Microglial responses after phagocytosis: Escherichia coli bioparticles,but not cell debris or amyloid beta,induce matrix metalloproteinase-9 secretion in cultured rat primary microglial cells

Upon infection or brain damage, microglia are activated to play roles in immune responses, including phagocytosis and soluble factor release. However, little is known whether the event of phagocytosis could be a trigger for releasing soluble factors from microglia. In this study, we tested if microglia secrete a neurovascular mediator matrix metalloproteinase-9 (MMP-9) after phagocytosis in vitro. Primary microglial cultures were prepared from neonatal rat brains. Cultured microglia phagocytosed Escherichia coli bioparticles within 2 hr after incubation and started to secrete MMP-9 at around 12 hr after the phagocytosis. A TLR4 inhibitor TAK242 suppressed the E. coli-bioparticle-induced MMP-9 secretion. However, TAK242 did not change the engulfment of E. coli bioparticles in microglial cultures. Because lipopolysaccharides (LPS), the major component of the outer membrane of E. coli, also induced MMP-9 secretion in a dose–response manner and because the response was inhibited by TAK242 treatment, we assumed that the LPS-TLR4 pathway, which was activated by adhering to the substance, but not through the engulfing process of phagocytosis, would play a role in releasing MMP-9 from microglia after E. coli bioparticle treatment. To support the finding that the engulfing step would not be a critical trigger for MMP-9 secretion after the event of phagocytosis in microglia, we confirmed that cell debris and amyloid beta were both captured into microglia via phagocytosis, but neither of them induced MMP-9 secretion from microglia. Taken together, these data demonstrate that microglial response in MMP-9 secretion after phagocytosis differs depending on the types of particles/substances that microglia encountered.     

Expression of membrane-type matrix metalloproteinases in synovial tissue from patients with rheumatoid arthritis or osteoarthritis

We investigated the expression of membrane-type matrix metalloproteinase (MT-MMP) and matrix metalloproteinase (MMP) mRNAs in synovial tissue from patients with rheumatoid arthritis (RA, n = 5) or osteoarthritis (OA, n = 5) by Northern blot analysis. Northern analysis demonstrated strong expression of MT1-MMP, MT3-MMP, MMP-1, and MMP-3 and weak expression of MT2-MMP and MMP-8 in synovial tissue from patients with RA or OA. MT4-MMP was not detected. No significant difference was shown in the expression of MT-MMP mRNAs between RA and OA. Synovial tissue of RA or OA patients expressed MT-MMPs as well as MMPs. These results indicate that, in addition to MMPs, MT1-MMP, MT3-MMP, and probably MT2-MMP may play a role in the degradation of bone and cartilage matrix in RA and OA. Such information may provide a clue to the development of a novel therapeutic approach targeted on the prevention of joint destruction. Received: April 30, 2000 / Accepted: September 19, 2000     

Tokyo Guidelines 2018: diagnostic criteria and severity grading of acute cholangitis (with videos)

Although the diagnostic and severity grading criteria on the 2013 Tokyo Guidelines (TG13) are used worldwide as the primary standard for management of acute cholangitis (AC), they need to be validated through implementation and assessment in actual clinical practice. Here, we conduct a systematic review of the literature to validate the TG13 diagnostic and severity grading criteria for AC and propose TG18 criteria. While there is little evidence evaluating the TG13 criteria, they were validated through a large‐scale case series study in Japan and Taiwan. Analyzing big data from this study confirmed that the diagnostic rate of AC based on the TG13 diagnostic criteria was higher than that based on the TG07 criteria, and that 30‐day mortality in patients with a higher severity based on the TG13 severity grading criteria was significantly higher. Furthermore, a comparison of patients treated with early or urgent biliary drainage versus patients not treated this way showed no difference in 30‐day mortality among patients with Grade I or Grade III AC, but significantly lower 30‐day mortality in patients with Grade II AC who were treated with early or urgent biliary drainage. This suggests that the TG13 severity grading criteria can be used to identify Grade II patients whose prognoses may be improved through biliary drainage. The TG13 severity grading criteria may therefore be useful as an indicator for biliary drainage as well as a predictive factor when assessing the patient's prognosis. The TG13 diagnostic and severity grading criteria for AC can provide results quickly, are minimally invasive for the patients, and are inexpensive. We recommend that the TG13 criteria be adopted in the TG18 guidelines and used as standard practice in the clinical setting. Free full articles and mobile app of TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47 . Related clinical questions and references are also included.     

