Sympathetic hyper-excitation in obesity and pulmonary hypertension: physiological relevance to the 'obesity paradox'.

BACKGROUND: Within the lung, sympathetic nerve activity (SNA) has an important role in facilitating pulmonary vasodilation. As SNA is elevated in obesity, we aimed to assess the impact of sympathetic hyper-excitation on pulmonary vascular homeostasis in obesity, and its potential role in ameliorating the severity of pulmonary hypertension (PH); the well-documented 'obesity paradox' phenomenon. METHODS: Zucker obese and lean rats were exposed to normoxia or chronic hypoxia (CH-10% O2) for 2 weeks. Subsequently, pulmonary SNA (pSNA) was recorded (electrophysiology), or the pulmonary microcirculation was visualized using Synchrotron microangiography. Acute hypoxic pulmonary vasoconstriction (HPV) was assessed before and after blockade of ß1-adrenergic receptors (ARs) (atenolol, 3 mg kg(-1)) and ß1+ß2-adrenergic (propranolol, 2 mg kg(-1)). RESULTS: pSNA of normoxic obese rats was higher than lean counterparts (2.4 and 0.5 µV s, respectively). SNA was enhanced following the development of PH in lean rats, but more so in obese rats (1.7 and 6.8 µV s, respectively). The magnitude of HPV was similar for all groups (for example, ~20% constriction of the 200-300 µm vessels). Although ß-blockade did not modify HPV in lean rats, it significantly augmented the HPV in normoxic obese rats (ß1 and ß2 blockade), and more so in obese rats with PH (ß2-blockade alone). Western blots showed, while the expression of pulmonary ß1-ARs was similar for all rats, the expression of ß2-ARs was downregulated in obesity and PH. CONCLUSIONS: This study suggests that sympathetic hyper-excitation in obesity may have an important role in constraining the severity of PH and, thus, contribute in part to the 'obesity paradox' in PH.

Evaluating the peak-to-valley dose ratio of synchrotron microbeams using PRESAGE fluorescence.

Synchrotron-generated microbeam radiotherapy holds great promise for future treatment, but the high dose gradients present conventional dosimetry with a challenge. Measuring the important peak-to-valley dose ratio (PVDR) of a microbeam-collimated synchrotron source requires both a dosimeter and an analysis method capable of exceptional spatial resolution. The PVDR is of great interest since it is the limiting factor for potential application of the microbeam radiation therapy technique clinically for its tissue-sparing properties (i.e. the valley dose should be below the tolerance of normal tissue). In this work a new method of measuring the dose response of PRESAGE dosimeters is introduced using the fluorescence from a 638 nm laser on a confocal laser-scanning microscope. This fluorescent microscopy method produces dosimetry data at a pixel size as low as 78 nm, giving a much better spatial resolution than optical computed tomography, which is normally used for scanning PRESAGE dosimeters. Using this technique the PVDR of the BL28B2 microbeam at the SPring-8 synchrotron in Japan is estimated to be approximately 52:1 at a depth of 2.5 mm. The PVDR was also estimated with EBT2 GAFchromic films as 30.5:1 at the surface in order to compare the PRESAGE fluorescent results with a more established dosimetry system. This estimation is in good agreement with previously measured ratios using other dosimeters and Monte Carlo simulations. This means that it is possible to use PRESAGE dosimeters with confocal microscopy for the determination of PVDR.

Drug delivery observation of hydrophobe ferrofluid and magnetite nanoparticals by SPring-8 synchrotron radiation.

In this study, the composite magnetic nanoparticles of coated SiO nano film with about 8 nm size and high saturation magnetization value, were synthesized by liquid phase precipitation method. The magnetic nanoparticles can be dispersed in various liquid media, widely known as magnetic fluids or ferrofluids with both magnetic and liquid properties. The materials been collected great interests and more and more attentions to focus into Drug Delivery System (DDS) as a new technology in this paper. We use the composite nanoparticles to disperse H2O and inject the solutions into rat's in-vivo organs. And, in the experiments by using a strong photon beam of SPring-8 Synchrotron Radiation facility, the distribution stat and the effects of magnetic field as well as drug delivery behaviour of nanoparticles in the rat' kidney are verified by the in-vivo observations.

