Minocycline suppresses experimental autoimmune encephalomyelitis by increasing tissue inhibitors of metalloproteinases

Matrix metalloproteinases (MMPs) that are secreted by activated T cells play a significant role in degradation of the extracellular matrix around the blood vessels and facilitate autoimmune neuroinflammation; however, it remains unclear how MMPs act in lesion formation and whether MMP‐targeted therapies are effective in disease suppression. In the present study, we attempted to treat experimental autoimmune encephalomyelitis (EAE) by administration of small interfering RNAs (siRNAs) for MMP‐2, MMP‐9, and minocycline, all of which have MMP‐inhibiting functions. Minocycline, but not siRNAs, significantly suppressed disease development. In situ zymography revealed that gelatinase activities were almost completely suppressed in the spinal cords of minocycline‐treated animals, while significant gelatinase activities were measured in the EAE lesions of control animals. However, MMP‐2 and MMP‐9 mRNAs and proteins in the spinal cords of treated rats were unexpectedly upregulated. At the same time, mRNA for tissue inhibitors of MMPs (TIMP)‐1 and ‐2 were also upregulated. The EnzChek Gelatinase/Collagenase assay using tissue containing native MMPs and TIMPs demonstrated that gelatinase activity levels in the spinal cords of treated rats were suppressed to the same level as those in normal spinal cord tissues. Finally, double immunofluorescent staining demonstrated that MMP‐9 immunoreactivities of treated rats were almost the same as those of control rats and that MMP‐9 and TIMP‐1 immunoreactivities were colocalized in the spinal cord. These findings suggest that minocycline administration does not suppress MMPs at mRNA and protein levels but that it suppresses gelatinase activities by upregulating TIMPs. Thus, MMP‐targeted therapies should be designed after the mechanisms of candidate drugs have been considered.     

Intracardiac echocardiography to diagnose pannus formation after aortic valve replacement

A 66-year-old female, under regular follow-up for 20 years after aortic valve replacement (19-mm Carbomedics), presented dyspnea on effort and hypotension during hemodialysis. A transthoracic echocardiogram showed elevation of transvalvular velocity up to 4 m/s, but the structure around the aortic prosthesis was difficult to observe due to artifacts. Fluoroscopy revealed normal motion of the leaflets of the mechanical valve. Intracardiac echocardiography (ICE) revealed a pannus-like structure in the left ventricular outflow tract. Transesophageal echocardiogram also revealed this structure. ICE can visualize structural abnormalities around a prosthetic valve after cardiac surgery even in patients in whom conventional imaging modalities failed.     

Helicobacter pylori infection is positively associated with gallstones: a large-scale cross-sectional study in Japan

Background

Our aim is to elucidate causative factors for gallstones, especially focusing on Helicobacter pylori (HP) infection.

Methods

We analyzed 15,551 Japanese adults who had no history of gastrectomy, cholecystectomy, HP eradication, and didn’t use proton pump inhibitors, anti-diabetic drugs, or anti-cholesterol drugs. 1,057 subjects who previously had HP eradication were analyzed separately.

Results

Gallstones were detected in 409 of 8,625 men (4.74 %) and 285 of 6,926 women (4.11 %) by ultrasonography. Among the 25 factors univariately analyzed, age, HP infection, alcohol intake, weight, body mass index (BMI), and 14 blood test values (AST, ALT, ALP, γ-GTP, T-Chol, HDL-Chol, LDL-Chol, TG, TP, Hb, HbA1c, pepsinogen I, pepsinogen II, and pepsinogen I/II ratio) displayed significant association with gallstones (p < 0.05), whereas gender, smoking, height, and three blood test values (Alb, T-Bil, MCV) did not. Multivariate analysis showed that age, gender, alcohol intake, BMI, γ-GTP, LDL-Chol, TP, and HP infection had significant association (p < 0.05). Successive multiple logistic regression analysis calculating odds ratio (OR) and standardized coefficients (β) showed that age (OR/β = 1.57/0.450), BMI (OR/β = 1.30/0.264), HP infection (OR/β = 1.51/0.206), lower alcohol intake (OR/β = 1.33/0.144), γ-GTP (OR/β = 1.15/0.139), and pepsinogen I/II ratio (OR/β = 1.08/0.038) have significant positive association with gallstones, whereas gender does not. The gallstone prevalence among HP-negative, HP-eradicated, and HP-positive subjects was 3.81, 4.73 and 6.08 %, respectively. The matched analysis controlling age, BMI, γ-GTP, alcohol intake, pepsinogen I/II ratio and gender also demonstrated that gallstone prevalence among HP-eradicated subjects was significantly lower compared with HP-positive subjects (p < 0.05).

Conclusions

HP infection is positively associated with gallstones. HP eradication may lead to prevention of gallstones.     

Periarticular osteophyte formation protects against total knee arthroplasty in rheumatoid arthritis patients with advanced joint damage

Clinical Rheumatology - Periarticular osteophyte formation is observed during the repair of damaged joints in rheumatoid arthritis (RA); however, little is known about its clinical and functional...     

Tannin-phytobezoars with Gastric Outlet Obstruction Treated by Dissolution with Administration and Endoscopic Injection of Coca-ColaⓇ, Endoscopic Crushing,and Removal (with Video)

A 77-year-old man complained of postmeal vomiting and sustained general fatigue. An abdominal computed tomography scan showed massive gastric expansion and fluid storage. Gastroscopy revealed four gastric bezoars that were considered to have caused pyloric ring obstruction. The patient was asked to drink 500 mL per day of Coca-Cola^Ⓡ for 4 days. On the fourth day, we performed endoscopic crushing and removal by injecting Coca-Cola^Ⓡ, cutting the softened bezoar with endoscopic snares, and collecting the pieces with endoscopic nets. We herein report (with a video presentation) a rare case of tannin-phytobezoars endoscopically removed with the administration and injection of Coca-Cola^Ⓡ.     

Prognostic impact of count of extratumoral lymphatic permeation in lung adenocarcinoma and its relation to the immune microenvironment

Extratumoral lymphatic permeation (ly‐ext) has been reported as an independent poor prognostic factor for lung adenocarcinoma, but whether or not the number of ly‐ext foci is associated with prognosis and its relationship to the immune microenvironment is unclear. We counted the number of ly‐ext foci on pathological slides from patients with completely resected lung adenocarcinoma with ly‐ext, and divided them into two groups: a group with a high number of ly‐ext foci (ly‐ext high) and one with a low number of ly‐ext foci (ly‐ext low). Among the patients with ly‐ext, only a high number of ly‐ext foci was an independent poor prognostic factor. The 3‐year recurrence‐free survival (RFS) rate of the ly‐ext high group was significantly lower than that of the ly‐ext low group (14.7% vs. 50.0%, P < 0.01). Then, we analyzed the immune microenvironment of pT1 lung adenocarcinoma with ly‐ext (13 cases of ly‐ext high and 11 cases of ly‐ext low tumor) by immunohistochemistry using antibodies for stem cell markers (aldehyde dehydrogenase 1 A1 and CD44), tumor‐promoting mucin (MUC1), tumor‐infiltrating lymphocytes (CD4, CD8, FOXP3, and CD79a), and tumor‐associated macrophages (CD204). The number of CD8+ TILs within the primary lesion was significantly lower and the number of FOXP3+ TILs within the primary lesion was significantly higher in the ly‐ext high group (P < 0.05 and P < 0.01, respectively). Our results indicated that a high number of ly‐ext foci was an independent poor prognostic factor. Moreover, tumors with high numbers of ly‐ext foci had a more immunosuppressive microenvironment.