Endothelin-1-induced alterations in phenylephrine-induced contractile responses are largely additive in physiologically diverse rabbit vasculature

ABSTRACT Endothelin-1 (ET-1) is an important modulator of vasomotor tone that is thought to participate in the etiology of cardiovascular disease by virtue of its ability to amplify the contractile responses of vascular smooth muscle cells to the effects of other vasoactive agents. Despite this fact, few studies have quantitated the expected contribution of ET-1 to the enhanced contractile responses elicited in the presence of another spasmogen. As a first step in this direction, ET-1 and phenylephrine (PE) were used to evaluate the effects of co-activation of the ET A/B or alpha-1 adrenergic receptors, respectively, on contractile responses in isolated rings of rabbit aorta, mesenteric and femoral artery, or strips of corporal tissue. Cumulative steady-state concentration-response curves (CRCs) were constructed to PE alone before the construction of a CRC to ET-1 alone, or a mixture of PE and ET-1 using a previously described drug concentration paradigm. Computer fits of the logistic equation to CRC data revealed that in all vascular tissues examined, the partial substitution of PE with ET-1 was associated with a significant vessel-dependent Ϸ3-to 30-fold leftward shift in the CRC (P Ͻ .01, Student's t test for paired samples), as judged by a significant increase in the pEC 50 (negative logarithm of the concentration of drug that elicits one-half of the calculated maximal effect), in the absence of any detectable effect on the calculated maximal contractile response (E max ) or the slope factor (). A theoretical CRC constructed using the Pö ch and Holzmann method for equiactive substitution demonstrated that the responses to mixtures of PE and ET-1 were often the result of simple additivity of agonist effects in these preparations, and thus, were "expected" based on detailed knowledge of the individual effects of these two agonists. Regardless of the precision of the Poch and Holzmann CRC in predicting the effects of this drug mixture in these vascular tissues, comparison of the "expected" contractile response with the "observed" response represents an important first step toward establishing a more uniform nomenclature for describing the physiological/pathophysiological effects of mixtures of drugs on diverse vasculature

Achieving Acetylcholine Receptor Clustering in Tissue-Engineered Skeletal Muscle Constructs In vitro through a Materials-Directed Agrin Delivery Approach

Volumetric muscle loss (VML) can result from trauma, infection, congenital anomalies, or surgery, and produce permanent functional and cosmetic deficits. There are no effective treatment options for VML injuries, and recent advances toward development of muscle constructs lack the ability to achieve innervation necessary for long-term function. We sought to develop a proof-of-concept biomaterial construct that could achieve acetylcholine receptor (AChR) clustering on muscle-derived cells (MDCs) in vitro. The approach consisted of the presentation of neural (Z+) agrin from the surface of microspheres embedded with a fibrin hydrogel to muscle cells (C2C12 cell line or primary rat MDCs). AChR clustering was spatially restricted to areas of cell (C2C12)-microsphere contact when the microspheres were delivered in suspension or when they were incorporated into a thin (2D) fibrin hydrogel. AChR clusters were observed from 16 to 72 h after treatment when Z+ agrin was adsorbed to the microspheres, and for greater than 120 h when agrin was covalently coupled to the microspheres. Little to no AChR clustering was observed when agrin-coated microspheres were delivered from specially designed 3D fibrin constructs. However, cyclic stretch in combination with agrin-presenting microspheres led to dramatic enhancement of AChR clustering in cells cultured on these 3D fibrin constructs, suggesting a synergistic effect between mechanical strain and agrin stimulation of AChR clustering in vitro. These studies highlight a strategy for maintaining a physiological phenotype characterized by motor endplates of muscle cells used in tissue engineering strategies for muscle regeneration. As such, these observations may provide an important first step toward improving function of tissue-engineered constructs for treatment of VML injuries

Diagnostic and prognostic value of procalcitonin among febrile critically ill patients with prolonged ICU stay

