Biomedical subjects

Takuya Osada

Publications and source records attributed to Takuya Osada.

At least 19 recordsLinked to original sources

PubMed2006

Sulforaphane induces inhibition of human umbilical vein endothelial cells proliferation by apoptosis.

Sulforaphane (SUL), one of the isothiocyanates (ITCs), has recently been focused due to its inhibitory effects on tumor cell growth in vitro and in vivo, which is dependent on the direct effect on cancer cells. In the present study, we aimed to investigate the potential anti-angiogenic effect of SUL and its mechanism of action. Using the human umbilical vein endothelial cells (HUVECs) as a model of angiogenesis, we investigated the effect of SUL on the various steps of angiogenesis, including the proliferation of endothelial cells, tubular formation, and matrix metalloproteinase (MMP) production. Sulforaphane induced a dose-dependent decrease in the proliferative activity of endothelial cells, which was dependent on cell apoptosis. Also SUL inhibited tube formation on matrigel, but did not affect MMP production. The present results demonstrate the anti-angiogenic activity of SUL and its potential use as an anti-cancer drug is suggested.

Angiogenesis Inhibitors↗

PubMed2006

Alterations in the blood velocity profile influence the blood flow response during muscle contractions and relaxations.

The present study examined the influences of the muscle contraction (MCP) and relaxation (MRP) phases, as well as systole and diastole, on the blood velocity profile and flow in the conduit artery at different dynamic muscle contraction forces. Eight healthy volunteers performed one-legged dynamic knee-extensor exercise at work rates of 5, 10, 20, 30, and 40 W at 60 contractions per minute. The time- and space-averaged, amplitude-weighted, mean (V(mean)) and maximum (V(max)) blood flow velocities were continuously measured in the common femoral artery during the cardiosystolic (CSP) and cardiodiastolic (CDP) phases during MCP and MRP, respectively. The V(max)/V(mean) ratio was used as a flow profile index where a ratio of approximately (~) 1 indicates a "flat" velocity profile, and a ratio significantly greater than (>>) 1 indicates a "parabolic" velocity profile. At rest, a "steeper" parabolic velocity profile was found during the CDP (ratio: 1.75 +/- 0.06) than during the CSP (ratio: 1.31 +/- 0.02). During the MRP of exercise, the V(max)/V(mean) ratio shifted to be less steep (p < 0.05) than at rest during the CDP (ratio: 1.41-1.54) at 5, 10, 20, 30, and 40 W; whereas it was slightly higher (p < 0.05) at 30 and 40 W than at rest during the CSP (ratio: 1.43-1.46). During the MCP, the parabolic blood velocity profile was enhanced (p < 0.05) at higher contraction forces, 20 W during the CDP (ratio: 2.15-2.52) and 30 W during the CSP (ratio: 1.49-1.77), potentially because of a greater retrograde flow component. A higher blood flow furthermore appeared during the MRP compared to during the MCP, coinciding with a greater uniformity of the red blood cells moving at higher blood velocities during the MRP. Thus part of the difference in the magnitude of blood flow during the MRP vs. MCP may be due to the alterations of the blood velocity flow profile.

Adult↗

PubMed2006

Impaired muscle oxygen metabolism in uremic children: improved after renal transplantation.

BACKGROUND: The purpose of this study is to clarify skeletal muscle oxidative metabolism in children with end-stage renal disease (ESRD) before and after renal transplantation. METHODS: We examined muscle oxygenation and metabolism by using noninvasive near-infrared spectroscopy in 10 patients (age, 12.4 +/- 3.1 years) 1 week before and 4 weeks after renal transplantation and in 10 controls (age, 12.8 +/- 2.6 years) during submaximal hand-grip exercise using the flexor digitorum superficialis muscle. We used 2 indicators to evaluate muscle metabolism. The rate of initial decrease in hemoglobin/myoglobin deoxygenation during arterial occlusion after exercise relative to the value at rest (S2/S1) was used as an indicator of mitochondrial oxygen consumption, whereas recovery time (TR) after exercise was used as an indicator of oxygen delivery to the muscle and aerobic capacity. RESULTS: S2/S1 and TR after exercise were significantly lower in patients before renal transplantation compared with the control group (P < 0.05). S2/S1 and TR after exercise improved significantly after renal transplantation (P < 0.01, P < 0.05) and were not significantly different from those of controls. CONCLUSION: Oxidative metabolism in skeletal muscle during exercise is impaired in children with ESRD and recovers after renal transplantation.

