Characteristics of Retinal Neovascularization in Proliferative Diabetic Retinopathy Imaged by Optical Coherence Tomography Angiography.

Purpose: To characterize the morphology of neovascularization at the disc (NVD) and neovascularization elsewhere (NVE) in treatment-naïve or previously treated proliferative diabetic retinopathy (PDR) patients using optical coherence tomography (OCT) angiography. Methods: En face OCT angiograms of NVD/NVE in 40 eyes of 33 patients with PDR were acquired using RTVue XR Avanti OCT. The morphology of NVD/NVE on OCT angiograms was evaluated, and the activity was determined by biomicroscopy and fluorescein angiography (FA). In 12 eyes that were treated or treatment-naïve, changes in the morphology and vessel area of NVD/NVE before and after panretinal photocoagulation (PRP) were investigated. Results: Twenty eyes had treatment-naïve PDR, whereas 20 eyes were previously treated with PRP. All treatment-naïve NVD/NVE had remarkable (i.e., active) leakage in early-phase FA. Ninety-five percent of treatment-naïve NVD/NVE observed by OCT angiography had exuberant vascular proliferation (EVP), identified as irregular proliferation of fine (smaller-caliber) new vessels; whereas, the presence of EVP in previously treated eyes (13/20) was significantly less than in treatment-naïve eyes (65% vs. 95%, P = 0.043). The remaining seven treated eyes had pruned NVD/NVE without EVP, observed as fibrotic changes or faint (inactive) leakage in FA. The vessel areas of NVD/NVE significantly decreased following PRP (n = 12, P = 0.019), and NVD/NVE morphology showed pruning and decreased EVP. Conclusions: Exuberant vascular proliferation on OCT angiograms should be considered as an active sign of neovascularization; therefore, morphologic evaluation of neovascularization using OCT angiography may be useful to estimate the activity of each neovascularization in eyes with PDR.

Effects of shear stress on the gene expressions of endothelial nitric oxide synthase, endothelin-1, and thrombomodulin in human retinal microvascular endothelial cells.

PURPOSE: Physiological shear stress is higher in the retinal microcirculatory network than in other organs. The effects of laminar shear stress on gene expression in human retinal microvascular endothelial cells (HRMECs) was investigated. METHODS: Cultured HRMECs on glass plates were exposed to a laminar shear stress of 0, 1.5, 6, 15, 30, 60, or 100 dyne/cm(2) for 24 hours and to 60 dyne/cm(2) for 0, 1, 3, 6, 12, 24, or 48 hours. The mRNA expressions of endothelial nitric oxide synthase (eNOS), endothelin-1 (ET-1), and thrombomodulin (TM) in the HRMECs were evaluated using real-time reverse transcription polymerase chain reaction. RESULTS: The HRMECs elongated and aligned parallel with the flow direction based on the shear stress and exposure times. The expression of eNOS mRNA gradually increased and became saturated at 60 dyne/cm(2); ET-1 mRNA expression increased at 1.5 dyne/cm(2) but decreased below that of the static control at shear stresses of 30 dyne/cm(2) or more. TM mRNA expression in response to shear stress increased linearly from 0 to 100 dyne/cm(2). A shear stress of 60 dyne/cm(2) for 6 hours or more promoted eNOS and TM mRNA expression but suppressed ET-1 mRNA expression in HRMECs. CONCLUSIONS: Long-term exposure to a physiological shear stress in the retinal arterioles up-regulated eNOS and TM mRNA expressions and downregulated ET-1 mRNA expression in HRMECs. These results suggest that shear stress may be associated with the vasoregulatory and antithrombotic properties of retinal vessels under physiological conditions present during retinal circulation.

Effects of lower-leg rhythmic cuff inflation on cardiovascular autonomic responses during quiet standing in healthy subjects.