Indications and techniques of biliary drainage for acute cholangitis in updated Tokyo Guidelines 2018

The Tokyo Guidelines 2013 (TG13) include new topics in the biliary drainage section. From these topics, we describe the indications and new techniques of biliary drainage for acute cholangitis with videos. Recently, many novel studies and case series have been published across the world, thus TG13 need to be updated regarding the indications and selection of biliary drainage based on published data. Herein, we describe the latest updated TG13 on biliary drainage in acute cholangitis with meta‐analysis. The present study showed that endoscopic transpapillary biliary drainage regardless of the use of nasobiliary drainage or biliary stenting, should be selected as the first‐line therapy for acute cholangitis. In acute cholangitis, endoscopic sphincterotomy (EST) is not routinely required for biliary drainage alone because of the concern of post‐EST bleeding. In case of concomitant bile duct stones, stone removal following EST at a single session may be considered in patients with mild or moderate acute cholangitis except in patients under anticoagulant therapy or with coagulopathy. We recommend the removal of difficult stones at two sessions after drainage in patients with a large stone or multiple stones. In patients with potential coagulopathy, endoscopic papillary dilation can be a better technique than EST for stone removal. Presently, balloon enteroscopy‐assisted endoscopic retrograde cholangiopancreatography (BE‐ERCP) is used as the first‐line therapy for biliary drainage in patients with surgically altered anatomy where BE‐ERCP expertise is present. However, the technical success rate is not always high. Thus, several studies have revealed that endoscopic ultrasonography‐guided biliary drainage (EUS‐BD) can be one of the second‐line therapies in failed BE‐ERCP as an alternative to percutaneous transhepatic biliary drainage where EUS‐BD expertise is present.     

Light chain cardiac amyloidosis in a nonagenarian

Cardiac amyloidosis is an infiltrative and restrictive cardiomyopathy caused by the extracellular deposition of amyloid fib-rils within the heart as systemic amyloidosis,lead-ing to heart failure,reduced quality of life,and death.[1]There are two major amyloid fibril proteins that af-fect the heart:amyloid immunoglobulin light chain(AL)and amyloid transthyretin(ATTR).The latter is further subdivided into wild-type ATTR and variant types based on the presence of a mutation in the transthyretin gene.     

SURVEILLANCE OF SMALL INTESTINAL ABNORMALITIES IN PATIENTS WITH HEPATOCELLULAR CARCINOMA: A PROSPECTIVE CAPSULE ENDOSCOPY STUDY

Background: Patients with hepatocellular carcinoma (HCC) sometimes suffer from obscure gastrointestinal bleeding. Portal hypertension (PH), common in cirrhosis, induces esophagogastric varices. Because of the location, PH also may influence mucosal abnormalities in the small intestine. The objective of this study is to estimate the prevalence of small intestinal mucosal abnormalities in HCC patients using capsule endoscopy (CE). Patients and Methods: We prospectively conducted CE in HCC patients, and analyzed the findings in relation to hepatic function, the number and size of HCC tumor and findings obtained by conventional endoscopy. Results: Thirty‐six patients (aged 66.7 ± 7.5 years, 29 men) underwent CE. Abnormal findings in the small bowel were found in 16 patients (44%), angioectasias in eight patients (22%), erosions in five (14%), varices in four (11%), polyps in four (11%), and submucosal tumor in one (3%). The patients with angioectasia had a larger spleen index than the no abnormal lesions group (85.4 ± 15.8 vs 59.0 ± 24.4, P = 0.02). The former group had been more frequently treated for esophageal varices endoscopically (62% vs 15%, P = 0.02). Large HCC nodules seemed more common in the patients with angioectasia than subjects without abnormal lesions (38% vs 5%, P = 0.06). Small intestinal varices also seemed to have a positive association with large HCC. During the follow up after CE, one patient with small intestinal polyps suffered from obscure gastrointestinal bleeding. Conclusions: CE revealed that HCC patients frequently have small intestinal mucosal lesions. In particular, small intestinal angioectasia, which may cause obscure gastrointestinal bleeding, seems to be associated with portal hypertension.     

