Correlating Papanicolaou Smear, Colposcopic Impression, and Biopsy: Results from the Women's Interagency HIV Study

Journal of Lower Genital Tract Disease. Oct, 2001  |  Pubmed ID: 17050978

OBJECTIVE: To determine associations among cervical cytology, colposcopy, and biopsy in HIV-seropositive women. MATERIALS AND METHODS: HIV-seropositive women and uninfected comparison women in a multicenter prospective cohort study underwent colposcopy for protocol indications. Women were eligible if they had a cervix, satisfactory cytology, and colposcopy between October 1994 and September 1999. Cytology, colposcopic impression, and biopsy were compared using equivalent categorizations. Kappa statistics with bootstrap sampling assessed strength of associations. RESULTS: Colposcopy was performed in 978/1370 HIV-seropositive women and in 154/224 seronegative women. Biopsies were performed on 603 (44%) seropositive women at least once during 1015 colposcopy visits and on 82 (37%) seronegative women at 116 visits. The positive predictive value of cytology was 72% for seropositive women and 60% for seronegative women. The positive predictive value of colposcopy was 71% for seropositive women and 55% for seronegative women. CONCLUSION: The correlation between either cervical cytology or colposcopic impression and colposcopic biopsy was poor.

Pulmonary Vein Internal Electrical Activity Does Not Contribute to the Maintenance of Atrial Fibrillation

Pacing and Clinical Electrophysiology : PACE. Jun, 2003  |  Pubmed ID: 12822752

Whether the electrical activity generated in the pulmonary veins (PVs) during atrial fibrillation (AF) contributes to the maintenance of arrhythmia is not known. The study population consisted of 22 patients (mean age 58 +/- 9.5 years, 16 men) with persistent (12 patients) or intermittent (10 patients) AF. Mapping of the left atrium (LA) was performed with a 64-electrode basket catheter. PVs were mapped simultaneously with the LA with a quadripolar catheter. PV were defined as arrhythmogenic (if frequent ectopic activity induced AF) or nonarrhythmogenic (if no ectopic activity was observed during the procedure). AF cycle lengths in arrhythmogenic and nonarrhythmogenic PV were 130 +/- 50 ms and 152 +/- 42 ms, respectively (P < 0.001). Both were significantly longer than simultaneous AF activity recorded from the posterior wall of the LA (116 +/- 49 ms, P < 0.001). AF cycle lengths in arrhythmogenic PVs as compared to nonarrhythmogenic PVs were: right superior PV 125 +/- 49 ms versus 148 +/- 51 ms; left superior PV 140 +/- 52 ms versus 161 +/- 30 ms; left inferior PV 127 +/- 48 ms versus 147 +/- 45 ms; and right inferior PV 129 +/- 38 versus 152 +/- 44 ms (P < 0.001 for all four comparisons). AF activity in the PV was more organized than in the posterior wall of the LA and the veins were activated in a proximal-to-distal direction during sustained AF episodes. In patients with AF not related to rheumatic heart disease, the posterior wall of the LA has faster activity than the PVs. The AF activity generated inside the PV during sustained AF episodes originates from the posterior wall of the LA rather than from focal firing.

Automated MALDI-TOF-MS Sample Preparation in Combinatorial Polymer Research

Journal of Combinatorial Chemistry. Jul-Aug, 2003  |  Pubmed ID: 12857104

A new automated matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) sample spotting technique that allows the integration of MALDI sample preparation in the workflow of combinatorial polymer research is described. The technique is performed utilizing a commercially available synthetic robot and was first evaluated with polymer standards of known composition and later on used for the monitoring of the living cationic ring-opening polymerization of 2-ethyl-2-oxazoline. The spotting was carried out as a multiple layer approach, which offers the ability of complex sample preparation without the requirement of premixing the different components. The described technique reduces the time required for sample preparation and offers the possibility of automated sample spotting during polymerization reactions performed in a synthetic robot. This allows the integration of molecular weight screening and polymer end/group determination utilizing MALDI-TOF-MS as a high-throughput tool in combinatorial polymer research.

LocaLisa Catheter Navigation Reduces Fluoroscopy Time and Dosage in Ablation of Atrial Flutter: a Prospective Randomized Study

Journal of Cardiovascular Electrophysiology. Jun, 2003  |  Pubmed ID: 12875418

Catheter ablation has become a well-established therapy for isthmus-dependent right atrial flutter (AFL). Recently, mapping and ablation of AFL have been performed using sophisticated three-dimensional mapping systems, such as electroanatomic and noncontact mapping systems. The LocaLisa system enables nonfluoroscopic navigation of intracardiac electrode catheters based on impedance changes related to catheter movements in transthoracic current fields. The aim of this randomized prospective study was to compare the efficacy of the LocaLisa system with the conventional mapping/ablation approach for radiofrequency ablation of AFL.

Doppler Microembolic Load Predicts Risk of Thromboembolic Complications in Novacor Patients

The Journal of Thoracic and Cardiovascular Surgery. Jul, 2003  |  Pubmed ID: 12878951

Left ventricular assist devices have become an established method to bridge patients with end-stage cardiac failure to heart transplantation. Besides infection and bleeding, thromboembolism represents one of the most serious complications. We evaluated the value of microembolic signals in predicting thromboembolic events for individual patients and distinctive left ventricular assist device periods.

Sizing Up the Heart: Development Redux in Disease

Genes & Development. Aug, 2003  |  Pubmed ID: 12893779

Robotic Bone Preparation Does Not Increase Cement Penetration into the Proximal Femur: a Matched-pair Cadaver Study Comparing Hand-broaching Versus Robotic Bone Preparation

Acta Orthopaedica Scandinavica. Jun, 2003  |  Pubmed ID: 12899546

In a cadaver study, we prepared 20 matched pairs of human femora using chipped-tooth broaches and robotic milling with the same geometry. For robotic bone preparation the CASPAR robotic system with a rotating milling head was used. Cancellous bone was irrigated with 1 liter of pulsed lavage and the specimens were embedded in specially-designed pots. After vacuum mixing, bone cement was introduced in a retrograde manner and subjected to a standard pressure protocol with a constant force of 3,000 N. Radiographs were taken and horizontal sections were obtained at predefined levels, using a diamond saw. Microradiographs of the bone slices were taken, digitized and analyzed to assess cement penetration into cancellous bone. No femoral fractures or fissures occurred with either preparation technique. The microradiographic evaluation showed no morphometric differences between chipped-tooth broaches and robotic milling as regards cement penetration into cancellous bone. Therefore, in the presence of pulsed lavage, we conclude that robotic bone preparation does not increase cement penetration into cancellous bone of the proximal end of the femur.

Nature of Rapid Pulmonary Vein Tachycardias: Reentry or Not Reentry?

Journal of Cardiovascular Electrophysiology. Sep, 2003  |  Pubmed ID: 12950536

HATs off to Hop: Recruitment of a Class I Histone Deacetylase Incriminates a Novel Transcriptional Pathway That Opposes Cardiac Hypertrophy

The Journal of Clinical Investigation. Sep, 2003  |  Pubmed ID: 12975465

Histone acetylation, regulated by two antagonistic enzymes - histone acetyltransferases (HATs) and histone deacetylases (HDACs) - results in transcriptional changes and also plays a critical role in cardiac development and disease. A new study shows that overexpression of the atypical transcriptional corepressor homeodomain-only protein (Hop) causes cardiac hypertrophy via recruitment of a class I HDAC. In contrast to the body of work on transcriptional mechanisms that drive cardiac hypertrophy, including class II HDACs, this report elucidates a novel growth-suppressing transcriptional pathway in cardiac muscle that opposes hypertrophic growth.

Cardiac Progenitor Cells from Adult Myocardium: Homing, Differentiation, and Fusion After Infarction

Proceedings of the National Academy of Sciences of the United States of America. Oct, 2003  |  Pubmed ID: 14530411

Potential repair by cell grafting or mobilizing endogenous cells holds particular attraction in heart disease, where the meager capacity for cardiomyocyte proliferation likely contributes to the irreversibility of heart failure. Whether cardiac progenitors exist in adult myocardium itself is unanswered, as is the question whether undifferentiated cardiac precursor cells merely fuse with preexisting myocytes. Here we report the existence of adult heart-derived cardiac progenitor cells expressing stem cell antigen-1. Initially, the cells express neither cardiac structural genes nor Nkx2.5 but differentiate in vitro in response to 5'-azacytidine, in part depending on Bmpr1a, a receptor for bone morphogenetic proteins. Given intravenously after ischemia/reperfusion, cardiac stem cell antigen 1 cells home to injured myocardium. By using a Cre/Lox donor/recipient pair (alphaMHC-Cre/R26R), differentiation was shown to occur roughly equally, with and without fusion to host cells.

Temtamy-like Syndrome Associated with Translocation of 2p24 and 9q32

Clinical Dysmorphology. Jul, 2003  |  Pubmed ID: 14564155

We describe the phenotype of a 5 year old girl with features resembling Temtamy syndrome, including agenesis of the corpus callosum, ventriculomegaly, frontal bossing, peaked eyebrows, ptosis, malformed and low set ears, a depressed nasal bridge, a long philtrum, and iris and chorioretinal colobomas. Features unique to this child include profound mental retardation, bilateral sensorineural hearing loss, agenesis of the corpus callosum, patent ductus arteriosus, ventricular septal defect, unilateral renal agenesis, neurogenic bladder and hydronephrosis. High resolution chromosome analysis demonstrated a de novo, balanced translocation [46,XX,t(2;9)(p24;q32)]; and her case has some overlapping phenotypic features with cases of monosomy for 2p. This is the first documented case of Temtamy syndrome with a specific chromosomal anomaly, and will assist with the elucidation of the syndrome's underlying genetic defect.

Cardiomyocyte-restricted Knockout of STAT3 Results in Higher Sensitivity to Inflammation, Cardiac Fibrosis, and Heart Failure with Advanced Age

Proceedings of the National Academy of Sciences of the United States of America. Oct, 2003  |  Pubmed ID: 14566054

Cytokines and inflammation have been implicated in the pathogenesis of heart failure. For example, IL-6 family cytokines and the gp130 receptor play important roles in cardiac myocyte survival and hypertrophy. Signal transducer and activator of transcription 3 (STAT3) is a major signaling protein that is activated through gp130. We have created mice with a cardiomyocyte-restricted deletion of STAT3. As measured by serial echocardiograms, mice with cardiac specific deletion of STAT3 are significantly more susceptible to cardiac injury after doxorubicin treatment than age-matched controls. Intriguingly, STAT3 appears to have a critical role in protection of inflammation-induced heart damage. STAT3-deficient mice treated with lipopolysaccharide demonstrated significantly more apoptosis than their WT counterparts. At the cellular level, cardiomyocytes with STAT3 deleted secrete significantly more tumor necrosis factor in response to lipopolysaccharide than those with WT STAT3. Furthermore, histologic examination of the cardiomyocyte-restricted STAT3-deficient mice reveals a dramatic increase in cardiac fibrosis in aged mice. Although no overt signs of heart failure are present in young STAT3-deficient mice, they spontaneously develop heart dysfunction with advancing age. These results indicate the crucial functions of STAT3 in cardiomyocyte resistance to inflammation and other acute injury and in pathogenesis of age-related heart failure.

Serum Immunoglobulin A Response to Human Papillomavirus Type 16 Virus-like Particles in Human Immunodeficiency Virus (HIV)-positive and High-risk HIV-negative Women

The Journal of Infectious Diseases. Dec, 2003  |  Pubmed ID: 14673762

Serum samples from 2008 human immunodeficiency virus (HIV)-positive and 551 HIV-negative women were tested for immunoglobulin A (IgA) to human papillomavirus (HPV) type 16 capsids. IgA seropositivity was lower than previously reported IgG seropositivity (7% vs. 51%), but, like IgG antibodies, HPV 16 IgA was associated with sexual behavior, cervicovaginal HPV 16 DNA, and cytological abnormalities. IgA seropositivity was higher in HIV-positive women than in HIV-negative women (7.7% vs. 4.9%; P=.02), but the association was lost after adjustment for HPV 16 cervicovaginal infection. IgA, but not IgG, seropositivity was associated with progression to high-grade cytological abnormalities (relative hazard [RH], 2.2 [95% confidence interval, 1.2-4.2]), raising the possibility that an IgA response to HPV 16, as described for other DNA viruses, may be a marker of persistent viral replication. The risk of incident infection with non-16-related HPV types was increased in IgA seropositive women (RH, 1.8 [95% confidence interval, 1.3-2.6]), compared with seronegative women (RH, 2.2 [95% confidence interval, 0.9-5.4]), but there was no difference in the risk of incident HPV 16 or HPV 16-related infections. This may be evidence of partial type-specific or clade-specific immunity conferred by seropositivity to HPV 16 capsids.

Influence of High-pass Filtering on Noncontact Mapping and Ablation of Atrial Tachycardias

Pacing and Clinical Electrophysiology : PACE. Jan, 2004  |  Pubmed ID: 14720153

The aim of the study was to define the impact of different high-pass filter settings (HPF) on the accuracy of mapping of ectopic atrial tachycardias (EAT) using a noncontact mapping (NCM) system. In 20 patients with 22 EAT a noncontact probe was deployed in the right (n = 19) or in the left atrium (n = 3). The device enables interpolation and analysis of unipolar electrograms. It provides information on focus localization and signal morphology. These parameters were compared in different HPF of 0.5 Hz, 2 Hz, 8 Hz, and 16 Hz. The NCM signal morphology was preserved at all HPF. An initial negative deflection recorded by NCM system showed a positive predictive value of 93% regarding the ablation success. The deviation (spatial disparity) between visualized focus origin and successful ablation site was 6.9 +/- 5.4 mm. Between two consecutive filter settings, the focus shift was more pronounced between 0.5 and 2 Hz (5.4 +/- 4.5 mm) compared to a setting between 8 and 16 Hz (2.9 +/- 2.9 mm; P < 0.05). Successful ablation was achieved in 15/18 right atrial tachycardias (83%) and in 2/3 left atrial arrhythmias. Different HPF influence NCM spatial analysis of EAT. However, a small variability in foci localization does not impact final ablation results.

Phosphorylation of RNA Polymerase II in Cardiac Hypertrophy: Cell Enlargement Signals Converge on Cyclin T/Cdk9

Recent Progress in Hormone Research. 2004  |  Pubmed ID: 14749500

Cardiac myocyte enlargement is the eponymous characteristic of cardiac hypertrophy, regardless of the instigating signal. Such triggers include biomechanical stress (e.g., work load, compensation for ischemic damage), sarcomeric protein mutations, cytoskeletal protein mutations, abnormal energetics, G protein-coupled receptors for ligands (including angiotensin II and endothelin-1), or their signal transducers within cells. In turn, increased myocyte size reflects increased RNA and protein content per cell as responses to these stimuli. In eukaryotic cells, the large subunit of RNA polymerase II (RNAPII) becomes extensively phosphorylated in its serine-rich C-terminal domain (CTD) during the transition from transcript initiation to transcript elongation - that is, "escape" of RNAPII from the promoter-proximal region into the open reading frame. Although this process is believed to be crucial to productive synthesis of mRNA and is known to be governed by two atypical cyclin-dependent kinases, Cdk7 and Cdk9, surprisingly little is understood of how regulatory pathways within cells intersect these RNAPII-directed protein kinases. Investigations of the CTD kinase module in cardiac hypertrophy provide a tentative initial map of a molecular circuit controlling cell size through regulated phosphorylation of RNAPII.

P21Cip1 Levels Differentially Regulate Turnover of Mature Endothelial Cells, Endothelial Progenitor Cells, and in Vivo Neovascularization

Circulation Research. Mar, 2004  |  Pubmed ID: 14752032

p21(Cip1) (p21) controls cell cycle progression and apoptosis in mature endothelial cells (ECs) and regulates size and cycling of the hematopoietic progenitor cell pool. Because circulating endothelial progenitor cells (EPCs) contribute to postnatal neovascularization in addition to mature ECs, we investigated the regulation of ECs and EPCs in p21-deficient mice. Mature aortic EC proliferation was increased in homozygous p21(-/-) and heterozygous p21(+/-) mice, in which p21 protein levels are reduced to one third of wild-type (WT). In contrast, apoptosis sensitivity was increased by 3.5-fold only in p21(-/-), but not in p21(+/-) mice. Consistently, in vivo apoptosis of ECs within areas of neovascularization was elevated in p21(-/-) but not in p21(+/-) mice. EPC numbers were elevated 2-fold in p21(-/-) mice compared with WT (P<0.001), and clonal expansion capacity of EPCs was increased from 25+/-4 (WT) to 57+/-8 colony-forming units in p21(-/-) mice (P<0.005). EPC numbers and expansion were likewise increased in p21(+/-) mice. As the integrative endpoint, in vivo neovascularization reflecting all p21-affected parameters was increased over WT only in p21(+/-) (P<0.001), but not in p21(-/-) mice. In conclusion, reduced p21 protein levels of mice lacking one p21 allele are associated with increased proliferation of ECs and EPCs, whereas survival of ECs to apoptotic stimuli in vitro and in vivo is not impaired. Under these conditions, neovascularization was increased. In contrast, complete p21 deficiency did not result in an increased neovascularization despite increased mature EC and EPC proliferation. This may be due to the sensitization of ECs against apoptosis.

Identification of Catalyst Surface Species During Asymmetric Platinum-catalysed Hydrogenation in a "supercritical" Solvent

Chemical Communications (Cambridge, England). Mar, 2004  |  Pubmed ID: 15010810

In situ attenuated total reflection infrared spectroscopy studies during the enantioselective hydrogenation of ethyl pyruvate in "supercritical" ethane over a chirally modified Pt/Al(2)O(3) catalyst show the preferential adsorption of ethyl pyruvate as cis-conformer and indicate a hydrogen bond interaction of this species with the co-adsorbed modifier cinchonidine.

Disruption of Rho Signaling Results in Progressive Atrioventricular Conduction Defects While Ventricular Function Remains Preserved

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. May, 2004  |  Pubmed ID: 15033930

Recent studies suggest that RhoA and Rac1 mediate hypertrophic signals in cardiac myocyte hypertrophy. However, effects on cardiac function caused by inhibition of their activity in the heart have yet to be evaluated. Cardiac-specific inhibition of Rho family protein activities was achieved by expressing Rho GDIalpha, an endogenous specific GDP dissociation inhibitor for Rho family proteins, using the alpha-myosin heavy-chain promoter. Increased expression of Rho GDIalpha led to atrial arrhythmias and mild ventricular hypertrophy in adult mice (4-7 months). However, left ventricular systolic and diastolic function was largely preserved before and after the development of cardiac hypertrophy, indicating that Rho GTPases are not required to maintain ventricular contractile function under basal physiological condition. Electrocardiography and intracardiac electrophysiological studies revealed first-degree atrioventricular (AV) block in the transgenic heart at 1 week of age, which further progressed into second-degree AV block at 4 weeks of age before the development of cardiac hypertrophy. Expression of connexin 40 dramatically decreased from 1 week to 4 weeks of age in the transgenic heart, which may contribute in part to the conduction defects in the transgenic mice. This study provides novel evidence for an important role of Rho GTPases in regulating AV conduction.

A Further Case of Coincidental Prader-Willi and Klinefelter Syndromes

American Journal of Medical Genetics. Part A. Apr, 2004  |  Pubmed ID: 15057989

HPV Testing for Triage of HIV-infected Women with Papanicolaou Smears Read As Atypical Squamous Cells of Uncertain Significance

Journal of Women's Health (2002). Mar, 2004  |  Pubmed ID: 15072728

To assess the utility of testing for high-risk human papillomavirus (HPV) DNA as a triage strategy for detecting cervical intraepithelial neoplasia (CIN) grade 2/3 in women with human immunodeficiency virus-1 (HIV-1) infection and cytology read as atypical cells of uncertain significance (ASCUS).

BMP10 is Essential for Maintaining Cardiac Growth During Murine Cardiogenesis

Development (Cambridge, England). May, 2004  |  Pubmed ID: 15073151

During cardiogenesis, perturbation of a key transition at mid-gestation from cardiac patterning to cardiac growth and chamber maturation often leads to diverse types of congenital heart disease, such as ventricular septal defect (VSD), myocardium noncompaction, and ventricular hypertrabeculation. This transition, which occurs at embryonic day (E) 9.0-9.5 in murine embryos and E24-28 in human embryos, is crucial for the developing heart to maintain normal cardiac growth and function in response to an increasing hemodynamic load. Although, ventricular trabeculation and compaction are key morphogenetic events associated with this transition, the molecular and cellular mechanisms are currently unclear. Initially, cardiac restricted cytokine bone morphogenetic protein 10 (BMP10) was identified as being upregulated in hypertrabeculated hearts from mutant embryos deficient in FK506 binding protein 12 (FKBP12). To determine the biological function of BMP10 during cardiac development, we generated BMP10-deficient mice. Here we describe an essential role of BMP10 in regulating cardiac growth and chamber maturation. BMP10 null mice display ectopic and elevated expression of p57(kip2) and a dramatic reduction in proliferative activity in cardiomyocytes at E9.0-E9.5. BMP10 is also required for maintaining normal expression levels of several key cardiogenic factors (e.g. NKX2.5 and MEF2C) in the developing myocardium at mid-gestation. Furthermore, BMP10-conditioned medium is able to rescue BMP10-deficient hearts in culture. Our data suggest an important pathway that involves a genetic interaction between BMP10, cell cycle regulatory proteins and several major cardiac transcription factors in orchestrating this transition in cardiogenesis at mid-gestation. This may provide an underlying mechanism for understanding the pathogenesis of both structural and functional congenital heart defects.

Two-to-one Conduction Block Between Left Atrium and Right Lower Pulmonary Vein Preceding Complete Vein Isolation During Radiofrequency Current Ablation

Pacing and Clinical Electrophysiology : PACE. Jun, 2004  |  Pubmed ID: 15189546

A 56-year-old patient with paroxysmal atrial fibrillation who developed a transient 2:1 block between the left atrium and right inferior pulmonary vein during a single application of radiofrequency current was described. The production of transient and complete atriovenous block by a single application of radiofrequency current demonstrates that a single connection between the pulmonary veins muscle and the left atrium may exist.

