Thyroid-Stimulating Antibody/Thyroid-Stimulating Hormone Receptor Antibody Ratio as a Sensitive Screening Test for Active Graves' Orbitopathy.

OBJECTIVE: Graves' orbitopathy (GO), an extrathyroidal manifestation of Graves' disease, can seriously threaten a patient's quality of life. Given that immunosuppressive treatment during the early active phase of GO has been found to reduce both disease activity and severity, sensitive screening tests are needed. METHODS: The present study included 86 patients with GO, in whom serum levels of thyroid-stimulating hormone (TSH), free triiodothyronine (T3), free thyroxine, thyroid-stimulating antibody, TSH receptor antibody, thyroid peroxidase antibody, thyroglobulin, and thyroglobulin antibody were measured within 2 months before magnetic resonance imaging (MRI) for orbit assessment. RESULTS: The thyroid-stimulating antibody/TSH receptor antibody ratio was able to distinguish MRI results with a correct classification rate of 81%. When focusing on patients without T3 predominant Graves' diseases, the ratio distinguished MRI results at a rate of 92%. Receiver operating characteristic curve analysis revealed a cutoff antibody ratio of 87, which yielded a sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of 91%, 95%, 18.2, and 0.0957, respectively, for distinguished MRI results. CONCLUSIONS: The thyroid-stimulating antibody/TSH receptor antibody ratio is a highly sensitive and specific indicator for active GO, especially in patients without T3 predominance, and serves as a good screening test for active GO in primary care settings.

Adenosine inhibits TNFα-induced MMP-3 production in MH7A rheumatoid arthritis synoviocytes via A2A receptor signaling.

Adenosine causes the anti-inflammatory effect of MTX; however, the contributions of synoviocyte adenosine receptors (AdoRs) are unknown, and matrix metalloproteinase 3 (MMP-3) is released by fibroblast-like synoviocytes in response to inflammatory signaling. To understand the mechanism of the clinical observation that the matrix proteinase-3 concentration of patients with rheumatoid arthritis treated successfully with methotrexate does not usually normalize, we investigated the effects of A2A AdoR activation and inhibition on tumor necrosis factor-alpha (TNFα)-induced MMP-3 release by MH7A human rheumatoid synovial cells. MH7A cells constitutively expressed membrane-associated A2A AdoRs, and HENECA enhanced intracellular cAMP. Stimulation with TNFα markedly enhanced release of MMP-3 from MH7A cells, whereas HENECA partially and dose-dependently inhibited TNFα-evoked MMP-3 release. Similarly, dbcAMP partially inhibited TNFα-induced MMP-3 release. Pretreatment with ZM241385 reversed the inhibitory effects of HENECA. Further, TNFα induced p38 MAPK and ATF-2 phosphorylation, whereas HENECA suppressed p38 MAPK and ATF-2 phosphorylation. We concluded that adenosine signaling via A2A AdoRs, adenylyl cyclase, and cAMP reduces TNFα-induced MMP-3 production by interfering with p38 MAPK/ATF-2 activity. Activation of A2A AdoR signaling alone using HENECA did not reduce TNFα-induced MMP-3 production to the basal levels, which may explain why MTX usually decreases but does not eliminate serum MMP-3.

The gut microbiome diversity of Clostridioides difficile-inoculated mice treated with vancomycin and fidaxomicin.

OBJECTIVE: To investigate the effect of vancomycin and fidaxomicin on the diversity of intestinal microbiota in a mouse model of Clostridioides difficile infection. METHODS: Mice were divided into 11 models (4 mice per model): 6 uninoculated models and 5 models inoculated with C. difficile BI/NAP1/027. Inoculated models were prepared using intraperitoneal clindamycin followed by inoculation with C. difficile BI/NAP1/027. Uninoculated and C. difficile-inoculated mice received 2 or 7 days' vancomycin or fidaxomicin. Clostridium butyricum MIYAIRI 588 probiotic and lactoferrin prebiotic were administered for 10 days to uninoculated mice. Intestinal microbiome composition was investigated by sequence analyses of bacterial 16S rRNA genes from faeces, and microbiota diversity estimated. RESULTS: In uninoculated, untreated ('normal') mice, Clostridia (57.8%) and Bacteroidia (32.4%) accounted for the largest proportions of gut microbiota. The proportion of Clostridia was numerically reduced in C. difficile-inoculated versus normal mice. Administration of vancomycin to C. difficile-inoculated mice reduced the proportions of Bacteroidia and Clostridia, and increased that of Proteobacteria. Administration of fidaxomicin to C. difficile-inoculated mice reduced the proportion of Clostridia to a lesser extent, but increased that of Bacteroidia. Microbiota diversity was lower in C. difficile-inoculated versus normal mice (164.5 versus 349.1 operational taxonomic units (OTUs), respectively); treatment of C. difficile-inoculated mice with 7 days' vancomycin reduced diversity to a greater extent than did 7 days' fidaxomicin treatment (26.2 versus 134.2 OTUs, respectively). CONCLUSIONS: Both C. difficile inoculation and treatment with vancomycin or fidaxomicin reduced microbiota diversity; however, dysbiosis associated with fidaxomicin was milder than with vancomycin.

