14. The number of lactobacilli decreased during the study and recovered on day 14. The number of bifidobacteria decreased on day 2 and normalized on day 21. The number of Bacteroides bacteria was unchanged. Clostridium difficile numbers decreased on days 7 and 9 and increased on days 14 and 21. A toxigenic C. difficile strain was detected in one volunteer on day 21 with no reported adverse events. Plasma samples were collected on days −1, 2, 5, and 7. Ceftaroline and avibactam concentrations were 0 to 34.5 mg/liter and 0 to 61.6 mg/liter, respectively, in plasma and 0 to 35.4 mg/kg and 0 to 98.5 mg/kg, respectively, in feces. (This study is registered in the European Clinical Trials Database [https://eudract.ema.europa.eu/] under number EudraCT 2012 004921-25.) PMID:25987638

  7. Ecological Effect of Ceftaroline-Avibactam on the Normal Human Intestinal Microbiota.

    PubMed

    Rashid, Mamun-Ur; Rosenborg, Staffan; Panagiotidis, Georgios; Söderberg-Löfdal, Karin; Weintraub, Andrej; Nord, Carl Erik

    2015-08-01

    Ceftaroline-avibactam is a new combination of the antibiotic ceftaroline with a novel non-β-lactam β-lactamase inhibitor, avibactam. The purpose of the present study was to investigate the effect of ceftaroline-avibactam on the human intestinal microbiota. Fourteen healthy volunteers received ceftaroline-avibactam (600 mg ceftaroline fosamil and 600 mg avibactam) intravenously over 2 h every 8 h on days 1 to 6 and as a single dose on day 7. Fecal samples were collected on day -1 (within 24 h of the first infusion on day 1) and on days 2, 5, 7, 9, 14, and 21. Escherichia coli numbers decreased during the study and normalized on day 21. An increased number of Klebsiella bacteria appeared on day 14 and normalized on day 21. The number of other enterobacteria decreased during the study, and the number of enterococci decreased from days 2 to 7 and normalized on day 9. Candida numbers increased from days 5 to 9 and normalized after day 14. The number of lactobacilli decreased during the study and recovered on day 14. The number of bifidobacteria decreased on day 2 and normalized on day 21. The number of Bacteroides bacteria was unchanged. Clostridium difficile numbers decreased on days 7 and 9 and increased on days 14 and 21. A toxigenic C. difficile strain was detected in one volunteer on day 21 with no reported adverse events. Plasma samples were collected on days -1, 2, 5, and 7. Ceftaroline and avibactam concentrations were 0 to 34.5 mg/liter and 0 to 61.6 mg/liter, respectively, in plasma and 0 to 35.4 mg/kg and 0 to 98.5 mg/kg, respectively, in feces. (This study is registered in the European Clinical Trials Database [https://eudract.ema.europa.eu/] under number EudraCT 2012 004921-25.). PMID:25987638

  8. Bengt E. Gustafsson memorial lecture. Function of the normal human microflora.

    PubMed

    Gorbach, S L

    1986-01-01

    The normal human microflora maintains a delicate balance between its constituent parts, numbering 10(11) bacteria per gram with over 400 different species. Certain metabolic functions and enzyme activities can be attributed to the microflora, and these play a role in metabolizing nutrients, vitamins, drugs, endogenous hormones and carcinogens. Our laboratory has studied estrogen and cholesterol metabolism and activation of colon carcinogens. Three techniques to change the flora and its enzymatic activities have been used. Switching the diet from an omnivore diet to a vegetarian diet decreases bacterial deconjugating enzymes in the intestine. Administering antibiotics also suppresses the metabolic activity of the microflora. Similar suppressive effects can be achieved by feeding a human strain of Lactobacillus that implants in the gastrointestinal tract. Manipulation of these various modalities can maximize the beneficial activities of the intestinal microflora. PMID:3103209

  9. Light scattering of normal human lens I. Application of random density and orientation fluctuation theory.

    PubMed Central

    Bettelheim, F A; Paunovic, M

    1979-01-01

    Light-scattering intensities in the I parallel and I+ mode were obtained on thin sections of three human lenses. Random density and orientation fluctuation theory, without cross correlation, was employed to evaluate light-scattering parameters. Both the density correlation distances, as well as the orientation correlation distances, were related to structural elements in the lens fiber cell that have been observed by other investigators with different techniques. The magnitude of these fluctuations were evaluated, and it was demonstrated that the density fluctuations are the main contributors to light scattering in normal human lenses. Changes in the light-scattering parameters were evaluated as a function of position within the lens. The changes observed agree with the biochemical data in the literature that reflects that an aging process occurs when one proceeds from the periphery of the lens toward the center. PMID:262413

  10. Expression of splice variants of mts1 gene in normal and neoplastic human tissues

    SciTech Connect

    Ambartsumyan, N.S. |; Grigorian, M.S.; Lukanidin, E.M.

    1995-09-01

    Data on cloning of cDNA corresponding to human mts1 gene transcripts are presented. By comparing nucleotide sequences of the genomic DNA clone and cDNA of mts1, it was shown that human osteosarcoma OHS cells contain two alternative splice variants of mts1 transcripts. Alternative splicing occurs in the 5{prime}-untranslated region of the mts1 pre-mRNA. Both splice variants, hu-mts1 and hu-mts1(var), demonstrate similar stability in the cells, and each contains one open reading frame for the MTS1 protein. However, the two types of transcripts are translated with different effectiveness. The level of transcription of mts1 splice variants in different normal and neoplastic tissues and cell lines varies significantly. The role of alternative splicing as the mechanism responsible for posttranscriptional regulation of mts1 gene expression is discussed. 31 refs., 5 figs.