Signal Transducer and Activator of Transcription 3 is Required for Myocardial Capillary Growth, Control of Interstitial Matrix Deposition, and Heart Protection from Ischemic Injury

Circulation Research. Jul, 2004  |  Pubmed ID: 15192020

The transcription factor signal transducer and activator of transcription 3 (STAT3) participates in a wide variety of physiological processes and directs seemingly contradictory responses such as proliferation and apoptosis. To elucidate its role in the heart, we generated mice harboring a cardiomyocyte-restricted knockout of STAT3 using Cre/loxP-mediated recombination. STAT3-deficient mice developed reduced myocardial capillary density and increased interstitial fibrosis within the first 4 postnatal months, followed by dilated cardiomyopathy with impaired cardiac function and premature death. Conditioned medium from STAT3-deficient cardiomyocytes inhibited endothelial cell proliferation and increased fibroblast proliferation, suggesting the presence of paracrine factors attenuating angiogenesis and promoting fibrosis in vitro. STAT3-deficient mice showed enhanced susceptibility to myocardial ischemia/reperfusion injury and infarction with increased cardiac apoptosis, increased infarct sizes, and reduced cardiac function and survival. Our study establishes a novel role for STAT3 in controlling paracrine circuits in the heart essential for postnatal capillary vasculature maintenance, interstitial matrix deposition balance, and protection from ischemic injury and heart failure.

Cardiac Muscle Plasticity in Adult and Embryo by Heart-derived Progenitor Cells

Annals of the New York Academy of Sciences. May, 2004  |  Pubmed ID: 15201159

The evidence of cardiomyocyte proliferation in damaged heart implied cardiac regeneration might occur by resident or extra cardiac stem cells. However, the specification and origin of these cells remain unknown. Here, we report using fluorescence-activated cell sorting that cardiac progenitor cells resided in adult heart and colocalized with small capillary vessels, within the stem cell antigen (Sca-1) population expressing high telomerase activity. Notably, hematopoietic stem cells capable of efflux Hoechst 33342, termed side population cells, also were identified within the heart-derived cells. The cardiac progenitor cells (CD45(-)/CD34(-)) express neither cardiac muscle nor endothelial cell markers at an undifferentiated stage. The exposure of 5-azacytidine induced cardiac differentiation, which depends, in part, on Bmpr1a, a type IA receptor for bone morphogenetic protein (BMP). The capability of adult Sca1(+) cells to adopt a cardiac muscle in embryogenesis was substantiated by blastocyst injection, using progenitors from the adult hearts of transgenic mice that harbor a bacterial artificial chromosome expressing GFP via the Nkx-2.5 locus. Intravenously injected progenitors, shortly after ischemic/reperfusion, homed and functionally differentiated 3.5% of total left ventricle in the host myocardium. Differentiation included both fusion-independent and fusion-associated components, proved by the Cre/loxP donor/recipient system. Our studies suggest that endogenous cardiac progenitors reside in the adult heart, regenerate cardiomyocytes functionally, and integrate into the existing heart circuitry.

First Annual Symposium of the American Heart Association Council on Basic Cardiovascular Sciences: Stress Signals, Molecular Targets, and the Genome

Circulation Research. Jun, 2004  |  Pubmed ID: 15217914

Lineage and Morphogenetic Analysis of the Cardiac Valves

Circulation Research. Sep, 2004  |  Pubmed ID: 15297379

We used a genetic lineage-labeling system to establish the material contributions of the progeny of 3 specific cell types to the cardiac valves. Thus, we labeled irreversibly the myocardial (alphaMHC-Cre+), endocardial (Tie2-Cre+), and neural crest (Wnt1-Cre+) cells during development and assessed their eventual contribution to the definitive valvar complexes. The leaflets and tendinous cords of the mitral and tricuspid valves, the atrioventricular fibrous continuity, and the leaflets of the outflow tract valves were all found to be generated from mesenchyme derived from the endocardium, with no substantial contribution from cells of the myocardial and neural crest lineages. Analysis of chicken-quail chimeras revealed absence of any substantial contribution from proepicardially derived cells. Molecular and morphogenetic analysis revealed several new aspects of atrioventricular valvar formation. Marked similarities are seen during the formation of the mural leaflets of the mitral and tricuspid valves. These leaflets form by protrusion and growth of a sheet of atrioventricular myocardium into the ventricular lumen, with subsequent formation of valvar mesenchyme on its surface rather than by delamination of lateral cushions from the ventricular myocardial wall. The myocardial layer is subsequently removed by the process of apoptosis. In contrast, the aortic leaflet of the mitral valve, the septal leaflet of the tricuspid valve, and the atrioventricular fibrous continuity between these valves develop from the mesenchyme of the inferior and superior atrioventricular cushions. The tricuspid septal leaflet then delaminates from the muscular ventricular septum late in development.

Activation of Cardiac Cdk9 Represses PGC-1 and Confers a Predisposition to Heart Failure

The EMBO Journal. Sep, 2004  |  Pubmed ID: 15297879

Hypertrophy allows the heart to adapt to workload but culminates in later pump failure; how it is achieved remains uncertain. Previously, we showed that hypertrophy is accompanied by activation of cyclin T/Cdk9, which phosphorylates the C-terminal domain of the large subunit of RNA polymerase II, stimulating transcription elongation and pre-mRNA processing; Cdk9 activity was required for hypertrophy in culture, whereas heart-specific activation of Cdk9 by cyclin T1 provoked hypertrophy in mice. Here, we report that alphaMHC-cyclin T1 mice appear normal at baseline yet suffer fulminant apoptotic cardiomyopathy when challenged by mechanical stress or signaling by the G-protein Gq. At pathophysiological levels, Cdk9 activity suppresses many genes for mitochondrial proteins including master regulators of mitochondrial function (peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1), nuclear respiratory factor-1). In culture, cyclin T1/Cdk9 suppresses PGC-1, decreases mitochondrial membrane potential, and sensitizes cardiomyocytes to apoptosis, effects rescued by exogenous PGC-1. Cyclin T1/Cdk9 inhibits PGC-1 promoter activity and preinitiation complex assembly. Thus, chronic activation of Cdk9 causes not only cardiomyocyte enlargement but also defective mitochondrial function, via diminished PGC-1 transcription, and a resulting susceptibility to apoptotic cardiomyopathy.

Transgenic Expression of Bcl-2 Modulates Energy Metabolism, Prevents Cytosolic Acidification During Ischemia, and Reduces Ischemia/reperfusion Injury

Circulation Research. Oct, 2004  |  Pubmed ID: 15345651

The antiapoptotic protein Bcl-2 is targeted to the mitochondria, but it is uncertain whether Bcl-2 affects only myocyte survival after ischemia, or whether it also affects metabolic functions of mitochondria during ischemia. Hearts from mice overexpressing human Bcl-2 and from their wild-type littermates (WT) were subjected to 24 minutes of global ischemia followed by reperfusion. During ischemia, the decrease in pH(i) and the initial rate of decline in ATP were significantly reduced in Bcl-2 hearts compared with WT hearts (P<0.05). The reduced acidification during ischemia was dependent on the activity of mitochondrial F1F0-ATPase. In the presence of oligomycin (Oligo), an F1F0-ATPase inhibitor, the decrease in pH(i) was attenuated in WT hearts, but in Bcl-2 hearts, Oligo had no additional effect on pH(i) during ischemia. Likewise, addition of Oligo to WT hearts slowed the rate of decline in ATP during ischemia to a level similar to that observed in Bcl-2 hearts, but addition of Oligo had no significant effect on the rate of decline in ATP in Bcl-2 hearts during ischemia. These data are consistent with Bcl-2-mediated inhibition of consumption of glycolytic ATP. Furthermore, mitochondria from Bcl-2 hearts have a reduced rate of consumption of ATP on uncoupler addition. This could be accomplished by limiting ATP entry into the mitochondria through the voltage-dependent anion channel, and/or the adenine nucleotide transporter, or by direct inhibition of the F1F0-ATPase. Immunoprecipitation showed greater interaction between Bcl-2 and voltage-dependent anion channel during ischemia. These data indicate that Bcl-2 modulation of metabolism contributes to cardioprotection.

Cardiomyocyte-restricted Peroxisome Proliferator-activated Receptor-delta Deletion Perturbs Myocardial Fatty Acid Oxidation and Leads to Cardiomyopathy

Nature Medicine. Nov, 2004  |  Pubmed ID: 15475963

Fatty acid oxidation (FAO) is a primary energy source for meeting the heart's energy requirements. Peroxisome proliferator-activated receptor-delta (PPAR-delta) may have important roles in FAO. But it remains unclear whether PPAR-delta is required for maintaining basal myocardial FAO. We show that cre-loxP-mediated cardiomyocyte-restricted deletion of PPAR-delta in mice downregulates constitutive expression of key FAO genes and decreases basal myocardial FAO. These mice have cardiac dysfunction, progressive myocardial lipid accumulation, cardiac hypertrophy and congestive heart failure with reduced survival. Thus, chronic myocardial PPAR-delta deficiency leads to lipotoxic cardiomyopathy. Together, our data show that PPAR-delta is a crucial determinant of constitutive myocardial FAO and is necessary to maintain energy balance and normal cardiac function. We suggest that PPAR-delta is a potential therapeutic target in treating lipotoxic cardiomyopathy and other heart diseases.

Heart Transplantation in a Patient with a Left Ventricular Assist Device and Methicillin-resistant Staphylococcus Aureus Infection

The Annals of Thoracic Surgery. Nov, 2004  |  Pubmed ID: 15511483

We report a patient who underwent implantation of a DeBakey left-ventricular assist device and developed a methicillin-resistant Staphylococcus aureus drive line infection on postoperative day 304. The patient was forwarded to urgent heart transplantation with a successful outcome.

Cyclin-dependent Kinase-9: an RNAPII Kinase at the Nexus of Cardiac Growth and Death Cascades

Circulation Research. Oct, 2004  |  Pubmed ID: 15514168

Over the past decade and a half, the paradigm has emerged of cardiac hypertrophy and ensuing heart failure as fundamentally a problem in signal transduction, impinging on the altered expression or function of gene-specific transcription factors and their partners, which then execute the hypertrophic phenotype. Strikingly, RNA polymerase II (RNAPII) is itself a substrate for two protein kinases-the cyclin-dependent kinases Cdk7 and Cdk9--that are activated by hypertrophic cues. Phosphorylation of RNAPII in the carboxyl terminal domain (CTD) of its largest subunit controls a number of critical steps subsequent to transcription initiation, among them enabling RNAPII to overcome its stalling in the promoter-proximal region and to engage in efficient transcription elongation. Here, we summarize our current understanding of the RNAPII-directed protein kinases in cardiac hypertrophy. Cdk9 activation is essential in tissue culture for myocyte enlargement and sufficient in transgenic mice for hypertrophy to occur and yet is unrelated to the "fetal" gene program that is typical of pathophysiological heart growth. Although this trophic effect of Cdk9 appears benign superficially, pathophysiological levels of Cdk9 activity render myocardium remarkably susceptible to apoptotic stress. Cdk9 interacts adversely with Gq-dependent pathways for hypertrophy, impairing the expression of numerous genes for mitochondrial proteins, and, in particular, suppressing master regulators of mitochondrial biogenesis and function, perioxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1), and nuclear respiratory factor-1 (NRF-1). Given the dual transcriptional roles of Cdk9 in hypertrophic growth and mitochondrial dysfunction, we suggest the potential usefulness of Cdk9 as a target in heart failure drug discovery.

Statins Enhance Migratory Capacity by Upregulation of the Telomere Repeat-binding Factor TRF2 in Endothelial Progenitor Cells

Circulation. Nov, 2004  |  Pubmed ID: 15520325

Cultivation of endothelial progenitor cells (EPCs) leads to premature replicative senescence, limiting ex vivo expansion for potential clinical cell therapy. Recent studies have linked senescence to the dysfunction of telomeres, the "ends" of chromosomes, via the so-called mitotic clock or culture-induced stress. The purpose of this study was to elucidate a possible role of telomere biology in the functional augmentation of EPCs by statins.

Large Germline Deletions of Mitochondrial Complex II Subunits SDHB and SDHD in Hereditary Paraganglioma

The Journal of Clinical Endocrinology and Metabolism. Nov, 2004  |  Pubmed ID: 15531530

More than 30% of adrenal pheochromocytomas are hereditary. These neuroendocrine tumors are major components of three inherited cancer syndromes: multiple endocrine neoplasia type 2, von Hippel-Lindau disease (VHL), and pheochromocytoma/paraganglioma syndrome (PC/PGL). Germline mutations in RET; VHL; and SDHB, SDHC, and SDHD are associated with multiple endocrine neoplasia type 2, VHL, and PC/PGL, respectively. The majority (>70%) of hereditary extraadrenal PCs [catecholamine-secreting paragangliomas (PGL)] are accounted for by germline intragenic mutations in SDHB, SDHC, or SDHD. Therefore, a subset of hereditary PGL is not accounted for. Here we report two unrelated hereditary PGL families, one with a germline whole-gene deletion of SDHD (family 4194), the other a partial deletion of SDHB (family BRZ01). Although they were initially designated mutation negative for all of the PC-associated genes after PCR-based analysis, we suspected that a large deletion or rearrangement might be present. Genotyping around the PC-associated genes demonstrated that both families were consistent with linkage with one of these genes. Using fine structure genotyping and semiquantitative duplex PCR analysis, we identified an approximately 96-kb deletion spanning SDHD in family 4194 and an approximately 1-kb deletion involving the 5' end of SDHB in family BRZ01. Thus, including SDHB and SDHD deletion analysis could increase gene-testing sensitivity for PGL patients, which would aid in genetic counseling and management of patients and families.

Near-critical CO2 in Mesoporous Silica Studied by in Situ FTIR Spectroscopy

Langmuir : the ACS Journal of Surfaces and Colloids. Mar, 2004  |  Pubmed ID: 15835169

Attenuated total reflection Fourier transform infrared spectroscopy was used to correlate the band shift of the nu2 vibrational band of carbon dioxide with the density of the fluid. Upon adsorption of CO2 on mesoporous silica and a nonporous SiO2 film, additional bands were detected due to interactions of CO2 with SiO2. Near the saturation pressure for the porous samples, the absorbance of the nu2 band increased strongly, which was concluded to be caused by liquidlike CO2 inside the pores. Integration of single-beam-sample-reference spectra between bulk CO2 and CO2 adsorbing on the mesoporous silica coated on one part of the internal reflection element revealed excess adsorption type isotherms with sharp maxima at 21 degrees C. A flatter curve shape could be observed at 25 degrees C, which allowed estimating the pore critical temperature. Moreover, the density of the fluid inside and outside the pores could be compared. Over the investigated ranges of pressure, temperature, and pore size, the results evidenced that the CO2 density was always higher in the silica pores than in the bulk, even under supercritical conditions. This has important consequences on the pressure dependence of dissolution power and diffusivity of fluids in mesoporous solids. An overview is given on the influences of fluid phase behavior in the bulk and in the pores at various conditions on solubility and diffusivity.

Regenerative Medicine: Prometheus Unbound

Nature. Nov, 2004  |  Pubmed ID: 15565135

The Hand1 and Hand2 Transcription Factors Regulate Expansion of the Embryonic Cardiac Ventricles in a Gene Dosage-dependent Manner

Development (Cambridge, England). Jan, 2005  |  Pubmed ID: 15576406

The basic helix-loop-helix transcription factors Hand1 and Hand2 display dynamic and spatially restricted expression patterns in the developing heart. Mice that lack Hand2 die at embryonic day 10.5 from right ventricular hypoplasia and vascular defects, whereas mice that lack Hand1 die at embryonic day 8.5 from placental and extra-embryonic abnormalities that preclude analysis of its potential role in later stages of heart development. To determine the cardiac functions of Hand1, we generated mice harboring a conditional Hand1-null allele and excised the gene by cardiac-specific expression of Cre recombinase. Embryos homozygous for the cardiac Hand1 gene deletion displayed defects in the left ventricle and endocardial cushions, and exhibited dysregulated ventricular gene expression. However, these embryos survived until the perinatal period when they died from a spectrum of cardiac abnormalities. Creation of Hand1/2 double mutant mice revealed gene dose-sensitive functions of Hand transcription factors in the control of cardiac morphogenesis and ventricular gene expression. These findings demonstrate that Hand factors play pivotal and partially redundant roles in cardiac morphogenesis, cardiomyocyte differentiation and cardiac-specific transcription.

Application of Case-crossover and Case-time-control Study Designs in Analyses of Time-varying Predictors of T-cell Homeostasis Failure

Annals of Epidemiology. Feb, 2005  |  Pubmed ID: 15652719

To evaluate the association of sexual behavior and recreational drug exposures with T-cell homeostasis failure (TCHF), which corresponds to the onset of a rapid decline in an individual's T lymphocyte count, which occurs on average approximately 1.75 years prior to an initial diagnosis of acquired immunodeficiency syndrome (AIDS).

Acute and Long-term Results of Slow Pathway Ablation in Patients with Atrioventricular Nodal Reentrant Tachycardia--an Analysis of the Predictive Factors for Arrhythmia Recurrence

Pacing and Clinical Electrophysiology : PACE. Feb, 2005  |  Pubmed ID: 15679639

Predictors of atrioventricular nodal reentrant tachycardia (AVNRT) recurrence after radiofrequency ablation including the importance of residual slow pathway conduction are not known. The aim of this study was to report the acute and long-term results of slow pathway ablation in a large series of consecutive patients with AVNRT and to analyze the potential predictors of arrhythmia recurrence with a particular emphasis on the residual slow pathway conduction after ablation.

Factors and Temporal Trends Associated with Highly Active Antiretroviral Therapy Discontinuation in the Women's Interagency HIV Study

Journal of Acquired Immune Deficiency Syndromes (1999). Apr, 2005  |  Pubmed ID: 15764968

We characterized factors and temporal trends associated with discontinuation of highly active antiretroviral therapy (HAART) among 936 HIV-infected women enrolled in the Women's Interagency HIV Study. A multivariate analysis of post-HAART initiation exposures found that high HIV RNA levels (relative hazard [RH] = 1.36, P < 0.001) and high depressive symptom scores (RH = 1.53, P = 0.012) were associated with HAART discontinuation. The adjusted hazard of discontinuation was higher in the 2 most recent calendar periods compared with the first (RH = 1.61, P = 0.026; RH = 1.56, P = 0.074, respectively). The increasing risk of HAART discontinuation in recent calendar periods and changes in the clinical factors associated with discontinuation reflect ongoing and dynamic shifts in the approach to HAART utilization.

Learning from Failure: Congestive Heart Failure in the Postgenomic Age

The Journal of Clinical Investigation. Mar, 2005  |  Pubmed ID: 15765130

The prognosis of heart failure is worse than that of most cancers, but new therapeutic interventions using stem and other cell-based therapies are succeeding in the fight against it, and old drugs, with new twists, are making a comeback. Genetically engineered animal models are driving insights into the molecular mechanisms that cause hearts to fail, accelerating drug discoveries, and inspiring cell-based therapeutic interventions for both acquired and inheritable cardiac diseases.

Unchain My Heart: the Scientific Foundations of Cardiac Repair

The Journal of Clinical Investigation. Mar, 2005  |  Pubmed ID: 15765139

In humans, the biological limitations to cardiac regenerative growth create both a clinical imperative--to offset cell death in acute ischemic injury and chronic heart failure--and a clinical opportunity; that is, for using cells, genes, and proteins to rescue cardiac muscle cell number or in other ways promote more efficacious cardiac repair. Recent experimental studies and early-phase clinical trials lend credence to the visionary goal of enhancing cardiac repair as an achievable therapeutic target.

Studies on the Cardenolide Sequestration in African Milkweed Butterflies (Danaidae)

Toxicon : Official Journal of the International Society on Toxinology. Apr, 2005  |  Pubmed ID: 15777953

Butterflies of the Danaidae family are considered to be toxic or distasteful due to the presence of cardiac glycosides sequestered from their larval food plants. Alcoholic extracts of specimens of Danaus chrysippus aegyptius and Amauris ochlea ochlea from southern Africa (Namibia, S.-Africa, Mozambique) were analyzed by thin-layer chromatography for these cardenolides. But only 4 of 75 specimens of D. chrysippus aegyptius contained trace amounts, all others including 13 specimens of A. ochlea ochlea were negative. Genetic analysis of the ouabain binding site of the Na(+), K(+)-ATPase revealed that both species do not present an amino acid replacement at the position 122, which otherwise makes the enzyme insensitive to cardenolides suggesting that other strategies of toxin tolerance must have been developed.

False Negative Magnetic Resonance Imaging Results: a Report of 2 Cases

Journal of Manipulative and Physiological Therapeutics. May, 2005  |  Pubmed ID: 15883582

The purpose of this study is to present 2 clinical case studies in which large herniated disks were not detected on magnetic resonance imaging (MRI), leading to false negative results, and discuss some issues regarding potential shortcomings of MRI.

Catheter Ablation of Left Atrial Focal Tachycardia Guided by Electroanatomic Mapping and New Insights into Interatrial Electrical Conduction

Heart Rhythm : the Official Journal of the Heart Rhythm Society. Jun, 2005  |  Pubmed ID: 15922263

Experience in catheter ablation of left atrial (LA) focal tachycardia and information about interatrial electrical connections during LA focal tachycardia are limited.

Conditional Mutagenesis of the Murine Serum Response Factor Gene Blocks Cardiogenesis and the Transcription of Downstream Gene Targets

The Journal of Biological Chemistry. Sep, 2005  |  Pubmed ID: 15929941

Serum response factor (SRF) homozygous-null embryos from our backcross of SRF(LacZ/)(+) "knock-in" mice failed to gastrulate and form mesoderm, similar to the findings of an earlier study (Arsenian, S., Weinhold, B., Oelgeschlager, M., Ruther, U., and Nordheim, A. (1998) EMBO J. 17, 6289-6299). Our use of embryonic stem cells provided a model system that could be used to investigate the specification of multiple embryonic lineages, including cardiac myocytes. We observed the absence of myogenic alpha-actins, SM22alpha, and myocardin expression and the failure to form beating cardiac myocytes in aggregated SRF null embryonic stem cells, whereas the appearance of transcription factors Nkx2-5 and GATA4 were unaffected. To study the role of SRF during heart organogenesis, we then performed cardiac-specific ablation of SRF by crossing the transgenic alpha-myosin heavy chain Cre recombinase line with SRF LoxP-engineered mice. Cardiac-specific ablation of SRF resulted in embryonic lethality due to cardiac insufficiency during chamber maturation. Conditional ablation of SRF also reduced cell survival concomitant with increased apoptosis and reduced cellularity. Significant reductions in SRF (> or =95%), atrial naturetic factor (> or =80%), and cardiac (> or =60%), skeletal (> or =90%), and smooth muscle (> or =75%) alpha-actin transcripts were also observed in the cardiac-conditional knock-out heart. This was consistent with the idea that SRF directs de novo cardiac and smooth muscle gene activities. Finally, quantitation of the knock-in LacZ reporter gene transcripts in the hearts of cardiac-conditional knock-out embryos revealed an approximately 30% reduction in gene activity, indicating SRF gene autoregulation during cardiogenesis.