Efficacy of tocilizumab for fulminant multiple sclerosis with a tumefactive cervical lesion: A 12-year-old boy.

Fulminant demyelinating disease including acute disseminating encephalitis, multiple sclerosis (MS) variants, and neuromyelitis optica spectrum disorder (NMOSD) are often managed with similar acute treatment such as intravenous methylprednisolone and plasma exchange. On the other hand, long-term management varies. The choice of the drug is based on several factors including the activity and severity of the disease course. Tocilizumab (TCZ), which is a humanized anti-interleukin-6 receptor antibody, is one of the promising therapies for NMOSD because of decreasing the relapse rates and possibly the neurological disability. However, the efficacy of TCZ for MS with tumefactive lesion is unknown. Here, we describe the clinical course of a 12-year-old Japanese boy who was diagnosed with fulminant MS with a tumefactive cervical lesion. Our case was refractory to aggressive immunosuppressive therapies and developed dependent on an intermediate dose of oral prednisolone (PSL) for relapse prevention. His neurological condition worsened with every attempt of tapering the PSL dose. Thus, we started treatment with tocilizumab, which allowed of tapering of the PSL dose without his symptom exacerbations, and effectively improved his Expanded Disability Status Scale score. Our findings may indicate that TCZ is effective for fulminant MS patients with a tumefactive cervical lesion.

Neonatal methicillin-resistant Staphylococcus aureus colonization and infection.

INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) is a common etiological agent of a life-threatening infection in neonatal intensive care units (NICUs). Neonates with very low birth weight and patients with serious diseases are more likely to be exposed to invasive procedures which make them at a high risk of MRSA colonization and infection. Since MRSA colonization is a risk factor for MRSA infection, prevention of MRSA transmission is an important issue in NICUs. NICUs in Japan practice standard contact precautions and active surveillance cultures (ASC) to prevent MRSA transmission. In this report, we analyzed the clinical characteristics of MRSA colonization and infection between January 2010 and December 2015 in our perinatal care center. METHODS: We conducted retrospective analysis of 1716 neonates hospitalized in our perinatal care center. RESULTS: 120 cases had MRSA colonization (6.99%) and among them 33 neonates were infected. The duration of stay (P≤0.001) and the birth weight (P≤0.001) showed statistically significant differences between MRSA-colonized neonates and non-MRSA-colonized neonates. The number of central venous catheterization showed statistically significant differences (P = 0.001) and the number of digestive system diseases showed marginally significant differences (P = 0.072) between MRSA-colonized non-infected neonates and MRSA-infected neonates. CONCLUSIONS: As previous reports have shown, we present that the neonates with central venous catheterization were more likely to be infected with MRSA. We also need to pay attention to neonates with digestive system diseases, showing signs of infection, because they may be potentially infected with MRSA.

Tetracyclines modulate protease-activated receptor 2-mediated proinflammatory reactions in epidermal keratinocytes.

In addition to their antibiotic effects, tetracyclines have anti-inflammatory action that is often beneficial in the control of inflammatory skin disorders. In this study, we examined the effects of tetracycline (TET) and two of its derivatives, doxycycline (DOX) and minocycline (MIN), on the production of interleukin-8 (IL-8) elicited by the activation of protease-activated receptor 2 (PAR2) in normal human epidermal keratinocytes (NHEK). In NHEK, the production of IL-8 stimulated by an agonist peptide of PAR2, SLIGKIV-NH(2), at 100 microM was significantly reduced by TET, DOX, or MIN at 5 and 10 microM, concentrations that are noncytotoxic. The tumor necrosis factor alpha (TNF-alpha)-induced production of IL-8 was synergistically augmented by SLIGKIV-NH(2), and that synergistic increase in the production of IL-8 was suppressed by 100 nM PAR2-specific small interfering RNA. It was also suppressed by TET, DOX, or MIN but not by the 14-membered-ring macrolide antibiotics erythromycin, roxithromycin, and clarithromycin, which also have anti-inflammatory activities, at 10 microM. These results suggest that tetracyclines attenuate the PAR2-IL-8 axis in keratinocytes and thereby effectively modulate proinflammatory responses in the skin.

Effect of 14-membered-ring macrolides on production of interleukin-8 mediated by protease-activated receptor 2 in human keratinocytes.

The production of interleukin-8 induced by the activation of protease-activated receptor 2 and its synergism with interleukin-1beta were modulated by 14-membered-ring macrolides, namely, roxithromycin, erythromycin, and clarithromycin, in cultured normal human epidermal keratinocytes. Those macrolides may attenuate the protease-activated receptor 2-interleukin-8 axis and thereby modulate proinflammatory responses in the skin.