Coherence between oscillations in the cardiorespiratory system and tissue oxygen index in muscle recovering from intensive exercise in humans.

It has been shown that the tissue oxygen index (TOI) measured by near-infrared spectroscopy oscillates at very low frequencies during recovery after exercise and that this oscillation is derived from interactions among biochemical substances involved in oxidative metabolism in skeletal muscle. As a further step, we examined whether TOI in muscle interacts through oscillation with factors related to oxygen in the cardiorespiratory system. For this examination, coherence and phase difference between the TOI in the vastus lateralis and heart rate (HR) and between TOI and arterial oxygen saturation (SpO2) were sequentially determined during recovery (2-60 min) after severe cycle exercise with a workload of 7.5% of body weight for 20 s. Significant coherence between TOI and HR was obtained in the very low-frequency band (approximate range: 0.002-0.03 Hz) and in the low-frequency band (approximate range: 0.06-0.12 Hz). The phase difference was negative in the low-frequency band and positive in the very low-frequency band. The coherence between TOI and SpO2 was significant in the very low-frequency band. The phase difference was negative. There were no sequential changes in these coherences and phase differences. The results suggest that TOI in skeletal muscle interrelates with factors related to the heart and lungs.

Oscillation in tissue oxygen index during recovery from exercise.

It was hypothesized that an oscillation of tissue oxygen index (TOI) determined by near-infrared spectroscopy during recovery from exercise occurs due to feedback control of adenosine triphosphate and that frequency of the oscillation is affected by blood pH. In order to examine these hypotheses, we aimed 1) to determine whether there is an oscillation of TOI during recovery from exercise and 2) to determine the effect of blood pH on frequency of the oscillation of TOI. Three exercises were performed with exercise intensities of 30 % and 70 % peak oxygen uptake (V(.)o(2)peak) for 12 min and with exercise intensity of 70 % V(.)o(2)peak for 30 s. TOI during recovery from the exercise was analyzed by fast Fourier transform in order to obtain power spectra density (PSD). There was a significant difference in the frequency at which maximal PSD of TOI appeared (Fmax) between the exercises with 70 % V(.)o(2)peak for 12 min (0.0039+/-0 Hz) and for 30 s (0.0061+/-0.0028 Hz). However, there was no significant difference in Fmax between the exercises with 30 % (0.0043+/-0.0013 Hz) and with 70 % V(.)o(2)peak for 12 min despite differences in blood pH and blood lactate from the warmed fingertips. It is concluded that there was an oscillation in TOI during recovery from the three exercises. It was not clearly shown that there was an effect of blood pH on Fmax.

Oscillation of tissue oxygen index in non-exercising muscle during exercise.

The purpose of the present study was to examine how oscillation of tissue oxygen index (TOI) in non-exercising exercise is affected during high-intensity and low-intensity exercises. Three exercises were performed with exercise intensities of 30% and 70% peak oxygen uptake (Vo(2)peak) for 12 min and with exercise intensity of 70% Vo(2)peak for 30 s. TOI in non-exercising muscle (biceps brachii) during the exercises for 12 min was determined by nearinfrared spectroscopy. TOI in the non-exercising muscle during the exercises was analyzed by fast Fourier transform (FFT) to obtain power spectra density (PSD). The frequency at which maximal PSD appeared (Fmax) during the exercise with 70% Vo(2)peak for 12 min (0.00477 ± 0.00172 Hz) was significantly lower than that during the exercise with 30% Vo2peak for 12 min (0.00781 ± 0.00338 Hz). There were significant differences in blood pH and blood lactate between the exercise with 70% Vo(2)peak and the exercise with 30% Vo(2)peak. It is concluded that TOI in nonexercising muscle oscillates during low-intensity exercise as well as during high-intensity exercise and that the difference in Fmax between the two exercises is associated with the difference in increase in blood lactate derived from the exercise.

Coherence between tissue oxygen indexes in vastus lateralis and gastrocnemius in repetition of impulse exercise with high intensity.