Cyclophilin D: Knocking on Death's Door

Science's STKE : Signal Transduction Knowledge Environment. Jun, 2005  |  Pubmed ID: 15942033

Two recent genetic studies have identified a critical role for cyclophilin D, a component of the mitochondrial membrane permeability transition pore, in cell death induced by calcium, reactive oxygen species, and cardiac ischemia-reperfusion injury. Transgenic mice lacking cyclophilin D developed normally but showed reduced infarct size after coronary artery ligation and reperfusion. Cells from the knockout mice were resistant to death imposed by excess calcium and H2O2, but not to death from x-irradiation, staurosporine, tumor necrosis factor-alpha, or forced expression of proapoptotic proteins. These data raise questions about the relationship between apoptotic and necrotic cell death, and they also highlight cyclophilin D as a potential therapeutic target in myocardial infarction.

Accuracy Assessment of Image-guided Implant Surgery: an Experimental Study

The International Journal of Oral & Maxillofacial Implants. May-Jun, 2005  |  Pubmed ID: 15973949

To accurately accomplish the drilling of an implant socket, the use of image-guided navigation has become an option. The aim of this study was to evaluate the 3-dimensional (3D) accuracy of navigation-guided drilled holes.

Covalent Binding of Acetone to Aminophospholipids in Vitro and in Vivo

Annals of the New York Academy of Sciences. Jun, 2005  |  Pubmed ID: 16037264

We have determined the ions characteristic of acetone adducts of reference aminophospholipids and have used them as markers for identification of acetone adducts of aminophospholipids in commercial lecithin, acetone extracts of tissue lipids, and in plasma and red blood cells of diabetic subjects. The acetonation products were determined by normal-phase high-performance liquid chromatography (HPLC) with on-line electrospray-mass spectrometry, and electrospray/collision-induced dissociation in the negative ion mode. The major acetone complexes of PtdEtn and PtdSer were identified as the diacetone derivatives [PtdEtn+116-H2O]- and [PtdSer+116-H2O]-, respectively, although ions corresponding to monoacetone [PtdEtn+58-H2O]- and doubly dehydrated diacetone adducts [PtdSer+116-2 x 18]- were also observed. Upon increase of the capillary exit voltage (CapEx) from -160 to -300 V, new ions appeared with the original retention time but with 58 masses (one acetone molecule) lower than the mass of the parent compounds, along with fragment ions corresponding to lysoGPE+40 and free fatty acids. Scanning of chloroform/methanol extracts of red blood cell lipids of two of five diabetic subjects examined yielded elevated levels (in relation to nondiabetic subjects) for ions corresponding to the diacetone adducts [M+98]- of the major molecular species of PtdEtn and PtdSer. Because of possible overlap with major molecular species of PtdIns, the identification of the acetonated PtdSer in diabetic blood requires further confirmation.

Alk3/Bmpr1a Receptor is Required for Development of the Atrioventricular Canal into Valves and Annulus Fibrosus

Circulation Research. Aug, 2005  |  Pubmed ID: 16037571

Endocardial cushions are precursors of mature atrioventricular (AV) valves. Their formation is induced by signaling molecules originating from the AV myocardium, including bone morphogenetic proteins (BMPs). Here, we hypothesized that BMP signaling plays an important role in the AV myocardium during the maturation of AV valves from the cushions. To test our hypothesis, we used a unique Cre/lox system to target the deletion of a floxed Alk3 allele, the type IA receptor for BMPs, to cardiac myocytes of the AV canal (AVC). Lineage analysis indicated that cardiac myocytes of the AVC contributed to the tricuspid mural and posterior leaflets, the mitral septal leaflet, and the atrial border of the annulus fibrosus. When Alk3 was deleted in these cells, defects were seen in the same leaflets, ie, the tricuspid mural leaflet and mitral septal leaflet were longer, the tricuspid posterior leaflet was displaced and adherent to the ventricular wall, and the annulus fibrosus was disrupted resulting in ventricular preexcitation. The defects seen in mice with AVC-targeted deletion of Alk3 provide strong support for a role of Alk3 in human congenital heart diseases, such as Ebstein's anomaly. In conclusion, our mouse model demonstrated critical roles for Alk3 signaling in the AV myocardium during the development of AV valves and the annulus fibrosus.

The Association of Race, Sociodemographic, and Behavioral Characteristics with Response to Highly Active Antiretroviral Therapy in Women

Journal of Acquired Immune Deficiency Syndromes (1999). Aug, 2005  |  Pubmed ID: 16044004

To determine the association of race with clinical and laboratory outcomes after initiation of highly active antiretroviral therapy (HAART) in HIV-1-infected women in the United States.

Energizer: PGC-1 Alpha Keeps the Heart Going

Cell Metabolism. Apr, 2005  |  Pubmed ID: 16054065

In the current issue of Cell Metabolism, Arany et al. (2005) demonstrate essential roles for PGC-1alpha in cardiac metabolism, proving several long-postulated functions while disproving others. These experiments conclusively reinforce the logic of rescuing PGC-1alpha as a novel therapeutic target in heart failure.

Determinants of Acute Mountain Sickness and Success on Mount Aconcagua (6962 M)

High Altitude Medicine & Biology. 2005  |  Pubmed ID: 16060850

To investigate the determinants of acute mountain sickness (AMS) and of summiting in expedition-style mountaineering, 919 mountaineers (15.4% female) leaving Aconcagua Provincial Park at the end of an expedition to Mt. Aconcagua (6962 m) via the normal route were retrospectively evaluated by questionnaires. Symptoms of AMS were reported from the day when mountaineers felt worst. The prevalence of AMS, defined as a Lake Louise Score (self-assessment) > 4, was 39%. Low AMS scores were associated with faster ascent rates. The following parameters were independent predictors for AMS: no susceptibility for AMS (odds ratio, OR, 0.24; 95% confidence interval 0.17 to 0.35) more than 10 exposures per year above 3000 m (OR 0.60; 0.41 to 0.86), and previous exposures above 6000 m (OR, 0.48; 0.33 to 0.68). This last variable increased the OR for summiting 3.7-fold while female gender reduced this OR to 0.41 (0.25 to 0.67). Susceptibility and few exposures to high altitude are major predictors for AMS on Aconcagua, but AMS does not substantially reduce the chances for summiting. Those who are often in the mountains and who have already climbed to altitudes above 6000 m and are not susceptible for AMS have the best options for summiting Aconcagua.

Atrioventricular Cushion Transformation is Mediated by ALK2 in the Developing Mouse Heart

Developmental Biology. Oct, 2005  |  Pubmed ID: 16140292

Developmental abnormalities in endocardial cushions frequently contribute to congenital heart malformations including septal and valvular defects. While compelling evidence has been presented to demonstrate that members of the TGF-beta superfamily are capable of inducing endothelial-to-mesenchymal transdifferentiation in the atrioventricular canal, and thus play a key role in formation of endocardial cushions, the detailed signaling mechanisms of this important developmental process, especially in vivo, are still poorly known. Several type I receptors (ALKs) for members of the TGF-beta superfamily are expressed in the myocardium and endocardium of the developing heart, including the atrioventricular canal. However, analysis of their functional role during mammalian development has been significantly complicated by the fact that deletion of the type I receptors in mouse embryos often leads to early embryonal lethality. Here, we used the Cre/loxP system for endothelial-specific deletion of the type I receptor Alk2 in mouse embryos. The endothelial-specific Alk2 mutant mice display defects in atrioventricular septa and valves, which result from a failure of endocardial cells to appropriately transdifferentiate into the mesenchyme in the AV canal. Endocardial cells deficient in Alk2 demonstrate decreased expression of Msx1 and Snail, and reduced phosphorylation of BMP and TGF-beta Smads. Moreover, we show that endocardial cells lacking Alk2 fail to delaminate from AV canal explants. Collectively, these results indicate that the BMP type I receptor ALK2 in endothelial cells plays a critical non-redundant role in early phases of endocardial cushion formation during cardiac morphogenesis.

Bcl-2 Antiapoptotic Proteins Inhibit Beclin 1-dependent Autophagy

Cell. Sep, 2005  |  Pubmed ID: 16179260

Apoptosis and autophagy are both tightly regulated biological processes that play a central role in tissue homeostasis, development, and disease. The anti-apoptotic protein, Bcl-2, interacts with the evolutionarily conserved autophagy protein, Beclin 1. However, little is known about the functional significance of this interaction. Here, we show that wild-type Bcl-2 antiapoptotic proteins, but not Beclin 1 binding defective mutants of Bcl-2, inhibit Beclin 1-dependent autophagy in yeast and mammalian cells and that cardiac Bcl-2 transgenic expression inhibits autophagy in mouse heart muscle. Furthermore, Beclin 1 mutants that cannot bind to Bcl-2 induce more autophagy than wild-type Beclin 1 and, unlike wild-type Beclin 1, promote cell death. Thus, Bcl-2 not only functions as an antiapoptotic protein, but also as an antiautophagy protein via its inhibitory interaction with Beclin 1. This antiautophagy function of Bcl-2 may help maintain autophagy at levels that are compatible with cell survival, rather than cell death.

Electrophysiological Characteristics of Septal Hypertrophy in Patients with Hypertrophic Obstructive Cardiomyopathy and Moderate to Severe Symptoms

Circulation. Oct, 2005  |  Pubmed ID: 16186424

In hypertrophic obstructive cardiomyopathy, regional hypertrophy, myocardial replacement scarring, expanded interstitial fibrosis, and myocardial disarray can be found. The electrophysiological consequences of this substrate have not yet been investigated. Thus, the aim of this study was to assess the local electrophysiological characteristics of regional left ventricular (LV) septal hypertrophy.

High Level of Cerebral Microembolization in Patients Supported with the DeBakey Left Ventricular Assist Device

The Journal of Thoracic and Cardiovascular Surgery. Oct, 2005  |  Pubmed ID: 16214534

Microembolic signals detected by transcranial Doppler ultrasonography have been demonstrated to be clinically relevant in patients supported with pulsatile left ventricular assist devices. We prospectively investigated the quantity of microembolic signals in patients supported with the continuous-flow DeBakey left ventricular assist device (MicroMed DeBakey VAD; MicroMed Technology, Inc, Houston, Tex) including the refined Carmeda BioActive Surface system (Carmeda AB, Stockholm, Sweden).

Patterns of the Hazard of Death After AIDS Through the Evolution of Antiretroviral Therapy: 1984-2004

AIDS (London, England). Nov, 2005  |  Pubmed ID: 16260908

To characterize changing survival patterns after development of clinical AIDS from 1984 to 2004, when different antiretroviral therapies were being introduced.

Deletion of and Novel Missense Mutation in POU3F4 in 2 Families Segregating X-linked Nonsyndromic Deafness

Archives of Otolaryngology--head & Neck Surgery. Dec, 2005  |  Pubmed ID: 16365218

To analyze the physical manifestations and genetic features of 2 families segregating X-linked deafness, which is most commonly reported to be caused by mutations of the POU domain gene POU3F4 at the DFN3 locus.

Activation of P21-activated Kinase 6 by MAP Kinase Kinase 6 and P38 MAP Kinase

The Journal of Biological Chemistry. Feb, 2005  |  Pubmed ID: 15550393

The p21-activated kinases (PAKs) contain an N-terminal Cdc42/Rac interactive binding domain, which in the group 1 PAKs (PAK1, 2, and 3) regulates the activity of an adjacent conserved autoinhibitory domain. In contrast, the group 2 PAKs (PAK4, 5, and 6) lack this autoinhibitory domain and are not activated by Cdc42/Rac binding, and the mechanisms that regulate their kinase activity have been unclear. This study found that basal PAK6 kinase activity was repressed by a p38 mitogen-activated protein (MAP) kinase antagonist and could be strongly stimulated by constitutively active MAP kinase kinase 6 (MKK6), an upstream activator of p38 MAP kinases. Mutation of a consensus p38 MAP kinase target site at serine 165 decreased PAK6 kinase activity. Moreover, PAK6 was directly activated by MKK6, and mutation of tyrosine 566 in a consensus MKK6 site (threonine-proline-tyrosine, TPY) in the activation loop of the PAK6 kinase domain prevented activation by MKK6. PAK6 activation by MKK6 was also blocked by mutation of an autophosphorylated serine (serine 560) in the PAK6 activation loop, indicating that phosphorylation of this site is necessary for MKK6-mediated activation. PAK4 and PAK5 were similarly activated by MKK6, consistent with a conserved TPY motif in their activation domains. The activation of PAK6 by both p38 MAP kinase and MKK6 suggests that PAK6 plays a role in the cellular response to stress-related signals.

Protein Chip Based Miniaturized Assay for the Simultaneous Quantitative Monitoring of Cancer Biomarkers in Tissue Extracts

Proteomics. Mar, 2006  |  Pubmed ID: 16440370

A multiplexed fluorescence immunoassay using a novel planar waveguide technology-based microarray system, ZeptoMARK (Zeptosens), was developed to detect simultaneously urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1), and vascular endothelial growth factor (VEGF) in extracts of breast cancer tissues. The three analytes assay was cross-validated with single-analyte ELISA/chemiluminescence immunosorbent assay tests, revealing good correlations and enhanced assay sensitivities (LODs) of 1 pg/mL for uPA, 33 pg/mL for PAI-1, and 1 pg/mL for VEGF. Values were well within the 80-120% limits for assay recovery and within the +/-20% limits for assay precision. The uPA, PAI-1, and VEGF results obtained from 50 breast cancer cytosols using the protein array system demonstrated that the microarray-based multiplexed assay is a sensitive and robust tool to be used for the simultaneous quantification of cancer markers in small breast cancer tissue samples (core biopsies). The miniaturized, multiplexed assay format has a potential to be used for the quantitative analysis of a larger set of validated markers with significance in disease management.

Profibrotic Cytokines and Lymphocyte Proliferation in Stable Renal Allograft Recipients Treated with or Without Cyclosporine A

Clinical Immunology (Orlando, Fla.). Apr, 2006  |  Pubmed ID: 16451828

Profibrotic cytokines such as transforming growth factor-beta 1 (TGF-beta1) and endothelin-1 (ET-1) are involved in the pathogenesis of chronic allograft nephropathy. We assessed the effect of maintenance immunosuppression with or without cyclosporine A on TGF-beta1 and ET-1 expression as well as lymphocyte proliferation in renal allograft recipients. Patients were divided into groups according to their maintenance immunosuppression: A, azathioprine + methylprednisolone; B, cyclosporine A + azathioprine + methylprednisolone. TGF-beta1 and ET-1 plasma concentrations were not different between both groups. TGF-beta1 concentrations in cell culture supernatants and lymphocyte proliferation were higher in group B as compared to group A. No correlation was found between TGF-beta1 plasma concentrations and lymphocyte proliferation. Multiple linear regression analysis revealed that patient characteristics influence TGF-beta1 and ET-1 expression. In conclusion, plasma levels of profibrotic cytokines do not reflect the existing profibrotic potential of immunosuppressive drugs. Demographic factors and the employed co-medication confound the results.

Hybrid-primed Lymphocytes and Hybrid Vaccination Prevent Tumor Growth of Lewis Lung Carcinoma in Mice

Journal of Immunotherapy (Hagerstown, Md. : 1997). Mar-Apr, 2006  |  Pubmed ID: 16531818

Dendritic cell (DC)-tumor cell hybrids are currently being evaluated as a novel antitumor vaccination strategy. We have explored in an animal model whether administration of DCs fused with poorly immunogenic carcinoma cells could elicit an antitumor response. Fusion of C57/BL6 mice bone marrow-derived DCs with Lewis lung carcinoma (LLC1) cells resulted in approximately 50% fusion efficiency. Hybrid cells (HCs) were used to explore 3 potential tumor therapy strategies: protective immunization, vaccination, and adoptive cellular therapy. Immunization with HCs induced activation of proliferating cytotoxic T cells, upregulation of distinct cytokines genes, and a significant retardation of tumor growth. Similar results were observed by vaccination with HCs in the tumor-bearing host. Finally, when T cells from HC-vaccinated mice were transferred into naive tumor-bearing mice, tumor growth was strongly retarded and an efficient proliferative and cytotoxic T-cell response was observed. Tumor growth was reduced by more than 50%, and tumor development was significantly delayed. Taken together, we demonstrate that HCs offer effective immunotherapy of poorly immunogenic carcinomas. This is independent of whether the HCs are taken for adoptive transfer or as a vaccine.

Cardiomyocyte-specific Deletion of the Coxsackievirus and Adenovirus Receptor Results in Hyperplasia of the Embryonic Left Ventricle and Abnormalities of Sinuatrial Valves

Circulation Research. Apr, 2006  |  Pubmed ID: 16543498

The coxsackievirus and adenovirus receptor (CAR), which mediates infection by the viruses most commonly associated with myocarditis, is a transmembrane component of specialized intercellular junctions, including the myocardial intercalated disc; it is known to mediate cell-cell recognition, but its natural function is poorly understood. We used conditional gene targeting to investigate the possible functions of CAR during embryonic development, generating mice with both germline and tissue-specific defects in CAR expression. Homozygous germline deletion of CAR exon 2 or cardiomyocyte-specific gene deletion at embryonic day 10 (E10) mediated by Cre recombinase expressed under the control of the cardiac troponin T promoter resulted in death by E12.5; embryos showed marked cardiac abnormalities by E10.5, with hyperplasia of the left ventricular myocardium, distention of the cardinal veins, and abnormalities of sinuatrial valves. Within the hyperplastic left ventricle, increased numbers of proliferating cells were evident; persistent expression of N-myc in the hyperplastic myocardium and attenuated expression of the trabecular markers atrial natriuretic factor and bone morphogenic protein 10 indicated that proliferating cardiomyocytes had failed to differentiate and form normal trabeculae. In electron micrographs, individual CAR-deficient cardiomyocytes within the left ventricle appeared normal, but intercellular junctions were ill-formed or absent, consistent with the known function of CAR as a junctional molecule; myofibrils were also poorly organized. When cardiomyocyte-specific deletion occurred somewhat later (by E11, mediated by Cre under control of the alpha-myosin heavy chain promoter), animals survived to adulthood and did not have evident cardiac abnormalities. These results indicate that during a specific temporal window, CAR expression on cardiomyocytes is essential for normal cardiac development. In addition, the results suggest that CAR-mediated intercellular contacts may regulate proliferation and differentiation of cardiomyocytes within the embryonic left ventricular wall.

Cytogenetic Analysis of Human Oocytes Remaining Unfertilized After Intracytoplasmic Sperm Injection

Fertility and Sterility. Feb, 2006  |  Pubmed ID: 16595204

Oocytes remaining unfertilized after intracytoplasmic sperm injection showed 12.0% aneuploidy (nondisjunction + unbalanced predivision), 3.4% structural aberrations, and 8.5% balanced predivision in fully karyotyped cells. However, the frequently observed complete or partial separation of chromatids, most probably caused by abortive activation, might complicate the evaluation of meiosis I-derived aneuploidy and questions the relevance of balanced predivision.

Serological Detection of Human Papillomavirus Type 16 Infection in Human Immunodeficiency Virus (HIV)-positive and High-risk HIV-negative Women

Clinical and Vaccine Immunology : CVI. Apr, 2006  |  Pubmed ID: 16603621

Serial measurement of antibodies has not been used to provide evidence of active viral replication of human papillomavirus (HPV). Serum specimens from sequential study visits contributed by 642 human immunodeficiency virus (HIV)-positive and 116 HIV-negative participants enrolled in the Women's Interagency HIV Study were used to detect significant rises in HPV type 16 (HPV-16) antibody levels. Factors associated with a significant rise were identified using multivariable logistic regression models with generalized estimating equations. Among HIV-positive women, 8.3% of 1,997 pairs showed antibody rises, compared to 6.1% of 361 pairs among HIV-negative women (P = 0.191). For HIV-positive women, rises were associated with current (odds ratio [OR], 23.4; P < 0.001) or past (OR, 8.9; P < 0.001) HPV-16 infection relative to never being HPV-16 infected and with CD4+ cell counts (OR per 100-cell increase, 0.8; P < 0.001) but not with sexual behavior. For HIV-negative women, rises were associated with past (OR, 10.9; P = 0.033) HPV-16 infection relative to no HPV-16, current cigarette smoking (OR, 5.0; P = 0.029) relative to no smoking history, and having 6 to 10 lifetime sexual partners compared to 0 to 5 partners (OR, 9.9; P = 0.036). Serial measurement of HPV-16 serum antibodies is a useful tool for identifying active HPV-16 viral replication. Rises among HIV-positive women may more often result from reactivation of a latent HPV infection in the context of HIV-induced immunosuppression, while rises among HIV-negative women may more often result from reinfection with HPV.

Association of Cigarette Smoking with HIV Prognosis Among Women in the HAART Era: a Report from the Women's Interagency HIV Study

American Journal of Public Health. Jun, 2006  |  Pubmed ID: 16670229

We assessed the association of cigarette smoking with the effectiveness of highly active antiretroviral therapy (HAART) among low-income women.

Targeted Deletion of ROCK1 Protects the Heart Against Pressure Overload by Inhibiting Reactive Fibrosis

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. May, 2006  |  Pubmed ID: 16675849

Ventricular myocyte hypertrophy is an important compensatory growth response to pressure overload. However, pathophysiological cardiac hypertrophy is accompanied by reactive fibrosis and remodeling. The Rho kinase family, consisting of ROCK1 and ROCK2, has been implicated in cardiac hypertrophy and ventricular remodeling. However, these previous studies relied heavily on pharmacological inhibitors,and not on gene deletion. Here we used ROCK1knockout (ROCK1-/-) mice to investigate role of ROCK1 in the development of ventricular remodeling induced by transverse aortic banding. We observed that ROCK1 deletion did not impair compensatory hypertrophic response induced by pressure overload. However, ROCK1-/- mice exhibited reduced perivascular and interstitial fibrosis, which was observed at 3 wk but not at 1 wk after the banding. The reduced fibrosis in the myocardium of ROCK1-/- mice was closely associated with reduced expression of a variety of extracellular matrix (ECM) proteins and fibrogenic cytokines such as TGFbeta2 and connective tissue growth factor. This inhibitory effect of ROCK1 deletion on pathophysiological induction of fibrogenic cytokines was further confirmed in the myocardium of transgenic mice with cardiomyocyte-specific overexpression of Gq. Thus, these results indicate that ROCK1 contributes to the development of cardiac fibrosis and induction of fibrogenic cytokines in cardiomyocytes in response to pathological stimuli.

CAMTA in Cardiac Hypertrophy

Cell. May, 2006  |  Pubmed ID: 16678087

In this issue of Cell, the Calmodulin binding transcription activator 2 (CAMTA2), is shown by Song et al. (2006) to be an indispensable transcription coactivator for cardiac hypertrophy. CAMTA2 is activated by the dissociation of class II histone deacetylase 5 and promotes transcription of genes involved in cardiac hypertrophy through its interaction with Nkx2-5.

