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Background and objective: To examine a possible mechanism for the antinociceptive action of the N-methyl-D-aspartate receptor antagonist ifenprodil, we compared its effects with those of ketamine on tetrodotoxin-resistant Na+ channels in rat dorsal root ganglion neurons, which play an important role in the nociceptive pain pathway. Methods: Experiments were performed on dorsal root ganglion neurons from Sprague—Dawley rats, recordings of whole-cell membrane currents being made using patch-clamp technique. Results: Both drugs blocked tetrodotoxin-resistant Na+ currents dose dependently, their half-maximal inhibitory concentrations being 145 ± 12.1 μmol (ketamine) and 2.6 ± 0.95 μmol (ifenprodil). Ifenprodil shifted the inactivation curve for tetrodotoxin-resistant Na+ channels in the hyperpolarizing direction and shifted the activation curve in the depolarizing direction. Use-dependent blockade of tetrodotoxin-resistant Na+ channels was more marked with ifenprodil than with ketamine. When paired with lidocaine, these drugs produced similar additive inhibitions of tetrodotoxin-resistant Na+ channel activity. Conclusions: The observed suppressive effects on tetrodotoxin-resistant Na+ channel activity may, at least in part, underlie the antinociceptive effects of these N-methyl-D-aspartate receptor antagonists. [ABSTRACT FROM AUTHOR]

Background: During one-lung ventilation (OLV), deterioration of pulmonary oxygenation reduces arterial oxygen saturation and cerebral oxygen saturation (rSO2). However, oxidative stress during OLV causes lung injury, so the fraction of inspiratory oxygen (FiO2) should be kept as low as possible. We investigated the changes in rSO2 under propofol or desflurane anesthesia while percutaneous oxygen saturation (SpO2) was kept as low as possible during OLV., Methods: Thirty-six patients scheduled for thoracic surgery under OLV in the lateral decubitus position were randomly assigned to propofol (n = 19) or desflurane (n = 17) anesthesia. FiO2 was set to 0.4 at the start of surgery under two-lung ventilation (measurement point: T3) and then adjusted to maintain an SpO2 of 92% to 94% after the initiation of OLV. The primary outcome was the difference in the absolute value of the decrease in rSO2 from T3 to 30 minutes after the initiation of OLV (T5), which was analyzed by an analysis of covariance adjusted for the rSO2 value at T3., Results: The mean rSO2 values were 61.5% ± 5.1% at T3 and 57.1% ± 5.3% at T5 in the propofol group and 62.2% ± 6.0% at T3 and 58.6% ± 5.3% at T5 in the desflurane group. The difference in the absolute value of decrease between groups (propofol group - desflurane group) was 0.95 (95% confidence interval, [-0.32, 2.2]; P = .152)., Conclusions: Both propofol and desflurane anesthesia maintain comparable cerebral oxygenation and can be used safely, even when the SpO2 is kept as low as possible during OLV., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: We investigated how preoperative sarcopenia and perioperative muscle mass changes affect postoperative nutritional parameters in patients undergoing pancreatectomy., Methods: This study included 164 patients undergoing pancreatectomy between January 2011 and October 2018. Skeletal muscle area was measured by computed tomography before and 6 months after surgery. Sarcopenia was defined as the lowest sex-specific quartile, and patients with muscle mass ratios less than -10% were classified into the high-reduction group. We examined the relationship between perioperative muscle mass and postoperative nutritional parameters 6 months after pancreatectomy., Results: There were no significant differences in nutritional parameters between the sarcopenia and nonsarcopenia groups at 6 months after surgery. In contrast, albumin (P < 0.001), cholinesterase (P < 0.001), and prognostic nutritional index (P < 0.001) were lower in the high-reduction group. According to each surgical procedure, albumin (P < 0.001), cholinesterase (P = 0.007), and prognostic nutritional index (P < 0.001) were lower in the high-reduction group of pancreaticoduodenectomy. In distal pancreatectomy cases, only cholinesterase (P = 0.005) was lower., Conclusions: Postoperative nutritional parameters were correlated with muscle mass ratios but not with preoperative sarcopenia in patients undergoing pancreatectomy. Improvement and maintenance of perioperative muscle mass are important to maintain good nutritional parameters., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Nonalcoholic fatty liver is a complication of pancreaticoduodenectomy (PD); however, liver fibrosis after PD is not well documented. Therefore, we estimated the hepatic fibrotic index of nonalcoholic fatty liver after PD., Methods: We retrospectively examined the electronic medical records of patients who had underwent PD and had computed tomography (CT) records preoperatively and 6 months postoperatively between 2011 and 2019 at the Shiga University of Medical Science Hospital., Results: Overall, 115 patients were enrolled. After 6 months from PD, body mass index significantly decreased from 21.90 to 19.57 kg/m2 (-10.6%). The Fibrosis-4 (FIB-4) index significantly increased from 1.756 to 2.384 (P &lt; 0.001). The FIB-4 grade significantly worsened. Contrarily, neither the albumin-bilirubin (ALBI) score nor the ALBI grade demonstrated significant differences. The CT attenuation value significantly decreased (P &lt; 0.001) from 57.6 to 49.5. Multivariate analysis predicted a high preoperative FIB-4 index, high ALBI index, and hypo-CT attenuation value (&lt;30 HU) as risk factors for a high postoperative FIB-4 index., Conclusions: The FIB-4 index worsened when the follow-up period was only 6 months, regardless of the eternalness in the ALBI score. Liver fibrosis should be assessed using the FIB-4 index for a long-term survivorship after PD., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: This study aimed to investigate the effect of early administration of delayed-release high-titer pancrelipase., Methods: The medical records of 120 patients who had undergone pancreatectomy with computed tomography (CT) before and 6 months after surgery were retrospectively reviewed. Delayed-release high-titer pancrelipase were administered daily starting on postoperative day 3, which was defined as the EP group. The postoperative nutritional status and CT attenuation values of the liver were compared between the EP and control groups., Results: Thirty-three patients (28%) were categorized into the EP group. With regard to the postoperative nutritional status 6 months after surgery, the body mass index, total lymphocyte count, and Onodera's prognostic nutritional index were higher, and controlling nutritional status score was lower in the EP group than that in the control group. The CT attenuation values of the liver were not significantly different. After propensity score matching analysis, body mass index (20.7 vs 19.2, P = 0.049) and Onodera's prognostic nutritional index (47.9 vs 44.2, P = 0.045) were significantly higher, and controlling nutritional status score was significantly lower in the EP group than that in the control group (1 vs 3, P = 0.046)., Conclusions: The early administration of pancrelipase after pancreatectomy improved nutritional status after pancreatectomy., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To establish a preoperative risk assessment method for loss of independence after hepatic resection., Summary Background Data: Hepatic resection often results in loss of independence in preoperatively self-sufficient elderly people. Elderly patients should therefore be carefully selected for surgery., Methods: In this prospective, multicenter study, 347 independently-living patients aged ≥65 years, scheduled for hepatic resection, were divided into study (n = 232) and validation (n = 115) cohorts. We investigated the risk factors for postoperative loss of independence in the study cohort and verified our findings with the validation cohort. Loss of independence was defined as transfer to a rehabilitation facility, discharge to residence with home-based healthcare, 30-day readmission for poor functionality, and 90-day mortality (except for cancer-related deaths)., Results: In the study cohort, univariate and multivariate analyses indicated that frailty, age ≥ 76 years, and open surgery were independent risk factors for postoperative loss of independence. Proportions of patients with postoperative loss of independence in the study and validation cohorts were respectively 3.0% and 0% among those with no applicable risk factors, 8.1% and 12.5% among those with 1 applicable risk factor, 25.5% and 25.0% among those with 2 applicable risk factors, and 56.3% and 50.0% among those with all 3 factors applicable (P < 0.001 for both cohorts). Areas under the receiver operating characteristic curves for the study and validation groups were 0.777 and 0.783, respectively., Conclusions: Preoperative risk assessments using these 3 factors may be effective in predicting and planning for postoperative loss of independence after hepatic resection in elderly patients., Competing Interests: The authors report no conflicts of interest., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: The authors have no funding or conflicts of interest to disclose.