Visualization of intracerebral arteries by synchrotron radiation microangiography.

BACKGROUND AND PURPOSE: Small cerebral vessels are a major site for vascular pathology leading to cerebral infarction and hemorrhage. However, such small cerebral vessels are difficult to visualize by using conventional methods. The goal of our study was the development of methodology allowing visualization of small cerebral arteries in rodents, suitable for experimental models. MATERIALS AND METHODS: Using barium sulfate as a contrast material, we obtained microangiographic images of physiologic and pathologic changes consequent to cerebral infarction in mouse brain by monochromatic synchrotron radiation (SR). To achieve high-resolution and high-contrast images, we used a new x-ray camera with a pixel size of 4.5 microm, and we set the energy level at 37.5 keV, just above the K absorption of barium. RESULTS: Small intracerebral arteries ( approximately 30 microm in diameter) were clearly visualized, as well as the cortical branches (50-70 microm in diameter) at the brain surface. The limit of detection appeared to be vessels approximately 10 microm in diameter. Compared with the noninfarcted side, the number of intracerebral arteries was dramatically decreased in the middle cerebral artery area affected by stroke. CONCLUSIONS: These results indicate the potential of SR for evaluating pathologic changes in small cerebral arteries and for monitoring the impact of pro- and antiangiogenic therapeutic strategies.

GENERALISATION OF RADIATOR DESIGN TECHNIQUES FOR PERSONAL NEUTRON DOSEMETERS BY UNFOLDING METHOD.

A novel technique for designing a radiator suitable for personal neutron dosemeter based on plastic track detector was discussed. A multi-layer structure has been proposed in the previous report, where the thicknesses of plural polyethylene (PE) layers and insensitive ones were determined by iterative calculations of double integral. In order to arrange this procedure and make it more systematic, unfolding calculation has been employed to estimate an ideal radiator containing an arbitrary hydrogen concentration. In the second step, realistic materials replaced it with consideration of minimisation of the layer number and commercial availability. A radiator consisting of three layers of PE, Upilex and Kapton sheets was finally designed, for which a deviation in the energy dependence between 0.1 and 20 MeV could be controlled within 18 %. An applicability of fluorescent nuclear track detector element has also been discussed.

Partitioning of triphenylalkylphosphonium homologues in gel bead-immobilized liposomes: chromatographic measurement of their membrane partition coefficients.

Unilamellar liposomes of small or large size, SUVs and LUVs, respectively, were stably immobilized in the highly hydrophilic Sepharose 4B or Sephacryl S-1000 gel beads as a membrane stationary phase for immobilized liposome chromatography (ILC). Lipophilic cations of triphenylmethylphosphonium and tetraphenylphosphonium (TPP+) have been used as probes of the membrane potential of cells. Interaction of TPP+ and triphenylalkylphosphonium homologues with the immobilized liposomal membranes was shown by their elution profiles on both zonal and frontal ILC. Retardation of the lipophilic cations on the liposome gel bed was increased as the hydrophobicity of the cations increased, indicating the partitioning of lipophilic cations into the hydrocarbon region of the membranes. The cations did not retard on the Sepharose or Sephacryl gel bed without liposomes, confirming that the cations only interact with the immobilized liposomes. Effects of the solute concentration, flow rate, and gel-matrix substance on the ILC were studied. The stationary phase volume of the liposomal membranes was calculated from the volume of a phospholipid molecule and the amount of the immobilized phospholipid, which allowed us to determine the membrane partition coefficient (KLM) for the lipophilic cations distributed between the aqueous mobile and membrane stationary phases. The values of KLM were generally increased with the hydrophobicity of the solutes increased, and were higher for the SUVs than for the LUVs. The ILC method described here can be applied to measure membrane partition coefficients for other lipophilic solutes (e.g., drugs).