Adolescent↗

PubMed2006

Age and activity status affect muscle reoxygenation time after maximal cycling exercise.

PURPOSE: The purpose of this study was to determine the interaction of age and habitual physical activity on recovery time of muscle oxygenation following maximal cycling exercise (CycEXmax). METHODS: Twelve sedentary middle-aged (50+/-6), 13 sedentary elderly (66+/-3), 13 active middle-aged (53+/-5), and 20 active elderly (67+/-5) women participated in this study. We evaluated the peak pulmonary oxygen uptake (VO2peak) during CycEXmax and the half-recovery time of muscle oxygenation (T1/2reoxy time) using near-infrared spectroscopy at the vastus lateralis (VL) during the recovery phase after CycEXmax. RESULTS: T1/2reoxy time was significantly greater in the elderly subjects than in the middle-aged subjects in both sedentary (P<0.05) and active groups (P<0.01). T1/2reoxy time of the active group was lower (P<0.01) than that of the sedentary group regardless of age. Age was significantly correlated to T1/2reoxy time in both sedentary and active groups (in both sedentary and active groups: P<0.01). The slope of T1/2reoxy time against age in the sedentary group was significantly greater (VL: P<0.05) than that of the active group. VO2peak showed significant inverse correlation with T1/2reoxy time at the VL in both sedentary and active groups. The slope of VO2peak against T1/2reoxy time showed no significant differences between middle-aged and elderly subjects. CONCLUSION: The results of this study suggest that T1/2reoxy time was prolonged with aging, regardless of habitual physical activity levels. However, habitual physical activity may prevent the age-related prolongation in T1/2reoxy time after CycEXmax. VO2peak appears to be one of the major factors determining T1/2reoxy time, not age.

Aged↗

PubMed2006

Recent clinical progress in virus-based therapies for cancer.

As our knowledge of the molecular basis of cancer expands, viral vectors have been increasingly studied as potential antitumour therapeutic agents. With their ability to invade and replicate within target cells, viruses have been utilised as oncolytic agents to directly lyse tumour cells. Viruses can also deliver their genetic payload into infected cells, allowing for the repair of defective tumour suppressor genes, disruption of oncogenic pathways, and production of cytokines that activate the immune system. Finally, viruses encoding tumour-associated antigens can infect dendritic cells, triggering the development of a tumour-specific immune response. The ability to engineer viruses with high levels of tumour specificity and efficient rates of infection has enhanced the safety profile of these agents, allowing for the development of viable therapeutic options that have been examined in the clinic, either alone or in conjunction with more conventional therapies. This review highlights the principles underlying virus-based therapies for cancer, with an emphasis on recent developments from the clinic.

Cancer Vaccines↗

PubMed2006

Role of natural killer cell function in dendritic cell-based vaccines.

Recent studies have elucidated the functional links between natural killer (NK) cells and, demonstrating the reciprocal activation of these cell types through NK-DC interactions. The subsets of cells and molecular pathways involved in such interactions have been defined, and the possible anatomical sites of these interactions have also been reported. Murine experiments have demonstrated that injection of mature DCs induces rapid recruitment of NK cells to lymph nodes and that these NK cells provide interferon-gamma for Type 1 priming. Thus, there is an increasing body of in vivo evidence indicating that NK-DC interactions during the early phase of innate immunity can impact the quality and magnitude of the subsequent adaptive immune response. Importantly, these studies imply that NK cells might not serve merely as cytotoxic lymphocytes combating viral pathogens and malignant tumors, but must also be considered as important immunoregulatory cells with a significant influence on adaptive immunity. In contrast to the large volume of knowledge obtained through basic research, there is a relative paucity of information regarding NK cell function in adaptive immunity from clinical trials, as few DC vaccine studies have attempted to evaluate the nonspecific, yet potentially clinically relevant, NK response to immunization. In this article, the authors will review studies focusing on NK-DC interactions and highlight the most recent clinical findings relating to the potential role of NK cells in DC-based vaccine therapy.

Adoptive Transfer↗

PubMed2005

NK cell activation by dendritic cell vaccine: a mechanism of action for clinical activity.