Background: Acute hyperglycemia causes vascular endothelial dysfunction in various organs including the cerebral vessels. It is associated with increased mortality and morbidity in the perioperative period. The impact of anesthetic agents on cerebral vasodilatory responses during hyperglycemia remains unclear. We investigated endothelial function in rat cerebral arterioles during acute hyperglycemia, under propofol or desflurane anesthesia., Materials and Methods: A closed cranial window preparation was used to measure changes in pial arteriole diameter induced by topical application of acetylcholine (ACh), an endothelium-dependent vasodilator, in rats anesthetized with propofol or desflurane. Pial arteriole responses to ACh were measured during normoglycemia and hyperglycemia. We then investigated whether the response of cerebral arterioles to acute hyperglycemia under propofol anesthesia were related to propofol or its vehicle, intralipid., Results: ACh resulted in a dose-dependent dilation of cerebral arterioles during propofol and desflurane anesthesia under normoglycemic conditions. The vasodilatory effects of ACh were also maintained under hyperglycemic conditions during propofol anesthesia, but the vasodilator response to ACh was significantly impaired during hyperglycemia compared with normoglycemia with desflurane anesthesia. The vasodilatory effects of ACh were maintained during normoglycemia and hyperglycemia in rats receiving propofol or intralipid., Conclusions: Rat pial arteriole responses to ACh are maintained during conditions of acute hyperglycemia with propofol anesthesia but suppressed compared with normoglycemia with desflurane anesthesia., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Double-lumen endobronchial tubes (DLTs) are used for one-lung ventilation (OLV) during thoracic surgery. Overinflation into the bronchial cuff causes damage to the tracheobronchial mucosa, whereas underinflation leads to an incomplete collapse of the nonventilated lung or incomplete ventilation of the ventilated lung. However, how to determine the appropriate bronchial cuff volume and pressure during OLV is unclear. The objective of this study is to compare the required bronchial cuff volume for lung separation obtained by 2 different cuff inflation methods under closed- and open-chest conditions., Methods: A total of 64 patients scheduled to undergo elective thoracic surgery requiring OLV were recruited. Left DLTs were used for both right- and left-sided surgery. The patients were randomly assigned to 1 of 2 inflation-type groups to estimate the bronchial cuff volume. In the capnogram waveform-guided bronchial cuff inflation group (capno group, n = 27), the bronchial cuff was inflated until a capnometer sampling gas containing CO2 from the nonventilated lung displayed a flat line. The corresponding bronchial cuff volume and pressure were then recorded. In the pressure-guided bronchial cuff inflation group (pressure group, n = 29), the bronchial cuff was inflated by a cuff inflator to a pressure of 20 cm H2O. Lung separation was confirmed when a flat line of a capnometer was observed after gas sampling from the nonventilated lung., Results: Under closed-chest conditions, the bronchial cuff sealing volume for the capno group was significantly lower than that for the pressure group (mean [standard deviation {SD}], 1.00 [0.65] mL vs 1.44 [0.59] mL, mean difference, -0.44; 97.5% confidence interval [CI], -0.78 to -0.11; P = .010). Under open-chest conditions, the bronchial cuff sealing volume for the capno group was also significantly lower than that for the pressure group (mean [SD], 0.65 [0.66] mL vs 1.22 [0.45] mL, mean difference, -0.58; 97.5% CI, -0.88 to -0.27; P < .001)., Conclusions: The lowest cuff volume providing an air-tight bronchial seal was obtained by the capnogram waveform-guided bronchial cuff inflation method. Since the cuff volume required to achieve an air-tight seal decreases after opening the chest, readjustment of the bronchial cuff volume to prevent bronchial cuff damage to the tracheobronchial mucosa after opening the chest may be advisable., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 International Anesthesia Research Society.)