Twenty-four hour time domain heart rate variability and heart rate: relations to age and gender over nine decades.

OBJECTIVES: This study sought to define the effects of age and gender effects on the normal range of time domain heart rate variability (HRV) over nine decades in healthy subjects. BACKGROUND: Low HRV is considered an independent marker of mortality risk. However, the age-related decline in HRV may limit its predictive value, particularly in the elderly. Delineation of the range of HRV in healthy subjects over the life span is needed. Gender-related differences in HRV also need clarification. METHODS: We determined, according to decade, 24-h heart rate (HR) and HRV of 260 healthy subjects (10 to 99 years old; 112 male, 148 female) by means of five standard time domain measures: standard deviation of all normal sinus RR intervals over 24 h (SDNN), standard deviation of the averaged normal sinus RR intervals for all 5-mm segments (SDANN), mean of the standard deviations of all normal sinus RR intervals for all 5-min segments (SDNN index), root-mean-square of successive normal sinus RR interval difference (rMSSD) and the percentage of successive normal sinus RR intervals >50 ms (pNN50). RESULTS: 1) HRV decreased with aging, the pattern of change being measure dependent. HRV (SDNN and SDANN) decreased only very gradually, reaching 60% of baseline (second-decade values) by the tenth decade. With the SDNN index, HRV decreased linearly with aging, reaching 46% of baseline by the tenth decade. Using pNN50 and rMSSD, HRV decreased most rapidly, reaching 24% and 47% of baseline, respectively, by the sixth decade and then stabilized. 2) Using the SDNN index, rMSSD and pNN50, HRV of subjects >65 years old fell below published cutpoints for increased risk of mortality in 25%, 12% and 4%, respectively. 3) At age <30 years, HRV for all measures was lower in female than male subjects. Gender differences decreased at age >30 years and disappeared at age >50 years. 4) HR also declined with aging but much more slowly. HR at age <50 years was faster in female than in male subjects. Gender differences disappeared thereafter. CONCLUSIONS: 1) Using all measures, HRV of healthy subjects declines with aging, with measure-dependent patterns. 2) Using the SDNN index, rMSSD and pNN50, HRV of healthy subjects, particularly those >65 years old, may decrease to below levels associated with increased risk of mortality. 3) Gender influences HRV. Gender differences in HRV are age and measure dependent. 4) Age and gender also affect heart rate.

Microangiographic assessment of collateral vessel formation following direct gene transfer of vascular endothelial growth factor in rats.

OBJECTIVE: The development of collateral microvessels following therapeutic angiogenesis with vascular endothelial growth factor (VEGF) was investigated using a new system of microangiography that employs monochromatic synchrotron radiation (SR) and a high definition video system to visualize arteries with a spatial resolution of 30 microns. METHODS: Ischemia was induced in the hindlimb of 20 rats by excision of the femoral artery, followed by transfection of the plasmid (400 micrograms) encoding VEGF or beta-galactosidase (control) into limb muscles. Microangiography was used to assess the development of collaterals in the ischemic limb four weeks after treatment. RESULTS: Gene transfer of VEGF produced morphologically similar, but significantly more extensive, collateral networks at the microvascular level as compared with the naturally occurring collateral arteries in the control animals (angiographic score: 0.88 +/- 0.08 versus 0.54 +/- 0.05, p < 0.01). No adverse vascular effects such as hemangiomas and/or arteriovenous (AV) fistulae were observed following VEGF treatment. The vasodilator effect of papaverine was evident in relatively large vessels in both groups. At the microvascular level (diameter < 100 microns), however, papaverine induced significant vasodilation in the VEGF-treated animals, and almost no vasodilation in the controls. CONCLUSIONS: SR microangiography allowed us to assess the development of small collateral arteries following VEGF-gene transfer. The information obtained may provide new insights regarding the collateral microcirculation and therapeutic angiogenesis.

Relation between QT interval dispersion and heart rate.