The purpose of this study was to determine whether tissue oxygen indices (TOIs) in two muscle groups oscillated and were synchronized in repetition of impulse exercise with high intensity. Five impulse exercises of 400 watts for 10 s were repeated with intervals of 6 min. During this period, TOI was determined by near-infrared spectroscopy in the vastus lateralis and gastrocnemius muscles. TOIs in the two muscles oscillated at rest. The TOIs rapidly decreased during each impulse exercise and then recovered and overshot after each impulse. The TOIs oscillated during each interval period. During this test period, coherent and phase differences were determined. There was high coherence between TOIs in the two muscles with a peak value at 0.019 Hz. There was a phase difference of -45 ± 32.4 degrees between TOIs in the two muscles. This phase difference corresponded to about 6 s in time scale. It seemed from this time delay that impulse exercise was not a trigger factor for the starting point of TOIs in the two muscles. It has been concluded that TOIs oscillate and are synchronized between two muscles in repetition of impulse exercise with high intensity.

Muscle pump in the vastus lateralis in the supine position in light prolonged exercise.

AIM: The purpose of this study was to examine whether the muscle pump in the supine position is attenuated during light prolonged exercise. METHODS: After rest for 5 min, constant-load exercise with 50% of peak oxygen uptake (VO2) determined by incremental exercises in the supine position was performed for 60 min with a pedaling rate of 60 rpm. Total hemoglobin and myoglobin (total Hb) in the vastus lateralis was determined by using a near-infrared spectroscopy (NIRS) system. The instrument was operating at 2 Hz. VO2, heart rate (HR), mean blood pressure (MBP) and muscle deep temperature (Tm) were measured in the constant-load exercise. RESULTS: After an increase at the onset of exercise, VO2 showed a steady state, HR showed a significant gradual increase and MBP significantly decreased. After an increase until 20 min of exercise, Tm showed a steady state. Level of total Hb increased until 20 min and showed a steady state in all subjects. Average Tm was significantly related to average total Hb (r=0.978). Total Hb oscillated, but its oscillation occasionally disappeared. Peak amplitude of oscillation in total Hb for 30 s after the start of exercise was significantly higher than that for 1 min before the end of exercise. CONCLUSION: The results suggest that the muscle pump operates in light exercise but is attenuated in the vastus lateralis in the supine position at the late phase of prolonged exercise.

Comparison of oscillations of skin blood flow and deoxygenation in vastus lateralis in light exercise.

The purpose of the present study was to compare oscillation of skin blood flow with that of deoxygenation in muscle during light exercise in order to determine the physiological significance of oscillations in deoxygenation. Prolonged exercise with 50% of peak oxygen uptake was performed for 60 min. Skin blood flow (SBF) was measured using a laser blood flow meter on the right vastus lateralis muscle. Deoxygenated haemoglobin/myoglobin (DHb/Mb) concentration in the left vastus lateralis were measured using a near-infrared spectroscopy system. SBF and DHb/Mb during exercise were analysed by fast Fourier transform. We classified frequency bands according to previous studies (Kvernmo et al. 1999, Kvandal et al. 2006) into phase I (0.005-0.0095 and 0.0095-0.02 Hz), phase II (0.02-0.06 Hz: phase II) and phase III (0.06-0.16 Hz). The first peak of power spectra density (PSD) in SBF appeared at 0.0078 Hz in phase I. The second peak of PSD in SBF appeared at 0.035 Hz. The third peak of PSD in SBF appeared at 0.078 Hz. The first peak of PSD in DHb/Mb appeared at 0.0039 Hz, which was out of phase I. The second peak of PSD in DHb/Mb appeared at 0.016 Hz. The third peak of PSD in DHb/Mb appeared at 0.035 Hz. The coefficient of cross correlation was very low. Cross power spectra density showed peaks of 0.0039, 0.016 and 0.035 Hz. It is concluded that a peak of 0.016 Hz in oscillations of DHb/Mb observed in muscle during exercise is associated with endothelium-dependent vasodilation (phase I) and that a peak of 0.035 Hz in DHb/Mb is associated with sympathetic nerve activity (phase II). It is also confirmed that each peak of SBF oscillations is observed in each phase.