Objective: The aim of this study was to assess the relationship between the computed tomography (CT) pancreatic parenchyma attenuation value and clinically relevant postoperative pancreatic fistula (POPF)., Methods: The medical records of 115 patients who underwent pancreaticoduodenectomy and preoperative dynamic CT were retrospectively reviewed. The CT attenuation values of the nonenhanced (N), arterial (A), portal venous (P), and late (L) phase in the pancreatic parenchyma were determined via CT, and the A/N, A/P, and P/L ratios were calculated. The CT attenuation values and value ratios were compared between the POPF and non-POPF groups., Results: Thirty-two patients (28%) were categorized in the POPF group. On univariate analysis, the A/P ratio (P < 0.001) and P/L ratio (P = 0.018) were significantly higher in the POPF group. On receiver operating characteristic curve analysis, the A/P and P/L ratio cutoff values for predicting POPF were 1.19 and 1.17, respectively. Of the preoperative evaluable factors, A/P ratio of 1.19 or greater (P < 0.001; odds ratio, 10.3) and P/L ratio of 1.17 or greater (P = 0.049; odds ratio, 3.23) were independent predictive factors for POPF, and the combination of the 2 ratios was useful in detecting POPF preoperatively., Conclusions: The enhancement pattern of the pancreatic parenchyma is associated with the development of clinically relevant POPF.

Introduction: The prognosis of Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL) has been dramatically improved since the introduction of tyrosine kinase inhibitors (TKIs). Although allogeneic hematopoietic cell transplantation (allo-HCT) is a major treatment option, the role of autologous peripheral blood stem cell transplantation (auto-PBSCT) has been reconsidered, especially in patients who achieved early molecular remission., Methods and Analysis: This is a multicenter exploratory study for Ph + ALL patients aged between 55 and 70 years who achieved complete molecular remission within 3 cycles of chemotherapy. The target sample size is 5, and the registration period is 2 years. The primary endpoint is Day100- mortality after transplantation, and the secondary endpoints are survival, relapse rate, nonrelapse mortality, and adverse events.This study is divided into 3 phases: peripheral blood stem cell harvest, transplantation, and maintenance. Chemomobilization is performed using a combination of cyclophosphamide (CPM), doxorubicin, vincristine (VCR), and prednisolone (PSL). As a preparative regimen, the LEED regimen is used, which consists of melphalan, CPM, etoposide, and dexamethasone. Twelve cycles of maintenance therapy using a combination of VCR, PSL, and dasatinib are performed.In association with relapse, the minimal residual disease (MRD) of BCR-ABL chimeric gene and T-cell subsets are analyzed both before and after auto-PBSCT., Ethics and Dissemination: The protocol was approved by the institutional review board of Nagoya University Hospital and all the participating hospitals. Written informed consent was obtained from all patients before registration, in accordance with the Declaration of Helsinki. Results of the study will be disseminated via publications in peer-reviewed journals., Trial Registration: Trial registration number UMIN000026445., (Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Environmental contamination with radioactive materials caused by the Fukushima Dai-ichi Nuclear Power Plant (NPP) accident in 2011 raised a serious health concern among residents in Japan, and the demand for radiation experts who can handle the radiation-associated problems has increased. The Human Resources Development Center (HRDC) of the National Institute of for Quantum and Radiological Science and Technology in Japan has offered a variety of training programs covering a wide range of technologies associated with radiation since 1959. In this study, the time-course change in the number and age of the applicants for training programs regularly scheduled at HRDC were analyzed to characterize the demand after the NPP accident. The results suggested that the demand for the training of industrial radiation experts elevated sharply after the NPP accident followed by a prompt decrease, and that young people were likely stimulated to learn the basics of radiation. The demand for the training of medical radiation experts was kept high regardless of the NPP accident. The demand for the training of radiation emergency experts fluctuated apparently with three components: a terminating demand after the criticality accident that occurred in 1999, an urgent demand for handling of the NPP accident, and a sustained demand from local governments that undertook reinforcement of their nuclear disaster prevention program. The demand for the training of school students appeared to be increasing after the NPP accident. It could be foreseen that the demand for training programs targeting young people and medical radiation experts would be elevated in future.

Background: Our aims are to investigate the effect of nicorandil, which is used for angina prevention and treatment, on the endothelial dysfunction induced by acute smoking and to clarify the underlying mechanism., Materials and Methods: A closed cranial window preparation was used to measure changes in pial vessel diameters in Sprague-Dawley rats. The responses of arterioles were examined to an endothelium-dependent vasodilator acetylcholine (ACh) before smoking. After intravenous nicorandil (200 μg/kg bolus infusion and then 60 μg/kg/min continuous infusion; n=6) or saline (control; n=6) pretreatment, the pial vasodilator response to topical 10 M ACh infusion was reexamined both before and 1 hour after 1-minute cigarette smoking. Thereafter, either glibenclamide or N-ω-nitro-L-arginine methyl ester (L-NAME) was infused 20 minutes before nicorandil infusion. In the glibenclamide (n=6) or L-NAME; n=6 pretreatment group, the pial vasodilator response to topical ACh was examined before and after smoking. Percentage changes in pial vessel diameters were used for the statistical analysis., Results: Cerebral arterioles were dilated during topical ACh infusion. After smoking, 10 M ACh constricted cerebral arterioles (-7.7±1.8%). After smoking, in the nicorandil-pretreatment group, 10 M ACh dilated cerebral pial arterioles by 10.5±3.0%. When given before nicorandil infusion, glibenclamide, but not L-NAME, abolished the preventive effects of nicorandil against smoking-induced endothelial dysfunction in pial vessels., Conclusions: Acute cigarette smoking causes dysfunction of endothelium-dependent pial vasodilatation, and nicorandil prevents this effect of smoking. The mechanism underlying this protective effect may depend mainly on adenosine triphosphate-sensitive potassium-channel activation.

If the brain structural coordinates could be estimated using the individual head shape, magnetoencephalography and near-infrared spectroscopy would be more ideal brain functional imaging methods especially for young human children. First, we propose an algorithm to estimate brain coordinates with reference to the head surface shape in preschool children. Second, we examined its spatial error range using a leave-one-out procedure within 38 samples of child head and brain structures. The mean error of landmarks was 13.6±5.3 mm on the head surface and 18.5±12.4 mm in the intracranial structure between estimated and actual brain coordinates.

