The Warburg effect and tumour immune microenvironment in extramammary Paget's disease: overexpression of lactate dehydrogenase A correlates with immune resistance.

BACKGROUND: Extramammary Paget's disease (EMPD) is a rare malignant skin cancer. One of the hallmarks of cancers, including EMPD, is an enhancement of aerobic glycolysis, which is also known as the Warburg effect. In the last step of glycolysis, the enzyme lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactic acid, the accumulation of which contributes to the creation of an acidic tumour microenvironment. This in turn results in immunosuppression in various types of cancers. However, the contribution of these pathways has not been well-studied in EMPD. OBJECTIVE: To investigate the significance of the Warburg effect and its contribution to the tumour immune microenvironment in EMPD. METHODS: The mRNA expression levels of molecules involved in glycolysis and immune-related cytokines were examined by ddPCR. The number of immune cells was assessed by immunohistochemistry (IHC). RESULTS: The levels of two glycolytic enzymes, HK2 and LDHA, in tumour tissues were significantly increased compared to those in paired-normal tissues. IHC analyses revealed increased numbers of PD-L1+ , PD-1+ , CD163+ M2 macrophages, Iba1+ macrophages and Foxp3+ Tregs that were associated with high LDHA levels in EMPD. ddPCR demonstrated that multiple cytokines including IL-4, IL-6, IL-10, TGF-ß and CCL-2 were upregulated and associated with high LDHA levels in EMPD. Statistical analyses showed that IL-6 mRNA expression correlated with the number of CD163+ , Iba-1+ and Foxp3+ cells. CONCLUSION: The Warburg effect contributes to immunomodulation in the tumour microenvironment and further elucidation may lead to better understanding of the pathogenesis of EMPD.

Involvement of transient receptor potential vanilloid 2 in intra-oral incisional pain.

OBJECTIVE: To examine whether transient receptor potential vanilloid 2 (TRPV2) contributes to the changes in intra-oral thermal and mechanical sensitivity following the incision of buccal mucosa. MATERIALS AND METHODS: Buccal mucosal pain threshold was measured after the incision. Changes in the number of TRPV2-immunoreactive (IR) trigeminal ganglion (TG) neurons which innervate the whisker pad skin and buccal mucosa, changes in the number of isolectin B4-negative/isolectin B4-positive TRPV2-IR TG neurons which innervate the whisker pad skin and the buccal mucosa, and the effect of peripheral TRPV2 antagonism on the pain threshold of incisional whisker pad skin and buccal mucosa were examined after these injuries. RESULTS: Buccal mucosal pain hypersensitivities were induced on day 3 following the incision. The total number of TRPV2-IR TG neurons and the number of isolectin B4-negative TRPV2-IR TG neurons which innervate the whisker pad skin and buccal mucosa were increased. Buccal mucosal TRPV2 antagonism completely suppressed the heat and mechanical hypersensitivities, but not cold hypersensitivity. TRPV2 antagonist administration to the incisional whisker pad skin only partially suppressed pain hypersensitivities. CONCLUSION: The increased expression of TRPV2 in peptidergic TG neurons innervating the incisional buccal mucosa is predominantly involved in buccal mucosal heat hyperalgesia and mechanical allodynia following buccal mucosal incision.

Circulating fibrocytes correlate with the asthma control test score.

BACKGROUND: Bronchial asthma is characterised by airway inflammation and remodelling with a decline of lung function. Fibrocytes are bone marrow-derived mesenchymal progenitor cells that play important roles in the pathogenesis of airway remodelling. Several clinical parameters are currently being used in routine clinical practice to assess outcome of therapy in asthma including frequency of rescue with short-acting ß2-agonist and the asthma control test. In this study, we hypothesised that asthma control test is associated with circulating levels of fibrocytes in bronchial asthma. METHODS: There were 20 patients with asthma and seven healthy controls. The number of CD45(+)Collagen I(+) circulating fibrocytes was assessed in the peripheral blood by flow cytometry. RESULTS: The number of circulating fibrocytes was significantly increased in asthma patients with moderate and severe disease compared to controls, and it was inversely correlated with % forced expiratory volume in one second and % forced vital capacity (%FVC). The frequency of inhalation of short-acting ß2 agonist and the asthma control test score was significantly and inversely correlated with the number of circulating fibrocytes. CONCLUSION: The results of this study showed that the number of circulating fibrocytes is inversely correlated with clinical asthma control parameters, further supporting the relevance of measuring circulating fibrocytes as a marker of clinical control in bronchial asthma.

