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ObjectiveAutoimmune autonomic ganglionopathy (AAG) is a rare disorder characterized by autonomic failure associated with the presence of anti-ganglionic acetylcholine receptor (gAChR) antibodies; however, several studies have reported that individuals with anti-gAChR antibodies present with central nervous system (CNS) symptoms such as impaired consciousness and seizures. In the present study, we investigated whether the presence of serum anti-gAChR antibodies correlated with autonomic symptoms in patients with functional neurological symptom disorder/conversion disorder (FNSD/CD).MethodsClinical data were collected for 59 patients presenting with neurologically unexplained motor and sensory symptoms at the Department of Neurology and Geriatrics between January 2013 and October 2017 and who were ultimately diagnosed with FNSD/CD according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Correlations between serum anti-gAChR antibodies and clinical symptoms and laboratory data were analyzed. Data analysis was conducted in 2021.ResultsOf the 59 patients with FNSD/CD, 52 (88.1%) exhibited autonomic disturbances and 16 (27.1%) were positive for serum anti-gAChR antibodies. Cardiovascular autonomic dysfunction, including orthostatic hypotension, was significantly more prevalent (75.0 vs. 34.9%, P = 0.008), whereas involuntary movements were significantly less prevalent (31.3 vs. 69.8%, P = 0.007), among anti-gAChR antibody-positive compared with -negative patients. Anti-gAChR antibody serostatus did not correlate significantly with the frequency of other autonomic, sensory, or motor symptoms analyzed.ConclusionsAn autoimmune mechanism mediated by anti-gAChR antibodies may be involved in disease etiology in a subgroup of FNSD/CD patients.

Vascular endothelial growth factor A (VEGF-A) plays pivotal roles in regulating tumor angiogenesis as well as physiological vascular function. The major VEGF-A isoforms, VEGF-A121 and VEGF-A165, in serum, plasma, and platelets have not been exactly evaluated due to the lack of the appropriate assay system. Antibodies against human VEGF-A121 and VEGF-A165 (hVEGF-A121 and hVEGF-A165) were successfully produced and Enzyme-Linked ImmunoSorbent Assay (ELISA) for hVEGF-A121 and hVEGF-A165 were separately created by these monoclonal antibodies. The measurement of recombinant hVEGF-A121 and hVEGF-A165 by the created ELISA showed no cross-reaction between hVEGF-A121 and hVEGF-A165 in conditioned media from HEK293 cells transfected with either hVEGF-A121 or hVEGF-A165 expression vector. The levels of VEGF-A121 and VEGF-A165 in serum, plasma, and platelets from 59 healthy volunteers proved that VEGF-A121 level was higher than VEGF-A165 in both plasma and serum in all the cases. VEGF-A121 or VEGF-A165 in serum represented higher level than that in plasma. In contrast, the level of VEGF-A165 was higher than VEGF-A121 in platelets. The newly developed ELISAs for hVEGF-A121 and hVEGF-A165 revealed different ratios of VEGF isoforms in serum, plasma, and platelets. Measuring these isoforms in combination provides useful information as biomarkers for diseases involving VEGF-A121 and VEGF-A165.

Abstract Background Rupture of an atherosclerotic plaque and subsequent exposure of the subendothelial prothrombotic matrix to blood cause arterial thrombosis. Circulating platelets play an indispensable role in the growth of arterial thrombi partially owing to their unique ability to adhere to the subendothelial matrix and to aggregate to each other under flow conditions. Recently, the Total Thrombus-formation Analysis System (T-TAS) was developed for ex vivo analysis of the thrombogenic potential of whole blood samples under flow conditions. Despite the potential clinical utility of the T-TAS in assessing the risk for thrombosis and bleeding, reference intervals for T-TAS analysis in healthy individuals have not been determined. Methods In total, 122 whole blood samples were collected from healthy volunteers ranging in age from 25 to 45 years. T-TAS analysis and hematological, physiological, and lifestyle assessments were conducted in these subjects. Whole blood samples anticoagulated with hirudin were perfused into a collagen-coated microchip (PL chip). The time to 10 kPa and the area under the flow pressure curve up to 10 min (AUC10) were analyzed as representative variables for thrombogenic potential. Reference intervals, which were defined as 2.5–97.5 percentiles, were determined. Additionally, univariate and multivariate analyses were performed to identify factors associated with the AUC10 in the T-TAS. Results The time to 10 kPa and the AUC10 widely varied, even in healthy volunteers. The reference intervals were 1.50–4.02 min and 223.4–456.8, respectively, at a shear rate of 1500 s− 1. Univariate and multivariate analyses showed that platelet counts were most significantly associated with the AUC10 of the T-TAS. The presence of one or more cardiovascular risk factors of a high body mass index, a high pulse pressure, high fasting serum glucose levels, high low-density lipoprotein-cholesterol levels, a history of smoking, and no habitual exercise, had the second largest effect on the AUC10 of the T-TAS. Conclusions Healthy volunteers who had any cardiovascular risk factors showed augmented thrombogenicity, even in artificial uniform capillaries, compared with those without any risk factors in the T-TAS.