Owing to changes in the treatment of skull-base tumors, such as perioperative radiotherapy and advances in approaching the skull base, the use of pericranial flaps should be reconsidered. Therefore, we reviewed the reliability of and indications for pericranial flaps in 26 cases in terms of patient background, the effects of preoperative and postoperative treatment, and the pattern of blood circulation. Flaps were harvested as 25 anteriorly based and 4 laterally based. As a result, postoperative complications were observed in 4 patients. No other risk factors, except for heavy smoking, were observed relative to patient background. Sixteen patients had perioperative radiotherapy, and complication rate was significantly higher in patients with preoperative radiotherapy than patients without preoperative radiotherapy (P=0.014). However, no complications, such as cerebral spinal fluid leakage and intracranial infection, were observed in patients receiving postoperative radiotherapy. Laterally based pericranial flaps had a high complication rate (25%), but it was not significantly higher than anteriorly based flaps (P=0.467). Five anteriorly based flaps were harvested with less feeding vessels as usual because of applying dismasking flap approach, but it did not lead to increasing in complication rate. We conclude that a pericranial flap can be used for skull base reconstruction even if postoperative radiotherapy is planned but might be avoided for patients who have received preoperative radiotherapy. In addition, particular care and flap design should be taken to preserve sufficient vascularity when pericranial flaps are raised as laterally based and less feeding vessels as usual.

Background: We hypothesized that autologous skeletal cell (SC) sheets regenerate the infract myocardium in porcine heart as a preclinical trial., Methods and Results: The impaired heart was created by implantation of ameroid constrictor on left anterior descending for 4 weeks. SCs isolated from leg muscle were cultured and detached from the temperature-responsive domain-coated dishes as single monolayer cell sheet at 20 degrees C. The following therapies were conducted: SC sheets (SC group, n=5); sham (C group n=5). Echocardiography demonstrated that cardiac performance was significantly improved in the SC group 3 and 6 months after operation (fractional area shortening, 3 months; SC vs. C=49.5+/-2.8 vs. 24.6+/-2.0%, P<0.05) and left ventricle dilatation was well attenuated in the SC group. Color kinesis index showed that distressed regional diastolic and systolic function in infarcted anterior wall was significantly recovered (SC vs. C=57.4+/-8.6 vs. 30.2+/-4.7%, P<0.05, diastolic: 58.5+/-4.5 vs. 35.4+/-6.6%, P<0.05, systolic). Factor VIII immunostains demonstrated that vascular density was significantly higher in the SC group than the C group. And % fibrosis and cell diameter were significantly lower in the SC group. And hematoxylin-eosin staining depicted that skeletal origin cells and well-developed-layered smooth muscle cells were detected in the implanted area. Positron emission tomography showed better myocardial perfusion and more viable myocardial tissue in the distressed myocardium receiving SC sheets compared with the myocardium receiving no sheets., Conclusions: SC sheet implantation improved cardiac function by attenuating the cardiac remodeling in the porcine ischemic myocardium, suggesting a promising strategy for myocardial regeneration therapy in the impaired myocardium.

Objective: Although thrombin-activatable fibrinolysis inhibitor (TAFI) has been implicated as a negative regulator of fibrinolysis, its pathophysiological significance remains to be unveiled. We performed the pharmacologic study to assess the effect of EF6265, a specific inhibitor of activated form of TAFI (TAFIa) on sepsis-induced organ dysfunction models., Design: A controlled, in vivo laboratory study., Setting: Company research laboratory., Subjects: Wistar and Sprague-Dawley rats., Interventions: Endotoxemia and sepsis models were induced by intravenous injection of lipopolysaccharide and Pseudomonas aeruginosa, respectively., Measurements and Main Results: In the endotoxemia model, posttreatment (1 hour) with EF6265 reduced fibrin deposits in the kidney and liver accompanied by no significant changes in platelet count and fibrinogen concentration in plasma. This compound also significantly decreased levels of plasma lactate dehydrogenase and aspartate aminotransferase, markers of organ dysfunction. In the sepsis model, EF6265, simultaneously administered with ceftazidime (CAZ) 2 hours after Pseudomonas aeruginosa injection, showed no influence on the antibiotic activity of CAZ. Meanwhile, it dramatically potentiated the interleukin-6-reducing effect of CAZ in plasma, suggesting that inhibition of TAFIa leads to the reduction in systemic inflammatory response associated with bacterial infection. This combined treatment also lowered plasma lactate dehydrogenase and blood urea nitrogen more potently than single treatment with CAZ., Conclusions: These results clearly suggest that TAFI plays an important role in the deterioration of organ dysfunction in sepsis and the inhibitor of TAFIa protects against sepsis-induced tissue damage through regulation of fibrinolysis and inflammation.

Background: Nicorandil, an adenosine triphosphate-sensitive potassium channel opener, is reported to have an antinociceptive effect by hyperpolarization through the K(+) channel. The activation of extracellular signal-regulated kinase (ERK), a family of mitogen-activated protein kinases, plays an important role in synaptic plasticity and noxious stimulation in the dorsal root ganglion, and spinal neurons have been reported to induce its activation. To understand the biological mechanisms of nicorandil, we examined the effects of nicorandil on muscarinic acetylcholine (ACh) receptor-mediated activation of ERK in a neuronal model cell, rat pheochromocytoma PC12 cells., Methods: PC12 cells were stimulated with ACh in the presence or absence of nicorandil, and phosphorylation of ERK was examined by a Western blot analysis. We also examined the effects of nicorandil on the ERK activation induced by 4beta-phorbol 12-myristate 13-acetate, an activator of protein kinase C, or ionomycin, a calcium ionophore. Intracellular Ca(2+) increase was visualized in fluo-3-loaded PC12 cells using fluorescence microscopy., Results: Nicorandil inhibited ACh-induced ERK activation in a concentration-dependent manner. The inhibition was abolished by glibenclamide, an adenosine triphosphate-sensitive potassium channel blocker. Nicorandil suppressed the ERK activation induced by ionomycin but not 4beta-phorbol 12-myristate 13-acetate. Pretreatment of PC12 cells with nicorandil reduced the intracellular Ca(2+) concentration stimulated by ACh., Conclusions: Nicorandil inhibits muscarinic activation of the ERK signaling pathway by reducing the intracellular Ca(2+) concentration.

Administration of spinal analgesics around the spinal cord requires safety assessment due to the possibility of inflicting neurotoxic damage. Thus, neurotoxicologic evaluation should be performed for effective, safer spinal antinociception. Every potential agent for spinal administration should be studied in animals for its effects on spinal blood flow or vessels before any attempt is made to administer the drug to humans. As the spinal cord normally has a marginal blood flow, excessive vasoconstriction might produce spinal cord ischemia and consequent neurologic dysfunction. This review therefore focuses on the effects on the spinal circulation induced by well-known spinal analgesics employed in the treatment of acute and chronic pain disorders.