Temporary auxiliary partial orthotopic liver transplantation using a small graft for familial amyloid polyneuropathy.

Donor shortage is a major issue in liver transplantation. We have successfully performed temporary auxiliary partial orthotopic liver transplantation (APOLT) using a small volume graft procured from a living donor for recipients with familial amyloid polyneuropathy (FAP). The aim of this study was to evaluate this procedure by comparing it with standard living donor liver transplantation (LDLT). We compared 13 recipients undergoing this procedure with 23 recipients undergoing a standard LDLT for the treatment of FAP. The estimated donor graft volume and the graft volume/recipient's standard liver volume ratio were significantly smaller in the temporary APOLT group than in the standard LDLT group. Postoperative complications were comparable, although the hospital stay was longer in the temporary APOLT group. All the patients safely underwent a remnant native liver resection about 2 months after their first operation in the temporary APOLT group. No symptoms related to FAP developed before the remnant liver resection, and no significant differences in graft and patient survival were observed between the two groups. We successfully performed temporary APOLT using a small volume liver graft without postoperative liver failure for FAP. Temporary APOLT for FAP might be a useful alternative procedure for expanding the donor pool for LDLT.

Arterial reconstruction in a case of subintimal dissection of celiac arterial tributaries in living donor liver transplantation: a case report.

BACKGROUND: Hepatic arterial reconstruction is one of the critical issues in living donor liver transplantation (LDLT). Herein we have reported an LDLT case whose celiac arterial trunk tributaries were insufficient as host arteries because of extensive subintimal dissection proceeding to all tributaries of the celiac arterial trunk. PATIENTS AND METHODS: A 45-year-old woman with fulminant hepatic failure underwent LDLT. After reperfusion of the hepatic and portal veins, subintimal dissection of the recipient right and left hepatic arteries was found to extend to all tributaries of the celiac arterial trunk, preventing an anastomosis using the more proximal part of these arteries. Therefore, a jejunal arterial arcade of Roux-en-Y limb mobilized for biliary reconstruction was anastomosed to the donor left hepatic artery in end-to-end fashion. RESULTS: Arterial blood flow to the grafted liver was established successfully, and the patient's postoperative recovery was excellent. Postoperative computed tomography demonstrated sufficient hepatic arterial blood flow. The patient is doing well 4 years after transplantation. CONCLUSION: The method of hepatic graft arterialization described herein is an important option for LDLT recipients when tributaries of the celiac arterial trunk are insufficient as host arteries.

Domino liver transplantation in living donors.

Domino liver transplantation (DLT) has been developed as a method to expand the donor pool. In living donors DLT, the prime concern is to avoid any disadvantage to the donor and the first recipient. Seven DLTs were performed among 211 patients who underwent living donor liver transplantation. The domino recipients included six with hepatocellular carcinoma and one with citrullinemia. The domino grafts were obtained from patients with familial amyloid polyneuropathy (FAP) including the left liver in three cases and the right liver in four. Among the seven domino recipients, a 64-year-old woman with advanced hepatocellular carcinoma died of lung metastasis. The other six domino recipients are alive without FAP symptoms. In living donor liver transplantation, because the vessels of the graft from the first donor are not long enough for anastomosis, the hepatic vessels must be left as long as possible when removing the liver from the FAP patients in order to ensure sufficient safety for vascular reconstruction. With careful decision making during the procedure, such as where to divide the vessels in the FAP patients, DLT may help address the shortage of liver grafts.

Involvement of TRPV1 and TRPA1 in incisional intraoral and extraoral pain.