Recent reports revealed that dendritic cell (DC)-natural killer (NK) cell interaction plays an important role in tumor immunity, but few DC vaccine studies have attempted to evaluate the non-specific, yet potentially clinically relevant, NK response to immunization. In this study, we first analyzed in vitro activation of NK cells by DCs similar to those used in clinical trials. Subsequently, NK cell responses were analyzed in a phase I clinical trial of a vaccine consisting of autologous DCs loaded with a fowlpox vector encoding CEA. The data were compared with the clinical outcome of the patients. DC enhances NK activity in vitro, partly by sustaining NK cell survival and by enhancing the expression of NK-activating receptors, including NKp46 and NKG2D. Among nine patients in our clinical trial, NK cytolytic activity increased in four (range 2.5-5 times greater lytic activity) including three who had increased NK cell frequency, was stable in two and decreased in three. NKp46 and NKG2D expression showed a good correlation with the patients' NK activity. When patients were grouped by clinical activity (stable disease/no evidence of disease (stable/NE, n=5) vs progressive disease (N=4) at 3 months), the majority in the stable/NE group had increases in NK activity (P=0.016). Anti-CEA T cell response was enhanced in all the nine patients analyzed, but was not significantly different between the two groups (P=0.14). Thus, NK responses following DC vaccination may correlate more closely with clinical outcome than do T cell responses. Monitoring of NK response during vaccine studies should be routinely performed.

Adenocarcinoma↗

PubMed2005

Early-outgrowth of endothelial progenitor cells can function as antigen-presenting cells.

Endothelial progenitor cells (EPCs) have been recently found to exist circulating in peripheral blood of adults, and home to sites of neovascularization in peripheral tissues. They can also be differentiated from peripheral blood mononuclear cells (PBMNCs). In tumor tissues, EPCs are found in highly vascularized lesions. Few reports exist in the literature concerning the characteristics of EPCs, especially related to their surface antigen expressions, except for endothelial markers. Here, we aimed to investigate the surface expression of differentiation markers, and the functional activities of early-outgrowth of EPCs (EO-EPCs), especially focusing on their antigen-presenting ability. EO-EPCs were generated from PBMNCs, by culture in the presence of angiogenic factors. These EO-EPCs had the morphological and functional features of endothelial cells and, additionally, they shared antigen-presenting ability. They induced the proliferation of allogeneic lymphocytes in a mixed-lymphocyte reaction, and could generate cytotoxic lymphocytes, with the ability to lyze tumor cells in an antigen-specific manner. The antigen-presenting ability of EO-EPCs, however, was weaker than that of monocyte-derived dendritic cells, but stronger than peripheral blood monocytes. Since EO-EPCs play an important role in the development of tumor angiogenesis, targeting EPCs would be an effective anti-angiogenic strategy. Alternatively, due to their antigen-presenting ability, EO-EPCs can be used as the effectors of anti-tumor immunotherapy. Since they share endothelial antigens, the activation of a cellular immunity against angiogenic vessels can be expected. In conclusion, EO-EPCs should be an interesting alternative for the development of new therapeutic strategies to combat cancer, either as the effectors or as the targets of cancer immunotherapy.

Antigen-Presenting Cells↗

PubMed2005

Ex vivo expanded human CD4+ regulatory NKT cells suppress expansion of tumor antigen-specific CTLs.

NKT cells can produce large amounts of both Th1- and Th2-type cytokines and are an important regulatory cell type. To elucidate their role in acquired immunity, we examined the effect of human Valpha24+Vbeta11+ NKT cells or CD1d-specific ligand alpha-galactosylceramide (alphaGalCer) on the in vitro generation of antigen-specific CTLs from PBMCs using autologous MART-1(26-35) peptide-pulsed dendritic cells as stimulators. Flow cytometry using tetramer for MART-1(26-35) peptide revealed that NKT cells have inhibitory effects on CTL generation. Cytokine analysis using cytometric bead array assay and ELISA showed higher IL-4 and IL-10 secretion in the alphaGalCer(+) and/or NKT cell(+) culture setting, whereas IL-13 secretion in the culture was not affected by the presence of alphaGalCer. The CD4+ NKT cell subset seemed to play a major role in this inhibitory effect by secreting large amounts of Th2-type cytokines. Interestingly however, unlike recent reports utilizing mouse models, IL-13 was not a main effector molecule in our human system. Culture with alphaGalCer in the presence of cytokine-neutralizing antibodies for the Th2 cytokines, IL-4, IL-5 and IL-10, resulted in enhanced CTL generation, suggesting the dominant role of Th2 cytokines over Th1 cytokines. Thus, CD4+ NKT cells can work as immunoregulatory T cells that suppress anti-tumor immune response and, therefore, NKT cells or alphaGalCer could be used as therapeutic modalities to modulate systemic immune responses, such as autoimmune diseases. Conversely, the use of NKT cells along with anti-Th2 cytokine-neutralizing antibodies or CD4-negative NKT cell subset could enhance the generation of antigen-specific CTLs for adoptive immunotherapy.