The Association of Serum Ferritin and Transferrin Receptor Concentrations with Mortality in Women with Human Immunodeficiency Virus Infection

Haematologica. Jun, 2006  |  Pubmed ID: 16704960

Whether degree of iron stores influences progression of human immunodeficiency virus (HIV) disease is controversial. We studied the relationship of indirect measures of iron stores with mortality in highly active antiretroviral therapy (HAART)-naive participants from the Women's Interagency HIV Study.

The Kinase TAK1 Integrates Antigen and Cytokine Receptor Signaling for T Cell Development, Survival and Function

Nature Immunology. Aug, 2006  |  Pubmed ID: 16799562

The kinase TAK1 is critical for innate and B cell immunity. The function of TAK1 in T cells is unclear, however. We show here that T cell-specific deletion of the gene encoding TAK1 resulted in reduced development of thymocytes, especially of regulatory T cells expressing the transcription factor Foxp3. In mature thymocytes, TAK1 was required for interleukin 7-mediated survival and T cell receptor-dependent activation of transcription factor NF-kappaB and the kinase Jnk. In effector T cells, TAK1 was dispensable for T cell receptor-dependent NF-kappaB activation and cytokine production, but was important for proliferation and activation of the kinase p38 in response to interleukins 2, 7 and 15. Thus, TAK1 is essential for the integration of T cell receptor and cytokine signals to regulate the development, survival and function of T cells.

Suppression of Canonical Wnt/beta-catenin Signaling by Nuclear Plakoglobin Recapitulates Phenotype of Arrhythmogenic Right Ventricular Cardiomyopathy

The Journal of Clinical Investigation. Jul, 2006  |  Pubmed ID: 16823493

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is a genetic disease caused by mutations in desmosomal proteins. The phenotypic hallmark of ARVC is fibroadipocytic replacement of cardiac myocytes, which is a unique phenotype with a yet-to-be-defined molecular mechanism. We established atrial myocyte cell lines expressing siRNA against desmoplakin (DP), responsible for human ARVC. We show suppression of DP expression leads to nuclear localization of the desmosomal protein plakoglobin and a 2-fold reduction in canonical Wnt/beta-catenin signaling through Tcf/Lef1 transcription factors. The ensuing phenotype is increased expression of adipogenic and fibrogenic genes and accumulation of fat droplets. We further show that cardiac-restricted deletion of Dsp, encoding DP, impairs cardiac morphogenesis and leads to high embryonic lethality in the homozygous state. Heterozygous DP-deficient mice exhibited excess adipocytes and fibrosis in the myocardium, increased myocyte apoptosis, cardiac dysfunction, and ventricular arrhythmias, thus recapitulating the phenotype of human ARVC. We believe our results provide for a novel molecular mechanism for the pathogenesis of ARVC and establish cardiac-restricted DP-deficient mice as a model for human ARVC. These findings could provide for the opportunity to identify new diagnostic markers and therapeutic targets in patients with ARVC.

MEF2 Activates a Genetic Program Promoting Chamber Dilation and Contractile Dysfunction in Calcineurin-induced Heart Failure

Circulation. Jul, 2006  |  Pubmed ID: 16847152

Hypertrophic growth, a risk factor for mortality in heart disease, is driven by reprogramming of cardiac gene expression. Although the transcription factor myocyte enhancer factor-2 (MEF2) is a common end point for several hypertrophic pathways, its precise cardiac gene targets and function in cardiac remodeling remain to be elucidated.

Essential Role of TAK1 in Thymocyte Development and Activation

Proceedings of the National Academy of Sciences of the United States of America. Aug, 2006  |  Pubmed ID: 16857737

The protein kinase TAK1 mediates the activation of NF-kappaB in response to stimulation by proinflammatory cytokines and microbial pathogens in the innate immunity pathways. However, the physiological function of TAK1 in the adaptive immunity pathways is unclear. By engineering mice lacking TAK1 in T cells, here, we show that TAK1 is essential for thymocyte development and activation in vivo. Deletion of TAK1 prevented the maturation of single-positive thymocytes displaying CD4 or CD8, leading to reduction of T cells in the peripheral tissues. Thymocytes lacking TAK1 failed to activate NF-kappaB and JNK and were prone to apoptosis upon stimulation. Our results provide the genetic evidence that TAK1 is required for the activation of NF-kappaB in thymocytes and suggest that TAK1 plays a central role in both innate and adaptive immunity.

Photodissociation of Thymine

Physical Chemistry Chemical Physics : PCCP. Jul, 2006  |  Pubmed ID: 16880915

We discuss the photochemistry and photodissociation dynamics of thymine as revealed by two-colour photofragment Doppler spectroscopy and by one-colour slice imaging. Thymine is optically excited into the pipi* state, known to deactivate quickly. The H atom photofragment spectra are dominated by two-photon excitation processes with subsequent statistical dissociation. This can be explained by absorption of a second photon from a long-lived dark state to a highly excited state that quickly deactivates to the electronic ground state. No evidence was found for an important role of the pisigma* excited state identified in adenine and many other heterocyclic molecules.

Generation of a Conditional Null Allele of Jumonji

Genesis (New York, N.Y. : 2000). Sep, 2006  |  Pubmed ID: 16900512

The jumonji (jmj) gene plays important roles in multiple organ development in mouse, including cardiovascular development. Since JMJ is expressed widely during mouse development, it is essential that conditional knockout approaches be employed to ablate JMJ in a tissue-specific manner to identify the cell lineage specific roles of JMJ. In this report, we describe the establishment of a jmj conditional null allele in mice by generating a loxP-flanked (floxed) jmj allele, which allows the in vivo ablation of jmj via Cre recombinase-mediated deletion. Gene targeting was used to introduce loxP sites flanking exon 3 of the jmj allele to mouse embryonic stem cells. Our results indicate that the jmj floxed allele converts to a null allele in a heart-specific manner when embryos homozygous for the floxed jmj allele and carrying the alpha-myosin heavy chain promoter-Cre transgene were analyzed by Southern and Northern blot analyses. Therefore, this mouse line harboring the conditional jmj null allele will provide a valuable tool for deciphering the tissue and cell lineage specific roles of JMJ.

Commentary: Differential Diagnosis of Fibromyalgia Syndrome: Proposal of a Model and Algorithm for Patients Presenting with the Primary Symptom of Chronic Widespread Pain

Journal of Manipulative and Physiological Therapeutics. Jul-Aug, 2006  |  Pubmed ID: 16904498

Cardiomyocyte-restricted Deletion of Connexin43 During Mouse Development

Journal of Molecular and Cellular Cardiology. Dec, 2006  |  Pubmed ID: 16963078

Although the gap junction protein Connexin43 (Cx43) is expressed in various cell types during embryonic development, mice with a global inactivation of Cx43 survive until birth but die perinatally due to an obstruction of the right ventricular outflow tract of the heart. To analyze the functional role of Cx43 gap junction channels in cardiomyocytes of the developing and early postnatal heart, we used alphaMyHC-Cre mice to ablate Cx43 expression selectively in cardiomyocytes during development. We found efficient ablation of Cx43 in cardiomyocytes during embryonic development starting at embryonic day (ED) 9.5 in the ventricular wall. Analyses of cardiac Cx43 protein at birth indicated complete loss of Cx43 expression in cardiomyocytes. All mice homozygously deficient for Cx43 in cardiomyocytes died until postnatal day (PD) 16. Heterozygous inactivation of Cx43 in cardiomyocytes neither altered atrial nor ventricular activation, but homozygous ablation led to changes in ventricular activation, i.e. significant decrease of the QRS-amplitude and prolonged QRS-duration already at PD 4. Cardiac morphology was similar to controls until PD 1, but subtle morphological changes were found in a subgroup of mutant mice at later stages. Besides narrowing of the ventricular outlet region at PD 6, hypertrophy of ventricular myocardium was found at PD 12. Our data indicate that complete inactivation of cardiac Cx43 during development predisposes hearts to develop postnatal morphological alterations, which differ from outflow tract obstructions described for Cx43 null mice. In addition, complete loss of cardiac Cx43 protein during development correlates with slowed ventricular activation at PD 4, impairs viability during development, and leads to death of all mutant mice until PD 16.

Activation of Rho-associated Coiled-coil Protein Kinase 1 (ROCK-1) by Caspase-3 Cleavage Plays an Essential Role in Cardiac Myocyte Apoptosis

Proceedings of the National Academy of Sciences of the United States of America. Sep, 2006  |  Pubmed ID: 16983089

Rho-associated coiled-coil protein kinase 1 (ROCK-1) is a direct cleavage substrate of activated caspase-3, which is associated with heart failure. In the course of human heart failure, we found marked cleavage of ROCK-1 resulting in a 130-kDa subspecies, which was absent in normal hearts and in an equivalent cohort of patients with left ventricular assist devices. Murine cardiomyocytes treated with doxorubicin led to enhanced ROCK-1 cleavage and apoptosis, all of which was blocked by a caspase-3 inhibitor. In addition, a bitransgenic mouse model of severe cardiomyopathy, which overexpresses Gq protein and hematopoietic progenitor kinase-/germinal center kinase-like kinase, revealed the robust accumulation of the 130-kDa ROCK-1 cleaved fragment. This constitutively active ROCK-1 subspecies, when expressed in cardiomyocytes, led to caspase-3 activation, indicating a positive feed-forward regulatory loop. ROCK-1-dependent caspase-3 activation was coupled with the activation of PTEN and the subsequent inhibition of protein kinase B (Akt) activity, all of which was attenuated by siRNA directed against ROCK-1 expression. Similarly, ROCK-1-null mice (Rock-1(-/-)) showed a marked reduction in myocyte apoptosis associated with pressure overload. These data suggest an obligatory role for ROCK-1 cleavage in promoting apoptotic signals in myocardial hypertrophy and/or failure.

Dual Roles of Telomerase in Cardiac Protection and Repair

Novartis Foundation Symposium. 2006  |  Pubmed ID: 17019817

Together, the limited capacity for regenerative growth in cardiac muscle after injury and the prevalence of ongoing sporadic cell death due to apoptosis in chronic heart failure states pose one of the paramount challenges in heart failure therapeutics. In adults, the unique self-renewal potential of progenitor/stem cells is associated with telomerase reverse transcriptase (TERT), an RNA-dependent DNA polymerase that maintains the lariat-like loop capping chromosome ends. We have identified telomere uncapping, mediated by down-regulation of telomere repeat-binding factor 2 (TRF2) as a novel trigger of cell death in human dilated cardiomyopathy. Conversely, we identified a residual TERT+ population in adult myocardium, as a potential source of cardiac progenitor cells. Residual TERT expression was localized to cells expressing stem cell antigen 1 (Sca1). Cardiac-resident Sca1+ cells lack haematopoietic stem cell markers and transcripts for cardiac structural genes, yet express many cardiogenic transcription factors. If given intravenously to mice just after ischemia-reperfusion injury, cardiac Sca1+ cells home selectively to injured myocardium and differentiate spontaneously in situ.

Genotypic Resistance and Immunologic Outcomes Among HIV-1-infected Women with Viral Failure

Journal of Acquired Immune Deficiency Syndromes (1999). Jan, 2006  |  Pubmed ID: 16340476

To describe the prevalence of specific protease inhibitor (PI) and nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations and the relationship between the presence of these mutations and immunologic outcomes following PI/NNRTI initiation among a cohort of HIV-1-infected women.

A Pivotal Role for Endogenous TGF-beta-activated Kinase-1 in the LKB1/AMP-activated Protein Kinase Energy-sensor Pathway

Proceedings of the National Academy of Sciences of the United States of America. Nov, 2006  |  Pubmed ID: 17085580

TGF-beta-activated kinase-1 (TAK1), also known as MAPKK kinase-7 (MAP3K7), is a candidate effector of multiple circuits in cardiac biology and disease. Here, we show that inhibition of TAK1 in mice by a cardiac-specific dominant-negative mutation evokes electrophysiological and biochemical properties reminiscent of human Wolff-Parkinson-White syndrome, arising from mutations in AMP-activated protein kinase (AMPK), most notably, accelerated atrioventricular conduction and impaired AMPK activation. To test conclusively the biochemical connection from TAK1 to AMPK suggested by this phenotype, we disrupted TAK1 in mouse embryos and embryonic fibroblasts by Cre-mediated recombination. In TAK1-null embryos, the activating phosphorylation of AMPK at T172 was blocked, accompanied by defective AMPK activity. However, loss of endogenous TAK1 causes midgestation lethality, with defective yolk sac and intraembryonic vasculature. To preclude confounding lethal defects, we acutely ablated floxed TAK1 in culture by viral delivery of Cre. In culture, endogenous TAK1 was activated by oligomycin, the antidiabetic drug metformin, 5-aminoimidazole-4-carboxamide riboside (AICAR), and ischemia, well established triggers of AMPK activity. Loss of TAK1 in culture blocked T172 phosphorylation induced by all three agents, interfered with AMPK activation, impaired phosphorylation of the endogenous AMPK substrate acetyl CoA carboxylase, and also interfered with activation of the AMPK kinase LKB1. Thus, by disrupting the endogenous TAK1 locus, we prove a pivotal role for TAK1 in the LKB1/AMPK signaling axis, an essential governor of cell metabolism.

Relation of Stavudine Discontinuation to Anthropometric Changes Among HIV-infected Women

Journal of Acquired Immune Deficiency Syndromes (1999). Jan, 2007  |  Pubmed ID: 17091021

To characterize changes in regional anthropometry associated with stavudine exposure and discontinuation.

Use of Palpable Tendons for Extramedullary Tibial Alignment in Total Knee Arthroplasty

The Journal of Arthroplasty. Feb, 2007  |  Pubmed ID: 17275637

For extramedullary tibial alignment in total knee arthroplasty, it is important to localize the center of the ankle mortise. Malpositioning of alignment jigs can produce varus or valgus implantation and can lead to inferior clinical and radiologic outcomes. In a cadaver study, we investigated the accuracy of palpable tendons as references for extramedullary tibial alignment in 86 anatomical specimens. To investigate tendon movement with pronation and supination in living patients, we additionally performed 10 magnetic resonance imaging scans. On average, the lateral border of the tibialis anterior tendon was measured 1 cm medial to the center of the talus. The extensor hallucis longus tendon was the most accurate anatomical landmark. Pronation had a small effect, but extensive supination can lead to tendon deviation greater than 1 cm. Our results suggest that the extensor hallucis longus can serve as a useful intraoperative reference to identify the center of the ankle mortise, particularly if marked preoperatively.

Ménage-à-trois 1 is Critical for the Transcriptional Function of PPARgamma Coactivator 1

Cell Metabolism. Feb, 2007  |  Pubmed ID: 17276355

The Cdk7/cyclin H/ménage-à-trois 1 (MAT1) heterotrimer has proposed functions in transcription as the kinase component of basal transcription factor TFIIH and is activated in adult hearts by Gq-, calcineurin-, and biomechanical stress-dependent pathways for hypertrophic growth. Using cardiac-specific Cre, we have ablated MAT1 in myocardium. Despite reduced Cdk7 activity, MAT1-deficient hearts grew normally, but fatal heart failure ensued at 6-8 weeks. By microarray profiling, quantitative RT-PCR, and western blotting at 4 weeks, genes for energy metabolism were found to be suppressed selectively, including targets of peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1). Cardiac metabolic defects were substantiated in isolated perfused hearts and isolated mitochondria. In culture, deleting MAT1 with Cre disrupted PGC-1 function: PGC-1alpha failed to activate PGC-1-responsive promoters and nuclear receptors, GAL4-PGC-1alpha was functionally defective, and PGC-1beta was likewise deficient. PGC-1 bound to both MAT1 and Cdk7 in coprecipitation assays. Thus, we demonstrate a requirement for MAT1 in the operation of PGC-1 coactivators that control cell metabolism.

A Cathepsin D-cleaved 16 KDa Form of Prolactin Mediates Postpartum Cardiomyopathy

Cell. Feb, 2007  |  Pubmed ID: 17289576

Postpartum cardiomyopathy (PPCM) is a disease of unknown etiology and exposes women to high risk of mortality after delivery. Here, we show that female mice with a cardiomyocyte-specific deletion of stat3 develop PPCM. In these mice, cardiac cathepsin D (CD) expression and activity is enhanced and associated with the generation of a cleaved antiangiogenic and proapoptotic 16 kDa form of the nursing hormone prolactin. Treatment with bromocriptine, an inhibitor of prolactin secretion, prevents the development of PPCM, whereas forced myocardial generation of 16 kDa prolactin impairs the cardiac capillary network and function, thereby recapitulating the cardiac phenotype of PPCM. Myocardial STAT3 protein levels are reduced and serum levels of activated CD and 16 kDa prolactin are elevated in PPCM patients. Thus, a biologically active derivative of the pregnancy hormone prolactin mediates PPCM, implying that inhibition of prolactin release may represent a novel therapeutic strategy for PPCM.

Cardiomyocyte-specific Inactivation of Transcription Factor CREB in Mice

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. Jun, 2007  |  Pubmed ID: 17307839

The transcription factor cAMP response element (CRE)-binding protein (CREB, Creb1) plays a critical role in regulating gene expression in response to activation of the cAMP-dependent signaling pathway, which is implicated in the pathophysiology of heart failure. Using the Cre-loxP system, we generated mice with a cardiomyocyte-specific inactivation of CREB and studied in this model whether CREB is critical for cardiac function. CREB-deficient mice were viable and displayed neither changes in cardiac morphology nor alterations of basal or isoproterenol-stimulated left ventricular function in vivo or of important cardiac regulatory proteins. Since CREB was proposed as a negative regulator of cardiomyocyte apoptosis by enhancing the expression of the antiapoptotic protein Bcl-2, we analyzed the fragmentation of DNA, the activity of caspases 3/7 and the expression of Bcl-2 and did not observe any differences between CREB-deficient and CREB-normal hearts. Our results suggest that the presence of CREB is not critical for normal cardiac function in mice.

Parametric Survival Analysis and Taxonomy of Hazard Functions for the Generalized Gamma Distribution

Statistics in Medicine. Oct, 2007  |  Pubmed ID: 17342754

The widely used Cox proportional hazards regression model for the analysis of censored survival data has limited utility when either hazard functions themselves are of primary interest, or when relative times instead of relative hazards are the relevant measures of association. Parametric regression models are an attractive option in situations such as this, although the choice of a particular model from the available families of distributions can be problematic. The generalized gamma (GG) distribution is an extensive family that contains nearly all of the most commonly used distributions, including the exponential, Weibull, log normal and gamma. More importantly, the GG family includes all four of the most common types of hazard function: monotonically increasing and decreasing, as well as bathtub and arc-shaped hazards. We present here a taxonomy of the hazard functions of the GG family, which includes various special distributions and allows depiction of effects of exposures on hazard functions. We applied the proposed taxonomy to study survival after a diagnosis of clinical AIDS during different eras of HIV therapy, where proportionality of hazard functions was clearly not fulfilled and flexibility in estimating hazards with very different shapes was needed. Comparisons of survival after AIDS in different eras of therapy are presented in terms of both relative times and relative hazards. Standard errors for these and other derived quantities are computed using the delta method and checked using the bootstrap. Description of standard statistical software (Stata, SAS and S-Plus) for the computations is included and available at http://statepi.jhsph.edu/software.

Quantifying Morbidity Associated with the Abuse and Misuse of Opioid Analgesics: a Comparison of Two Approaches

Clinical Toxicology (Philadelphia, Pa.). 2007  |  Pubmed ID: 17357378

Due to the rising nonmedical use of opioid analgesics, methods are needed to quantify the associated health-related consequences.

Sox17 is Essential for the Specification of Cardiac Mesoderm in Embryonic Stem Cells

Proceedings of the National Academy of Sciences of the United States of America. Mar, 2007  |  Pubmed ID: 17360443

Early steps for cardiac specification are problematic for the study of mammalian embryos, which has favored using pluripotent cells that recapitulate cardiac myogenesis. Furthermore, circuits governing cardiac specification have relevance to the application of ES cells and other cells for heart repair. In mouse teratocarcinoma cells, canonical Wnts that inhibit heart formation in avian or amphibian embryos and explants activate cardiogenesis, paradoxically. Here, we show that the Wnt/beta-catenin pathway also is essential for cardiac myogenesis to occur in ES cells, acting at a gastrulation-like stage, mediating mesoderm formation and patterning (two prerequisites for cardiac myogenesis itself). Among genes associated temporally with this step was Sox17, encoding an endodermal HMG-box transcription factor. Using lentiviral vectors for RNA interference in differentiating ES cells, an essential role for Sox17 was proven in cardiac muscle cell formation. Sox17 short-hairpin RNA suppresses cardiac myogenesis selectively, acting subsequent to mesoderm formation yet before induction of Mesp1 and Mesp2, a pair of related basic helix-loop-helix transcription factors that together are indispensable for creating heart mesoderm. Sox17 short-hairpin RNA blocks cardiac myogenesis non-cell autonomously and impairs the induction of Hex, a homeodomain transcription factor that is known to be required for the production of endoderm-derived heart-inducing factors.

Electrophysiological Differences of the Spontaneous Onset of Paroxysmal and Persistent Atrial Fibrillation

Pacing and Clinical Electrophysiology : PACE. Mar, 2007  |  Pubmed ID: 17367348

Information about the spatiotemporal organization of atrial activity at the onset of atrial fibrillation (AF) is still limited.

Positron Emission Tomography Imaging of Conditional Gene Activation in the Heart

Journal of Molecular and Cellular Cardiology. Jul, 2007  |  Pubmed ID: 17467733

The Cre-loxP system has been routinely used for conditional activation and deletion of gene expression. However, the spatiotemporal manner of these events in the heart has not yet been defined by in vivo imaging. Adenovirus (1 x 10(9 )pfu) carrying the silent positron emission tomography (PET) reporter gene, herpes simplex virus type 1 thymidine kinase (HSV1-tk), was injected into the left ventricular wall of male transgenic mice (n=15) or FVB controls (n=8). Transgenic mice expressed Cre recombinase driven by a cardiac-specific alpha-myosin heavy chain (alpha-MHC) promoter. Following injection of the 9-[4-fluoro-3-(hydroxymethyl)butyl]guanine ([18F]-FHBG; 137+/-25 microCi) reporter probe, microPET imaging was used to assess the expression of HSV1-tk reporter gene in the myocardium. Two days following adenoviral injection, cardiac HSV1-tk gene activation resulted in tracer uptake of 3.20+/-0.51% ID/g for alpha-MHC-Cre and 0.05+/-0.02%ID/g for control mice (P<0.01). The in vivo results were confirmed by RT-PCR and Western blot analysis. Similar transfections were evaluated in both cardiac-specific and non-cardiac-specific cell lines. Enzyme activity showed a robust correlation (r2=0.82) between in vivo molecular imaging technique and traditional in vitro enzyme assays. With further development and validation, PET imaging will likely play an important role in the noninvasive, repetitive, and quantitative measurement of conditional gene activation in the future.