Abstract Background and Aims The early and reliable detection of chronic kidney disease is important. In the present study, we aimed to compare the diagnostic results for proteinuria and hematuria between the dipstick test used in primary occupational health examinations and the quantitative tests used in more thorough examinations in clinics. Methods We conducted a single‐center observational study of male staff (N = 573) at Kagoshima University who underwent a health examination in 2017. Both dipsticks and biochemical methods were used to assess proteinuria and hematuria. Results For the dipstick test, the sensitivity, specificity, and positive predictive value were 55.6%, 92.4% and 10.4% for proteinuria, and 64.3%, 98.3% and 66.7% for hematuria, respectively. Four participants for whom false‐negative results were obtained using dipsticks for proteinuria, and two of these had 3+ urinary glucose. Conclusion Qualitative tests for proteinuria and hematuria had low sensitivities and positive predictive values. Therefore, for the early and reliable detection of chronic kidney disease, the use of quantitative urine tests should be considered during occupational health examinations.

Atrial fibrillation (AF) is the most common cardiac arrhythmia in the world and has a high risk of thromboembolism. The most effective approach, catheter ablation, requires evaluation by electrocardiography. The aim of our study was to investigate novel clinical markers that predict restoration of sinus rhythm (SR) after catheter ablation. Seventy-eight consecutive patients with AF underwent catheter ablation and were separated into 2 groups: restored SR and recurrent AF. The levels of 4 blood proteins (serum or plasma) and 3 mature microRNAs (miRNAs) and their primary miRNAs (pri-miRNAs) in serum were measured before and after ablation, and the associations between each parameter were analyzed statistically. Soluble thrombomodulin (s-TM) and plasminogen activator inhibitor-1 (PAI-1) levels increased above baseline after ablation in both the restored SR (s-TM 11.55 [2.92] vs 13.75 [3.38], P < .001; PAI-1 25.74 [15.25] vs 37.79 [19.56], P < .001) and recurrent AF (s-TM 10.28 [2.78] vs 11.67 [3.37], P < .001; PAI-1 26.16 [15.70] vs 40.74 [22.55], P < .001) groups. Levels of C-reactive protein and asymmetric dimethylarginine were not significantly changed. Pri-miR-126 levels significantly decreased after ablation in the recurrent AF group, but the other miRNAs and pri-miRNAs did not. The measurement of s-TM and pri-miR-126 in blood was a useful tool to reflect the condition of AF patients with catheter ablation.

Liver pathophysiology can, directly and indirectly, impose morphological or biochemical abnormalities of the platelets. Conversely, platelets are also able to regulate the promitogenic and profibrotic signals on liver pathobiology. Platelet contribution to the liver pathophysiology is typically facilitated by the platelet-derived growth factors that are sequestered in different subsets of alpha and dense granules, and the release of these growth factors is synchronized according to the stage and type of liver disease or injury. Thus, platelets harbor clinically relevant information with potential diagnostic and prognostic implications in liver diseases. Hepatocellular carcinoma (HCC) largely influences the platelet kinetics, and a growing body of evidence has recognized its association with HCC occurrence or prognosis. This narrative review summarizes the progress made on implicating platelet as a diagnostic and prognostic tool for HCC; the review also dissects the contradictory results from earlier studies and reflects how combining platelet-based information may enable more reliable test for diagnostic and prognostic evaluation of HCC.