  11. Immunohistochemical localization of the epidermal growth factor receptor in normal human tissues.

    PubMed

    Damjanov, I; Mildner, B; Knowles, B B

    1986-11-01

    A monoclonal antibody recognizing an epitope of the external domain of the human epidermal growth factor (EGF) receptor was used to localize this protein in selected normal human tissues. Two patterns of reactivity were recognized: strong linear or granular cell surface staining, and granular cytoplasmic staining. In one tissue, the endometrium, a change in the reaction pattern associated with changes in hormonal stimulation was observed. In some tissues such as epididymis and skin, the antibody showed surface reactivity with cells considered to represent part of the proliferating cell compartment, whereas in liver, pancreas, and prostate, all cells were reactive with the antibody, though the predominant reactivity was localized in the cytoplasm. The differential distribution of the epidermal growth factor receptor to specific cell types and cellular compartments may signify adaptations that permit growth factor responsiveness in a milieu of available ligand. PMID:3534450

  12. Protection of normal human reconstructed epidermis from UV by catalase overexpression.

    PubMed

    Rezvani, H R; Cario-André, M; Pain, C; Ged, C; deVerneuil, H; Taïeb, A

    2007-02-01

    Reactive oxygen species (ROS) generated by ultraviolet (UV) irradiation are counterbalanced by endogenous antioxidant systems. To test the hypothesis of a novel photoprotective approach, we irradiated epidermis reconstructed with normal human keratinocytes overexpressing sustainably lentivirus-mediated catalase (CAT), copper/zinc superoxide dismutase (CuZnSOD) or manganese superoxide dismutase (MnSOD) enzymes. We found that following UVB irradiation there was a marked decrease in sunburn cell formation, caspase-3 activation and p53 accumulation in human reconstructed epidermis overexpressing CAT. Moreover, UVA-induced hypertrophy and DNA oxidation (8-oxodeoxyguanosine) were decreased by CAT overexpression. These effects were not achieved by overexpression of CuZnSOD or MnSOD. In conclusion, vector-mediated CAT overexpression could be a promising photoprotective tool against deleterious effects of UV irradiation such skin cancer especially in monogenic/polygenic photosensitive disorders characterized by ROS accumulation. PMID:17053817

  13. Differential responsiveness of normal and simian virus 40-transformed human fibroblast cells to interferon-gamma.

    PubMed

    Karasaki, Y; Katoh, T; Higashi, K; Gotoh, S

    1992-06-01

    The effect of interferon-gamma (IFN-gamma) on epidermal growth factor (EGF) receptor binding and the proliferation of normal and simian virus 40 (SV40)-transformed human fibroblast cells was compared under identical culture conditions. IFN-gamma induced an enhancement of EGF binding to normal cells, whereas it decreased the EGF binding to SV40-transformed cells. Half-maximal enhancement occurred at 72 h after the normal cells were exposed to 10 U/ml of IFN-gamma, and maximal stimulation was obtained at about 10(2) U/ml of IFN-gamma at 72 h. On the other hand, half-maximal reduction was observed for SV40-transformed cells at less than 10 U/ml of IFN-gamma at 72 h, and maximal reduction was obtained at around 10(3) U/ml of IFN-gamma at 72 h. Scatchard analysis indicated that the number of EGF binding sites of normal and SV40-transformed cells was calculated to be 1.6 x 10(5) and 0.88 x 10(5) per cell, respectively, and was little altered by IFN-gamma treatment. The dissociation constant (Kd) of normal cells, however, decreased from 4.5 nM (control) to 2.0 nM (IFN-gamma-treated), while the Kd of SV40-transformed cells increased from 3.6 nM (control) to 17.0 nM (IFN-gamma-treated). The immunoprecipitation of 125I-labeled EGF-bound EGF receptors with anti-receptor antiserum indicated that a 72-h IFN-gamma treatment did not induce a conformational alteration in the EGF receptors of both normal and transformed cells. The DNA synthesis of normal cells was enhanced by EGF, and IFN-gamma treatment potentiated the effect of EGF on DNA synthesis, probably due to the increased binding affinity of EGF to the cells.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1640119

  14. Differential thioredoxin reductase activity from human normal hepatic and hepatoma cell lines.

    PubMed

    Jung, Haeng-Im; Lim, Hye-Won; Kim, Byung-Chul; Park, Eun-Hee; Lim, Chang-Jin

    2004-04-30

    Thioredoxin reductase (TrxR), a component of the thioredoxin system, including thioredoxin (Trx) and NADPH, catalyzes the transfer of electrons from NADPH to Trx, acts as a reductant of disulfide-containing proteins and participates in the defense system against oxidative stresses. In this study, the regulation pattern of TrxR in the presence of various stressful reagents was compared between Chang (human normal hepatic cell) and HepG2 (human hepatoma cell) cell lines. Aluminum chloride (0.5 mM) and zinc chloride (0.5 mM) enhanced the TrxR activity in the Chang cell line to a higher degree than in the HepG2 cell line, but cupric chloride (0.2 mM) and cadmium chloride (0.1 mM) enhanced the TrxR activity in the HepG2 cell line to a greater degree. The TrxR activities in both Chang and HepG2 cell lines were similarly induced by treatment with sodium selenite (0.02 mM) and menadione (0.5 and 1.0 mM). Lipopolysaccharide (2 micro g/m1) increased the TrxR activity upto 4.02- and 2.2-fold in the Chang and HepG2 cell lines, respectively, in time-dependent manners. Hydrogen peroxide (5 mM) markedly enhanced the TrxR activity in the HepG2 cell line, but not in the Chang cell line. NO-generating sodium nitroprusside (3.0 and 6.0 mM) induced TrxR activities in both human liver cell lines. The TrxR activity was also induced in human liver cells under limited growth conditions by serum deprivation. These results imply that the TrxR activities in normal hepatic and hepatoma cell lines are subject to different regulatory responses to various stresses. PMID:15118998

  15. Visual Acuity of Simulated Thalamic Visual Prostheses in Normally Sighted Humans

    PubMed Central

    Jeffries, Ailsa; Pezaris, John S.