Antigens, Neoplasm↗

PubMed2005

Phase I study of immunization with dendritic cells modified with fowlpox encoding carcinoembryonic antigen and costimulatory molecules.

PURPOSE: To determine the safety and immunologic and clinical efficacy of a dendritic cell vaccine modified to hyperexpress costimulatory molecules and tumor antigen. EXPERIMENTAL DESIGN: In this phase I study, we administered one or two cycles of four triweekly s.c./intradermal injections of ex vivo generated dendritic cells modified with a recombinant fowlpox vector encoding carcinoembryonic antigen (CEA) and a triad of costimulatory molecules [rF-CEA(6D)-TRICOM]. Controls consisted of immature dendritic cells loaded with tetanus toxoid and a HLA A2-restricted peptide derived from cytomegalovirus pp65 protein. RESULTS: Fourteen patients (11 with colorectal cancer and 3 with non-small cell lung cancer) were enrolled and 12 completed at least one cycle of immunization. There were no grade 3/4 toxicities directly referable to the immunizations. One patient had a decrease in the CEA level from 46 to 6.8 and a minor regression in adenopathy that occurred several months after completion of the immunizations. Five other patients were stable through at least one cycle of immunization (3 months). Direct analysis of peripheral blood mononuclear cells using the ELISpot assay showed an increase in the frequency of CEA-specific T cells in 10 patients (range, 10-541 CEA-specific cells/10(5) peripheral blood mononuclear cells). There was a trend for a greater peak frequency of CEA-specific T cells among those with either a minor response or a stable disease following at least one cycle of therapy. A second cycle was not associated with higher T-cell frequencies. Cytokine flow cytometry showed CEA-specific immune response among both CD4(+) and CD8(+) T cells in all immune responders. CONCLUSION: This immunization strategy is safe and activates potent CEA-specific immune responses.

B7-1 Antigen↗

PubMed2005

A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer.

BACKGROUND: There is a continued need to develop more effective cancer immunotherapy strategies. Exosomes, cell-derived lipid vesicles that express high levels of a narrow spectrum of cell proteins represent a novel platform for delivering high levels of antigen in conjunction with costimulatory molecules. We performed this study to test the safety, feasibility and efficacy of autologous dendritic cell (DC)-derived exosomes (DEX) loaded with the MAGE tumor antigens in patients with non-small cell lung cancer (NSCLC). METHODS: This Phase I study enrolled HLA A2+ patients with pre-treated Stage IIIb (N = 4) and IV (N = 9) NSCLC with tumor expression of MAGE-A3 or A4. Patients underwent leukapheresis to generate DC from which DEX were produced and loaded with MAGE-A3, -A4, -A10, and MAGE-3DPO4 peptides. Patients received 4 doses of DEX at weekly intervals. RESULTS: Thirteen patients were enrolled and 9 completed therapy. Three formulations of DEX were evaluated; all were well tolerated with only grade 1-2 adverse events related to the use of DEX (injection site reactions (N = 8), flu like illness (N = 1), and peripheral arm pain (N = 1)). The time from the first dose of DEX until disease progression was 30 to 429+ days. Three patients had disease progression before the first DEX dose. Survival of patients after the first DEX dose was 52-665+ days. DTH reactivity against MAGE peptides was detected in 3/9 patients. Immune responses were detected in patients as follows: MAGE-specific T cell responses in 1/3, increased NK lytic activity in 2/4. CONCLUSION: Production of the DEX vaccine was feasible and DEX therapy was well tolerated in patients with advanced NSCLC. Some patients experienced long term stability of disease and activation of immune effectors.

Journal Article↗

PubMed2005

CD11b-mediated migratory property of peripheral blood B cells.

