Thrombus-related focal in-stent restenosis after everolimus-eluting stent implantation

A 60-year-old man who had received repeated angioplasty for silent ischemia was suspected to have restenosis based on radioisotope imaging (exercise-RI) findings 6 months after everolimus-eluting stent (EES) implantation (3.5 × 28, 3.5 × 28, 3.0 × 18 mm). The stents had been implanted for chronic total occlusion of the right coronary artery (RCA), and the patient was on continuous dual antiplatelet therapy. Diagnostic angiography demonstrated in-stent restenosis in the proximal RCA, which was treated by optical coherence tomography (OCT)-guided cutting balloon angioplasty with distal protection. OCT findings of the stenotic segment before angioplasty showed that the lesion had complex features. The lesion was successfully dilated, and whitish material obtained by a distal protection device was composed of fibrin thrombi with neutrophils and small pieces of mature fibrocellular neointima. The mechanisms and patterns of restenosis after EES placement have not been well clarified. This case may reflect a restenosis pattern (i.e., asymptomatic, focal, and thrombi-related) in the era of the newer generation of drug-eluting stents.     

Diacylglycerol kinase α exacerbates cardiac injury after ischemia/reperfusion

Early coronary reperfusion of the ischemic myocardium is a desired therapeutic goal for the preservation of myocardial function. However, reperfusion itself causes additional myocardium injuries. Activation of the diacylglycerol–protein kinase C (DAG–PKC) cascade has been implicated in the cardioprotective effects occurring after ischemia/reperfusion (I/R). DAG kinase (DGK) controls cellular DAG levels by converting DAG to phosphatidic acid, and may act as an endogenous regulator of DAG–PKC signaling. In the present study, we examined the functional role of DGKα in cardiac injury after I/R in in vivo mouse hearts. We generated transgenic mice with cardiac-specific overexpression of DGKα (DGKα-TG). The left anterior descending coronary artery was transiently occluded for 20 min and reperfused for 24 h in DGKα-TG mice and wild-type littermate (WT) mice. The levels of phosphorylation activity of PKCε, extracellular-signal regulated kinase (ERK) 1/2, and p70 ribosomal S6 kinase (p70S6K) were increased after I/R in WT mouse hearts. However, in DGKα-TG mice, activation of PKCε, ERK1/2, and p70S6K was attenuated compared to WT mice. After 24 h, Evans blue/triphenyltetrazolium chloride double staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining showed that DGKα-TG mice had significantly larger myocardial infarctions and larger numbers of TUNEL-positive cardiomyocytes than WT mice. Echocardiography and cardiac catheterization revealed that left ventricular systolic function was more severely depressed in DGKα-TG mice than in WT mice after I/R. These findings suggest that DGKα exacerbates I/R injury by inhibiting the cardioprotective effects of PKCε, ERK1/2, and p70S6K activation.     

Narrowband ultraviolet B phototherapy ameliorates acute graft-versus-host disease by a mechanism involving in vivo expansion of CD4+CD25+Foxp3+ regulatory T cells

Narrowband ultraviolet B phototherapy (NB-UVB) is a therapeutic alternative for haematopoietic stem cell transplantation-related skin graft-versus-host disease (GVHD). The beneficial effects of this intervention may be induced by direct irradiation of inflammatory cells in the skin; however, the putative involvement of indirect effects on systemic immunity has not been elucidated. To address this issue, 11 acute skin GVHD patients refractory to standard corticosteroid treatment and with no gut/liver involvement were treated with NB-UVB irradiation. The median number of treatments was 10 times, with a mean cumulative exposure of 6.36 J/cm². No other immunosuppressive therapy was initiated during irradiation. Eight patients achieved an objective complete response, two had a partial response, and one showed no change. None of the patients experienced progressive skin GVHD or newly diagnosed gut/liver GVHD. NB-UVB was well tolerated, with no patients discontinuing irradiation due to toxicity. We additionally demonstrated by flow cytometry that NB-UVB irradiation induces the increment of the proportion of regulatory T cell (Tregs) in patients’ peripheral blood. These results suggest that NB-UVB may exert beneficial effects on steroid-refractory skin GVHD through the expansion of Tregs.     

Anti-erythropoietin receptor antibody-associated pure red cell aplasia accompanied by Coombs-negative autoimmune hemolytic anemia in a patient with T cell/histiocyte-rich large B cell lymphoma

A 79-year-old female diagnosed with T cell/histiocyte-rich large B cell lymphoma in complete remission after six cycles of rituximab-combined chemotherapy developed severe anemia, reticulocytopenia, and bone marrow erythroid hypoplasia. She was diagnosed with pure red cell aplasia (PRCA) accompanied by Coombs-negative autoimmune hemolytic anemia evidenced by a lack of glycophorin-A-positive cells in the bone marrow, haptoglobin under the detection level, and a high titer of RBC-bound IgG. Anti-erythropoietin receptor (EPOR) antibody was detected in the serum, and oligoclonal α/β and γ/δ T cells were also detected in her peripheral blood by Southern blotting analysis. Parvovirus B19 DNA was not detected by PCR. Although the treatment with rituximab had limited efficacy (specifically, only for hemolysis), subsequent cyclosporine therapy led to prompt recovery of erythropoiesis with the disappearance of anti-EPOR antibody and oligoclonal T cells. This is the first case report of anti-EPOR antibody-associated PRCA in a patient with malignant lymphoma treated successfully with cyclosporine.     