Thermal and mechanical hypersensitivity in the injured region is a common complication. Although it is well known clinically that thermal and mechanical sensitivity of the oral mucosa is different from that of the skin, the mechanisms underlying injured pain of the oral mucosa remain poorly understood. The transient receptor potential (TRP) vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) in primary afferent neurons are known to contribute to pathological pain. Therefore, we investigated whether TRPV1 and/or TRPA1 contribute to thermal and mechanical hypersensitivity following oral mucosa or whisker pad skin incision. Strong heat and mechanical and cold hypersensitivity was caused in the buccal mucosa and whisker pad skin following incisions. On day 3 after the incisions, the number of TRPV1-immunoreactive (IR) and TRPA1-IR trigeminal ganglion (TG) neurons innervating the buccal mucosa and whisker pad skin was significantly increased, and the number of TRPV1/TRPA1-IR TG neurons innervating whisker pad skin, but not the buccal mucosa, was significantly increased. Administration of the TRPV1 antagonist, SB366791, to the incised site produced a significant suppression of heat hyperalgesia in both the buccal mucosa and whisker pad skin, as well as mechanical allodynia in the whisker pad skin. Administration of the TRPA1 antagonist, HC-030031, to the incised site suppressed mechanical allodynia and cold hyperalgesia in both the buccal mucosa and whisker pad skin, as well as heat hyperalgesia in the whisker pad skin. These findings indicate that altered expressions of TRPV1 and TRPA1 in TG neurons are involved in thermal and mechanical hypersensitivity following the buccal mucosa and whisker pad skin incision. Moreover, diverse changes in the number of TRPV1 and TRPA1 coexpressed TG neurons in whisker pad skin-incised rats may contribute to the intracellular interactions of TRPV1 and TRPA1 associated with whisker pad skin incision, whereas TRPV1 and TRPA1 expression in individual TG neurons is involved in buccal mucosa-incised pain.

Living-Donor Liver Transplantation for Hepatic Metastasis From Meningeal Hemangiopericytoma: A Case Report.

We report the case of a 58-year-old man referred to our hospital for liver tumor treatment. The patient had a history of neurosurgery for a meningeal hemangiopericytoma 16 years previously. Pre-operative imaging revealed a hypervascular tumor extending from Couinaud segment 4 to segment 8 of the liver, measuring 95 mm in diameter, indicating an atypical hepatocellular carcinoma. Because right trisectionectomy of the liver was considered to be high risk, living-donor liver transplantation (LDLT) was indicated. After transcatheter arterial embolization, LDLT was performed with the use of a left-lobe liver graft from the patient's son. Post-operative histological findings of the liver tumor were identical to those for meningeal hemangiopericytoma, therefore the patient was diagnosed with meningeal hemangiopericytoma that had metastasized to the liver. After LDLT, the patient had a healthy, active life for 2 years; then, a subcutaneous relapse was discovered in the left chest. The patient did not undergo any systemic chemotherapy in response to the relapse. After thoracic and orthopedic surgeries and radiotherapy for multiple metastases, the patient died 5 years and 5 months after LDLT. LDLT could be an effective treatment for localized metastatic hemangiopericytoma in the liver, but it should be indicated only for carefully selected patients.

P300 and the thought disorder factor extracted by factor-analytic procedures in schizophrenia.

BACKGROUND: In order to clarify the clinical significance of P300 as a biologic marker that can reflect schizophrenic symptomatology, many previous studies have evaluated the relationship of P300 with the symptoms on the basis of a positive/negative dichotomy, but yielded inconsistent conclusions. Such a dichotomy has been criticized as being too reductionistic. Recently, most studies with factor-analytic procedures have extracted some symptom factors outside this dichotomy. Therefore, it is important to examine associations of P300 with the symptom factors extracted by these statistical analyses. METHODS: In the present study, the amplitudes of P300 were measured by using an auditory oddball paradigm for 73 schizophrenics whose psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS). RESULTS: The principal component analysis of the PANSS items revealed five factors labeled the thought disorder, negative, hostile/excitable, delusional/hallucinatory, and depressive factors. The score for the thought disorder factor correlated negatively with the amplitude of P300 recorded at Pz T5, and T6, but that for the other factors did not. CONCLUSIONS: These findings suggest that the reduction of P300 amplitudes recorded at the midline parietal and bilateral temporoparietal regions may be one of the electrophysiologic indices representing the thought disorder clinically observed in schizophrenia.