    2013-01-01

    Simulation in normally sighted individuals is a crucial tool to evaluate the performance of potential visual prosthesis designs prior to human implantation of a device. Here, we investigated the effects of electrode count on visual acuity, learning rate and response time in 16 normally sighted subjects using a simulated thalamic visual prosthesis, providing the first performance reports for thalamic designs. A new letter recognition paradigm using a multiple-optotype two-alternative forced choice task was adapted from the Snellen eye chart, and specifically devised to be readily communicated to both human and non-human primate subjects. Validation of the method against a standard Snellen acuity test in 21 human subjects showed no significant differences between the two tests. The novel task was then used to address three questions about simulations of the center-weighted phosphene patterns typical of thalamic designs: What are the expected Snellen acuities for devices with varying numbers of contacts, do subjects display rapid adaptation to the new visual modality, and can response time in the task provide clues to the mechanisms of perception in low-resolution artificial vision? Population performance (hit rate) was significantly above chance when viewing Snellen 20/200 optotypes (Log MAR 1.0) with 370 phosphenes in the central 10 degrees of vision, ranging to Snellen 20/800 (Log MAR 1.6) with 25 central phosphenes. Furthermore, subjects demonstrated learning within the 1–2 hours of task experience indicating the potential for an effective rehabilitation and possibly better visual performance after a longer period of training. Response time differences suggest that direct letter perception occurred when hit rate was above 75%, whereas a slower strategy like feature-based pattern matching was used in conditions of lower relative resolution. As pattern matching can substantially boost effective acuity, these results suggest post-implant therapy should specifically

  16. Single nucleotide polymorphisms in the MATP gene are associated with normal human pigmentation variation.

    PubMed

    Graf, Justin; Hodgson, Richard; van Daal, Angela

    2005-03-01

    Human physical pigmentation is determined by the type and amount of melanin and the process of pigmentation production probably involves more than 100 genes. A failure to synthesize melanin results in oculocutaneous albinism (OCA). A recently identified form of OCA results from mutations in the Membrane Associated Transporter Protein (MATP) gene. The role of MATP in human pigmentation is not clear. We investigated the role of two nonpathogenic nonsynonymous single nucleotide polymorphisms (SNPs) in the MATP gene to determine if they are associated with normal human skin, hair, and eye color variation. A total of 608 individuals from four different population groups (456 Caucasians, 31 Asians, 70 African-Americans, and 51 Australian Aborigines) were genotyped for c.814G>A (p.Glu272Lys) and c.1122C>G (p.Phe374Leu). Results indicate that the allele frequencies of both polymorphisms are significantly different between population groups. The two alleles, 374Leu and 272Lys, are significantly associated with dark hair, skin, and eye color in Caucasians. The odds ratios (ORs) of the LeuLeu genotype for black hair and olive skin are 25.63 and 28.65, respectively, and for the LysLys genotype are 43.23 and 8.27, respectively. The OR for eye color is lower at 3.48 for the LeuLeu and 6.57 for LysLys genotypes. This is the first report of this highly significant association of MATP polymorphisms with normal human pigmentation variation. PMID:15714523

  17. The role of apelin in central cardiovascular regulation in rats with post-infarct heart failure maintained on a normal fat or high fat diet.

    PubMed

    Czarzasta, Katarzyna; Cudnoch-Jedrzejewska, Agnieszka; Szczepanska-Sadowska, Ewa; Fus, Lukasz; Puchalska, Liana; Gondek, Agata; Dobruch, Jakub; Gomolka, Ryszard; Wrzesien, Robert; Zera, Tymoteusz; Gornicka, Barbara; Kuch, Marek

    2016-10-01

    Based on the available literature, it can be assumed that in cases of post-infarct heart failure (HF) and obesity, a significant change in the central regulation of the cardiovascular system takes place with, among others, the involvement of the apelinergic system. The main objective of the present study was to clarify the role of apelin-13 in the central regulation of the cardiovascular system in Sprague Dawley rats with HF or sham operated (SO) and fed on a normal fat (NFD) or a high fat diet (HFD). The study was divided into two parts: Part I, hemodynamic studies; and Part II, biochemical and molecular studies. The animals were subjected to the following research procedures. Part I and II: feeding NFD or HFD; experimental induction of HF or SO; Part I: intracerebroventricular (ICV) infusion of the examined substances, monitoring of mean arterial blood pressure (MABP) and heart rate (HR); Part II: venous blood and tissue samples collected. ICV infusion of apelin-13 caused significantly higher changes in ΔMABP in the SO NFD group. No changes were noted in ΔHR in any of the studied groups. Apelin and apelin receptor (APJ) mRNA expression in the brain and adipose tissues was higher in the HF rats. HFD causes significant increase in expression of apelin and APJ mRNA in the left ventricle. In conclusion, HF and HFD appear to play an important role in modifying the activity of the central apelinergic system and significant changes in mRNA expression of apelin and APJ receptor. PMID:27378063

  18. Incremental Prognostic Significance of the Elevated Levels of Pentraxin 3 in Patients With Heart Failure With Normal Left Ventricular Ejection Fraction

    PubMed Central

    Matsubara, Junichi; Sugiyama, Seigo; Nozaki, Toshimitsu; Akiyama, Eiichi; Matsuzawa, Yasushi; Kurokawa, Hirofumi; Maeda, Hirofumi; Fujisue, Koichiro; Sugamura, Koichi; Yamamoto, Eiichiro; Matsui, Kunihiko; Jinnouchi, Hideaki; Ogawa, Hisao

    2014-01-01

    Background Pentraxin 3 (PTX3) is a novel inflammatory marker produced by various cell types including those of the vasculature and the heart. The relationship between inflammatory markers and prognosis of patients with heart failure with normal ejection fraction (HFNEF) remains unknown. We investigated whether plasma PTX3 levels can predict future cardiovascular events in patients with HFNEF. Methods and Results Plasma PTX3, high‐sensitivity C‐reactive protein, and B‐type natriuretic peptide levels were measured prospectively in 360 stable patients with HFNEF. The subsequent incidence of cardiovascular events, including cardiovascular death, nonfatal myocardial infarction (MI), unstable angina pectoris, nonfatal ischemic stroke, hospitalization for heart failure decompensation, and coronary revascularization, was determined. During a mean 30‐month follow‐up, 106 patients experienced cardiovascular events. These events were more frequent in patients with high plasma PTX3 levels (>3.0 ng/mL) than low levels (≤3.0 ng/mL). Multivariable Cox hazard analysis showed that PTX3 (hazard ratio: 1.16; 95% CI: 1.05 to 1.27; P<0.01) and B‐type natriuretic peptide (hazard ratio: 1.08; 95% CI: 1.03 to 1.14; P<0.001), but not high‐sensitivity C‐reactive protein levels, were significant predictors of future cardiovascular events. Multivariable Cox analysis with the forced inclusion model, including 5 previously identified prognostic factors, found that PTX3 was a significant predictor of cardiovascular events (hazard ratio: 1.16; 95% CI: 1.06 to 1.27; P<0.01). The C‐statistics for cardiovascular events substantially increased from 0.617 to 0.683 when PTX3 was added to the 5 previously identified prognostic factors. Conclusions High plasma PTX3 levels, but not other inflammatory markers, are correlated with future cardiovascular events in patients with HFNEF. PTX3 may be a useful biomarker for assessment of risk stratification in HFNEF. Clinical Trial Registration