Background: Vasopressin is a drug of choice for use during cardiopulmonary resuscitation because several experimental studies have shown that it is better than epinephrine at increasing systemic perfusion pressure and improving cerebral perfusion pressure without increasing myocardial oxygen consumption. We used a pial window preparation to determine the effects of vasopressin when applied topically to pial vessels and whether any effects were altered after cerebral ischemia in rabbits (n = 27)., Methods: We first examined the effects of topical application of arginine-vasopressin (AVP) (10(-11) M, 10(-9) M, 10(-7) M, and 10(-5) M, sequentially). We then examined the effects of topical application of AVP (10(-9) M and 10(-7) M, sequentially) before and after a 5-min intervention consisting of cerebral ischemia produced by inflation of a neck tourniquet plus systemic hypotension or systemic hypotension alone., Results: Pial arteriolar diameters were (a) dilated by 10(-11) M AVP [7% +/- 11% (P = 0.014 versus baseline)], but constricted by 10(-9) M, 10(-7) M, and 10(-5) M AVP [7% +/- 14%, 20% +/- 14%, and 16% +/- 16% (each P < 0.05), respectively], and (b) constricted before hypotension (7% +/- 10% at 10(-9) M, 20% +/- 15% at 10(-7) M) or ischemia (7% +/- 11% at 10(-9) M, 21% +/- 15% at 10(-7) M). However, after the 5-min of ischemia, the decrease in diameter induced by 10(-7) M AVP was significantly reduced but not by hypotension alone [hypotension control group: 7% +/- 10% at 10(-9) M, 19% +/- 14% at 10(-7) M; ischemia group: 5% +/- 11% at 10(-9) M, 10% +/- 13% at 10(-7) M (P = 0.35 versus hypotension control)]., Conclusions: Topical application of AVP (except at the lowest concentration used here) induced concentration-dependent vasoconstriction of pial arterioles in anesthetized rabbits. The vasoconstrictor effect of 10(-7) M AVP was reduced after transient (5-min) cerebral ischemia.

Background and Purpose: Recent clinical evidences indicate that statins may have beneficial effects on the functional recovery after ischemic stroke. However, the effect of delayed postischemic treatment with statins is still unclear. In the present study, we evaluated the effects of fluvastatin in the chronic stage of cerebral infarction in a rat model., Methods: Rats exposed to permanent middle cerebral artery occlusion were treated for 3 months with fluvastatin beginning from 7 days after stroke. MRI, behavioral analysis, and immunohistochemistry were performed., Results: Two months of treatment with fluvastatin showed the significant recovery in spatial learning without the decrease in serum total cholesterol level and worsening of infarction. Microangiography showed a significant increase in capillary density in the peri-infarct region in fluvastatin-treated rats after 3 months of treatment. Consistently, BrdU/CD31-positive cells were significantly increased in fluvastatin-treated rats after 7 days of treatment. MAP1B-positive neurites were also increased in the peri-infarct region in fluvastatin-treated rats. In addition, rats treated with fluvastatin showed the reduction of superoxide anion after 7 days of treatment and the reduction of A beta deposits in the thalamic nuclei after 3 months of treatment., Conclusions: Thus, delayed postischemic administration of fluvastatin had beneficial effects on the recovery of cognitive function without affecting the infarction size after ischemic stroke. Pleiotropic effects of fluvastatin, such as angiogenesis, neuritogenesis, and inhibition of superoxide production and A beta deposition, might be associated with a favorable outcome.

Background: The resolution of a gamma camera is depth-dependent and worsens with increasing distance to the camera resulting in a loss of fine details in SPECT images. A common approach to reduce the effects of this resolution loss is to utilize body-contour acquisition orbits. Even though body-contour orbits can improve resolution of reconstructed images their effect on lesion detection is not well known., Objective: To investigate whether body-contour orbits offer better defect detection performance than circular orbits in cardiac SPECT., Methods: The mathematical cardiac torso (MCAT) phantom was used to model Tc-sestamibi uptake. A total of four phantoms (two male and two female) with eight defects (four locations and two sizes) were generated and projection data were simulated using an analytical projector with attenuation, scatter, collimator response and acquisition orbit modelling. The circular and body-contour projections were reconstructed using the OSEM algorithm with/without collimator response compensation. Defect detection performance was assessed by calculating area under the receiver operating characteristic (ROC) curve for channelized Hotelling observer., Results: The defect detection performance of circular and body-contour acquisition was very similar and the difference in the area under the ROC curve between the orbits was not statistically significant with or without collimator response compensation. The collimator response compensation, on the other hand, was noticed to be valuable and it provided significantly better defect detection performance than reconstruction without it regardless of the acquisition orbit type., Conclusions: We conclude that by replacing circular orbit with more complex body-contour orbit will not lead to statistically significant increase in defect detection performance in cardiac SPECT.

Objectives: To evaluate the clinical significance of a swollen main duodenal papilla and the associated immunohistopathologic findings in patients with autoimmune pancreatitis (AIP)., Methods: Seventeen consecutive patients with AIP registered between April 2001 and October 2005 who underwent both endoscopic retrograde cholangiopancreatography and endoscopic biopsy were enrolled in this study. The endoscopic features, stromal inflammatory cell infiltrate (SICI), and results of immunohistochemical examination of the duodenal papilla using IgG4, CD3, and CD79a antibodies were retrospectively reviewed. These findings in the AIP patients were compared with those in 12 patients with chronic alcoholic tumor-forming pancreatitis (CAP). The numbers of cells in the SICI and of IgG4-positive plasma cells per high-power field were counted in all the histopathologic specimens., Results: A swollen main duodenal papilla was observed in 11 (11 [64.7%]/17) patients with AIP and 4 (4 [33.3%]/12) patients with CAP (P < 0.05). Resolution of the swollen main duodenal papilla was observed in all of these 11 patients with AIP (11 [100%]/11) in response to treatment with corticosteroids. On the other hand, the 6 patients without elevated serum IgG4 or a swollen duodenal papilla, but with a swollen pancreas, improved even without corticosteroid treatment. The number of cells in the SICI in the AIP patients was significantly higher than that in the CAP patients. Although in 13 of 17 AIP patients, infiltration by IgG4-positive plasma cells was detected in the duodenal papilla, no such significant infiltration of the duodenal papilla by IgG4-positive plasma cells was observed in the patients with CAP (P < 0.05). More predominant T-cell infiltration of the duodenal papilla was recognized in the AIP patients than in the CAP patients (P < 0.05)., Conclusions: These results suggest that a swollen main duodenal papilla with IgG4-positive plasma cell and T-cell-dominant infiltration and an abundant stromal cell infiltrate are characteristic findings in AIP. We suggest that these findings may be valuable adjuncts to the diagnosis of AIP as well as for selecting suitable candidates for corticosteroid therapy.