Effect of calcium antagonists on rat liver during extended cold preservation-reperfusion.

BACKGROUND: Nisoldipine, a calcium antagonist, has been reported to improve the quality of grafted rat livers. We thus assessed the protective effect of two calcium antagonists, nisoldipine and nickel, during extended cold ischemia-reperfusion. METHODS: Rat livers were isolated and perfused before or after 24 hr of cold ischemia in University of Wisconsin solution (4 degrees C) with or without nisoldipine or nickel. Sinusoidal endothelial cell and hepatocyte functions were measured by hyaluronic acid and taurocholate elimination, respectively. RESULTS: Similar alterations in hepatocyte and sinusoidal cell functions were found in all groups after cold ischemia with or without calcium antagonists. In a second set of experiments, liver transplantation was performed in two groups of rats with livers stored under identical conditions with or without nisoldipine. Seven of 12 animals (62.5%) in both groups survived for over 10 days after 24-hr preservation in University of Wisconsin solution. Survival rates were similar in both groups. CONCLUSIONS: Calcium antagonists do not appear to have a direct protective effect on sinusoidal endothelial cell and hepatocyte functions, nor on the overall liver preservation after extended cold preservation-reperfusion.

Concomitant caudate lobe resection as an option for donor hepatectomy in adult living related liver transplantation.

In this article, we describe a successful adult living related partial liver transplantation (LRLT) using the left lobe with the left-side caudate lobe (the Spiegel lobe and the left side of the paracaval portion). The size of the donor's left lobe was 29% of the recipient's standard liver volume and did not seem to meet our criteria for adult-to-adult LRLT. However, the donor had a thick left-side caudate lobe. The estimated volume of the left lobe with the left-side caudate lobe was 32%, which met our criteria for the adult recipient. The recipient's CT scan on day 87 after transplantation showed the preserved blood flow and no biliary congestion in the left-side caudate lobe, which suggests maintenance of lobe function. This procedure may be an option for adult-to-adult LRLT in which the donor has a thick left-side caudate lobe.

Long-term results of living-related donor liver graft transplantation: a single-center analysis of 110 transplants.

BACKGROUND: Difficulties of cadaveric donation and serious donor shortage have led to the development and popularization of living-related donor liver graft transplantation (LRLT). Because the history of this procedure is rather short, important aspects specific to this procedure have not been sufficiently documented. The objective of this study was to analyze a single center's 10-year experience with 110 LRLT in pediatric and adult patients with end-stage liver diseases. METHODS: The medical records of 110 consecutive patients who underwent LRLT were reviewed. The recipients were comprised of 72 children and 38 adults. The graft volume corresponded to 26-192% of the recipient's standard liver volume. The relationship between pretransplant covariates and patient and graft survival was analyzed. Actuarial patient/graft survival rates were determined at 1, 3, and 5 years. The type and incidence of posttransplant complications were analyzed, as was long-term graft function. RESULTS: The 1-, 3-, and 5-year actuarial patient and graft survival rates were 88%, 85%, and 85%, respectively. Log-rank test demonstrated that ABO-compatibility predicted patient survival rate, whereas patient age, underlying disease, patient's clinical status, donor-recipient relation, donor age, and graft volume/standard liver volume ratio did not. Long-term liver function remains excellent. All the donors have returned to normal daily lives with an uneventful course. CONCLUSIONS: LRLT is an efficacious procedure that provides excellent short-term and long-term survival. The indication criteria for both recipient and donor were legitimate in this series, except for transplant across ABO-incompatibility. Cautious expansion of this procedure may be justified under the situation of serious shortage of cadaveric donor.

Redox properties of membrane-bound b-type cytochromes and a soluble c-type cytochrome of nitrate reductase in a photodenitrifier, Rhodopseudomonas sphaeroides forma sp. denitrificans.