BACKGROUND: CD11b belongs to the integrin family and is expressed on neutrophils, monocytes, natural killer cells, and a subset of lymphocytes. Although CD11b expressed on neutrophils and monocytes has been extensively investigated and has been reported to play an important role in the migration of these subsets of leukocytes, the function of CD11b expressed on a subset of B cells has not yet been clarified. OBJECTIVE: To elucidate the functional activity of CD11b expressed on B cells, we characterized the CD11b-expressing cells among the B-cell population and investigated their migratory ability. METHODS: Isolated peripheral blood CD19 + B cells were analyzed by flow cytometry. The migratory ability of B cells was evaluated by the transwell assay, and the contribution of CD11b to this ability was investigated by using an anti-CD11b blocking mAb. RESULTS: The majority of CD27 - IgD + naive B cells were CD11b - , whereas most CD27 + memory cells were CD11b +. Among the CD27 + memory cells, expression of CD11b was stronger on the IgD - cells than on the IgD + cells. In the transwell assay, the migrating cells were predominantly CD27 + IgD - cells, most of which expressed CD11b. The addition of an anti-CD11b blocking mAb resulted in the significant reduction of the number of migrating B cells. CONCLUSION: Memory B cells express CD11b and, in contrast with naive B cells, have high migratory ability. CD11b plays an essential role in the homing process of memory cells.

B-Lymphocyte Subsets↗

PubMed2005

Substrate availability and transcriptional regulation of metabolic genes in human skeletal muscle during recovery from exercise.

In skeletal muscle of humans, transcription of several metabolic genes is transiently induced during recovery from exercise when no food is consumed. To determine the potential influence of substrate availability on the transcriptional regulation of metabolic genes during recovery from exercise, 9 male subjects (aged 22-27) completed 75 minutes of cycling exercise at 75% Vo2 max on 2 occasions, consuming either a high-carbohydrate (HC) or low-carbohydrate (LC) diet during the subsequent 24 hours of recovery. Nuclei were isolated and tissue frozen from vastus lateralis muscle biopsies obtained before exercise and 2, 5, 8, and 24 hours after exercise. Muscle glycogen was restored to near resting levels within 5 hours in the HC trial, but remained depressed through 24 hours in the LC trial. During the 2- to 8-hour recovery period, leg glucose uptake was 5- to 15-fold higher with HC ingestion, whereas arterial plasma free fatty acid levels were approximately 3- to 7-fold higher with LC ingestion. Exercise increased (P < .05) transcription and/or mRNA content of the pyruvate dehydrogenase kinase 4, uncoupling protein 3, lipoprotein lipase, carnitine palmitoyltransferase I, hexokinase II, peroxisome proliferator activated receptor gamma coactivator-1 alpha, and peroxisome proliferator activated receptor alpha. Providing HC during recovery reversed the activation of pyruvate dehydrogenase kinase 4, uncoupling protein 3, lipoprotein lipase, and carnitine palmitoyltransferase I within 5 to 8 hours after exercise, whereas providing LC during recovery elicited a sustained/enhanced increase in activation of these genes through 8 to 24 hours of recovery. These findings provide evidence that factors associated with substrate availability and/or cellular metabolic recovery (eg, muscle glycogen restoration) influence the transcriptional regulation of metabolic genes in skeletal muscle of humans during recovery from exercise.

Adult↗

PubMed2005

Targeting Id1 and Id3 inhibits peritoneal metastasis of gastric cancer.

Inhibitor of DNA binding (Id) proteins are essential for cell differentiation, proliferation, migration, invasion and angiogenesis. Recently, they have been shown to correlate with less differentiated phenotypes, high malignant potential and poor clinical outcome in various kinds of tumors. In an attempt to develop new strategies for the treatment of peritoneal metastasis of gastric cancer, we prepared an Id1, 3 double-knockdown gastric cancer cell line, MKN45, by RNA interference and investigated its effects on the development of metastatic nodules in the peritoneal cavity. Both cell proliferation and migration capabilities were decreased in Id1, 3 double-knockdown cells, as was their ability to bind to laminin, which could be explained by the decreased expression of integrin alpha6. These are important steps in the metastatic process. In a mouse model, the number of peritoneal metastatic nodules formed by Id1, 3 double-knockdown cells was reduced compared to mock-transfected control cells, as was the size of individual tumors. In this study, we clearly demonstrated that Id1, 3 double-knockdown significantly impaired the ability of gastric cancer cells to form peritoneal metastasis. Id should be considered an ideal target for the treatment and prevention of gastric cancer, and RNA interference is an attractive and promising strategy to achieve it.