Neural substrate of sound duration discrimination during an auditory sequence in the guinea pig primary auditory cortex

Mismatch negativity (MMN) is a negative component of event-related brain potentials elicited by stimulus transitions. Stimulus duration transition also elicits MMN (duration MMN), with a magnitude that is related to the degree of duration change and the discrimination ability. The neural substrates of duration MMN have not yet been investigated. We therefore studied how duration transitions in an auditory stimulus train are represented in neurons in the primary auditory cortex of anesthetized guinea pigs. Two types of neuronal responses to the context of changes in stimulus duration were found. One was a reduced response as the duration of the preceding stimulus was increased. Second was an enhancement of the late components of the response including sustained and offset responses at the duration transition. The former may be explained by the previously proposed two-tone suppression, which is dependent on the preceding stimulus duration. The latter is likely to be caused by stimulus-specific adaptation that could be a possible neural generator of duration MMN.     

Evaluation of antipsychotic and relative drugs using disruption of prepulse inhibition as an animal model for schizophrenia

The prepulse inhibition (PPI) is a phenomenon in which a weak prepulse attenuates the response to a subsequent startling stimulus. The PPI, a model of sensorimotor gating, is deficient in patients with schizophrenia and some other psychiatric disorders. In rodents, PPI can be disrupted by methamphetamine or phencyclidine, which causes psychotomimetic symptoms, and the dopaminergic agonist-induced PPI is reversed by dopamine D2 receptor antagonists and a dopaminergic partial agonist aripiprazole. However, in general, the glutamate receptor antagonist-induced PPI is reversed by atypical antipsychotics such as clozapine, but not by typical antipsychotics such as haloperidol. Therefore, PPI is believed to have face, construct, and predictive validity for the PPI disruption in schizophrenia, and it is widely used as a model to study the neurobiology of this disorder and for screening antipsychotics. Recently, various inbred mouse strains and genetically modified mouse lines have been examined and the studies using PPI indicated the involvement of various neurotransmitters such as dopamine, glutamate, serotonin, GABA and neuropeptide in the biological basis of sensorimotor gating. In addtition, mood stabilizers such as valproate and lamotrigine or alpha7 nicotinic receptor agonists have reported to reverse the PPI disruption.     

Aberrant CYP1A1 Induction: Discrepancy of CYP1A1 mRNA and Aryl Hydrocarbon Hydroxylase Activity in Mutant Cells of Mouse Hepatoma Line, Hepa-1

We have isolated new benzo[α]pyrene-resistant clones, cl-21 and cl-32, of the mouse hepatoma line, Hepa-1. CYP1A1-dependent aryl hydrocarbon hydroxylase activity is not inducible by 2,3,7,8-tetrachlorodibenzo- p -dioxin or 3-methylcholanthrene in these two cell lines. However, mRNA of CYP1A1 is inducible in cl-21 and cl-32 cells, as in the wild-type cells, in spite of an undetectable level of cytosolic Ah receptor. The cl-21 cDNA of Cypla-1 was found to have a single mutation leading to an amino acid substitution from Leu (118) to Arg (118). However, the CYP1A1 protein band was not detected on Western immunoblots. The cDNA of cl-32 was found to have a single mutation leading to an amino acid change from Arg (359) to Trp (359). The presence of the mature protein in cl-32 was confirmed by Western blot analysis. Somatic cell hybridization experiments demonstrated that the phenotype of cl-21 and cl-32 is recessive and that these clones belong to the same complementation group. These data suggest that there may be a non-Ah receptor-mediated mechanism of CYP1A1 induction.     

Dormant chemotherapy by low-dose FP and low-dose UFT-E in recurrent gastric cancer with long-term survival--a case report

We experienced a case of recurrent gastric cancer with a long-term survival. A 64-year-old man was admitted to the hospital for advanced gastric cancer in the upper stomach. Abdominal CT scan revealed para-aortic lymph nodal metastases. The patient underwent total gastrectomy, distal pancreatectomy, splenectomy, left adrenectomy, and left nephrectomy with D4 lymph node dissection, in what was a curability B resection. Conclusive findings were t2 (ss), n4, H0, P0, M0, and stage IVb. One year after the operation, para-aortic lymph node recurrence was evaluated. The patient was treated with low-dose cisplatin-5-FU therapy, and a partial response was observed and continued for over 2 years with an administration of UFT-E (300 mg/day). He died of repeated aggravation of para-aortic lymph node metastases 6 years and 2 months after the operation. We considered that the long-term survival of this patient was attributable to a 3-year tumor dormancy induced by low-dose cisplatin-5-FU therapy and administration of low-dose UFT.