In order to identify the b-type cytochrome involved in the nitrate reduction in a photodenitrifier, Rhodopseudomonas sphaeroides forma sp. denitrificans, the b-type cytochromes in the spheroplast membranes were characterized. Difference spectra at 77K of spheroplast membranes indicated the presence of two b-type cytochromes with a bands at 556.5 and 562 nm. Three components considered to be of the b-type cytochrome were resolved by anaerobic potentiometric titration at 560-572 nm. Their midpoint potentials at pH 7, Em,7, were - 135 mV, +40 mV and +175 nm and their approximate reduced minus oxidized maxima were determined to be at 565 nm (562 nm at 77K), 560 nm (556.5 nm) and 560 nm (556.5 nm), respectively. These values are almost the same as those reported for R. sphaeroides. The Em,7 value of the cytochrome c involved in the nitrate reductase of this denitrifier was determined to be 250 mV. A b-type cytochrome reduced with NADH and FMN was oxidized by nitrate in chromatophore membranes. The possibility that cytochrome b (Em,7 = 175 mV) is involved in the nitrate reduction is discussed.

SPECT analysis of regional cerebral blood flow changes in patients with schizophrenia during the Wisconsin Card Sorting Test.

Single photon emission computed tomography (SPECT) images were obtained in 10 right-handed neuroleptic-treated schizophrenic patients and 10 healthy volunteers using Tc-99m-hexamethyl-propylenamine oxime (Tc99m-HMPAO) during performance of the Wisconsin Card Sorting Test (WCST) and at rest. None of the patients showed severe impairment on the WCST. The patient group showed a statistically insignificant trend to incur more unique errors. In both the patient and control groups, the left lateral prefrontal blood flow significantly increased during the WCST, as compared to during resting conditions. Only during the WCST, the patient group showed a significant regional cerebral blood flow (rCBF) decline in the left medial prefrontal cortex, as well as in the right side under both the test and resting conditions. This left medial prefrontal rCBF during the WCST correlated positively with the number of unique errors, although this correlation was statistically insignificant. The right fronto-parietal rCBF was significantly increased in the patient group under both the test and resting conditions. Moreover, in the left hippocampal region, the patient group showed a significant rCBF increase under resting conditions.

Regional cerebral blood flow in male schizophrenic patients performing an auditory discrimination task.

Regional cerebral blood flow (rCBF) was measured in 11 schizophrenic patients amid 10 normal controls, both at rest and while performing an auditory discrimination task. Single photon emission computed tomography with technetium-99m hexamethylpropylene amine oxime was used for quantitative evaluation of rCBF. The schizophrenic patients showed greater rCBF in the temporal and parietal regions at rest than the controls, but no abnormalities were found in frontal perfusion. During task performance. on the other hand, the patients showed a reduced frontal rCBF. whereas there was no group difference in rCBF in the temporal and parietal regions. In addition, the left> right hemisphere asymmetries of rCBF observed in the controls during task performance were not present in the patients. although there was no group difference in hemisphere laterality in rCBF at rest. These findings suggest that the employment of a cognitive task for neuroimaging studies is useful for detecting abnormalities of brain activation. such as hypofrontality and altered hemisphere laterality. in patients with schizophrenia.

Simultaneous observation of regional cerebral blood flow and event-related potential during performance of an auditory task.

Reduced amplitude of the P300 component has been reported consistently in patients with neurological and psychiatric disorders. It is unclear, however, how such patients' cognitive dysfunction is related to their P300 abnormality. Further basic knowledge regarding neural substrates for P300 generation is required for gaining an understanding of the pathological significance of the P300 amplitude reduction. To determine the brain structures involved in P300 generation, we observed the event-related potential and the regional cerebral blood flow (rCBF) in 10 normal subjects performing an oddball discrimination of pure tones. The rCBF value was assessed quantitatively with the aid of single photon emission computed tomography using technetium-99m hexamethylpropylene amine oxime. During the task performance, significant activation was observed in the posterior superior temporal and inferior parietal regions of the right hemisphere. In addition, positive correlation of the task-related increase in rCBF with the simultaneously recorded P300 amplitude was observed in the right but not the left posterior superior temporal region. These findings indicate that activation of the right non-verbal auditory area might modulate P300 generation during pure-tone discrimination.