We report the case of a 7-year-old boy with thoracolumbar scoliosis and central core disease who had a history of malignant hyperthermia. He had scoliosis with Cobb's angle deteriorating to 67 degrees (thoracic) and 59 degrees (lumbar). A provocation test of general anesthesia was performed to confirm no hyperthermic reaction. Then, he underwent surgical correction by a posterior approach. The thoracic curve was reduced to 38 degrees and the lumbar curve to 42 degrees . He has been followed up for 2 years without any complications. This is the first report with a detailed description of perioperative management on surgical treatment of scoliosis associated with central core disease.

Background: The potent vasodilators nicardipine and prostaglandin E1 (PGE1) are useful for the treatment of systemic hypertension or pulmonary hypertension during aortic surgery., Methods: We measured cerebral pial arteriolar diameters, using a rabbit closed cranial window preparation: before (baseline) and 15 min after the start of an IV infusion (preclamp) (0.9% saline [control group], nicardipine [at 0.1, 1.0, or 10 microg x kg(-1) x min(-1)], or PGE1 [at 0.1 or 1.0 microg x kg(-1) x min(-1)]), just after aortic clamping, 20 min after clamping, and at 0-60 min after unclamping., Results: In the control group, a significant decrease in diameter persisted for at least 60 min after unclamping (maximum [at 60 min], -16% for large [> or =75 microm], and -27% for small [<75 microm] arterioles versus baseline). Although the aortic unclamping-induced vasoconstriction was unaffected under the smallest dose of nicardipine, it was significantly attenuated under larger doses in both large and small arterioles (residual vasoconstriction, -10% and -6% for large and -18% and -10% for small arterioles; at 60 min). The pial arteriolar constriction observed at 5 min or more after unclamping in the control group was not altered by PGE1 in either large or small arterioles., Conclusions: The larger doses of nicardipine, but neither dose of PGE1, attenuated aortic unclamping-induced sustained cerebral pial arteriolar constriction.

Background and Objectives: Statistical reconstruction methods allow resolution recovery in tomographic reconstruction. Even though resolution recovery has the potential to improve overall image quality, pinhole SPECT images are still often reconstructed using simplified models of the acquisition geometry in order to reduce reconstruction time. This paper investigates the benefits of two resolution recovery methods, multi-ray and point-spread function based, in pinhole SPECT by comparing them to uncorrected reconstruction., Methods: Resolution recovery was incorporated into ordered subsets expectation maximization reconstruction algorithm. The first of the correction methods used a simple but very fast multiple projection ray approach, whereas the second, much slower, method modelled the acquisition geometry more accurately using the analytical point-spread function of the pinhole collimator. Line source, Jaszczak and contrast phantom studies were performed and used for comparison., Results: Resolution recovery improved resolution, contrast and visual quality of the images when compared to reconstructions without it. The method based on the point-spread function performed slightly better, but was almost 50 times slower than the much simpler multi-ray approach., Conclusion: The multiple projection ray approach is a promising method for very fast and easy resolution recovery in pinhole SPECT. It has a profound effect on image quality and can markedly improve the resolution-sensitivity trade-off.

Halothane and isoflurane potently depress airway ciliary motility. We compared the effect of sevoflurane on ciliary beat frequency (CBF) with that of halothane and isoflurane using purified and cultured rat tracheal epithelial cells. Rat tracheal epithelial cells were isolated from adult male Sprague-Dawley rats to establish an air-liquid interface culture. Apical surfaces of the cells were exposed to a fresh gas containing humidified and warmed (25 degrees C) air (vehicle) with or without sevoflurane (0%-4%), halothane (0%-2%), or isoflurane (0%-2%). The images of motile cilia were videotaped and CBF was analyzed using a computer. Baseline CBF (= 100%) and CBF 30 min after the exposure were measured. CBF 30 min after vehicle exposure was 101% +/- 4% (mean +/- sd). Exposures to 0.25%-2% sevoflurane did not change CBF significantly, although exposures to 0.25%-2% halothane or isoflurane decreased CBF dose-dependently. CBFs 30 min after exposures to 2% of sevoflurane, halothane, and isoflurane were 97% +/- 9%, 56% +/- 14%, and 47% +/- 6%, respectively (n = 5 each). Sevoflurane 4% reduced CBF significantly but slightly (84% +/- 2%, n = 5). These results show that sevoflurane has a direct cilioinhibitory action but its action is much weaker than that of halothane and isoflurane in isolated rat tracheal epithelial cells.

Overproduction of nitric oxide by inducible nitric oxide synthase contributes to the progression of cardiovascular disease. We investigated the effects of azelnidipine and other Ca2+-channel blockers on nitric oxide production by cultured aortic smooth muscle cells isolated from Wistar rats and human umbilical vein endothelial cells (HUVECs), using the Griess reaction and oxyhemoglobin method. Release of lactic dehydrogenase (LDH) was measured to evaluate cell damage, and immunohistochemistry was performed to examine the expression of inducible nitric oxide synthase and nitrotyrosine protein. Azelnidipine and other Ca2+-channel blockers inhibited the release of nitric oxide induced by lipopolysaccharide plus interferon-gamma. Azelnidipine inhibited it most potently among the Ca2+-channel blockers tested (azelnidipine, amlodipine, nifedipine, diltiazem, verapamil, and nicardipine) at a concentration of 10 microM. Longer stimulation with these agents induced the expression of inducible nitric oxide synthase and nitrotyrosine, with an increase of lactic dehydrogenase release, whereas azelnidipine suppressed these changes. In human umbilical vein endothelial cells, azelnidipine enhanced basal nitric oxide production by endothelial nitric oxide synthase. In conclusion, azelnidipine potently inhibited the induction of inducible nitric oxide synthase and then nitric oxide production in vascular smooth muscle cells, while enhancing constitutive nitric oxide production by endothelial cells. Azelnidipine may inhibit nitrotyrosine expression and cell damage caused by overproduction of nitric oxide, suggesting a mechanism for its cardiovascular protective effect.