  19. Characterization of Diffuse Fibrosis in the Failing Human Heart via Diffusion Tensor Imaging and Quantitative Histological Validation

    PubMed Central

    Abdullah, Osama M.; Drakos, Stavros G.; Diakos, Nikolaos A.; Wever-Pinzon, Omar; Kfoury, Abdallah G.; Stehlik, Josef; Selzman, Craig H.; Reid, Bruce B.; Brunisholz, Kim; Verma, Divya Ratan; Myrick, Craig; Sachse, Frank B.; Li, Dean Y.; Hsu, Edward W.

    2014-01-01

    Non-invasive imaging techniques are highly desirable as an alternative to conventional biopsy for characterizing remodeling of tissues associated with disease progression, including end-stage heart failure. Cardiac diffusion tensor imaging (DTI) has become an established method for characterizing myocardial microstructure. However, the relationships between diffuse myocardial fibrosis, which is a key biomarker for staging and treatment planning of the failing heart, and measured DTI parameters have yet to be systematically investigated. In this study, DTI was performed on left ventricular specimens collected from patients with chronic end-stage heart failure due to idiopathic dilated cardiomyopathy (n=14) and from normal donors (n=5). Scalar DTI parameters, including fractional anisotropy (FA), mean (MD), primary (D1), secondary (D2), and tertiary (D3) diffusivities, were correlated to collagen content measured by digital microscopy. Compared to hearts from normal subjects, the FA in failing hearts decreased by 22%, whereas the MD, D2 and D3 increased by 12%, 14%, and 24% respectively (P < 0.01). No significant change was detected for D1 between the two groups. Furthermore, significant correlation was observed between the DTI scalar indices and quantitative histological measurements of collagen (i.e., fibrosis). Pearson's correlation coefficient (r) between collagen content and either FA, MD, D2, and D3 was -0.51, 0.59, 0.56 and 0.62 (P < 0.05), respectively. The correlation between D1 and collagen content was not significant (r = 0.46, P = 0.05). Computational modeling analysis indicated that the behaviors of the DTI parameters as a function of the degree of fibrosis were well explained by compartmental exchange between myocardial and collagenous tissues. Combined, these findings suggest that scalar DTI parameters can be used as metrics for noninvasive assessment of diffuse fibrosis in failing hearts. PMID:25200106

  20. Distinct expression patterns of ERα and ERβ in normal human mammary gland

    PubMed Central

    Speirs, V; Skliris, G P; Burdall, S E; Carder, P J

    2002-01-01

    Aim: Two oestrogen receptors (ERs) have been identified to date—the “classic” ERα and the more recently described ERβ. Although much is known about ERα at the mRNA and protein levels, our knowledge of the expression and distribution of ERβ protein is much more limited. The aim of this study was to compare the cellular distribution of ERα and ERβ in normal human mammary gland. Methods: Formalin fixed, paraffin wax embedded material was obtained from reduction mammoplasty specimens, normal tissue adjacent to breast tumour, or fibroadenoma. Sections were immunohistochemically stained for ERα, ERβ, and the progesterone receptor. The staining pattern for each antibody was evaluated and compared. Results: ERα was restricted to the cell nuclei of epithelial cells lining ducts and lobules. Although ERβ was also seen in these cells, additional strong staining was detected specifically in the cell nuclei of myoepithelial cells. Occasional staining was seen in surrounding stromal and endothelial cell nuclei and in lymphocytes. Conclusions: ER subtypes have distinct distribution patterns in the normal mammary gland. The widespread distribution of ERβ suggests that it may be the dominant ER in the mammary gland where it may be acting as a natural suppressor. PMID:11986344

  1. Vertical normal modes of human ears: Individual variation and frequency estimation from pinna anthropometry.

    PubMed

    Mokhtari, Parham; Takemoto, Hironori; Nishimura, Ryouichi; Kato, Hiroaki

    2016-08-01

    Beyond the first peak of head-related transfer functions or pinna-related transfer functions (PRTFs) human pinnae are known to have two normal modes with "vertical" resonance patterns, involving two or three pressure anti-nodes in cavum, cymba, and fossa. However, little is known about individual variations in these modes, and there is no established model for estimating their center-frequencies from anthropometry. Here, with geometries of 38 pinnae measured, PRTFs were calculated and vertical modes visualized by numerical simulation. Most pinnae were found to have both Cavum-Fossa and Cavum-Cymba modes, with opposite-phase anti-nodes in cavum and either fossa or cymba, respectively. Nevertheless in both modes, fossa involvement varied substantially across pinnae, dependent on scaphoid fossa depth and cymba shallowness. Linear regression models were evaluated in mode frequency estimation, with 3322 measures derived from 31 pinna landmarks. The Cavum-Fossa normal mode frequency was best estimated [correlation coefficient r = 0.89, mean absolute error (MAE) = 257 Hz or 4.4%] by the distance from canal entrance to helix rim, and cymba horizontal depth. The Cavum-Cymba normal mode frequency was best estimated (r = 0.92, MAE = 247 Hz or 3.2%) by the sagittal-plane distance from concha floor to cymba anterior wall, and cavum horizontal depth. PMID:27586714

  2. Influence of free residual chlorine on cultured human epidermal keratinocytes from normal skin and hypertrophic scars.

