Background We experienced a case of early stage lung cancer involving a morbidly obese patient. O... more Background We experienced a case of early stage lung cancer involving a morbidly obese patient. Obesity is associated with a higher incidence of surgical complications. We examined the effectiveness of laparoscopic sleeve gastrectomy as a primary weight loss procedure in a morbidly obese patient who required oncological surgery. Case presentation A 64-year-old morbidly obese female with a body mass index of 43.5 kg/m2 was referred to our hospital to undergo weight loss. A right-sided lung mass was found incidentally on computed tomography conducted in preparation for laparoscopic sleeve gastrectomy, which was performed prior to tumor surgery. As a result, weight loss was achieved within 2.5 months after the laparoscopic sleeve gastrectomy, and the patient’s type-2 diabetes, hypertension, and dyslipidemia, which are linked to obesity, were markedly ameliorated. After a quick intraoperative pathological inspection revealed that the tumor was malignant, thoracoscopic right lung superio...
The arterial ketone body ratio (AKBR), an established clinical tool that reflects hepatic mitocho... more The arterial ketone body ratio (AKBR), an established clinical tool that reflects hepatic mitochondrial oxidation-reduction potential, predicts the outcome of patients with shock and multiple organ failure and the postoperative outcome in patients who have undergone major liver or heart surgery. The purpose of this study was to determine the prognostic significance of AKBR in patients with acute heart failure. The subjects of this study were 52 patients with acute heart failure. The following parameters were analyzed after Cox univariate hazard analysis was performed: AKBR, plasma norepinephrine, left ventricular ejection fraction, cardiac index, pulmonary arterial wedge pressure, sex, age, human atrial natriuretic peptide, endothelin-1, and cholesterol. The follow-up period was 30 weeks with cardiac death as the end point. Stepwise multivariate proportional hazard analysis revealed that AKBR was the most significant predictor of death, followed by norepinephrine and human atrial natriuretic peptide. Curve-fitting analysis revealed that the relationship between log (norepinephrine) and AKBR could best be described by two distinct lines, with their intersection at AKBR = 0.7 and norepinephrine = 418. With these results we conducted Kaplan-Meier analysis for AKBR > or = 0.7 and AKBR <0.7. The survival rate in patients with AKBR > or = 0.7 was 100%, whereas that in patients with AKBR <0.7 was 15% (p < 0.0001, log-rank analysis). These results indicate that AKBR is a novel independent predictor of death in heart failure.
The mechanism underlying the fatal complications in jaundiced states after shock has not been ful... more The mechanism underlying the fatal complications in jaundiced states after shock has not been fully clarified. The present study was designed to examine the effect of hemorrhagic shock on myocardial high-energy phosphate stores and the arterial ketone body ratio (AKBR:acetoacetate/beta-hydroxybutyrate), which reflects the redox state of the liver mitochondria, in normal and jaundiced rats. At 1 week after ligation of the common bile duct, hemorrhagic shock was induced by exsanguination (mean arterial blood pressure = 40 mmHg) and maintained for 2 h. Serial changes in AKBR were measured. The myocardial adenine nucleotides phosphocreatine (PCr) and inorganic phosphate (Pi) were determined before and after hemorrhagic shock. Before shock, myocardial ATP in the jaundiced group was lower than that in the sham group. However, the myocardial PCr levels in the two groups did not differ. After reinfusion of the shed blood, ATP and PCr recovered to the preshock levels in the sham group. However, ATP and PCr were further increased in the jaundiced group. At 60 min after reinfusion, AKBR recovered to the normal level in the sham group, but decreased below 0.7 in the jaundiced group. Metabolic acidosis was more severe in the jaundiced group than in the sham group. The decrease in AKBR indicated irreversible metabolic acidosis. As a result, fatal circulatory failure occurred, although the phosphoenergetic level in the myocardium was sufficiently maintained.