Background: Although hemipelvectomy has been the standard treatment for malignant tumors of the pelvis, limb salvage surgery is now the treatment of choice, even for patients with advanced tumors. For these patients, pelvic reconstruction is needed to maintain the stability of the pelvis and the spinal column and to allow ambulation. In this report, the authors' experiences with pelvic ring reconstruction are described., Methods: Pelvic ring reconstruction with free double-barreled vascularized fibular grafts was performed after resection of malignant pelvic tumors in five patients. The graft was fixed with a fixation plate and screws in three patients and with the Cotrel-Dubousset rod system in two patients. After surgery, perioperative and postoperative findings were evaluated., Results: In one patient, a pedicled rectus abdominis musculocutaneous flap was transferred to repair defects of the skin and underlying soft tissue. The free fibular graft was transferred successfully in four of five patients; however, the graft was removed in one patient because of infection with methicillin-resistant Staphylococcus aureus. After surgery, three of the four patients with successful grafts could walk with full weight bearing and without a cane; the fourth patient died as a result of multiple metastases to the lung before walking was attempted., Conclusions: The double-barreled fibular graft is well vascularized and can achieve satisfactory bone union. It is a safe and effective method for reconstructing the pelvic ring. Furthermore, the Cotrel-Dubousset rod system can provide rigid fixation soon after surgery and is useful for early rehabilitation of walking.

We previously reported that unclamping of an abdominal aortic cross-clamp causes initial dilation of pial arteries followed by sustained constriction. Both milrinone and colforsin daropate have a vasodilator action, and both have been used in such critical conditions as abdominal aortic aneurysmectomy. We measured cerebral pial arteriolar diameters using a rabbit closed cranial window preparation before (baseline) and 15 min after the start of an IV infusion of 0.9% saline (control group), milrinone, or colforsin daropate (0.05 and 0.5 microg . /kg(-1) . min(-1)) (pre-clamp), just after aortic clamping, 20 min after clamping, and at 0 to 60 min after unclamping. In the control group, a significant decrease in diameter persisted for at least 60 min after unclamping (maximum, -15% for large and -26% for small arterioles versus baseline). These values were significantly smaller after both doses of milrinone and the larger dose of colforsin daropate (-5% and -8%, 10% and 12%, and -2% and -5%, respectively vs baseline, at 60 min). In a second experiment, changes in regional cerebral blood flow and tissue oxygen tension reflected changes in vascular variables. Thus, sustained cerebral pial arteriolar constriction induced by aortic unclamping can be attenuated by IV milrinone or colforsin daropate.

We examined the acute toxicity of uranium (99.3% 238U, 0.7% 235U) and the effects of Catechol-3,6-bis(methyleiminodiacetic acid) (CBMIDA) and Ethane-1-hydroxy-1,1-bisphosphonate (EHBP) on the removal of uranium after intramuscular injection as a simulated wound intake in rats. In this experiment, male Wistar rats, 8 wk old, were injected intramuscularly with uranyl nitrate in the femoral muscles. Experiment I: Rats died from 3 to 7 d after they were injected with five doses of 7.9, 15.8, 31.5, 63, and 126 mg kg(-1) uranium. The uranium retained 8.4-13.6% of the injected doses in the kidneys, showing the relationship between the injected dose and the retained concentration (r = 0.997). The excretion rates of the injected doses in the 63 and 126 mg kg(-1) uranium-injected rats were 1.73% and 3.09% in urine and 0.81% and 1.06% in feces on the first day, and 0.54% and 0.56% in feces on the second day, respectively. Experiment II: The retention of uranium at 1, 3, 6, and 24 h was examined after rats were injected with 63 mg kg(-1) uranium. The concentration of uranium decreased in the plasma, while it increased in the kidneys and femur until 6 h, and it continued to increase in the liver until 24 h. Experiment III: Rats were divided into four groups (n = 10) and were injected with a dose of 2 mg kg(-1) uranium. Two of the groups were then injected intraperitoneally with 240 or 480 mg kg-1 CBMIDA, and one group was injected with 10 mg kg(-1) EHBP once daily for 28 d, beginning 1 h after uranium injection on the first day. The fourth group was the non-treated control group. The survival rates at the end of the experiment were 80% and 40% in the 240 and 480 mg kg(-1) CBMIDA groups, 50% in the EHBP group, and 20% in the non-treated group. The successive administration of chelating agents was effective in decreasing the concentration of uranium in the kidneys, bone, and liver. The results indicated that uranium induces acute death and renal dysfunction by chemical toxicity, and both CBMIDA and EHBP were effective agents to prevent these effects.

We previously demonstrated that lumbar intrathecal alpha(2) agonists attenuate hypercapnia-induced cerebral vasodilation. The combination of intrathecal clonidine and neostigmine is being investigated as pain therapy. The effects of their combination on cerebrovascular reactivity are unknown. We allocated rabbits anesthetized with pentobarbital to two groups: (a) clonidine (normal saline followed 30 min later by clonidine 2 microg/kg, both into the lumbar intrathecal space; n = 6), and (b) neostigmine-pretreatment (neostigmine 2 microg/kg followed 30 min later by clonidine 2 microg/kg, both into the lumbar intrathecal space; n = 6). We then evaluated the hypercapnia-induced changes in pial arteriolar diameter in these two groups using the closed cranial window preparation. The pial arteriolar dilator response to hypercapnia was significantly attenuated in the clonidine group (14% +/- 4%, 4% +/- 4%, 6% +/- 6%, and 5% +/- 7% for before and 30, 60, and 90 min, respectively). Neither normal saline nor neostigmine alone induced any change in the cerebral reactivity to hypercapnia. Pretreatment with neostigmine completely prevented the clonidine-induced attenuation of the hypercapnic cerebral vasodilation attenuated by intrathecal clonidine (16% +/- 7%, 15% +/- 6%, 12% +/- 6%, and 16% +/- 8%, respectively).