    PubMed

    Matsumoto, Y; Mori, H; Hayakawa, A; Ohashi, M

    1995-07-01

    In Japan, public health regulations state that the water in rinsing pools used before swimming should contain 50-100 mg/l of chlorine. We examined the influence of chlorination at high concentrations in rinsing pools on the skin using cultured human epidermal keratinocytes from normal skin and hypertrophic scars. Chlorination of cell culture for 15 min with 200 mg/l of free residual chlorine proved cytotoxic to both types of keratinocytes as did 100 mg/l of free residual chlorine for 1 or 3 consecutive days. Keratinocytes from hypertrophic scars, when cultivated in 100 mg/l of free residual chlorine, were more vulnerable to chlorine than those from normal skin. Cell characteristics of cultured keratinocytes from hypertrophic scars may be somewhat different from those of normal skin. The phenomena observed in this experimental model of the skin suggest that people exposed to chlorine in rinsing pools at concentrations in excess of 200 mg/l for about 15 min before swimming are at risk of developing cutaneous disorders, especially at sites of injury, e.g. scars. PMID:7577833

  3. An alternatively spliced surfactant protein B mRNA in normal human lung: disease implication.

    PubMed Central

    Lin, Z; Wang, G; Demello, D E; Floros, J

    1999-01-01

    We identified an alternatively-spliced surfactant protein B (SP-B) mRNA from normal human lung with a 12 nt deletion at the beginning of exon 8. This deletion causes a loss of four amino acids in the SP-B precursor protein. Sequence comparison of the 3' splice sites reveals only one difference in the frequency of U/C in the 11 predominantly-pyrimidine nucleotide tract, 73% for the normal and 45% for the alternatively-spliced SP-B mRNA (77-99% for the consensus sequence). Analysis of SP-B mRNA in lung indicates that the abundance of the alternatively-spliced form is very low and varies among individuals. Although the relative abundance of the deletion form of SP-B mRNA remains constant among normal lungs, it is found with relatively higher abundance in the lungs of some individuals with diseases such as congenital alveolar proteinosis, respiratory distress syndrome, bronchopulmonary dysplasia, alveolar capillary dysplasia and hypophosphatasia. This observation points to the possibility that the alternative splicing is a potential regulatory mechanism of SP-B and may play a role in the pathogenesis of disease under certain circumstances. PMID:10493923

  4. Simulation and Mechanistic Investigation of the Arrhythmogenic Role of the Late Sodium Current in Human Heart Failure

    PubMed Central

    Trenor, Beatriz; Cardona, Karen; Gomez, Juan F.; Rajamani, Sridharan; Ferrero, Jose M.; Belardinelli, Luiz; Saiz, Javier

    2012-01-01

    Heart failure constitutes a major public health problem worldwide. The electrophysiological remodeling of failing hearts sets the stage for malignant arrhythmias, in which the role of the late Na+ current (INaL) is relevant and is currently under investigation. In this study we examined the role of INaL in the electrophysiological phenotype of ventricular myocytes, and its proarrhythmic effects in the failing heart. A model for cellular heart failure was proposed using a modified version of Grandi et al. model for human ventricular action potential that incorporates the formulation of INaL. A sensitivity analysis of the model was performed and simulations of the pathological electrical activity of the cell were conducted. The proposed model for the human INaL and the electrophysiological remodeling of myocytes from failing hearts accurately reproduce experimental observations. The sensitivity analysis of the modulation of electrophysiological parameters of myocytes from failing hearts due to ion channels remodeling, revealed a role for INaL in the prolongation of action potential duration (APD), triangulation of the shape of the AP, and changes in Ca2+ transient. A mechanistic investigation of intracellular Na+ accumulation and APD shortening with increasing frequency of stimulation of failing myocytes revealed a role for the Na+/K+ pump, the Na+/Ca2+ exchanger and INaL. The results of the simulations also showed that in failing myocytes, the enhancement of INaL increased the reverse rate-dependent APD prolongation and the probability of initiating early afterdepolarizations. The electrophysiological remodeling of failing hearts and especially the enhancement of the INaL prolong APD and alter Ca2+ transient facilitating the development of early afterdepolarizations. An enhanced INaL appears to be an important contributor to the electrophysiological phenotype and to the dysregulation of [Ca2+]i homeostasis of failing myocytes. PMID:22427860

  5. Pulse wave imaging in normal, hypertensive and aneurysmal human aortas in vivo: a feasibility study

    NASA Astrophysics Data System (ADS)

    Li, Ronny X.; Luo, Jianwen; Balaram, Sandhya K.; Chaudhry, Farooq A.; Shahmirzadi, Danial; Konofagou, Elisa E.

    2013-07-01

    Arterial stiffness is a well-established biomarker for cardiovascular risk, especially in the case of hypertension. The progressive stages of an abdominal aortic aneurysm (AAA) have also been associated with varying arterial stiffness. Pulse wave imaging (PWI) is a noninvasive, ultrasound imaging-based technique that uses the pulse wave-induced arterial wall motion to map the propagation of the pulse wave and measure the regional pulse wave velocity (PWV) as an index of arterial stiffness. In this study, the clinical feasibility of PWI was evaluated in normal, hypertensive, and aneurysmal human aortas. Radiofrequency-based speckle tracking was used to estimate the pulse wave-induced displacements in the abdominal aortic walls of normal (N = 15, mean age 32.5 ± 10.2 years), hypertensive (N = 13, mean age 60.8 ± 15.8 years), and aneurysmal (N = 5, mean age 71.6 ± 11.8 years) human subjects. Linear regression of the spatio-temporal variation of the displacement waveform in the anterior aortic wall over a single cardiac cycle yielded the slope as the PWV and the coefficient of determination r2 as an approximate measure of the pulse wave propagation uniformity. The aortic PWV measurements in all normal, hypertensive, and AAA subjects were 6.03 ± 1.68, 6.69 ± 2.80, and 10.54 ± 6.52 m s-1, respectively. There was no significant difference (p = 0.15) between the PWVs of the normal and hypertensive subjects while the PWVs of the AAA subjects were significantly higher (p < 0.001) compared to those of the other two groups. Also, the average r2 in the AAA subjects was significantly lower (p < 0.001) than that in the normal and hypertensive subjects. These preliminary results suggest that the regional PWV and the pulse wave propagation uniformity (r2) obtained using PWI, in addition to the PWI images and spatio-temporal maps that provide qualitative visualization of the pulse wave, may potentially provide valuable information for the clinical characterization of aneurysms

  6. Three-dimensional counting of morphologically normal human red blood cells via digital holographic microscopy

    NASA Astrophysics Data System (ADS)

    Yi, Faliu; Moon, Inkyu; Lee, Yeon H.