Isolated hepatic caudate lobectomy.

BACKGROUND: Isolated caudate lobectomy is a challenging surgical procedure for which safe and reliable techniques have yet to be developed. METHODS: Isolated caudate lobectomy was performed by initial inflow control of the caudate lobe, full mobilization of the liver from the inferior vena cava by dividing all short hepatic veins, and parenchymal division dorsal to the major hepatic veins with a clockwise rotation of the liver while the liver was selectively devascularized by Pringle's maneuver and occlusion of the confluence of the major hepatic veins flush with the inferior vena cava. RESULTS: Two patients with cirrhosis underwent this procedure successfully without intraoperative hemodynamic instability or postoperative liver dysfunction. CONCLUSIONS: This technique allows safe and truly selective excision of the caudate lobe without the need for occlusion of the inferior vena cava or venovenous bypass.

Effect of diabetes mellitus on hepatic resection.

We evaluated the effect of diabetes mellitus on mortality and morbidity after elective hepatic resections. Of 209 patients who underwent hepatic resections between April 1985 and July 1990, 49 (23.4%) were diabetic. Postoperative morbidity was more common among diabetics than among nondiabetics (75.5% vs 51.3%), mainly due to hepatic decompensation (55.1% vs 36.3%) and intraperitoneal sepsis (18.4% vs 6.3%). However, their incidence of hospital death (2% vs 2.5%), mean +/- SD postoperative hospital stay (36.1 +/- 20.2 days vs 29.4 +/- 28.2 days), and long-term survival were comparable with those of nondiabetics. Diabetics with and without complications were similar in preoperative or postoperative insulin requirement, duration of diabetes, and preoperative fasting glucose. Nevertheless, all eight patients with 24-hour urinary glucose excretion above 1 g developed complications. We conclude that diabetics are at a high risk of morbidity, but not of mortality after elective hepatic resection.

Effect of endotoxin-induced reactive oxygen species on sperm motility.

OBJECTIVE: To define the mechanism of infection-induced damage of sperm. DESIGN: The effect of lipopolysaccharide (LPS)-induced reactive oxygen species (ROS) on sperm motility and its modification by scavengers were investigated. SETTING: Research laboratory of a university hospital. PATIENT(S): Normozoospermic semen samples were obtained from 37 healthy volunteers. INTERVENTION(S): The sperms were incubated in the presence of LPS with or without scavengers. MAIN OUTCOME MEASURE(S): Sperm motility was evaluated by a sperm quality analyzer (SQAIIB). ROS formation in semen samples was measured by a Berthold luminometer (LB953). RESULT(S): Motility of spermatozoa was decreased in the LPS-treated samples compared with that in the control groups. ROS was significantly higher in the LPS-treated groups than in the control groups. The addition of ROS scavengers restored the motility index and suppressed ROS production in the LPS-treated semen samples. CONCLUSION(S): These data suggest that endotoxin-induced excessive production of ROS is responsible for the decrease in sperm motility and that antioxidant therapy may be a therapeutic option for infertile men with bacterial genital tract infection.

Modulation of coagulation and fibrinolysis in hepatic resection: a randomized prospective control study using antithrombin III concentrates.

A randomized prospective control trial for determining the efficacy of antithrombin III concentrates in hepatic resection was performed using 24 patients with hepatocellular carcinoma. Thirteen patients were given antithrombin III concentrates (1,500 IU) immediately before operation, during hepatectomy and immediately after operation. Coagulant and fibrinolytic profiles were determined by molecular markers such as thrombin-antithrombin III complex and plasmin-alpha 2plasmin inhibitor complex. During hepatic resection, both hypercoagulability and mainly primary hyperfibrinolysis occurred. Regarding the effectiveness of antithrombin III concentrates, in the antithrombin III treatment group, only a significant lower incidence of positive soluble fibrin monomer complex at postoperative days 1 and 5 was found among all the parameters studied. Therefore, no definite evidence of clinical usefulness of the perioperative administration of antithrombin III concentrates in hepatic resection was proved.