Chest dynamics asymmetry facilitates earlier detection of pneumothorax.

Pneumothorax is usually diagnosed when signs of life-threatening tension pneumothorax develop. The case report describes novel data derived from miniature superficial sensors that continuously monitored the amplitude and symmetry of the chest wall tidal displacement (TDi) in a premature infant that suffered from pneumothorax. Off-line analysis of the TDi revealed slowly progressing asymmetric ventilation that could be detected 38 min before the diagnosis was made. The TDi provides novel and valuable information that can assist in early detection and decision making.

Monitoring the respiratory rate by miniature motion sensors in premature infants: a comparative study.

OBJECTIVE: Existing respiratory rate (RR) monitors suffer from inaccuracy. The study assesses the accuracy of a novel modality that monitors lung ventilation with miniature motion sensors. STUDY DESIGN: RR was measured by three methods: impedance technology, motion sensors and visual count, in babies (n=9) that breathed spontaneously or with respiratory support and babies (n=12) that received high-frequency oscillatory ventilation (HFOV). RESULTS: A line close to equality (slope=0.96, r(2)=0.83) was obtained between the motion sensor and the visual count of the RR with narrow 95% limits of agreements (<14.0 b.p.m.). The relationship between the impedance and the visual count showed a lower correlation (r(2)=0.65) and wider 95% limits of agreements (21.4 b.p.m.). The motion sensor- and the ventilator-determined RRs demonstrated a good agreement during HFOV, whereas the impedance failed to measure the RR during HFOV. CONCLUSION: Monitoring RR with motion sensors is more accurate compared with the impedance, in infants, in all ventilation modes.

Force-velocity relationship and biochemical-to-mechanical energy conversion by the sarcomere.

The intracellular control mechanism leading to the well-known linear relationship between energy consumption by the sarcomere and the generated mechanical energy is analyzed here by coupling calcium kinetics with cross-bridge cycling. A key element in the control of the biochemical-to-mechanical energy conversion is the effect of filament sliding velocity on cross-bridge cycling. Our earlier studies have established the existence of a negative mechanical feedback mechanism whereby the rate of cross-bridge turnover from the strong, force-generating conformation to the weak, non-force-generating conformation is a linear function of the filament sliding velocity. This feedback allows the analytic derivation of the experimentally established Hill's equation for the force-velocity relationship. Moreover, it allows us to derive the transient length response to load clamps and the transient force response to sarcomere shortening at constant velocity. The results are in agreement with experimental studies. The mechanical feedback regulates the generated power, maintains the linear relationship between energy liberated by the actomyosin-ATPase and the generated mechanical energy, and determines the efficiency of biochemical-to-mechanical energy conversion. The mechanical feedback defines three elements of the mechanical energy: 1) external work done; 2) pseudopotential energy, required for cross-bridge recruitment; and 3) energy dissipation caused by the viscoelastic property of the cross bridge. The last two elements dissipate as heat.

The effect of sarcomere shortening velocity on force generation, analysis, and verification of models for crossbridge dynamics.

The study tests the hypothesis that the transition rate (G) of the cardiac cross-bridge (XB) from the strong force generating state to the weak state is a linear function of the sarcomere shortening velocity (V(SL)). Force (F) was measured with a strain gauge in six trabeculae from the rat right ventricle in K-H solution [(Ca]0 = 1.5 mM, 25 degrees C). Sarcomere length (SL) was measured with laser diffraction techniques. Twitch F at constant SL and the F response to shortening at constant V(SL) (0-8 microm/s; deltaSL 50-100 nm) were measured at varied times during the twitch. The F response to shortening consisted of an initial fast exponential decline (tau = 2 ms), followed by a slow decrease of F. The instantaneous difference (deltaF) between the isometric F (F(M)) and F during the slow phase depended on the duration of shortening (deltat), the instantaneous F(M) and V(SL). deltaF = G1 x F(M) x deltat x V(SL) x (1 -V(SL)/V(MAX)), where V(MAX) is the unloaded V(SL) and G1 was 6.15+/-2.12 microm(-1) (mean +/- s.d.; n=6). DeltaF/F(M) was independent of the time onset of shortening. The linear interrelation between deltaF and V(SL) is consistent with the suggested feedback, whereby XB kinetics depends on V(SL). This feedback provides a more universal description of the interrelation between shortening and force, as well as the observed linear relation between energy consumption and the mechanical energy output.

Regulation of energy consumption in cardiac muscle: analysis of isometric contractions.

The well-known linear relationship between oxygen consumption and force-length area or the force-time integral is analyzed here for isometric contractions. The analysis, which is based on a biochemical model that couples calcium kinetics with cross-bridge cycling, indicates that the change in the number of force-generating cross bridges with the change in the sarcomere length depends on the force generated by the cross bridges. This positive-feedback phenomenon is consistent with our reported cooperativity mechanism, whereby the affinity of the troponin for calcium and, hence, cross-bridge recruitment depends on the number of force-generating cross bridges. Moreover, it is demonstrated that a model that does not include a feedback mechanism cannot describe the dependence of energy consumption on the loading conditions. The cooperativity mechanism, which has been shown to determine the force-length relationship and the related Frank-Starling law, is shown here to provide the basis for the regulation of energy consumption in the cardiac muscle.