Tetrodotoxin and Its Analogue 6-epitetrodotoxin in Newts (Triturus Spp.; Urodela, Salamandridae) from Southern Germany

Toxicon : Official Journal of the International Society on Toxinology. Aug, 2007  |  Pubmed ID: 17507070

Tetrodotoxin (TTX) and its analogue 6-epitetrodotoxin (6-epiTTX) were quantitatively assayed in 59 newts representing four Triturus species (Triturus alpestris, Triturus cristatus, Triturus helveticus, Triturus vulgaris) from southern Germany by a post-column fluorescent-HPLC system. Both toxins were detected in only 15 specimens of the four species. The toxins levels varied considerably among individuals (TTX: 0.11-9.0microg/g; 6-epiTTX: 0.05-17.0microg/g). 6-epiTTX was found to be the major component.

A Combination Hybrid-based Vaccination/adoptive Cellular Therapy to Prevent Tumor Growth by Involvement of T Cells

Cancer Research. Jun, 2007  |  Pubmed ID: 17545626

Cancer immunotherapy with dendritic cell-tumor cell fusion hybrids induces polyclonal stimulation against a variety of tumor antigens, including unknown antigens. Hybrid cells can prime CTLs, which subsequently develop antitumor responses. The aim of this study was to enhance the known antitumor effect of hybrid vaccination (HC-Vacc) and hybrid-primed adoptive T-cell therapy (HC-ACT) using the poorly immunogenic Lewis lung carcinoma (LLC1) model. The strategy used was a combination of a double HC-Vacc alternating with HC-ACT (HC-Vacc/ACT). Using flat-panel volumetric computer tomography and immunohistochemistry, we showed a significant retardation of tumor growth (85%). In addition, a significant delay in tumor development, a reduction in the number of pulmonary metastases, and increased survival times were observed. Furthermore, the tumors displayed significant morphologic changes and increased apoptosis, as shown by up-regulation of gene expression of the proapoptotic markers Fas, caspase-8, and caspase-3. The residual tumor masses seen in the HC-Vacc/ACT-treated mice were infiltrated with CD4+ and CD8+ lymphocytes and showed elevated IFNgamma expression. Moreover, splenic enlargement observed in HC-Vacc/ACT-treated mice reflected the increased functionality of T cells, as also indicated by increased expression of markers for CTL activation, differentiation, and proliferation (Cd28, Icosl, Tnfrsf13, and Tnfsf14). Our findings indicate that the combination therapy of dendritic cell-tumor cell HC-Vacc/ACT is a very effective and a promising immunotherapeutic regimen against poorly immunogenic carcinomas.

Advanced Placement. Move Your Web Site from a Line Item to an Organizational Priority

Marketing Health Services. 2007  |  Pubmed ID: 17619514

Cardiac-specific Haploinsufficiency of Beta-catenin Attenuates Cardiac Hypertrophy but Enhances Fetal Gene Expression in Response to Aortic Constriction

Journal of Molecular and Cellular Cardiology. Sep, 2007  |  Pubmed ID: 17673255

In addition to its role in cell adhesion, beta-catenin is an important signaling molecule in the Wnt/Wingless signaling pathway. Recent studies have indicated that beta-catenin is stabilized by hypertrophic stimuli and may regulate cardiac hypertrophic responses. To explore the role and requirement of beta-catenin in cardiac development and hypertrophy, we deleted the beta-catenin gene specifically in cardiac myocytes by crossing loxP-floxed beta-catenin mice with transgenic mice expressing a Cre recombinase under the control of the alpha-myosin heavy chain promoter. No homozygous beta-catenin-deleted mice were born alive and died before embryonic day 14.5, indicating significant and irreplaceable roles of beta-catenin in embryonic heart development. Heterozygous beta-catenin-deleted mice, however, demonstrated no structural and functional abnormality. The response of heterozygous beta-catenin-deleted mice to transverse aortic constriction, however, was significantly attenuated with decreased heart weight and heart weight/body weight ratio compared to controls with intact beta-catenin genes. Hemodynamic analysis revealed that there was no difference in cardiac function between wild-type and heterozygous beta-catenin-deleted mice. On the other hand, the expression of fetal genes, beta-myosin heavy chain, atrial and brain natriuretic peptides was significantly higher in heterozygous beta-catenin-deleted mice when compared to wild-type beta-catenin mice. These results suggest that the cytoplasmic level of beta-catenin modulates hypertrophic response and fetal gene reprogramming after pressure overload.

Direct Detection of Nonlinear Ferromagnetic Resonance in Thin Films by the Magneto-optical Kerr Effect

Physical Review Letters. May, 2007  |  Pubmed ID: 17677740

The longitudinal magneto-optical Kerr effect is used to obtain a calibrated measure of the dynamic magnetization response over the ferromagnetic resonance (FMR) profile for in-plane magnetized Permalloy films excited with high power in-plane transverse microwave fields at 1.25 to 3.75 GHz and in-plane precession angles up to about 20 degrees. The data provide a profound demonstration of the Suhl threshold effect for parametric spin wave generation for angles above about 14 degrees, the magnetization precession lock-up just above threshold, and the complicated response over the full FMR profile at very high powers.

Cardiac Peroxisome Proliferator-activated Receptor Gamma is Essential in Protecting Cardiomyocytes from Oxidative Damage

Cardiovascular Research. Nov, 2007  |  Pubmed ID: 17678635

Peroxisome proliferator-activated receptors (PPAR) alpha and beta/delta are essential transcriptional regulators of fatty acid oxidation in the heart. However, little is known about the roles of PPARgamma in the heart. The present study is to investigate in vivo role(s) of PPARgamma in the heart.

Antiretroviral Therapy Exposure and Incidence of Diabetes Mellitus in the Women's Interagency HIV Study

AIDS (London, England). Aug, 2007  |  Pubmed ID: 17690572

To determine the incidence of diabetes mellitus (DM) in a nationally representative cohort of HIV-infected women and a comparison group of HIV-uninfected women.

TNF Provokes Cardiomyocyte Apoptosis and Cardiac Remodeling Through Activation of Multiple Cell Death Pathways

The Journal of Clinical Investigation. Sep, 2007  |  Pubmed ID: 17694177

Transgenic mice with cardiac-restricted overexpression of secretable TNF (MHCsTNF) develop progressive LV wall thinning and dilation accompanied by an increase in cardiomyocyte apoptosis and a progressive loss of cytoprotective Bcl-2. To test whether cardiac-restricted overexpression of Bcl-2 would prevent adverse cardiac remodeling, we crossed MHCsTNF mice with transgenic mice harboring cardiac-restricted overexpression of Bcl-2. Sustained TNF signaling resulted in activation of the intrinsic cell death pathway, leading to increased cytosolic levels of cytochrome c, Smac/Diablo and Omi/HtrA2, and activation of caspases -3 and -9. Cardiac-restricted overexpression of Bcl-2 blunted activation of the intrinsic pathway and prevented LV wall thinning; however, Bcl-2 only partially attenuated cardiomyocyte apoptosis. Subsequent studies showed that c-FLIP was degraded, that caspase-8 was activated, and that Bid was cleaved to t-Bid, suggesting that the extrinsic pathway was activated concurrently in MHCsTNF hearts. As expected, cardiac Bcl-2 overexpression had no effect on extrinsic signaling. Thus, our results suggest that sustained inflammation leads to activation of multiple cell death pathways that contribute to progressive cardiomyocyte apoptosis; hence the extent of such programmed myocyte cell death is a critical determinant of adverse cardiac remodeling.

Investigation of the Expansion Properties of Osmotic Expanders with and Without Silicone Shell in Animals

Plastic and Reconstructive Surgery. Sep, 2007  |  Pubmed ID: 17700108

Particularly in clinical studies, it has been found that rapid swelling of tissue expanders leads to high-pressure peaks that can cause hypoxia in the tissue and thus also skin damage. For this reason, the present study in animals investigated whether an osmotic expander with silicone shell is capable of expanding in tissue and bringing about useful tissue expansion without complications. It was also examined whether and what quantitative and qualitative differences there are between conventional osmotic expanders and the new expanders with silicone shell.

Interexaminer Reliability of the Prone Leg Length Analysis Procedure

Journal of Manipulative and Physiological Therapeutics. Sep, 2007  |  Pubmed ID: 17870420

The purpose of this study was to perform an interexaminer reliability evaluation of the prone leg length analysis procedure.

Abnormal Conduction and Morphology in the Atrioventricular Node of Mice with Atrioventricular Canal Targeted Deletion of Alk3/Bmpr1a Receptor

Circulation. Nov, 2007  |  Pubmed ID: 17998461

The atrioventricular (AV) node is essential for the sequential excitation and optimized contraction of the adult multichambered heart; however, relatively little is known about its formation from the embryonic AV canal. A recent study demonstrated that signaling by Alk3, the type 1a receptor for bone morphogenetic proteins, in the myocardium of the AV canal was required for the development of both the AV valves and annulus fibrosus. To test the hypothesis that bone morphogenetic protein signaling also plays a role in AV node formation, we investigated conduction system function and AV node morphology in adult mice with conditional deletion of Alk3 in the AV canal.

Photodissociation of Uracil

Physical Chemistry Chemical Physics : PCCP. Dec, 2007  |  Pubmed ID: 18004416

We investigate the photochemistry and photodissociation dynamics of uracil by two-colour photofragment Doppler spectroscopy and by two-colour slice imaging at excitation wavelengths between 268 and 235 nm. We observe the loss of a hydrogen atom upon excitation into the pipi* state. The angular distribution indicates a statistical process, while the translational energy distribution agrees with a dissociation that takes place on the electronic ground state. The pipi* state most likely deactivates via the lower-lying npi* state. In addition there is evidence for a second pathway: direct decay of the pipi* state to the electronic ground state with subsequent dissociation. Experiments on uracil-1,3-D(2) show that there is no site selectivity in the dissociation process. No evidence was found for the direct dissociation via a pisigma* excited state that seems to be relevant in the photochemistry of adenine and many other heterocyclic molecules. Overall, the photochemistry of uracil is similar to that of thymine.

Association Between Complementary and Alternative Medicine Use and Adherence to Highly Active Antiretroviral Therapy in the Women's Interagency HIV Study

Journal of Alternative and Complementary Medicine (New York, N.Y.). Dec, 2007  |  Pubmed ID: 18166114

Spatial Patterns and Dynamic Responses of Arctic Food Webs Corroborate the Exploitation Ecosystems Hypothesis (EEH)

The American Naturalist. Feb, 2008  |  Pubmed ID: 18197777

According to the exploitation ecosystems hypothesis (EEH), productive terrestrial ecosystems are characterized by community-level trophic cascades, whereas unproductive ecosystems harbor food-limited grazers, which regulate community-level plant biomass. We tested this hypothesis along arctic-alpine productivity gradients at the Joatka field base, Finnmark, Norway. In unproductive habitats, mammalian predators were absent and plant biomass was constant, whereas herbivore biomass varied, reflecting the productivity of the habitat. In productive habitats, predatory mammals were persistently present and plant biomass varied in space, but herbivore biomass did not. Plant biomass of productive tundra scrublands declined by 40% when vegetation blocks were transferred to predation-free islands. Corresponding transfer to herbivore-free islands triggered an increase in plant biomass. Fertilization of an unproductive tundra heath resulted in a fourfold increase in rodent density and a corresponding increase in winter grazing activity, whereas the total aboveground plant biomass remained unchanged. These results corroborate the predictions of the EEH, implying that the endotherm community and the vegetation of the North European tundra behaves dynamically as if each trophic level consisted of a single population, in spite of local co-occurrence of >20 plant species representing different major taxonomic groups, growth forms, and defensive strategies.

Magnetic-guided Percutaneous Coronary Intervention Enabled by Two-dimensional Guidewire Steering and Three-dimensional Virtual Angioscopy: Initial Experiences in Daily Clinical Practice

Journal of Interventional Cardiology. Apr, 2008  |  Pubmed ID: 18248356

Percutaneous coronary intervention (PCI) has been broadly established and often includes highly complex stenoses that require difficult navigation. The purpose of this study is to assess the feasibility of a new magnetic navigation system (MNS) to enable intracoronary guidewire deployment and PCI in daily clinical practice and to compare the 2D guidance to the virtual 3D angioscopy feature.

Targeted Deletion of Dicer in the Heart Leads to Dilated Cardiomyopathy and Heart Failure

Proceedings of the National Academy of Sciences of the United States of America. Feb, 2008  |  Pubmed ID: 18256189

Cardiovascular disease is the leading cause of human morbidity and mortality. Dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy associated with heart failure. Here, we report that cardiac-specific knockout of Dicer, a gene encoding a RNase III endonuclease essential for microRNA (miRNA) processing, leads to rapidly progressive DCM, heart failure, and postnatal lethality. Dicer mutant mice show misexpression of cardiac contractile proteins and profound sarcomere disarray. Functional analyses indicate significantly reduced heart rates and decreased fractional shortening of Dicer mutant hearts. Consistent with the role of Dicer in animal hearts, Dicer expression was decreased in end-stage human DCM and failing hearts and, most importantly, a significant increase of Dicer expression was observed in those hearts after left ventricle assist devices were inserted to improve cardiac function. Together, our studies demonstrate essential roles for Dicer in cardiac contraction and indicate that miRNAs play critical roles in normal cardiac function and under pathological conditions.

Cerebrospinal Fluid Neurochemical Phenotypes in Vascular Dementias: Original Data and Mini-review

Dementia and Geriatric Cognitive Disorders. 2008  |  Pubmed ID: 18270488

The study evaluated the patterns of cerebrospinal fluid (CSF), amyloid-beta (Abeta) peptides, total tau and phospho-tau among Alzheimer's disease (AD) and vascular dementias (VAD).

Myocardial Pitx2 Differentially Regulates the Left Atrial Identity and Ventricular Asymmetric Remodeling Programs

Circulation Research. Apr, 2008  |  Pubmed ID: 18292603

The Pitx2 gene regulates left-right (L/R) asymmetrical cardiac morphogenesis. Constitutive Pitx2 knock out (ko) mice die before birth and display, among other defects, right atrial isomerism, atrial and ventricular septal defects, and double outlet right ventricle. The myocardial role of the gene has not been dissected. In particular, how Pitx2 regulates the differential L/R cardiac identity program is not clear. Additionally, the relation between Pitx2 ko ventricular defects and the gene expression pattern is not understood. In this article we analyze Pitx2 myocardial function during mouse heart development. By in situ hybridization analysis we show that myocardial Pitx2 expression delineates the remodeling of the left atrioventricular canal, the inner curvature, the ventral part of the interventricular ring, and the ventral portion of the right and left ventricle. By genetic analysis using an allelic series of Pitx2 mutants, among which a myocardial specific ko (ko(myo)) we show it has a crucial role in this process. Pitx2 ko(myo) mutants survive to adulthood, when they present strong cardiac morphological and functional defects. Confocal analysis of embryonic Pitx2 ko(myo) hearts reveals delayed cardiomyocyte development in the ventricular but not in the atrial Pitx2 null areas. Conversely, selective left atrial BMP10 mRNA downregulation which normally occurs at fetal stages is not found in the Pitx2 ko(myo) mice. This is the first evidence for distinct Pitx2 action in mediating L/R atrial identity and asymmetrical ventricular remodeling.

Clinical Characteristics Associated with Isolation of Small-colony Variants of Staphylococcus Aureus and Pseudomonas Aeruginosa from Respiratory Secretions of Patients with Cystic Fibrosis

Journal of Clinical Microbiology. May, 2008  |  Pubmed ID: 18322058

During a 3-month period, small-colony variant phenotypes of both Staphylococcus aureus and Pseudomonas aeruginosa were isolated from respiratory secretions of 8.2% and 9.2%, respectively, of 98 patients with cystic fibrosis, particularly those with advanced pulmonary disease and prolonged antibiotic exposure.

Influence of Inflow Cannula Length in Axial-flow Pumps on Neurologic Adverse Event Rate: Results from a Multi-center Analysis

The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. Mar, 2008  |  Pubmed ID: 18342745

The application of axial-flow pumps in patients with end-stage heart failure reveals a significantly reduced infectious complication rate as compared with rates observed with pulsatile devices. The remaining adverse event rate relates mainly to thromboembolic complications with neurologic consequences. We investigated the dependence of the neurologic adverse event rate on the length of the inflow cannula.

Association Between Living with Children and Adherence to Highly Active Antiretroviral Therapy in the Women's Interagency HIV Study

Pediatrics. Apr, 2008  |  Pubmed ID: 18381507

The purpose of this work was to evaluate whether living with children adversely affects adherence to highly active antiretroviral therapy in HIV-infected women.

Long-term Outcomes After Acute Kidney Injury

Critical Care Medicine. Apr, 2008  |  Pubmed ID: 18382193

Acute kidney dysfunction is a common problem in intensive care units. It is not only associated with increased morbidity and mortality but also with increased healthcare costs. Limited healthcare budgets have now raised the issue of how much therapy should be dedicated to these critically ill patients. A precondition for any further discussion on this topic is the question on the long-term outcome and quality of life of these patients. However, only limited data are available in this field. In this review, we will focus on the existing literature, considering not only acute renal failure patients requiring renal replacement therapy but also those patients with mild or moderate impaired renal function. The intention of this review is to show that acute kidney injury is an important but often underestimated disease and a disease that deserves major attention because it is associated with impaired short- and long-term outcome. We will demonstrate that acute kidney injury patients requiring dialysis have a reasonable long-term survival rate and good quality of life. There is no doubt that aggressive intensive care unit treatment is justified in these patients, irrespective of the health costs.

Changes in Pressure Pain Sensitivity in Latent Myofascial Trigger Points in the Upper Trapezius Muscle After a Cervical Spine Manipulation in Pain-free Subjects

Journal of Manipulative and Physiological Therapeutics. Mar, 2008  |  Pubmed ID: 18394505

Phosphorylation of Thr-178 and Thr-184 in the TAK1 T-loop is Required for Interleukin (IL)-1-mediated Optimal NFkappaB and AP-1 Activation As Well As IL-6 Gene Expression

The Journal of Biological Chemistry. Sep, 2008  |  Pubmed ID: 18617512

TAK1 (transforming growth factor-beta-activated kinase 1), a mitogen-activated protein kinase kinase kinase, is activated by various cytokines, including interleukin-1 (IL-1). However, the precise regulation for TAK1 activation at the molecular level is still not fully understood. Here we report that dual phosphorylation of Thr-178 and Thr-184 residues within the kinase activation loop of TAK1 is essential for TAK1-mediated NFkappaB and AP-1 activation. Once co-overexpressed with TAB1, TAK1 mutant with alanine substitution of these two residues fails to activate IKKbeta-mediated NFkappaB and JNK-mediated AP-1, whereas TAK1 mutant with replacement of these two sites with acidic residues acts like the TAK1 wild type. Consistently, TAK1 mutant with alanine substitution of these two residues severely inhibits IL-1-induced NFkappaB and AP-1 activities, whereas TAK1 mutant with replacement of these two sites with acidic residues slightly enhances IL-1-induced NFkappaB and AP-1 activities compared with the TAK1 wild-type. IL-1 induces the phosphorylation of endogenous TAK1 at Thr-178 and Thr-184. Reconstitution of TAK1-deficient mouse embryo fibroblast cells with wild-type TAK1 or a TAK1 mutant containing threonine 178 and 184 to alanine mutations revealed the importance of these two sites in IL-1-mediated IKK-NFkappaB and JNK-AP-1 activation as well as IL-1-induced IL-6 gene expression. Our finding is the first report that substitution of key serine/threonine residues with acidic residues mimics the phosphorylated state of TAK1 and renders TAK1 active during its induced activation.

Circumferential Pulmonary Vein Isolation with the Cryoballoon Technique Results from a Prospective 3-center Study

Journal of the American College of Cardiology. Jul, 2008  |  Pubmed ID: 18634982

The purpose of this study was to investigate the efficacy safety of the novel cryoballoon device (Arctic Front, Cryocath, Quebec, Canada).

Fibroblast Growth Factor 21 Corrects Obesity in Mice

Endocrinology. Dec, 2008  |  Pubmed ID: 18687777

Fibroblast growth factor 21 (FGF21) is a metabolic regulator that provides efficient and durable glycemic and lipid control in various animal models. However, its potential to treat obesity, a major health concern affecting over 30% of the population, has not been fully explored. Here we report that systemic administration of FGF21 for 2 wk in diet-induced obese and ob/ob mice lowered their mean body weight by 20% predominantly via a reduction in adiposity. Although no decrease in total caloric intake or effect on physical activity was observed, FGF21-treated animals exhibited increased energy expenditure, fat utilization, and lipid excretion, reduced hepatosteatosis, and ameliorated glycemia. Transcriptional and blood cytokine profiling studies revealed effects consistent with the ability of FGF21 to ameliorate insulin and leptin resistance, enhance fat oxidation and suppress de novo lipogenesis in liver as well as to activate futile cycling in adipose. Overall, these data suggest that FGF21 exhibits the therapeutic characteristics necessary for an effective treatment of obesity and fatty liver disease and provides novel insights into the metabolic determinants of these activities.

Spinal Palpation for Lumbar Segmental Mobility and Pain Provocation: an Interexaminer Reliability Study

Journal of Manipulative and Physiological Therapeutics. Jul-Aug, 2008  |  Pubmed ID: 18722203

This study determined the degree of interexaminer reliability using 2 experienced clinicians performing 3 palpation procedures over the lumbar facet joints and sacroiliac joints.

How Can Chiropractic Become a Respected Mainstream Profession? The Example of Podiatry

Chiropractic & Osteopathy. 2008  |  Pubmed ID: 18759966

The chiropractic profession has succeeded to remain in existence for over 110 years despite the fact that many other professions which had their start at around the same time as chiropractic have disappeared. Despite chiropractic's longevity, the profession has not succeeded in establishing cultural authority and respect within mainstream society, and its market share is dwindling. In the meantime, the podiatric medical profession, during approximately the same time period, has been far more successful in developing itself into a respected profession that is well integrated into mainstream health care and society.

Human Oocyte Chromosome Analysis: Complicated Cases and Major Pitfalls

Journal of Genetics. Aug, 2008  |  Pubmed ID: 18776643

Human oocytes that remained unfertilized in programmes of assisted reproduction have been analysed cytogenetically for more than 20 years to assess the incidence of aneuploidy in female gametes. However, the results obtained so far are not indisputable as a consequence of difficulties in evaluating oocyte chromosome preparations. Because of the lack of guidelines, we decided to summarize for the first time, the possible pitfalls in human oocyte chromosome analysis. Therefore, we screened the material from our previous studies and compiled representative, complicated cases with recommendations for their cytogenetic classification. We point out that maturity and size of the oocyte are important parameters and that fixation artefacts, as well as the particular structure of oocyte chromosomes, may predispose one to misinterpretations. Moreover, phenomena related to oocyte activation and fertilization are illustrated and explained. This compilation may help to avoid major problems in future studies and contribute to a more precise, and uniform assessment of human oocyte chromosomes.