Clinical Effectiveness of Tolvaptan in Patients with Acute Decompensated Heart Failure and Renal Failure: Design and Rationale of the AQUAMARINE Study

Purpose

Over half of all admitted acute decompensated heart failure (ADHF) patients have renal failure. Although diuretics represent the mainstay of treatment strategy even in this population, there are unmet needs for safer and more effective treatment. Tolvaptan is a vasopressin-2 receptor antagonist, and we hypothesized that adding tolvaptan to standard diuretic therapy would be more effective in ADHF patients with renal function impairment.

Methods

The Answering question on tolvaptan’s efficacy for patients with acute decompensated heart failure and renal failure (AQUAMARINE) is a multicenter, randomized controlled clinical trial, which will enroll 220 patients from 17 hospitals in Japan. ADHF patients whose estimated glomerular filtration rate is above 15 and below 60 mL/min/1.72 m² will be randomly assigned within 6 h after admission to usual care with furosemide or tolvaptan add-on therapy. Primary endpoint is achieved urine output within 48 h. Secondary endpoints include dyspnea relief measured by 7-points Likert scale, incidence of worsening renal function, dose of furosemide used within 48 h, and changes of brain natriuretic peptide.

Conclusion

This study is the first multicenter study in Japan to evaluate clinical effectiveness of tolvaptan add-on therapy in ADHF patients with renal failure. The results of this study address the treatment strategy of this high-risk population (UMIN Clinical Trial Registry Number: UMIN000007109).     

Telaprevir-induced,but not pegylated interferon-associated,retinopathy as a noteworthy adverse effect during triple antiviral therapy in patients with chronic hepatitis C

Background

The significance of retinopathy during triple therapy with telaprevir is uncertain.

Methods

Ophthalmologic examination was done prospectively before and every month during the therapy in 95 CHC patients.

Results

Retinopathy was found in 46 (48.4 %), and the specialists recommended discontinuation of the therapy in 9 (9.5 %). Such lesions may develop as adverse effects by telaprevir, since the lesions disappeared following discontinuation of telaprevir in a 65-year-old man, in whom both pegylated-interferon (Peg-IFN) and ribavirin were continued, and reappeared when he took telaprevir again by his decision. Multivariate analysis revealed that interleukin 28B single-nucleotide polymorphism (IL28B SNP) and anemia development during the therapy were independent factors associating retinopathy.

Conclusion

Ophthalmologic examinations should be done carefully during triple therapy, since the incidence was higher than that in previous Peg-IFN therapy, and lesions may develop as adverse effects by telaprevir, but not by Peg-IFN, especially in those showing preferable IL28B SNPs allele and/or anemia during the therapy.     

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.     

Persistent epicardial adipose tissue accumulation is associated with coronary plaque vulnerability and future acute coronary syndrome in non-obese subjects with coronary artery disease

Objective. Epicardial adipose tissue (EAT) is recognized as a novel risk factor for coronary artery disease (CAD), and its contribution is thought to be stronger in non-obese patients than in obese patients. However, the prognostic impact of the progression of EAT accumulation after comprehensive management for atherosclerotic risk factors remains unclear. This study aimed to investigate whether an increase of the EAT volume during follow-up predicts future acute coronary syndrome (ACS) events in non-obese CAD patients. Methods. This study consisted of 517 non-obese CAD patients (368 men; age, 66 ± 10 years) who underwent serial multidetector computed tomography (MDCT) examinations to evaluate coronary atherosclerosis progression. The MDCT examination was used to assess the severity of stenosis, plaque characteristics, and EAT volume. All patients received comprehensive management to reduce CAD risk factors after the first MDCT examination. The MDCT examination was repeated at 6–24 months, and patients were followed-up for more than 1 year or until the occurrence of ACS events. Results. Of 517 patients, 159 (31%) patients were classified into increase of EAT volume during follow-up, 91 (18%) into decrease of EAT volume during follow-up, and 267 (51%) patients into constant of EAT volume during follow-up. The prevalence of obstructive plaques and MDCT-derived vulnerable features of coronary plaques were significantly elevated in patients with increase of EAT volume during follow-up. In contrast, no significant changes were observed in the other 2 groups. During the follow-up period of 4.1 ± 1.8 years (median 4.4 years) after the second MDCT examination, ACS occurred in 43 (8.3%) patients. Multivariate Cox regression analysis showed that the presence of low-attenuation plaque (hazard ratio [HR]; 1.78, p = 0.04) and napkin-ring sign (HR; 3.74, p < 0.001) at second MDCT examination, and changes of EAT volume per 10 ml (HR; 1.34, p = 0.004) were associated with future ACS events. Conclusion. Patients with increase of EAT volume during follow-up despite comprehensive management for CAD risks had an increased prevalence of obstructive plaques and plaques with high-risk features, which could be associated with unfavorable ACS outcomes in non-obese CAD patients.