Animals↗

PubMed2005

Alterations in the rheological flow profile in conduit femoral artery during rhythmic thigh muscle contractions in humans.

The present study examined the rheological blood velocity profile in the conduit femoral artery during rhythmic muscle contractions at different muscle forces. Eight healthy volunteers performed one-legged, dynamic knee-extensor exercise at work rates of 5, 10, 20, 30, and 40 W at 60 contractions per minute. The time and space-averaged, amplitude-weighted mean (V(mean)) and maximum (V(max)) blood flow velocities in the common femoral artery were measured during the cardiosystolic phase (CSP) and cardiodiastolic phase (CDP) by the Doppler ultrasound technique. The V(max)/V(mean) ratio was used as a flow profile index, in which a ratio of approximately 1 indicates a "flat velocity flow profile" and a ratio significantly >1 indicates a "parabolic velocity flow profile." At rest, the V(max)/V(mean) ratio was approximately 1.3 and approximately 1.8 during the CSP and CDP, respectively. The V(max)/V(mean) ratio was higher (p < 0.01) during the CDP than during the CSP, both at rest and at all work rates. The V(max)/V(mean) ratio during the CSP was higher (p < 0.01) at 30 and 40 W compared to at rest. The V(max)/V(mean) ratio during the CDP was lower (p < 0.05) at 5 and 10 W compared to at rest. There was a positive linear correlation between blood flow and incremental work rates during both the CSP and CDP, respectively. Thus under resting conditions, the findings indicate a "steeper" parabolic velocity profile during the CDP than during the CSP. The velocity profile during the CDP furthermore shifts to being less "steep" during rhythmic muscle contractions at lower intensities, but to being reelevated and normalized as at rest during higher intensities. The "steepness" of the parabolic velocity profile observed during the CSP at rest increased during muscle contraction at higher intensities. In conclusion, the blood velocity in the common femoral artery is parabolic both at rest and during exercise for both the CSP and CDP, indicating the persistence of laminar flow. The occurrence of any temporary slight disturbance or turbulence in the flow at the sight of measurement in the common femoral artery does consequently not induce a persisting "disturbed" and fully flat "plug-like" velocity profile. Instead, the "steepness" of the parabolic velocity profile is only slightly modified, whereby blood flow is not impaired. Thus the blood velocity profile, besides being influenced by the muscle contraction-relaxation induced mechanical "impedance," seems also to be modulated by the cardiac- and blood pressure-phases, consequently influencing the exercise blood flow response.

Adult↗

PubMed2004

Effects of blackcurrant anthocyanin intake on peripheral muscle circulation during typing work in humans.

This double-blind, placebo-controlled, crossover study investigated the effect of blackcurrant anthocyanin (BCA) intake on peripheral circulation during rest and during typing work by using near-infrared spectroscopy (NIRS), and it also assessed improvement in shoulder stiffness caused by poor local circulation. In a resting circulation study, nine healthy male subjects took capsules of BCA at a dosage of 17 mg kg(-1) or placebo (isoenergetic sugar). NIRS was used to measure left forearm blood flow (FBF) following venous occlusion and muscle oxygen consumption following arterial occlusion prior to and hourly for 4 h after ingestion of BCA. Plasma anthocyanin concentration was measured prior to ingestion and 1, 2, and 4 h later. FBF increased significantly 2 h after BCA ingestion [BCA 1.22 (0.13)-fold increase relative to pre-values vs placebo 0.83 (0.06) of pre-values; P < 0.05] and then tended to increase for a further 3 h after ingestion [BCA 1.26 (0.15)-fold increase relative to pre-values vs placebo 0.82 (0.07) of pre-values; P = 0.078]. There was, however, no significant difference in muscle oxygen consumption between BCA and placebo intake at any time point. In a typing work study, 11 healthy subjects took capsules of BCA (7.7 mg kg(-1)) or placebo (isoenergetic sugar) daily for 2 weeks. The subjects then performed intermittent typing workload for 30 min in order to induce acute shoulder stiffness. During the workload, total hemoglobin and oxygenated hemoglobin (oxy-Hb) were determined using NIRS and myoelectric signals measured in the right trapezius muscle using electromyography (EMG). The viscoelasticity of the trapezius muscle was also evaluated using a muscle stiffness meter before and after the typing workload. BCA intake prevented the decrease in oxy-Hb significantly (P < 0.05), and also tended to alleviate the increase in root mean square (RMS) of the EMG during the typing workload, and also muscle stiffness after the workload. There was no improvement in typing performance with BCA intake. The results of this study suggest that intake of BCA may improve shoulder stiffness caused by typing work by increasing peripheral blood flow and reducing muscle fatigue.