Oscillation in O2 uptake in impulse exercise.

The purpose of the present study was to examine 1) whether O(2) uptake (VO(2)) oscillates during light exercise and 2) whether the oscillation is enhanced after impulse exercise. After resting for 1 min on a bicycle seat, subjects performed 5-min pre-exercise with 25 watts work load, 10-s impulse exercise with 200 watts work load and 15-min post exercise with 25 watts work load at 80 rpm. VO(2) during pre-exercise significantly increased during impulse exercise and suddenly decreased and re-increased until 23 s after impulse exercise. In the cross correlation between heart rate (HR) and VO(2) after impulse exercise, VO(2) strongly correlated to HR with a time delay of -4 s. Peak of power spectral density (PSD) in HR appeared at 0.0039 Hz and peak of PSD in VO(2) appeared at 0.019 Hz. The peak of the cross power spectrum between VO(2) and HR appeared at 0.0078 Hz. The results suggested that there is an oscillation in O(2) uptake during light exercise that is associated with the oscillation in O(2) consumption in active muscle. The oscillation is enhanced not only by change in O(2) consumption but also by O(2) content transported from active muscle to the lungs.

Effect of work intensity on time delay in mediation of ventilation by arterial carbon dioxide during recovery from impulse exercise.

Time delay in the mediation of ventilation (V(.)E) by arterial CO(2) pressure (PaCO(2)) was studied during recovery from short impulse-like exercises with different work loads of recovery. Subjects performed two tests including 10-s impulse like exercise with work load of 200 watts and 15-min recovery with 25 watts in test one and 50 watts in test two. V(.)E, end tidal CO(2) pressure (PETCO(2)) and heart rate (HR) were measured continuously during rest, warming up, exercise and recovery. PaCO(2) was estimated from PETCO(2) and tidal volume (V(T)). Results showed that predicted arterial CO(2) pressure (PaCO(2 pre)) increased during recovery in both tests. In both tests, V(.)E increased and peaked at the end of exercise. V(.)E decreased in the first few seconds of recovery but started to increase again. The highest correlation coefficient between PaCO(2 pre) and V(.)E was obtained in the time delay of 7 s (r=0.854) in test one and in time delays of 6 s (r=0.451) and 31 s (r=0.567) in test two. HR was significantly higher in test two than in test one. These results indicate that PaCO(2 pre) drives V(.)E with a time delay and that higher work intensity induces a shorter time delay.

Oscillation of oxygenation in skeletal muscle at rest and in light exercise.

The aim of the present study was to compare the frequency of oxygenation determined in the vastus lateralis by near-infrared spectroscopy (NIRS) in light exercise with that at rest. A subject rested in a recumbent position for 5 min and changed body position to a sitting position on a cycle ergometer for 9 min. Then exercise with low intensity (work rate of 60% of maximal oxygen uptake) was carried out for 30 min. Total hemoglobin and myoglobin (THb/Mb) suddenly decreased after the start of exercise and gradually increased for 6 min. Oxygenated hemoglobin and myoglobin (Hb/MbO2) suddenly decreased and returned to a steady-state after the start of exercise. The difference between Hb/MbO2 and THb/Mb showed a sudden decrease and then a steady-state. This difference was analyzed by fast Fourier transform. The peak frequencies of the power spectrum density (PSD) were 0.0169 ± 0.0076 Hz at rest and 0.0117 ± 0.0042 Hz in exercise. The peak frequency of PSD was significantly decreased in exercise. In exercise, the range of frequencies was expanded. It is concluded that there are oscillations at rest as well as in exercise and that the frequency of peak PSD becomes lower in exercise than at rest.

Relationship between ventilation and predicted arterial CO2 pressure during recovery from an impulse-like exercise without metabolic acidosis.