Background: Complex fractionated atrial electrogram (CFAE)-targeted catheter ablation (CFAE ablation) requires a high rate of atrial fibrillation (AF) termination to provide good outcomes. We determined the optimal settings of CFAE software. Methods: In our 430 consecutive patients, AF was terminated in 97 (234/242) and 79% (149/188) of patients with paroxysmal and persistent AF, respectively, by CFAE ablation combined with (31%) or without (69%) pulmonary vein isolation, occasionally with nifekalant infusion. We analyzed 109 consecutive patients who underwent CFAE ablation to determine the optimal settings for comparing subjective versus objective decisions by the CFAE software on CARTO3. We compared three settings: the default setting (0.05–0.15 mV, 50–120 ms) and two modified settings (#1: 0.05–0.30 mV, 40–70 ms, #2: 0.05–0.13 mV, 10–20 ms). We retrospectively analyzed 11,425 points during left atrial mapping before ablation and 10,306 points that were subjectively detected and ablated as CFAE points. An interval confidence level ≥6 denoted a site with CFAE. Results: With the default setting, the accuracy, sensitivity, specificity, positive productive value, and negative productive values were 67, 42, 77, 48, and 73%, respectively. With modified setting #1, the values were 78, 55, 87, 74, and 77%, respectively, versus 64, 82, 60, 53, and 91%, respectively, for modified setting #2. Conclusion: These data suggest that setting #1 was generally superior to the default setting, whereas setting #2 was optimal for excluding areas not requiring ablation. The optimal CFAE software setting was a voltage of 0.05–0.30 mV and an interval parameter of 40–70 ms.

Liver regeneration (LR) involves an early inductive phase characterized by the proliferation of hepatocytes, and a delayed angiogenic phase distinguished by the expansion of non-parenchymal compartment. The interest in understanding the mechanism of LR has lately shifted from the proliferation and growth of parenchymal cells to vascular remodeling during LR. Angiogenesis accompanied by LR exerts a pivotal role to accomplish the process. Vascular endothelial growth factor (VEGF) has been elucidated as the most dynamic regulator of angiogenesis. From this perspective, platelet derived/Intra-platelet (IP) VEGF-A should be associated with LR.Thirty-seven patients diagnosed with hepatocellular carcinoma and undergoing partial hepatectomy (PH) were enrolled in the study. Serum and IP VEGF-A was monitored preoperatively and at four weeks of PH. Liver volumetry was determined on computer models derived from computed tomography (CT) scan.Serum and IP VEGF-A was significantly elevated at four weeks of PH. Preoperative IP VEGF-A was higher in patients with advanced cancer and vascular invasion. Postoperative IP VEGF-A was higher after major liver resection. There was a statistically significant correlation between postoperative IP VEGF-A and the future remnant liver volume. Moreover, the soluble vascular endothelial growth factor receptor-1 (sVEGFR1) was distinctly down-regulated suggesting a fine-tuned angiogenesis at the later phase of LR.IP VEGF-A is overexpressed during later phase of LR suggesting its implications in inducing angiogenesis during LR.

Yoshiko Ohno1,2, Teruto Hashiguchi1, Ryuichi Maenosono1, Hidetoshi Yamashita3, Yukio Taira3, Kazufumi Minowa3, Yoshihito Yamashita3, Yuko Kato3, Ko-ichi Kawahara1, Ikuro Maruyama11Department of Laboratory and Vascular Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima City, Kagoshima Prefecture, Japan; 2Department of Community Health Nursing/Nursing Informatics, School of Health Sciences, Faculty of Medicine, Kagoshima University, Kagoshima City, Kagoshima Prefecture, Japan; 3Kagoshima Seikyo General Hospital, Kagoshima City, Kagoshima Prefecture, JapanPurpose: Many epidemiological research studies have shown that vital exhaustion and psychosocial factors are associated with the occurrence of cerebrocardiovascular disease (CCVD). Fatigue is thought to induce endothelial dysfunction and may be linked to the occurrence of CCVD; however, no studies have investigated this potential link. We studied to determine the effect of fatigue on endothelial function in healthy subjects with no traditional CCVD risk factors or potential confounding factors to be controlled.Subjects and methods: Peripheral arterial tonometry (PAT) was used to evaluate endothelial function. The influence of the following parameters on endothelial function was analyzed in 74 office workers without traditional CCVD risk factors at health check-ups: endothelial function before and after work, subjective fatigue, lifestyle factors such as sleeping time, and psychosocial factors such as depression and social support.Results: Twenty-five subjects (33.8%) had low endothelial function; reactive hyperemia (RH)-PAT index