Because the relation between QT dispersion (QTd) and heart rate (HR) are different from that between QT interval and HR, QTd could be overadjusted at a high HR and be underadjusted at a slow HR if we use Bazett's formula to adjust QTd. HR adjustment of QTd is not needed to evaluate repolarization dispersion.

Regional myocardial sympathetic dysinnervation in patients with coronary vasospasm.

The purpose of this study was to assess the presence and location of impaired myocardial sympathetic innervation by using 123I metaiodobenzylguanidine (123I MIBG) in 15 patients with coronary vasospasm induced by intracoronary acetylcholine. The results were compared with those using thallium-201 (Tl-201). We also examined 14 patients with severe coronary stenosis (> 90%) and 8 control subjects without significant coronary stenosis (< 50%) and provokable coronary vasospasm. Regional myocardial sympathetic dysinnervation was detected by 123I MIBG single-photon emission computed tomography (SPECT) in all patients with coronary vasospasm, despite normal uptake during Tl-201 SPECT. This regional uptake-mismatch between 123I MIBG and Tl-201 Spect occurred specifically in the vasospasm group (p < 0.001 vs stenosis and control groups). Moreover, regional myocardial sympathetic dysinnervation was located in the distribution of perfusion in 25 of the 27 vasospasm-induced vessels. Normal uptake of 123I MIBG was observed in the perfused areas in 16 of the 18 non-vasospasm-induced vessels. The sensitivity ans specificity of 123I MIBG for detection of coronary vasospasm were 92% and 88% respectively. In patients with coronary vasospasm, we found regional myocardial sympathetic dysinnervation to be present. Furthermore, we were able to distinguish these patients from patients with critical coronary stenosis by 123I MIBG and Tl-201 SPECT.

Limited reproducibility of circadian variation in blood pressure dippers and nondippers.

The relation between blood pressure (BP) variation and hypertensive organ damage is controversial. The reproducibility of the circadian variation pattern acceptable as the standard for discriminating between "dippers" and "nondippers" has not yet been evaluated. We evaluated the reproducibility of "dipper" and "nondipper" patterns in essential hypertensives by monitoring BP for 48 h. Noninvasive ambulatory BP and heart rate (HR) monitoring for 48 h every 30 min were performed in 253 untreated patients with mild-to-moderate essential hypertension. Mean daytime (awake) and nighttime (sleeping) systolic BP, diastolic BP, and HR values were analyzed by reviewing the patients' diaries. Patients were divided into two groups by presence (dippers) and absence (nondippers) of a reduction of both systolic and diastolic BP during the night of > 10% of the daytime pressure. A subject who was a dipper on day 1 remained a dipper on day 2 in 41% (n = 103, DD group) and changed to nondipper in 16% (n = 41, DN group). A subject who was a nondipper on day 1 remained a nondipper on day 2 in 30% (n = 75, NN group) and changed to a dipper in 13% (n = 34, ND group). Our findings indicate that there is a high risk of false-positive or false-negative results when 24-h recordings are used to identify dipper and nondipper profiles.

Electrophysiological and morphological correlates in the development of visual cortical circuitry in infant kittens.

Geniculate axons in cat visual cortex establish excitatory connections with cortical cells in supragranular and granular layers at birth. They are localized to the granular layer for the first month after birth. Retraction of geniculocortical synapses parallels axonal extension of spiny stellate cells to the supragranular layer and establishment of synapses for intracortical transmission.

Choreoathetoid movements associated with a spleno-renal shunt.

A 73-year-old woman without liver cirrhosis developed choreoathetoid movements of the limbs due to portal-systemic encephalopathy. A prominent spleno-renal shunt was demonstrated by non-invasive methods (abdominal computed tomography and sonography) as well as arterial portography. The choreoathetoid movements were improved by a protein-restricted diet and administration of lactulose. A portal systemic shunt should be considered when investigating choreoathetosis, even in patients without liver cirrhosis.

Alterations of autonomic nervous activity in recurrence of variant angina.