We investigated ventilation (V(.)E) control factors during recovery from light impulse-like exercise (100 watts) with a duration of 20 s. Blood ions and gases were measured at rest and during recovery. V(.)E, end tidal CO(2) pressure (PETCO(2)) and respiratory exchange ratio (RER) were measured continuously during rest, exercise and recovery periods. Arterial CO(2) pressure (PaCO(2) (pre) was estimated from PETCO(2) and tidal volume (V(T)). RER at 20 s of exercise and until 50 s during recovery was significantly lower than RER at rest. Despite no change in arterialized blood pH level, PaCO(2) (pre) was significantly higher in the last 10 s of exercise and until 70 s during recovery than the resting value. V(.)E increased during exercise and then decreased during recovery; however, it was elevated and was significantly higher than the resting value until 155 s (p<0.05). There was a significant relationship between V(.)E and PaCO(2) (pre) during the first 70 s of recovery in each subject. The results suggest that PaCO(2) drives V(.)E during the first 70 s of recovery after light impulse-like exercise. Elevated V(.)E in the interval from 70 s until 155 s during recovery might be due to neural factors.

Comparison of oscillation of oxygenation in skeletal muscle between early and late phases in prolonged exercise.

The aim of the present study was to compare the oscillations of oxygenation in skeletal muscle between early and late phases in prolonged exercise. During prolonged exercise at 60 % of peak oxygen uptake (V(.)o(2)) for 60 min and at rest, oxygenated hemoglobin/myoglobin (Hb/MbO(2)) and total Hb/Mb (THb/Mb) were determined by near-infrared spectroscopy in the vastus lateralis. Power spectra density (PSD) for the difference between Hb/MbO(2) and THb/Mb (-HHb/MbO(2): deoxygenation) was obtained by fast Fourier transform at rest, in the early phase (1-6 min) and in the late phase (55-60 min) in exercise. Peak PSD in the early phase was significantly higher than that at rest. There were at least three peaks of PSD in exercise. The highest peak was a band around 0.01 Hz, the next peak was a band around 0.04 Hz, and the lowest peak was a band around 0.06 Hz. PSD in the early phase was not significantly different from that in the late phase in exercise. Heart rate (HR) showed a continuous significant increase from 3 min in exercise until the end of exercise. Skin blood flow (SBF) around the early phase was significantly lower than that around the late phase. It was concluded that oscillation of oxygenation in the muscle oxygen system in the early phase is not different from that in the late phase in prolonged exercise despite cardiovascular drift.

Minimal change oesophagitis: a disease with characteristic differences to erosive oesophagitis.

BACKGROUND: The majority of gastro-oesophageal reflux disease (GERD) seems to be non-erosive reflux disease. Nonerosive reflux disease includes minimal change oesophagitis (whitish or reddish, oedematous change and erosion that is not regarded as mucosal break) and no endoscopic abnormalities. AIM: To investigate the accurate proportion of those with minimal change oesophagitis and to clarify its characteristics. In addition, we evaluated the effect of famotidine (40 mg/day) in those with minimal change. METHODS: Prospective endoscopic assessment was performed for consecutive 606 out-patients. Of the 582 patients suitable for analysis, 347 were non-treated. The latter were divided into those with erosive GERD or minimal change, and their endoscopic findings and characteristics were compared. RESULTS: Among 347 non-treated patients, 88 (25%) had erosive GERD and 249 (72%) had minimal change. Compared with patients who have erosive GERD and those with minimal change, the latter were less likely to have hiatal hernia or bile reflux, but more likely to have gastric atrophy. Symptomatic patients (n = 55) with minimal change oesophagitis were more likely to have hiatal hernia than those who were asymptomatic (n= 194). Most patients preferred taking famotidine on-demand, during a 4-week follow-up period. CONCLUSIONS: Most non-erosive reflux disease can be classified as minimal change oesophagitis, and that have different characteristics from erosive GERD. On-demand famotidine may be a suitable alternative treatment for patients with minimal change disease.