    2015-01-01

    Counting morphologically normal cells in human red blood cells (RBCs) is extremely beneficial in the health care field. We propose a three-dimensional (3-D) classification method of automatically determining the morphologically normal RBCs in the phase image of multiple human RBCs that are obtained by off-axis digital holographic microscopy (DHM). The RBC holograms are first recorded by DHM, and then the phase images of multiple RBCs are reconstructed by a computational numerical algorithm. To design the classifier, the three typical RBC shapes, which are stomatocyte, discocyte, and echinocyte, are used for training and testing. Nonmain or abnormal RBC shapes different from the three normal shapes are defined as the fourth category. Ten features, including projected surface area, average phase value, mean corpuscular hemoglobin, perimeter, mean corpuscular hemoglobin surface density, circularity, mean phase of center part, sphericity coefficient, elongation, and pallor, are extracted from each RBC after segmenting the reconstructed phase images by using a watershed transform algorithm. Moreover, four additional properties, such as projected surface area, perimeter, average phase value, and elongation, are measured from the inner part of each cell, which can give significant information beyond the previous 10 features for the separation of the RBC groups; these are verified in the experiment by the statistical method of Hotelling's T-square test. We also apply the principal component analysis algorithm to reduce the dimension number of variables and establish the Gaussian mixture densities using the projected data with the first eight principal components. Consequently, the Gaussian mixtures are used to design the discriminant functions based on Bayesian decision theory. To improve the performance of the Bayes classifier and the accuracy of estimation of its error rate, the leaving-one-out technique is applied. Experimental results show that the proposed method can

  7. The Fate of a Normal Human Cell Traversed by a Single Charged Particle

    NASA Astrophysics Data System (ADS)

    Fournier, C.; Zahnreich, S.; Kraft, D.; Friedrich, T.; Voss, K.-O.; Durante, M.; Ritter, S.

    2012-09-01

    The long-term ``fate'' of normal human cells after single hits of charged particles is one of the oldest unsolved issues in radiation protection and cellular radiobiology. Using a high-precision heavy-ion microbeam we could target normal human fibroblasts with exactly one or five carbon ions and measured the early cytogenetic damage and the late behaviour using single-cell cloning. Around 70% of the first cycle cells presented visible aberrations in mFISH after a single ion traversal, and about 5% of the cells were still able to form colonies. In one third of selected high-proliferative colonies we observed clonal (radiation-induced) aberrations. Terminal differentiation and markers of senescence (PCNA, p16) in the descendants of cells traversed by one carbon ion occurred earlier than in controls, but no evidence of radiation-induced chromosomal instability was found. We conclude that cells surviving single-ion traversal, often carrying clonal chromosome aberrations, undergo accelerated senescence but maintain chromosomal stability.

  8. The Fate of a Normal Human Cell Traversed by a Single Charged Particle

    PubMed Central

    Fournier, C.; Zahnreich, S.; Kraft, D.; Friedrich, T.; Voss, K.-O.; Durante, M.; Ritter, S.

    2012-01-01

    The long-term “fate” of normal human cells after single hits of charged particles is one of the oldest unsolved issues in radiation protection and cellular radiobiology. Using a high-precision heavy-ion microbeam we could target normal human fibroblasts with exactly one or five carbon ions and measured the early cytogenetic damage and the late behaviour using single-cell cloning. Around 70% of the first cycle cells presented visible aberrations in mFISH after a single ion traversal, and about 5% of the cells were still able to form colonies. In one third of selected high-proliferative colonies we observed clonal (radiation-induced) aberrations. Terminal differentiation and markers of senescence (PCNA, p16) in the descendants of cells traversed by one carbon ion occurred earlier than in controls, but no evidence of radiation-induced chromosomal instability was found. We conclude that cells surviving single-ion traversal, often carrying clonal chromosome aberrations, undergo accelerated senescence but maintain chromosomal stability. PMID:22966418

  9. Wound healing properties of ethyl acetate fraction of Moringa oleifera in normal human dermal fibroblasts

    PubMed Central

    Gothai, Sivapragasam; Arulselvan, Palanisamy; Tan, Woan Sean; Fakurazi, Sharida

    2016-01-01

    Background/Aim: Wounds are the outcome of injuries to the skin that interrupt the soft tissue. Healing of a wound is a complex and long-drawn-out process of tissue repair and remodeling in response to injury. A large number of plants are used by folklore traditions for the treatment of cuts, wounds and burns. Moringa oleifera (MO) is an herb used as a traditional folk medicine for the treatment of various skin wounds and associated diseases. The underlying mechanisms of wound healing activity of ethyl acetate fraction of MO leaves extract are completely unknown. Materials and Methods: In the current study, ethyl acetate fraction of MO leaves was investigated for its efficacy on cell viability, proliferation and migration (wound closure rate) in human normal dermal fibroblast cells. Results: Results revealed that lower concentration (12.5 µg/ml, 25 µg/ml, and 50 µg/ml) of ethyl acetate fraction of MO leaves showed remarkable proliferative and migratory effect on normal human dermal fibroblasts. Conclusion: This study suggested that ethyl acetate fraction of MO leaves might be a potential therapeutic agent for skin wound healing by promoting fibroblast proliferation and migration through increasing the wound closure rate corroborating its traditional use. PMID:27069722

  10. Raman Spectroscopy of DNA Packaging in Individual Human Sperm Cells distinguishes Normal from Abnormal Cells

    SciTech Connect

    Huser, T; Orme, C; Hollars, C; Corzett, M; Balhorn, R

    2009-03-09

    Healthy human males produce sperm cells of which about 25-40% have abnormal head shapes. Increases in the percentage of sperm exhibiting aberrant sperm head morphologies have been correlated with male infertility, and biochemical studies of pooled sperm have suggested that sperm with abnormal shape may contain DNA that has not been properly repackaged by protamine during spermatid development. We have used micro-Raman spectroscopy to obtain Raman spectra from individual human sperm cells and examined how differences in the Raman spectra of sperm chromatin correlate with cell shape. We show that Raman spectra of individual sperm cells contain vibrational marker modes that can be used to assess the efficiency of DNA-packaging for each cell. Raman spectra obtained from sperm cells with normal shape provide evidence that DNA in these sperm is very efficiently packaged. We find, however, that the relative protein content per cell and DNA packaging efficiencies are distributed over a relatively wide range for sperm cells with both normal and abnormal shape. These findings indicate that single cell Raman spectroscopy should be a valuable tool in assessing the quality of sperm cells for in-vitro fertilization.