OBJECTIVE: To investigate whether autonomic nervous activity is involved in the recurrence of spontaneous coronary spasm in variant angina. DESIGN: Retrospective analysis. SETTING: Cardiology department of a university hospital. PATIENTS: 18 patients with variant angina were divided into single attack group (SA; nine patients) and multiple attack group (MA; nine patients) according to the frequency of ischaemic episodes with ST segment elevation during 24 hour Holter monitoring. METHODS: Heart rate variability indices were calculated using MemCalc method, which is a combination of the maximum entropy method for spectral analysis and the non-linear least squares method for fitting analysis, at 30 second intervals for 30 second periods, from 40 minutes before the attack to 30 minutes after the attack. High frequency (HF; 0.04-0.15 Hz) was defined as a marker of parasympathetic activity, and the ratio of low frequency (LF; 0.15-0.40 Hz) to high frequency (LF/HF) as an indicator of sympathetic activity. The averaged value during the 40 to 30 minute period before an attack was defined as the baseline. RESULTS: Compared with baseline, the HF component decreased in both groups at two minutes before the attack (p < 0.01), and the LF/HF ratio decreased at three minutes before the attack (p < 0.01). The baseline LF/HF was lower in the MA group than in the SA group (p < 0. 01). CONCLUSIONS: A reduction of sympathetic activity may play a key role in determining the recurrence of transient ischaemic events caused by spontaneous coronary spasm in patients with variant angina.

Digitized cerebral synchrotron radiation angiography: quantitative evaluation of the canine circle of Willis and its large and small branches.

BACKGROUND AND PURPOSE: Conventional X-ray angiography lacks the sensitivity and spatial resolution needed to detect small amounts of iodinated contrast material and to quantitate diameters of the small vessels in the brain. The purpose of this study was to ascertain whether digitized synchrotron radiation microangiography, with the use of a high-definition TV camera system, can accurately show small cerebral vessels. METHODS: Six anesthetized dogs were exposed to monochromatic synchrotron radiation with an energy level of 33.3 keV optimized for iodine detection while iodinated contrast material was injected into the brachiocephalic and vertebral arteries. The images were detected with a high-definition TV camera system with a spatial resolution of 30 microm. In all, 26 cerebral angiograms of the circle of Willis with its branches were obtained, and the images were digitized at a workstation. RESULTS: The small branches of the circle of Willis were clearly visible on all images. Vasodilatation of the circle of Willis and its large and small branches induced by CO2 inhalation was quantitatively confirmed on the images: for example, the diameter of one small branch was increased from 0.24 +/- 0.04 mm to 0.38 +/- 0.12 mm. Temporal subtraction improved the image quality. CONCLUSION: The synchrotron radiation angiographic system is useful for visualizing large and small vessels deep in the brain as well as for quantitating their diameters.

Refraction-enhanced x-ray imaging of mouse lung using synchrotron radiation source.

The low divergent x-ray beam from the third-generation synchrotron radiation source such as SPring-8 enables us to observe refraction of x rays that is in the range of microradians. Under an experimental condition for which ray optics is a good approximation, we found that the refraction produces a high-contrast projection image of a mouse when it was recorded at 6.5 m behind the specimen. Especially, the lung is visualized far better than with the conventional imaging which utilizes absorption of x rays. This is a promising new technique for the diagnosis of diseases in the human lung with a low radiation dose.

Responsiveness of Clare-Bishop neurons to visual cues associated with motion of a visual stimulus in three-dimensional space.

Photic responsiveness of cells in the medial bank of the lateral suprasylvian cortex (Clare-Bishop area) was studied using a three-dimensional visual stimulator that reproduced two visual cues (motion disparity and change in size) for perception of three-dimensional motion of a visual stimulus. About one third of them (48/148) were selectively responsive to motion disparity corresponding to approaching (AP cells, n = 30) or recessive motion (RC cells, N = 18), another half to motion of retinal images in the same direction between the two eyes corresponding to fronto-parallel motion (FP cells, n = 75), and the remaining cells were rather equally responsive to these types of stimuli (NS cells, n = 25). More than a half of the AP (19/30) or RC (11/18) cells were also responsive to increase or decrease in stimulus size, respectively, and they were optimally activated by a combination of the motion and size stimuli while relatively few FP and NS cells were sensitive to change in stimulus size. These findings indicate that the Clare-Bishop cells encode three-dimensional motion on the basis of photic responsiveness to the motion and size cues.