Objective. Allantoin is the primary active compound in yams (Dioscorea spp.). Recently, allantoin has been demonstrated to activate imidazoline 3 (I3) receptors located in pancreatic tissues. Thus, the present study aimed to investigate the role of allantoin in the effect to improve damage induced in pancreatic β-cells by streptozotocin (STZ) via the I3 receptors.Research Design and Methods. The effect of allantoin on STZ-induced apoptosis in pancreatic β-cells was examined using the ApoTox-Glo triplex assay, live/dead cell double staining assay, flow cytometric analysis, and Western blottings. The potential mechanism was investigated using KU14R: an I3 receptor antagonist, and U73122: a phospholipase C (PLC) inhibitor. The effects of allantoin on serum glucose and insulin secretion were measured in STZ-treated rats.Results. Allantoin attenuated apoptosis and cytotoxicity and increased the viability of STZ-induced β-cells in a dose-dependent manner; this effect was suppressed by KU14R and U73112. Allantoin decreased the level of caspase-3 and increased the level of phosphorylated B-cell lymphoma 2 (Bcl-2) expression detected by Western blotting. The improvement in β-cells viability was confirmed using flow cytometry analysis. Daily injection of allantoin for 8 days in STZ-treated rats significantly lowered plasma glucose and increased plasma insulin levels. This action was inhibited by treatment with KU14R.Conclusion. Allantoin ameliorates the damage of β-cells induced by STZ. The blockade by pharmacological inhibitors indicated that allantoin can activate the I3 receptors through a PLC-related pathway to decrease this damage. Therefore, allantoin and related analogs may be effective in the therapy for β-cell damage.

INTRODUCTION: Recent studies have shown that histones, the chief protein component of chromatin, are released into the extracellular space during sepsis, trauma, and ischemia-reperfusion injury, and act as major mediators of the death of an organism. This study was designed to elucidate the cellular and molecular basis of histone-induced lethality and to assess the protective effects of recombinant thrombomodulin (rTM). rTM has been approved for the treatment of disseminated intravascular coagulation (DIC) in Japan, and is currently undergoing a phase III clinical trial in the United States. METHODS: Histone H3 levels in plasma of healthy volunteers and patients with sepsis and DIC were measured using enzyme-linked immunosorbent assay. Male C57BL/6 mice were injected intravenously with purified histones, and pathological examinations were performed. The protective effects of rTM against histone toxicity were analyzed both in vitro and in mice. RESULTS: Histone H3 was not detectable in plasma of healthy volunteers, but significant levels were observed in patients with sepsis and DIC. These levels were higher in non-survivors than in survivors. Extracellular histones triggered platelet aggregation, leading to thrombotic occlusion of pulmonary capillaries and subsequent right-sided heart failure in mice. These mice displayed symptoms of DIC, including thrombocytopenia, prolonged prothrombin time, decreased fibrinogen, fibrin deposition in capillaries, and bleeding. Platelet depletion protected mice from histone-induced death in the first 30 minutes, suggesting that vessel occlusion by platelet-rich thrombi might be responsible for death during the early phase. Furthermore, rTM bound to extracellular histones, suppressed histone-induced platelet aggregation, thrombotic occlusion of pulmonary capillaries, and dilatation of the right ventricle, and rescued mice from lethal thromboembolism. CONCLUSIONS: Extracellular histones cause massive thromboembolism associated with consumptive coagulopathy, which is diagnostically indistinguishable from DIC. rTM binds to histones and neutralizes the prothrombotic action of histones. This may contribute to the effectiveness of rTM against DIC.

High mobility group box chromosomal protein 1 (HMGB-1), a nuclear DNA binding protein, was recently rediscovered as a new proinflammatory cytokine. The purpose of this study was to demonstrate HMGB-1 expression in vivo and to identify the role of HMGB-1 in the pathogenesis of rheumatoid arthritis (RA). HMGB-1 concentrations in synovial fluid (SF) and serum from RA and osteoarthritis (OA) patients were measured by immunoblot analysis. The protein's specific receptor, receptor for advanced glycation end products (RAGE), was examined in SF macrophages (SFMs). We measured levels of proinflammatory cytokines released by SFMs treated with HMGB-1 via enzyme-linked immunosorbent assay and used soluble RAGE (sRAGE) to block the release of tumor necrosis factor α (TNFα). Immunohistochemical analysis and immunofluorescence assay were employed to examine localization of HMGB-1 in RA synovium and its translocation in SFMs after TNFα stimulation. HMGB-1 concentrations were significantly higher in SF of RA patients than in that of OA patients. SFMs expressed RAGE and released TNFα, interleukin-1β (IL-1β), and IL-6 upon stimulation with HMGB-1. HMGB-1 was found in CD68-positive cells of RA synovium, and TNFα stimulation translocated HMGB-1 from the nucleus to the cytosol in SFMs. Blockade by sRAGE inhibited the release of TNFα from SFMs. HMGB-1 was more strongly expressed in SF of RA patients than in that of OA patients, inducing the release of proinflammatory cytokines from SFMs. HMGB-1 plays a pivotal role in the pathogenesis of RA and may be an original target of therapy as a novel cytokine. [ABSTRACT FROM AUTHOR]