Endosomal TLRs (TLR3/7/8/9) are highly analogous innate immunity sensors for various viral or bacterial RNA/DNA molecular patterns. Among them, TLR7, in particular, has been suggested to be a target for various inflammatory disorders and autoimmune diseases including systemic lupus erythematosus (SLE); but few small-molecule inhibitors with elaborated mechanism have been reported in literature. Here, we reported a well-characterized human TLR7-specific small-molecule inhibitor, TH-407b, with promising potency and negligible cytotoxicity through a novel binding mechanism. Notably, TH-407b not only effectively inhibited TLR7-mediated pro-inflammatory signaling in a variety of cultured cell lines but also demonstrated potent inflammation suppressing activities in primary peripheral blood mononuclear cells (PBMCs) derived from SLE patients. Furthermore, TH-407b showed prominent efficacy in vivo, improved survival rate and ameliorated symptoms of SLE model mice. To obtain molecular insights into the TH-407b derivatives' inhibition mechanism, we performed the structural analysis of TLR7/TH-407b complex using cryogenic electron microscopy (cryo-EM) method. As an atomistic resolution cryo-EM structure of the TLR family, it not only of value to facilitate structure-based drug design, but also shed light to methodology development of small proteins using EM. Significantly, TH-407b has unveiled an inhibition strategy for TLR7 via stabilizing its resting/inactivated state. Such a resting state could be generally applicable to all TLRs, rendering a useful method for targeting this group of important immunological receptors.

BACKGROUND: Human T cell leukemia virus type-1 (HTLV-1) stimulates inflammation activity. Our previous study revealed a positive association between asymptomatic HTLV-1 infection and advanced periodontitis among elderly Japanese individuals with low levels of hematopoietic activity (reflected by reticulocyte levels). Since low hematopoietic activity has been correlated with low-grade inflammation and low-grade inflammation is associated with atherosclerosis, the status of atherosclerosis could, in turn, determine the nature of this association. METHODS: To this end, a cross-sectional study of 907 elderly Japanese individuals (aged 60-99 years), who had participated in dental health check-up during the period 2016-2018, was conducted. Advanced periodontitis was defined as periodontal pocket ≥ 6.0 mm. RESULTS: Among the study population, 295 (32.5%) were found to have atherosclerosis defined as a carotid intima-media thickness (CIMT) of ≥ 1.1 mm. HTLV-1 infection was positively associated with advanced periodontitis in participants with atherosclerosis, but no significant associations were observed among the participants without atherosclerosis. The known risk factors' (including reticulocyte and CIMT) adjusted odds ratio (OR) and 95% confidence interval (CI) of advanced periodontitis were OR 2.01 and 95% CI 1.06-3.81 for participants with atherosclerosis and OR 0.61 and 95% CI 0.34-1.12 for participants without atherosclerosis. CONCLUSION This study found a significant association between HTLV-1 infection and advanced periodontitis among elderly Japanese with atherosclerosis. However, this association is absent in individuals without atherosclerosis, suggesting that atherosclerosis might act as a determinant in the association between HTLV-1 infection and advanced periodontitis among elderly Japanese.

BACKGROUND: We reported that human T cell leukemia virus 1 (HTLV-1) infection is positively associated with atherosclerosis. Recent evidence has revealed a close association of periodontitis with atherosclerosis, endothelial dysfunction, and disruption of the microcirculation. However, the association between HTLV-1 and advanced periodontitis has not been investigated to date. Since hematopoietic activity is closely linked to endothelial maintenance activity and is known to decline with age, we hypothesized that the state of hematopoietic activity influenced the association between HTLV-1 and advanced periodontitis in elderly participants. METHODS: A cross-sectional study was performed including 822 elderly participants aged 60-99 years who participated in a dental health check-up. Advanced periodontitis was defined as a periodontal pocket ≥ 6.0 mm. Participants were classified as having low or high hematopoietic activity according to the median values of reticulocytes. RESULTS: HTLV-1 infection was positively related to advanced periodontitis among participants with lower hematopoietic activity (lower reticulocyte count), but not among participants with higher hematopoietic activity (higher reticulocyte count). The adjusted odds ratio (95% confidence interval) considering potential confounding factors was 1.92 (1.05-3.49) for participants with a lower reticulocyte count and 0.69 (0.35-1.36) for participants with a higher reticulocyte count. CONCLUSIONS Among elderly participants, the association between HTLV-1 infection and advanced periodontitis is influenced by hematopoietic activity. Since hematopoietic activity is associated with endothelial maintenance, these findings provide an efficient tool for clarifying the underlying mechanism of the progression of periodontitis among elderly participants.
Aged ; Aged, 80 and over ; Cross-Sectional Studies ; Female ; HTLV-I Infections ; physiopathology ; Hematopoiesis ; physiology ; Human T-lymphotropic virus 1 ; physiology ; Humans ; Japan ; epidemiology ; Male ; Middle Aged ; Odds Ratio ; Periodontitis ; epidemiology ; virology ; Prevalence ; Risk Factors

A 78-year-old woman who had undergone an axillobifemoral artery bypass with a prosthetic graft for Leriche syndrome presented 1 month later with cough and fever. A clinical examination revealed obvious redness in the right groin. Routine laboratory tests uncovered inflammation and methicillin-sensitive-Staphylococcus aureus was cultured from blood samples. Mitral valve vegetations were identified by echocardiography, and after a diagnosis of infective endocarditis, specific intravenous antibiotics were immediately administered. One month later, CT revealed a large pseudoaneurysm of the posterior left ventricular wall that had not been present at the time of admission. Transesophageal echocardiography and magnetic resonance imaging showed an aneurysmal cavity arising from the wall just below the posterior mitral valve leaflet. The patient agreed to undergo cardiac surgery due to the high likelihood that the pseudoaneurysm would rupture. The mitral annulus and leaflet were normal at surgery. We resected the posterior leaflet, closed the cavity using a Xenomedica patch, and reconstructed the leaflet. We did not remove the pseudoaneurysm using an extracardiac approach because the likelihood of damaging the coronary arteries and the coronary sinus was quite high. The postoperative course was uneventful. At follow-up 1 year later, the patient was afebrile and both CT and echocardiography showed that the cavity was completely filled by the thrombus. The imaging findings were useful in determining the surgical approach.

To identify indications for acupuncture treatment, we examined certain evidence-based medicine (EBM) practices by acupuncture/moxibustion clinicians who are novices in this field and identified problems and solutions from the perspective of an acupuncture/moxibustion clinician.
We collected cases of lumbago, shoulder disorders and strokes from the literature, and critically assessed these reports. We also investigated Cochrane Library's acupuncture/moxibustion reviews and evaluated the quality of domestic studies using randomized controlled trials and controlled clinical trials (RCT/CCT). Simultaneously, one of the authors evaluated her own clinical reports in light of EBM.
As a result, acupuncture/moxibustion treatments showed promise for treating lumbago and shoulder disorders, but the higher the quality of studies, the lower the effect of treatment after stroke. According to research by the Cochrane Library (as of issue 1, 2003), the effects of acupuncture/moxibustion was measured only for cases of idiopathic headache but those for other disorders were measured more severely. In Japan, RCT started as early as the 1960 s, but the studies were sluggish and high quality studies were not produced until the late 1990 s.
We presented problems of RCT assessment score, the gap between RCT designs and actual clinical scenes, and the difficulty of masking at the bed-side. To contribute to the accumulation of more evidence-based data, it would be desirable for clinicians to acquire EBM methods, consider clinical problems and collaborate positively with investigators in the field.