Molecular control of myocardial mechanics and energetics: the chemo-mechanical conversion.

Energy consumption in the cardiac muscle is characterized by two basic phenomena: 1) The well known linear relationship between energy consumption by the sarcomere and the mechanical energy it generates, and 2) the ability to modulate the generated mechanical energy and energy consumption to the various loading conditions, as is manifested by the Frank-Starling Law and the Fenn effect. These basic phenomena are analyzed here based on coupling calcium kinetics with crossbridge (Xb) cycling. Our previous studies established the existence of two feedback mechanism: 1) a positive feedback mechanism, the cooperativity, whereby the affinity of the troponin for calcium, and hence Xb and actomyosin-ATPase recruitment, depends on the number of force generating Xbs, and 2) a mechanical feedback, whereby the filaments shortening velocity, or the Xb strain rate, determines the rate of Xb turnover from the strong to the weak conformation. The cooperativity mechanism determines the force-length relationship (FLR) and the related Frank-Starling Law. It also provides the basis for the regulation of energy consumption and the ability of the muscle to adapt its energy consumption to the loading conditions. The mechanical feedback regulates the shortening velocity and provides the analytical solution for the experimentally derived Hill's equation for the force-velocity relationship (FVR). The mechanical feedback regulates the generated power and provides the linear relationship between energy consumption and the generated mechanical energy, i.e., the external work done and the liberated heat. Thus, the two feedback mechanisms that regulate sarcomere dynamics, and determine the FLR and FVR, also regulate the energy consumption and the mechanical energy generated by the muscle.

Effect of cellular inhomogeneity on cardiac tissue mechanics based on intracellular control mechanisms.

Our earlier description of the intracellular control (IC) of contraction of a single cell, based on coupling calcium kinetics with cross-bridge cycling, is extended here to study the performance of a multicellular inhomogeneous tissue common in pathophysiological situations. Inhomogeneity in calcium affinity or in cross-bridge kinetics is first simulated by analyzing two fiber segments connected as parallel or serial duplexes. The calculated characteristics of the parallel duplex are tested against our experimental data with two parallel nonuniform rat papillary fibers. The predicted serial duplex behavior is compared with reported experimental data of the effects of segmental hypoxia along a papillary fiber. Fiber inhomogeneity leads to polyphasic contraction of the fiber segments, reduces muscle length shortening, and affects the control of relaxation. We next investigated the force generated by a nonuniform tissue containing small areas of necrosis, evident in subendocardial infarction. Theoretical analysis suggests that the IC mechanism decreases the extension of cell necrosis by lowering the energy consumption of the viable cells in the ischemic zone. The study emphasizes the importance of IC in determining the global and local function of the inhomogeneous myocardium.

End-systolic pressure-volume relationship and intracellular control of contraction.

The left ventricular (LV) pressure-volume relationship and the effect of ejection on pressure generation are predicted theoretically based on the intracellular control mechanisms. The control of contraction is described based on coupling calcium kinetics and cross-bridge cycling. The analysis of published skinned and intact cardiac muscle data suggests two feedback control loops: 1) a positive cooperative mechanism that determines the force-length relationship, the length dependence calcium sensitivity of the contractile filaments, and the related Frank Starling law; and 2) a negative mechanical feedback that determines the force-velocity relationship and the generated power. The interplay between these two feedback mechanisms explains the wide spectrum of phenomena associated with the end-systolic pressure-volume relationship (ESPVR); it provides an explanation for the "shortening deactivation" and for the recent observations of the positive effect of ejection on the ESPVR, i.e., the increase of the end-systolic pressure of the ejecting beat over the pressure of the isovolumic beat at the same end-systolic volume. Furthermore, the analysis suggests that the LV contractility depends on the balance between the two intracellular mechanisms and that the effect of loading conditions is determined through these intracellular mechanisms.

Crossbridge dynamics in muscle contraction.

The study deals with the description of muscle contraction based on biochemical studies and describes four major approaches for coupling calcium kinetics with crossbridge (Xb) cycling. The analysis illuminates two controversial points: 1) the relationship between Xb attachment/detachment and Xb cycling, i.e., the transition between weak to strong conformations, and 2) the effect of calcium on Xb function: does it regulate Xb kinetics or Xb recruitment.

Mechanical regulation of cardiac muscle by coupling calcium kinetics with cross-bridge cycling: a dynamic model.