The production of free radicals in tissues can be continually monitored by measurement of low-lev... more The production of free radicals in tissues can be continually monitored by measurement of low-level chemiluminescence. In these experiments the effects of ethanol on luminol (1 microM)-enhanced chemiluminescence were recorded in isolated perfused livers from control rats, and from rats that had undergone a 30-min period of ischemia, followed by 3 h of reinstitution of blood flow. Our previous experiments showed considerable neutrophil accumulation at this time. A routine concentration of 100 mM ethanol added after 20 min of perfusion with Krebs-Henseleit solution caused an increase in chemiluminescence of about 2000 cpm above the resting level (1600 cpm) in both control livers and livers from rats after 3 h of ischemia reperfusion in vivo. However, if ethanol was added to the perfusing medium of the isolated liver after at least 1 h of in vitro perfusion, then the magnitude of the response was very much greater (peak approximately 27000 cpm) in livers that had undergone ischemia reperfusion than in control livers (peak approximately 7000 cpm). Experiments combining addition of ethanol and the potent neutrophil stimulator, phorbol myristate acetate (PMA), plus the use of rat antineutrophil serum have shown conclusively that the very large chemiluminescent response to ethanol after prolonged in vitro perfusion is due to stimulation of neutrophil radical production.
Patients undergoing hepatectomy have an increased susceptibility to infection. We therefore studi... more Patients undergoing hepatectomy have an increased susceptibility to infection. We therefore studied the energy metabolism of the polvmorphonuclear leucocvte (PMN), focusing on energy charge and function, especially superoxide anion (O2−) generation, in relation to the hepatic mitochondrial redox state. By labelling the PMN adenine nucleotide pool with radioactive adenine and by superoxide dismutase-inhibitahle reduction of ferricytochrome c, the energy charge and O2− production was measured in 18 patients with hepatoma (non-cirrhotic, seven; cirrhotic, 11) undergoing hepatectomy. Their arterial ketone body ratios (KBRs), reflecting the hepatic mitochondrial redox potential, were above 0.7 before operation. After surgery, the 18 patients were divided into two groups: group A. KBR > 0.7, n = 10; and group B, KBR < 0.7, n = 8. The energy charge and O2− release in group B decreased significantly from preoperative values (P < 0.001 and P < 0.01 respectively) and when compared...
The mechanism underlying immunosuppression after partial hepatectomy remains unclear. Hepatectomy... more The mechanism underlying immunosuppression after partial hepatectomy remains unclear. Hepatectomy induces lymphopenia, which is related to immunomodulation. The aim of this study was to determine whether peripheral blood lymphocytes (PBL) are susceptible to mitochondria-mediated apoptosis after hepatic resection. We compared the changes in mitochondrial membrane potential in lymphocytes from hepatectomized patients with metastatic liver tumor with the corresponding changes in lymphocytes from cholechystectomized patients, because changes in mitochondrial membrane potential have been reported to frequently occur during the early stages of apoptosis. Mitochondrial membrane potential, subpopulation, and apoptosis of lymphocytes were estimated with flow cytometry. Hepatectomy significantly (P&amp;amp;lt;0.001) reduced postoperative mitochondrial membrane potential, while cholecystectomy slightly decreased it. Apoptosis of lymphocytes was increased on post-hepatectomy day, and this increase was correlated with the extent of mitochondrial membrane potential reduction. The major subset of lymphocytes with low mitochondrial membrane potential consisted of CD56(+) natural killer (NK) cells, and NK cell activity and cell counts significantly decreased after hepatectomy. Mitochondrial membrane potential of PBL was reduced after hepatectomy, and some lymphocytes underwent apoptosis through the mitochondrial pathway, which was one of the causes for lymphopenia. NK cells were more responsible for the decrease of mitochondrial membrane potential after hepatectomy than other lymphocytes, and the reduction in mitochondrial membrane potential in NK cells appeared to reflect modulation of the innate immune system.