To determine the effects of muscle pump function on cardiac autonomic activity in response to quiet standing, we simulated the muscle pump effect by rhythmic lower-leg cuff inflation (RCI) with four cuff pressures of 0 (sham), 40, 80, and 120 mmHg at 5 cycles/min. The R-R interval (RRI) and beat-to-beat blood pressure (BP) were acquired in healthy subjects (6 males and 5 females, aged 21-24 yr). From the continuous BP measurement, stroke volume (SV) was calculated by a pulse-contour method. Using spectral and cross-spectral analysis, RRI and systolic BP variability as well as the gain of spontaneous cardiac baroreflex sensitivity (sBRS) were estimated for the low- and high-frequency (HF) bands. Compared with the sham condition, RCI with cuff pressures of 80 and 120 mmHg led to increases in the mean RRI (P < 0.01) and HF power of RRI fluctuation (P < 0.05 for 80 mmHg and P < 0.01 for 120 mmHg) during quiet standing. Reduction in SV during standing was suppressed, and the sBRS of the HF band for standing were increased by RCI for either cuff pressure (P < 0.05 for 80 mmHg and P < 0.01 for 120 mmHg). However, at 40 mmHg RCI, these remained unchanged. These results suggest that, during standing, RCI of the lower leg increases cardiac vagal outflow when the cuff pressure is raised enough to oppose the hydrostatic-induced venous pressure in the calf.

Quantitative assessments of morphological and functional properties of biological trees based on their fractal nature.

The branching systems in our body (vascular and bronchial trees) and those in the environment (plant trees and river systems) are characterized by a fractal nature: the self-similarity in the bifurcation pattern. They increase their branch density toward terminals according to a power function with the exponent called fractal dimension (D). From a stochastic model based-on this feature, we formulated the fractal-based integrals to calculate such morphological parameters as aggregated branch length, surface area, and content volume for any given range of radius (r). It was followed by the derivation of branch number and cross-sectional area, by virtue of the logarithmic sectioning of the r axis and of the branch radius-length relation also given by a power function of r with an exponent (alpha). These derivatives allowed us to quantify various hydrodynamic parameters of vascular and bronchial trees as fluid conduit systems, including the individual branch flow rate, mean flow velocity, wall shear rate and stress, internal pressure, and circumferential tension. The validity of these expressions was verified by comparing the outcomes with actual data measured in vivo in the vascular beds. From additional analyses of the terminal branch number, we found a simple equation relating the exponent (m) of the empirical power law (Murray's so-called cube law) to the other exponents as (m=D+alpha). Finally, allometric studies of mammalian vascular trees revealed uniform and scale-independent distributions of terminal arterioles in organs, which afforded an infarct index, reflecting the severity of tissue damage following arterial infarction.

Compensatory increase in extracellular dopamine in the nucleus accumbens of adult rats with neonatal 6-hydroxydopamine treatment.

To characterize a compensatory function of the dopaminergic system of residual dopamine (DA) neurons in the mesolimbic pathway with DA-depleting lesions, we compared tissue and extracellular concentrations of DA and its metabolites in the nucleus accumbens (NACC) of adult rats with neonatal 6-hydroxydopamine (6-OHDA) treatment with those of control rats with neonatal vehicle treatment using high-performance liquid chromatography. The tissue concentration of DA for 6-OHDA-treated rats was 26.9% of that for the control rats, whereas the extracellular DA was not significantly different from the controls. Furthermore, the extracellular DA concentration in the NACC of 6-OHDA-treated rats was significantly increased compared to the controls following neurotensin (NT) microinjection into the ventral tegmental area (VTA). These results suggest that the extracellular DA of the adult rat brain following neonatal 6-OHDA treatment was compensated for by increasing the release of DA from terminals in the NACC of remaining DA neurons through increased mesolimbic pathway afferents (increased demand), as well as by decreasing the synaptic DA reuptake sites and/or D4 receptors. This study supports our hypothesis that the compensatory mechanism(s) of remaining DA neurons in the mesolimbic system are underlying in behavioral characteristics of adult rats with neonatal depletion of brain DA.

Changes in cardiovascular function on treatment of inhibitors of apoptotic signal transduction pathways in left ventricular remodeling after myocardial infarction.

INTRODUCTION: It has been suggested that apoptosis in cardiac remodeling after myocardial infarction (MI) occurs in cardiomyocytes and is critically involved in the process of postinfarct cardiac remodeling. We investigated the pathophysiological link between myocardial apoptosis and cardiovascular function by modulating apoptotic signal transduction pathways. METHODS: Either a caspase-3 inhibitor (CasI) or a calpain inhibitor (CalI) was administered immediately after MI in a rat model of MI. Blood pressure (BP), heart rate (HR), and blood flow velocity (BFV) were measured, and pressure-rate product (PRP) was calculated to estimate the changes in cardiovascular function (n=6 for each group). RESULTS: BFV showed no remarkable changes in any of the groups. Both systolic blood pressure (SBP) and HR changed significantly (P<.01) in the MI+CasI and MI+CalI groups at 1 day after MI and returned to control levels thereafter. In contrast, SBP and HR remained significantly (P<.01) altered in the MI group. PRP in the MI groups was significantly decreased (P<.05 in the MI and MI+CasI groups; P<.01 in the MI+CalI group) at 1 day after MI and returned to control levels at 4 days. CONCLUSION: This study suggests that inhibition of apoptosis during left ventricular remodeling ameliorates cardiovascular function in remodeled hearts.