Induction of vasculogenesis in breast cancer models.

Recently, there have been reports of postnatal vasculogenesis in cases of ischaemia models. The aim of the present study is to provide evidence of postnatal vasculogenesis in breast-cancer-bearing mice. Based on cell surface antigen expression, we isolated endothelial precursor cells from bone marrow, peripheral blood and tumour-infiltrating cells from mice that had received six human breast cancer xenografts. In all three areas (bone marrow, peripheral blood and tumour-infiltrating cells), endothelial precursor cell population was elevated in all transplanted mice. Differentiation and migration activities of endothelial precursor cells were measured by comparing levels of the endothelial precursor cell maturation markers Flk-1, Flt-1, Tie2, VE-cadherin and CD31 among these three areas. The endothelial precursor cell population was 14% or greater in the gated lymphocyte-size fraction of the inflammatory breast cancer xenograft named WIBC-9, which exhibits a hypervascular structure and de novo formation of vascular channels, namely vasculogenic mimicry (Shirakawa et al, 2001). In vitro, bone marrow-derived endothelial precursor cells from four human breast cancer xenografts proliferated and formed multiple clusters of spindle-shaped attaching cells on a vitronectin-coated dish. The attaching cells, which incorporated DiI-labelled acetylated low-density lipoprotein (DiI-acLDL) and were negative for Mac-1. The putative bone marrow derived endothelial precursor cell subset, which was double positive of CD34 and Flk-1, and comparative bone marrow derived CD34 positive with Flk-1 negative subset were cultured. The former subset incorporated DiI-acLDL and were integrated with HUVECs. Furthermore, they demonstrated significantly higher levels of murine vascular endothelial growth factor and interleukin-8 in culture supernatant on time course by enzyme-linked immunosorbent assay. These findings constitute direct evidence that breast cancer induces postnatal vasculogenesis in vivo.

Effect of trapidil on effector functions of monocytes related to atherosclerotic plaque.

The infiltration and activation of inflammatory cells play an important role in the formation and stability of coronary atherosclerotic plaque in patients with acute coronary syndrome. In this study, we evaluated the effect of trapidil, an anti-platelet agent, on atheroma-related functions of human T cells and monocytes. Trapidil and anti-CD154 (CD40 ligand) antibody inhibited the increase of procoagulant activity in the mixed lymphocyte reaction; trapidil also suppressed the induction of tissue factor, monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-9 in the mixed lymphocyte reaction. Trapidil did not alter CD154 expression on isolated T cells, but it diminished CD40 expression on isolated monocytes and human monocytic leukemia THP-1 cells stimulated with interferon-gamma. Moreover, trapidil reduced MCP-1 production of isolated monocytes and THP-1 cells stimulated with interferon-gamma plus CD154-transfected cells. This effect was not seen with other tested anti-platelet agents and coronary vasodilators. In conclusion, trapidil directly acts on monocytes/macrophages to lower their susceptibility to CD154 on T cells.

Lack of correlation between clinical characteristics and serum soluble Fas ligand levels in patients with multiple myeloma.

Multiple myeloma is characterized by the accumulation of malignant plasma cells in the bone marrow and rarely cured by chemotherapy. Villunger et al. showed that the neoplastic plasma cells express Fas ligand (FasL), which transmits a signal of apoptosis upon ligation to Fas, and suggested that the FasL suppresses the T-cells activated against malignant cells, resulting in escape from tumour immunity. We examined serum soluble FasL (sFasL) levels in 35 multiple myeloma patients to evaluate the correlation between sFasL levels and clinical characteristics. The serum sFasL levels were not affected by the disease status, serum monoclonal protein levels, or other prognostic factors. We could not determine whether the expression of FasL is involved in the poor clinical course of the disease.

Efficient gene transduction by RGD-fiber modified recombinant adenovirus into dendritic cells.