  11. Deceleration of senescence in normal human fibroblasts by withanone extracted from ashwagandha leaves.

    PubMed

    Widodo, Nashi; Shah, Navjot; Priyandoko, Didik; Ishii, Tetsuro; Kaul, Sunil C; Wadhwa, Renu

    2009-10-01

    Ashwagandha is an Ayurvedic shrub that forms a common ingredient of health supplements, tonics, and Indian home remedies designed to promote health and quality of life. Though sustained through experience and history, there are only a limited laboratory studies and experimental evidence to its effects. In our efforts to characterize Ashwagandha activities and their molecular mechanisms, we initially prepared leaf extract of Ashwagandha (i-Extract) that showed tumor-inhibitory activity. In the present study, we demonstrate that a major component of i-Extract and withanone (i-Factor) protected the normal human fibroblasts against the toxicity caused by withaferin A. It increased the in vitro division potential of normal human cells that appeared to be mediated by decreased accumulation of molecular damage, downregulation of the senescence-specific beta-galactosidase activity and the senescence marker protein, p21(WAF-1), protection against oxidative damage, and induction of proteasomal activity. To the best of our knowledge, we provide the first example of phytochemical(s) (i-Extract and withanone) that have both anticancer and antiaging activities and point to the molecular link between aging and cancer. PMID:19587106

  12. MRI-based surface area estimates in the normal adult human brain: evidence for structural organisation.

    PubMed Central

    Sisodiya, S; Free, S; Fish, D; Shorvon, S

    1996-01-01

    There are a number of quantitative relationships between geometric parameters describing the structure of the normal human cerebral cortex examined in vivo using volumetric magnetic resonance imaging. A voxel-counting method is used to estimate grey-white interface surface area. The effects of bias associated with the method are considered. In 33 normal controls, the cerebral hemispheres were symmetric in terms of total volume, irrespective of handedness, but not in terms of surface areas for right-handers. The surface area of the grey matter-white matter interface was directly proportional to the cortical grey matter volume, suggesting that growth of the neocortex is primarily tangential, with repetition of a basic structural element rather than gross alterations in the thickness of the cortex. The majority of the surface area of the grey-white interface lies within gyral white matter cores. The mean thickness of the cortex of the right cerebral hemisphere in vivo was 3.0 mm and that of the left 3.3 mm. There was a relationship between the cross-sectional area of the corpus callosum and grey-white interface surface area, suggesting that a fixed proportion and cortical neurons extend interhemispheric axons. These findings suggest that there are general architectural principles governing the organisation of the complex, but ordered, human cerebral cortex. Images Fig. 1 Fig. 2 PMID:8621342

  13. Expression of microRNA-370 in human breast cancer compare with normal samples

    PubMed Central

    Mollainezhad, Halimeh; Eskandari, Nahid; Pourazar, Abbasali; Salehi, Mansoor; Andalib, Alireza

    2016-01-01

    Background: Breast cancer is the second leading cause of deaths from cancer in the woman. MicroRNAs (miRNAs) are endogenous noncoding RNAs that are known critical player in carcinogenesis. The role of miR-370 in malignancies remains controversial because of its levels varying in different cancers according to its targets while the role of miR-370 in breast cancer has not been addressed so far. The aim of this study was to identify the expression pattern of miR-370 in human breast cancer tissue compared to adjacent healthy tissue. Materials and Methods: Twenty-two fresh frozen tissues (normal and malignant) from patients with breast cancer were examined for miR-370 by quantitative real-time polymerase chain reaction method at 2013. Results: We observed up-regulation (six-fold higher) of miR-370 in breast cancer tissue compared with normal adjacent tissue. Tumor samples in stage III, invasive ductal type, larger tumor size, human epidermal growth-factor receptor 2+, estrogen receptor/progesterone receptor−, P53 − status showed significantly increased expression in miR-370. Conclusion: Together, miR-370 may acts as an onco-miRNA, and it may have a novel role in breast cancer. Detection of miR-370 and its targets could be helpful as a diagnostic biomarker and therapeutic target. PMID:27563639

  14. Particle irradiation induces FGF2 expression in normal human lens cells

    NASA Technical Reports Server (NTRS)

    Chang, P. Y.; Bjornstad K, A.; Chang, E.; McNamara, M.; Barcellos-Hoff, M. H.; Lin, S. P.; Aragon, G.; Polansky, J. R.; Lui, G. M.; Blakely, E. A.

    2000-01-01

    Particle Irradiation Induces FGF2 Expression in Normal Human Lens Cells. Particle radiations, including both proton and helium-ion beams, have been used to successfully treat choroidal melanoma, but with the complication of radiation-induced cataract. We have investigated a role for radiation-induced changes in the expression of basic fibroblast growth factor (FGF2) gene expression as part of the mechanism(s) underlying lens cell injury associated with cataract. Normal human lens epithelial (HLE) cells were cultured in vitro on extracellular matrix (ECM) originated from bovine corneal endothelial cells. This study reports evidence for rapid but transient induction of FGF2 transcripts, an increase of between 5- and 8-fold, within 0.5 h after exposure to particle radiation, followed by another wave of increased transcription at 2-3 h postirradiation. Immunofluorescence results confirm the enhanced levels of FGF2 protein rapidly after exposure to protons or helium ions, followed by another wave of increased activity unique to helium at 6 h postirradiation. This second wave of increased immunoreactivity was not observed in the proton-irradiated samples. Total FGF2 protein analysis after helium-ion exposures shows induced expression of three FGF2 isoforms, with an increase of up to 2-fold in the 18-kDa low-molecular-weight species. Studies of the effects of protons on individual FGF2 protein isoforms are in progress. Several mechanisms involving a role for FGF2 in radiation-induced cataract are discussed.