Association of Complementary and Alternative Medicine Use with Highly Active Antiretroviral Therapy Initiation

Alternative Therapies in Health and Medicine. Sep-Oct, 2008  |  Pubmed ID: 18780580

To assess whether complementary and alternative medicine (CAM) use is associated with the timing of highly active antiretroviral therapy (HAART) initiation among human immunodeficiency virus (HIV)-infected participants of the Women's Interagency HIV Study.

Automatic Magnetic-guided Electroanatomical Mapping and Remote-controlled Ablation of Atypical and Typical Atrial Flutter

Pacing and Clinical Electrophysiology : PACE. Oct, 2008  |  Pubmed ID: 18811821

Two patients with inconclusive surface electrocardiogram patterns underwent nonfluoroscopy automatic mapping and remote-controlled ablation of nonisthmus and isthmus-dependent right atrial flutter. METHODS AND RESULTS: A 0.08 magnetic vector force and a motor drive enable a complex steering of a new 8-mm magnet tip electrode. The navigation system performs atrial electroanatomical mapping fully automatically. Total procedural fluoroscopy time for ablation of nonisthmus-related atypical and isthmus-dependent flutter was 8.5 and 3.2 minutes, respectively. CONCLUSION: Automatic electroanatomical mapping offers a promising option to effectively guide the remote-controlled ablation of atrial reentry tachycardias and to reduce fluoroscopy time.

Antiretroviral Therapy Exposure and Insulin Resistance in the Women's Interagency HIV Study

Journal of Acquired Immune Deficiency Syndromes (1999). Dec, 2008  |  Pubmed ID: 19186350

Evidence suggesting an increased risk of cardiovascular disease in HIV-infected individuals has heightened the need to understand the relation of HIV infection, antiretroviral therapy use, and non-HIV-related factors with insulin resistance (IR).

Predictive Factors Influencing Fast Track Rehabilitation Following Primary Total Hip and Knee Arthroplasty

Archives of Orthopaedic and Trauma Surgery. Dec, 2009  |  Pubmed ID: 19198860

Fast track rehabilitation after primary total hip (THR) and total knee replacement (TKR) is gaining popularity. We performed a prospective clinical trial to identify predictive factors for successful fast track rehabilitation.

Relationship of Injection Drug Use, Antiretroviral Therapy Resistance, and Genetic Diversity in the HIV-1 Pol Gene

Journal of Acquired Immune Deficiency Syndromes (1999). Apr, 2009  |  Pubmed ID: 19214121

To determine if a history of injection drug use influences genotypic protease inhibitor (PI) resistance to antiretroviral agents.

Fibroblasts Inform the Heart: Control of Cardiomyocyte Cycling and Size by Age-dependent Paracrine Signals

Developmental Cell. Feb, 2009  |  Pubmed ID: 19217417

Within the developing and adult heart, the fibroblast is often dismissed as merely a structural element, important just to mechanical integrity or to scarring when excessive in disease. Ieda et al. in this issue of Developmental Cell now report an essential program of paracrine factor production in cardiac fibroblasts that controls heart muscle cell growth, driving cycling or enlargement depending on the fibroblasts' developmental stage.

Resonance-enhanced Multiphoton Ionisation of Purine

Chemphyschem : a European Journal of Chemical Physics and Physical Chemistry. Mar, 2009  |  Pubmed ID: 19219888

State-of-the-art molecular-beam techniques reveal that the lowest lying electronic excited state in purine is the n pi* state. Using multiphoton ionization spectroscopy, the origin is found to occur at 31,309 cm(-1), and a vibrational structure is visible that is assigned to the skeletal motion of the ring (see figure).

Association of Child Care Burden and Household Composition with Adherence to Highly Active Antiretroviral Therapy in the Women's Interagency HIV Study

AIDS Patient Care and STDs. Apr, 2009  |  Pubmed ID: 19243274

Our objective was to describe the association that childcare burden, household composition, and health care utilization have with adherence to highly active antiretroviral therapy (HAART) among women in the United States. The primary outcome was 95% or more adherence to HAART evaluated at 10,916 semiannual visits between October 1998 and March 2006 among 1419 HIV-infected participants enrolled in the Women's Interagency HIV Study. HAART adherence levels of 95% or more were reported at 76% of the semiannual visits. At only 4% of the person-visits did women report either quite a bit or extreme difficulty in caring for child; at 52% of the person-visits women reported at least one child 18 years of age or older living in the household. We found a one-unit increase in the difficulty in caring for children (childcare burden was assessed on a 5-point scale: not difficult [1] to extremely difficult [5]) was associated with a 6% decreased odds of 95% or more HAART adherence (adjusted odds ratio [OR] = 0.94; p = 0.07). Each additional child 18 years of age or less living in the household was associated with an 8% decreased odds of 95% or more adherence (adjusted OR = 0.92, p = 0.03). Both the number and type of adult living in the household, as well as health care utilization were not associated with HAART adherence. Greater child care burden and number of children 18 years old or younger living in household were both inversely associated with HAART adherence. Assessing patients' difficulties in caring for children and household composition are important factors to consider when addressing adherence to HAART.

Separation of a Pronucleus by Premature Cytokinesis: a Mechanism for Immediate Diploidization of Tripronuclear Oocytes?

Fertility and Sterility. Jul, 2009  |  Pubmed ID: 19338999

To describe an oocyte with a peculiar combination of abnormalities in terms of cytoplasmic fragmentation and formation of pronuclei.

A Safe Citrate Anticoagulation Protocol with Variable Treatment Efficacy and Excellent Control of the Acid-base Status

Critical Care Medicine. Jun, 2009  |  Pubmed ID: 19384210

Citrate anticoagulation is an excellent alternative to heparin anticoagulation for critically ill patients requiring continuous renal replacement therapy. In this article, we provide a safe and an easy-to-handle citrate anticoagulation protocol with variable treatment doses and excellent control of the acid-base status.

X-ray Vs. NMR Structures As Templates for Computational Protein Design

Proteins. Oct, 2009  |  Pubmed ID: 19422060

Certain protein-design calculations involve using an experimentally determined high-resolution structure as a template to identify new sequences that can adopt the same fold. This approach has led to the successful design of many novel, well-folded, native-like proteins. Although any atomic-resolution structure can serve as a template in such calculations, most successful designs have used high-resolution crystal structures. Because there are many proteins for which crystal structures are not available, it is of interest whether nuclear magnetic resonance (NMR) templates are also appropriate. We have analyzed differences between using X-ray and NMR templates in side-chain repacking and design calculations. We assembled a database of 29 proteins for which both a high-resolution X-ray structure and an ensemble of NMR structures are available. Using these pairs, we compared the rotamericity, chi(1)-angle recovery, and native-sequence recovery of X-ray and NMR templates. We carried out design using RosettaDesign on both types of templates, and compared the energies and packing qualities of the resulting structures. Overall, the X-ray structures were better templates for use with Rosetta. However, for approximately 20% of proteins, a member of the reported NMR ensemble gave rise to designs with similar properties. Re-evaluating RosettaDesign structures with other energy functions indicated much smaller differences between the two types of templates. Ultimately, experiments are required to confirm the utility of particular X-ray and NMR templates. But our data suggest that the lack of a high-resolution X-ray structure should not preclude attempts at computational design if an NMR ensemble is available.

Cantharidin and Demethylcantharidin (palasonin) Content of Blister Beetles (Coleoptera:Meloidae) from Southern Africa

Toxicon : Official Journal of the International Society on Toxinology. Jan, 2009  |  Pubmed ID: 19470350

In two species of meloid beetles, Hycleus oculatus and H. tinctus, from southern Africa, cantharidin and demethylcantharidin (palasonin) were assayed quantitatively. For cantharidin the mean value per specimen was about 1mg for H. oculatus and 0.2mg for H.tinctus, the mean palasonin concentration was 20 (H. oculatus) and 12 times (H. tinctus) lower, respectively. However, considerable individual variation in the cantharidin concentration was observed and values of more than 6mg of this compound per beetle were measured pointing to the high risk of severe and even fatal poisoning when ingesting these insects.

Multiple-infection and Recombination in HIV-1 Within a Longitudinal Cohort of Women

Retrovirology. 2009  |  Pubmed ID: 19493346

Recombination between strains of HIV-1 only occurs in individuals with multiple infections, and the incidence of recombinant forms implies that multiple infection is common. Most direct studies indicate that multiple infection is rare. We determined the rate of multiple infection in a longitudinal study of 58 HIV-1 positive participants from The Women's Interagency HIV Study with a richer sampling design than previous direct studies, and we investigated the role of recombination and sampling design on estimating the multiple infection rate.

TAK1 is an Essential Regulator of BMP Signalling in Cartilage

The EMBO Journal. Jul, 2009  |  Pubmed ID: 19536134

TGFbeta activated kinase 1 (TAK1), a member of the MAPKKK family, controls diverse functions ranging from innate and adaptive immune system activation to vascular development and apoptosis. To analyse the in vivo function of TAK1 in cartilage, we generated mice with a conditional deletion of Tak1 driven by the collagen 2 promoter. Tak1(col2) mice displayed severe chondrodysplasia with runting, impaired formation of secondary centres of ossification, and joint abnormalities including elbow dislocation and tarsal fusion. This phenotype resembled that of bone morphogenetic protein receptor (BMPR)1 and Gdf5-deficient mice. BMPR signalling was markedly impaired in TAK1-deficient chondrocytes as evidenced by reduced expression of known BMP target genes as well as reduced phosphorylation of Smad1/5/8 and p38/Jnk/Erk MAP kinases. TAK1 mediates Smad1 phosphorylation at C-terminal serine residues. These findings provide the first in vivo evidence in a mammalian system that TAK1 is required for BMP signalling and functions as an upstream activating kinase for Smad1/5/8 in addition to its known role in regulating MAP kinase pathways. Our experiments reveal an essential role for TAK1 in the morphogenesis, growth, and maintenance of cartilage.

Integrating Nine Prescription Opioid Analgesics And/or Four Signal Detection Systems to Summarize Statewide Prescription Drug Abuse in the United States in 2007

Pharmacoepidemiology and Drug Safety. Sep, 2009  |  Pubmed ID: 19536784

Integrate statewide rankings of abuse across different drugs and/or signal detection systems to summarize prescription drug abuse in each state in 2007.

Association of Hepatitis C Virus and HIV Infection with Subclinical Atherosclerosis in the Women's Interagency HIV Study

AIDS (London, England). Aug, 2009  |  Pubmed ID: 19553807

Whether hepatitis C virus coinfection might accelerate atherosclerosis in HIV-infected individuals is unclear. We examined the relationship of HIV and hepatitis C virus with carotid artery intima media thickness and the presence of carotid plaques in the Women's Interagency HIV Study. Hepatitis C virus infection was not associated with greater carotid artery intima media thickness after adjustment for demographic and traditional cardiovascular risk factors. Further follow-up is needed to clarify whether HIV/hepatitis C virus coinfection may be associated with a greater risk of carotid plaque.

Cryoballoon Ablation of Paroxysmal Atrial Fibrillation Within the Dilated Coronary Sinus in a Case of Persistent Left Superior Vena Cava

Europace : European Pacing, Arrhythmias, and Cardiac Electrophysiology : Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology. Oct, 2009  |  Pubmed ID: 19648587

Trigger sources of paroxysmal atrial fibrillation (PAF) are not limited to a pulmonary vein origin and may be achievable by cardiac vascular structures like the coronary sinus (CS), the vena cava superior and in some rare cases by a persistent left superior vena cava (LSVC). Cryoballoon ablation has been shown to be effective in pulmonary vein isolation. We report an unusual case of using this technique in the dilated CS in case of a persistent LSVC. A 64 year old patient presented PAF recurrences after cryo pulmonary vein isolation 4 months before. A maintaining pulmonary vein isolation could be demonstrated by transseptal mapping. Further bi-atrial mapping localized repetitive atrial trigger activity in a dilated CS proceeding to a LSVC. A cryoballoon was deployed in the CS target area and during cryoablation the triggered activity suspended. Ablation side effects were excluded by coronary angiography. During a follow up time of 8 months the patient has remained free of PAF recurrences. The current report underlines the importance of a patient-tailored ablation approach. Cryothermic balloon technology may be more applicable in delicate cardiac structures by developing new anatomically adapted balloon shapes and sizes.

Cantharidin and Demethylcantharidin (palasonin) Content of Blister Beetles (Coleoptera: Meloidae) from Southern Africa

Toxicon : Official Journal of the International Society on Toxinology. Mar, 2009  |  Pubmed ID: 19708124

In two species of meloid beetles, Hycleus oculatus and Hycleus tinctus, from southern Africa, cantharidin and demethylcantharidin (palasonin) were assayed quantitatively. For cantharidin the mean value per specimen was about 1 mg for H. oculatus and 0.2 mg for H. tinctus, the mean palasonin concentration was 20 (H. oculatus) and 12 times (H. tinctus) lower, respectively. However, considerable individual variation in the cantharidin concentration was observed and values of more than 6 mg of this compound per beetle were measured pointing to the high risk of severe and even fatal poisoning when ingesting these insects.

Evaluating the Use of the Cleo 90 Infusion Set for Patients on a Palliative Care Unit

International Journal of Palliative Nursing. Aug, 2009  |  Pubmed ID: 19773700

Although the use of subcutaneous infusion is common in palliative care, problems can occur. Normally, butterfly needles are used; however, there are occasional issues with patients being able to walk around or with restless patients who suffer from delirium. In these cases, needles often dislocate; therefore, a small observational study was undertaken to evaluate the use of the Cleo 90 infusion set. The use of this needle system has been well established in diabetic patients who require continuous subcutaneous infusion of insulin, but has never been tested in a wider range of patients with other medications. In this 6-month study, 45 patients were identified for subcutaneous infusion and a total of 112 needles were used for this study, since we initially changed each site after 2 days to control the local site for adverse reactions. We have not observed any complications with drug combinations delivered via the attached tube and the needle, and have used up to five different drugs mixed together in a single syringe. Needles could be used for a mean time of 5 +/- 2 days (range 2-12 days). Local site reactions have been observed only with sodium chloride infusions, which were not delivered via a pump system. Reddening and induration of the skin occurred, but they were reversible after removing the needle. As this was a small study in only one unit, without standardization the results can only be observational. However, it has shown, for the first time, that the Cleo 90 needle can be safe and comfortable.

BMP Signaling Regulates Sympathetic Nervous System Development Through Smad4-dependent and -independent Pathways

Development (Cambridge, England). Nov, 2009  |  Pubmed ID: 19793887

Induction of the sympathetic nervous system (SNS) from its neural crest (NC) precursors is dependent on BMP signaling from the dorsal aorta. To determine the roles of BMP signaling and the pathways involved in SNS development, we conditionally knocked out components of the BMP pathways. To determine if BMP signaling is a cell-autonomous requirement of SNS development, the Alk3 (BMP receptor IA) was deleted in the NC lineage. The loss of Alk3 does not prevent NC cell migration, but the cells die immediately after reaching the dorsal aorta. The paired homeodomain factor Phox2b, known to be essential for survival of SNS precursors, is downregulated, suggesting that Phox2b is a target of BMP signaling. To determine if Alk3 signals through the canonical BMP pathway, Smad4 was deleted in the NC lineage. Loss of Smad4 does not affect neurogenesis and ganglia formation; however, proliferation and noradrenergic differentiation are reduced. Analysis of transcription factors regulating SNS development shows that the basic helix-loop-helix factor Ascl1 is downregulated by loss of Smad4 and that Ascl1 regulates SNS proliferation but not noradrenergic differentiation. To determine if the BMP-activated Tak1 (Map3k7) pathway plays a role in SNS development, Tak1 was deleted in the NC lineage. We show that Tak1 is not involved in SNS development. Taken together, our results suggest multiple roles for BMP signaling during SNS development. The Smad4-independent pathway acts through the activation of Phox2b to regulate survival of SNS precursors, whereas the Smad4-dependent pathway controls noradrenergic differentiation and regulates proliferation by maintaining Ascl1 expression.

Desmoplastic Fibroma of the Mandible--review of the Literature and Presentation of a Rare Case

Head & Face Medicine. 2009  |  Pubmed ID: 19930688

Desmoplastic fibroma (DF) is a rare, benign but locally aggressive, intraosseous lesion with a high tendency of local recurrence. In this report the actual literature is reviewed regarding epidemiological data, pathology, clinical diagnostic criterias, therapy and prognosis. Moreover, a report of an interesting case is included localized in the mandibular corpus.

Chiropractic Management of Myofascial Trigger Points and Myofascial Pain Syndrome: a Systematic Review of the Literature

Journal of Manipulative and Physiological Therapeutics. Jan, 2009  |  Pubmed ID: 19121461

Myofascial pain syndrome (MPS) and myofascial trigger points (MTrPs) are important aspects of musculoskeletal medicine, including chiropractic. The purpose of this study was to review the most commonly used treatment procedures in chiropractic for MPS and MTrPs.

Chiropractic Management of Fibromyalgia Syndrome: a Systematic Review of the Literature

Journal of Manipulative and Physiological Therapeutics. Jan, 2009  |  Pubmed ID: 19121462

Fibromyalgia syndrome (FMS) is one of the most commonly diagnosed nonarticular soft tissue conditions in all fields of musculoskeletal medicine, including chiropractic. The purpose of this study was to perform a comprehensive review of the literature for the most commonly used treatment procedures in chiropractic for FMS and to provide evidence ratings for these procedures. The emphasis of this literature review was on conservative and nonpharmaceutical therapies.

New Equations to Estimate GFR in Children with CKD

Journal of the American Society of Nephrology : JASN. Mar, 2009  |  Pubmed ID: 19158356

The Schwartz formula was devised in the mid-1970s to estimate GFR in children. Recent data suggest that this formula currently overestimates GFR as measured by plasma disappearance of iohexol, likely a result of a change in methods used to measure creatinine. Here, we developed equations to estimate GFR using data from the baseline visits of 349 children (aged 1 to 16 yr) in the Chronic Kidney Disease in Children (CKiD) cohort. Median iohexol-GFR (iGFR) was 41.3 ml/min per 1.73 m(2) (interquartile range 32.0 to 51.7), and median serum creatinine was 1.3 mg/dl. We performed linear regression analyses assessing precision, goodness of fit, and accuracy to develop improvements in the GFR estimating formula, which was based on height, serum creatinine, cystatin C, blood urea nitrogen, and gender. The best equation was: GFR(ml/min per 1.73 m(2))=39.1[height (m)/Scr (mg/dl)](0.516) x [1.8/cystatin C (mg/L)](0.294)[30/BUN (mg/dl)](0.169)[1.099](male)[height (m)/1.4](0.188). This formula yielded 87.7% of estimated GFR within 30% of the iGFR, and 45.6% within 10%. In a test set of 168 CKiD patients at 1 yr of follow-up, this formula compared favorably with previously published estimating equations for children. Furthermore, with height measured in cm, a bedside calculation of 0.413*(height/serum creatinine), provides a good approximation to the estimated GFR formula. Additional studies of children with higher GFR are needed to validate these formulas for use in screening all children for CKD.

Conditional Ablation of Nonmuscle Myosin II-B Delineates Heart Defects in Adult Mice

Circulation Research. Nov, 2009  |  Pubmed ID: 19815823

Germline ablation of the cytoskeletal protein nonmuscle myosin II (NMII)-B results in embryonic lethality, with defects in both the brain and heart. Tissue-specific ablation of NMII-B by a Cre recombinase strategy should prevent embryonic lethality and permit study of the function of NMII-B in adult hearts.

Best Practices Recommendations for Chiropractic Care for Infants, Children, and Adolescents: Results of a Consensus Process

Journal of Manipulative and Physiological Therapeutics. Oct, 2009  |  Pubmed ID: 19836600

There has been much discussion about the role of chiropractic care in the evaluation, management, and treatment of pediatric patients. To date, no specific guidelines have been adopted that address this issue from an evidence based perspective. Previous systematic reviews of the chiropractic literature concluded that there is not yet a substantial body of high quality evidence from which to develop standard clinical guidelines. The purpose of this project was to develop recommendations on "best practices" related primarily to the evaluation and spinal manipulation aspects of pediatric chiropractic care; nonmanipulative therapies were not addressed in detail.

T-box 2, a Mediator of Bmp-Smad Signaling, Induced Hyaluronan Synthase 2 and Tgfbeta2 Expression and Endocardial Cushion Formation

Proceedings of the National Academy of Sciences of the United States of America. Nov, 2009  |  Pubmed ID: 19846762

During early heart development, Tbx2 gene expression is initiated in the cardiac crescent and then becomes restricted to the outflow tract and the atrioventricular region. We identified a Tbx2 regulatory region, enriched in multiple Smad sites, sufficient to reproduce Tbx2 expression patterns overlapping Bmp2 and Bmp4 gene activity in the heart. The role of Tbx2 in cardiogenesis was analyzed by using Cre-LoxP activated Tbx2 transgenic misexpression in chamber myocardium. Ventricular Tbx2 misexpression exhibited an abnormally narrow chamber lumen owing to the expansion of Hyaluronan synthase 2 expression in the ECM or cardiac jelly and the appearance of the endocardial cushions (ECs). Excessive Tbx2 also induced Tgfbeta2, which coincided with the outgrowth epithelial-mesenchymal transformed cells in ventricular and atrial tissues modifying cardiomyocyte identity from chamber type to non-chamber type. Tbx2, a central intermediary of Bmp-Smad signaling, has a central part in directing Has2 and Tgfbeta2 expression, facilitating EC formation.

The Cellular Prion Protein Identifies Bipotential Cardiomyogenic Progenitors

Circulation Research. Jan, 2010  |  Pubmed ID: 19910576

The paucity of specific surface markers for cardiomyocytes and their progenitors has impeded the development of embryonic or pluripotent stem cell-based transplantation therapy. Identification of relevant surface markers may also enhance our understanding of the mechanisms underlying differentiation.

The Numerical Stroop Effect in Primary School Children: a Comparison of Low, Normal, and High Achievers

Child Neuropsychology : a Journal on Normal and Abnormal Development in Childhood and Adolescence. 2010  |  Pubmed ID: 20437281

Sixty-six primary school children were selected, of which 21 scored low on a standardized math achievement test, 23 were normal, and 22 high achievers. In a numerical Stroop experiment, children were asked to make numerical and physical size comparisons on digit pairs. The effects of congruity and numerical distance were determined. All children exhibited congruity and distance effects in the numerical comparison. In the physical comparison, children of all performance groups showed Stroop effects when the numerical distance between the digits was large but failed to show them when the distance was small. Numerical distance effects depended on the congruity condition, with a typical effect of distance in the congruent, and a reversed distance effect in the incongruent condition. Our results are hard to reconcile with theories that suggest that deficits in the automaticity of numerical processing can be related to differential math achievement levels. Immaturity in the precision of mappings between numbers and their numerical magnitudes might be better suited to explain the Stroop effects in children. However, as the results for the high achievers demonstrate, in addition to numerical processing capacity per se, domain-general functions might play a crucial role in Stroop performance, too.