Two-dimensional aortographic coronary arteriography with above-K-edge monochromatic synchrotron radiation.

RATIONALE AND OBJECTIVES: The diagnostic potential of two-dimensional aortographic coronary arteriography with synchrotron radiation was examined in dogs. METHODS: The experiment was performed at a wiggler beam line by using a silicon monocrystal, fluorescent plate, and avalanche-type camera. The x-ray energy was adjusted to just above the iodine K-edge to obtain the highest contrast. Quantitative densitometry was used to compare intravenous coronary arteriography with aortographic coronary arteriography. RESULTS: Aortographic coronary arteriography clearly depicted the branches of the coronary arteries such as the left anterior descending coronary artery, circumferential coronary artery, and right coronary artery to sizes of less than 0.2 mm without major overlap of coronary arteries. Intravenous coronary arteriography depicted only the branches of the left anterior descending coronary artery and right coronary artery with poor image quality. The ratio of contrast material dilution was about 2.4 to 3.4 in aortographic procedures, whereas in intravenous procedures it ranged widely from 7.7 to 15.6. CONCLUSION: These preliminary investigations indicate that two-dimensional aortographic coronary arteriography with synchrotron radiation promises to be a minimally invasive and easily repeatable method of clearly imaging the coronary arteries.

The inhibitory effects of carvedilol against arrhythmias induced by coronary reperfusion in anesthetized rats.

BACKGROUND: Previous study has shown the antiarrhythmic effects of carvedilol on isolated rat hearts, but little is known about the mechanism of this protective action. This article examines the inhibitory effect of carvedilol against arrhythmias induced by reperfusion in anesthetized rats. In addition, the results are compared with those with propranolol, superoxide dismutase (SOD) plus catalase, and a combination of both in order to elucidate the mechanism of the protective actions. METHODS AND MATERIALS: Ninety percent of the rats in the control group showed lethal ventricular fibrillation (VF). Carvedilol at the doses of 0.03, 0.1, and 0.3 mg/kg significantly reduced the incidence of lethal VF to 0%, 0%, and 10%, respectively (P <.05). In contrast, propranolol at the doses of 0.3, 1.0, and 3.0 mg/kg and SOD (35,000 units/kg) plus catalase (400,000 units/kg) did not reduce the incidence of lethal VF (80%, 60%, 70%, and 70%, respectively). However, administration of a combination of propranolol (1.0 mg/kg) and SOD plus catalase completely inhibited the occurrence of lethal VF to 0% (P<.05). CONCLUSION: These results indicate that carvedilol has the inhibitory effect against reperfusion arrhythmias in rats and suggest that the mechanism of action of this compound is related to the combined effects of beta-blocking and antioxidant.

Successfully treated complete atrioventricular block with corticosteroid in a patient with cardiac sarcoidosis: usefulness of gallium-67 and thallium-201 scintigraphy.

A 71-year-old male with sarcoidosis was followed for 6 years without steroid therapy. He was admitted because of complete atrioventricular block. Chest X-ray showed hilar lymphadenopathy. Echocardiogram showed mild left ventricular hypertrophy without local wall thinning. Cardiac sarcoidosis was diagnosed by a defect of Thallium-201 (Tl-201) imaging and abnormal uptake of Gallium-67 (Ga-67). After the start of corticosteroid therapy, complete atrioventricular block was recovered. Abnormal uptake of Ga-67 was improved. Tl-201 and Ga-67 are useful to diagnose cardiac sarcoidosis, to evaluate the lesion of cardiac involvement and to estimate the efficacy of corticosteroid therapy.