<p>Abstract</p> <p>Background</p> <p>Procalcitonin (PCT) has been proposed as a diagnostic and prognostic sepsis marker, but has never been validated in febrile patients with prolonged ICU stay.</p> <p>Methods</p> <p>Patients were included in the study provided they were hospitalised in the ICU for > 10 days, were free of infection and presented a new episode of SIRS, with fever >38°C being obligatory. Fifty patients fulfilled the above criteria. PCT was measured daily during the ICU stay. The primary outcome was proven infection.</p> <p>Results</p> <p>Twenty-seven out of 50 patients were diagnosed with infection. Median PCT on the day of fever was 1.18 and 0.17 ng/ml for patients with and without proven infections (p < 0.001). The area under the curve for PCT was 0.85 (95% CI; 0.71-0.93), for CRP 0.65 (0.46-0.78) and for WBC 0.68 (0.49-0.81). A PCT level of 1 ng/mL yielded a negative predictive value of 72% for the presence of infection, while a PCT of 1.16 had a specificity of 100%. A two-fold increase of PCT between fever onset and the previous day was associated with proven infection (p 0.001) (OR = 8.55; 2.4-31.1), whereas a four-fold increase of PCT of any of the 6 preceding days was associated with a positive predictive value exceeding 69.65%. A PCT value less than 0.5 ng/ml on the third day after the advent of fever was associated with favorable survival (p 0.01).</p> <p>Conclusion</p> <p>The reported data support that serial serum PCT may be a valuable diagnostic and prognostic marker in febrile chronic critically ill patients.</p

A Study of Time-Dependent CP-Violating Asymmetries and Flavor Oscillations in Neutral B Decays at the Upsilon(4S)

We present a measurement of time-dependent CP-violating asymmetries in neutral B meson decays collected with the BABAR detector at the PEP-II asymmetric-energy B Factory at the Stanford Linear Accelerator Center. The data sample consists of 29.7 ${\rm fb}^{-1}$ recorded at the $\Upsilon(4S)$ resonance and 3.9 ${\rm fb}^{-1}$ off-resonance. One of the neutral B mesons, which are produced in pairs at the $\Upsilon(4S)$, is fully reconstructed in the CP decay modes $J/\psi K^0_S$, $\psi(2S) K^0_S$, $\chi_{c1} K^0_S$, $J/\psi K^{*0}$ ($K^{*0}\to K^0_S\pi^0$) and $J/\psi K^0_L$, or in flavor-eigenstate modes involving $D^{(*)}\pi/\rho/a_1$ and $J/\psi K^{*0}$ ($K^{*0}\to K^+\pi^-$). The flavor of the other neutral B meson is tagged at the time of its decay, mainly with the charge of identified leptons and kaons. The proper time elapsed between the decays is determined by measuring the distance between the decay vertices. A maximum-likelihood fit to this flavor eigenstate sample finds $\Delta m_d = 0.516\pm 0.016 {\rm (stat)} \pm 0.010 {\rm (syst)} {\rm ps}^{-1}$. The value of the asymmetry amplitude $\sin2\beta$ is determined from a simultaneous maximum-likelihood fit to the time-difference distribution of the flavor-eigenstate sample and about 642 tagged $B^0$ decays in the CP-eigenstate modes. We find $\sin2\beta=0.59\pm 0.14 {\rm (stat)} \pm 0.05 {\rm (syst)}$, demonstrating that CP violation exists in the neutral B meson system. (abridged)Comment: 58 pages, 35 figures, submitted to Physical Review

Measurement of the Branching Fraction for B- --> D0 K*-

We present a measurement of the branching fraction for the decay B- --> D0 K*- using a sample of approximately 86 million BBbar pairs collected by the BaBar detector from e+e- collisions near the Y(4S) resonance. The D0 is detected through its decays to K- pi+, K- pi+ pi0 and K- pi+ pi- pi+, and the K*- through its decay to K0S pi-. We measure the branching fraction to be B.F.(B- --> D0 K*-)= (6.3 +/- 0.7(stat.) +/- 0.5(syst.)) x 10^{-4}.Comment: 7 pages, 1 postscript figure, submitted to Phys. Rev. D (Rapid Communications

Evidence for the Rare Decay B -> K*ll and Measurement of the B -> Kll Branching Fraction

We present evidence for the flavor-changing neutral current decay $B\to K^*\ell^+\ell^-$ and a measurement of the branching fraction for the related process $B\to K\ell^+\ell^-$, where $\ell^+\ell^-$ is either an $e^+e^-$ or $\mu^+\mu^-$ pair. These decays are highly suppressed in the Standard Model, and they are sensitive to contributions from new particles in the intermediate state. The data sample comprises $123\times 10^6$ $\Upsilon(4S)\to B\bar{B}$ decays collected with the Babar detector at the PEP-II $e^+e^-$ storage ring. Averaging over $K^{(*)}$ isospin and lepton flavor, we obtain the branching fractions ${\mathcal B}(B\to K\ell^+\ell^-)=(0.65^{+0.14}_{-0.13}\pm 0.04)\times 10^{-6}$ and ${\mathcal B}(B\to K^*\ell^+\ell^-)=(0.88^{+0.33}_{-0.29}\pm 0.10)\times 10^{-6}$, where the uncertainties are statistical and systematic, respectively. The significance of the $B\to K\ell^+\ell^-$ signal is over $8\sigma$, while for $B\to K^*\ell^+\ell^-$ it is $3.3\sigma$.Comment: 7 pages, 2 postscript figues, submitted to Phys. Rev. Let