Endogenous Retinoic Acid Regulates Cardiac Progenitor Differentiation

Proceedings of the National Academy of Sciences of the United States of America. May, 2010  |  Pubmed ID: 20439714

Retinoic acid (RA) has several established functions during cardiac development, including actions in the fetal epicardium required for myocardial growth. An open question is if retinoid effects are limited to growth factor stimulation pathway(s) or if additional actions on uncommitted progenitor/stem populations might drive cardiac differentiation. Here we report the dual effects of RA deficiency on cardiac growth factor signaling and progenitor/stem biology using the mouse retinaldehyde dehydrogenase 2 (Raldh2) knockout model. Although early heart defects in Raldh2(-/-) embryos result from second-heart-field abnormalities, it is unclear whether this role is transient or whether RA has sustained effects on cardiac progenitors. To address this, we used transient maternal RA supplementation to overcome early Raldh2(-/-) lethality. By embryonic day 11.5-14.5, Raldh2(-/-) hearts exhibited reduced venticular compact layer outgrowth and altered coronary vessel development. Although reductions in Fgf2 and target pERK levels occurred, no alterations in Wnt/beta-catenin expression were observed. Cell proliferation is increased in compact zone myocardium, whereas cardiomyocyte differentiation is reduced, alterations that suggest progenitor defects. We report that the fetal heart contains a reservoir of stem/progenitor cells, which can be isolated by their ability to efflux a fluorescent dye and that retinoid signaling acts on this fetal cardiac side population (SP). Raldh2(-/-) hearts display increased SP cell numbers, with selective increases in expression of cardiac progenitor cell markers and reduced differentiation marker levels. Hence, although lack of RA signaling increases cardiac SP numbers, simultaneous reductions in Fgf signaling reduce cardiomyocyte differentiation, possibly accounting for long-term defects in myocardial growth.

The Posterior Approach Reduces the Risk of Thin Cement Mantles with a Straight Femoral Stem Design

Acta Orthopaedica. Jun, 2010  |  Pubmed ID: 20446829

The properties of the cement mantle around a prosthesis are important. We investigated whether the surgical approach to the hip influences the quality and thickness of the cement mantle when using a straight femoral stem design.

Illustrating Risk Difference and Number Needed to Treat from a Randomized Controlled Trial of Spinal Manipulation for Cervicogenic Headache

Chiropractic & Osteopathy. 2010  |  Pubmed ID: 20497573

The number needed to treat (NNT) for one participant to benefit is considered a useful, clinically meaningful way of reporting binary outcomes from randomized trials. Analysis of continuous data from our randomized controlled trial has previously demonstrated a significant and clinically important difference favoring spinal manipulation over a light massage control.

The P38 MAPK Pathway is Essential for Skeletogenesis and Bone Homeostasis in Mice

The Journal of Clinical Investigation. Jul, 2010  |  Pubmed ID: 20551513

Nearly every extracellular ligand that has been found to play a role in regulating bone biology acts, at least in part, through MAPK pathways. Nevertheless, much remains to be learned about the contribution of MAPKs to osteoblast biology in vivo. Here we report that the p38 MAPK pathway is required for normal skeletogenesis in mice, as mice with deletion of any of the MAPK pathway member-encoding genes MAPK kinase 3 (Mkk3), Mkk6, p38a, or p38b displayed profoundly reduced bone mass secondary to defective osteoblast differentiation. Among the MAPK kinase kinase (MAP3K) family, we identified TGF-beta-activated kinase 1 (TAK1; also known as MAP3K7) as the critical activator upstream of p38 in osteoblasts. Osteoblast-specific deletion of Tak1 resulted in clavicular hypoplasia and delayed fontanelle fusion, a phenotype similar to the cleidocranial dysplasia observed in humans haploinsufficient for the transcription factor runt-related transcription factor 2 (Runx2). Mechanistic analysis revealed that the TAK1-MKK3/6-p38 MAPK axis phosphorylated Runx2, promoting its association with the coactivator CREB-binding protein (CBP), which was required to regulate osteoblast genetic programs. These findings reveal an in vivo function for p38beta and establish that MAPK signaling is essential for bone formation in vivo. These results also suggest that selective p38beta agonists may represent attractive therapeutic agents to prevent bone loss associated with osteoporosis and aging.

NADPH Oxidase 4 (Nox4) is a Major Source of Oxidative Stress in the Failing Heart

Proceedings of the National Academy of Sciences of the United States of America. Aug, 2010  |  Pubmed ID: 20713697

NAD(P)H oxidases (Noxs) produce O(2)(-) and play an important role in cardiovascular pathophysiology. The Nox4 isoform is expressed primarily in the mitochondria in cardiac myocytes. To elucidate the function of endogenous Nox4 in the heart, we generated cardiac-specific Nox4(-/-) (c-Nox4(-/-)) mice. Nox4 expression was inhibited in c-Nox4(-/-) mice in a heart-specific manner, and there was no compensatory up-regulation in other Nox enzymes. These mice exhibited reduced levels of O(2)(-) in the heart, indicating that Nox4 is a significant source of O(2)(-) in cardiac myocytes. The baseline cardiac phenotype was normal in young c-Nox4(-/-) mice. In response to pressure overload (PO), however, increases in Nox4 expression and O(2)(-) production in mitochondria were abolished in c-Nox4(-/-) mice, and c-Nox4(-/-) mice exhibited significantly attenuated cardiac hypertrophy, interstitial fibrosis and apoptosis, and better cardiac function compared with WT mice. Mitochondrial swelling, cytochrome c release, and decreases in both mitochondrial DNA and aconitase activity in response to PO were attenuated in c-Nox4(-/-) mice. On the other hand, overexpression of Nox4 in mouse hearts exacerbated cardiac dysfunction, fibrosis, and apoptosis in response to PO. These results suggest that Nox4 in cardiac myocytes is a major source of mitochondrial oxidative stress, thereby mediating mitochondrial and cardiac dysfunction during PO.

Identification of PEX33, a Novel Component of the Peroxisomal Docking Complex in the Filamentous Fungus Neurospora Crassa

European Journal of Cell Biology. Dec, 2010  |  Pubmed ID: 20728240

The docking complex of peroxisomal matrix protein import is composed of PEX13 and PEX14 in all species analyzed so far, whereas only yeast appears to possess an additional component, PEX17. In this report we isolated PEX14 complexes of Neurospora crassa. Among the complex constituents, one protein designated as PEX33 possessed homology to PEX14 but only in a short N-terminal domain. The PEX14/PEX33 interaction was verified by means of two-hybrid analysis. Moreover, PEX33 was shown to interact with itself and the PTS1-receptor PEX5. Localization studies demonstrated that PEX33 constitutes a glyoxysomal protein. Growth tests of the pex33 deletion strain revealed a defect of this strain in the biogenesis of glyoxysomes and Woronin bodies. As the function of PEX33 was not redundant to that of PEX14, it is a genuine novel peroxin. Based on our experimental data, the function of PEX33 seems to resemble that of yeast PEX17 despite clear structural differences.

Best Practices Recommendations for Chiropractic Care for Older Adults: Results of a Consensus Process

Journal of Manipulative and Physiological Therapeutics. Jul-Aug, 2010  |  Pubmed ID: 20732584

At this time, the scientific evidence base supporting the effectiveness of chiropractic care for musculoskeletal conditions has not yet definitively addressed its appropriateness for older adults. Expert consensus, as a form of evidence, must be considered when higher levels of evidence are lacking. The purpose of this project was to develop a document with evidence-based recommendations on the best practices for chiropractic care of older adults.

Making Muscle: Overview to "Cardiovascular Lineage Commitment During Development and Regeneration" Series

Circulation Research. Sep, 2010  |  Pubmed ID: 20814027

Sex Differences in the Clinical and Serologic Presentation of Early Lyme Disease: Results from a Retrospective Review

Gender Medicine. Aug, 2010  |  Pubmed ID: 20869632

Lyme disease is the most common vector-borne disease in the United States, and the number of reported cases has more than doubled between 1992 and 2008. Few studies have explicitly examined sex-based differences in the clinical presentation of or serologic response to early Lyme disease. It is unknown whether the sex-based variability observed in other infectious diseases is relevant to this clinical setting.

HIV, HAART, and Lipoprotein Particle Concentrations in the Women's Interagency HIV Study

AIDS (London, England). Nov, 2010  |  Pubmed ID: 20871387

Changes in lipoprotein particle concentrations, especially greater small low-density lipoprotein particle (LDL-p) and lower small high-density lipoprotein particle (HDL-p) may provide information regarding cardiovascular disease (CVD) risk above and beyond that which is provided by standard lipids. We quantified the association HIV and HAART use had with LDL-p and HDL-p.

Representations of the Magnitudes of Fractions

Journal of Experimental Psychology. Human Perception and Performance. Oct, 2010  |  Pubmed ID: 20873937

We tested whether adults can use integrated, analog, magnitude representations to compare the values of fractions. The only previous study on this question concluded that even college students cannot form such representations and instead compare fraction magnitudes by representing numerators and denominators as separate whole numbers. However, atypical characteristics of the presented fractions might have provoked the use of atypical comparison strategies in that study. In our 3 experiments, university and community college students compared more balanced sets of single-digit and multi-digit fractions and consistently exhibited a logarithmic distance effect. Thus, adults used integrated, analog representations, akin to a mental number line, to compare fraction magnitudes. We interpret differences between the past and present findings in terms of different stimuli eliciting different solution strategies.

Sleep and Fatigue Symptoms in Children and Adolescents with CKD: a Cross-sectional Analysis from the Chronic Kidney Disease in Children (CKiD) Study

American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. Feb, 2010  |  Pubmed ID: 20034719

Although symptoms of sleepiness and fatigue are common in adults with chronic kidney disease (CKD), little is known about the prevalence of these symptoms in children with CKD.

Lysine 63-linked Polyubiquitination of TAK1 at Lysine 158 is Required for Tumor Necrosis Factor Alpha- and Interleukin-1beta-induced IKK/NF-kappaB and JNK/AP-1 Activation

The Journal of Biological Chemistry. Feb, 2010  |  Pubmed ID: 20038579

Transforming growth factor-beta-activated kinase 1 (TAK1) plays an essential role in the tumor necrosis factor alpha (TNFalpha)- and interleukin-1beta (IL-1beta)-induced IkappaB kinase (IKK)/nuclear factor-kappaB (NF-kappaB) and c-Jun N-terminal kinase (JNK)/activator protein 1 (AP-1) activation. Here we report that TNFalpha and IL-1beta induce Lys(63)-linked TAK1 polyubiquitination at the Lys(158) residue within the kinase domain. Tumor necrosis factor receptor-associated factors 2 and 6 (TRAF2 and -6) act as the ubiquitin E3 ligases to mediate Lys(63)-linked TAK1 polyubiquitination at the Lys(158) residue in vivo and in vitro. Lys(63)-linked TAK1 polyubiquitination at the Lys(158) residue is required for TAK1-mediated IKK complex recruitment. Reconstitution of TAK1-deficient mouse embryo fibroblast cells with TAK1 wild type or a TAK1 mutant containing a K158R mutation revealed the importance of this site in TNFalpha and IL-1beta-mediated IKK/NF-kappaB and JNK/AP-1 activation as well as IL-6 gene expression. Our findings demonstrate that Lys(63)-linked polyubiquitination of TAK1 at Lys(158) is essential for its own kinase activation and its ability to mediate its downstream signal transduction pathways in response to TNFalpha and IL-1beta stimulation.

The Developmental Relations Between Conceptual and Procedural Knowledge: a Multimethod Approach

Developmental Psychology. Jan, 2010  |  Pubmed ID: 20053016

Interactions between conceptual and procedural knowledge influence the development of mathematical competencies. However, after decades of research, these interrelations are still under debate, and empirical results are inconclusive. The authors point out a source of these problems. Different kinds of knowledge and competencies only show up intertwined in behavior, making it hard to measure them validly and independently of each other. A multimethod approach was used to investigate the extent of these problems. A total of 289 fifth and sixth graders' conceptual and procedural knowledge about decimal fractions was measured by 4 common hypothetical measures of each kind of knowledge. Study 1 tested whether treatments affected the 2 groups of measures in consistent ways. Study 2 assessed, across 3 measurement points, whether conceptual and procedural knowledge could be modeled as latent factors underlying the measures. The results reveal substantial problems with the validities of the measures, which might have been present but gone undetected in previous studies. A solution to these problems is essential for theoretical and practical progress in the field. The potential of the multimethod approach for this enterprise is discussed.

Previews. Unleashing Cardiopoiesis: a Novel Role for G-CSF

Cell Stem Cell. Mar, 2010  |  Pubmed ID: 20207218

Identifying pathways for cardiac muscle creation is a paramount objective of cardiac stem cell biology. In this issue of Cell Stem Cell, Shimoji and colleagues (2010) report the unforeseen ability of granulocyte colony-stimulating factor (G-CSF) to drive cardiopoiesis in mouse, primate, and human pluripotent cells.

Fresh Goat's Milk for Infants: Myths and Realities--a Review

Pediatrics. Apr, 2010  |  Pubmed ID: 20231186

Many infants are exclusively fed unmodified goat's milk as a result of cultural beliefs as well as exposure to false online information. Anecdotal reports have described a host of morbidities associated with that practice, including severe electrolyte abnormalities, metabolic acidosis, megaloblastic anemia, allergic reactions including life-threatening anaphylactic shock, hemolytic uremic syndrome, and infections. We describe here an infant who was fed raw goat's milk and sustained intracranial infarctions in the setting of severe azotemia and hypernatremia, and we provide a comprehensive review of the consequences associated with this dangerous practice.

Mechanical Vs Manual Manipulation for Low Back Pain: an Observational Cohort Study

Journal of Manipulative and Physiological Therapeutics. Mar-Apr, 2010  |  Pubmed ID: 20350672

This is an observational prospective cohort study to explore the treatment effect of mechanical vs manual manipulation for acute low back pain.

Photoionization of Three Isomers of the C9H7 Radical

The Journal of Physical Chemistry. A. Apr, 2010  |  Pubmed ID: 19813740

Three resonance-stabilized radicals, 1-indenyl (Ind), 1-phenylpropargyl (1PPR), and 3-phenylpropargyl (3PPR), all isomers of the composition C(9)H(7), were generated by jet flash pyrolysis. Their photoionization was examined by VUV synchrotron radiation. The mass spectra show a clean and efficient radical generation when the pyrolysis is turned on. To study the photoionization, photoion yield measurements and threshold photoionization spectroscopy techniques were applied. We determined adiabatic ionization energies (IE(ad)) of 7.53 eV for Ind, 7.20 eV for 3PPR, and 7.4 eV for 1PPR. Ab initio calculations show no major change in geometry upon ionization, in agreement with ionization from a nonbonding molecular orbital. The IEs were also computed and are in agreement with the measured ones. The difference in the IE might allow a distinction of the three isomers in flames. In the indenyl spectrum, an excited a(+) (3)B(2) state of the cation was identified at 8.10 eV, which shows a low-energy vibrational progression of 61 meV. Furthermore, we have examined the dissociative photoionization of the precursors. The indenyl precursor, 1-indenyl bromide, undergoes dissociative photoionization to Ind(+). An appearance energy (AE(0K)) of 10.2 eV was obtained from fitting the experimental breakdown diagram. A binding energy of 1.8 eV can thus be determined for the C-Br bond in 1-indenyl bromide. The phenylpropargyl precursors 1PPBr (1-phenylpropargyl bromide/3-phenyl-3-bromopropyne) and 3PPBr (3-phenylpropargyl bromide/1-phenyl-3-bromopropyne) also lose a bromine atom upon dissociative photoionization. Approximate appearance energies of 9.8 eV for 3PPBr and 9.3 eV for 1PPBr have been determined.

Anatomic Stem Design Reduces Risk of Thin Cement Mantles in Primary Hip Replacement

Archives of Orthopaedic and Trauma Surgery. Jan, 2010  |  Pubmed ID: 19513737

To analyse the influence of femoral stem design in the lateral plane (anatomic vs. straight) on the cement mantle quality.

Mid-term Results of 155 Patients Treated with a Collum Femoris Preserving (CFP) Short Stem Prosthesis

International Orthopaedics. May, 2011  |  Pubmed ID: 20437260

Short stem prostheses that preserve the femoral neck are becoming more and more popular. The CFP (collum femoris preserving) has been introduced especially for the treatment of younger patients. However, information about remodelling, complications and learning curve are thus far rare. We present a retrospective study of 155 patients (average age 59.3 ± 9.9 years) who underwent total hip replacement with the CFP prosthesis. Follow-up was obtained 74.3 ± 9.4 months postoperatively. The Harris hip score revealed excellent and good results in 96%. One stem had to be exchanged due to aseptic loosening revealing a survival rate of 99% and 100% for stem and cup, respectively. Radiological analysis showed typical patterns of remodelling with appearance of cortical thickening predominantly in the distal part of the prosthesis. Implant related revision rate was <1%, with further complication rate independent of the surgeon's individual experience. With regard to outcome, survivorship and complication rate, the medium-term results of the CFP prosthesis are promising.

The Association Between Abnormal Birth History and Growth in Children with CKD

Clinical Journal of the American Society of Nephrology : CJASN. Jan, 2011  |  Pubmed ID: 21030583

Poor linear growth is a well described complication of chronic kidney disease (CKD). This study evaluated whether abnormal birth history defined by low birth weight (LBW; <2500 g), prematurity (gestational age <36 weeks), small for gestational age (SGA; birth weight <10th percentile for gestational age), or intensive care unit (ICU) at birth were risk factors for poor growth outcomes in children with CKD.

Modulation of Human Embryonic Stem Cell-derived Cardiomyocyte Growth: a Testbed for Studying Human Cardiac Hypertrophy?

Journal of Molecular and Cellular Cardiology. Feb, 2011  |  Pubmed ID: 21047517

Human embryonic stem cell-derived cardiomyocytes (hESC-CM) are being developed for tissue repair and as a model system for cardiac physiology and pathophysiology. However, the signaling requirements of their growth have not yet been fully characterized. We showed that hESC-CM retain their capacity for increase in size in long-term culture. Exposing hESC-CM to hypertrophic stimuli such as equiaxial cyclic stretch, angiotensin II, and phenylephrine (PE) increased cell size and volume, percentage of hESC-CM with organized sarcomeres, levels of ANF, and cytoskeletal assembly. PE effects on cell size were separable from those on cell cycle. Changes in cell size by PE were completely inhibited by p38-MAPK, calcineurin/FKBP, and mTOR blockers. p38-MAPK and calcineurin were also implicated in basal cell growth. Inhibitors of ERK, JNK, and CaMK II partially reduced PE effects; PKG or GSK3β inhibitors had no effect. The role of p38-MAPK was confirmed by an additional pharmacological inhibitor and adenoviral infection of hESC-CM with a dominant-inhibitory form of p38-MAPK. Infection of hESC-CM with constitutively active upstream MAP2K3b resulted in an increased cell size, sarcomere and cytoskeletal assembly, elongation of the cells, and induction of ANF mRNA levels. siRNA knockdown of p38-MAPK inhibited PE-induced effects on cell size. These results reveal an important role for active protein kinase signaling in hESC-CM growth and hypertrophy, with potential implications for hESC-CM as a novel in vitro test system. This article is part of a special issue entitled, "Cardiovascular Stem Cells Revisited".

Cardiopoietic Factors: Extracellular Signals for Cardiac Lineage Commitment

Circulation Research. Jan, 2011  |  Pubmed ID: 21212394

Cardiac muscle creation during embryogenesis requires extracellular instructive signals that are regulated precisely in time and space, intersecting with intracellular genetic programs that confer or fashion the ability of the cells to respond. Unmasking the essential signals for cardiac lineage decisions has paramount importance for cardiac development and regenerative medicine, including the directed differentiation of progenitor and stem cells to a cardiac muscle fate.

Equivalent Benefits/risks of Cervical Manipulation and Mobilization

Archives of Physical Medicine and Rehabilitation. Feb, 2011  |  Pubmed ID: 21272733

Inhibition of Transcription, Expression, and Secretion of the Vascular Epithelial Growth Factor in Human Epithelial Endometriotic Cells by Romidepsin

Fertility and Sterility. Apr, 2011  |  Pubmed ID: 21295294

To investigate whether the histone deacetylase (HDAC) inhibitor romidepsin down-regulates VEGF (vascular endothelial growth factor) gene expression and abrogates VEGF protein secretion in human epithelial endometriotic cells.

Cardiac Muscle Regeneration: Lessons from Development

Genes & Development. Feb, 2011  |  Pubmed ID: 21325131

The adult human heart is an ideal target for regenerative intervention since it does not functionally restore itself after injury yet has a modest regenerative capacity that could be enhanced by innovative therapies. Adult cardiac cells with regenerative potential share gene expression signatures with early fetal progenitors that give rise to multiple cardiac cell types, suggesting that the evolutionarily conserved regulatory networks that drive embryonic heart development might also control aspects of regeneration. Here we discuss commonalities of development and regeneration, and the application of the rich developmental biology heritage to achieve therapeutic regeneration of the human heart.

A Hospital-based Standardized Spine Care Pathway: Report of a Multidisciplinary, Evidence-based Process

Journal of Manipulative and Physiological Therapeutics. Feb, 2011  |  Pubmed ID: 21334541

A health care facility (Jordan Hospital) implemented a multidimensional spine care pathway (SCP) using the National Center for Quality Assurance (NCQA) Back Pain Recognition Program (BPRP) as its foundation. The purpose of this report is to describe the implementation and results of a multidisciplinary, evidence-based, standardized process to improve clinical outcomes and reduce costs associated with treatment and diagnostic testing.