  15. Using infrared and Raman microspectroscopies to compare ex vivo involved psoriatic skin with normal human skin

    NASA Astrophysics Data System (ADS)

    Leroy, Marie; Lefèvre, Thierry; Pouliot, Roxane; Auger, Michèle; Laroche, Gaétan

    2015-06-01

    Psoriasis is a chronic dermatosis that affects around 3% of the world's population. The etiology of this autoimmune pathology is not completely understood. The barrier function of psoriatic skin is known to be strongly altered, but the structural modifications at the origin of this dysfunction are not clear. To develop strategies to reduce symptoms of psoriasis or adequate substitutes for modeling, a deep understanding of the organization of psoriatic skin at a molecular level is required. Infrared and Raman microspectroscopies have been used to obtain direct molecular-level information on psoriatic and healthy human skin biopsies. From the intensities and positions of specific vibrational bands, the lipid and protein distribution and the lipid order have been mapped in the different layers of the skin. Results showed a similar distribution of lipids and collagen for normal and psoriatic human skin. However, psoriatic skin is characterized by heterogeneity in lipid/protein composition at the micrometer scale, a reduction in the definition of skin layer boundaries and a decrease in lipid chain order in the stratum corneum as compared to normal skin. A global decrease of the structural organization is exhibited in psoriatic skin that is compatible with an alteration of its barrier properties.

  16. Human pluripotent stem cells as a model of trophoblast differentiation in both normal development and disease.

    PubMed

    Horii, Mariko; Li, Yingchun; Wakeland, Anna K; Pizzo, Donald P; Nelson, Katharine K; Sabatini, Karen; Laurent, Louise Chang; Liu, Ying; Parast, Mana M

    2016-07-01

    Trophoblast is the primary epithelial cell type in the placenta, a transient organ required for proper fetal growth and development. Different trophoblast subtypes are responsible for gas/nutrient exchange (syncytiotrophoblasts, STBs) and invasion and maternal vascular remodeling (extravillous trophoblasts, EVTs). Studies of early human placental development are severely hampered by the lack of a representative trophoblast stem cell (TSC) model with the capacity for self-renewal and the ability to differentiate into both STBs and EVTs. Primary cytotrophoblasts (CTBs) isolated from early-gestation (6-8 wk) human placentas are bipotential, a phenotype that is lost with increasing gestational age. We have identified a CDX2(+)/p63(+) CTB subpopulation in the early postimplantation human placenta that is significantly reduced later in gestation. We describe a reproducible protocol, using defined medium containing bone morphogenetic protein 4 by which human pluripotent stem cells (hPSCs) can be differentiated into CDX2(+)/p63(+) CTB stem-like cells. These cells can be replated and further differentiated into STB- and EVT-like cells, based on marker expression, hormone secretion, and invasive ability. As in primary CTBs, differentiation of hPSC-derived CTBs in low oxygen leads to reduced human chorionic gonadotropin secretion and STB-associated gene expression, instead promoting differentiation into HLA-G(+) EVTs in an hypoxia-inducible, factor-dependent manner. To validate further the utility of hPSC-derived CTBs, we demonstrated that differentiation of trisomy 21 (T21) hPSCs recapitulates the delayed CTB maturation and blunted STB differentiation seen in T21 placentae. Collectively, our data suggest that hPSCs are a valuable model of human placental development, enabling us to recapitulate processes that result in both normal and diseased pregnancies. PMID:27325764

  17. Validation of Normal Human Bronchial Epithelial Cells as a Model for Influenza A Infections in Human Distal Trachea

    PubMed Central

    Davis, A. Sally; Chertow, Daniel S.; Moyer, Jenna E.; Suzich, Jon; Sandouk, Aline; Dorward, David W.; Logun, Carolea; Shelhamer, James H.

    2015-01-01

    Primary normal human bronchial/tracheal epithelial (NHBE) cells, derived from the distal-most aspect of the trachea at the bifurcation, have been used for a number of studies in respiratory disease research. Differences between the source tissue and the differentiated primary cells may impact infection studies based on this model. Therefore, we examined how well-differentiated NHBE cells compared with their source tissue, the human distal trachea, as well as the ramifications of these differences on influenza A viral pathogenesis research using this model. We employed a histological analysis including morphological measurements, electron microscopy, multi-label immunofluorescence confocal microscopy, lectin histochemistry, and microarray expression analysis to compare differentiated NHBEs to human distal tracheal epithelium. Pseudostratified epithelial height, cell type variety and distribution varied significantly. Electron microscopy confirmed differences in cellular attachment and paracellular junctions. Influenza receptor lectin histochemistry revealed that α2,3 sialic acids were rarely present on the apical aspect of the differentiated NHBE cells, but were present in low numbers in the distal trachea. We bound fluorochrome bioconjugated virus to respiratory tissue and NHBE cells and infected NHBE cells with human influenza A viruses. Both indicated that the pattern of infection progression in these cells correlated with autopsy studies of fatal cases from the 2009 pandemic. PMID:25604814

  18. Radiographic comparison of human lung shape during normal gravity and weightlessness.

    PubMed

    Michels, D B; Friedman, P J; West, J B

    1979-10-01

    Human lung shape was measured during zero gravity (0 G) to decide whether the normal vertical regional differences in ventilation are due directly to distortion of the elastic lung by its own weight, or instead, due indirectly to the effect of gravity on the shape of the rib cage and diaphragm. This was important because we previously established that weightlessness virtually abolishes the normal topographical inequality of ventilation (J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 45: 987-998, 1978). Chest radiographs were made after 10 s of a weightless flight trajectory aboard a NASA-Ames Research Center Learjet in both posterior-anterior and left lateral projections on five seated volunteers at residual volume, functional residual capacity, and total lung capacity. Lung shape was assessed by measuring lung heights and widths in upper, middle, and lower lung regions. We found no significant differences between any of the normal gravity (1 G) and o G measurements, although there was a slight tendency for the lung to become shorter and wider at o