Administration, Oral↗

PubMed2004

Tumor-infiltrating effector cells of alpha-galactosylceramide-induced antitumor immunity in metastatic liver tumor.

BACKGROUND: alpha-Galactosylceramide (alpha-GalCer) can be presented by CD1d molecules of antigen-presenting cells, and is known to induce a potent NKT cell-dependent cytotoxic response against tumor cells. However, the main effector cells in alpha-GalCer-induced antitumor immunity are still controversial. METHODS: In order to elucidate the cell phenotype that plays the most important role in alpha-GalCer-induced antitumor immunity, we purified and analyzed tumor-infiltrating leukocytes (TILs) from liver metastatic nodules of a colon cancer cell line (Colon26), comparing alpha-GalCer- and control vehicle-treated mice. Flow cytometry was performed to analyze cell phenotype in TILs and IFN-gamma ELISA was performed to detect antigen-specific immune response. RESULTS: Flow cytometry analysis showed a significantly higher infiltration of NK cells (DX5+, T cell receptor alphabeta (TCR)-) into tumors in alpha-GalCer-treated mice compared to vehicle-treated mice. The DX5+TCR+ cell population was not significantly different between these two groups, indicating that these cells were not the main effector cells. Interestingly, the CD8+ T cell population was increased in TILs of alpha-GalCer-treated mice, and the activation level of these cells based on CD69 expression was higher than that in vehicle-treated mice. Moreover, the number of tumor-infiltrating dendritic cells (DCs) was increased in alpha-GalCer-treated mice. IFN-gamma ELISA showed stronger antigen-specific response in TILs from alpha-GalCer-treated mice compared to those from vehicle-treated mice, although the difference between these two groups was not significant. CONCLUSIONS: In alpha-GalCer-induced antitumor immunity, NK cells seem to be some of the main effector cells and both CD8+ T cells and DCs, which are related to acquired immunity, might also play important roles in this antitumor immune response. These results suggest that alpha-GalCer has a multifunctional role in modulation of the immune response.

Journal Article↗

PubMed2004

Brain and central haemodynamics and oxygenation during maximal exercise in humans.

During maximal exercise in humans, fatigue is preceded by reductions in systemic and skeletal muscle blood flow, O(2) delivery and uptake. Here, we examined whether the uptake of O(2) and substrates by the human brain is compromised and whether the fall in stroke volume of the heart underlying the decline in systemic O(2) delivery is related to declining venous return. We measured brain and central haemodynamics and oxygenation in healthy males (n= 13 in 2 studies) performing intense cycling exercise (360 +/- 10 W; mean +/-s.e.m.) to exhaustion starting with either high (H) or normal (control, C) body temperature. Time to exhaustion was shorter in H than in C (5.8 +/- 0.2 versus 7.5 +/- 0.4 min, P < 0.05), despite heart rate reaching similar maximal values. During the first 90 s of both trials, frontal cortex tissue oxygenation and the arterial-internal jugular venous differences (a-v diff) for O(2) and glucose did not change, whereas middle cerebral artery mean flow velocity (MCA V(mean)) and cardiac output increased by approximately 22 and approximately 115%, respectively. Thereafter, brain extraction of O(2), glucose and lactate increased by approximately 45, approximately 55 and approximately 95%, respectively, while frontal cortex tissue oxygenation, MCA V(mean) and cardiac output declined approximately 40, approximately 15 and approximately 10%, respectively. At exhaustion in both trials, systemic VO(2) declined in parallel with a similar fall in stroke volume and central venous pressure; yet the brain uptake of O(2), glucose and lactate increased. In conclusion, the reduction in stroke volume, which underlies the fall in systemic O(2) delivery and uptake before exhaustion, is partly related to reductions in venous return to the heart. Furthermore, fatigue during maximal exercise, with or without heat stress, in healthy humans is associated with an enhanced rather than impaired brain uptake of O(2) and substrates.

Adenosine Triphosphate↗