Increased levels of nitric oxide (NO) at an inflammatory site may affect the biological activity ... more Increased levels of nitric oxide (NO) at an inflammatory site may affect the biological activity of lymphoid cells. To investigate the effects of NO on the immune system, we measured the mitochondrial membrane potential (delta psi m) of the peripheral blood lymphocytes (PBL) cultured with a chemical NO donor. PBL from healthy volunteers were cultured with NOC18, a NO-generating compound, at various concentrations. The delta psi m of the PBL was measured by flow-cytometry using 3,3-dihexyloxacarbocyanine iodide (DiOC6(3)). NOC18 induced a decrease in the delta psi m of the PBL in a dose-dependent fashion, induced an increase in the levels of reactive oxygen species (ROS), and caused these cells to undergo apoptosis. Dual-color staining of the delta psi m and lymphocyte surface markers demonstrated that CD3-CD56+ natural killer (NK) cells were responsive to NO. Trolox, a vitamin E analog, partially reversed the NO-induced decrease in the delta psi m of the PBL. We showed that the delta psi m of peripheral NK cells were decreased by NO, which suggests that abundant NO at an inflammatory site may impair NK cell function.
Changes in lipoprotein metabolism after liver transplantation from living related donors were inv... more Changes in lipoprotein metabolism after liver transplantation from living related donors were investigated in nine pediatric patients by means of biochemical and proton nuclear magnetic resonance (NMR) analyses of lipoprotein. NMR offers rapid and nondestructive measurement of lipoprotein. The ratio of esterified cholesterol to total cholesterol, expected to be a prognostic indicator after liver transplantation, was low before the operation (0.44) and recovered to over 0.6 at 3 weeks. The half line width of the methylene peak of lipoprotein, as measured by proton NMR, was correlated with the ratio of esterified cholesterol to total cholesterol. It is suggested that proton NMR analysis can provide information about the biophysical changes in lipoprotein associated with liver transplantation.
Background We experienced a case of early stage lung cancer involving a morbidly obese patient. O... more Background We experienced a case of early stage lung cancer involving a morbidly obese patient. Obesity is associated with a higher incidence of surgical complications. We examined the effectiveness of laparoscopic sleeve gastrectomy as a primary weight loss procedure in a morbidly obese patient who required oncological surgery. Case presentation A 64-year-old morbidly obese female with a body mass index of 43.5 kg/m2 was referred to our hospital to undergo weight loss. A right-sided lung mass was found incidentally on computed tomography conducted in preparation for laparoscopic sleeve gastrectomy, which was performed prior to tumor surgery. As a result, weight loss was achieved within 2.5 months after the laparoscopic sleeve gastrectomy, and the patient’s type-2 diabetes, hypertension, and dyslipidemia, which are linked to obesity, were markedly ameliorated. After a quick intraoperative pathological inspection revealed that the tumor was malignant, thoracoscopic right lung superio...
The arterial ketone body ratio (AKBR), an established clinical tool that reflects hepatic mitocho... more The arterial ketone body ratio (AKBR), an established clinical tool that reflects hepatic mitochondrial oxidation-reduction potential, predicts the outcome of patients with shock and multiple organ failure and the postoperative outcome in patients who have undergone major liver or heart surgery. The purpose of this study was to determine the prognostic significance of AKBR in patients with acute heart failure. The subjects of this study were 52 patients with acute heart failure. The following parameters were analyzed after Cox univariate hazard analysis was performed: AKBR, plasma norepinephrine, left ventricular ejection fraction, cardiac index, pulmonary arterial wedge pressure, sex, age, human atrial natriuretic peptide, endothelin-1, and cholesterol. The follow-up period was 30 weeks with cardiac death as the end point. Stepwise multivariate proportional hazard analysis revealed that AKBR was the most significant predictor of death, followed by norepinephrine and human atrial natriuretic peptide. Curve-fitting analysis revealed that the relationship between log (norepinephrine) and AKBR could best be described by two distinct lines, with their intersection at AKBR = 0.7 and norepinephrine = 418. With these results we conducted Kaplan-Meier analysis for AKBR &gt; or = 0.7 and AKBR &lt;0.7. The survival rate in patients with AKBR &gt; or = 0.7 was 100%, whereas that in patients with AKBR &lt;0.7 was 15% (p &lt; 0.0001, log-rank analysis). These results indicate that AKBR is a novel independent predictor of death in heart failure.