Effects of the muscle pump and body posture on cardiovascular responses during recovery from cycle exercise.

The purpose of the study was to characterize the effects of muscular contractions (the muscle pump) and body posture on cardiovascular responses during recovery from moderate exercise in the upright-sitting or supine positions. Heart rate (HR), stroke volume (SV), and cardiac output (CO) were measured in seven young male subjects at rest and during 10-min of cycle exercise at 60% of peak oxygen uptake (VO2peak). This was followed by either complete rest for 5 min (inactive recovery) or cycling at VO2peak for 5 min (active recovery) in the upright or supine positions. In the upright position, an initial rapid decrease in HR was followed by a gradual decrease in HR, and this response was similar when comparing inactive and active recoveries. Upright SV during inactive recovery decreased gradually to the pre-exercise resting level, whereas upright SV during active recovery remained significantly elevated. In contrast, in the supine position, the HR during active recovery decreased, but remained significantly higher than that during inactive recovery. Changes in supine SV were similar when comparing inactive and active recovery. Thus, maintenance of SV and HR resulted in significantly greater CO during active recovery than during inactive recovery, regardless of body position. HR was greater during supine active-recovery than during supine inactive-recovery, and there was no difference in SV. These data suggest that the muscle pump is less important in facilitating venous return and vagal resumption in the supine position as compared to the upright position.

Control characteristics of an automatic matching control system for in vivo EPR spectroscopy.

A method for estimating the characteristics of an automatic matching control (AMC) system for in vivo electron paramagnetic resonance (EPR) spectroscopy is described. AMC is also known as automatic coupling control (ACC) and is used to compensate for perturbation due to movement of the subject animal. The open-loop function of the AMC system is derived and the characteristics (gain, phase margin, steady-state error, system bandwidth, and disturbance rejection) of the system are examined. The proposed method is supported by experimental findings. The frequency response of perturbation due to the movement of an anesthetized rat was measured with a 1.1-GHz continuous-wave EPR spectrometer. Disturbance rejection with the AMC system was also considered for respiratory motion and the heartbeat of the anesthetized rat, and these perturbations were reduced by about 40 dB in the power spectrum of the output of the diode detector in the spectrometer.

Influence of cool-down exercise on autonomic control of heart rate during recovery from dynamic exercise.

The recovery of post-exercise heart rate (HR) is enhanced by a procedure of cooling down; however, the mechanism of this facilitated reduction is unknown. To determine whether more cardiac vagal reactivation is associated with a decrease in HR following cool-down exercise, we examined high-frequency R-R interval variability (HF, 0.15-0.40 Hz), an index of cardiac vagal tone, in six young healthy male subjects with a comparison between sitting rest after 6 minutes of cool-down cycling at 20% peak oxygen uptake (VO2peak) and sitting complete rest, following 5 min of upright cycle exercise at 70% VO2peak. During the last minute of exercise, there was no difference in HR between the two exercise tests before performing or not performing cool-down exercise (mean +/- SE, 148.7 +/- 6.9 versus 149.7 +/- 7.0 beats/min, respectively, by a Wilcoxon signed-ranks test). After exercise, a similar initial rapid decrease in HR and subsequent decline was observed during the first 6 min of recovery, regardless of cool-down exercise. However, the resting HR average following cool-down exercise was significantly lower than the corresponding HR without cool-down exercise (92.1 +/- 3.0 versus 100.8 +/- 3.6 beats/min, P < 0.05). The corresponding HF amplitude was slightly, but significantly greater with than without cool-down exercise (10.6 +/- 2.2 versus 9.0 +/- 1.9, P < 0.05). Thus the increase in HF amplitude corresponded to a decrease in resting HR following cool-down exercise, as compared to complete rest without cool-down exercise. Therefore, we conclude that after moderate exercise, the decrease in resting HR following cool-down exercise is associated with an increase in cardiac vagal tone.