Synergy Between Intercellular Communication and Intracellular Ca2+ Handling in Arrhythmogenesis

Calcium is the primary signalling component of excitation-contraction coupling, the process linking electrical excitability of cardiac muscle cells to coordinated contraction of the heart. Understanding Ca2þ handling processes at the cellular level and the role of intercellular communication in the emergence of multicellular synchronization are key aspects in the study of arrhythmias. To probe these mechanisms, we have simulated cellular interactions on large scale arrays that mimic cardiac tissue, and where individual cells are represented by a mathematical model of intracellular Ca2þ dynamics. Theoretical predictions successfully reproduced experimental findings and provide novel insights on the action of two pharmacological agents (ionomycin and verapamil) that modulate Ca2þ signalling pathways via distinct mechanisms. Computational results have demonstrated how transitions between local synchronisation events and large scale wave formation are affected by these agents. Entrainment phenomena are shown to be linked to both ntracellular Ca2þ and coupling-specific dynamics in a synergistic manner. The intrinsic variability of the cellular matrix is also shown to affect emergent patterns of rhythmicity, providing insights into the origins of arrhythmogenic Ca2þ perturbations in cardiac tissue in situ

Measurement of the branching fraction and CP content for the decay B(0) -> D(*+)D(*-)

This is the pre-print version of the Article. The official published version can be accessed from the links below. Copyright @ 2002 APS.We report a measurement of the branching fraction of the decay B0→D*+D*- and of the CP-odd component of its final state using the BABAR detector. With data corresponding to an integrated luminosity of 20.4  fb-1 collected at the Υ(4S) resonance during 1999–2000, we have reconstructed 38 candidate signal events in the mode B0→D*+D*- with an estimated background of 6.2±0.5 events. From these events, we determine the branching fraction to be B(B0→D*+D*-)=[8.3±1.6(stat)±1.2(syst)]×10-4. The measured CP-odd fraction of the final state is 0.22±0.18(stat)±0.03(syst).This work is supported by DOE and NSF (USA), NSERC (Canada), IHEP (China), CEA and CNRS-IN2P3 (France), BMBF (Germany), INFN (Italy), NFR (Norway), MIST (Russia), and PPARC (United Kingdom). Individuals have received support from the A.P. Sloan Foundation, Research Corporation, and Alexander von Humboldt Foundation

Mitochondria-localized AMPK responds to local energetics and contributes to exercise and energetic stress-induced mitophagy

Mitochondria form a complex, interconnected reticulum that is maintained through coordination among biogenesis, dynamic fission, and fusion and mitophagy, which are initiated in response to various cues to maintain energetic homeostasis. These cellular events, which make up mitochondrial quality control, act with remarkable spatial precision, but what governs such spatial specificity is poorly understood. Herein, we demonstrate that specific isoforms of the cellular bioenergetic sensor, 5′ AMP-activated protein kinase (AMPKα1/α2/β2/γ1), are localized on the outer mitochondrial membrane, referred to as mitoAMPK, in various tissues in mice and humans. Activation of mitoAMPK varies across the reticulum in response to energetic stress, and inhibition of mitoAMPK activity attenuates exercise-induced mitophagy in skeletal muscle in vivo. Discovery of a mitochondrial pool of AMPK and its local importance for mitochondrial quality control underscores the complexity of sensing cellular energetics in vivo that has implications for targeting mitochondrial energetics for disease treatment

Measurement of the B0-anti-B0-Oscillation Frequency with Inclusive Dilepton Events

The $B^0$-$\bar B^0$ oscillation frequency has been measured with a sample of 23 million \B\bar B pairs collected with the BABAR detector at the PEP-II asymmetric B Factory at SLAC. In this sample, we select events in which both B mesons decay semileptonically and use the charge of the leptons to identify the flavor of each B meson. A simultaneous fit to the decay time difference distributions for opposite- and same-sign dilepton events gives $\Delta m_d = 0.493 \pm 0.012{(stat)}\pm 0.009{(syst)}$ ps$^{-1}$.Comment: 7 pages, 1 figure, submitted to Physical Review Letter