The mechanism underlying the fatal complications in jaundiced states after shock has not been ful... more The mechanism underlying the fatal complications in jaundiced states after shock has not been fully clarified. The present study was designed to examine the effect of hemorrhagic shock on myocardial high-energy phosphate stores and the arterial ketone body ratio (AKBR:acetoacetate/beta-hydroxybutyrate), which reflects the redox state of the liver mitochondria, in normal and jaundiced rats. At 1 week after ligation of the common bile duct, hemorrhagic shock was induced by exsanguination (mean arterial blood pressure = 40 mmHg) and maintained for 2 h. Serial changes in AKBR were measured. The myocardial adenine nucleotides phosphocreatine (PCr) and inorganic phosphate (Pi) were determined before and after hemorrhagic shock. Before shock, myocardial ATP in the jaundiced group was lower than that in the sham group. However, the myocardial PCr levels in the two groups did not differ. After reinfusion of the shed blood, ATP and PCr recovered to the preshock levels in the sham group. However, ATP and PCr were further increased in the jaundiced group. At 60 min after reinfusion, AKBR recovered to the normal level in the sham group, but decreased below 0.7 in the jaundiced group. Metabolic acidosis was more severe in the jaundiced group than in the sham group. The decrease in AKBR indicated irreversible metabolic acidosis. As a result, fatal circulatory failure occurred, although the phosphoenergetic level in the myocardium was sufficiently maintained.
The production of free radicals in tissues can be continually monitored by measurement of low-lev... more The production of free radicals in tissues can be continually monitored by measurement of low-level chemiluminescence. In these experiments the effects of ethanol on luminol (1 microM)-enhanced chemiluminescence were recorded in isolated perfused livers from control rats, and from rats that had undergone a 30-min period of ischemia, followed by 3 h of reinstitution of blood flow. Our previous experiments showed considerable neutrophil accumulation at this time. A routine concentration of 100 mM ethanol added after 20 min of perfusion with Krebs-Henseleit solution caused an increase in chemiluminescence of about 2000 cpm above the resting level (1600 cpm) in both control livers and livers from rats after 3 h of ischemia reperfusion in vivo. However, if ethanol was added to the perfusing medium of the isolated liver after at least 1 h of in vitro perfusion, then the magnitude of the response was very much greater (peak approximately 27000 cpm) in livers that had undergone ischemia reperfusion than in control livers (peak approximately 7000 cpm). Experiments combining addition of ethanol and the potent neutrophil stimulator, phorbol myristate acetate (PMA), plus the use of rat antineutrophil serum have shown conclusively that the very large chemiluminescent response to ethanol after prolonged in vitro perfusion is due to stimulation of neutrophil radical production.
Patients undergoing hepatectomy have an increased susceptibility to infection. We therefore studi... more Patients undergoing hepatectomy have an increased susceptibility to infection. We therefore studied the energy metabolism of the polvmorphonuclear leucocvte (PMN), focusing on energy charge and function, especially superoxide anion (O2−) generation, in relation to the hepatic mitochondrial redox state. By labelling the PMN adenine nucleotide pool with radioactive adenine and by superoxide dismutase-inhibitahle reduction of ferricytochrome c, the energy charge and O2− production was measured in 18 patients with hepatoma (non-cirrhotic, seven; cirrhotic, 11) undergoing hepatectomy. Their arterial ketone body ratios (KBRs), reflecting the hepatic mitochondrial redox potential, were above 0.7 before operation. After surgery, the 18 patients were divided into two groups: group A. KBR > 0.7, n = 10; and group B, KBR < 0.7, n = 8. The energy charge and O2− release in group B decreased significantly from preoperative values (P < 0.001 and P < 0.01 respectively) and when compared...