Dendritic cells (DC) are important antigen-presenting cells in the development of an anti-tumor T cell response. To extend the range of current immuno / gene therapies, we tested luciferase-expressing RGD-adenovirus (Ad) (Ad5lucRGD)-mediated transduction into DC. Phenotypically characterized DC were generated from peripheral blood CD14(+) cells by incubation with granulocyte-macrophage colony-stimulating factor, interleukin-4 and tumor necrosis factor alpha. On the 7th day of culture, the cells became mature DC with a CD1a(+), CD11c(+), CD80(+), CD83(+), CD86(+), human leukocyte antigen (HLA)-DR(+), CD14- phenotype. The expression of alpha( v)beta(3) integrin was enhanced on day 3 and returned to the basal level on day 7. We then compared the transduction efficiency of an Ad5lucRGD system to that using conventional Ad, in cells harvested on days 1, 3 and 7 of culture. Luciferase activity was negligible in AdCMVLuc, but remarkable in cells processed with Ad5lucRGD. Activity was maximal in cells that had been cultured for 3 days. Recombinant Ad5 fiber knob protein blocked AdCMVLuc- and Ad5lucRGD-mediated gene transduction by 90% and 20%, respectively. Surface markers and cytokine production were not affected by Ad5lucRGD-mediated transduction.

FK960, a novel potential anti-dementia drug, enhances high K(+)-evoked release of somatostatin from rat hippocampal slices.

We have demonstrated that FK960 [N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate], a novel putative anti-dementia drug of piperazine derivative, ameliorates memory deficits in a variety of animal models of dementia in rats and monkeys, and also augments long-term potentiation (LTP) in the mossy fiber-CA3 pathway in guinea-pig hippocampal slices. Our recent studies have further suggested that somatostatin activation could be a primary mechanism of the pharmacological action of FK960. To clarify the mode of action of FK960 on somatostatinergic neurotransmission, FK960 was examined for its effects on somatostatin release from rat hippocampal slices. FK960 significantly enhanced high K(+)-evoked release, but not basal release, of somatostatin with similar concentration-dependency to its LTP augmenting action. On the other hands, FK960 had no effects on the release of neurotransmitters such as acetylcholine, 5-HT, D-aspartate or GABA from hippocampal slices. Our results provide compelling evidence that FK960 exerts specific and facilitatory actions on neural mechanisms involved in the activity-dependent release of somatostatin from nerve terminals of the hippocampus. These results also strengthen the view that FK960 regulates cognitive functions and augments LTP through an activation of the somatostatinergic nervous system in the hippocampus.

Absence of endothelial cells, central necrosis, and fibrosis are associated with aggressive inflammatory breast cancer.

We recently established a new human inflammatory breast cancer (IBC) xenograft (WIBC-9) originating from a patient with IBC. The graft was transplantable in BALB/c nude and severe combined immunodeficient (SCID) mice. WIBC-9 was frequently accompanied by lung metastasis and exhibited erythema of the overlying skin, reflecting its human counterpart. Histological study of the original tumor and WIBC-9 revealed invasive ductal carcinoma with a hypervascular structure of solid nests and marked lymphatic permeation in the overlying dermis. In the central part of the solid nests, absence of endothelial cells, central necrosis, and fibrosis were observed. In vitro, WIBC-9 formed tube-like structures and loops, reflecting its in vivo feature and its human counterpart. WIBC-9 exhibited aneuploidy, ErbB-2 gene amplification, and an absence of estrogen receptor and progesterone receptor, which is consistent with IBC. Comparative studies of WIBC-9, three established non-IBC xenografts, and a human breast cancer cell line (SK-BR3) by reverse transcription-PCR, ELISA, and immunohistochemistry indicated that certain human genes (interleukin 8, vascular epidermal growth factor, basic fibroblast growth factor, angiopoietin 13, Flt-1, Tie-2, and Tie-1) and certain murine genes (integrin alpha(v)beta3, flt-1, tie-2, vascular epidermal growth factor, and CD31) were overexpressed in exposure to tumor cells. The molecular basis and these unique histological features may be associated with aggressive IBC on angiogenic and nonangiogenic pathways.