TGF-β1-activated Kinase-1 Regulates Inflammation and Fibrosis in the Obstructed Kidney

American Journal of Physiology. Renal Physiology. Jun, 2011  |  Pubmed ID: 21367917

Activation of c-Jun amino kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and the transcription factor nuclear factor-κB (NF-κB) drives renal inflammation and fibrosis. However, the upstream MAP kinase kinase kinase (MAP3K) enzyme(s) that activate these pathways in kidney disease are unknown. We determined the role of one candidate MAP3K enzyme, transforming growth factor-β1-activated kinase-1 (TAK1/ MAP3K7), in activation of JNK, p38, and NF-κB in the obstructed kidney using conditional gene deletion in adult mice, and assessed the potential protective effect of TAK1 deletion on renal pathology. TAK1 deletion in cultured tubular epithelial cells substantially inhibited IL-1 and TNF-α-induced JNK, p38, and NF-κB signaling and the proinflammatory response. Map3k7(f/f)Cre-ER(TM) mice (in which tamoxifen induces global TAK1 deletion) and control Map3k7(f/f) mice were given tamoxifen at the time of unilateral ureteric obstruction (UUO) and then killed 2, 4, or 5 days later. Tamoxifen-treated control Map3k7(f/f) mice showed the expected activation of JNK, p38, and NF-κB signaling on days 2, 4, and 5, with macrophage infiltration and upregulation of mRNA levels of proinflammatory molecules (IL-1α, TNF-α, NOS2, and CCL2). Control Map3k7(f/f) mice also showed interstitial myofibroblast accumulation and collagen deposition in the obstructed kidney. Tamoxifen treatment of Map3k7(f/f)Cre-ER(TM) mice caused a 60% reduction in renal TAK1 expression on day 4 and >80% on day 5 UUO. Coincident with TAK1 deletion, activation of JNK, p38, and NF-κB signaling was markedly suppressed on days 4 to 5 UUO, which halted renal macrophage accumulation and expression of proinflammatory molecules. TAK1 deletion also halted the development of renal fibrosis in terms of myofibroblast accumulation, collagen deposition, and expression of profibrotic molecules. In conclusion, these studies establish TAK1 as a major upstream activator of JNK, p38, and NF-κB signaling in the obstructed kidney, and they define a pathologic role for TAK1 in renal inflammation and fibrosis.

ERCC5 P.Asp1104His and ERCC2 P.Lys751Gln Polymorphisms Are Independent Prognostic Factors for the Clinical Course of Melanoma

The Journal of Investigative Dermatology. Jun, 2011  |  Pubmed ID: 21390047

Genetic variants in DNA repair enzymes contribute to the susceptibility to cutaneous melanoma; consequently, we analyzed whether common nonsynonymous single-nucleotide polymorphisms in DNA repair enzyme genes might also influence the course of disease. To this end, we determined eight polymorphisms of seven different DNA repair enzymes in 742 patients with cutaneous melanoma, and correlated these with overall survival. Univariate Cox proportional hazards model analyses revealed that ERCC5 (XPG) 1104 His/His was significantly associated with impaired survival. Indeed, the univariate hazard ratio (HR) was 2.8 times higher for patients with ERCC5 1104 His/His (P<0.001) compared with ERCC5 1104 Asp/Asp. Accordingly, the 5-year survival rate was 55% (95% confidence interval 43-71) for patients with ERCC5 1104 His/His, whereas 82% (95% confidence interval 78-86) of patients with ERCC5 1104 Asp/Asp were still alive at this time. Importantly, adjusted Cox regression analysis not only confirmed ERCC5 1104 His/His as an independent prognostic factor (multivariate HR=4.5; P<0.001), but also revealed the significant impact of ERCC2 (XPD) 751 Gln/Gln on prognosis, with a 2.2-fold increased HR compared with ERCC2 751 Lys/Lys (P=0.009). Thus, ERCC5 codon 1104 and ERCC2 codon 751 polymorphisms are independent prognostic factors in patients with cutaneous melanoma.

Predictive Power of Hepatitis B 1762T/1764A Mutations in Plasma for Hepatocellular Carcinoma Risk in Qidong, China

Carcinogenesis. Jun, 2011  |  Pubmed ID: 21474708

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality with nearly 700,000 deaths occurring annually. Hepatitis B virus (HBV) is a major contributor to HCC and acquired mutations in the HBV genome may accelerate its pathogenesis. In this study, a matched case-control investigation of 345 men who died of HCC and 625 controls were nested within a cohort of male hepatitis B surface antigen (HBsAg) carriers from Qidong, China. Matched preserving odds ratios (ORs) were used as a measure of association and 95% confidence intervals (CIs) as a measure of precision. Real-time polymerase chain reaction allowed for a quantitative comparison of the levels of the HBV 1762(T)/1764(A) mutation in cases and controls. A total of 278 (81%) of the cases were positive for the HBV 1762(T)/1764(A) mutation compared with 250 (40%) of the controls. The matched preserving OR of 6.72 (95% CI: 4.66 to 9.68) strongly indicated that cases were significantly more probably than controls to have the mutation. Plasma levels of DNA harboring the HBV mutation were on average 15-fold higher in cases compared with controls (P < 0.001). Most strikingly, the level of the mutation in the 20 controls who later developed and died of HCC were on average 274-fold higher than controls who did not develop HCC. Thus, within this cohort of HBsAg carriers at high risk of developing HCC, individuals positive for the HBV 1762(T)/1764(A) mutation at enrollment were substantially more probably to subsequently develop HCC, with a higher concentration of the mutation in plasma enhancing predisposition for cancer development.

Development. A Cardiac Nonproliferation Treaty

Science (New York, N.Y.). Apr, 2011  |  Pubmed ID: 21512022

An Integrated Theory of Whole Number and Fractions Development

Cognitive Psychology. Jun, 2011  |  Pubmed ID: 21569877

This article proposes an integrated theory of acquisition of knowledge about whole numbers and fractions. Although whole numbers and fractions differ in many ways that influence their development, an important commonality is the centrality of knowledge of numerical magnitudes in overall understanding. The present findings with 11- and 13-year-olds indicate that, as with whole numbers, accuracy of fraction magnitude representations is closely related to both fractions arithmetic proficiency and overall mathematics achievement test scores, that fraction magnitude representations account for substantial variance in mathematics achievement test scores beyond that explained by fraction arithmetic proficiency, and that developing effective strategies plays a key role in improved knowledge of fractions. Theoretical and instructional implications are discussed.

Molecular Mechanism of the E99K Mutation in Cardiac Actin (ACTC Gene) That Causes Apical Hypertrophy in Man and Mouse

The Journal of Biological Chemistry. Aug, 2011  |  Pubmed ID: 21622575

We generated a transgenic mouse model expressing the apical hypertrophic cardiomyopathy-causing mutation ACTC E99K at 50% of total heart actin and compared it with actin from patients carrying the same mutation. The actin mutation caused a higher Ca(2+) sensitivity in reconstituted thin filaments measured by in vitro motility assay (2.3-fold for mice and 1.3-fold for humans) and in skinned papillary muscle. The mutation also abolished the change in Ca(2+) sensitivity normally linked to troponin I phosphorylation. MyBP-C and troponin I phosphorylation levels were the same as controls in transgenic mice and human carrier heart samples. ACTC E99K mice exhibited a high death rate between 28 and 45 days (48% females and 22% males). At 21 weeks, the hearts of the male survivors had enlarged atria, increased interstitial fibrosis, and sarcomere disarray. MRI showed hypertrophy, predominantly at the apex of the heart. End-diastolic volume and end-diastolic pressure were increased, and relaxation rates were reduced compared with nontransgenic littermates. End-systolic pressures and volumes were unaltered. ECG abnormalities were present, and the contractile response to β-adrenergic stimulation was much reduced. Older mice (29-week-old females and 38-week-old males) developed dilated cardiomyopathy with increased end-systolic volume and continuing increased end-diastolic pressure and slower contraction and relaxation rates. ECG showed atrial flutter and frequent atrial ectopic beats at rest in some ACTC E99K mice. We propose that the ACTC E99K mutation causes higher myofibrillar Ca(2+) sensitivity that is responsible for the sudden cardiac death, apical hypertrophy, and subsequent development of heart failure in humans and mice.

Occult Hypermobility of the Craniocervical Junction: a Case Report and Review

The Journal of Orthopaedic and Sports Physical Therapy. Jun, 2011  |  Pubmed ID: 21628827

Resident's case problem.

Going Paperless: Implementing an Electronic Laboratory Notebook in a Bioanalytical Laboratory

Bioanalysis. Jul, 2011  |  Pubmed ID: 21702721

AIT Bioscience, a bioanalytical CRO, implemented a highly configurable, Oracle-based electronic laboratory notebook (ELN) from IDBS called E-WorkBook Suite (EWBS). This ELN provides a high degree of connectivity with other databases, including Watson LIMS. Significant planning and training, along with considerable design effort and template validation for dozens of laboratory workflows were required prior to EWBS being viable for either R&D or regulated work. Once implemented, EWBS greatly reduced the need for traditional quality review upon experiment completion. Numerous real-time error checks occur automatically when conducting EWBS experiments, preventing the majority of laboratory errors by pointing them out while there is still time to correct any issues. Auditing and reviewing EWBS data are very efficient, because all data are forever securely (and even remotely) accessible, provided a reviewer has appropriate credentials. Use of EWBS significantly increases both data quality and laboratory efficiency.

UW is Superior Compared with HTK After Prolonged Preservation of Renal Grafts

The Journal of Surgical Research. Sep, 2011  |  Pubmed ID: 21741054

In recent clinical studies, the efficacy of histidine-tryptophan-ketoglutarate (HTK) in kidney transplantation was questioned. This study compares the efficacy of University of Wisconsin (UW) and HTK solutions on transplantation outcome.

The Establishment of a Primary Spine Care Practitioner and Its Benefits to Health Care Reform in the United States

Chiropractic & Manual Therapies. 2011  |  Pubmed ID: 21777444

It is widely recognized that the dramatic increase in health care costs in the United States has not led to a corresponding improvement in the health care experience of patients or the clinical outcomes of medical care. In no area of medicine is this more true than in the area of spine related disorders (SRDs). Costs of medical care for SRDs have skyrocketed in recent years. Despite this, there is no evidence of improvement in the quality of this care. In fact, disability related to SRDs is on the rise. We argue that one of the key solutions to this is for the health care system to have a group of practitioners who are trained to function as primary care practitioners for the spine. We explain the reasons we think a primary spine care practitioner would be beneficial to patients, the health care system and society, some of the obstacles that will need to be overcome in establishing a primary spine care specialty and the ways in which these obstacles can be overcome.

EPO and Super-EPO: Erythropoietins Direct Neoangiogenesis by Cardiac Progenitor Cells

Cell Stem Cell. Aug, 2011  |  Pubmed ID: 21816360

Erythropoietin, the red blood cell-making cytokine, is also a potential cytoprotective agent in heart disease. In this issue of Cell Stem Cell, Hoch et al. (2011) use two heart failure models, including chemotherapeutic cardiotoxicity, to reveal a mechanistic connection between reduced cardiomyocyte production of erythropoietin and neoangiogenesis by cardiac progenitors.

Fetal Reduction for Hyperreactio Luteinalis

Fertility and Sterility. Oct, 2011  |  Pubmed ID: 21820654

To present an unusual case of hyperreactio luteinalis and a comprehensive review of the recent literature. Hyperreactio luteinalis is a benign ovarian condition of pregnancy that at times becomes life threatening. The medical literature provides only case reports.

Relations Among Conceptual Knowledge, Procedural Knowledge, and Procedural Flexibility in Two Samples Differing in Prior Knowledge

Developmental Psychology. Nov, 2011  |  Pubmed ID: 21823791

Competence in many domains rests on children developing conceptual and procedural knowledge, as well as procedural flexibility. However, research on the developmental relations between these different types of knowledge has yielded unclear results, in part because little attention has been paid to the validity of the measures or to the effects of prior knowledge on the relations. To overcome these problems, we modeled the three constructs in the domain of equation solving as latent factors and tested (a) whether the predictive relations between conceptual and procedural knowledge were bidirectional, (b) whether these interrelations were moderated by prior knowledge, and (c) how both constructs contributed to procedural flexibility. We analyzed data from 2 measurement points each from two samples (Ns = 228 and 304) of middle school students who differed in prior knowledge. Conceptual and procedural knowledge had stable bidirectional relations that were not moderated by prior knowledge. Both kinds of knowledge contributed independently to procedural flexibility. The results demonstrate how changes in complex knowledge structures contribute to competence development.

Complementary and Alternative Medicine in the Treatment of Pain in Fibromyalgia: a Systematic Review of Randomized Controlled Trials

Journal of Manipulative and Physiological Therapeutics. Sep, 2011  |  Pubmed ID: 21875523

The purpose of this study was to systematically review the literature for randomized trials of complementary and alternative medicine (CAM) interventions for fibromyalgia (FM).

Prevalence and Correlates of Multiple Cardiovascular Risk Factors in Children with Chronic Kidney Disease

Clinical Journal of the American Society of Nephrology : CJASN. Dec, 2011  |  Pubmed ID: 21980183

Although prevalence of traditional cardiovascular risk factors (CVRF) has been described in children with CKD, the frequency with which these CVRF occur concomitantly and the clinical characteristics associated with multiple CVRF are unknown. This study determined the prevalence and characteristics of multiple CVRF in children in the Chronic Kidney Disease in Children study.

Who Participates in Seasonal Influenza Vaccination? Past Behavior Moderates the Prediction of Adherence

Advances in Preventive Medicine. 2011  |  Pubmed ID: 21991430

Background. Vaccination effectively prevents seasonal influenza. To promote vaccination adherence, it is necessary to understand the motivational process that underlies vaccination behavior. This was examined along with the moderating influence of past behavior on intention formation. Methods. German employees (N = 594) completed questionnaires at baseline and at 7-month followup. Regression analyses were conducted for mediation and moderated mediation. Results. Intention at Time 1 mediated the effect of risk perception, and positive and negative outcome expectancies on Time 2 vaccination. Past behavior moderated this effect: there was a mediation effect for risk perception and outcome expectancies only for those individuals who did not participate annually. Conclusions. Risk perception and outcome expectancies influenced intentions to receive vaccination, which in turn predicted participation. Hence, these social-cognitive variables could be targeted in vaccination campaigns to increase intentions. However, vaccination experience affected the formation of intentions and should be accounted for when developing interventions.

The Structure of Active Opsin As a Basis for Identification of GPCR Agonists by Dynamic Homology Modelling and Virtual Screening Assays

FEBS Letters. Nov, 2011  |  Pubmed ID: 22027616

Most of the currently available G protein-coupled receptor (GPCR) crystal structures represent an inactive receptor state, which has been considered to be suitable only for the discovery of antagonists and inverse agonists in structure-based computational ligand screening. Using the β(2)-adrenergic receptor (B2AR) as a model system, we show that a dynamic homology model based on an "active" opsin structure without further incorporation of experimental data performs better than the crystal structure of the inactive B2AR in finding agonists over antagonists/inverse agonists. Such "active-like state" dynamic homology models can therefore be used to selectively identify GPCR agonists in in silico ligand libraries.

BRCA2 Deficiency Exaggerates Doxorubicin-induced Cardiomyocyte Apoptosis and Cardiac Failure

The Journal of Biological Chemistry. Dec, 2011  |  Pubmed ID: 22157755

The tumor suppressor BRCA2 plays an important role in the repair of DNA damage and loss of BRCA2 predisposes carriers to breast and ovarian cancers. Doxorubicin (DOX) remains the cornerstone of chemotherapy in such individuals. However, it is often associated with cardiac failure which once manifests carries a poor prognosis. Since BRCA2 regulates genome-wide stability and facilitates DNA damage repair, we hypothesized that loss of BRCA2 may increase susceptibility to DOX-induced cardiac failure. To this aim, we generated cardiomyocyte-specific BRCA2 knockout (CM-BRCA2-/-) mice using the Cre-loxP technology, and evaluated their basal and post-DOX treatment phenotypes. Although CM-BRCA2-/- mice exhibited no basal cardiac phenotype, DOX treatment resulted in markedly greater cardiac dysfunction and mortality in CM-BRCA2-/- mice compared to control mice. Apoptosis in left ventricular (LV) sections from CM-BRCA2-/- mice, compared to that in corresponding sections from wild-type (WT) littermate controls, was also significantly enhanced after DOX treatment. Microscopic examination of LV sections from DOX-treated CM-BRCA2-/- mice revealed a greater number of DNA double stranded breaks (DSBs) and the absence of RAD51-foci formation, an essential marker of DSB repair. The levels of P53 and the P53-related pro-apoptotic proteins, PUMA and Bax, were significantly increased in samples from CM-BRCA2-/- mice. This corresponded with increased Bax to Bcl-2 ratios and elevated cytochrome c release in the LV sections of DOX-treated CM-BRCA2-/- mice. Taken together, these data suggest a critical and previously unrecognized role of BRCA2 as a gatekeeper of DOX-induced cardiomyocyte apoptosis and susceptibility to overt cardiac failure. Pharmacogenomic studies evaluating cardiac function in BRCA2 mutation carriers treated with doxorubicin are encouraged.

BRCA1 is an Essential Regulator of Heart Function and Survival Following Myocardial Infarction

Nature Communications. 2011  |  Pubmed ID: 22186889

The tumour suppressor BRCA1 is mutated in familial breast and ovarian cancer but its role in protecting other tissues from DNA damage has not been explored. Here we show a new role for BRCA1 as a gatekeeper of cardiac function and survival. In mice, loss of BRCA1 in cardiomyocytes results in adverse cardiac remodelling, poor ventricular function and higher mortality in response to ischaemic or genotoxic stress. Mechanistically, loss of cardiomyocyte BRCA1 results in impaired DNA double-strand break repair and activated p53-mediated pro-apoptotic signalling culminating in increased cardiomyocyte apoptosis, whereas deletion of the p53 gene rescues BRCA1-deficient mice from cardiac failure. In human adult and fetal cardiac tissues, ischaemia induces double-strand breaks and upregulates BRCA1 expression. These data reveal BRCA1 as a novel and essential adaptive response molecule shielding cardiomyocytes from DNA damage, apoptosis and heart dysfunction. BRCA1 mutation carriers, in addition to risk of breast and ovarian cancer, may be at a previously unrecognized risk of cardiac failure.

A Sensor Network to IPhone Interface Separating Continuous and Sporadic Processes in Mobile Telemedicine

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. Aug, 2011  |  Pubmed ID: 22254611

In this contribution, a new concept for interfacing sensor network nodes (motes) and smartphones is presented for the first time. In the last years, a variety of telemedicine applications on smartphones for data reception, display and transmission have been developed. However, it is not always practical or possible to have a smartphone application running continuously to accomplish these tasks. The presented system allows receiving and storing data continuously using a mote and visualizing or sending it on the go using the smartphone as user interface only when desired. Thus, the processes of data reception and storage run on a safe system consuming less energy and the smartphone's potential along with its battery are not demanded continuously. Both, system concept and realization with an Apple iPhone are presented.

Ephrin-B1 Is a Novel Specific Component of the Lateral Membrane of the Cardiomyocyte and Is Essential for the Stability of Cardiac Tissue Architecture Cohesion

Circulation Research. Feb, 2012  |  Pubmed ID: 22302788

Rationale:Cardiac tissue cohesion relying on highly ordered cardiomyocytes (CM) interactions is critical because most cardiomyopathies are associated with tissue remodeling and architecture alterations.Objective:Eph/ephrin system constitutes a ubiquitous system coordinating cellular communications which recently emerged as a major regulator in adult organs. We examined if eph/ephrin could participate in cardiac tissue cyto-organization.Methods and Results:We reported the expression of cardiac ephrin-B1 in both endothelial cells and for the first time in CMs where ephrin-B1 localized specifically at the lateral membrane. Ephrin-B1 knock-out (KO) mice progressively developed cardiac tissue disorganization with loss of adult CM rod-shape and sarcomeric and intercalated disk structural disorganization confirmed in CM-specific ephrin-B1 KO mice. CMs lateral membrane exhibited abnormal structure by electronic microscopy and notably increased stiffness by atomic force microscopy. In wild-type CMs, ephrin-B1 interacted with claudin-5/ZO-1 complex at the lateral membrane, wherease the complex disappeared in KO/CM-specific ephrin-B1 KO mice. Ephrin-B1 deficiency resulted in decreased mRNA expression of CM basement membrane components and disorganized fibrillar collagen matrix, independently of classical integrin/dystroglycan system. KO/CM-specific ephrin-B1 KO mice exhibited increased left ventricle diameter and delayed atrioventricular conduction. Under pressure overload stress, KO mice were prone to death and exhibited striking tissue disorganization. Finally, failing CMs displayed downregulated ephrin-B1/claudin-5 gene expression linearly related to the ejection fraction.Conclusions:Ephrin-B1 is necessary for cardiac tissue architecture cohesion by stabilizing the adult CM morphology through regulation of its lateral membrane. Because decreased ephrin-B1 is associated with molecular/functional cardiac defects, it could represent a new actor in the transition toward heart failure.

Improved Estimation of the Distribution of Suppressed Plasma HIV-1 RNA in Men Receiving Effective Antiretroviral Therapy

Journal of Acquired Immune Deficiency Syndromes (1999). Jan, 2012  |  Pubmed ID: 22217679

ABSTRACT: Plasma HIV-1 RNA was measured in 306 samples, collected from 273 highly active antiretroviral therapy (HAART)-experienced men, using both the Roche COBAS TaqMan (limit of detection [LD]=20 copies/mL) and Roche Amplicor (LD=50 copies/mL) assays. Mixtures of Gaussian distributions incorporating left-censored data were used in analyses. The more sensitive TaqMan assay estimated that 23% and 0.0003% of HIV-1 RNA values would be below 1 copy/mL and 1 copy/3L, respectively. This is in sharp contrast to the overestimation provided by the less sensitive Amplicor assay, whereby the corresponding predicted percentages were 51% and 1%. Both assays appropriately characterized sub-optimal virologic response as the rightmost peaks of both distributions provided an excellent fit to the observed data. Our results based on a widely available 20 copies/mL sensitive assay reproduce those obtained using customized assays that quantified HIV-1 RNA values as low as 1 copy/mL.

The UniProt-GO Annotation Database in 2011

Nucleic Acids Research. Jan, 2012  |  Pubmed ID: 22123736

The GO annotation dataset provided by the UniProt Consortium (GOA: http://www.ebi.ac.uk/GOA) is a comprehensive set of evidenced-based associations between terms from the Gene Ontology resource and UniProtKB proteins. Currently supplying over 100 million annotations to 11 million proteins in more than 360,000 taxa, this resource has increased 2-fold over the last 2 years and has benefited from a wealth of checks to improve annotation correctness and consistency as well as now supplying a greater information content enabled by GO Consortium annotation format developments. Detailed, manual GO annotations obtained from the curation of peer-reviewed papers are directly contributed by all UniProt curators and supplemented with manual and electronic annotations from 36 model organism and domain-focused scientific resources. The inclusion of high-quality, automatic annotation predictions ensures the UniProt GO annotation dataset supplies functional information to a wide range of proteins, including those from poorly characterized, non-model organism species. UniProt GO annotations are freely available in a range of formats accessible by both file downloads and web-based views. In addition, the introduction of a new, normalized file format in 2010 has made for easier handling of the complete UniProt-GOA data set.