Increased IP-10 production by blood–nerve barrier in multifocal acquired demyelinating sensory and motor neuropathy and multifocal motor neuropathy

Objective Dysfunction of the blood–nerve barrier (BNB) plays important roles in chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). The aim of the present study was to identify the candidate cytokines/chemokines that cause the breakdown of the BNB using sera from patients with CIDP and MMN. Methods We determined the levels of 27 cytokines and chemokines in human peripheral nerve microvascular endothelial cells (PnMECs) after exposure to sera obtained from patients with CIDP variants (typical CIDP and multifocal acquired demyelinating sensory and motor neuropathy [MADSAM]), MMN and amyotrophic lateral sclerosis (ALS), and healthy controls (HC), using a multiplexed fluorescent bead-based immunoassay system. Results The induced protein (IP)10 level in the cells in both the MADSAM and MMN groups was markedly increased in comparison with the typical CIDP, ALS and HC groups. The other cytokines, including granulocyte colony-stimulating factor, vascular endothelial growth factor (VEGF) and interleukin-7, were also significantly upregulated in the MADSAM group. The increase of IP-10 produced by PnMECs was correlated with the presence of conduction block in both the MADSAM and MMN groups. Conclusion The autocrine secretion of IP-10 induced by patient sera in PnMECs was markedly upregulated in both the MADSAM and MMN groups. The overproduction of IP-10 by PnMECs leads to the focal breakdown of the BNB and may help to mediate the transfer of pathogenic T cells across the BNB, thereby resulting in the appearance of conduction block in electrophysiological studies of patients with MADSAM and MMN

Inhibition of c-Jun NH2-terminal kinase activity improves ischemia/reperfusion injury in rat lungs

Although c-Jun NH 2 -terminal kinase (JNK) has been implicated in the pathogenesis of transplantation-induced ischemia/reperfusion (I/R) injury in various organs, its significance in lung transplantation has not been conclusively elucidated. We therefore attempted to measure the transitional changes in JNK and AP-1 activities in I/R-injured lungs. Subsequently, we assessed the effects of JNK inhibition by the three agents including SP600125 on the degree of lung injury assessed by means of various biological markers in bronchoalveolar lavage fluid and histological examination including detection of apoptosis. In addition, we evaluated the changes in p38, extracellular signal-regulated kinase, and NF-B-DNA binding activity. I/R injury was established in the isolated rat lung preserved in modified Euro-Collins solution at 4°C for 4 h followed by reperfusion at 37°C for 3 h. We found that AP-1 was transiently activated during ischemia but showed sustained activation during reperfusion, leading to significant lung injury and apoptosis. The change in AP-1 was generally in parallel with that of JNK, which was activated in epithelial cells (bronchial and alveolar), alveolar macrophages, and smooth muscle cells (bronchial and vascular) on immunohistochemical examination. The change in NF-B qualitatively differed from that of AP-1. Protein leakage, release of lactate dehydrogenase and TNF-␣ into bronchoalveolar lavage fluid, and lung injury were improved, and apoptosis was suppressed by JNK inhibition. In conclusion, JNK plays a pivotal role in mediating lung injury caused by I/R. Therefore, inhibition of JNK activity has potential as an effective therapeutic strategy for preventing I/R injury during lung transplantation

Clinical Significance of Measuring Urinary Sulfated Bile Acids in Adult Patients with Hepatobiliary Diseases.

Background/Aims: Measurement of urinary sulfated bile acid (USBA) level is a simple urine test that reflects the degree of cholestasis in newborns. The aim of this study was to clarify the clinical significances of this test for liver diseases in adults. Methodology: We examined the relationship between USBA level in a urine sample by enzymatic assay and clinical parameters and postoperative complications in 27 patients with hepatobiliary diseases who underwent surgical procedures between 2002 and 2007. Results: Mean USBA in all patients before surgery was 39.8 ± 64.0 μmol/L (median value was 6.6). USBA level was increased in patients with cholestasis. USBA level was significantly correlated with serum total bile acid, total bilirubin level and serum hyaluronic acid level (r=0.850, 0.602 and 0.504, respectively) (p<0.05) and, furthermore, tended to be correlated with liver-uptake ratio (LHL15) by technetium-99m galactosyl human serum albumin (99mTc-GSA) scintigraphy and alanine aminotransferase level (r=-0.469 and 0.436, respectively but not significant). USBA level tended to be associated with postoperative uncontrolled ascites (p=0.050, not significant). Postoperative USBA level by day 7 was not changed; however, USBA level in patients with cholestatic diseases was decreased Conclusions: USBA is a simple and sensitive noninvasive test for cholestasis and also useful to predict postoperative uncontrolled ascites after hepatic resections

Blood–Nerve Barrier (BNB) Pathology in Diabetic Peripheral Neuropathy and In Vitro Human BNB Model

In diabetic peripheral neuropathy (DPN), metabolic disorder by hyperglycemia progresses in peripheral nerves. In addition to the direct damage to peripheral neural axons, the homeostatic mechanism of peripheral nerves is disrupted by dysfunction of the blood&ndash;nerve barrier (BNB) and Schwann cells. The disruption of the BNB, which is a crucial factor in DPN development and exacerbation, causes axonal degeneration via various pathways. Although many reports revealed that hyperglycemia and other important factors, such as dyslipidemia-induced dysfunction of Schwann cells, contributed to DPN, the molecular mechanisms underlying BNB disruption have not been sufficiently elucidated, mainly because of the lack of in vitro studies owing to difficulties in establishing human cell lines from vascular endothelial cells and pericytes that form the BNB. We have developed, for the first time, temperature-sensitive immortalized cell lines of vascular endothelial cells and pericytes originating from the BNB of human sciatic nerves, and we have elucidated the disruption to the BNB mainly in response to advanced glycation end products in DPN. Recently, we succeeded in developing an in vitro BNB model to reflect the anatomical characteristics of the BNB using cell sheet engineering, and we established immortalized cell lines originating from the human BNB. In this article, we review the pathologic evidence of the pathology of DPN in terms of BNB disruption, and we introduce the current in vitro BNB models

Chronic Kidney Disease Patients Visiting Various Hospital Departments: An Analysis in a Hospital in Central Tokyo, Japan

To further improve care for chronic kidney disease (CKD) patients, healthcare providers’ awareness of CKD must be raised. Proteinuria testing is essential for CKD care, and collaboration with specialists is recommended for advanced cases. We reviewed data from the electronic medical records of outpatients at our hospital to analyze the clinical departments visited by CKD patients, and the frequency of proteinuria testing and referrals to nephrologists. We defined CKD as an estimated glomerular filtration rate (eGFR) 2 or a urine protein concentration (U-pro) ≥ +1. We found that 31.1% of the CKD tests in September 2021 were performed in clinical departments other than internal medicine. Furthermore, within 1 year, 68.0% of CKD patients identified in September 2020 underwent a urine dipstick test, and 33.7% underwent a quantitative test for urinary protein or albumin. Additionally, 27.5% of individuals with an eGFR 2 or U-pro ≥ +1 identified by non-nephrology departments in September 2020 visited the nephrology department within 1 year. Repeated assessments of these quality indicators may be useful for progress management in improving CKD care. Because CKD patients visited various departments in our hospital, campaigns to raise CKD awareness must reach a wide range of healthcare providers in hospitals