This study describes the regulation of mechanical activity in the intact cardiac muscle, the effects of the free calcium transients and the mechanical constraints, and emphasizes the central role of the troponin complex in regulating muscle activity. A "loose coupling" between calcium binding to troponin and cross-bridge cycling is stipulated, allowing the existence of cross bridges in the strong conformation without having bound calcium on the neighboring troponin. The model includes two feedback mechanisms: 1) a positive feedback, or cooperativity, in which the cycling cross bridges affect the affinity of troponin for calcium, and 2) a negative mechanical feedback, where the filament-sliding velocity affects cross-bridge cycling. The model simulates the reported experimental force-length and force-velocity relationships at different levels of activation. The dependence of the shortening velocity on calcium concentration, sarcomere length, internal load, and rate of cross-bridge cycling is described analytically in agreement with reported data. Furthermore, the model provides an analytic solution for Hill's equation of the force-velocity relationship and for the phenomena of unloaded shortening velocity and force deficit. The model-calculated changes in free calcium in various mechanical conditions are in good agreement with the available experimental results.

Coupling calcium binding to troponin C and cross-bridge cycling in skinned cardiac cells.

This study examines the coupling of calcium binding to troponin with the force developed by the cross bridges in the skinned cardiac muscle. It emphasizes the key role of the troponin complex in regulating cross-bridge cycling and defines four distinct states of the troponin complex in the single-overlap region. These include a "loose-coupling" state, wherein cross bridges can exist in the strong conformation without having calcium bound to the neighbor troponin C. Published simultaneous measurements of the force and the bound calcium are used to calculate the apparent calcium binding coefficients. The force-length relationships at different free calcium concentrations are used to evaluate the cooperative mechanism. The dependence of the affinity of troponin for calcium on the number of force-generating cross bridges is the dominant cooperative mechanism. The proposed loose-coupling model, with a positive feedback of force on calcium binding, describes the role of calcium in force regulation and the force-length relationship in skinned cardiac muscle. The ability to simulate the rate of force development is demonstrated.

Calcium kinetic and mechanical regulation of the cardiac muscle.

A comprehensive dynamic model of the excitation contraction coupling, developed for a single cardiac muscle, is extended to a multi-cell system (duplex). The model defines the mechanical activation level based on calcium kinetics and crossbridge cycling and emphasizes the central role of the troponin regulatory proteins in regulating muscle activity. The intracellular control mechanism includes two feedback loops that affect the affinity of troponin for calcium and the crossbridge cycling. The model is used to simulate the basic mechanical characteristics of the cardiac muscle, i. e. the force-length and the force-velocity relationships, and describes their dependence on the mechanical activation level. The two-cell duplex unit is used to study the influence of inter-cellular interactions and the effect of inhomogeneity on muscle performance, due to non-uniformity in the electrical stimulation or inhomogeneity in calcium kinetics. Better understanding of the performance of the inhomogeneous muscle is obtained due to our ability to describe the control of the activation level in each cell.

In vitro and in vivo cytokine-induced facilitation of immunohematopoietic reconstitution in mice undergoing bone marrow transplantation.

The aim of this study was to test whether colony stimulating factors (CSF) and other cytokines facilitate the recovery of a variety of immunohematopoietic functions in lethally irradiated mice undergoing bone marrow transplantation (BMT). Two experimental systems were employed: (a) lethally irradiated mice transplanted with syngeneic or T cell-depleted semi-allogeneic bone marrow (BM) cells (0.1-10 x 10(6)), subsequently treated by multiple doses of cytokines; and (b) lethally irradiated mice transplanted with BM cells that had previously been cultivated with cytokines. The cytokines used were: pure natural mouse interleukin-3 (IL-3); recombinant mouse granulocyte-macrophage CSF (rGM-CSF); recombinant human interleukin-2 (rIL-2); and crude cytokine preparations obtained from the culture supernatants of murine leukemia WEHI-3b cells (containing mainly IL-3), and of phorbol myristate acetate (PMA)-stimulated EL4 leukemia cells and concanavalin A-stimulated rat splenocytes (each containing a multitude of cytokines). For BM cultures (1-9 days), the cytokines were used at a dosage of 1-100 U/ml; for in vivo treatment, 2 x 10(2)-5 x 10(4) units were administered intraperitoneally and subcutaneously at different schedules for varying periods (1-3 weeks). The following parameters were tested 1-10 weeks post-BMT: white blood cell count, colony formation in agar and in the spleen of lethally irradiated mice, proliferative responses to mitogens and alloantigens, allocytotoxicity and antibody production (serum agglutinins and plaque-forming cells) against sheep red blood cells. Under appropriate conditions, cytokine treatment either in vitro or in vivo significantly enhanced (2- to 50-fold compared with controls) most functions tested at 2-8 weeks post-BMT, and shortened the time interval required for full immunohematopoietic recovery by 2-5 weeks. In recipients of semi-allogeneic, T lymphocyte-depleted BM no evidence of graft-versus-host disease was found. It is suggested that judicious application in vitro and/or in vivo of certain pure cytokines (e.g. GM-CSF, IL-3) or cytokine 'cocktails' might be beneficial in enhancing hematopoiesis and in the treatment of immunodeficiency associated with BMT.