The mechanism underlying immunosuppression after partial hepatectomy remains unclear. Hepatectomy... more The mechanism underlying immunosuppression after partial hepatectomy remains unclear. Hepatectomy induces lymphopenia, which is related to immunomodulation. The aim of this study was to determine whether peripheral blood lymphocytes (PBL) are susceptible to mitochondria-mediated apoptosis after hepatic resection. We compared the changes in mitochondrial membrane potential in lymphocytes from hepatectomized patients with metastatic liver tumor with the corresponding changes in lymphocytes from cholechystectomized patients, because changes in mitochondrial membrane potential have been reported to frequently occur during the early stages of apoptosis. Mitochondrial membrane potential, subpopulation, and apoptosis of lymphocytes were estimated with flow cytometry. Hepatectomy significantly (P&amp;amp;lt;0.001) reduced postoperative mitochondrial membrane potential, while cholecystectomy slightly decreased it. Apoptosis of lymphocytes was increased on post-hepatectomy day, and this increase was correlated with the extent of mitochondrial membrane potential reduction. The major subset of lymphocytes with low mitochondrial membrane potential consisted of CD56(+) natural killer (NK) cells, and NK cell activity and cell counts significantly decreased after hepatectomy. Mitochondrial membrane potential of PBL was reduced after hepatectomy, and some lymphocytes underwent apoptosis through the mitochondrial pathway, which was one of the causes for lymphopenia. NK cells were more responsible for the decrease of mitochondrial membrane potential after hepatectomy than other lymphocytes, and the reduction in mitochondrial membrane potential in NK cells appeared to reflect modulation of the innate immune system.
Increased levels of nitric oxide (NO) at an inflammatory site may affect the biological activity ... more Increased levels of nitric oxide (NO) at an inflammatory site may affect the biological activity of lymphoid cells. To investigate the effects of NO on the immune system, we measured the mitochondrial membrane potential (delta psi m) of the peripheral blood lymphocytes (PBL) cultured with a chemical NO donor. PBL from healthy volunteers were cultured with NOC18, a NO-generating compound, at various concentrations. The delta psi m of the PBL was measured by flow-cytometry using 3,3-dihexyloxacarbocyanine iodide (DiOC6(3)). NOC18 induced a decrease in the delta psi m of the PBL in a dose-dependent fashion, induced an increase in the levels of reactive oxygen species (ROS), and caused these cells to undergo apoptosis. Dual-color staining of the delta psi m and lymphocyte surface markers demonstrated that CD3-CD56+ natural killer (NK) cells were responsive to NO. Trolox, a vitamin E analog, partially reversed the NO-induced decrease in the delta psi m of the PBL. We showed that the delta psi m of peripheral NK cells were decreased by NO, which suggests that abundant NO at an inflammatory site may impair NK cell function.
Changes in lipoprotein metabolism after liver transplantation from living related donors were inv... more Changes in lipoprotein metabolism after liver transplantation from living related donors were investigated in nine pediatric patients by means of biochemical and proton nuclear magnetic resonance (NMR) analyses of lipoprotein. NMR offers rapid and nondestructive measurement of lipoprotein. The ratio of esterified cholesterol to total cholesterol, expected to be a prognostic indicator after liver transplantation, was low before the operation (0.44) and recovered to over 0.6 at 3 weeks. The half line width of the methylene peak of lipoprotein, as measured by proton NMR, was correlated with the ratio of esterified cholesterol to total cholesterol. It is suggested that proton NMR analysis can provide information about the biophysical changes in lipoprotein associated with liver transplantation.
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