Objective: At the present time, the anterior cervical discectomy and fusion procedure is widely accepted for treating cervical disc herniation. Recently, however, several authors have reported new disease due to degeneration of an adjacent segment. On the other hand, posterior discectomy, which can preserve mobility at the affected disc level, has been considered risky and technically difficult, especially for central or paracentral disc herniation. We are performing a new surgical technique, microsurgical posterior herniotomy with en bloc laminoplasty, for patients with myelopathy and radiculomyelopathy caused by cervical disc herniation., Methods: Here, the surgical outcomes and radiographic changes were retrospectively investigated. Thirty patients (13 patients with myelopathy, 13 patients with radiculomyelopathy, and 4 patients with C5 dissociated motor loss) who underwent this procedure were reviewed. The average age was 50 years (range 31-70 years), and the average follow-up period was 28 months (range 12-76 months). Neurologic improvements were evaluated using the Japanese Orthopaedic Association (JOA) Scoring System as well as radicular pain and deltoid muscle power. Postoperative axial symptoms were scored, and radiographic changes were noted., Results: The mean JOA score improvement was 74.2% (range 27.3-100%). In all 13 patients, preoperative radicular pain completely resolved after surgery. Deltoid power (in cases of C5 dissociated motor loss) markedly increased postoperatively. Cervical lordosis significantly increased at the time of the last follow-up (P = 0.01). The postoperative axial symptom score significantly correlated with the numbers of opened laminae (P = 0.03)., Conclusions: This technique was safe and effective. Radiographically, the range of motion in the cervical spine and at the affected disc levels was preserved. In the future, this surgical procedure can become an alternative method for cervical disc herniation treatment.

IV or oral administration of antiarrhythmics has been reported to be effective for relieving neuropathic pain. Recent reports have indicated that tetrodotoxin-resistant (TTX-R) Na(+) channels play important roles in the nerve conduction of nociceptive sensation. In the present study, we investigated the effects of flecainide, pilsicainide (class Ic antiarrhythmics), and lidocaine (a class Ib drug) on TTX-R Na(+) currents in rat dorsal root ganglion neurons using the whole-cell patch-clamp method. Flecainide, pilsicainide, and lidocaine reversibly blocked the peak amplitude of TTX-R Na(+) currents in a concentration-dependent manner with half-maximum inhibitory concentration values of 8.5 +/- 6.6 microM (n = 7), 78 +/- 6.9 microM (n = 7), and 73 +/- 6.8 microM (n = 7), respectively. Each drug shifted the inactivation curve for the TTX-R Na(+) currents in the hyperpolarizing direction and caused a use-dependent block. We also studied an interaction between these antiarrhythmics on TTX-R Na(+) channels. Additional application of flecainide or pilsicainide to lidocaine resulted in an additive increase of tonic and use-dependent block. These results suggest that the inhibition of TTX-R Na(+) currents of dorsal root ganglion neurons by such antiarrhythmics is attributable, at least partly, to their antinociceptive effects.

Unlabelled: Studies have indicated that mild to moderate hypothermia or dexmedetomidine may have neuroprotective properties in animal models. In this study, we investigated the effects of hypothermia on dexmedetomidine-induced responses in cerebral vessels in anesthetized rabbits by using the cranial-window preparation. After instrumentation under pentobarbital anesthesia, 12 rabbits were assigned to 1 of 2 equal groups: normothermic (nasopharyngeal and intrawindow temperature, 38.5 degrees C-39.5 degrees C) or hypothermic (33.0 degrees C-34.0 degrees C). Each rabbit received three different concentrations (10(-7), 10(-5), and 10(-3) M) of dexmedetomidine under the window, and cerebral pial vessel diameters were measured in a sequential manner. In the normothermic group, dexmedetomidine induced a significant concentration-dependent dilation in both large and small arterioles. In the hypothermia group, dexmedetomidine produced a U-shaped dose-response in both large and small cerebral arterioles (concentration-related vasoconstriction at 10(-7) and 10(-5) M, but vasodilation at 10(-3) M). In cerebral venules, a similar pattern of results was obtained, but changes were generally smaller than in arterioles. In conclusion, topically applied dexmedetomidine induces concentration-dependent dilation in cerebral arterioles in normothermic rabbits anesthetized with pentobarbital, but mild to moderate hypothermia attenuates these responses, with smaller dexmedetomidine concentrations causing vasoconstriction., Implications: In normothermic rabbits anesthetized with pentobarbital, topically applied dexmedetomidine induces a concentration-dependent dilation in both large and small cerebral arterioles, but mild to moderate hypothermia attenuates these responses.

Background: We have recently established a new method for bone marrow transplantation (BMT) in mice: bone marrow cells are directly injected into the intra-bone marrow (IBM) cavity. IBM-BMT induces persistent donor-specific tolerance and enhances the rapid recovery or reconstitution of the hematolymphoid system of donor origin without any signs of graft-versus-host disease (GVHD) or graft failure. Furthermore, the prior injection of fludarabine can reduce the irradiation dose to the sublethal level (4.5 Gy x 2). Therefore, we hypothesize that IBM-BMT plus fludarabine is applicable to allogeneic leg transplantation in rats., Methods: Brown Norway (BN; RT1An) rats were injected intravenously with 50 mg/kg of fludarabine phosphate, followed by sublethal fractionated irradiation (4.5 Gy x 2) 1 day before IBM-BMT. The hind limbs from Fischer 344 (F344; RT1Al) rats were transplanted on day 0, and bone marrow cells (3 x 10(7) cells/50 microL) obtained from the donor F344 rats were injected into the bone marrow cavity of the left tibias of the recipient BN rats., Results: The hematolymphoid cells in the recipient BN rats were completely reconstituted by the cells of the donor F344 rats. The limbs transplanted from the donor F344 rats were accepted for >1 year without any clinical signs of rejection (10 of 10). The lymphocytes of the BN rats showed tolerance to both donor-type and recipient-type major histocompatibility complex determinants in mixed lymphocyte reaction, but showed a significant response to the third-party major histocompatibility complex determinants., Conclusions: Using a combination of the injection of fludarabine, low-dose irradiation, and IBM-BMT, we have succeeded in allogeneic limb transplantation without using any immunosuppressants after the operation. This strategy would be applicable to the transplantation of other vascularized organs in humans.